Volume 71 - Issue 14

CURRENT OPINION
Drugs 2011; 71 (14): 1797-1806 0012-6667/11/0014-1797/$55.55/0
2011 Adis Data Information BV. All rights reserved.
Management of Antiplatelet Therapy in Patients at Risk for Coronary Stent Thrombosis Undergoing Non-Cardiac Surgery
Zuzana Motovska
Third Medical Faculty of Charles University and University Hospital Kralovske Vinohrady, Prague, Czech Republic
Abstract
Percutaneous coronary interventions (PCIs) have become the most commonly performed coronary revascularization procedures. At the same time, there is an increased likelihood that patients with intracoronary stents will need to undergo surgery. Two serious consequences emerge from this situation: (i) stent thrombosis in relation to discontinuation of antiplatelet therapy, and (ii) major bleeding in relation to continuation of antiplatelet therapy. The best solution to overcome the risks resulting from surgery performed in patients after stent implantation is to postpone the operation until after re-endothelialization of the vessel surface is completed. Expert recommendations advise that patients can be sent for non-cardiac surgery 3 months after bare-metal stent PCI and 12 months after drug-eluting stent PCI, with continuation of aspirin therapy. Difficult decisions regarding antiplatelet management arise when a patient that is still receiving dual antiplatelet therapy with aspirin and a thienopyridine has to undergo surgery that cannot be postponed. Discussions between the treating cardiologist, the surgeon and the anaesthesiologist about this situation are recommended in order to achieve a reasonable expert consensus.
Use of dual oral antiplatelet therapy, aspirin plus a P2Y12 receptor antagonist, has permitted a rapid increase in the use of intracoronary stents. Percutaneous coronary interventions (PCIs) have become the most commonly performed coronary revascularization procedures, accounting for approximately 60% of all revascularizations.[1,2] At the same time, there is an increased likelihood that patients with (recently implanted) intracoronary stents will need to undergo (urgent) surgery. Two serious consequences emerge from this situation:
(i) stent thrombosis in relation to discontinuation of antiplatelet therapy; and (ii) major bleeding in relation to continuation of antiplatelet therapy. 1. Epidemiological Data There is a trend towards an increasing number of coronary interventions.[3,4] In Europe, a total of 800 000 stenting procedures were reported in 2005, which was a 4% increase compared with
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2004.[3] The number of PCIs in 2010 was projected to be about 1.5 million, with a stenting rate of almost 100%.[4] In the US, 1.3 million PCI procedures were performed in 2006, and >70% of PCIs were performed with drug-eluting as opposed to bare-metal stents.[5,6] In addition, the number of general surgical procedures is also steadily increasing.[7] To et al.[8] recently published the first systematic assessment of the incidence of noncardiac surgery in a group of 11 000 patients following PCI. During the 5-year follow-up, 26% (one in four patients) underwent at least one noncardiac surgical procedure; the 6-month occurrence of surgery was 5.1%, whereas at 12 months the cumulative rate was 8.6%. The annual incidence of surgery did not change significantly during the 5 years of follow-up. 2. Surgery Promotes Thrombosis The stress response to surgery includes sympathetic activation that may trigger adverse cardiovascular outcomes.[9,10] Release of neuroendocrine hormones (epinephrine, norepinephrine, cortisol and renin) promotes (i) shear stress on arterial plaques; (ii) enhanced platelet activation; and (iii) vascular reactivity leading to vasospasm. Furthermore, the surgical patient is in a hypercoagulable state due to an increase in plasma clotting factors while fibrinolysis is decreased.[11,12] This alteration of haemostasis, which occurs during the perioperative period, may also increase the risk of intracoronary stent thrombosis. 3. Antiplatelet Therapy and Surgery Prevention of Thrombosis versus Bleeding Risk Secondary prevention with low-dose aspirin reduces the risk of stroke and myocardial infarction by about one-third and, most importantly, the risk of cardiovascular death by about onesixth.[13] Spontaneous aspirin discontinuation after 1 year of therapy occurs in up to 18% of patients with established coronary artery disease.[14] A systematic review in over 50 000 patients at risk of or with coronary artery disease demonstrated that aspirin withdrawal was associated with
a 3-fold higher risk of major adverse cardiac events (cardiovascular death, myocardial infarction or stroke) [odds ratio (OR) 3.14; 95% CI 1.8, 5.6; p = 0.0001].[15] A highly significant increase in the risk of adverse events occurred an average of 10 days after discontinuing aspirin. Discontinuation of aspirin therapy in patients treated with either bare-metal or drug-eluting stents was identified as an independent predictor of stent thrombosis (OR 1.91; 95% CI 1.01, 3.88; p = 0.0487).[16] Surgery is a prothrombotic condition. However, perioperative continuation of antiplatelet agents increases the hazard of procedural bleeding. Burger et al.[17] published a systematic review focusing on cardiovascular risks after perioperative withdrawal of aspirin versus bleeding risks associated with its continuation. They found that aspirin withdrawal led to up to 10.2% of acute cardiovascular syndromes. Whereas aspirin increased the rate of perioperative bleeding complications by a factor of 1.5, it did not lead to increased severity of bleeding complications (except in intracranial surgery and transurethral prostatectomy). The addition of a platelet P2Y12 receptor antagonist (table I) to aspirin after stent implantation is essential for prevention of stent thrombosis until re-endothelialization of the vessel surface is complete. Analysis of the Dutch stent thrombosis registry[16] (21 009 patients and a total of 31 065 bare-metal or drug-eluting stents) showed that discontinuation of antiplatelet therapy, using clopidogrel, was a strong independent predictor of stent thrombosis. Cessation of clopidogrel in the first 30 days after PCI increased the hazard ratio for stent thrombosis to 36.5 (95% CI 8.0, 167.8), and the absence of clopidogrel therapy between 30 days and 6 months was also linked to a significantly increased risk of stent thrombosis (hazard ratio 4.6; 95% CI 1.4, 15.3). Patients with stent thrombosis had discontinued clopidogrel for a median of 5 days.[16] Premature discontinuation of clopidogrel after stent placement, because of non-cardiac surgery, can have fatal consequences. Schouten et al.[18] analysed a total of 192 patients who underwent surgery within 2 years after bare-metal or drugeluting stent implantation. Discontinuation of
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Table I. Purinergic P2Y12 receptor antagonists Drug Ticlopidine Clopidogrel Prasugrel Ticagrelor Cangrelor Structure Thienopyridine Thienopyridine Thienopyridine ATP analogue ATP analogue Direct/indirect action Indirect Indirect Indirect Direct Direct Reversible No No No Yes (half-life 812 h) Yes (half-life 3 min) Route of administration Oral Oral Oral Oral Parenteral Frequency of administration Twice daily Once daily Once daily Twice daily Continuous infusion
ATP = adenosine triphosphate.
clopidogrel antiplatelet therapy before the recommended time (bare-metal stents 1 month, sirolimus-eluting stents 3 months, paclitaxeleluting stents 6 months) was strongly related to adverse outcomes. The incidence of major adverse cardiac events was 30.7% in the discontinuation group versus 0% in patients who continued antiplatelet therapy per guidelines (p = 0.026). All postoperative major adverse cardiac events were fatal. No difference was observed with respect to the type of stent. A clear relationship was documented between perioperative bleeding and administration of dual antiplatelet therapy, including platelet P2Y12 receptor antagonists, shortly before or at the time of coronary bypass surgery.[19,20] Van Kuijk et al.[21] presented data concerning bleeding risk in 550 patients who were undergoing non-cardiac surgery after intracoronary stent implantation (376 with a drug-eluting stent and 174 with a baremetal stent). A strong relationship was found between perioperative use of dual antiplatelet therapy and the risk of bleeding. Every fourth patient on dual antiplatelets experienced a major bleeding complication. The risk of severe bleeding in patients receiving dual antiplatelet therapy was 5-fold higher than in patients receiving aspirin alone (21% vs 4%, p < 0.001). Unfortunately, no data were found about the bleeding risk associated with non-cardiac surgery in patients receiving clopidogrel monotherapy. Clopidogrel monotherapy is associated with a lower risk of bleeding than aspirin monotherapy when evaluated in highrisk cardiovascular patients not undergoing surgery.[22] Badreldin et al.[23] reviewed the effect of preoperative clopidogrel as monotherapy (n = 48) and combined therapy with aspirin (n = 277) on bleeding-related complications in patients under 2011 Adis Data Information BV. All rights reserved.
going coronary artery bypass graft surgery. No significant difference was reported with clopidogrel monotherapy compared with its use in combination with aspirin. The comparison of bleeding risk between clopidogrel monotherapy and aspirin monotherapy was not presented. 4. Timing is Everything The combination of antiplatelet therapy cessation and clotting activation during surgery has been implicated in the pathogenesis of stent thrombosis in the perioperative period, especially in incompletely endothelialized stents. The best solution to overcome the risks resulting from surgery performed in patients after stent implantation is to postpone the operation until after re-endothelialization of the vessel surface is completed. Because only approximately 510% of surgeries are performed as an urgent procedure, this could be a significant way to increase the safety of non-cardiac surgical procedures following stent implantation.[24,25] The time required to establish complete baremetal stent endothelialization in humans is unknown but probably requires at least 3 months.[26] Nuttall et al.[24] published a retrospective analysis of 899 patients who underwent non-cardiac surgery within 1 year of bare-metal stent PCI at the Mayo Clinic (MN, USA). This is the largest study published, to date, addressing perioperative adverse cardiac events in non-cardiac surgical patients after recent bare-metal stent implantation. The analyses assessing the association of time between PCI and surgery with major adverse cardiac events and bleeding are summarized in table II. Shorter time intervals between PCI and surgery were related to an increased likelihood of cardiac events. The
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adjusted OR for major adverse cardiac events was 3.2 for surgery performed 030 days after baremetal stent implantation. This value decreased significantly (OR 1.4) for surgery performed 3190 days after PCI (p = 0.006). The incidence of major adverse cardiac events was lowest when surgery was performed at least 90 days following bare-metal stent implantation.[24] Drug-eluting stents take longer to endothelialize because of the cytotoxic drugs used to reduce vascular smooth muscle cell growth after coronary intervention,[27] therefore the period with the highest risk of stent thrombosis is prolonged. Schulz et al.[28] studied the influence of duration of dual antiplatelet therapy on the incidence of drugeluting stent thrombosis in a cohort of 6816 consecutive patients during a 4-year observational period. The protective effect of clopidogrel, relative to stent thrombosis, was mostly confined to the first 6 months after drug-eluting stent implantation with no substantial benefit thereafter.[28] Two large recent studies documented
that the risk of major postoperative adverse cardiac events is inversely related to the time interval following drug-eluting stent placement.[21,25] Although stabilization of the risks of adverse cardiac events after 6 months was demonstrated, an overall reduction in the incidence of cardiac events was only seen when non-cardiac surgery was performed more than 1 year after drug-eluting stent placement (table II). Non-cardiac surgery within 1 year of PCI was associated with an 80% increase in the rate of major adverse cardiac events compared with surgery postponed for at least 1 year (18% vs 10%, p = 0.015).[25] The multivariate hazard ratio for adverse cardiac events was 2.0 (95% CI 1.1, 3.5) for surgery within 1 year of stent placement compared with longer time intervals. 5. Elective versus Emergency Surgery Emergency surgery, per se, is usually associated with haemodynamic instability, blood loss
Table II. Univariate analysis of characteristics associated with major adverse cardiac events or bleeding events in patients with bare-metal and drug-eluting stents undergoing non-cardiac surgery Characteristic Major adverse cardiac events bare-metal stenta % Days from stent to surgery 30 3190 91180 181270 271365 >365 Emergent surgery yes no Surgical risk low intermediate high a b c d Nuttall et al.[24] Rabbitts et al.[25] van Kuijk et al.[21] 181365 days from stent to surgery. 2.2 5.8 6.2 11.7 4.4 0.136 0.003 17.9 4.7 NA 1.6 2.2 10.2 10.5 3.8 3.0 2.6 2.7 6d 9 0.006 9.7 4.1 <0.001 NA 0.016 NA p-value 0.003 35 13 15 drug-eluting stentb,c % p-value <0.001 6.9 4.6 4.2 2.6 3.6 Bleeding events bare-metal stenta % p-value 0.046 drug-eluting stent % NA p-value
NA = not available.
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and activation of haemostasis. There is no time for careful back-up preparation. Studies with patients who underwent non-cardiac surgery following bare-metal and drug-eluting stent implantation have documented that emergency surgery was independently associated with both major adverse cardiac events and bleeding complications (table II).[21,24,25] In a retrospective analysis of patients with stents, the need for emergency surgery was the strongest variable associated with major cardiovascular events. The rate of major adverse cardiac events was 17.9% for patients undergoing emergency procedures after drug-eluting stents and 11.7% with baremetal stents versus 4.7% in patients undergoing non-emergency surgery after drug-eluting stent and 4.4% after bare-metal stent PCI, respectively.[24,25] Monitoring of myocardial ischaemia in these patients is necessary, especially since perioperative ischaemia is often underdiagnosed.[29] 6. Treatment of Perioperative Stent Thrombosis Stent thrombosis is mostly associated with total occlusion of the coronary artery and manifests as an ST-segment elevation acute myocardial infarction; it must be treated with immediate reperfusion.[30,31] Primary PCI should be performed as the reperfusion of choice in the perioperative period. Unfortunately, PCI also carries an increased risk of bleeding when performed shortly after surgery because antithrombin (heparin, bivalirudin) and antiplatelet agents (including glycoprotein IIb/IIIa antagonists) need to be administered during the procedure. If major bleeding complicates the PCI procedure in patients with stent thrombosis early after surgery, a vicious circle is established, often with fatal outcomes.[32,33] It may therefore be safer to avoid stenting and proceed to a dilatation of the coronary artery in the first 2448 hours after surgery. 7. Recommendations The high risk of mortality,[18] due to stent thrombosis and major bleeding, in patients undergoing non-cardiac surgery following PCI with
stents, indicates that the best option for dealing with these situations is to prevent them. European and American expert opinion guidelines address the problem of non-cardiac surgery in patients following stent implantation.[34-36]
7.1 Before Stent Placement
Many patients with coronary disease who require non-cardiac surgery do not benefit from preoperative revascularization.[37,38] The CARP (Coronary Artery Revascularization Prophylaxis) trial[37] enrolled 510 stable patients with angiographic coronary artery disease (one-third had 3-vessel disease, left-main disease was excluded) undergoing major vascular surgery (abdominal aortic aneurysm repair, lower extremity revascularization). Patients were randomized to revascularization (PCI in 59%) versus no revascularization before surgery. No benefit was observed in terms of postoperative acute myocardial infarction and survival in revascularized patients compared with patients without preoperative revascularization. Therefore, if a patient with coronary disease is known to require surgery, the first question to ask is whether the patient really needs revascularization prior to surgery. If PCI has to be performed (patients with an acute coronary syndrome, an early positive stress test indicating severe ischaemia, or life-threatening coronary anatomy), the use of drug-eluting stents has to be avoided. A promising approach to solving drugeluting stent-associated problems with delayed re-endothelialization are bioabsorbable stents (table III).[39,40] Bioabsorbable stents with polymers that are either more biocompatible or biodegradable, or completely free from polymers, disappear within months and avoid the need for prolonged dual antiplatelet therapy. Bioabsorbable stent platforms are currently undergoing clinical trials.[40]
7.2 After Stent Placement
7.2.1 Timing of the Operation
Guidelines recommend delaying non-cardiac surgery for at least 6 weeks and optimally up to 3 months after bare-metal stent implantation (table II).[34-36] After drug-eluting stent implantaDrugs 2011; 71 (14)
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Table III. Drug-eluting stents Drug-eluting stents First generation Sirolimus-eluting stents Paclitaxel-eluting stents Second generation Everolimus-eluting stents Zotarolimus-eluting stents Third generation New drugs Novolimus: a metabolite of sirolimus with high potency to inhibit neointimal proliferation Biolimus A9: a sirolimus derivative with antiproliferative and immunosuppressive properties Myolimus: a sirolimus analogue Biodegradable polymers Supralimus (Matrix; Sahajanand Medical Technologies Pvt. Ltd., Surat, Gujarat, India) Excel (JW Medical System, Weihai, China) Nevo (Cordis Corporation, Bridgewater, NJ, USA) Infinnium (Sahajanand Medical Technologies Pvt. Ltd.) JACTAX (Boston Scientific Corporation, Natick, MA, USA) Costar (Conor MedSystems, Menlo Park, CA, USA) Microdrop spray crystallization process Microporous stainless steel platform Poly-L-lactide stents Magnesium stents Everolimus: an analogue of sirolimus with increased solubility Zotarolimus: an analogue of sirolimus with shorter in vivo half-life and increased solubility Durable polymer Durable polymer Cobalt-chromium alloy Cobalt-chromium alloy Sirolimus (rapamycin): a macrolide immunosuppressant Paclitaxel: an antiproliferative agent Durable polymer Durable polymer Cobalt-chromium alloy Cobalt-chromium alloy Drug Polymer Platform
Polymer-free stents Biodegradable stents
tion, elective surgery should not take place until after at least 12 months of continuous dual antiplatelet therapy.[33,34] The need for surgery in relation to its timing and the specific pathology should be balanced against the risk of stent thrombosis, and careful case-by-case consideration is advisable.
7.2.2 Antiplatelet Therapy
Expert recommendations advise that 3 months after bare-metal stent PCI and 12 months after drug-eluting stent PCI, patients can be sent for non-cardiac surgery, with continuation of aspirin therapy.[34-36] Aspirin should only be discontinued if the bleeding risk outweighs the po 2011 Adis Data Information BV. All rights reserved.
tential cardiac benefits. Discontinuation of aspirin should be considered in those in whom haemostasis is difficult to control during the operative procedure (neurosurgery, ophthalmosurgery, transurethral prostatectomy). Difficult decisions regarding antiplatelet management arise when a patient who is still receiving dual antiplatelet therapy with aspirin and a P2Y12 antagonist (in most patients, the irreversible thienopyridine clopidogrel) is required to undergo surgery that cannot be postponed. A universal recommendation for this situation is unrealistic. Discussion between the treating cardiologist (cardiovascular risk), the surgeon (bleeding risk) and the anaesthesiologist (functional reserve,
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back-up preparation) about this situation is recommended in order to achieve a reasonable expert consensus.[36,37,41] Aspirin should be continued if possible. Neither observational nor randomized study data are available regarding continuation of monotherapy with clopidogrel in this situation. If discontinuation of clopidogrel therapy is necessary, a P2Y12 antagonist should be resumed if there is adequate haemostasis after 24 hours (or the next morning) post-surgery. In patients who require temporary interruption of aspirin or clopidogrel, or both, before surgery, it is recommended that this treatment be stopped at least 5 days, preferably 10 days, prior to the procedure.[34] Heparin therapy, either unfractionated heparin or low-molecularweight heparin, via subcutaneous injection, has been proposed during the period of time when the thienopyridine is stopped, but efficacy has not been proven.[41,42] Heparin therapy is unlikely to protect against stent thrombosis since it has no antiplatelet properties. Another approach may be bridging with glycoprotein IIb/IIIa inhibitors. Tirofiban and eptifibatide have a reversible mode of action, and platelet function is completely restored 24 hours after stopping the infusion. In a small prospective study of 30 patients requiring non-cardiac surgery within 12 months after drugeluting stent placement, tirofiban was started 24 hours after clopidogrel withdrawal, continued until 4 hours before surgery, and resumed 2 hours after surgery until clopidogrel was restarted. There were no adverse cardiac events during the index hospitalization, and no patient required surgical re-exploration because of bleeding.[43] To date, however, no large-scale clinical testing has been performed proving the advantage of this approach. Continuation of dual antiplatelet therapy is justified if the risk of stent thrombosis outweighs the risk of procedure-associated bleeding (table IV). In this situation, perioperative caregivers should be on guard for ischaemic events and should be prepared for surgical bleeding. In recently published observational analyses, the incidence of surgical bleeding complications was low despite the high rate of dual antiplatelet therapy.[8,25] The increased incidence of operations performed on patients using combined antiplatelet therapy[8]
Table IV. Non-cardiac surgery and risk of bleeding complications Risk of bleeding Low Type of non-cardiac surgery Endoscopy; biopsies Eye anterior chamber (cataract surgery) Dental extraction and dental surgery Otolaryngology surgery Minor orthopaedic surgery Cutaneous surgery; plastic surgery Intermediate Visceral surgery Major orthopaedic surgery Urologic surgery High Intracranial neurosurgery; spinal canal surgery Eye posterior chamber surgery Transurethral prostatectomy
has enhanced the knowledge and ability of surgeons and anaesthetists to manage it without serious complications.[44] For patients receiving antiplatelet therapy (i.e. aspirin, clopidogrel, or both) with excessive or life-threatening perioperative bleeding, transfusion of platelets and administration of other prohaemostatic agents is recommended. 8. The Future Ticagrelor is the first reversible, oral P2Y12 receptor antagonist of the non-thienopyridine class; however, it is not yet US FDA approved. It has a rapid onset of action and a half-life of approximately 812 hours, suggesting a possible use in patients referred for surgery. However, due to the higher degree of platelet inhibition achieved with ticagrelor compared with clopidogrel, platelet inhibition remains similar to or higher with ticagrelor for at least 48 hours after treatment.[45] Cangrelor is the only reversible P2Y12 receptor antagonist that is administered intravenously (table I). A role for cangrelor in PCIs has not yet been established. CHAMPION (Cangrelor vs Standard Therapy to Achieve Optimal Management of Platelet Inhibition)-PLATFORM and CHAMPION-PCI,[46] two phase III trials evaluating cangrelor, were stopped prematurely in 2009 because the drug was unlikely to demonstrate persuasive clinical efficacy needed for regulatory apDrugs 2011; 71 (14)
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proval. Cangrelor rapidly achieves near complete inhibition of adenosine diphosphate-induced platelet aggregation. Steady-state platelet inhibition is reached within 30 minutes after infusion starts and returns to pre-treatment levels within an hour after cessation of treatment.[47] These attributes suggest that cangrelor would be a potential bridging therapy in the perioperative setting. The BRIDGE (Maintenance of Platelet Inhibition with Cangrelor After Discontinuation of Thienopyridines in Patients Undergoing Surgery) study[48] is an ongoing study (expected completion date is July 2011) designed to demonstrate that patients receiving cangrelor infusion before coronary artery bypass grafting have an acceptable safety profile and can undergo surgery without excessive bleeding perioperatively. 9. Conclusions Non-cardiac surgery in patients following intracoronary stent implantation involves a risk of stent thrombosis, especially if surgery has to be performed within the period when dual antiplatelet therapy is necessary. Awareness, prevention and early treatment of perioperative complications in these patients are best achieved by collaboration between surgeons, anaesthesiologists and cardiologists. In the future, reversible and parenteral P2Y12 receptor antagonists (ticagrelor, cangrelor) may prove to be of value perioperatively. Acknowledgements
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This article was supported by the Internal Grant Agency of the Ministry of Health, Czech Republic, Project No. NT11506. The author has no financial or personal relationships that could inappropriately influence (or bias) the authors decisions, work or manuscript.
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33. Bhatt DL. Antiplatelet, anticoagulant, and fibrinolytic drugs. In: Braunwald E, Fauci AS, Isselbacher KJ, et al., editors. Harrisons online. New York: McGraw Hill; 2005 34. Poldermans D, Bax JJ, Boersma E, et al. Guidelines for preoperative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery: The Task Force for Preoperative Cardiac Risk Assessment and Perioperative Cardiac Management in Non-cardiac Surgery of the European Society of Cardiology (ESC) and endorsed by the European Society of Anaesthesiology (ESA). Eur Heart J 2009; 30: 2769-812 35. Grines CL, Bonow RO, Casey Jr DE, et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. J Am Coll Cardiol 2007; 49: 734-9 36. Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 Guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Circulation 2007; 116: e418-99 37. McFalls EO, Ward HB, Moritz TE, et al. Coronary-artery revascularization before elective major vascular surgery. N Engl J Med 2004; 351: 2795-804 38. Poldermans D, Schouten O, Vidakovic R, et al. DECREASE Study Group A clinical randomized trial to evaluate the safety of a noninvasive approach in highrisk patients undergoing major vascular surgery: the DECREASE-V pilot study. J Am Coll Cardiol 2007; 49: 1763-9 39. Onuma Y, Serruys PW. Bioresorbable scaffold: the advent of a new era in percutaneous coronary and peripheral revascularization? Circulation 2011; 123: 779-97 40. Serruys PW, Ormiston JA, Onuma Y, et al. A bioabsorbable everolimus-eluting coronary stent system (ABSORB): 2year outcomes and results from multiple imaging methods. Lancet 2009; 373: 897-910 41. Collet JP, Montalescot G. Premature withdrawal and alternative therapies to dual oral antiplatelet therapy. Eur Heart J Suppl 2006; 8 Suppl. G: G46-52 42. Dent H, Lekic Z, Vicenzi M. Unfractionated heparin and coronary artery stenting [letter]. Br J Anaesth 2006; 97: 582 43. Savonitto S, DUrbano M, Caracciolo M, et al. Urgent surgery in patients with a recently implanted coronary drug-eluting stent: a phase II study of bridging antiplatelet therapy with tirofiban during temporary withdrawal of clopidogrel. Br J Anaesth. 2010; 104: 285-91 44. Vicenzi MN, Meislitzer T, Heitzinger B, et al. Coronary artery stenting and non-cardiac surgery: a prospective outcome study. Br J Anaesth 2006; 96: 686-93
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45. Gurbel PA, Bliden KP, Butler K, et al. Randomized doubleblind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation 2009; 120: 2577-85 46. Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 2009; 361: 2318-29 47. Greenbaum AB, Grines CL, Bittl JA, et al. Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: results from a 2-part, phase II, multicenter, randomized, placebo- and active-controlled trial. Am Heart J 2006; 151: 689.e1-10
48. National Heart, Lung, and Blood Institute (NHLBI). The BRIDGE study: Effectiveness of bridging anticoagulation for surgery [ClinicalTrials.gov identifier NCT00786474]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov [Accessed 2011 Aug 3]
Correspondence: Associate Professor Zuzana Motovska, MD, PhD, FESC, 3rd Medical Faculty of Charles University, Cardiocentre University Hospital Vinohrady, Srobarova 50, 100 34 Prague 10, Czech Republic. E-mail: zuzana.motovska@iex.cz
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LEADING ARTICLE
Drugs 2011; 71 (14): 1807-1819 0012-6667/11/0014-1807/$55.55/0
Neuraxial Morphine and Respiratory Depression

Finding the Right Balance
Pervez Sultan, Maria Cristina Gutierrez and Brendan Carvalho
Stanford University School of Medicine, Stanford, CA, USA
Abstract
Morphine is a drug commonly administered via the epidural or intrathecal route, and is regarded by many as the gold-standard single-dose neuraxial opioid due to its postoperative analgesic efficacy and prolonged duration of action. However, respiratory depression is a recognized side effect of neuraxial morphine administered in the perioperative setting. We conducted an extensive review of articles published since 1945 that examine respiratory depression or failure associated with perioperative intrathecal or epidural morphine use. Respiratory depression was previously thought to result from the interaction of opioid in the cerebrospinal fluid with ventral medullary opioid receptors. More recently, the preBotzinger complex located in the medulla has been identified as the site responsible for the decrease in respiratory rate following systemic administration of opioids. Neurons in the preBotzinger complex expressing neurokinin-1 receptors are selectively inhibited by opioids, and therefore are the mediators of opioid-induced respiratory depression. Epidural, intrathecal and plasma pharmacokinetics of opioids are complex, vary between neuraxial compartments, and can even differ within the epidural space itself depending upon level of insertion. Caution should be exercised when prescribing systemic opioids (intravenous or oral) in addition to neuraxial morphine as this can compound the potential for early or delayed respiratory depression. There is a wide range of incidences for respiratory depression following neuraxial morphine in a perioperative setting. Disparity of definitions used for the diagnosis of respiratory depression in the literature precludes identification of the exact incidence of this rare event. The optimal neuraxial opioid dose is a balance between the conflicting demands of providing optimal analgesia while minimizing dose-related adverse effects. Dose-response studies show that neuraxial morphine appears to have an analgesic efficacy ceiling. The optimal single-shot intrathecal dose appears to be 0.0750.15 mg and the ideal single-shot epidural morphine dose is 2.53.75 mg. Analgesic efficacy studies have not been adequately powered to show differences in the incidence of clinically significant respiratory depression. Opioid antagonists such as naloxone to prevent or treat opioidinduced respiratory depression have a number of limitations. Researchers have recently focused on non-opioid drugs such as serotonin receptor agonists.
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Early evidence suggests that ampakine (a-amino-3-hydroxy-5-methyl-4isoxazole-propionic acid [AMPA]) receptor modulators may be effective at reducing opioid-induced respiratory depression while maintaining analgesia. Sodium/proton exchanger type 3 (NHE3) inhibitors, which act centrally on respiratory pathways, also warrant further study.
1. Introduction The discovery that opioid receptors are localized within lamina II of the dorsal horn in the CNS suggested that exogenous opioids could be administered via the neuraxial route to produce analgesia.[1] A number of published reports of intrathecal[2] and epidural[3] morphine administration in humans have since been published, and in 1984 preservative-free morphine received US FDA approval for neuraxial administration. Analgesia delivered via the neuraxial route lasts longer than the systemic route, with effects persisting 1224 hours,[4] and in some cases longer, following administration.[5] Recognized benefits of neuraxial opioids when compared with intravenous administration include better postoperative analgesia, increased functional ability, earlier ambulation and earlier return of bowel function.[6,7] Furthermore, unlike with neuraxial local anaesthetics, there is negligible motor, sensory or autonomic blockade associated with neuraxial opioids.[2,3,8] Neuraxial morphine is now extensively used in the perioperative setting[9] due to improved analgesia, greater duration of action and dosesparing effects when compared with its administration via the systemic route. Despite significant analgesic advantages of neuraxial morphine over systemic administration, there are a number of potential adverse effects of which respiratory depression is the most concerning. Cases of lifethreatening respiratory depression were reported soon after clinical administration of neuraxial morphine.[10-12] Recent closed-claims data found that 13 of 93 claims made between 1995 and 2007 were due to respiratory depression; six cases involved intravenous opioids, three cases involved neuraxial opioids, and in the remaining four cases the drug and route were not named. The majority
of these cases resulted in significant morbidity or permanent brain damage, and resulted in treatment costs of approximate d2.75million.[13] Although the absolute risk of respiratory depression is small, concern for this adverse effect may result in underuse of neuraxial morphine for routine postoperative analgesia.[14] This article reviews relevant publications addressing the issue of respiratory depression secondary to neuraxial morphine. A literature review of studies that examined neuraxial morphine-induced respiratory depression was performed. Published articles written in English between 1945 and 2010 were identified using the MEDLINE, Cochrane, EMBASE and Web of Science databases. Literature written in English using the terms intrathecal or spinal or neuraxial or extradural or epidural or neuraxial and opioid, were combined with respiratory depression or respiratory failure. 360 articles were reviewed by hand, of which 165 were excluded. We selected 63 articles containing opioids and neuraxial and 132 articles containing morphine and neuraxial. Additional articles were reviewed to explain certain points. 2. Pathophysiology of Respiratory Depression Respiratory depression has been reported following both intrathecal and epidural morphine.[15,16] Respiratory depression following epidural morphine is classically described as biphasic,[17] with early (<2 hours) and delayed (>2 hours) presentations. Most reports of early respiratory depression involve lipophilic opioids (sufentanil or fentanyl) administered via the epidural route.[18-22] Delayed respiratory depression is a phenomenon associated with hydrophilic morphine rather than lipophilic neuraxial opioids.[15,16] It usually
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occurs 612 hours following intrathecal or epidural administration and may persist up to 24 hours.[17,23,24] Delayed respiratory depression is caused by rostral spread in the cerebrospinal fluid (CSF) and slow penetration into the brainstem. High concentrations of m-opioid receptors exist within the ventral medulla, which are important in the normal regulation of respiration. Direct application of small doses of opioid to the chemosensitive anterolateral surface of the medulla,[25,26] fourth or lateral ventricles,[27,28] or pontine or medullary respiratory centres can induce significant respiratory depression.[29] Respiratory depression was previously thought to result from the interaction of opioid in the CSF with ventral medullary opioid receptors.[30] Studies in rats suggested that respiratory depression occurring after the administration of opioids resulted from a dual effect involving m- and dreceptors.[31] More recently, the preBotzinger com plex located in the medulla has been identified as the site responsible for the decrease in respiratory rate following systemic administration of opioids. Neurons in the preBotzinger complex expressing neurokinin-1 receptors are selectively inhibited by opioids, and therefore are the mediators of opioidinduced respiratory depression.[32] 3. Pharmacokinetics of Neuraxial Morphine Epidural, intrathecal and plasma pharmacokinetics of opioids are complex, vary between neuraxial compartments, and can even differ within the epidural space itself depending upon level of insertion. The bioavailability of opioids in the intrathecal and epidural compartments is determined primarily by the drugs hydrophobicity.[33] Hydrophilic morphine has a high CSF bioavailability, excellent spinal penetration, prolonged duration and less systemic absorption than lipophilic opioids. Morphine penetrates the spinal cord slowly, facilitating cephalad spread in the CSF. A poor correlation between the analgesic effect and plasma levels of morphine has been observed following epidural administration, suggesting a predominantly spinal effect.[34,35] Morphine levels within the CSF following intrathecal
morphine administration are approximately 3 times those in plasma. Supra-spinal redistribution of morphine through the CSF plays an important role in the generation of analgesia and CNS side effects.[36] The long duration of action of morphine is due to the slow rate of clearance of the drug from the opioid receptors.[37,38] In addition, morphine is absorbed more slowly from the intrathecal space than following epidural or intramuscular administration, further prolonging its analgesic effect.[39] Direct administration of morphine into the CSF is the most efficient method of delivering opioid to the spinal cord receptors. Appreciable cervical CSF concentrations occur 15 hours after lumbar intrathecal morphine administration. Morphine reaches the cisterna magna and fourth and lateral ventricles by 12 and 36 hours, respectively.[40] The hyperbaric form of morphine decreases cephalad diffusion and minimizes the central depressant effects of the drug.[41] It remains within the CSF for prolonged periods and slowly diffuses to the plasma compartment.[42] Morphine is not metabolized within the CNS, and therefore morphine-6-glucoronide cannot be detected in CSF following intrathecal administration.[43] Elimination is thought to be dependent on reabsorption via arachnoid granulations.[44] The terminal elimination half-life of morphine within the CSF is 24 hours, similar to that within plasma.[45,46] Peak blood and CSF levels of morphine occur at 1015 minutes and 14 hours, respectively, following epidural administration.[38,46-48] Approximately 3% of the epidural morphine dose crosses the dura to enter the CSF.[46,47] Epidural morphine administration produces blood concentrations similar to those seen following an equivalent intra-muscular dose.[49] Animal studies examining behavioural and toxicological effects have failed to demonstrate neurotoxicity secondary to long-term administration of epidural and intrathecal morphine.[50] 4. Patients at Risk of Respiratory Depression There are a number of well described risk factors for developing respiratory depression after neuraxial morphine (table I).[15,51-60] In 2009, the
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Table I. Risk factors for respiratory depression Risk factor Pharmacological High opioid doses Hydrophilic opioids (morphine) Repeated opioid administration Concomitant administration of systemic opioids Co-administration of sedatives Anaesthesia General anaesthesia Thoracic epidurals Patient Advanced age Female Co-existing cardiopulmonary disease Opioid-nave patient Morbid obesity Obstructive sleep apnoea Genetic (OPRM1:c.118A > G polymorphism) Miscellaneous Co-administration of magnesium Increased intrathoracic pressure (controlled ventilation, coughing, vomiting) Non-obstetric population 60 59 15,55 56 55 55 55,57 52 58 54 51 52 53 15,52 53 References
American Society of Anesthesiologists published practice guidelines for the prevention, detection and management of respiratory depression associated with neuraxial opioid administration.[52] These guidelines suggest that a history and physical examination directed at identifying risk factors, in particular sleep apnoea, should be performed in all patients prior to administration of neuraxial opioids. Importantly, opioid-induced respiratory depression can still occur in healthy patients receiving neuraxial morphine without co-existing morbidity,[53] and clinicians must anticipate this rare but hazardous event.[53,61] Caution should be exercised when prescribing systemic opioids (intravenous or oral) in addition to neuraxial morphine as this can compound the potential for early or delayed respiratory depression. 5. Incidence of Respiratory Depression Numerous publications including randomized controlled trials, case reports, prospective and
retrospective analyses of databases, surveys and meta-analyses have attempted to define the true incidence of respiratory depression associated with neuraxial morphine use. Disparity of definitions used for the diagnosis of respiratory depression precludes identification of the exact incidence of this rare event. Definitions have included respiratory rate, hypercarbia, low arterial oxygen saturation (SaO2), decreased level of consciousness, increased level of sedation, treatment with naloxone and decreased ventilator response to hypoxia or hypercarbia.[62] In addition, the incidence of respiratory depression following neuraxial morphine has been shown to be dose-dependent. Therefore, the reported incidence of respiratory depression from earlier studies using larger doses may not be relevant to current clinical practice which utilizes smaller neuraxial morphine doses.[15,63,64] The incidences of respiratory depression determined from large retrospective and prospective database analyses are outlined in table II.[57,65-73] The incidence is 0.263% for intrathecal morphine in dose ranges of 0.150.8 mg, and 02.8% for epidural morphine administration with dose ranges of 25 mg. These incidences are similar to those reported by Etches et al.[64] in 1989 (0.09 3%). In their review, the authors commented that the true incidence was unknown due to the lack of well designed prospective studies at the time. More recently, two meta-analyses determined the incidence of respiratory depression in patients receiving low-dose (<0.2 and 0.20.3 mg) intrathecal morphine to be 01.2%.[51,74] Table III shows recent randomized controlled trials performed since 2000 not included in the two mentioned meta-analyses.[75-88] The incidence of respiratory depression in these studies ranges from 0% to 3.4% in the 985 patients receiving intrathecal morphine in dose ranges between 0.025 to 0.4 mg. Differences in the incidences among the studies may reflect different doses, additional analgesics utilized, different surgical populations, and various definitions used to define respiratory depression. Studies indicate that the incidence of respiratory depression is not greater with neuraxial compared with systemic administration of morphine.[51,66,74,89]
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Table II. Studies with incidence data for respiratory depression secondary to neuraxial morphine Study (year) Kato et al. (2008)[65] Shapiro et al. (2005)[66] Type of surgery CD n 1915 Design Retrospective Outcome measured Bradypnoea: RR 10 Severe RD: required use of naloxone RR <10 Route IT 0.15 mg Additional opioids? Yes Incidence (%) Bradypnoea: 0.26 Severe RD: 0.052 IV-PCA: 1.86 E: 0.59 IT: 0.69 E group: 0.04 IV-PCA group: 1.2 3 2.8
General
1524
Retrospective
IV-PCA vs E 4 mg every 1624 h 3 vs IT 0.2 mg E 24 mg + PCEA vs IV-PCA IT 0.20.8 mg E 36 mg + infusion
No (first 24 h)
Flisberg et al. (2003)[67] Gwirtz et al. (1999)[68] Tsui et al. (1997)[69] Rygnestad et al. (1997)[70] Abouleish et al. (1991)[57] Fuller et al. (1990)[71] Leicht et al. (1986)[72] Kotelko et al. (1984)[73]
General General General
2696 5969 245
Prospective Prospective Prospective
RR <8 RR 8 or PaCO2 >50 mmHg RR <10 or SaO2 <90% or PaCO2 >7 kPa RR <8
No Yes No
General
2000
Prospective
E bolus 2 mg with 0.05% bupivacaine + infusion IT 0.2 mg E 25 mg E 5 mg
Yes
1.7
CD CD CD
856 4880 1000
Prospective Retrospective Prospective
SaO2 85% or RR 10 RR <10 RR <10, poor depth of respirations, or signs of airway obstruction RR <10
Yes Yes
0.9 0.25 0.4
CD
276
Prospective
E 5 mg
Yes
CD = caesarean delivery; E = epidural; IT = intrathecal; IV-PCA = intravenous patient-controlled analgesia; n = number of patients; PaCO2 = partial pressure of arterial carbon dioxide; PCEA = patient-controlled epidural analgesia; RD = respiratory depression; RR = respiratory rate (breaths/min); SaO2 = oxygen saturation.
Although earlier studies suggested that respiratory depression was greater with intrathecal morphine compared with epidural administration,[15,37] these differences may be attributed to the higher intrathecal morphine doses used in those studies. More recent studies indicate that epidural and intrathecal morphine appear to provide similar analgesia and adverse effects (such as sedation, pruritus, nausea and vomiting) when an equipotent analgesia conversion ratio of 2030 : 1 is used.[84,90,91] One potential disadvantage of epidural administration of morphine is that inadvertent subdural or intrathecal administration with a dose intended for the epidural route can lead to profound sedation and respiratory depression, potentially requiring opioid reversal, intensive care monitoring and ventilatory support.[92]
6. Neuraxial Morphine Analgesic Ceiling, Dose-Response and Dose-Related Adverse Effects The optimal neuraxial opioid dose is essentially a balance between the conflicting demands of providing optimal analgesia while minimizing dose-related adverse effects. Several studies have attempted to determine the optimal dose of intrathecal and epidural morphine for postoperative analgesia.
6.1 Intrathecal Morphine Doses
Due to the widespread use of neuraxial opioids in obstetric patients, intrathecal and epidural morphine have been extensively studied in this setting. Palmer et al.[93] compared the analgesic
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Table III. Recent key randomized controlled trials with intrathecal morphine Study (year) Frassanito et al. (2010)[75] Duman et al. (2010)[76] Yamashita et al. (2009)[77] Draisci et al. (2009)[78] Type of surgery TKA TURP TURP CD n 52 54 20 64 RR <10 RR <10 Outcome measured Dose IT 0.1 mg vs femoral nerve block IT 0.0250.05 mg IT 0.05 mg IT 0.15 mg + sufentanil 5 mg vs SC 10 mg + sufentanil 5 mg RR <8 or SaO2 <90% or PaO2 >70 mmHg RR <8 RR <8 or PaCO2 70 mm Hg RR 10 IT 4 mg/kg; IT 1 mg/kg + clonidine; morphine PCA IT 0.15 mg + fentanil vs GA IT 0.4 mg vs PCA IT 00.2 mg Additional opioids? Yes No No Yes Incidence (%) 0 0 0 0
Andrieu et al. (2009)[79]
Retropubic prostatectomy TAH Donor right hepatectomy Orthopaedics
50
Yes
Massicotte et al. (2009)[80] Ko et al. (2009)[81] Gehling et al. (2009)[82]
40 40 188
Yes Yes Yes
IT: 0 GA: 5 0 Placebo: 1.5 0.1 mg: 1.6 0.2 mg: 3.4 0 0 0 0 0 0
Ziegeler et al. (2008)[83] Duale et al. (2003)[84] Techanivate et al. (2003)[85] Devys et al. (2003)[86] Fournier et al. (2000)[87] Culebras et al. (2000)[88]
PSF CD Laminectomy Abdominal surgery THA CD
52 53 40 60 40 90
Naloxone requirement Not disclosed
IT 0.4 mg vs placebo IT 0.075 vs epidural morphine 2 mg IT 0.3 mg vs placebo IT 00.4 mg IT 0.16 mg vs nalbuphine IT 0.2 mg vs nalbuphine
Yes Yes Yes Yes Yes Yes
RR <10 RR <8 RR <10
CD = caesarean delivery; GA = general anaesthesia; IT = intrathecal; n = number of patients; PaCO2 = partial pressure of arterial carbon dioxide; PCA = patient-controlled analgesia; PSF = posterior spinal fusion; RR = respiratory rate (breaths/min); SaO2 = oxygen saturation; SC = subcutaneous; TAH = total abdominal hysterectomy; THA = total hip arthroplasty; TKA = total knee arthroplasty; TURP = transurethral resection of the prostate.
efficacy of increasing intrathecal morphine doses (0, 0.025, 0.05, 0.075, 0.1, 0.2, 0.3, 0.4 and 0.5 mg) following caesarean delivery and found no significant analgesic benefit using doses greater than 0.075 mg. Another dose-response study of intrathecal morphine 0.05, 0.1 and 0.2 mg in the post-caesarean population observed that 0.1 and 0.2 mg provided comparable effective postcaesarean analgesia, while the 0.05 mg dose was less effective.[94] However, the incidence of adverse effects was greater with the 0.2 mg dose. Milner et al.[95] reported that intrathecal morphine 0.1 mg produced similar post-caesarean analgesia to that of 0.2 mg. There were no reports of respiratory depression, but the lower dose resulted in less nausea and vomiting. Similarly, Yang et al.[96] found that intrathecal morphine 0.1 mg compared with
0.25 mg, provided similar analgesia but with fewer adverse effects post-caesarean delivery. A postcaesarean analgesia study using a wide range of intrathecal morphine doses (00.2 mg), found that the dose that produced a 50% effective response (ED50) was 0.02 0.05 mg; however, significant analgesic variability was noted.[97] A systematic review recommended 0.1 mg as the optimal intrathecal morphine dose for caesarean delivery analgesia.[4] The use of multimodal adjuvant analgesia including NSAIDs postoperatively may further reduce dose requirements. Cardoso et al.[98] found that 0.025 mg of intrathecal morphine when combined with systemic diclofenac was as effective as 0.05 or 0.1 mg. A number of dose-response studies with intrathecal morphine have been conducted in non-obstetric surgical populations. Sarma and
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Bostrom[99] examined the dose-response of intrathecal morphine (0, 0.1, 0.3 and 0.5 mg) in patients undergoing total abdominal hysterectomy under general anaesthesia. The analgesic ceiling in this study was 0.3 mg. Another dose-response study observed pain relief and adverse effects of intrathecal morphine doses (0, 0.04, 0.06, 0.08, 0.1, 0.12, 0.15 and 0.2 mg) in patients undergoing cholecystectomy with spinal anaesthesia.[100] Optimal analgesia without respiratory depression was obtained in the 0.060.12 mg dose range. The incidence of respiratory depression was greater with doses of 0.15 and 0.2 mg. Hassett et al.[101] examined the analgesic efficacy and adverse effect profile of 0.1, 0.2 and 0.3 mg intrathecal morphine in patients undergoing elective total knee replacement. They found morphine 0.2 mg to be the optimal analgesic dose, but observed no differences between adverse effects or respiratory depression amongst the doses studied. Slappendel et al.[102] studied various intrathecal morphine doses (0.025, 0.05, 0.1 or 0.2 mg) for total hip surgery and concluded that 0.1 mg was the optimal analgesic dose. The incidence of pruritus and requirement for antipruritic medication was dose-related, although there were no reports of respiratory depression or differences in oxygen desaturation among the different groups within this study. In a study of patients undergoing lumbar fusion randomized to receive morphine (0.2, 0.3 or 0.4 mg) injected into the dural sac under direct visualization, pain scores were better with 0.3 and 0.4 mg doses.[103] However, respiratory rate was lower and the partial pressure of arterial carbon dioxide (PaCO2) was consistently higher in patients receiving the 0.4 mg dose. The effects of increasing intrathecal morphine doses (0.2, 0.4 and 0.6 mg) were assessed in nonsurgical healthy, young, adult male volunteers.[23] The authors reported dose-related respiratory depression with significant decreases in SpO2 (measured by pulse oximetry), the need for supplemental oxygen, and increased peak mean PaCO2. The PaCO2 peaks occurred 6.57.5 hours after intrathecal morphine administration. A metaanalysis of 28 studies (n = 790) determined adverse effects of intrathecal morphine in patients undergoing surgery with spinal anaesthesia.[51]
The authors found that intrathecal morphine resulted in an increased incidence of adverse effects (pruritus, nausea and vomiting) compared with patients not receiving intrathecal morphine. The incidence of pruritus was found to be dosedependent. Higher doses (0.3 mg) of intrathecal morphine were associated with a greater number of episodes of respiratory depression, 9% (7/80) compared with lower doses 1% (2/247), but the difference in incidence was not statistically significant.
6.2 Epidural Morphine Doses
The dose-effect relationship of epidural morphine has also been studied. A dose-response study by Palmer et al.[104] determined that the optimal postcaesarean analgesic dose of epidural morphine was 3.75 mg. In the dose range studied (0, 1.25, 2.5, 3.75 and 5 mg), increasing the dose beyond this analgesic ceiling did not improve postoperative analgesia or reduce opioid use (figure 1). A 3 mg dose of epidural morphine was similarly recommended by Fuller et al.[71] based on a large retrospective post-caesarean study. Chumpathong et al.[105] found similar post-caesarean analgesia and adverse effects with 2.5, 3 and 4 mg doses of epidural morphine. A study by Rosen et al.[106] demonstrated that 2 mg did not provide adequate post-caesarean analgesia compared with 5 and 7.5 mg of epidural morphine.
100 90 24 h PCA morphine use (mg) 80 70 60 50 40 30 20 10 0 0 1 2 3 4 Epidural morphine dose (mg) 5
Fig. 1. Dose-response relationship of intrathecal morphine for postcaesarean analgesia. PCA = patient-controlled analgesia [reproduced from Palmer et al.,[104] with permission].
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The analgesic and adverse effects of 1, 2, 3, 4 and 5 mg epidural morphine were examined in patients undergoing orthopaedic procedures.[107] Authors recommended 3 mg of epidural morphine as the optimal dose. Patients receiving 2 mg required less postoperative analgesia and experienced less postoperative pain, but the 5 mg dose produced mild respiratory depression (mean PaCO2 5 mm Hg greater than control group). A dose-dependent increase in pruritus and urinary catheterization was also observed. Rawal and Wattwil[63] performed a dose-response study in healthy volunteers administering epidural morphine doses of 2, 4 or 10 mg, and in the clinical part of the study administering epidural morphine 4 mg in surgical patients undergoing cholecystectomy. The authors found a dose-related depression in ventilatory drive (reduction in minute ventilation and increase in partial pressure of end tidal carbon dioxide [PETCO2]) in the healthy volunteers. PETCO2 levels were higher and remained elevated longer in surgical patients than in volunteers given the same 4 mg dose. An infusion of naloxone (5 mg/kg/hour) was also found to prevent respiratory depression in the volunteers.
6.3 Optimal Intrathecal and Epidural Morphine Dose Recommendations in the Surgical Setting
Dose-response studies show that neuraxial morphine appears to have an analgesic efficacy ceiling. The optimal single-shot intrathecal dose appears to be 0.0750.15 mg and the ideal singleshot epidural morphine dose is 2.53.75 mg. Analgesic efficacy studies have not been adequately powered to show differences in the incidence of clinically significant respiratory depression. However, opioid-related adverse effects, particularly pruritus, have been found to be dose-related in a number of studies. 7. Drugs to Minimize Opioid-Related Respiratory Depression Opioid antagonists such as naloxone are available clinically to treat opioid-induced respiratory depression.[108] However, their use may
lead to a loss in analgesia resulting in difficult pain management.[109] Moreover, the potential for re-narcotization exists due to the relatively short elimination half-life of naloxone. A number of adverse effects secondary to reversal of analgesia and release of catecholamines by a central mechanism have been described following the use of opioid antagonists such as naloxone. These adverse effects include pain, psychological stimulation, and sympathomimetic responses including pulmonary oedema in severe circumstances.[110] A continuous naloxone infusion of 34 mg/kg/hour for up to 10 hours has been recommended by some to avoid such adverse effects,[111] whereas others recommend naloxone infusions with intermittent supplemental dose titration with repeated small boluses of 0.8 mg/kg until adequate reversal of respiratory depression is achieved.[112] There is much interest in developing therapeutic interventions that reverse respiratory depression secondary to opioids whilst preserving their analgesic effects. Researchers have recently focused on using non-opioid drugs such as serotonin receptor agonists, ampakines (a-amino3-hydroxy-5-methyl-4-isoxazole-propionic acid [AMPA] receptor modulators) and minocycline. A number of studies examining these newer drugs have proven effective in animal models;[113,114] however, few have thus far shown to be clinically beneficial. Glutamate-mediated neurotransmission via AMPA receptors at the preBotzinger complex is crucial part of the generation of rhythmic respiratory pattern.[115-117] In 2010, Oertel et al.[118] studied ampakine CX717 in 16 healthy male volunteers in whom intravenous alfentanil at a target concentration of 100 ng/mL was used to induce respiratory depression. A decrease in respiratory rate was noted to be 3 33% in those receiving a 1.5 g oral dose of CX717 prior to the alfentanil compared with 26 28% in the placebo group receiving no ampakine. Ventilator response to hypercapnic challenge and blood oxygenation were also shown to be less significantly affected with CX717 compared with the placebo group. Importantly, the authors observed that the analgesic effects of alfentanil were unchanged by the CX717. The mechanism of action is thought to be an AMPA receptor neuronal excitation by
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the CX717, which counteracts the depression caused by the m-opioid receptors at the preBotzinger complex.[119] Although early in its de velopment, there is considerable potential for the use of this drug in patients receiving neuraxial morphine. Repinotan is a selective serotonin (5HT)1A receptor agonist, which has been investigated in humans for its neuroprotective effects following stroke[120] and traumatic brain injury.[121] Guenther and colleagues[122] demonstrated spontaneous breathing in anaesthetized rats following morphine-induced respiratory depression. The doseresponse curve of spontaneous breathing following morphine-induced ventilatory depression appears to be bell shaped after 5HT1A receptor stimulation, which suggests diminished stimulatory effects at higher concentrations.[123] The effects on opioid-induced respiratory depression and nociception are yet to be established in humans. Microglial inhibitors have shown potential to enhance the analgesic efficacy of morphine. Minocycline, a tetracycline derivative and microglial inhibitor,[124] improved analgesia and reduced opioid-induced respiratory depression in rats.[114] These findings may stimulate future research of this drug in a clinical setting. Sodium/ proton exchanger type 3 (NHE3) inhibitors that act centrally on respiratory pathways are another class of drugs that warrant further study.[125,126] 8. Conclusion Neuraxial morphine has contributed significantly to improve analgesia in many surgical settings. The analgesic benefits related to neuraxial morphine administration far outweigh the risks associated with the rare incidence of respiratory depression. In addition, the risk of respiratory depression following neuraxial morphine is not greater than that following systemic morphine administration.[66,89] Neuraxial morphine appears to have an analgesic efficacy ceiling and utilizing larger doses may increase adverse effects without necessarily improving analgesia. The optimal intrathecal dose appears to be 0.075 0.15 mg and the ideal epidural morphine dose is 2.53.75 mg. There are a number of novel non 2011 Adis Data Information BV. All rights reserved.
opioid drugs such as serotonin receptor agonists, ampakines and minocycline being developed that may reduce the risk of opioid-induced respiratory depression in the future. Acknowledgements
No sources of funding were used in the preparation of this review. Brendan Carvalho reports receiving funding from EKR Therapeutics as principal investigator for study conduct (DepoDur), and Epimed International, Inc. for research efforts. Drs Sultan and Gutierrez report no conflicts of interest that are directly relevant to the content of this review.
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Correspondence: Associate Professor Brendan Carvalho, MBBCh, FRCA, 300 Pasteur Dr, H3580 MC 5640, Stanford, CA 94305, USA. E-mail: bcarvalho@stanford.edu
Drugs 2011; 71 (14)
REVIEW ARTICLE
Drugs 2011; 71 (14): 1821-1837 0012-6667/11/0014-1821/$55.55/0
Biomarkers of Therapeutic Response in Patients with Chronic Obstructive Pulmonary Disease

A Critical Review of the Literature
Ho Il Yoon1,2 and Don D. Sin1,3
1 UBC James Hogg Research Center, The Providence Heart and Lung Institute, St. Pauls Hospital, Vancouver, BC, Canada 2 Department of Internal Medicine and Lung Institute, Division of Respiratory and Critical Care Medicine, Seoul National University Bundang Hospital, Bundang, Korea 3 Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Characteristics of Ideal Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1 Phenotypes of Chronic Obstructive Pulmonary Disease (COPD) . . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Other Challenges of Finding Suitable Biomarkers in COPD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Sources of Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Sputum Neutrophils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Other Sputum Indices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Fraction of Exhaled Nitric Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Other Exhaled Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Desmosine/Isodesmosine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Proline-Glycine-Proline (PGP), N-a-PGP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Leukotriene A4 Hydrolase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Markers of Systemic Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1 C-Reactive Protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2 Fibrinogen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3 Interleukin-6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Lung Predominant Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1 Surfactant Protein D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2 Clara Cell Secretory Protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.3 Pulmonary and Activation-Regulated Chemokine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Multiple Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Molecular Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1821 1822 1823 1824 1824 1825 1826 1826 1827 1827 1828 1828 1829 1830 1830 1830 1831 1831 1832 1832 1832 1832 1832
Abstract
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality across the world. Unfortunately, none of the current therapies, except for smoking cessation and supplemental domiciliary oxygen
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for hypoxaemic patients, can modify its natural course or alter survival. The pipeline for new compounds is not very promising owing to repeated failures, and many large pharmaceutical companies have abandoned COPD drug discovery altogether. One major barrier to new drug discovery is the lack of modifiable biomarkers that can be used as surrogates of clinical outcomes such as exacerbation and mortality. The only accepted marker in COPD is forced expiratory volume in 1 second (FEV1). However, by definition, COPD is a non-reversible or poorly reversible condition with respect to FEV1. Thus, very few drugs except for bronchodilators have been able to address this endpoint. Of many candidate molecules, sputum neutrophil counts, exhaled corrected alveolar nitric oxide and proline-glycine-proline (PGP) and N-aPGP, which are breakdown products of collagen, are promising lung-based biomarkers. However, their clinical utility has not been validated in large clinical trials. Promising blood biomarkers include surfactant protein D, and pulmonary- and activation-regulated chemokine (PARC/CCL-18). However, the clinical data have been inconsistent. Non-specific inflammatory biomarkers such as C-reactive protein and interleukin-6 lack specificity for COPD and thus are of limited clinical usefulness.
Chronic obstructive pulmonary disease (COPD) is a major health burden across the world. Globally, more than 300 million people have COPD[1] and nearly 3 million die each year from this disease.[2] COPD mortality continues to climb at an alarming rate, such that by 2030, nearly 9 million people will die annually from COPD.[3] The economic burden of COPD is also enormous. In the US alone, COPD accounted for $US29.5 billion in direct and $US20.4 billion in indirect costs in 2004.[4] Regrettably, the pipeline for new drugs for COPD is relatively dry compared with other major causes of mortality such as HIV/AIDS, cancer and diabetes mellitus.[5] One major barrier to drug discovery in COPD is the paucity of well accepted and well validated biomarkers. Currently, the only marker that is widely accepted by regulatory agencies for new drug approval in COPD is forced expiratory volume in 1 second (FEV1), which is a robust measure of lung function. However, FEV1, does not take into account the heterogeneity of the underlying pathogenic processes that lead to disease and is often difficult to modify. The discovery of a validated, reliable, robust and reproducible blood biomarker would provide a major boost to the development of novel compounds because it would allow investigators (and companies) to demonstrate the therapeutic
promise of a drug in small (usually phase II) trials before proceeding to much more expensive and logistically difficult phase III trials. Without such data, pharmaceutical companies are hesitant to invest millions of dollars on large phase III studies to bring compounds to market. For this reason, some international companies have recently abandoned COPD drug development altogether, while many others have scaled back their efforts significantly. The purpose of this article is to review potential biomarkers of COPD, especially those that could be used in predicting treatment responses. 1. Characteristics of Ideal Biomarkers The National Institutes of Health defines biomarker as a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.[6] In practical terms, an ideal biomarker must possess several important properties (table I). First, it must associate closely and consistently with a health outcome of interest. CD4+ lymphocyte count in HIV/AIDS is an example of a blood-based biomarker that fulfils this criterion, as a rapid decline in CD4+ lymphocyte count is associated with increased risk of opportunistic
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Table I. Characteristics of an ideal biomarker in chronic obstructive pulmonary disease (COPD) The biomarker must associate closely and consistently with a health outcome of interest in COPD such as rate of decline in lung function over time, exacerbations or mortality The biomarker should have a biologically plausible role in the pathogenesis of COPD The biomarker should be modifiable with interventions that are known to improve health outcomes in COPD
infections, morbidity and mortality in HIV/ AIDS.[7] Second, an ideal biomarker should have a biologically plausible and salient role in the pathogenesis of the disease. Serum cholesterol is an example of a blood-based biomarker that fulfils this criterion in cardiovascular disease, as lipid homeostasis is an important determinant of atherosclerostic plaques. Third, an ideal biomarker should be modifiable with interventions that unequivocally change health outcomes for that disease. An example of such a biomarker is blood glucose in diabetes. By reducing fasting blood glucose to normal levels, oral and systemic insulin sensitizers can improve morbidity and mortality of patients with diabetes. The US FDA indicates that for the moment with the exception of lung function tests, there are no well-validated biomarkers or surrogate endpoints that can be used to establish efficacy of a drug for COPD.[8] Accordingly, therapeutic trials in COPD have largely relied on FEV1 as the primary endpoint. FEV1 is relatively easy to obtain, highly reproducible and tracks health outcomes in COPD. However, FEV1 is not an ideal surrogate for short-term drug trials because it (i) does not provide information regarding disease activity or the underlying pathological process; (ii) cannot separate the various phenotypes of COPD; (iii) is not specific for COPD as it is modified by common co-morbidities such as chronic infections, heart failure or neuromuscular diseases,[9,10] and lung conditions such as asthma and pulmonary fibrosis; and, most importantly, (iv) is relatively unresponsive to known therapies that prolong survival (e.g. supplemental oxygen) or other clinical outcomes in COPD.[11-13] One major barrier towards finding surrogate biomarkers is that COPD is not a single disease
entity. It is a disease with multiple phenotypes, with each phenotype likely representing distinct mechanisms and pathophysiologies.[14] Indeed, Rennard and Vestbo[15] have recently argued that COPD should be considered as an orphan disease because it is not one disease but rather a collection of multiple different small COPDs. Thus, it is highly likely that multiple (rather than just one) biomarkers will be required to characterize the pathogenic factors in COPD and its various phenotypes and their natural history over time.
1.1 Phenotypes of Chronic Obstructive Pulmonary Disease (COPD)
COPD is a complex disease with multiple phenotypes.[14] Morphologically, there are at least two striking pathological features that are commonly observed in COPD lungs: small airways disease and emphysema.[16] It is now well established that all smokers develop inflammation in the small airways,[17] but, interestingly, only about 1520% of smokers go on to develop significant airflow limitation.[18] The small airways of COPD patients are characterized by accumulation of mucus in the lumen (i.e. mucus plugging), peribronchiolar fibrosis, development of lymphoid follicles in the wall and the presence of inflammatory cells (both innate and adaptive immune cells).[16] Emphysema is observed in lung tissue beyond the terminal bronchioles and is characterized by destruction and dilation of respiratory bronchioles and acinar units. With a1-antitrypsin deficiency, the emphysematous process is usually panacinar and predominant in the lower lung zones; whereas with the conventional tobacco-related emphysema, the destructive process is confined to primary (or secondary) lobules (i.e. centrilobular) and is predominantly located in the upper lung zones.[16] With the recent advent of macro-imaging techniques such as computed tomography (CT), it is now possible to visualize these pathological processes non-invasively.[19] It is hotly debated whether or not the pathogenic processes in the small airways are the same as those in the parenchyma. Recent data suggest that they may be quite different.[20] There may also be other distinct phenotypes
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of COPD. For instance, some patients with COPD experience frequent and recurrent exacerbations, requiring oral corticosteroid or antimicrobial therapy and hospitalization (i.e. frequent exacerbator phenotype).[21] Furthermore, some COPD patients demonstrate bronchodilator reversibility, bronchial hyper-responsiveness or both, while others do not.[22,23] Thus, it is plausible that each of these phenotypes may be associated with its own unique set of biomarkers.
1.2 Other Challenges of Finding Suitable Biomarkers in COPD
factor (TNF)-a have been commonly assessed as possible biomarkers of smoking[25,26] as well as of COPD.[12] 2. Sources of Biomarkers Biomarkers can originate from any organ. However, because COPD is predominantly a lung disease, the airways are the most logical source for identifying novel biomarkers in COPD. There are three major sources of airway samples. They include sputum (spontaneous or induced), exhaled gases or condensates, or bronchial washes or brushes. The latter source requires bronchoscopy, which is invasive. Thus, repeated measurements are usually not feasible. Furthermore, bronchial sampling is limited to one or two airways, which may result in sampling errors because the human lung contains more than 40 000 terminal bronchioles.[16] For these and other reasons, bronchoscopic samples have not been used for biomarker discovery in COPD and will not be discussed any further in this paper. Both spontaneous and induced sputum and exhaled gases and condensates also have methodological challenges that limit their utility as a source of biomarker discovery. For example, induced sputum is hard to process and may contain contaminants such as saliva that makes it difficult to relate sputum findings to the pathophysiological processes that are occurring in the lungs.[27] Exhaled gases and, more recently, condensates have been used to identify novel biomarkers in COPD. However, the data to date have been variable and inconsistent, owing to lack of standardization of methods and heterogeneity in the techniques employed for sample collection and analysis,[28] and the relatively low abundance of most proteins (often below the limits of detection) in these samples.[29] Nevertheless, these sources are commonly used for biomarker discovery in COPD because they are readily accessible and non-invasive. In the future, it is essential that biomarkers from these sources are validated within and across different laboratories and platforms to ensure their reproducibility, the robustness of their signals and clinical relevance in the targeted COPD populations.[30]
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In the Western world, cigarette smoking is the single most important risk factor for COPD and many patients diagnosed with COPD are still smoking at the time of assessment.[24] Thus, the effects of smoking may confound or obfuscate biomarker discovery in COPD. For clinical and research purposes, separating (or subtracting) out the effects of cigarette smoking from those of COPD are essential. In practice, however, this is difficult to achieve. For example, biomarkers related to oxidant-antioxidant stress pathways, which are variably perturbed in COPD, are also modified by cigarette smoking. Chronic smoking increases the oxidative burden in both airways (as assessed by induced sputum) and in the systemic circulation (as assessed by plasma). Biomarkers of oxidative stress include (i) direct measurements of oxidative burden using release assays of reactive oxygen species for circulating phagocytes, release assays of superoxides from circulating neutrophils, and intraplatelet peroxynitrite activity assays; and (ii) indirect measurements of oxidative stress using expression assays of oxidized or nitrated proteins (e.g. oxidized lipoproteins), lipid peroxidation products (e.g. isoprostanes) and antioxidants (e.g. reduced glutathiones). Similarly, both COPD and chronic smoking induce a state of low-grade systemic and lung inflammation. In blood, inflammatory cells such as circulating leukocyte count or platelets and mediators such as C-reactive protein (CRP), fibrinogen or interleukin (IL)-6 have been commonly measured, while, in the sputum, inflammatory cells (e.g. neutrophils) and mediators such as IL-6, IL-8 and tumour necrosis
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3. Sputum Neutrophils By far, induced sputum has been the most popular source of biomarker discovery in COPD. Sputum contains a mixture of mucins (approximately 24% of the total weight), salts, tissue plasma, lipids and inflammatory cells from tissue and airway lumen, microbial products, cellular debris and inhaled particles from the environment.[27] The predominant mucins in sputum are MUC5B and MUC5AC.[27] Induced sputum is an attractive source of biomarker discovery because it is relatively non-invasive to obtain, even in subjects who do not spontaneously expectorate, and may reflect the inflammatory process in the airways. However, there are several challenges in identifying possible biomarkers in sputum. These include (i) the use of liquefaction agents such as DTT (dithiothreitol) or NAC (N-acetylcysteine), which may disturb or interfere with protein measurements in sputum; (ii) the lack of consistent markers that can be used to normalize sputum data, making it difficult to compare results across subjects and across studies; (iii) contamination of sputum by saliva, which may obscure biomarkers in sputum samples (largely by dilution); and (iv) lack of standardization in the collection and processing of samples and in data analysis. Furthermore, the source of the induced sputum is likely the large (central) airways and not the small peripheral airways, which are thought to be the major site of disease in COPD.[16] The use of spontaneous sputum has similar limitations but may be better tolerated by patients, which makes it possible to collect sequential samples, thereby increasing the accuracy of the measurements.[31] Notwithstanding these limitations, sputum has been used for biomarker discovery because it can be procured non-invasively, and some components of sputum may reflect the active inflammatory process in the airways of COPD patients. One such biomarker is the neutrophil count in induced sputum. It is an attractive biomarker in COPD because neutrophils are thought to play an important role in the pathogenesis of COPD,[32,33] secreting various cytokines that provoke and perpetuate lung inflammation.[34,35] Furthermore, neutrophils are easily measurable in the sputum
of COPD patients.[36] With smoking and with COPD progression, the sputum contains increasing percentages of neutrophils.[37] Interestingly, once COPD is firmly established, neutrophil count remains elevated even following smoking cessation.[38] Most importantly, elevated expression of sputum neutrophils has been associated with rapid decline in FEV1, highlighting the importance of neutrophils in COPD pathogenesis.[39] It is important to note that the relationship between the neutrophil count and percent neutrophils is exponential and absolute count may therefore be more relevant. Neutrophil counts in sputum have also been used as a biomarker to evaluate well established COPD drugs. For instance, in the study by Barnes et al.,[40] sputum neutrophil count was used as a co-primary endpoint to evaluate the possible efficacy of fluticasone/salmeterol combination in the treatment of COPD. Over 3 months, they did not find a significant change in sputum neutrophil count between fluticasone/salmeterol combination and placebo.[40] This was surprising as fluticasone/salmeterol combination has been shown to reduce the rate of COPD progression (albeit marginally) in patients with established COPD,[41] which suggests that the study may have been underpowered.[31] Similarly, Lapperre et al.[42] evaluated the effects of fluticasone alone and in combination with salmeterol on a variety of different outcomes included sputum neutrophil count. They showed that, at 30 months of therapy, the group that received fluticasone had significantly lower sputum neutrophil count than did the placebo group. On the other hand, salmeterol by itself had no significant effect on sputum neutrophilia.[42] These data are consistent with a meta-analysis published in 2005, showing that inhaled corticosteroid therapy for at least 6 weeks results in a significant reduction in sputum neutrophil count in patients with stable COPD.[43] Together, these studies validate the concept of using sputum neutrophilia as a biomarker to evaluate neutrophilic airway inflammation in patients with COPD. Recently, several investigators have applied this biomarker to evaluate emerging (new) therapies in COPD. For instance, He and colleagues[44]
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used sputum neutrophil count to assess the possible beneficial effects of erythromycin on airway inflammation. In this randomized controlled trial, they found that erythromycin (at 125 mg three times per day) significantly reduced sputum neutrophilia by 3 months and, interestingly, also reduced the risk of exacerbations, suggesting their anti-inflammatory and/or antibacterial effects.[44] Ford and colleagues[45] used sputum neutrophils to assess the possible benefits of low-dose theophylline in the management of COPD patients. Thirty patients with COPD were treated with placebo theophylline capsules plus either inhaled fluticasone propionate (500 mg twice daily) or inhaled placebo for 4 weeks in a double-dummy, randomized, double-blind, parallel study. Then, following a 2-week washout period, patients were given active theophylline. However, contrary to expectations, they found that combination treatment with fluticasone and theophylline did not reduce total sputum neutrophils. However, in another study, 8 weeks of low-dose theophylline therapy was associated with reduced sputum neutrophil count.[46] Sputum neutrophil count has also been used as a primary endpoint in clinical studies evaluating promising but not yet approved COPD drugs. For example, Gronke et al.[47] used sputum neutrophils in a study of a leukotriene B4 receptor antagonist, which in vitro and in animal studies had decreased neutrophil recruitment to the lungs. Unfortunately the study failed to show a difference compared with placebo among patients with COPD. Although neutrophil counts in sputum have been widely used to assess possible therapeutic benefits of drugs for COPD, it has not been fully validated as a biomarker in COPD because sputum neutrophil measurements are only weakly associated with FEV1 or with health status.[48] There have been no large-scale studies that have demonstrated its utility in predicting important health outcomes in COPD such as exacerbation or mortality,[48] though sputum neutrophilia has been associated with rapid decline in lung function.[39,49] Furthermore, despite the implication of neutrophils in the pathogenesis of emphysema, sputum neutrophils do not appear to correlate with the extent of emphysema in COPD patients,[48]
which may be expected given that sputum neutrophil counts mainly reflect conditions in the large airways and not lung parenchyma.
3.1 Other Sputum Indices
There are other cellular elements in induced sputum that have been used as possible biomarkers in COPD. These include total cell count and sputum eosinophil and lymphocyte counts.[43,50] The long-term use of inhaled corticosteroids has been shown to reduce total cell and lymphocyte counts, and eosinophilia in induced sputum.[43] However, as with sputum neutrophilia, none of these measurements has been consistently shown to predict important health outcomes in COPD. As such, their usefulness as biomarkers in COPD remains uncertain. Some investigators have used supernatants from induced sputum to measure levels of inflammatory and oxidative molecules, which have been implicated in COPD pathogenesis. These include IL-8, IL-6, myeloperoxidase and matrix metalloproteinase (MMP)-9. However, as with cellular components of induced sputum, the relationship of these inflammatory and oxidative stress molecules in sputum to health outcomes such as COPD progression and mortality has not been well established. Furthermore, the use of liquefaction agents, as previously described, may modify protein expression in sputum, which reduces the reliability of these measurements. 4. Fraction of Exhaled Nitric Oxide Given these limitations of induced sputum, there has been growing enthusiasm for developing exhaled gases as biomarkers in COPD.[51] Of these, the best studied has been fraction of exhaled nitric oxide (FENO).[52] In general, FENO shows good specificity as a diagnostic marker in asthma,[53] and a useful biomarker in assessing severity and control[54] and in evaluating treatment responses, especially to inhaled corticosteroids.[55,56] The data in COPD are more scarce and generally less impressive. Levels of FENO are usually normal or only modestly elevated in COPD, except during exacerbations,[57-59] and
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have not been demonstrated to predict important health outcomes in COPD. Thus, FENO is not a promising biomarker in COPD. However, with recent innovations in FENO measurements, there is renewed optimism for using FENO as a biomarker in COPD. One such modification is multiple exhalation flow technique (MEFT), which allows separate measurement of nitric oxide derived from small airways and alveoli (called corrected alveolar nitric oxide [CALV]) from those of larger airways. The subdivision of FENO into small and large airway compartments is very attractive in COPD as COPD is thought to involve largely the small airways and lung parenchyma. A recent study showed that CALV was elevated in COPD patients but, disappointingly, it was not associated with COPD severity or smoking status of the patients.[60] Furthermore, CALV was not affected by inhaled corticosteroid treatment.[60] Additional work will be needed to understand the value, if any, that FENO has in COPD.
4.1 Other Exhaled Biomarkers
5. Desmosine/Isodesmosine While the pathogenesis of COPD is complex and poorly understood, there is some agreement that excess breakdown and turnover of extracellular matrix in the lungs is likely to be very important for the emphysema phenotype of COPD.[64] The extracellular matrix in the lungs acts as a threedimensional scaffold, providing strength and support for the alveolar units. The extracellular matrix consists mostly of collagens (type 1 and 3), which provide tensile strength, elastin, which confers flexibility to the lung tissues, and glycosaminoglycans.[65] In healthy lungs, the collagen fibres tightly wrap around elastic bands in an orderly manner. However, in COPD, this structure is disrupted, leading to a random distribution of collagen and elastic fibres.[66] Furthermore, with COPD disease progression, the ratio of collagen to elastin surrounding the alveolar units becomes distorted, owing largely to a severe loss in elastin.[66] The functional consequence is a loss in elastic recoil pressure and floppy airways. Consistent with these observations, deletion of the elastin gene in mice results in emphysematous changes in the lungs, and mutations in the elastin gene in humans (e.g. cutix laxa) have been associated with severe, early-onset emphysema.[67,68] Based on these and other findings, there has been some interest in using markers of elastin turnover as possible biomarkers in COPD. Of these, the best studied have been desmosine and isodesmosine.[69] Because these proteins are present only in mature elastin, it is thought that their expression in blood, urine or sputum mostly reflects elastin degradation.[70] Consistent with this theory, injection of pancreatic elastase into animals leads to an acute loss of elastin and emphysematous changes in the lungs. Degradation of elastic fibres in the lungs in turn can be detected in the urine in the form of desmosine.[71] These changes have also been noted in mice exposed to acute cigarette smoke.[72] Interestingly, mice that are deficient in TNFa or its receptors are protected against elastic fibre degradation and their urinary desmosine excretion is relatively normal in the presence of cigarette smoke. These mice are also relatively protected against smoking-induced emphysematous changes in the lungs.[72,73]
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There are a number of other potential biomarkers from exhaled breath condensates (EBC). EBC pH is an acidification marker, which may be lower in smokers and in patients with COPD compared with control non-smokers. However, there are no convincing data that EBC pH can be used to separate COPD from smokers without COPD, or to relate to the severity of underlying disease, or to gauge responsiveness to medications such as inhaled corticosteroids.[61] Concentrations of leukotriene B4 and 8-isoprostane are biomarkers of inflammation and oxidative stress, respectively. They have been shown to be over-expressed during COPD exacerbations and to decrease with antibacterial treatment.[62] However, owing to large variability in the measurements, their exact roles as biomarkers in COPD have not been fully elucidated. Another promising oxidative stress biomarker is hydrogen peroxide, which may be elevated in COPD. However, to date, the measurements have not been standardized and its role in the diagnosis and follow-up of patients with COPD remains unknown.[63]
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Human data, recently reviewed by Luisetti et al.,[69] have been more mixed and less optimistic, with some studies showing a significant relationship of urinary (or plasma) desmosine/ isodesmosine to COPD, and others failing to demonstrate this relationship. The heterogeneity in the human data reflects in part major differences in the modalities of measurement (e.g. immunoassays vs high-performance liquid chromatography), the biological source of assays (e.g. urine vs plasma), and the underlying clinical characteristics of the patients across the studies. Furthermore, most of the human studies to date have been relatively small in scope and did not consider the large variations in the phenotypes of the patients. Notwithstanding these limitations, the totality of data suggests that desmosine or isodesmosine is elevated in the urine of COPD patients.[74-76] Very few studies have evaluated these markers in therapeutic trials, demonstrating mixed results. For instance, a study by Stone and colleagues[77] showed that short-term treatment with a1-antitrypsin replacement therapy led to significant reductions in urinary excretion of desmosine in two patients with severe COPD secondary to a1-antitrypsin deficiency. However, in another study, the use of a1-antitrypsin replacement therapy did not modify urinary excretion of desmosine in these patients.[78] Ma and colleagues[79] evaluated plasma, urine and sputum expression of desmosine and isodesmosine related to the use of tiotropium, which is a long-acting muscarinic bronchodilator, and found that after 2 months of therapy, their expression decreased in COPD patients. However, all of these studies contained very small sample sizes, which reduces the reliability of these reports. Thus, the possible role of desmosine or isodesmosine as a biomarker in COPD remains obscure. 6. Proline-Glycine-Proline (PGP), N-a-PGP It is increasingly recognized that breakdown products of collagen in the lungs may be proinflammatory and exacerbate the inflammatory process in COPD, creating a vicious cycle. One such molecule produced by collagen metabolism
is proline-glycine-proline (PGP). PGP shares structural homology with alpha chemokines and, similarly to these chemokines, induces the recruitment of neutrophils into the lungs by stimulating chemokine (C-X-C motif) receptor (CXCR)-1 and, most importantly, CXCR-2,[80] which in turn augment the inflammatory cascade in the COPD lungs.[81-83] In mouse models, instillation of Na-PGP into the lungs of mice causes a marked recruitment of neutrophils to the airways and chronic airway exposure causes COPD-like pathology in the lungs characterized by alveolar enlargement and right ventricular hypertrophy.[80] Blockage of PGP using monoclonal antibody, on the other hand, suppresses both the in vitro chemotactic activity and in vivo recruitment of inflammatory cells into the lungs related to cigarette smoke.[80,84] Additionally, treatment of these mice with a complementary peptide, L-argininethreonine-arginine (RTR), which binds to PGP sequences, inhibits neutrophil infiltration and prevents development of pulmonary emphysema.[85] A brief summary of the PGP pathway in the lungs is provided in figure 1. Could PGP or N-a-PGP be a useful biomarker in COPD? On the affirmative side, PGP is detectable in bronchoalveolar lavage (BAL) samples of patients with COPD but not in control individuals.[80] Similarly, these markers are detectable in sputum samples of COPD patients but not in those of control subjects.[86] In serum, PGP levels are also significantly higher in COPD patients than in controls.[86] Interestingly, patients with cystic fibrosis also have increased PGP expression in sputum as in COPD, likely related to the intense neutrophilic inflammation observed in these conditions.[81] However, to date, neither PGP nor N-a-PGP has been associated with important health outcomes in COPD and they have not been used in therapeutic trials. Thus, their possible role in evaluating new products in COPD is uncertain. 7. Leukotriene A4 Hydrolase Leukotriene A4 hydrolase (LTA4H) is an enzyme released from neutrophils and epithelial cells that generates leukotriene A4 (LTA4) via its
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PGP degradation PGP N--PGP LTB4 LTA4 hydrolation Hydrolase activity LTA4H Peptidase activity
Collagen
Neutrophil recruitment
MMP
Pulmonary neutrophilic inflammation COPD, cystic fibrosis

Fig. 1. The possible role of proline-glycine-proline (PGP) and its acetylated form (N-a-PGP) and leukotriene A4 (LTA4) hydrolase (LTA4H) in lung inflammation. As a result of neutrophil recruitment and activation by environmental triggers such as bacterial infections or cigarette smoke, matrix metalloproteinase (MMP) is released, which in turn degrades extracellular matrix proteins such as collagen. PGP and N-a-PGP are generated in this process. These molecules are important chemoattractants for neutrophils and recruit additional neutrophils into the lungs, thus creating a vicious cycle. LTA4H catalyses LTA4 into leukotriene B4 (LTB4), which is another potent chemoattractant for neutrophils. LTA4H also has a peptidase activity that degrades PGP or N-a-PGP into non-active metabolites, putting the brakes on the inflammatory cascade. Inhibition of PGP and N-aPGP could thus be an attractive target for managing neutrophilic inflammation in chronic obstructive pulmonary disease (COPD). This could be done by directly inhibiting tripeptides via an antibody or their complementary peptide, or by blocking their receptor (CXCR2). Another possible therapeutic target would be LTA4H.
modern techniques, high throughput (and relatively inexpensive) assays can be developed for blood-based protein measurements. In COPD, there are no such blood biomarkers currently approved for use. Moreover, because blood samples are usually obtained in peripheral veins (e.g. antecubital fossa) and not from pulmonary veins or arteries, there is concern that blood biomarkers in COPD may not adequately reflect the disease activity (or severity) in the lungs, which are the primary site of disease in COPD. Nevertheless, there is increasing evidence that the inflammatory processes in the lungs spill over into the systemic circulation, which may result in an inflammatory signature in blood related to COPD.[88] However, with the current methodologies, it may be difficult to detect the signal in peripheral blood.[89] A conceptual diagram of this process is shown in figure 2 and a list of candidate systemic biomarkers is shown in table II.
Smoke; LPS; PM10 Alveolae
hydrolase activity in the cytosol. LTA4 is a potent chemoattractant for neutrophils. LTA4H also has a peptidase activity. In the extracellular milieu, it degrades PGP or N-a-PGP, which, in turn, down-regulates neutrophilic inflammation. Interestingly, cigarette smoking inhibits the peptidase but not the hydrolase activity of LTA4H, thus up-regulating neutrophilic inflammation.[87] The balance between these two enzymatic activities of LTA4H may be important in determining the extent and duration of neutrophilic inflammation in the lungs of COPD patients, though the studies validating this notion are currently lacking. 8. Markers of Systemic Inflammation Although biomarkers can be obtained from any organ, the most successful ones are from blood because blood is easy to obtain and its measurements can be standardized. Furthermore, with
MCP-1 IL-8, IL-6 SP-D CC-16

M
M Blood vessel
3 C D
PARC
Fig. 2. A schema of how lung inflammation could translate into possible blood biomarkers in chronic obstructive pulmonary disease (COPD) patients. Environmental insults such as cigarette smoke, bacterial lipopolysaccharides (LPS) or air pollution particles trigger the release of inflammatory cytokines from resident inflammatory cells such as alveolar macrophages (M), and structural cells such as bronchial epithelial cells. The cytokines act mostly locally to contain the insult but also systemically to induce the recruitment of additional inflammatory cells into the lungs. The most active cytokines in this process are thought to be tumour necrosis factor, interleukin (IL)-1b, IL-6 and IL-8. However, these are non-specific, early phase inflammatory cytokines and as such are of limited use as biomarkers in COPD. Proteins such as pulmonary and activation-regulated chemokine (PARC/CCL-18), surfactant protein D (SP-D) and Clara cell protein 16 (CC-16) are more specific for the lungs and are easily measurable in plasma. Thus, there is growing enthusiasm in developing these proteins as biomarkers in COPD. However, their pathogenic role, if any, in COPD is unknown. PM10 = particulate matter in ambient air pollution that is less than 10 microns in diameter; MCP-1 = monocyte chemotactin protein-1; MU = monocyte.
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Table II. Summary of serum/plasma biomarkers of chronic obstructive pulmonary disease (COPD) Biomarker CRP IL-6 Fibrinogen TNF receptor 1 Eotaxin 2 Serum amyloid A IL-1 SP-D CC-16 PARC/CCL-18 Lung function Yes[90] Yes[95] Yes
[95,98]
Exacerbation Yes[91] Yes[96] Yes

[99]
Mortality Yes[92,93] Not known Not known Not known Not known Not known Not known Not known Not known Yes
[107]
Modified by drug(s) Yes[94] Yes[97] Not known Not known Not known Yes[100] Not known Yes[102,104] Yes[105] Yes[107]
Not known Not known Not known Not known Yes[101] Not known Yes
[106]
Yes[91] Yes[91] Yes[100] Yes[91] Yes[102,103] Not known Yes

[91]
CC-16 = Clara cell secretory protein 16; CRP = C-reactive protein; IL = interleukin; PARC/CCL-18 = pulmonary and activation-regulated chemokine; SP-D = surfactant protein D; TNF = tumour necrosis factor.
8.1 C-Reactive Protein
It is now well accepted that lung inflammation is an important component in the pathogenesis of COPD and this inflammatory process carries over into the systemic circulation.[88] Accordingly, many groups of investigators are endeavouring to identify plasma proteins that are specific to the inflammatory process in COPD and relate these biomarkers to salient clinical health outcomes such as exacerbations and mortality. Of these, the best studied to date is CRP. CRP is a sensitive but not a specific marker of systemic inflammation and tissue damage. It has been extensively studied in patients with ischaemic heart disease and other cardiovascular diseases (CVD)[108,109] and has been shown to predict CVD morbidity and mortality. Importantly, CRP has also been shown to be a useful biomarker in guiding statin (HMG-CoA reductase inhibitor) therapy for patients who do not have raised serum cholesterol levels.[110] CRP may also be useful in COPD.[111] Serum levels of CRP are associated with health status of COPD patients[112] and with all-cause, cardiovascular and cancer-specific mortality.[92] Elevated levels are also associated with increased risk for hospitalization and mortality from COPD.[93] During acute exacerbations, CRP levels rise.[91] Oral corticosteroid therapy (e.g. prednisone at 30 mg/day for 2 weeks) reduces serum CRP levels.[94] However, serum CRP is relatively in 2011 Adis Data Information BV. All rights reserved.
sensitive to the effects of inhaled corticosteroids.[104,113] It remains uncertain whether COPD is a steroid-sensitive or steroid-resistant condition. Thus, the role of CRP as a biomarker for therapeutic drugs in COPD remains uncertain.
8.2 Fibrinogen
Fibrinogen is another widely used biomarker of systemic inflammation. Plasma fibrinogen levels strongly associate with coronary heart disease, stroke, other vascular mortality and nonvascular mortality.[114] Pertinent to lung disease, plasma fibrinogen levels are associated with reduced lung function and disease progression independent of smoking status.[98] They also predict future risk of moderate and severe exacerbations[115] and hospitalizations from COPD.[116] However, similar to CRP, plasma fibrinogen levels are not easily modifiable with medications[117,118] and as such are not very useful biomarkers to evaluate novel treatments for COPD.
8.3 Interleukin-6
The main up-stream regulator of CRP, fibrinogen and other acute phase proteins such as serum amyloid A is IL-6.[119] IL-6, along with other primary inflammatory cytokines such as TNFa and IL-1b, responds to an acute insult by orchestrating and unleashing a cocktail of inflammatory mediators from the liver and other organs
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to contain the insult and protect the body from harm.[120] In the lungs, IL-6 is synthesized predominantly by alveolar macrophages and bronchial epithelial cells and is released in response to environmental triggers such as cigarette smoke and air pollution particles.[121] IL-6 in turn stimulates the synthesis of certain chemokines (e.g. CXCL1) that recruit inflammatory cells including neutrophils into the lungs and limits the effects of the environmental trigger. The mechanism by which this occurs is obscure, but there are data suggesting that it may be mediated through a STAT3dependent pathway.[122] In certain circumstances, the IL-6 response can become dysregulated and spill into the systemic circulation, causing acute deleterious effects in the vascular system,[123] and contributing to cardiovascular dysfunction related to acute lung injury.[123] Given its properties, IL-6 has been investigated as a possible biomarker in COPD. COPD patients in general have higher serum IL-6 levels than those without COPD.[124,125] However, serum IL-6 as a biomarker is limited in that it is not lung specific and is widely expressed throughout the body. Thus, serum IL-6 levels are poorly responsive to COPD medications and as such IL-6 is not an ideal biomarker in COPD. 9. Lung Predominant Proteins To enhance the specificity of biomarkers, recent investigations have focused on proteins that are mostly synthesized in the lungs. These include surfactant proteins and Clara cell secretory protein-16 (CC-16).
9.1 Surfactant Protein D
Surfactant proteins are produced predominantly by type II pneumocytes. Together with phospholipids they form pulmonary surfactants which act to reduce surface tension of alveoli, preventing atelectasis. There are four kinds of surfactant proteins, A, B, C and D. Of these, surfactant protein D (SP-D) has been the most widely explored biomarker in COPD because, dissimilar to other surfactant proteins, it is hydrophilic and is well expressed in plasma.[126]
Although it has some minor role in regulating surface tension of alveoli, the main function of SP-D is to modulate innate immunity.[127,128] SP-D is a large, multimeric, calcium-dependent, collagenous glycoprotein that is part of the collectin family of carbohydrate-binding proteins.[129] SP-D is composed of three polypeptide chains of 43 kDa monomers, which aggregate to form a stable helical trimeric structure. Each trimeric structure contains four major domains: a cysteine-containing cross-linking domain, a carbohydrate recognition domain, a collagenous domain and a peptide linking domain.[130] The main collagens in the trimeric complex are hydroxylysine and hydroxylysyl glycosides. In most cases, the trimeric structures are further modified into a complex quaternary cruciate structure, consisting of four trimeric subunits that undergo disulfide cross-linking within their amino-terminal domain, which results in a dodecamer. Under oxidizing conditions (e.g. in the presence of cigarette smoke), cysteine residues in the N-terminus can become nitrosylated, leading to the disruption of the multimeric structure into smaller trimers or monomers,[131] which, unlike the dodecamers, are thought to be pro-inflammatory and are more likely to pass into the systemic circulation. SP-D translocates from the lung into systemic circulation, which is dependent on several factors including rate of synthesis and the permeability of the alveolar-capillary barrier (i.e. lung permeability).[128] With cigarette smoking, lung permeability increases. Thus, in smokers, the serum level of SP-D is elevated compared with non-smokers but the concentration in the bronchoalveolar lavage fluid is reduced.[132,133] Similarly, with COPD, lung permeability increases independent of cigarette smoking.[102] Thus, with COPD progression, lung expression of SP-D decreases but the ratio of plasma SP-D to BAL SP-D increases.[101] Importantly, treatment of COPD patients with inhaled corticosteroids with or without long-acting b-2 agonists or oral corticosteroids for 4 weeks significantly decreased measurable serum SP-D levels,[102] which in turn was associated with improved health status of these patients. Serum SP-D levels may also identify patients at high risk of recurrent exacerbations.[21,103] Together, these
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data suggest that SP-D is a promising modifiable biomarker in COPD.

9.2 Clara Cell Secretory Protein
Clara cell secretory protein-16 (CCSP, CC-16, CC-10, uteroglobin) is a member of the secretoglobin family of secreted disulfide-bridged dimeric proteins.[134] It is produced almost exclusively by non-ciliated Clara cells[135,136] and its main function is to protect the lungs against oxidative stress and carcinogenesis.[135] Serum levels of CC-16 become elevated after acute exposure to various environmental triggers such as cigarette smoke, chlorine and lipopolysacharides.[137] They can also rise after ozone exposure and can be suppressed by inhaled corticosteroids.[105] Interestingly, serum CC-16 levels are relatively low in obliterative bronchiolitis and asthma, and in healthy smokers.[138-140] In patients with COPD, serum CC-16 levels are lower than in smokers without COPD.[141,142] However, it is uncertain whether serum CC-16 levels are modifiable in COPD.
9.3 Pulmonary and Activation-Regulated Chemokine
realistic to ascertain a panel of biomarkers, rather than just one.[144] This approach is particularly appealing for protein or gene array experiments wherein hundreds or even thousands of different molecules and pathways can be investigated all at once.[106,148] Using this approach, Pinto-Plata et al.[106] identified a panel of 24 biomarkers (mostly proteins) that were significantly associated with lung function and the BODE (Body mass index, Obstruction, Dyspnoea, Exercise capacity) index of patients with COPD. However, using a similar protein platform, Hurst et al.[91] did not identify a panel of biomarkers that could be used clinically to diagnose and follow exacerbation episodes in patients with COPD. Thus, additional studies are warranted to better understand this technology and to generate a more promising panel of biomarkers in COPD. 11. Molecular Biomarkers There is a growing effort to find useful biomarkers using gene expression profiling. This approach has already been successful in some other fields of medicine.[149,150] There have been several publications in COPD that have used largely microarray technologies to identify possible candidate biomarkers in the lungs.[148,151,152] Although these studies have generated a long list of candidate biomarkers, there are significant methodological limitations that preclude their application in a clinical setting. These include lack of reproducibility, confounding effects of cigarette smoking and technical issues with microarrays (e.g. hybridization and batch effects). Future research will need to address these limitations and determine how (and if) high throughput wholeomic techniques can yield useful biomarkers in COPD. 12. Conclusion
Pulmonary and activation-regulated chemokine (PARC/CCL-18) is a protein that is mostly produced by monocytes, macrophages and dendritic cells in lungs.[143] Serum levels of PARC/ CCL-18 are elevated in acute coronary syndromes and idiopathic pulmonary fibrosis.[144-146] Serum PARC/CCL-18 levels are also significantly elevated in COPD and associated with the risk of cardiovascular hospitalization and mortality in mild to moderate disease and with total mortality in more advanced diseases.[107] Importantly, shortterm use of oral but not inhaled corticosteroids can down-regulate systemic expression of PARC/ CCL-18 levels in COPD.[107,147] 10. Multiple Biomarkers Although the main focus of previous investigations has been to find a small number of promising biomarkers (usually one or two), given the complexity of COPD pathogenesis and the multiplicity of different phenotypes, it may be more
To date, there is no universally accepted biomarker in COPD. However, with the assembly of large cohorts and infusion of capital from various sources including government agencies and industry, there is renewed hope of finding a modifiable biomarker that will be useful in the discovery of
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novel compounds to treat COPD. Since COPD is a heterogeneous disorder with multiple different (but related) phenotypes, it is essential that future endeavours in biomarker discovery consider these phenotypes. Although biomarkers can originate from any source, sputum and blood are the most readily available sources and thus are the most promising sites for large-scale biomarker discovery in COPD. However, a clearer understanding of the pathophysiological role of the putative biomarkers, their variability and, importantly, their relationship to disease progression is crucial. Acknowledgements
No sources of funding were used in the preparation of this review. Dr Sin has received honoraria for speaking engagements and grant funding from AstraZeneca and GlaxoSmithKline. Dr Yoon has no conflicts of interest to declare.
References
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97. Cosio BG, Iglesias A, Rios A, et al. Low-dose theophylline enhances the anti-inflammatory effects of steroids during exacerbations of COPD. Thorax 2009 May 1; 64 (5): 424-9 98. Dahl M, Tybjoerg-Hansen A, Vestbo J, et al. Elevated plasma fibrinogen associated with reduced pulmonary function and increased risk of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001 Sep 15; 164 (6): 1008-11 99. Wedzicha JA, Seemungal TA, MacCallum PK, et al. Acute exacerbations of chronic obstructive pulmonary disease are accompanied by elevations of plasma fibrinogen and serum IL-6 levels. Thromb Haemost 2000 Aug; 84 (2): 210-5 100. Bozinovski S, Hutchinson A, Thompson M, et al. Serum amyloid A is a biomarker of acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008 Feb 1; 177 (3): 269-78 101. Tkacova R, McWilliams A, Lam S, et al. Integrating lung and plasma expression of pneumo-proteins in developing biomarkers in COPD: a case study of surfactant protein D. Med Sci Monit 2010 Nov; 16 (11): CR540-4 102. Lomas DA, Silverman EK, Edwards LD, et al. Serum surfactant protein D is steroid sensitive and associated with exacerbations of COPD. Eur Respir J 2009 Jul; 34 (1): 95-102 103. Shakoori TA, Sin DD, Ghafoor F, et al. Serum surfactant protein D during acute exacerbations of chronic obstructive pulmonary disease. Dis Markers 2009; 27 (6): 287-94 104. Sin DD, Man SF, Marciniuk DD, et al. The effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008 Jun 1; 177 (11): 1207-14 105. Alexis NE, Lay JC, Haczku A, et al. Fluticasone propionate protects against ozone-induced airway inflammation and modified immune cell activation markers in healthy volunteers. Environ Health Perspect 2008 Jun; 116 (6): 799-805 106. Pinto-Plata V, Toso J, Lee K, et al. Profiling serum biomarkers in patients with COPD: associations with clinical parameters. Thorax 2007 Jul; 62 (7): 595-601 107. Sin DD, Miller B, Duvoix A, et al. Serum PARC/CCL-18 concentrations and health outcomes in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2011 May 1; 183 (9): 1187-92 108. Danesh J, Collins R, Appleby P, et al. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA 1998 May 13; 279 (18): 1477-82 109. Kaptoge S, Di Angelantonio E, Lowe G, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant metaanalysis. Lancet 2010 Jan 9; 375 (9709): 132-40 110. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008 Nov 20; 359 (21): 2195-207 111. Karadag F, Kirdar S, Karul AB, et al. The value of Creactive protein as a marker of systemic inflammation in stable chronic obstructive pulmonary disease. Eur J Intern Med 2008; 19 (2): 104-8
112. Garrod R, Marshall J, Barley E, et al. The relationship between inflammatory markers and disability in chronic obstructive pulmonary disease (COPD). Prim Care Respir J 2007; 16 (4): 236-40 113. Perng DW, Tao CW, Su KC, et al. Anti-inflammatory effects of salmeterol/fluticasone, tiotropium/fluticasone or tiotropium in COPD. Eur Respir J 2009 Apr; 33 (4): 778-84 114. Fibrinogen Studies Group. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality. JAMA 2005 Oct 12; 294 (14): 1799-809 115. Groenewegen KH, Postma DS, Hop WCJ, et al. Increased systemic inflammation is a risk factor for COPD exacerbations. Chest 2008 Feb 1; 133 (2): 350-7 116. Engstrom G, Segelstorm N, Ekberg-Aronsson M, et al. Plasma markers of inflammation and incidence of hospitalisations for COPD: results from a population-based cohort study. Thorax 2009 Mar; 64 (3): 211-5 117. Dentener MA, Creutzberg EC, Pennings HJ, et al. Effect of infliximab on local and systemic inflammation in chronic obstructive pulmonary disease: a pilot study. Respiration 2008; 76 (3): 275-82 118. Kaczmarek P, Sladek K, Skucha W, et al. The influence of simvastatin on selected inflammatory markers in patients with chronic obstructive pulmonary disease. Pol Arch Med Wewn 2010; 120 (1-2): 11-7 119. Weinhold B, Ruther U. Interleukin-6-dependent and -independent regulation of the human C-reactive protein gene. Biochem J 1997 Oct 15; 327 (Pt 2): 425-9 120. Kishimoto T. IL-6: from its discovery to clinical applications. Int Immunol 2010 May; 22 (5): 347-52 121. Ishii H, Hayashi S, Hogg JC, et al. Alveolar macrophageepithelial cell interaction following exposure to atmospheric particles induces the release of mediators involved in monocyte mobilization and recruitment. Respir Res 2005; 6: 87 122. Fielding CA, McLoughlin RM, McLeod L, et al. IL-6 regulates neutrophil trafficking during acute inflammation via STAT3. J Immunol 2008 Aug 1; 181 (3): 2189-95 123. Kido T, Tamagawa E, Bai N, et al. Particulate matter induces translocation of IL-6 from the lung to the systemic circulation. Am J Respir Cell Mol Biol 2011 Feb; 44 (2): 197-204 124. Thorleifsson SJ, Margretardottir OB, Gudmundsson G, et al. Chronic airflow obstruction and markers of systemic inflammation: results from the BOLD study in Iceland. Respir Med 2009 Oct; 103 (10): 1548-53 125. Walter RE, Wilk JB, Larson MG, et al. Systemic inflammation and COPD: the Framingham Heart Study. Chest 2008 Jan; 133 (1): 19-25 126. Cole FS. Surfactant protein B: unambiguously necessary for adult pulmonary function. Am J Physiol Lung Cell Mol Physiol 2003 Sep 1; 285 (3): L540-L2 127. Hartl D, Griese M. Surfactant protein D in human lung diseases. Eur J Clin Invest 2006 Jun; 36 (6): 423-35 128. Sin DD, Pahlavan PS, Man SFP. Surfactant protein D: a lung specific biomarker in COPD? Ther Adv Respir Dis 2008 Apr 1; 2 (2): 65-74 129. Kishore U, Greenhough TJ, Waters P, et al. Surfactant proteins SP-A and SP-D: structure, function and receptors. Mol Immunol 2006 Mar; 43 (9): 1293-315
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130. Crouch EC. Surfactant protein-D and pulmonary host defense. Respir Res 2000; 1 (2): 93-108 131. Guo CJ, Atochina-Vasserman EN, Abramova E, et al. S-nitrosylation of surfactant protein-D controls inflammatory function. PLoS Biol 2008 Nov 11; 6 (11): e266 132. More JM, Voelker DR, Silveira LJ, et al. Smoking reduces surfactant protein D and phospholipids in patients with and without chronic obstructive pulmonary disease. BMC Pulm Med 2010; 10: 53 133. Honda Y, Takahashi H, Kuroki Y, et al. Decreased contents of surfactant proteins A and D in BAL fluids of healthy smokers. Chest 1996 Apr 1; 109 (4): 1006-9 134. Umland TC, Swaminathan S, Singh G, et al. Structure of a human Clara cell phospholipid-binding protein-ligand complex at 1.9 A resolution. Nat Struct Biol 1994 Aug; 1 (8): 538-45 135. Broeckaert F, Bernard A. Clara cell secretory protein (CC16): characteristics and perspectives as lung peripheral biomarker. Clin Exp Allergy 2000 Apr; 30 (4): 469-75 136. Yoneda K. Ultrastructural localization of phospholipases in the Clara cell of the rat bronchiole. Am J Pathol 1978 Dec; 93 (3): 745-52 137. Lakind JS, Holgate ST, Ownby DR, et al. A critical review of the use of Clara cell secretory protein (CC16) as a biomarker of acute or chronic pulmonary effects. Biomarkers 2007; 12 (5): 445-67 138. Shijubo N, Itoh Y, Yamaguchi T, et al. Serum and BAL Clara cell 10 kDa protein (CC10) levels and CC10-positive bronchiolar cells are decreased in smokers. Eur Respir J 1997 May; 10 (5): 1108-14 139. Shijubo N, Itoh Y, Yamaguchi T, et al. Clara cell proteinpositive epithelial cells are reduced in small airways of asthmatics. Am J Respir Crit Care Med 1999 Sep; 160 (3): 930-3 140. Mattsson J, Remberger M, Andersson O, et al. Decreased serum levels of clara cell secretory protein (CC16) are associated with bronchiolitis obliterans and may permit early diagnosis in patients after allogeneic stem-cell transplantation. Transplantation 2005 May 27; 79 (10): 1411-6 141. Tsoumakidou M, Bouloukaki I, Thimaki K, et al. Innate immunity proteins in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Exp Lung Res 2010 Aug; 36 (6): 373-80 142. Lomas DA, Silverman EK, Edwards LD, et al. Evaluation of serum CC-16 as a biomarker for COPD in the ECLIPSE cohort. Thorax 2008 Dec; 63 (12): 1058-63
143. Gunther C, Bello-Fernandez C, Kopp T, et al. CCL18 Is Expressed in Atopic Dermatitis and Mediates Skin Homing of Human Memory T Cells. J Immunol 2005 Feb 1; 174 (3): 1723-8 144. Prasse A, Probst C, Bargagli E, et al. Serum CC-chemokine ligand 18 concentration predicts outcome in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009 Apr 15; 179 (8): 717-23 145. Prasse A, Pechkovsky DV, Toews GB, et al. CCL18 as an indicator of pulmonary fibrotic activity in idiopathic interstitial pneumonias and systemic sclerosis. Arthritis Rheum 2007 May; 56 (5): 1685-93 146. Kraaijeveld AO, de Jager SCA, de Jager WJ, et al. CC Chemokine ligand-5 (CCL5/RANTES) and CC chemokine ligand-18 (CCL18/PARC) are specific markers of refractory unstable angina pectoris and are transiently raised during severe ischemic symptoms. Circulation 2007 Oct 23; 116 (17): 1931-41 147. Man SF, Xuekui Z, Vessey R, et al. The effects of inhaled and oral corticosteroids on serum inflammatory biomarkers in COPD: an exploratory study. Ther Adv Respir Dis 2009 Apr; 3 (2): 73-80 148. Wang IM, Stepaniants S, Boie Y, et al. Gene expression profiling in patients with chronic obstructive pulmonary disease and lung cancer. Am J Respir Crit Care Med 2008 Feb 15; 177 (4): 402-11 149. Toedter G, Li K, Marano C, et al. Gene expression profiling and response signatures associated with differential responses to infliximab treatment in ulcerative colitis. Am J Gastroenterol 2011 Jul; 106 (7): 1272-80 150. Elashoff MR, Wingrove JA, Beineke P, et al. Development of a blood-based gene expression algorithm for assessment of obstructive coronary artery disease in nondiabetic patients. BMC Med Genomics 2011; 4 (1): 26 151. Bhattacharya S, Srisuma S, Demeo DL, et al. Molecular biomarkers for quantitative and discrete COPD phenotypes. Am J Respir Cell Mol Biol 2009 Mar 4; 40 (3): 359-67 152. Steiling K, Berge M, Sebastiani P, et al. Airway gene expression as a molecular phenotype of COPD [abstract]. Proc Am Thorac Soc 2011 May; 8 (2): 208
Correspondence: Dr Don D. Sin, St. Pauls Hospital, 1081 Burrard Building, Vancouver, BC V6Z 1Y6, Canada. E-mail: don.sin@hli.ubc.ca
Drugs 2011; 71 (14)
REVIEW ARTICLE
Drugs 2011; 71 (14): 1839-1864 0012-6667/11/0014-1839/$55.55/0
Clinically Significant Drug Interactions with Antacids

An Update
Ryuichi Ogawa and Hirotoshi Echizen
Department of Pharmacotherapy, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan
Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Drug-Drug Interactions (DDIs) with Antacids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Chemical Composition of Antacids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Mechanisms of Antacid-Related DDIs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Alteration of Dissolution of Susceptible Drugs with pH-Dependent Dissolution . . . . . . . . . . . . . . 3.2 Chelation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1 Countermeasures against Antacid-Induced DDIs Caused by Chelation. . . . . . . . . . . . . 3.3 Alteration of Gastrointestinal Motility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Alteration of Urinary Drug Elimination by Alkalinization of Urine . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Database of DDIs with Antacids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Antimicrobial Agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1 Tetracyclines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2 Fluoroquinolones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.3 b-Lactams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.4 Other Antibacterial Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.5 Anti-Tuberculosis and Anti-Leprosy Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.6 Oral Antifungal Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.7 HIV Protease Inhibitors and Other Antiretrovirals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.8 Other Antiviral Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Anti-Inflammatory Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1 NSAIDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2 Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 Cardiovascular Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1 b-Blockers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.2 Renin-Angiotensin System Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.3 Cardiac Glycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.4 Oral Anticoagulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.5 Other Cardiovascular Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4 Oral Antidiabetic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5 Antiulcer Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6 Molecular Targeted Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7 Bisphosphonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8 CNS Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9 Other Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1840 1840 1842 1842 1842 1843 1849 1850 1850 1851 1851 1851 1852 1852 1854 1854 1854 1854 1855 1855 1855 1855 1856 1856 1856 1856 1856 1857 1857 1857 1857 1858 1858 1858 1858
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Abstract
One may consider that drug-drug interactions (DDIs) associated with antacids is an obsolete topic because they are prescribed less frequently by medical professionals due to the advent of drugs that more effectively suppress gastric acidity (i.e. histamine H2-receptor antagonists [H2RAs] and proton pump inhibitors [PPIs]). Nevertheless, the use of antacids by ambulant patients may be ever increasing, because they are freely available as overthe-counter (OTC) drugs. Antacids consisting of weak basic substances coupled with polyvalent cations may alter the rate and/or the extent of absorption of concomitantly administered drugs via different mechanisms. Polyvalent cations in antacid formulations may form insoluble chelate complexes with drugs and substantially reduce their bioavailability. Clinical studies demonstrated that two classes of antibacterials (tetracyclines and fluoroquinolones) are susceptible to clinically relevant DDIs with antacids through this mechanism. Countermeasures against this type of DDI include spacing out the dosing interval taking antacid either 4 hours before or 2 hours after administration of these antibacterials. Bisphosphonates may be susceptible to DDIs with antacids by the same mechanism, as described in the prescription information of most bisphosphonates, but no quantitative data about the DDIs are available. For drugs with solubility critically dependent on pH, neutralization of gastric fluid by antacids may alter the dissolution of these drugs and the rate and/or extent of their absorption. However, the magnitude of DDIs elicited by antacids through this mechanism is less than that produced by H2RAs or PPIs; therefore, the clinical relevance of such DDIs is often obscure. Magnesium ions contained in some antacid formulas may increase gastric emptying, thereby accelerating the rate of absorption of some drugs. However, the clinical relevance of this is unclear in most cases because the difference in plasma drug concentration observed after dosing shortly disappears. Recent reports have indicated that some of the molecular-targeting agents such as the tyrosine kinase inhibitors dasatinib and imatinib, and the thrombopoietin receptor agonist eltrombopag may be susceptible to DDIs with antacids. Finally, the recent trend of developing OTC drugs as combination formulations of an antacid and an H2RA is a concern because these drugs will increase the risk of DDIs by dual mechanisms, i.e. a gastric pH-dependent mechanism by H2RAs and a cation-mediated chelation mechanism by antacids.
1. Drug-Drug Interactions (DDIs) with Antacids Antacids are time-honoured remedies and were once considered the drugs of choice for the treatment of acid-related upper gastrointestinal diseases (e.g. peptic ulcer disease, gastro-oesophageal reflux disease [GORD/GERD]). Because the prevalence of GORD (as defined by at least weekly heartburn and/or acid regurgitation) is 1020% in the Western world and about 5% in Asia,[1] ant 2011 Adis Data Information BV. All rights reserved.
acids are used widely and various drug-drug interactions (DDIs) have been reported. Antacids are chemically weak basic substances (e.g. hydroxides) used for neutralizing hydrochloric acid in the gastric juice. They are formulated as salts by being combined, in most cases, with one of the polyvalent cations such as calcium (Ca2+), aluminium (Al3+) or magnesium (Mg2+). Until the 1980s, antacids were used more frequently as prescription drugs than they are today. At that time, medical professionals considered the potential
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DDIs with concomitantly prescribed oral medications more seriously. Many extensive review articles were published until the 1990s. With the advent of more effective and easier to use acid-suppressing agents than antacids (e.g. histamine H2-receptor antagonists [H2RAs] in the 1990s and proton pump inhibitors [PPIs] in the 2000s), antacids gradually lost their popularity as prescription drugs and were marketed as nonprescription, over-the-counter (OTC) drugs. However, a surge of public interest on self-medication and intensive, direct-to-consumer promotions of many pharmaceutical companies have made antacids one of the most popular OTC drugs. As a result, antacids are as much a part of routine household remedies as antipyretics. They are used for occasional dyspeptic symptoms or heartburn on the patients own judgement. The Consumer Healthcare Products Association (CHPA) and the Nielsen Company conducted a survey on 17 412 individuals with heartburn during the previous 12 months[2] and revealed that only 61% of the individuals consulted with physicians for their symptoms and 55% self-medicated using only OTC drugs; 95% of the OTC users were satisfied with the results of treatment, while saving approximately $US174 (2010 values) otherwise needed for visits to doctors and prescribed medications. In addition, a recent double-blind clinical trial has suggested that for the treatment of new-onset dyspepsia, a stepwise treatment with antacid, H2RA and PPI in that order would be as effective as the approach with these drugs in the reverse order and be more cost effective than the latter.[3] In this context, antacids may be reappraised in the future from the viewpoint of cost effectiveness. Collectively, these data indicate that DDIs with antacids remain a clinically relevant issue, although most of them are hidden from the medical profession. Since comprehensive reviews featuring DDIs with antacids were published in the 1990s, many clinically relevant DDIs between antacids and various classes of drugs have been reported. For instance, fourth-generation fluoroquinolones (such as gemifloxacin) are shown to be susceptible to DDIs with antacids. Substantial controversies exist over DDIs between antacids and HIV protease
inhibitors (PIs), particularly atazanavir. Bisphosphonates are claimed to be susceptible to DDIs with antacids in prescription information provided by manufacturers, whereas no convincing data are available in the literature. In this context, another updated and comprehensive review is now required. We have performed a systematic search through MEDLINE (1964 to August 2011) and Japana Centra Revuo Medicina (1983 to August 2011). We limited our search to humans and Englishand Japanese-language articles with the following strategy: (antacids [MeSH] OR antacids [Pharmacological Action] OR antacid* [All Fields] OR acid lowering [All Fields] OR acid reducing [All Fields] OR anti acid [All Fields] OR aluminum hydroxide [MeSH] OR aluminum oxide [MeSH] OR magnesium hydroxide [MeSH] OR magnesium oxide [MeSH] OR calcium carbonate [MeSH] OR sodium bicarbonate [MeSH]) AND (drug interactions [MeSH] OR drug interaction* [All Fields] OR interaction [All Fields]) AND (pharmacokinetic* [All Fields] OR pharmacodynamic* [All Fields] OR pharmacokinetics [MeSH]). In addition, we scrutinized the references of previous review articles. Of 767 retrieved articles, 155 were included in this review. The remaining articles were excluded for various reasons including lack of in vivo data, comments on the original articles and non-original articles. Previous review articles revealed that antacidrelated DDIs are almost exclusively associated with the interference of intestinal absorption of concomitantly administered drugs. Clinical implications of DDIs in the absorption process can be assessed by the changes in the rate and extent of absorption. We consider that changes in the extent of drug absorption (quantified by area under the concentration-time curves [AUC]) are more important than changes in the rate of absorption (quantified by maximum drug concentration [Cmax] and time to Cmax [tmax]), because the former is more directly associated with the cumulative systemic exposure to the drug and hence with therapeutic responses. In this context, we assessed the clinical relevance of DDIs based on changes in AUC. When the pharmacological effect of a drug of interest is concentration-dependent (e.g.
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some antibacterials), we also referred to changes in Cmax. In addition, we scrutinized prescribing information provided by manufacturers. 2. Chemical Composition of Antacids While many bases (such as hydroxide, trisilicate and carbonate) were used in antacids, hydroxide is most commonly used and is combined with one of the polyvalent anions (including aluminium, magnesium and calcium) to formulate the antacid. Aluminum hydroxide either alone or in combination with magnesium hydroxide is the main ingredient of many formulations of antacids (such as liquids, suspensions, powders, gels, drops, effervescent salts, tablets and capsules). For critical analysis of literature reporting DDIs with antacids, it is very important to obtain detailed information of antacids (including types of formulation and neutralization capacity), because the magnitude of any interaction would depend on the characteristics of the antacid. In this context, we have summarized in table I the formulas and strengths of various antacids available as prescription and OTC drugs according to the prescription information of the respective drugs available from the manufacturers. 3. Mechanisms of Antacid-Related DDIs
3.1 Alteration of Dissolution of Susceptible Drugs with pH-Dependent Dissolution
Because most drugs are administered as solid preparations (such as tablets and capsules), they have to be dissolved in gastric or intestinal fluids to be absorbed. Many factors influence the dissolution. Among them, gastric pH has a crucial influence on the absorption of weakly acidic or basic drugs, because their solubility may be critically dependent on pH. It is well known that the dissolution rate of a formula in the gastric fluid is a rate-limiting step for absorption for some drugs. For these drugs, the rate and sometimes the extent of absorption from solid dosage preparations are noticeably slower than from a liquid solution (i.e. dissolution-limited absorption). A classic example can be seen in some imidazole antifungal agents (such as ketoconazole and
itraconazole). Because these drugs are weak bases with an acid dissociation constant (pKa) of approximately 3.0, they are nearly insoluble at pH >4.0. If coadministration of an antacid elevates the gastric pH to >4.0 for a period longer than the gastric empting time (for liquid: 1020 minutes), the drug may reach the small intestine before dissolution takes place and hence absorption is decreased. Indeed, one study demonstrated that coadministration of antacids with itraconazole reduced its AUC by 66% compared with the control value.[4] However, the magnitude of DDIs caused by this mechanism differs substantially among imidazole antifungal agents, because antacids did not influence the AUCs of fluconazole and ketoconazole.[5,6] Thus, the mechanism of altered gastrointestinal absorption of a drug concomitantly administered with antacids may be attributable to altered dissolution of the affected drug when its solubility is known to be pH dependent, and coadministration of an H2RA or PPI produces comparable changes in the AUC of the drugs. Readers may refer to detailed descriptions in our previous article.[7] On the other hand, many weakly acidic drugs (such as NSAIDs) are sparingly soluble in the strongly acidic gastric fluid but are soluble in neutral pH. Therefore, the elevation of gastric fluid pH by antacids may increase their solubility in the stomach, and consequently accelerate the rate and sometimes even the extent of absorption. Interestingly, studies have reported that magnesium hydroxide or sodium bicarbonate may increase the rate of absorption of some NSAIDs and sulfonylurea antidiabetic agents (including glipizide and glibenclamide) as well as the extent of absorption of some of them (table II). For instance, a single dose of magnesium hydroxide (850 mg as milk of magnesia in water) given immediately after the ingestion of nonmicronized glibenclamide (glyburide) preparation increased the Cmax and AUC of the drug 3-fold compared with the respective control values.[108] While the insulin responses were augmented significantly, no appreciable changes in plasma glucose levels were observed in healthy volunteers. However, antacids did not alter the Cmax or AUC of the micronized formulation of the drug. Micronized
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Table I. Major brands of antacids and their contents worldwide Brand name, manufacturer Maalox, Novartis Maalox Quick Dissolve Chewables Maalox Quick Dissolve Chewables Maximum Maalox Maalox TC Mylanta, Johnson & Johnson-Merck Mylanta Childrens Upset Stomach Relief Mylanta Fast-Acting Mylanta Fast-Acting Double Strength Mylanta Supreme Fast-Acting Mylanta Gelcaps Mylanta Fast-Acting Maximum Strength Gaviscon, GlaxoSmithKline Gaviscon Gaviscon Liquid Gaviscon Extra Strength Amphojel, Wyeth Amphojel Titralac, 3M Titralac Regular Titralac Plus Alka-Seltzer, Bayer Alka-Seltzer Gold Effervescent Antacid Milk of Magnesia Phillips Milk of Magnesia [Bayer] Phillips Milk of Magnesia Concentrate [Bayer] Milk of Magnesia Concentrate [Roxane] Tablets Suspension Suspension Tablets Suspension Suspension 400 400 300 800 1200 958 Milk of Magnesia, IVAX/Roxane/Rugby/Sandoz/UDL/United Research/Bayer Chewable Tablets 420 420 Suspension Tablets 320 300 Chewable Suspension Suspension Chewable 80 31.7 254 160 119.3 237.5 105 20 Suspension Tablets Suspension Chewable Suspension Suspension Tablets Liquid Chewable 500 400 200 200 150 400 135 125 500 300 700 400 550 350 400 400 Chewable Chewable Suspension Suspension 225 600 200 300 600 1000 Forms Content (mg per tablet or per 5 mL) Al(OH)3 MgCO3 Mg(OH)2 Mg2Si3O8 CaCO3 NaHCO3
glibenclamide has better dissolution characteristics than the non-micronized preparation. Therefore, the effect of pH-dependent dissolution of a drug is also influenced by the dissolution characteristics of the preparations. Interestingly, the administration of a solution (10 mL) containing a mixture of aluminium hydroxide and magnesium hydroxide with glibenclamide significantly increased the Cmax and AUC of the drug by 3040%, respect 2011 Adis Data Information BV. All rights reserved.
ively, compared with the control values, whereas no remarkable changes in clinical effects were observed.[108]
3.2 Chelation
Chelation reaction occurs when polyvalent metallic ions (such as Al3+ and Mg2+) and organic molecules that can form a ring complex coexist in
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Table II. Changes in area under the concentration-time curve (AUC), maximum plasma concentration (Cmax) and amount of urinary excretion of the drug as unchanged form (AUE) of various agents when concomitantly administered with antacids (published data) Agent affected by DDI Antimicrobial agents Tetracyclines Doxycycline Tetracycline Fluoroquinolones Ciprofloxacin Enoxacin Garenoxacin Gatifloxacin Gemifloxacin Levofloxacin Lomefloxacin Moxifloxacin Norfloxacin Ofloxacin Pefloxacin Rufloxacin Sitafloxacin Sparfloxacin Temafloxacin Tosufloxacin b-Lactams and b-lactamase inhibitors Amoxicillin Clavulanic acid Cefetamet pivoxil Cefixime Cefpodoxime proxetil Cefprozil Cefteram pivoxil Ceftibuten Cephalexin Tebipenem pivoxil 26 26 18 12 10 8 6 18 10 12 +21 to NS NS NS NS -40 NS NS NS NS -21 NS NS NS NS -39 NS NS NS NS -44 +23 to NS NS NS NS -32 NS NS NS -18 -17 8,31 8,31 32 33 34 35 36 37 8 38 Continued next page
b
Clinical significance
Total number of participants
Percentage change (vs alone) AUC Cmax AUE
References
10 17 26 16 20 12 28 10 14 12 14 14 10 12 9 26 12 6
-85 -27a to -90 -41 to -85 -73 to -84 -56 -65 -23 to -83 NA NS to -63 -59 -97 to NA -53 or NA -54 -38 -26 to -73 -23b to -35 -61c -32
-83 -21a or NA -38 to -80 -70 to -80 -59 -68 NS to -85 -19 or NA -14 to -70 -61 -100 or NA -61 or NA -61 -43 -37 to -81 -22 to -29b -59c -41
-77 NA -29 to -85 -66 or NA NA -57 NA -50 or NA NS or NA NA -86 to -90 NS or NA NA NA -24 to -67 NA -54c -42
8 9,10 11-13 14,15 16 17 18,19 20,21 15,22 23 15,24 12,15 25 26 27 15,28 29 30
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Table II. Contd Agent affected by DDI Other antibacterial agents Azithromycin Clindamycin Erythromycin stearate Linezolid Nitrofurantoin Sulfamethoxazole Trimethoprim Anti-tuberculosis, anti-leprosy and anti-parasitic drugs Clofazimine Cycloserine Dapsone Ethambutol Ethionamide Halofantrine Isoniazid Para-aminosalicylic acid Pyrazinamide Rifampin Oral antifungal agents Fluconazole Itraconazole Ketoconazole Posaconazole Genaconazole (SCH39304) HIV protease inhibitors and other antiretrovrals Atazanavir Fosamprenavir Lersivirine Raltegravir 86 26 13 12 NA -15 NS NS -83d -35 NS NS NA NA NA NA 59 60 61 62 14 12 14 12 9 NS -66 NA NS NS NS -35 NS NS NS NA NA NA NA NS 6 4 5 57 58 16 12 21 14 12 7 16 16 14 14 NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS -49 NS NS NS NS NA NS NA NS NA NA NS NS NS NS 45 46 47,48 49 50 51 52 53 54,55 56 39 16 8 18 6 8 8 NS -23 NS NS NA NS -12 NS -67 NS NS NA NS -20 NA NA NA NA -57 NA NA 39 40 41 42 43 44 44 Clinical significance Total number of participants Percentage change (vs alone) AUC Cmax AUE References
Drug Interactions with Antacids 1845
Continued next page
Table II. Contd Agent affected by DDI Other antiviral drugs Oseltamivir Valaciclovir Anti-inflammatory drugs NSAIDs Paracetamol (acetaminophen) Aspirin Dexketoprofen trometamol Diclofenac Diflunisal Etoricoxib Fendosal Flurbiprofen Ibuprofen Indomethacin Isofezolac Ketoprofen Mefenamic acid Meloxicam Nabumetone Piroxicam Tenidap Tolfenamic acid Tolmetin Corticosteroids Prednisolone Prednisone Cardiovascular agents b-Blockers 41 13 NS NS to -39 NS NS to -45 NA NA 84,85 86,87 28 15 24 6 12 12 12 19 14 12 6 16 6 6 15 20 21 6 24 NS NS NS NS +10 to -26 NS -80 NS NS -35 NS NS +36 NS NS NA -10e +44 to -21 NS +33 +69 to -72 NS NS NS to -46 NS -80 NS +31 to NS -27 NS NS +126 NS NS NSe -21e +193 to -60 NS NA NA NA NA NS to -14 NA NA NA NA NA NA NA NS NA NA NA NA NS NS 65 66,67 68 69 70 71 72 73 69,74 75 76 69,77 78 79 80 81 82 78 83 12 18 NS NS NS NS NS NA 63 64 Clinical significance Total number of participants Percentage change (vs alone) AUC Cmax AUE References
1846 Ogawa & Echizen
Atenolol Metoprolol Propranolol
6 6 6
-42 NS NS
-50 -20 NS
NA NA NA
88 88 89 Continued next page
Table II. Contd Agent affected by DDI Sotalol Renin-angiotensin system inhibitors Captopril Olmesartan medoxomil Cardiac glycosides b-acetyldigoxin Digoxin Oral anticoagulants Dicoumarol (bishydroxycoumarin) Rivaroxaban (BAY59-79369) Warfarin Other cardiovascular agents Cerivastatin Diltiazem Quinidine Rosuvastatin Oral antidiabetic agents Acarbose Chlorpropamide Glibenclamide (glyburide) Glipizide Tolbutamide Antiulcer drugs Cimetidine Famotidine Misoprostol Nizatidine Omeprazole Pantoprazole Rabeprazole Ranitidine 76 44 12 44 5 18 12 36 NS to -26 -19 to -37 -16j NS to -10 -66 NS NS NS to -26 NS to -33 -25 to -33 NSj NS to -12 -74 NS NS NS to -41 NA NA NA NA NA NA NA NA 84,112-115 113,116,117 118 113,119 20 120 121 113,119 h 24 22 21 15 16 NAg NS +33 to NSi or -63h NS NS NAg NS +46 to NSi or -72h NS NS NAg NA NA NA NA 106 107 108,109 110,111 107 8 5 12 14 NS NA NS -55 NS NA NS -50 NA NS NS or NA NA 101 102 103,104 105 6 12 12 NS to +77 NS NS or NA NS to +75 NS NS NA NS NA 98 99 98,100 f 6 40 NS NS to -60f NS NS to -77f NA NS to -42f 93 94-97 10 24 -42 -22 -50 -36 NA -33 91 92 Clinical significance Total number of participants 6 Percentage change (vs alone) AUC -21 Cmax -27 AUE NA 90 References
Drug Interactions with Antacids 1847
Continued next page
Table II. Contd Agent affected by DDI Molecular targeted drugs Dasatinib Eltrombopag Imatinib CNS drugs Clorazepate dipotassium Diazepam Levodopa Lithium carbonate Midazolam Ondansetron Phenytoin Sertindole Sulpiride Temazepam Ziprasidone Other agents Aminophylline Cilomilast Febuxostat Ferrous sulfate Levothyroxine Muzolimine Mycophenolate mofetil Penicillamine Pirfenidone Pseudoephedrine Roflumilast Theophylline Zinc 12 24 24 28 23n 6 10 6 16 6 30 30 12 NSm NS -15 NA NA NS -17 -52 NS NA NS NS -72 NSm NS -31 NS to -66 -12o NS -38 -44 NS NA NS NS NA NA NA NA NA NA NS NA -37 NA NS to -9 NA NA NA 137 138 139 140 141-143 144 145 146 147 55 148 149-151 152 10 9 8 6 16 12 11 16 2 10 11 NA NS NA NS NS NS NS to -27 NS NA +8% NS NSk -34 NS NS NS NS NS or NA -13 NA NS NS NA NA NS NA NA NA NA NA -39l NA NA 125 126 127 128 129 130 131,132 133 134 135 136 24 26 12 -48 -70 NS -58 -70 NS NA NA NA 122 123 124 Clinical significance Total number of participants Percentage change (vs alone) AUC Cmax AUE References
1848 Ogawa & Echizen
a b
Pepto-Bismol and Veegum were administered simultaneously. Sparfloxacin was administered 2 h after antacid dosing. Continued next page
1849
DDI = drug-drug interaction; NA = not applicable; NS = not significant; indicates clinically significant DDIs, defined as >50% reduction in one of the parameters (AUC, Cmax and AUE) compared with the respective control values.
The interaction was assessed by pharmacodynamic parameters (blood glucose and serum insulin levels).
Digoxin was administered orally simultaneous with kaolin-pectin containing aluminium trisilicate.
Data obtained from a study performed with non-micronized glibenclamide.
Data obtained from a study performed with micronized glibenclamide.
The susceptible drug was administered 30 min after antacid dosing.
Mean value of the steady-state mean plasma concentrations.
m Aminophylline was administered 4 h before taking antacids.
The sampling time was not specified in the original article.
c Temafloxacin was administered 1 h after antacid dosing.
Misoprostol was administered 1 h before antacid dosing.
solution. Classical examples of this type of DDI were reported for the concomitant administration of tetracycline antibacterials and a mixture of aluminium hydroxide and magnesium hydroxide (e.g. Maalox). Coadministration of these drugs reduced the oral bioavailability of tetracycline and its analogues by 80% compared with the respective control values.[8,9] Since this interaction was not observed with concomitant administration of a H2RA or PPI, the mechanism of DDIs was explained by chelation rather than elevation of gastric pH. The tetracycline structure contains various sites at which chelation with metallic cations can occur. For instance, the lower tier of the tetracycline molecule contains two 1,3-diketones with two of the ketones in the enol form. Such monoenols in 1,3-diketons would chelate di- or trivalent metallic ions to form six-membered rings. The rank order of stability of tetracycline-metal complexes is Fe3+ > Al3+ > Cu2+ > Ni2+ > Fe2+ > Co2+ > Zn2+ > Mn2+.[153] Some of these complexes are insoluble and thus cannot be absorbed into the mucosa. Likewise, fluoroquinolone antibacterials are thought to form complexes with polyvalent metal cations at its 3-carboxyl and 4-oxo functional groups.[154] Aluminum ions form a very stable and insoluble complex with quinolones and prevent their intestinal absorption.[155,156] Because antacids were shown to reduce AUCs of many tetracyclines and fluoroquinolones by >50% compared with the respective control values, concomitant administration of antacids with these antibacterials should either be avoided or spaced out to appropriate intervals. Detailed discussion will be given in section 3.2.1.
3.2.1 Countermeasures against Antacid-Induced DDIs Caused by Chelation
Including three patients of two case reports.
Data obtained from two subjects.
Mean value for free T4 (thyroxine) level.
It may appear rather simple to alleviate DDIs based on the chelation mechanism. In order to interfere with the absorption of a concomitantly administered drug, a large amount of polyvalent cations must coexist with the susceptible drug in the upper gastrointestinal lumen for long enough to form substantial amounts of chelate complexes before absorption of the susceptible drug is completed. As a result, the magnitude of this type of DDI is maximal when antacids are administered
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Table II. Contd
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simultaneously with the susceptible drug. Many studies have been conducted to search for optimal intervals of antacid dosing before or after the administration of susceptible drugs in order to alleviate clinically relevant DDIs. We have retrieved the data from studies where the magnitudes of changes in Cmax and AUC of fluoroquinolone antibacterials were measured under different dosing intervals between antacid and the drugs (figure 1). The results clearly showed that clinically relevant DDIs can be avoided if antacids are administered either 4 hours earlier or 2 hours later than dosing of the fluoroquinolone antibacterials. For drugs that are less susceptible to chelation, such as tosufloxacin, rufloxacin and sparfloxacin, antacids may be given with these drugs using shorter dosing intervals without causing clinically significant DDIs.[11,14,16-18,20,23-25,27,29]
3.3 Alteration of Gastrointestinal Motility
a 0
CPFX ENX GRNX GTFX GMFX MXFX PEFX STFX TMFX
Change in Cmax (%)
50
100 10 b 0 8 6 4 2 0 2 4 6
Antacids containing aluminium hydroxide have been shown to delay gastric emptying,[157] whereas those containing magnesium have been shown to increase intestinal motility and the probability of diarrhoea.[158] The administration of an antacid formula containing both aluminium and magnesium, which is widely used nowadays, did not alter the gastric emptying time as if the effects of aluminium and magnesium on gastric or intestinal motility are counterbalanced.[159] Theoretically, delayed gastric emptying would attenuate the rate of drug absorption (i.e. reduce Cmax and prolong tmax of drugs) but would not alter the extent of absorption (i.e. decrease AUC), as far as the drug is stable in the acidic environment of the stomach. To the best of our knowledge, there is no report in the literature of clinically significant DDIs with antacids attributed to changes in gastric motility.
3.4 Alteration of Urinary Drug Elimination by Alkalinization of Urine
Change in AUC (%)
50
100 10 8 6 4 2 0 2 Timing of antacid dosing relative to that of the antibacterials (h) 4
Antacids are basic substances and may therefore increase urinary pH. This effect is most evident for antacids containing absorbable bases (such as sodium bicarbonate and calcium carbonate). Prolonged administration of these antacids in patients with impaired renal function is known
Fig. 1. The effects of concomitant administration of antacids on changes in (a) the maximum plasma concentration (Cmax) and (b) the area under the concentration-time curves (AUC) of fluoroquinolones as a function of timing of antacid dosing relative to that of the fluoroquinolone (time 0 means simultaneous administration). The magnitude of change in each parameter is expressed as the percentage relative to that obtained after administration of the respective fluoroquinolones alone. These data were derived from a number of different studies[11,14,16-18,23,25,27,29] that showed a >50% decrease in either Cmax or AUC of the fluoroquinolone when used concomitantly with antacids. CPFX = ciprofloxacin; ENX = enoxacin; GRNX = garenoxacin; GTFX = gatifloxacin; GMFX = gemifloxacin; MXFX = moxifloxacin; PEFX = pefloxacin; STFX = sitafloxacin; TMFX = temafloxacin.
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to cause severe metabolic alkalosis secondary to reduced elimination of bicarbonate. Nevertheless, therapeutic doses of non-absorbable antacids containing a mixture of aluminium hydroxide and magnesium hydroxide (Maalox) at 15 mL four times daily increased the mean urinary pH (from 5.8 to 6.8) significantly in healthy subjects.[160] Because weakly basic drugs are less ionized in alkaline urine than in acidic urine, their urinary excretion will be increased by alkalinization of urine. For drugs that are eliminated mainly via renal excretion, antacids may increase systemic clearance of these drugs. Gerhardt et al.[161] reported that alkalinization of urine (pH 7.0) using acetazolamide and sodium bicarbonate resulted in a 50% reduction in urinary excretion of quinidine compared with that observed with acidic urine (pH <6.0), and prolongation of QT intervals in four healthy volunteers. However, their data appear controversial. Since the pKa values of quinidine are 4.0 and 8.6, the change in urinary pH as they reported would result in only small changes in the ionized form of the drug. More importantly, the fractional urinary excretion of quinidine as an unchanged form is <0.2, indicating that reduction in urinary quinidine excretion would cause at most a 20% increase in systemic clearance of the drug. Subsequent studies confirmed a lack of DDIs between quinidine and antacids.[103,104] Taken together, we consider it rather unlikely that the administration of antacids would cause clinically relevant DDIs via alkalinization of urine pH. 4. Database of DDIs with Antacids Since antacids are widely used not only as prescription drugs but also as OTC drugs, they may be coadministered with any of the new drugs launched in the market. Many studies of DDIs with antacids have been reported. We tentatively define that DDIs with antacids would be clinically relevant if antacids alter the AUC or Cmax of a concomitantly administered drug by 50% compared with the respective control values obtained when the drug is administered alone. We understand that the clinical relevance of DDIs should be evaluated not only by the average change
in AUC or Cmax but also by the inter-patient variability.[162] However, it would be difficult to draw a critical line arbitrarily for patient variability to define clinical relevance. We consider that studies revealing pertinent absence of DDIs with antacids have clinical significance. Such information will give us assurance of the compatibility of antacids with the concomitant medications and a clue to choose an alternative medication whenever needed. In this context, we have performed a systematic survey on the electronic databases (see section 1). We present here the most updated and comprehensive database of antacid-related DDIs according to the therapeutic class of drugs.
4.1 Antimicrobial Agents
4.1.1 Tetracyclines
It was discovered as early as 1950 that coadministration of aluminium hydroxide gel substantially interfered with the absorption of chlortetracycline.[163] Subsequent studies also reported that antacids containing aluminium and magnesium hydroxides interfered with the intestinal absorption of tetracycline, doxycycline and demeclocycline by approximately 90% compared with the respective control values.[164] The responsible mechanism was considered to be chelate formation with divalent cations in antacids. Garty and Hurwitz[9] demonstrated that simultaneous administration of an aluminium and magnesium hydroxide gel (30 mL) with a tetracycline capsule (250 mg) reduced the AUC of tetracycline by 90% compared with tetracycline alone in five healthy volunteers. They also demonstrated that coadministration of cimetidine or sodium bicarbonate produced no appreciable changes in the AUC of tetracycline, indicating that the responsible mechanism of the DDIs with antacid was not neutralization of gastric pH. Because of their structures, as discussed in section 3.2, tetracycline analogues including chlortetracycline, tetracycline, doxycycline and demeclocycline are susceptible to DDIs with antacids. To ensure adequate antimicrobial effects, concomitant administration of antacids with tetracycline analogues should be avoided. Interestingly, a report demonstrated that oral
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administration of an antacid (aluminium hydroxide gel 30 mL four times daily for 4 days beginning 2 days prior to doxycycline dosing) reduced the AUC of intravenously administered doxycycline by 30%.[165] It is difficult to find a reasonable explanation for this phenomenon.
4.1.2 Fluoroquinolones
Fluoroquinolones were launched in the mid1980s and have been widely used ever since. Soon after the introduction of these antibacterials, Hoffken et al.[166] reported that coadministration of aluminium and magnesium hydroxides with ciprofloxacin reduced Cmax and AUC of the antibacterial by 90% compared with the corresponding values obtained after administration of the antibacterial alone. Clinical relevance of this DDI was substantiated by a circumspect clinical observation of a patient who failed to respond to a standard dose of norfloxacin for the treatment of norfloxacin-sensitive Pseudomonas aeruginosa infection, likely due to unexpectedly low plasma drug concentration.[167] Subsequent pharmacokinetic studies confirmed that concomitant administration of antacids containing magnesium, aluminium or calcium reduced AUC and urinary recoveries of many fluoroquinolones by >50% compared with the respective control values (table II). Because the magnitudes of reduction in AUC and Cmax are >50% for some of the fluoroquinolones, DDIs with antacids are considered clinically relevant for those drugs. Concomitant administration of an H2RA (e.g. ranitidine) produces no appreciable changes in the AUC of ciprofloxacin, indicating that the mechanism involved in the DDI between fluoroquinolone and antacids is largely associated with chelate complex formation between the drugs.[8] Polk[168] suggested that the 3-carboxyl and 4carbonyl groups of quinolones are involved in chelate formation with polyvalent cations. His hypothesis was subsequently confirmed by a study using 13C-NMR.[169] Mizuki et al.[170] studied the effects of antacids on the AUC of many fluoroquinolone derivatives orally administered to animals and suggested that those having many substitutions in both quinolone and piperazine structures (e.g. levofloxacin, tosufloxacin, rufloxacin
and sparfloxacin) may be less susceptible to chelation compared with those having fewer substitutions (i.e. norfloxacin, ciprofloxacin and enoxacin). Their theory is largely supported by the data obtained from pharmacokinetic studies in humans, although there are many exceptions (such as gemifloxacin, sitafloxacin and gatifloxacin) [figure 2]. Nix et al.[11] studied the magnitude of reduction in AUC of ciprofloxacin as a function of antacid dosing interval before or after administration of the antibacterial in order to find the optimal dosing interval. They found that concomitant administration of aluminium and magnesium hydroxides (Maalox) significantly reduced the AUCs of ciprofloxacin when the antacid was given simultaneously or 2 or 4 hours before ciprofloxacin administration, but did not alter the AUCs of the antibacterial when antacid was given 2 hours after or 6 hours before the antibacterial. Subsequent studies performed for other fluoroquinolones largely agreed with the finding of Nix et al. (figure 1).
4.1.3 b-Lactams
b-Lactams (penicillins and cephalosporins) consist of compounds having diverse chemical structures. Therefore, it is not surprising to see marked differences in the effect of antacids on their intestinal absorption. In general, coadministration of antacids produced no significant changes in the AUCs of the first- or second-generation cephalosporins (such as cephalexin and cefixime) compared with the respective control values. However, some of the third-generation cephalosporins that were developed as prodrugs (e.g. cefpodoxime proxetil) may be susceptible to DDIs with antacids. Coadministration of antacids containing aluminium and magnesium hydroxides significantly reduced the AUC of cefpodoxime proxetil,[34] whereas antacids had no significant effects on the AUC of cefteram pivoxil[36] or cefetamet pivoxil[32] compared with the respective control values. The reason why cefpodoxime proxetil is susceptible to DDIs with antacids may be due to its higher degree of pH-dependent dissolution (LogP values are 0.08 and 1.64 at pH of 1.2 and 6.4, respectively). Coadministration of antacids
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Norfloxacin (97%)
O F OH N HN CH3 N HN O
Ciprofloxacin (85%)
O F OH H N N HN O
Moxifloxacin (59%)
O F OH N O H3C H
H3C
Garenoxacin (57%)
O
F OH N HN O F F O O
Enoxacin (84%)
O F OH
H3C O N
Gemifloxacin (83%)
O
F OH N N N O O
Pefloxacin (54%)
O F OH N N H3C N N CH3 H3C O
Ofloxacin (53%)
O F OH N O CH3 N O
N HN
N CH3
H2N
Sitafloxacin (73%)
O F OH H3C N Cl H2N F N HN O
Gatifloxacin (65%)
O F OH N O H3 C H3C N N O
Levofloxacin (50%)
O F OH N O CH3 H2 N N N O F
Tosufloxacin (42%)
O O OH N N F
Lomefloxacin (63%)
O F OH H3C N HN CH3 F CH3 N HN O
Temafloxacin (61%)1
O F OH N N F H3C N O
Rufloxacin (38%)
O F OH H3C N S N HN O
Sparfloxacin (35%)
NH2 F OH N F CH3 N O O
Fig. 2. Chemical structures of fluoroquinolones and their susceptibility to drug-drug interactions with antacids. Bracketed values represent reduction in oral bioavailability by coadministration of antacids. These were calculated as percentage reduction of either the area under the plasma concentration-time curve or the amount of urinary excretion of the drug as unchanged form following coadministration of the drug and antacids vs the drug alone. The highest values are shown when multiple studies were available for the same drug. 1 One hour after antacid dosing.
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has no clinically significant effect on the AUCs of amoxicillin,[8,31] clavulanic acid[8,31] or tebipenem pivoxil.[38]
4.1.4 Other Antibacterial Agents
The Cmax and AUC of clindamycin were reportedly reduced by 67% and 23%, respectively, with coadministration of antacids compared with the respective control values, indicating that the rate but not the extent of absorption may be reduced to a clinically insignificant degree.[40] Coadministration of magnesium trisilicate reduced the urinary excretion of the unchanged form of nitrofurantoin by 57% from the control value.[43] While this drug is only rarely used nowadays for the treatment and prophylaxis of uncomplicated lower urinary tract infection, it remains unclear whether the DDIs with antacids have any clinically relevant effect. No clinically significant DDIs were observed when antacids were coadministered with azithromycin,[39] erythromycin stearate,[41] sulfamethoxazole,[44] trimethoprim[44] and linezolid.[42]
4.1.5 Anti-Tuberculosis and Anti-Leprosy Drugs
nazole with an antacid (0.5 g sodium bicarbonate) compared with those given ketoconazole alone.[172] A recent study[4] also demonstrated that concurrent administration of 240 mL of antacid suspension (aluminium and magnesium hydroxides) reduced the AUC of orally administered itraconazole capsules by 66% compared with the control value. Taken together, it may be advisable to avoid using antacids, or space out the dosing intervals between antacid and these azoles when the antifungal drugs are to be prescribed for the treatment of systemic fungal infection. In contrast, concomitant administration of antacids (e.g. 20 mL of aluminium and magnesium hydroxide mixture) with other antifungal drugs (fluconazole,[6] posaconazole,[57] genaconazole[58]) was not associated with clinically relevant changes in the AUCs.
4.1.7 HIV Protease Inhibitors and Other Antiretrovirals
None of the clinical studies reported revealed clinically relevant DDIs between antacids and anti-tuberculosis or anti-leprosy drugs (isoniazid,[52] pyrazinamide,[54] rifampicin (rifampin),[56] ethambutol,[49] para-aminosalicylic acid,[53] cycloserine,[46] ethionamide,[50] dapsone[47,48] and clofazimine[45]).
4.1.6 Oral Antifungal Agents
Some of the orally active antifungal agents are weakly basic compounds with pH-dependent dissolution. For instance, an in vitro study demonstrated that disintegration of ketoconazole tablets was not affected by buffer pH but its dissolution is significantly reduced at pH >6.0.[171] As a result, coadministration of 30 mL of antacid (Maalox) with ketoconazole was associated with a 40% reduction of AUC compared with the control value, but the difference was not significant due mainly to a small number of subjects (n = 4) and large inter-individual variability.[5] In addition, Van der Meer et al.[172] reported that the AUC of ketoconazole was reduced by more than 90% in two healthy volunteers who were given ketoco 2011 Adis Data Information BV. All rights reserved.
HIV PIs are one of the mainstays of highly active antiretroviral therapy for HIV-1 infection. Because they frequently cause abdominal discomfort,[173] the use of one of the acid-reducing agents (such as antacids, H2RAs and PPIs) is widespread among patients. The dissolution of some PIs is known to be dependent on pH. For instance, atazanavir is sparingly soluble at pH >4.0.[174] When a combination of atazanavir + ritonavir was administered with lansoprazole (60 mg/day), the AUC of atazanavir was dramatically reduced by 90% compared with the control value.[175] Similarly, a clinical report indicated that a single dose of buffered didanosine tablets containing magnesium hydroxide and calcium carbonate (Videx) given with atazanavir resulted in a substantial reduction in the AUC and Cmax of atazanavir by 87% and 89%, respectively, in 32 healthy subjects.[176] Because concomitant administration of enteric-coated didanosine containing no antacid buffer (Videx EC) with atazanavir produced no appreciable changes in the AUC of atazanavir,[177] the antacid buffer components, rather than didanosine per se, were considered to be responsible for the DDIs with atazanavir. Subsequently, many attempts have been made to confirm this finding not only for atazanavir
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but also for other PIs used with various types of acid-reducing agents.[178] Because PPIs are the most potent acid-reducing agents and tend to have a longer-lasting effect than H2RAs and antacids,[179] most of the studies chose one of the PPIs as the acid-reducing agent. Results obtained from these studies showed that coadministration of PPIs reduced the AUC and Cmax of atazanavir by 50%,[59,175,180] whereas they do not alter the AUCs of other PIs and may increase the AUC of saquinavir.[181,182] Only three additional studies have been performed to examine the issue of whether coadministration of antacids interferes with the absorption of PIs. Administration of Maalox TC (30 mL) reduced the AUC and Cmax of fosamprenavir only by 15% and 35%, respectively,[60] whereas coadministration of buffered didanosine resulted in no appreciable changes in the AUC and Cmax of indinavir. Collectively, the available data to date do not preclude the use of antacids with PIs, despite a lack of pertinent data ensuring the absence of DDIs between antacids and most PIs. Neither a newly developed integrase inhibitor (raltegravir) nor a next generation non-nucleoside reversetranscriptase inhibitor (lersivirine) for the treatment of HIV infection are susceptible to DDIs with antacids.[61,62]
4.1.8 Other Antiviral Drugs
Studies have shown that the intestinal absorption of oseltamivir and valaciclovir is not susceptible to DDIs with antacids.[63,64]
4.2 Anti-Inflammatory Agents
4.2.1 NSAIDs
NSAIDs are not only the most frequently prescribed drugs but also the most popular OTC drugs. They are widely used as analgesics for acute or short-term pain as well as anti-inflammatory agents for chronic inflammatory diseases (such as rheumatoid arthritis), particularly in the aged population. Because NSAIDs cause dyspepsia and upper gastrointestinal mucosal damages, there is a high potential for coadministration of antacids with NSAIDs.
There are considerable controversies regarding DDIs between NSAIDs and antacids. As a result, no comprehensive recommendation can be made for NSAIDs as a class of agents. Previous studies have shown that antacids containing only aluminium hydroxide or a mixture of aluminium and magnesium hydroxides cause no change or clinically insignificant reduction in the AUC of most NSAIDs. As exceptions, antacids reduce the AUCs of indomethacin[75] and fendosal[72] by 35% and 80%, respectively. While the clinical relevance of the DDIs with antacids for these two NSAIDs remains to be established, it would be advisable to discontinue administering antacids with these drugs only when inadequate clinical responses are observed. There is an interesting but not fully confirmed observation that antacids containing magnesium hydroxide or sodium bicarbonate, but not those containing aluminium hydroxide, may enhance the rate and in some cases the extent of intestinal absorption of some NSAIDs. Previous reports showed that coadministration of magnesium hydroxide or sodium bicarbonate increased the early plasma concentrations and sometimes AUC of naproxen,[183] diflunisal,[70] tolfenamic acid,[78] mefenamic acid[78] and ibuprofen.[69] Since magnesium hydroxide not only neutralizes gastric pH but also accelerates gastric emptying, it may increase the solubility of these weakly acidic drugs in the gastric fluid and also promote more rapid transit of gastric contents into the jejunum where most of the drug absorption takes place. In contrast, aluminium hydroxide prolongs gastric emptying, thus counterbalancing its effect of increasing solubility of acidic drugs by elevating gastric pH. Taken together, the clinical relevance of the DDIs between NSAIDs and some antacids described is not clear, while accelerated absorption of NSAIDs by some antacids may be beneficial when rapid pain relief is desired. The intake of antacids with paracetamol (acetaminophen) may increase Cmax (by 33%), but not AUC, of the drug, although such change has no significant clinical consequences.[65]
4.2.2 Corticosteroids
Concomitant administration of antacids with prednisone, but not prednisolone, has been
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shown to reduce both the Cmax and AUC of the drug by approximately 40% compared with the control values.[84-87] Prednisone is known to be metabolized to prednisolone and there is a high degree of interconversion between the two. Since the above studies measured only serum concentrations of prednisolone, the clinical relevance of the DDI remains unclear.
4.3 Cardiovascular Agents
4.3.1 b-Blockers
There are controversies regarding the effect of antacids on the absorption of b-adrenergic receptor antagonists (b-blockers). A report indicated that concomitant administration of antacids with atenolol significantly reduced the AUC and Cmax of the drug by about 35%.[88] Nevertheless, the clinical relevance of this DDI is unclear, because the concentration-response curve of the drug is flat.
4.3.2 Renin-Angiotensin System Inhibitors
One study investigated the effects of concomitant intake of food or antacids on the oral absorption of captopril in healthy subjects.[91] The results indicated that food and antacid reduced the AUC of the drug by 52% and 42%, respectively, compared with the control value, whereas food but not antacid significantly delayed the hypotensive activity of captopril. To our knowledge, no data are available regarding DDIs between antacids and other ACE inhibitors. Laeis et al.[92] reported that the intake of 800 mg aluminium and magnesium hydroxides 15 minutes before the administration of olmesartan medoximil, an angiotensin II type 1 receptor antagonist (angiotensin receptor blocker), significantly reduced the Cmax, AUC and urinary recoveries of olmesartan by 36%, 22% and 33%, respectively, in healthy subjects. However, the small reduction in bioavailability of the drug would not be considered clinically significant.
4.3.3 Cardiac Glycosides
cate, magnesium hydroxide or aluminium hydroxide) with digoxin tablets significantly reduced the AUC and urinary recovery of digoxin by 2048% in healthy volunteers. However, a subsequent study revealed that concomitant administration of 60 mL of aluminium and magnesium hydroxides (Maalox) with digoxin tablets or capsules produced no significant changes in Cmax and AUCs compared with the control values, although the 24-hour urinary excretion of digoxin tended to be reduced by antacids.[95] These reports indicate that DDIs between antacids and digoxin are clinically insignificant. No interaction was observed between antacids and b-acetyldigoxin.[93] Kaolin-pectin is a non-prescription drug that has been used as an antidiarrhoea suspension. While this compound is not considered an antacid, kaolin consists of naturally occurring hydrated aluminium silicate. Pectin is a carbohydrate polymer consisting primarily of partially methoxylated poly-galacturonic acids. Coadministration of kaolin-pectin with digoxin tablets or capsules was shown to reduce the AUC and urinary recovery of the drug by 2062%.[94,96] The effect of kaolin-pectin was less for digoxin capsules than for tablets.[95] This interaction was avoided when kaolin-pectin was given 2 hours after the administration of digoxin.[97]
4.3.4 Oral Anticoagulants
There was controversy over whether concomitant administration of antacids alters digoxin absorption. Brown and Juhl[94] reported that coadministration of antacids (magnesium trisili 2011 Adis Data Information BV. All rights reserved.
Ambre and Fischer[98] reported that coadministration of magnesium hydroxide with dicoumarol increased the AUC from 0 to 48 hours (AUC48) and Cmax of the drug by 50% and 75%, respectively, compared with the control values. The antacid (15 mL of milk of magnesia) was administered concomitantly with dicoumarol and 3 hours later. Because the dose-response relationship of dicoumarol is rather steep and an overdose may be associated with major bleeding, it may be prudent to space out the dosing interval of the two drugs. In addition, since another antacid, aluminium hydroxide, given in a similar manner elicited no appreciable changes in plasma dicoumarol concentrations,[98] this antacid may be a useful alternative to magnesium hydroxide. In contrast, coadministration of magnesium hydroxide
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or aluminium hydroxide did not alter the plasma concentrations of warfarin.[98,100] Rivaroxaban is a newly developed orally active direct factor Xa inhibitor and is intended to be used for the prevention of thromboembolic disease. Coadministration of either antacids (aluminium and magnesium hydroxides) and ranitidine had no appreciable effects on the AUC or Cmax of the drug.[99]
4.3.5 Other Cardiovascular Drugs
the sulfonylureas are likely to have no clinical significance. Because acarbose is a non-absorbable compound, DDIs between antacids and the drug were assessed by pharmacodynamic responses such as serum glucose and insulin levels measured after administration of the drug with or without antacids. No changes in these parameters were observed by coadministration of the antacids compared with the control values.[106]
4.5 Antiulcer Drugs
Coadministration of antacids was shown to reduce the Cmax and AUC of rosuvastatin by 50% and 55%, respectively, compared with the control values, but had no effect on cerivastatin.[101,105] Because HMG-CoA reductase inhibitors (statins) are taken for a lifetime, it will be valuable to determine whether the statins are susceptible to DDIs with antacids. No clinically relevant DDI was observed between diltiazem and antacids.[102]
4.4 Oral Antidiabetic Agents
A group of researchers undertook a series of studies assessing DDIs between various sulfonylurea antidiabetic agents and antacids in healthy volunteers. They reported that coadministration of 850 mg of magnesium hydroxide as milk of magnesia, but not aluminium hydroxide, may accelerate the rate of absorption of the non-micronized form of glibenclamide[108,109] and tolbutamide,[107] based on the findings that the fractional AUC calculated from 0 to 1 or 2 hours after dosing and Cmax of these drugs increased significantly compared with the respective control values. For glipizide, however, only the fractional AUC increased significantly.[110,111] The total AUCs of these drugs were not altered significantly by antacids compared with the control values, indicating that antacids may increase the rate, but not the extent, of absorption of these drugs. While DDIs with antacids may lead to transient changes in plasma drug concentrations during the absorption phase as reflected by the corresponding brief increases in plasma insulin concentration, no clinically relevant changes in plasma glucose levels were observed in these studies. These reports suggest that the DDI between antacids and
For the treatment of gastric acid-related upper gastrointestinal disease (such as peptic ulcer and reflux oesophagitis), antacids may be coadministered with a H2RA or PPI. Several studies have demonstrated that concomitant administration of antacids may significantly reduce Cmax and AUC of many H2RAs by 3040%.[112,113,116,184,185] However, because the magnitude of changes is relatively small, DDIs between these drugs are probably clinically insignificant. Concomitant administration of antacid with omeprazole was shown to reduce Cmax and AUC of omeprazole by 74% and 66%, respectively, compared with the respective control values, but coadministration of antacids with pantoprazole or rabeprazole had no effect.[20,120,121] The DDI may be of clinical relevance only in patients treated for resistant reflux oesophagitis or Zollinger-Ellison syndrome, who are given large doses of PPIs as basic acid suppression therapy supplemented with antacids for symptom relief. Misoprostol was not susceptible to DDIs with antacids.[118]
4.6 Molecular Targeted Drugs
Recently, many small-molecule drugs designed to interact with specific molecular targets (such as tyrosine kinase) have been developed and widely used in the treatment of various diseases. Coadministration of antacids (30 mL of aluminium and magnesium hydroxides) with the tyrosine kinase inhibitor dasatinib reduced Cmax and AUC of the drug by 58% and 48%, respectively, compared with the control values.[122] On the other hand, antacid coadministration does not affect imatinib absorption.[124] It appears that pH-dependent
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solubility of dasatinib is responsible for the DDIs. However, when the antacid was administered 2 hours prior to the dasatinib dosing, no appreciable changes in the AUC of the drug were observed. While the clinical relevance of this DDI has not been verified in clinical studies, it is advisable to avoid antacid coadministration or at least to space out the dosing of antacids at least 2 hours before or after the administration of dasatinib.[186] Eltrombopag is the first orally self-administered, small-molecule, nonpeptide thrombopoietin receptor agonist for the treatment of chronic idiopathic thrombocytopenic purpura. Coadministration of an antacid containing aluminium hydroxide and magnesium carbonate reduced the AUC from time zero to infinity (AUC) and Cmax of the drug by approximately 70% compared with the respective control values.[123] While the clinical relevance of this DDI has not been verified in clinical studies, it may be prudent to avoid using this drug with antacids.
4.7 Bisphosphonates
relevant DDIs have been reported for these combinations.[125-136]

4.9 Other Agents
Many other studies have been conducted to search for the effects of concomitant administration of antacids on systemic exposure to various drugs (including aminophylline, cilomilast, febuxostat, ferrous sulfate, levothyroxine, muzolimine, mycophenolate mofetil, pirfenidone, pseudoephedrine, roflumilast and theophylline). No statistically or clinically significant DDIs have been observed except with penicillamine and zinc.[55,137-152] 5. Conclusions We have conducted a systematic search for clinically relevant DDIs with antacids, and analysed the data retrieved. Among the 132 drugs scrutinized, 68 drugs were considered to be susceptible to statistically significant DDIs with antacids and 24 showed >50% decrease in systemic exposure as assessed by changes in AUC. According to the data obtained from DDIs between antacids and fluoroquinolones, DDIs associated with the chelation mechanism can be avoided by spacing out the time of antacid dosing to at least 4 hours before or 2 hours after that of the susceptible drugs. Recently, antacids are available as combination formulations with H2RAs. For instance, the active ingredients in Pepcid Complete and TUMS Dual Action are famotidine (H2RA), calcium carbonate (antacid) and magnesium hydroxide (antacid). We consider this trend would be an unwise drug development strategy because the combination of antacid and H2RA may interfere with the absorption of concomitantly administered drugs by dual mechanisms: a pHdependent dissolution mechanism by H2RAs and a cation-mediated chelation mechanism by antacids. An attempt to develop a combination formula of a PPI and an antacid as an OTC drug would be even worse, because PPIs have stronger and longer-lasting inhibitory effects on the gastric acid secretion than H2RAs. In summary, DDIs associated with antacids are a perpetual problem that is present everywhere
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Bisphosphonates are a class of agents widely used mainly for the prevention and treatment of osteoporosis and other bone disorders. Because they have a high affinity for calcium and other multivalent cations,[187] coadministration of antacids theoretically would result in chelate complex formation and interfere with their gastrointestinal absorption. Based mainly on such theoretical consideration, most manufacturers of bisphosphonates recommend in their prescribing information that patients using bisphosphonates should wait at least half an hour after taking the drugs before consuming antacids containing calcium, aluminium or magnesium. Surprisingly, to the best of our knowledge, there are no published data that convincingly support this recommendation.
4.8 CNS Agents
Many clinical studies have been conducted to evaluate possible DDIs between antacids and CNS agents (including benzodiazepines, levodopa, lithium carbonate, ondansetron, phenytoin, sertindole, sulpiride and ziprasidone). No clinically
1859
if one cares to look carefully, and is an issue that will continue to evolve with the development of more new drugs. Acknowledgements
13.
14.
No sources of funding were used to assist in the preparation of the present review article. The authors have no conflicts of interest that are directly relevant to the contents of this article.
15.
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Correspondence: Dr Ryuichi Ogawa, Department of Pharmacotherapy, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan. E-mail: smridron@my-pharm.ac.jp
Drugs 2011; 71 (14)
ADIS DRUG EVALUATION
Drugs 2011; 71 (14): 1865-1891 0012-6667/11/0014-1865/$55.55/0
Subcutaneous Recombinant Interferon-b-1a (Rebif)

A Review of its Use in the Treatment of Relapsing Multiple Sclerosis
Mark Sanford and Katherine A. Lyseng-Williamson
Adis, a Wolters Kluwer Business, Auckland, New Zealand
Various sections of the manuscript reviewed by: E.G. Celius, Department of Neurology, Oslo University Hospital, Ullevaal, Oslo, Norway; F. Deisenhammer, Department of Neurology, Innsbruck Medical University, Innsbruck, Austria; M.S. Freedman, Multiple Sclerosis Research Clinic, University of Ottawa, Ottawa, ON, Canada; H-P. Hartung, Department of Neurology, Heinrich-Heine University, Dusseldorf, Germany; R. Lam, Neuro-Immunology Laboratory, University of British Columbia, Vancouver, BC, Canada; Z. Szolnoki, Department of Cerebrovascular Diseases, Pandy Kalman County Hospital, Gyula, Hungary.
Data Selection Sources: Medical literature (including published and unpublished data) on interferon b 1a was identified by searching databases since 1996 (including MEDLINE and EMBASE and in-house AdisBase), bibliographies from published literature, clinical trial registries/databases and websites (including those of regional regulatory agencies and the manufacturer). Additional information (including contributory unpublished data) was also requested from the company developing the drug. Search strategy: MEDLINE, EMBASE and AdisBase search terms were interferon beta 1a and (multiple sclerosis or relapsing remitting multiple sclerosis or multiple sclerosis relapsing remitting or clinically isolated syndrome). Searches were last updated 2 September 2011. Selection: Studies in patients with relapsing-remitting multiple sclerosis who received interferon b 1a. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included. Index terms: Interferon b 1a, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability, pharmacoeconomics.
Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Neutralizing Antibodies to Subcutaneous Interferon-b-1a (IFNb-1a). . . . . . . . . . . . . . . . . . . . . . . 3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Compared with Placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1 Efficacy Over 2 Years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2 Longer-Term Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.3 Serum-Free Formulation of Subcutaneous IFNb-1a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.4 In Patients with Secondary Progressive Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Compared with Intramuscular IFNb-1a. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1 Efficacy Over 24 and 48 Weeks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2 Longer-Term Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1866 1867 1867 1867 1868 1869 1869 1870 1870 1872 1874 1874 1875 1875 1875
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5.
6. 7. 8.
4.3 Compared with Other Disease-Modifying Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4 In Combination with Add-On Methylprednisolone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 General. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.1 Compared with Placebo. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.2 Longer-Term Follow-Up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.3 Serum-Free Formulation of Subcutaneous IFNb-1a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.4 Compared with Intramuscular IFNb-1a and Other Disease-Modifying Agents . . . . . . . . 5.2 Hepatic Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3 Haematological and Other Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacoeconomic and Other Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1 Pharmacoeconomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2 Patient Satisfaction and Treatment Adherence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Place of Subcutaneous Recombinant IFNb-1a in the Treatment of Relapsing Multiple Sclerosis . . .
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Abstract
Subcutaneous recombinant interferon-b-1a (SC IFNb-1a) [Rebif] is indicated as monotherapy for the prevention of relapses and progression of physical disability in patients with relapsing multiple sclerosis (MS). This article reviews the efficacy and tolerability of SC IFNb-1a in this indication, with further discussion of its pharmacological properties and pertinent pharmacoeconomic studies. SC IFNb-1a efficacy and tolerability were evaluated in randomized, doubleblind, multinational trials in patients with relapsing-remitting MS (RRMS). Its efficacy was demonstrated in the 2-year PRISMS trial, as SC IFNb-1a 22 or 44 mg three times weekly (tiw) significantly reduced relapse rates, with an 30% relative risk reduction compared with placebo. SC IFNb-1a was also associated with significantly delayed progression of disability, and lower disease activity according to MRI, relative to placebo. In the 24-week EVIDENCE trial, a significantly higher proportion of SC IFNb-1a 44 mg tiw than intramuscular IFNb-1a (Avonex) 30 mg once weekly recipients remained relapse free. A serum-free formulation of SC IFNb1a 44 mg tiw was more efficacious than placebo in preventing the development of brain lesions in the 16-week IMPROVE trial. In the 96-week REGARD trial, the efficacy of SC IFNb-1a 44 mg tiw was not significantly different to that of glatiramer acetate for clinical endpoints, although it was associated with reduced development of brain lesions compared with glatiramer acetate, according to some MRI endpoints. In the 36-month CAMMS223 trial, alemtuzumab led to significantly lower relapse rates and risk of developing sustained disability than SC IFNb-1a 44 mg tiw, and was generally more efficacious according to other clinical and MRI endpoints. Across trials, influenza-like symptoms, injection-site reactions, haematological disturbances and hepatic enzyme abnormalities were the most common treatment-emergent adverse events occurring with SC IFNb-1a. In the PRISMS trial, SC IFNb-1a 22 and 44 mg tiw recipients had more injection-site reactions than placebo recipients and, at the higher dosage, haematological disturbances and increases in ALT levels were also significantly more frequent than with placebo. Pooled data from clinical trials and postmarketing surveillance indicate that haematological and hepatic adverse events are generally asymptomatic and rarely result in treatment discontinuation. Nevertheless, some cases of serious hepatic complications have been reported. In cost-utility studies, first-line therapies for RRMS, including SC IFNb-1a, all exceeded commonly accepted US thresholds for incremental cost per qualityadjusted life-years gained relative to symptomatic treatment. However, because of patient need and the difficulty in adequately assessing cost utility in a gradually
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Subcutaneous Interferon-b-1a: A Review
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progressive disease, these agents have been made available to many patients worldwide through special access programmes. Overall, SC IFNb-1a has a favourable risk-benefit ratio and is a valuable firstline treatment option for patients with relapsing MS.
1. Introduction Multiple sclerosis (MS) is a debilitating disease characterized by multifocal demyelination and grey matter atrophy in the CNS.[1] These changes arise early in the course of the disease and cause a variety of neurological symptoms and signs.[1] The median estimated prevalence of MS worldwide is 30 per 100 000 population, with twice as many women affected as men.[2] There are marked variations in disease rates between world regions, with prevalence rates ranging from 0.3 per 100 000 population in Africa to 80 per 100 000 population in Europe.[2] The mean age of onset of MS is 29.2 years,[2] making it the commonest cause in the Western world of nonaccidental neurological disability in young adults.[3] The diagnosis of MS rests on evidence of lesions typical of the disease that are disseminated in space and time, occurring in patients with neurological symptoms.[4] The International Panel on the Diagnosis of Multiple Sclerosis guidelines specify that both clinical and MRI evidence may be used to reach a diagnosis, with the most recent 2010 guidelines updating earlier guidelines to simplify imaging criteria and broaden the applicability of the criteria to populations other than Western Caucasian adults.[4] The most common initial clinical presentation is a single attack of neurological symptoms associated with demyelination, referred to as clinically isolated syndrome (CIS); 63% of patients with CIS will go on to develop MS over a 20-year period.[5] While the clinical course of MS itself is highly variable, 8090% of patients have relapsing-remitting MS (RRMS), which lasts for approximately two decades, after which it may become progressive (secondary progressive MS [SPMS]).[3] In 620% of patients, the disease is progressive from the outset with only minor improvements or plateaus over time (primary progressive MS [PPMS]).[3] Although there is currently no cure for MS, there is good evidence that several disease-modifying
agents (DMAs) reduce relapses, slow the progression of symptoms and disability, and reduce MRI evidence of disease activity in patients with RRMS.[6] Among these treatment options, subcutaneous (SC) interferon-b-1a (IFNb-1a) [Rebif] is approved for the treatment of relapsing forms of MS in more than 90 countries worldwide.[7-9] Relapsing MS includes patients with RRMS or SPMS with superimposed relapses. SC IFNb-1a is not approved for use in PPMS or in patients with SPMS without ongoing relapse activity.[7,8] A serum-free formulation of SC IFNb-1a has been developed without using fetal bovine serum during manufacture, and without human serum albumin as an excipient, in order to reduce immunogenicity and improve tolerability.[10,11] This serum-free formulation of Rebif is approved in the EU for the treatment of relapsing MS, replacing the original formulation.[12] Various Rebif injection devices (Rebiject II, RebiDose and RebiSmart) aimed at increasing ease of injection are now available in many countries in Europe and elsewhere.[13] This article focuses on the pharmacology, efficacy and tolerability of SC IFNb-1a in patients with relapsing MS. The definitions of acronyms for key efficacy and tolerability studies discussed in this article are shown in table I. 2. Pharmacodynamic Properties This section overviews the pharmacodynamic properties of SC IFNb-1a, including its mechanism of action as discussed in earlier reviews (section 2.1),[14-17] and the production of neutralizing antibodies (NAbs) [section 2.2].[11]
2.1 Mechanism of Action
SC IFNb-1a is a mammalian glycoprotein immunomodulator produced by recombinant DNA techniques.[8] It has the same amino acid sequence and molecular weight as endogenous
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Table I. Acronym definitions for efficacy/tolerability studies of subcutaneous interferon-b-1a in patients with relapsing multiple sclerosis Study CAMMS223 EVIDENCE IMPROVE NORMIMS Definition International Campath-iH in Multiple Sclerosis 223 EVidence for Interferon Dose-response EuropeanNorth American Comparative Efficacy Investigating MRI Parameters with Rebif imprOVEd formulation NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta for the treatment of relapsing-remitting Multiple Sclerosis Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis REbif vs Glatiramer Acetate in Relapsing MS Disease Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS
PRISMS REGARD SPECTRIMS
human IFNb and has immunomodulatory, antiviral and antiproliferative actions that are the same as those of IFNb-1b,[6,15,17] another available immunomodulatory therapy for MS, although the two forms differ in the potency of their biological effects.[18] Although the cause of MS is unknown, T-cellmediated autoimmunity is thought to be involved.[16] T cells that are presumed to be specific to myelin basic protein and other CNS proteins are activated to form T-helper (Th) cells. This occurs when MHC presents antigens on the surface of antigen-presenting cells to the surrounding T cells. In turn, these activated, pro-inflammatory Th cells recruit other inflammatory cells (e.g. B cells and monocytes), resulting in an influx of inflammatory cells across the blood-brain barrier (BBB).[16] Thus, activated CD4+, CD8+ and gamma delta T cells, along with other inflammatory components, are found within MS lesions.[17] The precise mechanism of action responsible for the benefits of IFNb in MS is also unknown. However, IFNb activates a transmembrane IFNb receptor triggering a complex cellular cascade that includes up- and downregulation of the expression of more than 800 genes, many of which control pathways that could compensate for abnormal immune processes observed in patients with MS.[16,19] The efficacy of IFNb in MS is likely to be related, at least in part, to its actions on the reg 2011 Adis Data Information BV. All rights reserved.
ulatory pathways that control T-cell differentiation and the transfer of inflammatory cells across the BBB.[16] Specifically, IFNb reduces the activation of T cells, and the formation of pro-inflammatory IFNg, by reducing levels of MHC class II molecules and co-stimulatory molecules on antigenpresenting cells.[16,20] This has the effect of shifting the response towards an anti-inflammatory Th2 immune response.[16,20] The Th2 response results in a reduction in pro-inflammatory cytokines (e.g. interleukin [IL]-2, IL-12 and IFNg) and increased release of cytokines, such as IL-4 and IL-10, that have an inhibitory effect on autoimmune processes.[16,17] The observed reduction in inflammatory cytokine secretion may result from Toll-like receptor 7 upregulation.[21] By reducing pro-inflammatory cytokines, IFNb further inhibits the recruitment of other inflammatory cells.[16] Activated Th cells are supported in crossing the BBB by trophic chemokines that attract them to the blood vessel wall, and by matrix metalloproteinases that facilitate their transfer across the wall.[16] IFNb appears to reduce both trophic chemokine levels and the expression of matrix metalloproteinases, thereby reducing Th cell influx into the CNS.[16] IFNb also increases levels of soluble vascular cell adhesion molecule (sVCAM)-1 and this may be a mechanism whereby IFNb reduces T-cell flux across the BBB, as sVCAM1 may bind very late antigen-4 on T cells preventing their adherence to cerebral endothelium.[22] IFNb has a variety of other effects that may be of importance in MS.[16,23-25] For instance, it increases the capacity of circulating regulatory T cells and myeloid dendritic cells, which also play a part in controlling T-cell differentiation.[23-25] It may also promote T-cell death by reducing levels of the anti-apoptosis factor, FLICE-inhibitory protein, while inhibiting production of cytotoxic reactive oxygen intermediates and nitric oxide, which are damaging to nerve cells.[16]
2.2 Neutralizing Antibodies to Subcutaneous Interferon-b-1a (IFNb-1a)
During treatment with IFNb, some patients develop NAbs, which may be associated with reduced IFNb bioavailability[26] and reduced effiDrugs 2011; 71 (14)
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cacy.[15,27-29] NAbs to one IFNb formulation are cross-reactive to others, although different formulations are not equal with regard to the proportion of patients in whom NAbs are produced.[15] For instance, SC IFNb-1b is associated with a higher rate of NAbs development than SC IFNb-1a,[15] which is more likely to produce NAbs than intramuscular (IM) IFNb-1a.[29] In a post hoc analysis in patients with RRMS in the PRISMS study (n = 368), NAbs to SC IFNb-1a were common (see section 4.1 for study design details). Overall, 30% and 19% of SC IFNb-1a 22 and 44 mg three times weekly (tiw) recipients had a NAbs-positive sample (defined as an antibody titre of 20 neutralizing units/mL) at any time during the 4-year study; 24% and 14% of patients in these groups were persistently NAbs positive to the final assessment.[28] Most patients who developed antibodies did so within the first 12 months of treatment. Titres increased rapidly over 12 to 18 months, and then only marginally subsequently. In all, 22% of patients who were NAbs positive sero-reverted to a NAbsnegative status, most after only a single positive assay. There was no significant relationship between NAbs development and patient age, duration of MS, number of exacerbations in the 2 years prior to the study, corticosteroid use, baseline burden of disease (BOD) or disability scores, but there was evidence of a relationship between NAbs development and reduced efficacy (see section 4.1 for further details).[28] In a 96-week, open-label study in patients with relapsing MS, NAbs developed in 17.4% of 259 patients receiving the serum-free formulation of Rebif 44 mg SC tiw.[11] These data were compared with historical data from the EVIDENCE and REGARD trials; NAbs developed in 21.4% and 27.3% of patients receiving the original formulation of Rebif in the respective trials[11] (see sections 4.2.1 and 4.3 for details of the latter two trials). 3. Pharmacokinetic Properties As the pharmacokinetic profile of SC IFNb-1a has not been evaluated in patients with MS,[14] pharmacokinetic data are from studies in healthy adult volunteers,[30,31] with supplemental in 2011 Adis Data Information BV. All rights reserved.
formation from the EU summary of product characteristics.[7] After SC injection, serum IFNb-1a concentrations are low, but remain measurable for up to 1224 hours.[7] In healthy volunteers (n = 11), after a single dose of SC IFNb-1a 66 mg, the mean peak serum IFNb-1a concentration (Cmax) was 7.5 IU/mL, the mean time to Cmax was 10 hours, and the mean area under the serum concentration-time curve (AUC) from time 0 to 48 hours was 95 IU h/mL.[30] After repeated doses of SC IFNb-1a every other day for four doses, there was moderate accumulation, as the IFNb-1a AUC was increased approximately 2.5-fold over that of a single dose.[7] IFNb-1a is chiefly metabolized and eliminated via the liver and kidneys, and has a long apparent elimination half-life (t).[7] After intravenous injection of IFNb-1a 66 mg, there was a sharp, multi-exponential decline in concentration, with the possibility of a deep compartment. The distribution t was reached in minutes and the terminal elimination t after several hours.[7] The pharmacokinetics of the drug have not been studied in patients with renal or hepatic impairment. The overall pharmacokinetics of the serumfree formulation of Rebif appear to be similar to those of the original formulation.[31] In a study in 48 healthy volunteers, three formulations of SC IFNb-1a (the original Rebif formulation and SC IFNb-1a administered in two test vehicles, one of which is now available as the serum-free formulation of Rebif) had generally similar pharmacokinetic profiles, although there was considerable inter-subject variability in systemic exposure to SC IFNb-1a with all three formulations.[31] Although there are no studies in humans of interactions between SC IFNb-1a and other drugs, interferons may reduce the activity of cytochrome P450 (CYP) enzymes.[7] Therefore, SC IFNb-1a should be administered with caution in patients taking drugs with a narrow therapeutic window that are extensively metabolized by CYP enzymes.[7]
4. Therapeutic Efficacy The efficacy of SC IFNb-1a has been evaluated in randomized, double-blind[32-34] or evalDrugs 2011; 71 (14)
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uator-blind,[29,35,36] multinational trials in patients with RRMS. SC IFNb-1a was compared with placebo (PRISMS)[32] [section 4.1], IM IFNb-1a (EVIDENCE)[29] [section 4.2], glatiramer acetate (REGARD)[35] and alemtuzumab (CAMMS223)[36] [section 4.3]. A further trial evaluated the efficacy of methlyprednisolone as an add-on to SC IFNb-1a (NORMIMS)[33] [section 4.4]. The PRISMS and EVIDENCE trials had crossover extension phases commencing at the end of the comparative phase.[37,38] The efficacy of the serum-free formulation of SC IFNb-1a was assessed against placebo in the IMPROVE trial (section 4.1.3).[34] The efficacy of SC IFNb-1a was also evaluated in patients with SPMS in the randomized, double-blind, placebo-controlled, multinational SPECTRIMS trial (section 4.1.4).[39] Across all trials that evaluated clinical endpoints, relapses were defined as new or worsening symptoms lasting 24[32,39] or 48[29,33,35,36] hours in association with objective neurological changes after a period of clinical stability. Disability endpoint measures were chiefly based on scores on the Kurtzke Expanded Disability Status Scale (EDSS), an ordinal scale rated in half points from 0 (normal neurological examination) to 10 (death due to MS).[40] MRI scans were performed at baseline and at intervals across the trials in all patients,[29,32-34,36,39] or in a subset of patients.[35] Selected design details and patient characteristics at baseline for these trials are shown in table II.
4.1 Compared with Placebo
4.1.1 Efficacy Over 2 Years
PRISMS (table II) was a large, placebocontrolled trial of SC IFNb-1a 22 or 44 mg tiw in patients with RRMS.[32,41,42] SC IFNb-1a was effective in reducing relapses relative to placebo during 2 years of randomized treatment.[32] In both SC IFNb-1a 22 and 44 mg dosage groups, the mean 2-year relapse rate was significantly lower than in the placebo group (table III), with relative risk reductions of 27% and 33%. In the corresponding groups, the median times to first relapse were 3 and 5 months
longer than in the placebo group (statistical analyses not reported).[32] SC IFNb-1a recipients also had less progression of disability than placebo recipients.[32] Compared with placebo, both SC IFNb-1a dosage groups had significantly smaller increases in mean EDSS scores, and the first quartile time to sustained progression was significantly longer (table III). In patients with a higher level of disability at baseline (i.e. EDSS score >3.5), SC IFNb-1a 44 mg recipients, but not 22 mg SC recipients, had a significantly longer (p < 0.05) first quartile time to sustained progression than placebo recipients.[32] For other clinical endpoints, treatment with SC IFNb-1a was generally more efficacious than placebo.[32] Both dosages were associated with a higher percentage of patients who were relapsefree, a lower moderate or severe relapse rate and lower rates of corticosteroid use, than placebo. SC IFNb-1a 44 mg, but not the lower dosage, led to fewer patients hospitalized for MS and a lower progression in the Hauser Ambulation Index (indicating better mobility) than placebo. All of the above-mentioned between-group differences were significant at the p < 0.05 or a higher significance level.[32] SC IFNb-1a was also more efficacious than placebo, in terms of MRI endpoints.[41] Both SC IFNb-1a groups had significantly more favourable median changes from baseline in BOD at 2 years than the placebo group (table III). The SC IFNb-1a groups also had significantly fewer T2weighted (T2W) and combined unique (CU) active lesions per patient per scan than the placebo group (table III). Overall, 50% and 25% of SC IFNb-1a 22 mg and 44 mg recipients had T2W active scans versus 75% of placebo recipients (p < 0.0001 for both SC IFNb-1a groups vs placebo). In the corresponding groups, 19%, 31% and 8% of patients had no T2W activity (p < 0.001 for both SC IFNb-1a groups vs placebo).[41] SC IFNb-1a 44 mg recipients also had significantly fewer T2W active lesions per patient per scan than SC IFNb-1a 22 mg recipients (table III).[41] In an intensively-scanned subgroup of 205 patients who had monthly MRI scans for 9 months, 13%, 11% and 44% of SC IFNb-1a 22 mg, SC IFNb-1a 44 mg and placebo recipients, respectively,
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Table II. Design details and patient (pt) characteristics in randomized, double-blind[32-34] or evaluator-blind,[29,35,36] multinational trials of subcutaneous (SC) interferon-b-1a (IFNb1a) in adult pts with relapsing-remitting multiple sclerosis. Primary analyses were in the intent-to-treat (ITT) populations.[29,32-36] Baseline data are means/medians in the full ITT population or the range across treatment groups Parameter Trial duration (no. of pts) Treatment arms SC IFNb-1a tiw comparatorb Key inclusion criteriac MS diagnostic criteria EDSS score relapses other Poser 05.0 2 in prior 2 y McDonald 5.5 1 in prior 6 mo 1 enhancing lesion in prior 6 mo 2-y relapse rate Number of CU active lesions at wk 16 Proportion of pts relapse-free at 24 wk Poser 05.5 2 in prior 2 y McDonald 05.5 1 in prior 12 mo stable or improving in 4 wk before randomization Time to first relapse McDonald 3 2 in prior 2 y 1 enhancing lesion; symptom onset within 36 mo Time to sustained disability; annualized relapse rate over 36 mo Poser 5.5 1 in prior 12 mo IFNb-1a treatmentd 22 or 44 mg PL 44 mg PL 44 mg IM IFNb-1a 44 mg SC glatiramer acetate 44 mg IV alemtuzumab 44 mg + MTPa SC IFNb-1a 44 mg tiw + PL PRISMS[32,41] 2 y (560) IMPROVE[34] 16 wk (180) EVIDENCE[29] 24 wk (677) REGARD[35] 96 wk (764) CAMMS223[36] 36 mo (334) NORMIMS[33] 96 wk (130)
Primary endpoint(s)
Annualized relapse rate over 36 mo
Baseline characteristics age (y) female (%) EDSS score no. of relapses (prior 2 y) illness duration (y) time since first relapse (y) a b Oral MTP 200 mg on 5 consecutive days q4wk for 96 wk. IM IFNb-1a 30 mg qw; glatiramer acetate 20 mg od; alemtuzumab 12 or 24 mg od for 3 cycles (5 consecutive days in month 1 and on 3 consecutive days in months 12 and 24). 35 69 2.5 3.0 5.3 3738 75 2.3 2.6 6.56.7 5.96.6 1.31.4 5.37.0 37 6972 2.32.4 12 3233 64 1.92.0 2 39 5667 2.52.9 1.0
c Key exclusion criteria were treatment with interferons,[29,32,35] treatment with other disease-modifying treatments,[29,32,33,35] clinically significant medical conditions or autoimmunity.[33,36] d SC IFNb-1a for 12 mo (44 mg tiw for most recent 3 mo). CU = combined unique; EDSS = Kurtzke Expanded Disability Status Scale; IM = intramuscular; IV = intravenous; MS = multiple sclerosis; MTP = methylprednisolone; od = once daily; PL = placebo; qw = once weekly; q4wk = every 4 weeks; tiw = three times weekly.
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Table III. Efficacy of subcutaneous (SC) interferon-b-1a (IFNb-1a) administered three times weekly (tiw) in patients (pts) with relapsing-remitting multiple sclerosis. Results from the randomized, double-blind, placebo (PL)-controlled PRISMS trial[32,41] and its controlled, 2-year, crossover extension (PRISMS-4).[37] In PRISMS-4, completers who received PL in PRISMS were re-randomized and crossed over to SC IFNb-1a 22 mg tiw or 44 mg SC tiw, while completers from the active treatment groups continued with their dosage unchanged. Proton-density T2-weighted (T2W) scans were performed at baseline and every 6 mo in PRISMS and annually in PRISMS-4; T2W and gadolinium-enhanced T1-weighted (T1W) scans were performed once monthly in some pts. Pt numbers are shown in square parentheses PL Crossover extension phase (y 24)[37] SC IFNb-1a SC IFNb-1a PL - SC IFNb-1a 22 mg tiw 44 mg tiw 22 mg tiw PL - SC IFNb-1a 44 mg tiw 1.06 [87]a 24.2 [87] 9.7 [NR] 2.7 [92]
Endpoints
Comparison phase (y 02)[32,41] SC IFNb-1a SC IFNb-1a 22 mg tiw 44 mg tiw
1.73** [184]a 2.56 [187]a Mean 2-y relapse rate 1.82** [189]a Annualized relapse rateb 0.80--- [167]a 0.72--- [167]a 0.99 [85]a Mean change in EDSS score 0.23* [189] 0.24* [184] 0.48 [187] Time to progression in disability (mo)c 18.5* [189] 21.3* [184] 11.9 [187] 35.9 [187] 42.1- [167] 24.9 [85] -1.2*** [172] -3.8*** [171] 10.9 [172] 3.4 [NR] -6.2-- [NR] 7.2 [NR] Median change in disease burden (%)d Median T2W active lesions per pt per scan 0.75*** [185] 0.5*** [182] 2.25 [184] 1.3--- [180] 0.5--- [180] 2.0 [90] Median CUA lesions per pt per scan 0.17*** [64] 0.11*** [68] 0.88 [66] a Primary endpoint. b Estimates from a Poisson regression model. c First quartile[32] or 40th percentile[37] time to disability progression, defined as a 1-point increase in EDSS score from baseline sustained over 3 mo. d Measured as the volume of T2W active lesions on MRI after 2 y.
CUA = combined unique active lesions from T1W and T2W scans; EDSS = Kurtzke Expanded Disability Status Scale; NR = not reported; - indicates randomized to; * p < 0.05, ** p < 0.005, *** p < 0.0001 vs PL; - p < 0.05, -- p < 0.01, --- p < 0.001 vs PL crossover group at the corresponding dosage; p = 0.009, p < 0.001 vs SC IFNb-1a 22 mg tiw.
had CU active scans (p < 0.0001 for SC IFNb-1a groups vs placebo); in the corresponding groups, 31%, 41% and 11% of patients had no CU activity (p < 0.01 for both SC IFNb-1a groups vs placebo).[41]
4.1.2 Longer-Term Efficacy
Efficacy in Early-Onset Relapsing-Remitting Multiple Sclerosis
PRISMS-4
Consenting PRISMS trial completers who were suitable for continuing blinded treatment (n = 506) were included in the PRISMS crossover extension (PRISMS-4).[37] Patients who received SC IFNb-1a during the PRISMS trial continued on their randomized treatment, while placebo recipients were re-randomized to SC IFNb-1a 22 or 44 mg tiw.[37] Continuous SC IFNb-1a treatment was more efficacious than placebo for 2 years followed by SC IFNb-1a treatment for 2 years, and treatment with SC IFNb-1a 44 mg was associated with greater benefits than treatment with 22 mg for some endpoints.[37] At the 4-year follow-up, patients continuing on SC IFNb-1a had significantly lower annualized relapse rates than patients who crossed over to SC IFNb-1a (table III). Patients who received continuous SC IFNb-1a were also significantly (p < 0.05) more likely to be relapse free than patients in the crossover groups (14.4% and 19.0% of patients in the SC IFNb-1a 22 and
A post hoc exploratory analysis of the PRISMS trial compared the efficacy of SC IFNb-1a 44 mg tiw (n = 38) with placebo (n = 31) in a subgroup of patients with early-stage RRMS (defined as disease duration of 3 years and EDSS score of 2) [data are from an abstract].[43] At 2 years, the mean number of relapses was reduced from 3.1 to 1.1 in SC IFNb-1a versus from 3.5 to 2.3 in placebo recipients (p = 0.0109), and a significantly higher proportion of SC IFNb-1a recipients were free of relapses (52.6% vs 22.6% of placebo recipients; p = 0.0115). The median time to first relapse was 24 months in the SC IFNb-1a group versus 6 months with placebo (p = 0.0046). At 2 years, the SC IFNb-1a subgroup had a mean of 0.8 T2W active lesions per patient per scan (vs 3.3 in the placebo group; p < 0.0001).[43]
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44 mg groups vs 6.7% in the crossover groups combined).[37] Time to disability progression was significantly longer in patients who continued SC IFNb-1a 44 mg than in patients who crossed over from placebo to SC IFNb-1a 44 mg (table III).[37] At the end of the fourth year, 51%, 56% and 46% of patients were progression-free in the continuous SC IFNb-1a 22 mg, continuous SC IFNb-1a 44 mg and crossover groups (combined), respectively.[37] Continuous SC IFNb-1a 44 mg recipients, but not continuous SC IFNb-1a 22 mg recipients, had a significant reduction in BOD, relative to those in the corresponding crossover groups (table III).[37] Continuous SC IFNb-1a 22 and 44 mg recipients also had significantly fewer T2W active lesions per patient per scan than the patients in the crossover groups; recipients of continuous SC IFNb-1a 44 mg had significantly fewer T2W active lesions than SC IFNb-1a 22 mg recipients (table III). Crossover patients also had a significantly (p < 0.001) lower proportion of scans with T2W active lesions during the crossover phase than in the placebo phase.[37] Prospective crossover analyses conducted in placebo recipients who crossed over to SC IFNb1a 22 or 44 mg tiw in years 34 adopted a beforeafter analytic strategy, whereby each individual patient acted as their own control (n = 172).[44] In general, patients had improved clinical and MRI outcomes while receiving active treatment with SC IFNb-1a compared with the placebo phase. For instance, the 2-year relapse rates in years 12 (placebo phase) and years 34 (active treatment phase) were 2.6 and 1.2 in patients who switched to SC IFNb-1a 22 or 44 mg (p < 0.001 vs the year 12 baseline in both dosage groups). The 25th percentile time to confirmed progression of disability was 12 months during years 12 (both groups) versus 18 months in the 22 mg dosage group during years 34, and was not reached in this time period in the 44 mg dosage group. The difference in the mean number of T2W active lesions between years 12 and years 34 was -3.1 and -3.6 in the SC IFNb-1a 22 and 44 mg groups, with a significant decrease in the median lesion area during years 34 compared with years 12 (p < 0.001 for both groups).[44]
Post hoc exploratory analyses evaluated the effect of NAbs on clinical and MRI endpoints in SC IFNb-1a recipients, including 90 patients who were NAbs positive and 278 who were NAbs negative (see section 2.2 for details of NAbs development in this population).[28] Although findings were inconsistent, the weight of the evidence was that NAbs development was associated with reduced efficacy of SC IFNb-1a.[28] Based on the proportion of NAbs-positive patients at the end of a specified 6-month interval, the 4-year mean annualized relapse rate was 0.86 in NAbspositive patients versus 0.74 in NAbs-negative patients (p = 0.02). Furthermore, there was a positive association between the NAbs titre and the relapse rate (p = 0.008). Over the 4-year study period, there was also a significant group difference in the disability progression rate (rate ratio for NAbs positive : NAbs negative was 1.5; 95% CI 1.03, 2.17; p = 0.03).[28] Patients who had a NAbs-positive sample at any time during the 4-year study generally had poorer outcomes on MRI endpoints than NAbsnegative patients.[28] For example, in SC IFNb-1a 22 mg and 44 mg tiw recipients, the median cumulative percentage changes in T2W lesion burden from baseline to year 4 were -4.3% and -8.5% and 16.3% and 17.6% in the NAbs-negative and NAbs-positive groups, respectively (p < 0.001 for NAbs negative vs NAbs positive for both dosage groups).[28]
PRISMS Long-Term Follow-up
Of 560 patients enrolled in the PRISMS trial, 382 patients were included in a long-term follow-up (LTFU), which comprised a single visit assessment 78 years after enrolment in the PRISMS study.[45] As with other LTFUs, the results may be subject to bias resulting from loss of participants. At the LTFU assessment, 72% of LTFU participants were receiving SC IFNb-1a 22 or 44 mg tiw (42% were at the 44 mg dosage) and 21% of participants were not receiving a DMA.[45] Thus, not all patients received continuous treatment with SC IFNb-1a during the follow-up period. At the LTFU assessment, the mean EDSS score was 3.5, representing a mean increase of 1.1 points relative to PRISMS baseline.[45]
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Approximately 50% of the patients had a onestep progression in disability (i.e. a 1 point increase in EDSS score), and progression to SPMS occurred in 19.7% of patients, with a mean time to SPMS (10th percentile) of 5.3 years.[45] Based on all available data from the full PRISMS population, the estimated annualized relapse rate for the whole study period (baseline to 78 years) was 0.67 per patient, with relapse rates of 0.63 and 0.60 in SC IFNb-1a 22 mg and 44 mg recipients; 71 patients (13%) were relapsefree during their observed follow-up (32 of these patients were evaluated at the LTFU visit and were presumably relapse-free for 78 years).[45] At the LTFU assessment, the mean percentage change in T2W BOD scores was +5.0% in patients originally randomized to SC IFNb-1a 44 mg versus +24.5% in patients randomized to placebo (p = 0.002).[45] These between-group differences in BOD appeared to accrue chiefly during the first 2 years of treatment. Across all treatment groups, brain parenchymal volume (BPV) had declined, with a median change from baseline to LTFU of -3.9%. In the first 24 months of the PRISMS trial, the decline in BPV was significantly greater in the SC IFNb-1a 44 mg group than the SC IFNb-1a 22 mg (p = 0.009) and placebo (p = 0.010) groups, with differences converging by LTFU assessment. It is thought that this early loss of BPV may relate to a stronger anti-inflammatory effect of higherdosage treatment.[45]
4.1.3 Serum-Free Formulation of Subcutaneous IFNb-1a
The serum-free formulation of SC IFNb-1a was more efficacious than placebo in preventing the development of brain lesions detected by MRI.[34] Using the baseline MRI as the reference scan, SC IFNb-1a recipients had significantly fewer CU active lesions than placebo recipients at week 16 (0.9 vs 3.0; p < 0.001) [primary endpoint], with the estimated ratio of means indicating that there were 69% fewer lesions in the SC IFNb-1a than the placebo group. In a post hoc analysis, the mean cumulative rate of CU active lesions was significantly (p 0.015) lower in the SC IFNb-1a group than in the placebo group at each 4-week assessment point from the initial week-4 follow-up.[34]
4.1.4 In Patients with Secondary Progressive Multiple Sclerosis
The IMPROVE trial (table II) evaluated the effects of the serum-free formulation of SC IFNb-1a on MRI endpoints.[34] Patients were randomized to receive SC IFNb-1a (serum-free formulation of Rebif) 44 mg tiw (n = 120) or placebo (n = 60) in a double-blind fashion for 16 weeks, after which all patients received openlabel SC IFNb-1a 44 mg tiw for a further 24 weeks, followed by a 4-week safety observation period.[34] In all, 110 and 56 SC IFNb-1a and placebo recipients completed the full 40-week trial period; in the respective groups, 112 and 57 patients were included in analyses of secondary endpoints.[34]
The 3-year placebo-controlled SPECTRIMS trial evaluated the efficacy of SC IFNb-1a 22 or 44 mg tiw in patients with SPMS.[39] Patients were required to have an EDSS score of 36.5 and evidence of clinical progression in the prior 2 years, but with no relapses in the prior 8 weeks.[39] There were no significant differences between the SC IFNb-1a 22 mg (n = 209), SC IFNb-1a 44 mg (n = 204) and placebo (n = 205) groups in the time to progression of disability (increase in EDSS score of 1 point, or 0.5 points if the baseline EDSS score was 5.5) [primary endpoint].[39] However, SC IFNb-1a 22 mg and 44 mg groups had significantly lower mean annualized relapse rates than the placebo group (0.5 in both SC IFNb-1a groups vs 0.71 in the placebo group; p < 0.001), which represents an 30% relative risk reduction.[39] SC IFNb-1a was also associated with significant (p < 0.0001) reductions in T2W active lesions, CU active lesions and accumulation of BOD, compared with placebo.[46] Subgroup analyses were conducted at the request of regulatory authorities.[39] In patients with and without relapses in the prior 2 years, the hazard ratios (HRs) [SC IFNb-1a 44 mg : placebo] for time to progression of disability were 0.76 (95% CI 0.53, 1.10) in the subgroup with relapses and 0.93 (95% CI 0.65, 1.33) in the subgroup without relapses (HRs were not significant).[39] For patients with prior relapses, the proportion
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of SC IFNb-1a 22 or 44 mg recipients who had progression of disability was significantly lower than in placebo recipients (odds ratio [OR] 0.52; 95% CI 0.29, 0.93; p = 0.027), whereas there was no significant between-group difference in patients without prior relapses (OR 1.07; 95% CI 0.64, 1.78).[39] These results suggest that SC IFNb-1a may be efficacious in patients with SPMS who experience relapses.[39]
4.2 Compared with Intramuscular IFNb-1a
4.2.1 Efficacy Over 24 and 48 Weeks
IFNb-1a 44 mg recipients who were NAbs negative had significantly fewer T2W-active lesions at week 48 than SC IFNb-1a 44 mg recipients who were NAbs positive (0.6 vs 1.6; p = 0.0004).[29]
4.2.2 Longer-Term Efficacy
The EVIDENCE trial (table II) compared high-dosage SC IFNb-1a (44 mg tiw) with lowdosage IM IFNb-1a (Avonex) [30 mg once weekly].[29] As these recommended dosages were markedly different, this trial is chiefly a test of a high- versus low-dosage IFN regimen.[29] A significantly higher proportion of SC IFNb1a 44 mg recipients remained relapse-free after 24 weeks of treatment than IM IFNb-1a 30 mg recipients (table IV).[29] SC IFNb-1a 44 mg recipients were also significantly more likely to be relapse-free at 48 weeks than IM IFNb-1a 30 mg recipients (table IV). Compared with IM IFNb1a 30 mg, SC IFNb-1a 44 mg recipients had a significantly longer time to first relapse (HR 0.70; 95% CI 0.55, 0.88; p = 0.003), and significantly lower relapse rates at 24 weeks, but not at 48 weeks (table IV). Similarly, SC IFNb-1a 44 mg recipients had a significantly (p < 0.05) lower mean number of corticosteroid courses than IM IFNb-1a 30 mg recipients.[29] At 24 weeks, SC IFNb-1a 44 mg recipients had significantly fewer CU active lesions per patient per scan than IM IFNb-1a 30 mg recipients (0.8 vs 1.2; p < 0.0001) [principal MRI endpoint].[29] Similarly, reductions in T2W active lesion endpoints were observed over 48 weeks (table IV).[29] Patients who received SC IFNb-1a 44 mg for 48 weeks were more likely than IM IFNb-1a 30 mg recipients to develop NAbs (25% vs 2%; p < 0.001), but in the SC IFNb-1a 44 mg group, there were no significant differences between the NAbs-positive and -negative patients in the proportion remaining relapse-free, the probability of first relapse, or relapse rates.[29] However, SC
The EVIDENCE crossover extension included 495 completers from the EVIDENCE trial who continued treatment for a median of 34 weeks during the crossover phase.[38,47] Patients who had been randomized to low-dosage IM IFNb-1a 30 mg weekly during the earlier EVIDENCE comparative phase were switched to high-dosage SC IFNb-1a 44 mg tiw, while patients randomized to high-dosage SC IFNb-1a continued their treatment unchanged.[38] Among patients who crossed over to SC IFNb-1a 44 mg, there was a significant reduction in the mean annualized relapse rate (table IV).[38] The mean annualized relapse rate was also significantly reduced in patients who received continuous SC IFNb-1a treatment group (table IV), but the reduction was significantly (p = 0.047) smaller than in the crossover group.[38] During the post-transition period, patients who crossed over to SC IFNb-1a 44 mg also had significant improvements in MRI-related outcomes, including the median number of T2Wactive lesions per patient per scan and proportion of active scans per patient, although there was no significant change in the proportion of patients with no active scans (table IV).[38] These parameters did not show any significant additional improvement from pre-crossover values in patients who continued treatment with SC IFNb-1a 44 mg.[38]
4.3 Compared with Other Disease-Modifying Agents
The efficacy of SC IFNb-1a was compared with SC glatiramer acetate in the REGARD trial,[35] and with intravenous alemtuzumab in the CAMMS223 trial (table II).[36] In the REGARD trial, there were no significant benefits of SC IFNb-1a 44 mg tiw over glatiramer acetate 20 mg once daily for any clinical endpoint.[35] There was no significant difference
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Table IV. Efficacy of interferon-X-1a (IFNX-1a) 44 mg subcutaneous (SC) three times weekly (tiw) in comparison with intramuscular (IM) IFNb-1a 30 mg once weekly (qw) in patients (pts) with relapsing-remitting multiple sclerosis. Results from the randomized, evaluator-blind, multinational EVIDENCE trial[29] and its 8-mo evaluator-blinded, crossover extension study.[38,47] During the extension phase, pts who had previously been randomized to IM IFNX-1a received SC IFNX-1a, whereas pts randomized to SC IFNX-1a continued their treatment unchanged. Proton-density T2-weighted (T2W) scans were performed every 4 wk for 24 wk, and at 24-wk intervals, thereafter. In the comparison phase, analyses were in the intent-to-treat population with missing data imputed using random number allocation based on proportions of pts not experiencing relapse
between SC IFNb-1a and glatiramer acetate in time to first relapse (primary endpoint) [HR 0.94; 95% CI 0.74, 1.21; p = 0.64), with 30th percentile times to first relapse of 495 and 432 days in the respective groups. Similarly, there were no significant between-group differences in the proportions of patients who remained relapse-free, the annualized relapse rate, or months to sustained disability. In this trial, relapses occurred at a much lower frequency than expected, reducing the likelihood of significant between-treatment differences.[35] For MRI endpoints, there were no betweengroup differences in measures of T2W active lesions or new T1 hypointense lesions on MRI.[35] However, SC IFNb-1a recipients had significantly (p 0.01) better outcomes than glatiramer acetate recipients in terms of gadolinium-enhancing lesions (lesions per patient per scan; scans per patient with lesions; and patients with no lesions) and CU active lesions (lesions per patient per scan; and scans per patient with no lesions). Glatiramer acetate recipients had significantly (p < 0.05) smaller reductions in brain volume over 96 weeks than SC IFNb-1a recipients.[35] In the CAMMS223 trial, intravenous alemtuzumab was more efficacious than SC IFNb-1a 44 mg tiw in preventing relapses and in reducing the risk of developing sustained disability.[36] The annualized relapse rates in alemtuzumab recipients were significantly lower than in SC IFNb-1a recipients (table V). The HR for the annualized relapse rate represented a relative risk reduction of 74%. Alemtuzumab was also associated with a significantly lower proportion of patients with progression of disability (table V), with a relative risk reduction of 71%. Alemtuzumab recipients also had a significantly more favourable mean change from baseline in EDSS score than SC IFNb-1a recipients, representing a relative improvement in function (table V).[36] All treatments led to an improvement in T2W lesion load from baseline to 36 months.[36] While there was no significant difference between treatments in the percentage change in this parameter at 36 months (table V), the alemtuzumab groups had significantly (p = 0.05) greater improvements in lesion load than SC IFNb-1a at 12 and
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IM IFNX-1a 30 mg qw - SC IFNX-1a 44 mg tiw (n = 223)a
2448 wk
0.32--c,b
0.70.9
26-37
pre-cross
81
0.64
Crossover phase (8 mo)[38,47]
60
61
Relapse free (% of pts)
Mean annualized relapse rate
pre-cross = pre-crossover; - indicates randomized to; * p < 0.05, ** p < 0.01, *** p < 0.001 vs IM IFNb-1a; - p < 0.05, -- p < 0.001 vs pre-cross value.
SC IFNX-1a 44 mg tiw (n = 272a)
2448 wk
0.34-b
1.1 0.8
24 22
pre-cross
82
0.46
(n = 338) 48 wk
74
71
c The reduction from baseline was significantly greater than for the continuous SC IFNb-1a group (p = 0.047).
IM IFNX-1a 30 mg qw
T2W active scans (% of scans/pt)
Mean T2W active lesions/pt/scan
No T2W active scan (% of pts)
There were 235 and 188 pts in the continuous SC IFNb-1a and crossover groups in the MRI analyses. a
0.64
1.4
***
52
43
***
SC IFNX-1a 44 mg tiw
(n = 339) 48 wk
62**
0.54
0.9 0.6
***
27 27
***
Comparison phase (12 y)[29]
IM IFNX-1a 30 mg qw
(n = 338) 24 wk
0.40
63b
(n = 339) 24 wk
SC IFNX-1a 44 mg tiw
75***b
0.29*
0.3
15
60
***
43
63
***
45
Mean relapse rate
Endpoints
Primary endpoint.
1877
Table V. Efficacy of subcutaneous (SC) interferon-b-1a (IFNb-1a) 44 mg three times weekly (tiw) in comparison with intravenous (IV) alemtuzumab (ALEM),[36] and when used alone or in combination with oral methylprednisolone (MTP)[33] in patients (pts) with relapsing-remitting multiple sclerosis. Clinical and MRI endpoints in randomized, double-blind[33] and evaluator-blind,[36] multinational trials Trial (duration) Regimen [no. of pts] Clinical endpoints annualized relapse rate CAMMS223[36] (36 mo) NORMIMS[33] (96 wk) a b c d e f g h SC IFNb-1a [111] ALEM 12 mg [112]
f
MRI endpointsa progression of disability (% of pts) 26.2e

***
relapsefree (% of pts) 51.6 77.0 76-34 83.5***
mean change in EDSS score 0.38 -0.32** -0.45***
change in T2W lesion load/volumeb -13.3 -18.2 -13.5 -136.6464.7
change in brain volumec -1.8 -0.9 0* -1.33 -1.60
0.36d 0.11
***d
8.5***e 9.5**e 16 25
ALEM 24 mg [110]f SC IFNb-1a+ MTPg [66] SC IFNb-1a +PLg [64]
0.08***d 0.22--h 0.59h
The MRI data are shown as median changes from baseline in 227 patients across treatment groups[36] or mean changes from baseline to trial completion in the intent-to-treat population.[33] Percentage[36] or mm change from baseline.[33] Percentage change from baseline. Coprimary endpoint; HR (ALEM groups combined vs SC IFNb-1a) was 0.26 (95% CI 0.16, 0.41; p < 0.001). Coprimary endpoint; HR (ALEM groups combined vs SC IFNb-1a) was 0.29 (95% CI 0.16, 0.54; p < 0.001). ALEM was administered as daily IV infusions for 3 cycles (5 consecutive days in month 1 and on 3 consecutive days in months 12 and 24) MTP 200 mg or placebo were administered on 5 consecutive days every 4 wk for at least 96 wk. Primary endpoint.
EDSS = Kurtzke Expanded Disability Status Scale; HR = hazard ratio; PL = placebo; T2W = proton-density T2-weighted; * p 0.05, ** p < 0.01, *** p < 0.001 vs SC IFNb-1a; - p < 0.05, -- p < 0.0001 vs SC IFNb-1a + PL.
24 months, and in a multivariate comparison for all timepoints. SC IFNb-1a recipients had a significantly greater loss of brain volume than recipients of the alemtuzumab 24 mg, but not 12 mg, regimen (table V).[36]
4.4 In Combination with Add-On Methylprednisolone
The NORMIMS trial (table II) evaluated whether oral methylprednisolone was effective as an add-on treatment in patients who had experienced relapse despite being treated with SC IFNb-1a 44 mg tiw.[33] Enrolment was stopped after inclusion of 130 of the planned 300 patients because of slow recruitment. Of 130 randomized patients, 55 discontinued study medication, with approximately half (27 patients) discontinuing after week 96.[33] In light of inadequate power and the high dropout rate, the findings should be considered as tentative. Patients who received combined treatment with SC IFNb-1a 44 mg tiw plus oral methlyprednisolone had a significantly lower mean annualized relapse rate over 96 weeks than patients
who received SC IFNb-1a 44 mg tiw plus placebo (table V), with a relapse relative risk reduction of 62%.[33] These findings were robust, according to sensitivity analyses that assessed the impact of patient withdrawals from the study.[33] In addition, significantly more combinedtreatment recipients than SC IFNb-1a plus placebo recipients remained relapse free (table V). However, there were no significant differences between treatments in terms of other clinical and MRI endpoints, except that the combined-treatment groups had a significantly more favourable change from baseline in the volume of T2W active lesions than the SC IFNb-1a plus placebo group (table V).[33] 5. Tolerability
5.1 General
SC IFNb-1a was generally well tolerated in the clinical trials in RRMS discussed in section 4, with most adverse events being of mild to moderate severity and manageable without need to discontinue treatment.[7] The most common treatment-emergent adverse events were influenza-like
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symptoms, injection-site reactions, haematological disturbances and hepatic enzyme abnormalities.[7] The most common serious treatment-emergent adverse events reported with SC IFNb-1a were psychiatric disorders, which can include depression and suicidal ideation.[8] Laboratory abnormalities also occur, particularly disturbances in hepatic enzymes and cytopenias (see section 5.2).[7]
5.1.1 Compared with Placebo
In the PRISMS trial, treatment-emergent adverse events were common, although only 3% of patients across treatment groups discontinued treatment because of adverse events.[32] Adverse events were reported most frequently in the first month of treatment, with the frequency declining thereafter.[42] Adverse events at 3 months are shown in figure 1; data at this timepoint provided the best indication of drug-placebo differences in rates.[32] Injection-site reactions were the most common adverse events associated with SC IFNb-1a 22 or 44 mg tiw and were significantly more frequent than with placebo at both SC IFNb-1a dosages. SC IFNb-1a 44 mg, but not
70 60 50 40 30 20 * *
22 mg, recipients also had significantly more haematological disturbances and increases in hepatic enzymes.[32] There was no difference between the SC IFNb-1a 22 and 44 mg dosage groups in the rate of injection-site reactions (60.8% and 61.9%).[32] In all, 1% and 3% of SC IFNb-1a 22 and 44 mg recipients developed injection-site necrosis during the 2-year study period.[8] In logistic regression analyses, SC IFNb-1a recipients who were NAbs positive at the end of a specified 6-month period had significantly lower rates of injection-site reactions (OR 0.22; p < 0.001), fever (OR 0.46; p = 0.02), lymphopenia (OR = 0.48; p = 0.03), leukopenia (OR 0.44; p = 0.03) and elevated liver transaminases (OR 0.44; p = 0.03) than patients who were NAbs negative,[28] which is consistent with reduced pharmacodynamic effects in the presence of antibody formation.
5.1.2 Longer-Term Follow-Up
The PRISMS study provides the best evidence regarding the longer-term tolerability of SC IFNb-1a, as patients were followed for up to 8 years.[42] During the first 4 years of follow-up,
SC IFN-1a 22 g (n = 189) SC IFN-1a 44 g (n = 184) PL (n = 187)
Incidence (% of pts)
* 10 0
ns ia e ue ia a ia s r T ve om ch en lg ni en AL M ya da Fe op pe ac Fa to op pt ea m AS tio tig T
ph
sy
cy nu lo
ke
n-
-li
Ly
si
za
io
ct
je
In
Clinical Adverse Events
flu
In
en
Fig. 1. Tolerability of subcutaneous (SC) interferon-b-1a (IFNb-1a) 22 or 44 mg three times weekly compared with placebo (PL) in patients (pts) with relapsing-remitting multiple sclerosis in the randomized, double-blind, multinational PRISMS trial.[32] Treatment-emergent adverse events occurring after 3 mo of treatment. indicates increased; * p < 0.05 vs PL.
ra
Laboratory Abnormalities
Le
te
uk
re
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27 patients (4.8%) withdrew from treatment because of adverse events, most commonly injectionsite reactions (eight patients) and influenza-like symptoms (five patients). Overall, the frequency of adverse events was highest in the first month of therapy.[42] No new safety concerns were raised at the LTFU.[45]
5.1.3 Serum-Free Formulation of Subcutaneous IFNb-1a
In a trial designed to assess the transition from the original to the serum-free formulation of Rebif administered at a dosage of 44 mg tiw in patients with RRMS (n = 117), there was no clinically meaningful change in influenza-like symptoms during the 4 weeks after the switch; influenza-like symptoms that did occur rarely required treatment.[48] A descriptive analysis compared adverse event rates in IFNb-naive patients with relapsing MS who were treated with the serum-free formulation of Rebif 44 mg tiw (n = 260) in an open-label study with those reported for the original formulation in the EVIDENCE and REGARD trials. Injection-site reactions occurred in 31% of serum-free formulation recipients, which is a numerically lower rate than that observed in the trials of the original formulation (86% in the EVIDENCE trial and 41% in the REGARD trial).[11] Although statistical testing could not be performed, influenza-like symptoms appeared to be more frequent in recipients of the serum-free formulation (72% vs 49% and 36% in the EVIDENCE and REGARD trials), whereas rates of other adverse events appeared to be similar or lower (hepatic disorders [14% vs 19% and 10%], cytopenias [14% vs 13% and 8%], depression and suicidal ideation [7% vs 23% and 9%], skin rashes [6% vs 17% and 7%], hypersensitivity reactions [6% vs 6% and 5%] and thyroid disorders [4% vs 7% and 3%]). In all, 5.8% of patients treated with the serum-free formulation had serious adverse events and 12% had adverse events that led to permanent discontinuation of treatment.[11]
5.1.4 Compared with Intramuscular IFNb-1a and Other Disease-Modifying Agents
In the EVIDENCE trial, injection-site reactions (inflammation, pain, other), elevated ALT,
liver function abnormalities (in general) and white blood cell abnormalities were significantly (p < 0.05) more common in SC IFNb-1a 44 mg tiw than IM IFNb-1a 30 mg once-weekly recipients.[29] In all, 84% and 92% of injection-site reactions events in the SC and IM IFNb-1a groups were considered by physicians to be of mild severity.[29] In the REGARD trial, 6% and 5% of SC IFNb-1a 44 mg tiw and glatiramer acetate 20 mg once-daily recipients discontinued treatment because of adverse events; in both groups, 95% of adverse events were of mild or moderate severity.[35] Treatment-emergent adverse events occurring in 5% of patients in either group and those that differed significantly between groups are shown in figure 2a. Influenza-like illnesses, headache, myalgia and increased ALT levels were significantly more frequent in SC IFNb-1a than glatiramer acetate recipients, whereas injection-site reactions, dyspnoea and post-injection reactions were significantly more frequent in glatiramer acetate than SC IFNb-1a recipients.[35] In the CAMMS223 trial, 12.1% of patients who received SC IFNb-1a and 1.4% of patients who received alemtuzumab discontinued treatment because of an adverse event.[36] Treatmentemergent adverse events occurring during the trial and for which there were significant betweengroup differences are shown in figure 2b. Neurological events, injection-site reactions, influenza-like illnesses, dygeusia, abnormal liver function tests and abdominal pain were significantly more common in SC IFNb-1a than alemtuzumab recipients, whereas upper and lower respiratory tract infections, rash, stomatitis and thyroid disorders were significantly more common in alemtuzumab recipients.[36] Immune thrombocytopenic purpura occurred in six (3%) alemtuzumab recipients and one (1%) SC IFNb-1a recipient, in whom it persisted at a grade 1 level of severity to the end of the study despite treatment withdrawal. Among alemtuzumab recipients with immune thrombocytopenic purpura, one patient died, one patient remitted without treatment and four patients remitted with treatment. Hyperthyroidism and hypothyroidism were associated with thyroid antibodies in 96% of affected patients, most of whom required antithyroid
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a 70 60 Incidence (% of pts) 50 40 30 20 10 0
ia e n a s s T es iti ch tio g oe AL illn ya ur da ra el pr sw du M pn ea ys re n ac tio lin lg n
SC IFN-1a (n = 381) SC GLA (n = 375)
** ** * *
ke
te
in
-li
si
te
D Po st in je
te
za
n-
si
en
io
n-
flu
ct
io
je
ct
In
In
je
b 70 60 Incidence (% of pts) 50 40 30 20 10 0
n at iti s m si a as h illn es s nt TI re ac tio LF T pa i TI oi di s ca le ve U R ge u LR St om in al al er th yr hy r H yp ot
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SC IFN-1a (n = 107) IV ALEM (n = 216)
In
In
je
ct
io
n-
si
ct
io
ke
ys
or m
si te
ol og i
ali
Ab n
io n-
Ab d
om
flu en z
eu r
je ct
Fig. 2. Tolerability of subcutaneous (SC) interferon-b-1a (IFNb-1a) 44 mg three times weekly compared with (a) SC glatiramer acetate (GLA) 20 mg once daily (od) and (b) intravenous (IV) alemtuzumab (ALEM) 12 or 24 mg od for three cycles in patients (pts) with relapsing-remitting multiple sclerosis during the 96-wk REGARD[35] and 36-month CAMMS223[36] trials. Treatment-emergent adverse events occurring in 5% of SC IFNb-1a or GLA recipients, and in >5% (infection-associated events) and >10% (other events) of SC IFNb-1a or ALEM recipients that were significantly different between treatment groups. LFT = liver function test; LRTI = lower respiratory tract infection; URTI = upper respiratory tract infection; * p < 0.01, ** p < 0.001 vs GLA; - p < 0.05, -- p < 0.01, --- p < 0.001 vs SC IFNb-1a; p < 0.05, p < 0.01, p < 0.001 vs ALEM..
and/or thyroid replacement therapies. Serious adverse events occurred in 22.4% and 23.6% of SC IFNb-1a and alemtuzumab recipients, with serious infusion reactions in 1.4% of alemtuzumab recipients.[36]
In
In
5.2 Hepatic Effects
Consistent with the effects of other IFNs,[7] SC IFNb-1a 44 mg tiw recipients were significantly more likely to have increased ALT levels than
yp
oi d
is
1881
placebo recipients.[32] Additionally, a comparative trial found a similar heightened risk compared with glatiramer acetate (figure 2).[29,32,35] SC IFNb-1a recipients were also significantly more likely to have liver function abnormalities than were recipients of IM IFNb-1a (grade 3 level of severity)[29] and alemtuzumab (any abnormal liver function test) [figure 2].[36] Pooled data from clinical trials in MS or CIS and postmarketing surveillance in patients with MS (n = 2819 recipients of IFNb-1a or placebo) indicated that dose-related elevations in blood ALT levels occur in the majority of patients treated with SC or IM IFNb-1a (up to 59%, 64% and 67% at 6, 12 and 24 months, respectively).[49] These disturbances were asymptomatic and occurred early in treatment, such that after 2 years of treatment with SC IFNb-1a 44 mg tiw, only 11% of patients had abnormal hepatic enzymes (vs 6% of placebo recipients).[49] In observational studies, two-thirds of patients with elevated aminotransferase levels had levels return to normal levels despite continuing treatment. However, in post-marketing surveillance, 30 instances of serious hepatic dysfunction were observed over a 5-year period, representing one instance per 4000 patient-years.[15] Monitoring of hepatic function is necessary for patients treated with SC IFNb-1a, along with special precautions in patients with elevations in serum ALT, known hepatic disease or symptoms of hepatic disease.[7]
5.3 Haematological and Other Events
Based on pooled data across six trials in patients with MS or CIS who were followed for at least 6 months and up to 6 years (n = 2482), clinically significant haematological events were common, occurring in up to 35% of patients.[50] These events were dose-related and almost universally asymptomatic, mild and transient, therefore, having minimal effect on treatment.[50] The initiation of SC IFNb-1a is contraindicated in pregnancy because of a suspected increase in spontaneous abortion.[7] However, in women with MS exposed to SC or IM IFNb-1a during pregnancy and with prospective data regarding pregnancy outcomes in the Merck Serono Global Drug Safety database (n = 425), spontaneous abortion and major congenital abnormality rates were consistent with those observed in the general population.[51] A further study utilizing data from 12 clinical trials in MS (n = 3746) and the Merck Serono Global Drug Safety database found no evidence of an increased risk of malignancy in patients treated with SC IFNb-1a compared with the general population.[52] 6. Pharmacoeconomic and Other Considerations
6.1 Pharmacoeconomics
In the PRISMS trial, SC IFNb-1a 44 mg tiw, but not 22 mg SC tiw, was associated with significantly higher rates of lymphopenia, leukopenia and granulocytopenia than placebo after 3 months (figure 1).[32] Longer-term follow-up of patients in the PRISMS trial who received continuous treatment with SC IFNb-1a revealed that asymptomatic cytopenias were common during the first 4 years of treatment, especially in the higher dosage group,[37,42] but declined in frequency beyond 4 years.[45] Similarly, in the EVIDENCE trial SC IFNb-1a 44 mg tiw was associated with shifts from baseline to lower than reference values in haematological variables.[29]
Pharmacoeconomic analyses have estimated the cost utility or cost effectiveness of SC IFNb1a relative to other treatments in RRMS.[53-58] The discussion in this section is limited to fully published, modelled analyses with efficacy data for SC IFNb-1a based on results of key clinical trials discussed in section 4,[29,32,37,41] or a longitudinal survey,[58] and that had a year of costing 2005 or later. Analyses were conducted in the US[53-56,58] or Germany.[57] Only one analysis directly estimated the cost effectiveness of SC IFNb-1a relative to that of another DMA based on the results of a head-tohead clinical trial in patients with RRMS.[53] A discrete-event simulation model was used to estimate the cost effectiveness of SC IFNb-1a 44 mg tiw versus IM IFNb-1a 30 mg once weekly, based on clinical efficacy data from the EVIDENCE
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trial (section 4.2.1) and other literature. The analysis was conducted from the perspective of a healthcare payer in the US, discounted costs and benefits at 3% per year, had a 4-year time horizon, and the year of costing was 2006. In the base case analysis, the incremental cost per relapse avoided with SC IFNb-1a versus IM IFNb-1a was estimated to be $US10 755; the corresponding incremental cost per relapse-free days gained was $US232. Results were most sensitive to changes in treatment efficacy, time horizon and cost of treatment parameters.[53] All other analyses evaluated the cost effectiveness of SC IFNb-1a versus symptomatic management (i.e. no DMA) [table VI].[54-58] Although these analyses also evaluated the cost effectiveness of other DMAs (i.e. IM IFNb-1a, SC IFNb-1b, glatiramer acetate) versus symptomatic management, they did not directly estimate the relative cost effectiveness of these agents. As head-to-head trials of these agents are generally lacking, the analyses incorporated the best available efficacy data, which was generally from placebo-controlled trials of individual drugs or meta-analyses.[54-57] Comparisons of the cost effectiveness of individual agents are limited by the use of efficacy data from clinical trials with differences in design and patient populations. Based on the results of cost-utility studies conducted in the US,[54,55] there is uncertainty as to the cost effectiveness of SC IFNb-1a, but also of the other DMAs evaluated. In the base case analyses, the incremental costs per quality-adjusted life-year (QALY) gained with SC IFNb-1a treatment and the other DMAs versus symptomatic treatment were all predicted to be >$US100 000 (table VI). The estimates in one study were sensitive to plausible changes in input parameters, such as in health state utilities, disease progression rates, time horizon and drug costs, indicating that there is considerable uncertainty around these estimates.[54] However, modelled differences in the incidence of NAbs had minimal impact on the results.[54] In the other study, cost-effectiveness estimates were more favourable under a scenario where the DMA was stopped once MS had progressed to an EDSS score of 7.0 points (table VI).[55] According to a
Table VI. Summary of findings from cost-utility and cost-effectiveness analyses of subcutaneous (SC) interferon-b-1a (IFNb-1a) in patients with relapsing-remitting multiple sclerosis (MS).[54-57] Most modelled analyses incorporated efficacy estimates from placebo-controlled clinical trials and literature for each of the drugs, and natural history and local cost data from other sources. One analysis used data from a longitudinal MS survey.[58] Data reported here are for SC IFNb-1a 44 mg tiw and comparators at recommended dosages. Costs and outcomes were discounted at 3%[54-56,58] or 5%[57]
$US309 173
$US202 648
$US2 178 555
$US258 465
$US88 310 $US87 061
SC IFNb-1b
$US158 466
$US97 382
$US1 123 162
$US310 691
h54 475
h71 416
SC GA
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EDSS = Kurtzke Expanded Disability Status Scale; GA = glatiramer acetate; IC = incremental cost; IM = intramuscular; QALY = quality-adjusted life-year.
Cost effectiveness (disease-modifying therapy vs symptomatic management)
$US303 968
$US901 319
IM IFNb-1a
$US103 762
$US60 052
$US141 721 $US80 589
$US128 728
SC IFNb-1a
$US79 002
$US1 487 306
$US416 301
h133 770 Nuijten and Mittendorf[57] (Germany) [2008] a An EDSS score of 7 indicates that the patient is essentially wheelchair bound as unable to walk >5 m even with an aid. 4y IC per relapse avoided h51 250
Cost-utility analyses (based on a Markov model with a cycle length of 1 mo[54] or 1 y[55,58])
IC per QALY gained (treatment stopped upon progression to EDSSa 7.0) IC per QALY gained Cost-effectiveness analyses (based on decision models) 10 y Societal Noyes et al.[58] (US) [2005]
IC per QALY gained (no treatment discontinuation rule)
Time horizon
Lifetime
Lifetime
Perspective
Tappenden et al.[55] (US) [2005]
Study (country) [y of costing]
Bell et al.[54] (US) [2005]
Goldberg et al.[56] (US) [2008]
Healthcare payer Societal
Healthcare payer
Societal
2y
IC per relapse avoided
outcome
IC per QALY gained
1883
probabilistic sensitivity analysis, none of the treatments are likely to be cost effective relative to symptomatic treatment, as the probability that any therapy had an incremental cost per QALY gained of <$US60 000 was 0.08 or lower, although stopping treatment at EDSS 7.0 increased this probability to 0.47 or lower.[55] Likewise, a modelled cost-utility analysis based on data from a longitudinal MS survey in 1121 individuals found that the cost per QALY gained with DMAs was high. Relative to standard basic supportive therapy, the cost per QALY gained with a DMA was >$US900 000 over a 10-year time horizon (table VI).[58] The cost-effectiveness analyses[56,57] included the important therapeutic target of reducing relapses. From the perspective of a healthcare payer in the US and of society in Germany, the most favourable incremental costs per relapse avoided versus symptomatic treatment were predicted for SC IFNb-1a, SC IFNb-1b and glatiramer acetate, whereas those for IM IFNb-1a were higher (table VI).[56,57] Sensitivity analyses suggested that the models were generally robust to plausible changes in key parameters,[56,57] with the exception of relapse frequency in the German analysis.[57] The studies were generally well conducted (e.g. appropriate discounting of costs and benefits was applied and sensitivity analyses were included to evaluate plausible changes in key assumptions).[53-58] However, the results should be interpreted cautiously in view of the heterogeneity and inherent limitations in these modelled pharmacoeconomic analyses. Modelled pharmacoeconomic analyses extrapolate the results of clinical trials to the general population and may also extrapolate results of short-term trials to a lifetime horizon; however, patient populations, rates of compliance and major outcomes in clinical trials may differ from those observed in real-life practice. Moreover, the analyses were based on clinical outcomes primarily derived from placebo-controlled clinical trials, rather than head-to-head comparisons of the DMAs.[53-57] Furthermore, results of pharmacoeconomic analyses may not be applicable to other geographical regions because of differences in healthcare systems, medical practice and unit costs.
6.2 Patient Satisfaction and Treatment Adherence
As with all medical illnesses, treatment adherence is essential for the effective treatment of MS and this is especially difficult to achieve with therapies for chronic illnesses where there are many barriers to taking medications.[59] However, in a retrospective database study of patients with MS treated with SC IFNb-1a, SC IFNb-1b, IM IFNb1a or SC glatiramer acetate (n = 6134), compliance to treatment was 80% for all drugs, with the best compliance reported for IM IFNb-1a.[60] In the trial to assess the transition from the original to the serum-free formulation of Rebif (section 5.1.3), patients generally experienced no change in satisfaction after the transition, according to Multiple Sclerosis Treatment Concerns Questionnaire (MSTCQ) scores, with results on the MSTCQ injection system satisfaction score suggesting an increased satisfaction with the serum-free formulation.[48] It is possible that even higher compliance rates may be achieved with better designed injection systems. In an open-label, single-arm study, patients with relapsing MS who were switched from their current method of injection to a singleuse autoinjector (n = 109) found it easy or very easy to use (87%) and reported that convenience of use was its most important benefit (data are from an abstract).[61] A 1-year, prospective, observational study also evaluated patient satisfaction with the Rebiject II system in patients with RRMS.[62] In patients who received at least one dose of SC IFNb-1a by the autoinjector (n = 71), 80.3% were satisfied with the system, most commonly citing its convenience over previous injection methods.[62] RebiSmart is a multidose, autoinjection device for SC IFNb-1a that was developed to reduce patient concerns about self-injection, with the aim of improving patient adherence and treatment satisfaction.[63] In a 12-week, single-arm study in patients with RRMS (n = 102), 71.6%, 20.6% and 7.8% of patients reported the RebiSmart device as suitable or very suitable, a little suitable and not suitable, respectively. Generally, patients found it easy to use and convenient.[63]
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7. Dosage and Administration In relapsing MS, the recommended dosage of SC IFNb-1a is 44 mg tiw, although a lower dosage of 22 mg tiw is also effective and is recommended for patients who are unable to tolerate the higher dosage.[7,8] Treatment should be initiated at a lower dosage and increased gradually over a 4-week period.[7,8] The US prescribing information recommends that the starting dosage is 20% that of the target dosage (i.e. 4.4 or 8.8 mg tiw) during weeks 12, increased to 50% of the target dosage (i.e. 11 or 22 mg tiw) during weeks 34, and increased to 22 or 44 mg tiw, thereafter.[8] An antipyretic analgesic can be administered prior to the injection to decrease influenza-like symptoms associated with SC IFNb-1a.[7,8] In the EU, it is recommended that patients be evaluated by the prescribing physician at least every 2 years to determine whether or not to continue treatment.[7] In the EU, initiation of SC IFNb-1a is contraindicated in pregnancy and in patients with current severe depression or suicidal ideation.[7] There are no formal clinical trials of SC IFNb1a in paediatric populations,[7,8] although limited data suggest that its safety profile in adolescents aged 1216 years is similar to that in adults.[7] In the EU, it is recommended that SC IFNb-1a is not used in children younger than 12 years of age.[7] Local prescribing information should be consulted for detailed information including contraindications, warnings and precautions, use in special populations, management of injection-site reactions, and recommendations regarding dosage adjustment or discontinuation in the event of significant haematological or hepatic disturbances. 8. Place of Subcutaneous Recombinant IFNb-1a in the Treatment of Relapsing Multiple Sclerosis MS is a chronic, disabling neurological disorder that was considered to be untreatable until the second half of the last century when corticosteroids were found to be efficacious in reducing its acute symptoms.[64] Subsequently, IFNb-1a, IFNb-1b, glatiramer acetate and azathioprine
were shown to be effective in preventing relapses in MS, and in slowing progression of disability.[64] The recent history is one of the development and testing of new therapies with specific molecular, cellular and anatomical targets.[65] A number of these therapies have diseasemodifying effects in MS and are now in phase III clinical trials or have been newly approved for the treatment of RRMS.[65,66] Table VII provides a summary of the key properties and characteristics of established and newer therapies for RRMS. The most recent published guidelines for prescribing in MS are from the Association of British Neurologists (ABN) [2009],[69] and their recommendations for the use of DMAs can be summarized as follows. Patients with RRMS who are ambulant (EDSS score of 6.5) and who have had at least two clinically significant relapses in the prior 2 years can be treated with IFNb or glatiramer acetate.[69] Further treatment options are natalizumab or mitoxantrone, which are recommended for patients with RRMS whom specialist neurologists consider to have disease that is rapidly evolving and likely to become severe.[69] Three other patient groups can be considered for treatment with DMAs: patients with CIS with MRI evidence of a high recurrence risk; patients with MS who are aged <18 years; and patients with MS who have had only one relapse in the prior 2 years, but who have MRI evidence of disease activity; this latter group would include patients with SPMS. The ABN offers the proviso that the evidence for the efficacy of DMAs is less secure for these three indications. In patients with SPMS, disease-modifying treatments should only be considered when relapses are the main cause of increasing disability.[69] The 2010 revisions to the McDonald criteria released after the ABN guidelines allow for a diagnosis of MS after just one attack (which must be typical of CIS) if there is MRI evidence of dissemination of disease in space and time, which may on occasion be established on the basis of a single scan.[4] Use of these criteria may lead to earlier diagnosis of MS,[4] and earlier consideration for treatment with DMAs. Three IFNb formulations are used extensively as first-line therapies in MS: SC IFNb-1a, IM
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Table VII. Key properties and characteristics of disease-modifying agents (DMAs) approved for use in relapsing multiple sclerosis (MS) or relapsing-remitting MS (RRMS), or that have been evaluated in phase III clinical trials DMA Approved IFNb-1a Cytokine Reduced activation and entry of T cells into the CNS, reduced adhesion molecules and reduced Th cell proinflammatory cytokines[16] As above Binding MHC class II molecules on peripheral MBPrecognizing APCs and promoting a shift to a Th2 inflammatory profile[67] Inhibits topoisomerase II leading to suppression of B cells and T cells, and induction of apoptosis in T cells and APCs[16] Inhibits leukocyte adhesion to, and migration across, the blood-brain barrier by blocking adhesion molecule very late activating antigen-4[68] Reduces autoaggressive lymphocytes in the circulation and CNS by down-regulating the SIP receptor[66] SC tiw or IM qw SC q2d SC od EU and US Class Possible immunomodulatory mechanism Administration EU and US approval status
IFNb-1b Glatiramer acetate Mitoxantrone
Cytokine Analogue of MSassociated antigen, MBP Anthracenedione cytotoxic agent Humanized monoclonal antibody SIP receptor partial agonist
EU and US EU and US
IV q3mo
US (worsening RRMS) and some European countriesa EU and US (restricted use)a,b US and EU (EU specified as highly active RRMS) Not yet approved
Natalizumab
IV q4w
Fingolimod
PO od
Under development Alemtuzumab Humanized monoclonal antibody Quinoline-3carboxamide Dihydroorotate dehydrogenase inhibitor Fumaric acid salt Binds to the CD52 antigen which is expressed at the cell surface of T cells, B cells, natural killer and other immune cells resulting in complement production and cell-mediated cell lysis[68] Inhibits infiltration of inflammatory cells into the CNS and promotes a shift to a Th2 profile[66] Prevents proliferation of T cells and B cells by inhibiting pyrimidine synthesis[66] Neuroprotection resulting from antioxidant and antiinflammatory effects mediated through the nuclear factorE2-related factor signalling pathway, which attenuates proinflammatory stimuli[66] IV annual cycles (23 per y) PO od PO od
Laquinimod Teriflunomide
Not yet approved Not yet approved
Dimethyl fumarate
PO bid or tid
Not yet approved
a b
Also used in patients with breakthrough disease while receiving first-line treatment. Approved use varies between countries. Restricted to prescribers, infusion centres and pharmacists in the TOUCH Prescribing Program.
APCs = antigen-presenting cells; bid = twice daily; IFN = interferon; IM = intramuscular; IV = intravenous; MBP = myelin basic protein; od = once daily; PO = by mouth; qw = once weekly; q2d = every 2nd day; q3mo = every 3 months; q4w = every 4 weeks; SC = subcutaneous; SIP = sphingosine 1-phosphate; Th = T-helper; tid = three times daily; tiw = three times weekly.
IFNb-1a and SC IFNb-1b. The mechanism of action of the three formulations is presumed to be the same and is thought to involve reduced T-cell autoimmunity, as IFNb shifts the inflammatory response towards an inhibitory Th2 response and reduces the influx of activated T cells into the CNS across the BBB (section 2.1). The efficacy of SC IFNb-1a in RRMS was confirmed in the randomized, double-blind PRISMS trial.[32] Compared with placebo, SC IFNb-1a 22 or 44 mg tiw administered for 2 years
reduced relapse rates, delayed the progression of disability and lowered disease activity, based on MRI. In post hoc analyses, SC IFNb-1a 44 mg also provided some benefit over placebo in patients who were more disabled (section 4.1.1). For secondary endpoints, treatment effects were more consistent in patients who received SC IFNb-1a 44 mg than 22 mg SC. Patients who received continuous SC IFNb-1a over 4 years generally had better clinical outcomes, and reduced disease activity on MRI, than patients who received placebo
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for 2 years followed by SC IFNb-1a for 2 years (section 4.1.2). At an assessment 78 years after inception into the PRISMS study, three-quarters of the patients who were successfully followed were continuing SC IFNb-1a treatment and approximately half of these patients had a one-step progression in disability (section 4.1.2). These longer-term results should be interpreted with caution, as approximately one-third of the patients were lost to follow-up.[45] In the PRISMS study, SC IFNb-1a was generally well tolerated, with the most common treatment-emergent adverse events being influenza-like symptoms, injection-site reactions, haematological disturbances and hepatic enzyme abnormalities (section 5.1). Adverse events tended to occur early, rarely led to treatment withdrawal (section 5.1.1) and no unexpected events occurred over longer-term follow-up (section 5.1.2). While most adverse events were of mild or moderate severity, some cases involving serious medical complications have been observed during postmarketing surveillance.[7] In the EVIDENCE trial, high-dosage SC IFNb-1a 44 mg tiw was more efficacious than low-dosage IM IFNb-1a 30 mg once weekly (section 4.2.1), with further supportive evidence of its greater efficacy coming from an open-label crossover phase (section 4.2.2). The IM formulation was generally better tolerated than SC IFNb-1a (section 5.1.4). Therefore, for individual patients, the favourable tolerability of the IM formulation needs to be weighed against the greater efficacy of the SC formulation. There were no significant differences between SC IFNb-1a 44 mg tiw and SC glatiramer acetate 20 mg once daily for any clinical efficacy endpoint in the REGARD trial, whereas SC IFNb1a recipients generally had significantly reduced MRI evidence of disease activity compared with glatiramer acetate recipients (section 4.3). With respect to tolerability, SC IFNb-1a was associated with more influenza-like symptoms, headache, myalgia and elevated ALT levels and glatiramer acetate with more injection-site reactions and dyspnoea (section 5.1.4). In the CAMMS223 trial, intravenous alemtuzumab was more efficacious than SC IFNb1a
44 mg tiw, as there were consistent significant differences favouring alemtuzumab on most clinical and MRI endpoints (section 4.3). Thus, alemtuzumab appears to be a more powerful DMA than SC IFNb-1a and is a possible candidate for further therapy in patients who have progressed despite initial treatment. SC IFNb-1a and alemtuzumab had quite different tolerability profiles; the SC IFNb-1a group had significantly higher rates of neurological events, injection-site reactions, influenza-like illnesses and abnormal liver function tests, whereas the alemtuzumab group had significantly higher rates of upper and lower respiratory tract infections, rash, stomatitis and thyroid disorders (section 5.1.4), with 3% of recipients experiencing immune thrombocytopenic purpura.[36] A prospective study of patients with MS treated with alemtuzumab reported a cumulative risk for autoimmune disorders of 22.2% over a median follow-up of 34.3 months, with 2.4% developing potentially serious disorders.[70] Alemtuzumab offers an interesting alternative to the established agents, but given its association with serious cytopenias, infections and immune reactions, it is unlikely that it will displace IFNb or glatiramer acetate as first-line treatment. The use of SC IFNb-1a in patients with SPMS was assessed in the SPECTRIMS trial.[39] In this trial, although SC IFNb-1a 22 or 44 mg tiw had no significant effect on progression of disability, it was efficacious in reducing relapses (section 4.1.4), providing support for its use in patients with SPMS who continue to have relapses. The serum-free formulation of SC IFNb-1a was developed with the intention of reducing immune effects such as injection-site reactions, and limited data from an indirect trial comparison suggest that it may be better tolerated in this regard (section 5.1.3).[11] In a subsequent trial (IMPROVE) that evaluated MRI outcomes in patients with RRMS, the serum-free formulation of SC IFNb-1a 44 mg tiw was more efficacious than placebo (section 4.1.3). It is difficult to adequately assess the relative efficacy and tolerability of the various DMAs, as indirect comparisons of treatment effects from clinical trials are likely to be unreliable. Recent
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trials in MS include clinical populations with lower levels of disease activity than earlier trials, as they have lower placebo group relapse rates and a lower disease burden at baseline.[71] As a result, relapse rates in the active treatment groups may be lower in recent trials, as was evidenced in the REGARD trial, which as a consequence was not adequately powered to detect differences between treatments (section 4.3). Therefore, further head-to-head comparisons of first-line treatments with newer agents are needed. In a 12-month trial in patients with RRMS, fingolimod lowered the annualized relapse rate to a significantly greater extent than IM IFNb-1a, although there was no difference between the treatments in progression of disability.[72] Fingolimod was generally well tolerated, although it was associated with transient bradycardia, macular oedema, viral infection and cancers, with two deaths reported in fingolimod recipients as a result of disseminated herpes infection.[72] Fingolimod is now approved for treatment of RRMS, but further clinical experience is needed with the drug to assess whether there is a causal link between fingolimod and these adverse events. There are similar uncertainties about the safety and tolerability of natalizumab (progressive multifocal leukoencephalopathy)[65] and mitoxantrone (cardiotoxicity and myelosuppression),[73] whereas no major safety concerns have yet been raised regarding dimethyl fumarate, laquinimod or teriflunomide.[66] Ongoing head-to-head trials of laquinimod (vs IM IFNb-1a) and teriflunomide (vs SC IFNb-1a) will be helpful in further elucidating the short-term efficacy and tolerability of these drugs, while longer-term experience with all the newer agents is required to adequately evaluate their safety.[66] For the foreseeable future, IFNb and glatiramer acetate will be first-line treatments for RRMS, as they now have considerable support from randomized trials, favourable tolerability profiles and have been in clinical use for some years. As there appears to be little to choose between them in terms of efficacy, drug choice will depend heavily on patient preference given their different tolerability profiles. Although DMAs positively influence the clinical course of MS and lower MRI measures of
disease burden, patients continue to relapse and experience disease progression.[33] Combination therapies may provide greater clinical benefits. As many patients with MS receive corticosteroids to control the acute symptoms that occur during relapses, there is interest in evaluating whether combining IFNb with intermittent oral corticosteroids would further reduce relapses. In the NORMIMS trial in patients with RRMS who had relapsed despite treatment with SC IFNb-1a 44 mg tiw, adding methylprednisolone was generally associated with significantly better outcomes at 96 weeks, suggesting that combination treatment may be of value for some patients (section 4.4). However, further study is required, as there was a high dropout rate in this trial, including treatment withdrawal because of adverse events in the combined treatment group.[33] Furthermore, the results were not consistent with those of another trial in which there was no significant prolongation of time to sustained progression of disability with IM IFNb-1a plus methylprednisolone over IM IFNb-1a alone.[74] Despite the evidence regarding the efficacy of IFNb formulations and other DMAs in MS, there has been uncertainty as to what stage of the disease is optimal for the initiation of diseasemodifying therapy.[75] However, the early introduction of DMAs reduces progression of CIS to clinically definite MS, provides immediate clinical benefits and reduction in MRI markers of disease activity, and could potentially reduce the disease burden over the longer term.[75] In clinical trials, SC IFNb-1a, SC IFNb-1b, IM IFNb-1a and glatiramer acetate all reduced the rate of conversion from CIS to clinically definite MS.[76-80] For instance, the efficacy of SC IFNb-1a 44 mg administered tiw or once weekly in CIS was evaluated in the recently completed, placebocontrolled REFLEX (REbif FLEXible dosing in early multiple sclerosis) trial.[76] For patients with CIS with at least two significant clinically silent T2W active lesions, the time to progression (McDonald criteria and clinically definite MS) was significantly longer in patients treated with SC IFNb-1a than placebo, with more pronounced treatment effects seen with SC IFNb-1a SC tiw than when administered once weekly.[76]
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SC IFNb-1a is not yet approved for this indication. The decision as to whether to continue or discontinue disease-modifying therapies in MS is made on an individual basis, with the primary emphasis being on patient choice.[69] The ABN recommend that despite there being no clear-cut stopping criteria that would apply to all patients that treatment discontinuation be considered in patients with no change in relapse frequency despite treatment, with the development of NAbs to IFNb (especially if sustained with high titres), or with progression to non-relapsing SPMS with loss of ability to ambulate.[69] In the PRISMS, EVIDENCE and REGARD trials, NAbs developed in a substantial minority of patients, although they were sometimes short-lived (section 2.2). NAbs may reduce the efficacy of SC IFNb-1a, although the findings of clinical trials are mixed. In the PRISMS trial, the development of NAbs was associated with reduced efficacy on clinical and MRI endpoints (section 4.1.2), whereas in the EVIDENCE trial they were not generally associated with reduced efficacy (section 4.2). Treatment discontinuation may be an option in patients with persistent NAbs, if accompanied by suboptimal treatment effect. Disease-modifying therapy for MS is costly and, according to the results of cost-utility analyses in the the US, exceeds commonly accepted thresholds for the incremental cost per QALY gained relative to symptomatic treatment (section 6.1). However, it is difficult to evaluate cost utility in a chronic disease such as MS where treatments are aimed chiefly at preventing or slowing gradual disease progression. In light of these difficulties and high patient need, these agents have been made available to many patients worldwide through special access programmes. Ideally, future pharmacoeconomic studies will address the problems that are associated with pharmacoeconomic analyses, such as the lack of efficacy data from real-world settings, where treatment compliance and clinical outcomes may be quite different, and difficulties in extrapolating from short-term efficacy data to distant time horizons. Pharmacoeconomic analyses that directly evaluate the cost effectiveness of SC IFNb-1a versus
other DMAs (either as part of prospective headto-head comparative trials or by incorporating the results of such trials in well designed models) are needed to clarify the relative cost effectiveness of these agents in MS. In MS, patient adherence to the prescribed drug regimen is essential if optimum treatment benefits are to be achieved.[60] While many factors will influence adherence to SC IFNb injections, it is likely that ease and comfort of injection are important. SC IFNb-1a is now available for use in injection devices designed to ease administration (Rebiject II, RebiSmart and RebiDose) and to increase the patients awareness of their dosing history (RebiSmart). In recent studies, patients generally report that they are satisfied with these new devices, finding them convenient and easy to use (section 6.2). In conclusion, SC IFNb-1a is an efficacious treatment for relapsing MS, as it reduced relapses, and lowered disease activity according to MRI, both in comparison with placebo and with IM IFNb-1a, which is administered at a lower dosage. Compared with placebo it also slowed progression of disability. SC IFNb-1a was generally well tolerated in the short and longer term, although its tolerability profile was less favourable than that of IM IFNb-1a. Although there are few trials comparing its efficacy with other DMAs, SC IFNb-1a was not significantly different from glatiramer acetate for clinical outcomes, although it was more efficacious according to MRI endpoints. Its tolerability profile was distinctly different to that of glatiramer acetate. SC IFNb-1a was less efficacious than alemtuzumab, according to clinical and MRI endpoints. Again, the two drugs had distinctly different tolerability profiles. Given its association with potentially serious adverse events, the tolerability of alemtuzumab in MS requires further evaluation. Overall, SC IFNb-1a has a favourable riskbenefit ratio and is a valuable first-line treatment option for patients with relapsing MS. Disclosure
The preparation of this review was not supported by any external funding. During the peer review process, the manu-
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facturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the authors on the basis of scientific and editorial merit.
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Correspondence: Mark Sanford, Adis, a Wolters Kluwer Business, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand. E-mail: demail@adis.co.nz
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Drugs 2011; 71 (14): 1893-1915 0012-6667/11/0014-1893/$55.55/0
Fibrin Sealant (Evicel [Quixil/Crosseal])

A Review of its Use as Supportive Treatment for Haemostasis in Surgery
Sohita Dhillon
Various sections of the manuscript reviewed by: M.T. de Boer, Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, Netherlands; E.N. Papacharalabous, Department of Gynaecological Oncology, The Royal Surrey County Hospital, Guildford, England; M. Schwartz, Department of Surgery, Mount Sinai Medical Center, New York, NY, USA.
Data Selection Sources: Medical literature (including published and unpublished data) on liquid fibrin sealant was identified by searching databases since 1996 (including MEDLINE, EMBASE and in-house AdisBase), bibliographies from published literature, clinical trial registries/ databases and websites (including those of regional regulatory agencies and the manufacturer). Additional information (including contributory unpublished data) was also requested from the company developing the drug. Search strategy: MEDLINE, EMBASE and AdisBase search terms were (fibrin sealant and liquid) or ((fibrin sealant or fibrin tissue adhesive or fibrin glue) and (surgical blood loss or blood loss, surgical or surgical bleeding)). Searches were last updated 19 August 2011. Selection: Studies in patients undergoing surgery who received fibrin sealant (Evicel, Quixil or Crosseal). Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included. Index terms: Evicel, Quixil, Crosseal, fibrin sealant, surgery, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.
Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Mechanical Properties of the Fibrin Clot . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Haemostatic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Other Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 In Vascular Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1 Efficacy of Evicel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2 Efficacy of Quixil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 In Liver Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 In Retroperitoneal and Intra-abdominal Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4 In Orthopaedic Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.1 Efficacy of Evicel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.2 Efficacy of Quixil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1894 1894 1895 1895 1895 1897 1897 1897 1898 1898 1898 1899 1899 1900 1901 1902 1902
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4.5 In Nose and Throat Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.1 Endonasal Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.2 Tonsillectomy and Adenoidectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Tolerability of Evicel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Tolerability of Quixil/Crosseal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Place of Fibrin Sealant (Evicel [Quixil/Crosseal]) in the Management of Haemostasis in Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1903 1904 1905 1906 1906 1907 1908 1908
Abstract
Evicel is a fibrin sealant consisting of two components, human clottable protein (predominantly human fibrinogen) and human thrombin. It is indicated as supportive treatment in patients undergoing surgery when control of bleeding by standard surgical techniques is ineffective or impractical. Evicel is a new formulation of the previously available fibrin sealant Quixil (in the EU) or Crosseal (in the US). Evicel differs from Quixil/Crosseal in that its fibrinogen component does not contain the antifibrinolytic agent tranexamic acid, which is potentially neurotoxic, resulting in Quixil/Crosseal being contraindicated for use in neurosurgery. The removal of tranexamic acid did not affect the haemostatic efficacy or longevity of Evicel fibrin clots and allowed the sealant to be granted an expanded indication. Evicel and Quixil/Crosseal are easy to use and, since they do not contain synthetic or bovine aprotinin, have a reduced potential for hypersensitivity reactions. This article reviews the pharmacological properties, clinical efficacy and tolerability of Evicel and its previous formulation as supportive treatment for haemostasis in surgery. In clinical studies, Evicel and Quixil/Crosseal were generally well tolerated and effective haemostatic agents for adjunctive use in various types of surgeries when conventional methods were impractical or ineffective in controlling bleeding. Two pivotal, randomized studies showed that Evicel was significantly more effective than manual compression in patients undergoing vascular surgery, and significantly more effective than Surgicel in patients undergoing retroperitoneal or intra-abdominal surgery, as assessed by the proportion of patients achieving haemostasis. In another similarly designed pivotal study in patients undergoing liver resection, Crosseal was significantly more effective than standard haemostatic agents (e.g. Surgicel), as assessed by the mean time to haemostasis. The incidences of treatment-emergent adverse events in these studies were generally similar between the Evicel or Crosseal groups and the comparator groups. Quixil was also generally well tolerated and an effective haemostatic agent in endonasal surgeries, and tonsillectomies and/or adenoidectomies, with some benefit of treatment with Evicel or Quixil also observed in orthopaedic surgeries. Although additional comparative studies with other haemostatic agents would help to definitively position Evicel with respect to these agents, current evidence suggests that Evicel is useful in surgeries for improving haemostasis where standard surgical techniques are insufficient.
1. Introduction Reducing blood loss during surgery may help to reduce postoperative morbidity and mortality, as well as minimizing the duration of hospitali 2011 Adis Data Information BV. All rights reserved.
zation.[1] Haemostasis in surgery can be achieved with conventional techniques such as manual pressure and ligature; however, these are labour intensive and less effective in controlling bleeding from complex injuries and in difficult-to-reach
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areas.[2] Energy-based methods, such as electrocauterization or laser cauterization, can also be used; however, they create charred areas and necrotic tissue, which increases the likelihood of infection and is damaging to the wound edges.[2] Topical haemostatic agents, like fibrin sealants, are another option for providing haemostasis and may be particularly useful for complex injuries and difficult-to-treat areas.[2] Several such agents, which exert their effects in various ways, are currently available (section 7). Of these agents, fibrin sealants are used largely in surgery, both for suture support and in situations where sutures cannot control or would aggravate bleeding.[3,4] Fibrin sealants are two-component products, consisting of fibrinogen and thrombin, which interact during application to form a clot (section 2.1).[1,2,5] Evicel, one such fibrin sealant composed of only human products (section 7), is a new formulation of a previously available fibrin sealant, Quixil (in the EU) or Crosseal (in the US). Evicel differs from Quixil/Crosseal in that its fibrinogen component (comprised of clottable proteins, predominantly fibrinogen) does not contain the antifibrinolytic agent tranexamic acid, which inhibits degradation of fibrinogen.[6] Tranexamic acid (a competitive inhibitor of plasminogen) is potentially neurotoxic,[6,7] because of which Quixil is contraindicated for use in neurosurgery or in procedures where contact with cerebrospinal fluid (CSF) or dura mater may occur.[8] In Evicel, plasminogen has been removed from the fibrinogen component by chromatographic techniques and, therefore, tranexamic acid is not required as a stabilizer.[6] Consequently, Evicel has an expanded indication and can be used as supportive treatment for haemostasis in patients undergoing surgery (section 6);[9] in the US, Crosseal has been replaced by Evicel.[10] This article reviews the pharmacological properties, therapeutic efficacy and tolerability of Evicel and the previousgeneration fibrin sealant Quixil/Crosseal as supportive treatment for haemostasis in surgery. 2. Pharmacodynamic Properties Animal studies reported in the European Medicines Agency assessment report of Evicel in 2011 Adis Data Information BV. All rights reserved.
dicated that Evicel and the previous-generation fibrin sealant Quixil/Crosseal were similar in terms of haemostatic efficacy and longevity of clots (quantitative data were not reported).[6] Therefore, this section discusses the properties of both sealants.
2.1 Mechanism of Action
Fibrin sealants, such as Evicel, mimic the final stages of the blood coagulation process.[11] When fibrinogen and thrombin, the two components of fibrin sealants, are mixed during application of the sealant to the tissue surface, thrombin cleaves the fibrinogen to fibrin monomers, which polymerize to form a soluble mesh.[5,11,12] Thrombin also activates factor XIII to factor XIIIa, which covalently crosslinks the soluble fibrin mesh to form a stable clot.[5,11,12] Both these steps, the conversion of fibrinogen and the crosslinkage of fibrin, require the presence of calcium ions.[12]
2.2 Mechanical Properties of the Fibrin Clot
Fibrin clots formed with Quixil had significantly more adhesive strength than those formed with Tissucol or Tisseel in an in vitro study comparing the adhesive properties of Quixil with those of other fibrin sealants using a skin adhesion test (table I).[13] With regard to the tensile strength of fibrin clots, an in vitro study showed that clots formed with Evicel had higher resistance to stretching and more tensile strength than clots formed with Tisseel, indicating that Evicel clots were more capable of maintaining their structure against applied force (table I).[14] The greater strength and resilience of Evicel clots may be largely because of the presence of factor XIII in the fibrinogen component of the sealant (9 IU/mL in Evicel vs undetectable in Tisseel). In addition, the clot formation kinetics of Evicel were significantly faster than those of Tisseel (table I).[14] However, results from an in vivo study comparing fibrin sealants (Quixil and Tisseel), a semisynthetic sealant (Bioglue), and cyanoacrylates (Histoacryl, Dermabond and Glubran 2) in a pancreaticojejunal attachment model in rats suggested that the tensile strength (as assessed by
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Table I. Mechanical and pharmacodynamic properties of Evicel or the previous-generation fibrin sealant Quixil (in the EU) or Crosseal (in the US) Adhesive strength and stiffness/elasticity of the fibrin clot Fibrin clots formed with Quixil and other fibrin sealants (including Beriplast P) had more (p 0.006) adhesive strength than clots formed with Tissucol or Tisseel (maximum strength 0.25 N for Quixil vs 0.80.11 N; values estimated from a graph).[13] Fibrin clots formed with Evicel had a higher resistance to stretching (mean 38 vs 15 kPa) and more tensile strength (mean 135 vs 29 kPa) than clots formed with Tisseel (both p < 0.001), as assessed by applying mechanical force.[14] The clot formation kinetics of Evicel, as assessed by thromboelastography, were significantly (p < 0.001) faster than those of Tisseel; other clot properties, e.g. the time to initial clot formation, clot strength and elasticity constant, did not differ significantly between the two sealants[14] Quixil use was associated with significantly (p < 0.05) more cases of no attachment between pancreas and jejunum than Tisseel, Bioglue or Glubran 2 in a pancreaticojejunal attachment model in rats (11 vs 3, 3, and 1 case[s], respectively); there were no unattached cases with Dermabond and five cases of no attachment with Histoacryl[15] Crosseal was significantly (p = 0.004) more compliant than Tisseel (but not Coseal), while Bioglue was significantly (p < 0.001) stiffer than Crosseal, Tisseel and Coseal, as assessed by a planar biaxial testing system.[16] In addition, Crosseal, Tisseel and Coseal were at least 4 times more compliant than aortic root placement materials, while Bioglue was at least 2 times stiffer than aortic root placement materials (historical values were used for aortic root placement materials) The adhesion index score (reflects the no. of intra-abdominal adhesions and their tenacity) of Quixil was significantly (p < 0.05) lower than that of Beriplast P and Tissucol (0.9 vs 5.7 and 7.6) in a rabbit partial liver resection model[17] Haemostatic effects Beriplast P was significantly (p < 0.05) more effective than Quixil in terms of early and late haemostasis in rabbit partial liver or kidney resection models; success rates with Beriplast P compared with Quixil were 100% vs 40% for early haemostasis and 100% vs 0% for late haemostasis in the kidney model, and 100% vs 30% for early haemostasis in the liver model[13] In a rabbit partial liver resection model, bleeding times were significantly (p 0.002) shorter with Quixil than Beriplast P or Tissucol (mean 33 vs 169 and 255 sec), and significantly (p < 0.0001) less Quixil than Tissucol was required to stop the bleeding (mean 3.6 vs 9.5 mL); the difference between Quixil and Beriplast P for the amount of sealant required was not statistically significant (mean 3.6 vs 4.4 mL).[17] Other effects In a pancreaticojejunal attachment model in rats, on day 1, Quixil, Tisseel, Bioglue, Histoacryl and Glubran 2 (but not Dermabond), significantly (p < 0.05) increased amylase activity from baseline; amaylase activity reduced to baseline levels by day 3 and remained at these levels until day 21.[15] All tissue adhesives induced changes in pancreatic tissue histology (such as oedema, leukocyte infiltration and necrosis), which were most prominent on days 3 and 7; on day 21, these changes were minimal with Quixil, Tisseel and Bioglue. The overall median histology score over the 21-day observation period was 3.1 with Quixil compared with 2.8, 3.4, 3.9, 4.2 and 6.3 with Tisseel, Glubran 2, Bioglue, Histoacryl and Dermabond, respectively In a study in rats, 12 wk postoperatively, recovery of nerve conduction velocities and wave amplitudes was significantly (p < 0.0001) faster in rats receiving Quixil than in rats with microsuture repair of the right sciatic nerve. In addition, at 6 and 12 wk postoperatively, rats receiving Quixil returned to baseline-performance on the walking-track analysis significantly (p < 0.0001) faster than rats in the comparator group[18] In an in vivo study, direct application of Evicel to bilateral cavernous nerves in rats had no detrimental effect on penile neuronal nitric oxide synthase expression, the histological architecture of the rat penis, or erectile responses on d 14 or d 45 post-application[19]
a pulling test) of the attachment induced with Quixil was not as strong as that induced with Tisseel, Bioglue, Glubran 2 or Dermabond (table I).[15] In cardiovascular surgery, the mechanical properties of sealants may be important for determining the choice of agent used for haemostasis at suture lines, as sealants with greater stiffness than aortic root placement material may restrict normal physiological dilation and cause anastomotic strictures.[16] In a study comparing the mechanical properties of several sealants and aortic root placement materials (Dacron grafts, gluteraldehyde-fixed porcine roots or human
aortic homografts), Crosseal was significantly more compliant than Tisseel (but not Coseal [a synthetic sealing agent]), while Bioglue was significantly stiffer than Crosseal, Tisseel and Coseal (table I). In addition, Crosseal, Tisseel and Coseal were more compliant than aortic root placement materials, while Bioglue was much stiffer (table I). An in vivo study assessed the adhesions formed between the liver lobes and surrounding tissues and organs following the use of Quixil, Tissucol and Beriplast P in a rabbit partial liver resection model.[17] Adhesions were found mostly between the dissected liver lobe and the omentum.[17]
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When these intra-abdominal adhesions were scored, based on manifestations of blood vessels and size, the adhesion index score for Quixil was significantly lower than that for Beriplast P and Tissucol (table I), suggesting that the seal formed with Quixil was more secure postoperatively than the seals formed with other sealants, resulting in a lower incidence and severity of re-bleeding.[17]
2.3 Haemostatic Effects
In a study comparing the haemostatic properties of several fibrin sealants, Beriplast P was shown to be significantly more effective than Quixil in terms of early and late haemostasis in rabbit partial liver or kidney resection models (table I).[13] However, in another study, Quixil was associated with the shortest bleeding times and the least volume of sealant used when its haemostatic properties were compared with those of Tissucol and Beriplast P in a rabbit partial liver resection model.[17] The reduced bleeding time and amount of sealant used may be attributed to the higher concentration of thrombin in Quixil than in Beriplast P and Tissucol (800 1200 vs 400625 and 500 IU/mL), which accelerates coagulation of the fibrinogen component of the sealant and probably also the clottable proteins in blood at the site of injury.[17] The study authors suggested that the difference between this study[17] and the study discussed previously[13] in terms of results for immediate haemostasis may be due to differences in rabbit models and study designs. The haemostatic effects of Evicel and Quixil/ Crosseal in large clinical studies are discussed in section 4.
2.4 Other Effects
In a study assessing functional nerve responses after repair of the right sciatic nerve in rats, the use of Quixil was associated with faster nerve and behavioural recovery than the use of epineural microsuture (table I).[18] However, in vitro[7] and in vivo[8] studies have shown that tranexamic acid contained in the fibrinogen component of Quixil is neurotoxic when applied directly to CSF or dura mater; therefore, Quixil is contraindicated for use in neurosurgery or in procedures where contact with CSF or dura mater may occur.[8] In contrast, Evicel, which does not contain tranexamic acid, had no detrimental effects on neuroregulatory control of erection in a rat model (table I).[19] 3. Pharmacokinetic Properties Evicel is intended only for topical use and intravascular administration is contraindicated (section 6); therefore, its intravascular pharmacokinetics have not been determined in humans.[20,21] Data discussed here are from a radiolabelling study in rabbits, which assessed the pharmacokinetics of a-thrombin and tranexamic acid contained in the previous-generation fibrin sealant, Quixil;[22] these data are supplemented with data from the Evicel US prescribing information[21] and the EU summary of product characteristics (SPC).[20] After local application of Quixil to the cut surface of the liver after partial resection, there was slow absorption of biologically inactive peptides resulting from the degradation of thrombin[20-22] (1 mL of Quixil was applied containing 500 units of 125I-a-thrombin[22]). The peak plasma concentration (Cmax) of thrombin-related proteins was reached 68 hours after Quixil application.[20,21] The Cmax of thrombin-related proteins represented only 12% of the applied dose[20-22] and never exceeded 56 mU of thrombin equivalent per mL, which was less than the endogenous thrombin generated in abdominal surgery.[22] On the other hand, the Cmax (0.015 mg/mL) of 3 H-labelled tranexamic acid was reached quickly (after 60 minutes) and the compound was slowly cleared within 10 hours.[22] It is probable that the
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In a pancreaticojejunal attachment model in rats, all tissue adhesives assessed, including Quixil, were shown to induce histopathological changes in the pancreas (table I), which may potentially be harmful and may compromise the use of these sealants for pancreatic applications.[15]
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plasma concentration of tranexamic acid reached following Quixil application may be sufficient to inhibit fibrinolysis of the fibrin sealant and the injury site, thereby preventing recurrence of local bleeding.[22] Fibrin sealants are metabolized by fibrinolysis and phagocytosis in the same way as endogenous fibrin.[20,21] Plasmin induces increased fibrinolytic activity as wound healing progresses, initiating the metabolism of fibrin to fibrin degradation products.[20,21] 4. Therapeutic Efficacy This section focuses on the use of Evicel or the previous-generation fibrin sealant Quixil/ Crosseal as supportive treatment for haemostasis in surgery. The haemostatic efficacies of these fibrin sealants were evaluated in several clinical trials (n 20) in patients undergoing vascular surgery (section 4.1), liver surgery (section 4.2), retroperitoneal or intra-abdominal surgery (section 4.3), orthopaedic surgery (section 4.4), or nose and throat surgeries (section 4.5).
4.1 In Vascular Surgery
vascular surgery, including bypass surgery and prosthetic implantation.[4] Two studies assessed the haemostatic efficacies of Evicel[23] and Quixil[24] during vascular surgery.
4.1.1 Efficacy of Evicel
In vascular surgery, as in other surgeries, a reduced time to haemostasis is widely accepted to be beneficial[23] and fibrin sealants have been used successfully in several procedures in cardio-
A randomized, controlled, multicentre study compared the haemostatic efficacy of Evicel with that of manual compression in adult patients (aged 18 years; mean 66 years) undergoing a vascular procedure using uncoated or heparincoated polytetrafluoroethylene (PTFE) graft material on an end-to-side femoral or upper extremity arterial anastomosis (see table II for study design details).[23] Apart from one patient who received a heparin-coated PTFE graft, all patients received an uncoated PTFE graft. Key exclusion criteria included revascularization with prosthetic material other than PTFE or intraoperative findings (e.g. no anastomotic bleeding) that precluded the conduct of study procedures. The surgical procedure was not standardized at each site and each surgeon performed the surgery according his or her standard practice.[23] Evicel was significantly more effective than manual compression in achieving haemostasis at the anastomosis 4 minutes post-randomization in patients undergoing vascular surgery (primary endpoint; table II).[23] The majority (85%) of patients in the Evicel group compared with less
Table II. Haemostatic efficacy of Evicel in adult patients (pts) undergoing vascular surgery in a randomized, multicentre study.[23] During surgery, if it was determined that adjunctive haemostatic measures were required, arterial clamps were re-applied and pts were randomized to receive Evicel or manual compression (MC). Analyses were based on the intent-to-treat population (all randomized pts) Treatmenta [no. of pts] Evicel [75] MC [72] OR (95% CI) a b c d e
Pts achieving haemostasis (%) 7 min at 4 minb 85 39 11.34 (4.67, 27.52)

*
10 min 96.0
*e
Incidence (%) TFc 8

*
complicationsd 16 21 1.46 (0.58, 3.69)
90.7
*e
59.7e 7.88 (2.84, 21.86)
69.4e 18.53 (3.74, 91.77)
32 0.14 (0.05, 0.45)
All pts received heparin after arterial clamping (mean dose 66.9 units/kg in the Evicel group and 67.9 units/kg in the MC group). Evicel was dripped onto the anastomosis; MC was applied to the anastomosis with gauze sponges. Primary endpoint. Presence of bleeding at the anastomosis 10 min post-randomization, or the requirement of additional haemostatic measures during the initial 10-min period. Potentially related to bleeding, including anaemia and low haemoglobin levels, assessed up to 5 wk after surgery. Values obtained from the Evicel assessment report by the European Medicines Agency.[6]
OR = odds ratio; TF = treatment failure; * p < 0.001 vs MC.
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than half (39%) of the patients in the manual compression group achieved haemostasis at this timepoint (table II). Moreover, exploratory analyses showed that Evicel was effective regardless of artery type, with 85% of patients in the Evicel group (vs 43% of patients in the manual compression group) achieving haemostasis at 4 minutes after an upper extremity surgical procedure, and 85% (vs 37%) of patients achieving haemostasis at this timepoint after a femoral surgical procedure.[23] The proportions of patients who achieved haemostasis within 7 and 10 minutes of randomization were also greater in the Evicel group than in the manual compression group (table II).[23] It should be noted that the time lapsed between randomization and application of fibrin sealant or manual compression may have affected the proportion of patients achieving haemostasis within each timepoint. The incidence of treatment failures was also significantly lower in the Evicel group than in the manual compression group, but the rate of complications potentially related to bleeding did not differ significantly between the two groups (table II).[23]
4.1.2 Efficacy of Quixil
of treatment with Quixil over Kaltostat and further enrolment in the study was terminated. Quixil was more effective than Kaltostat in reducing bleeding at the suture line in patients undergoing elective carotid endarterectomy with expanded PTFE reconstruction.[24] The median time to achieve haemostasis was significantly (p < 0.001) shorter in the Quixil group than in the Kaltostat group (2.5 vs 17 minutes); median blood loss was also significantly (p < 0.001) reduced with Quixil relative to Kaltostat (24.5 vs 203 mL).
4.2 In Liver Surgery
The haemostatic efficacy of Quixil versus that of Kaltostat (a calcium sodium alginate dressing) was evaluated in a small, randomized, pilot study in patients (mean age 71.1 years) undergoing elective carotid endarterectomy with expanded PTFE reconstruction.[24] Eligibility criteria included a normal clotting profile (assessed by partial thromboplastin time and activated partial thromboplastin time) and treatment with aspirin 75 mg for at least 2 weeks. Patients with known coagulopathy or those who were taking other medications that interfered with haemostasis, platelet function or wound healing were excluded; patients requiring other methods to control bleeding at the suture line (e.g. tacking sutures) were withdrawn from the study.[24] Quixil was dripped onto the suture line (n = 10 patients); Kaltostat was applied to the suture line as 7 12 cm sheets (n = 10).[24] The study planned to enrol 30 patients; however, an interim analysis of data from 20 patients showed a benefit
Despite recent advances in surgical techniques, operative blood loss in patients undergoing liver resection remains a major problem.[25] Adjunctive measures (e.g. microfibrillar collagen and fibrin sealants) have been developed to promote haemostasis, which may be particularly important in liver surgery, since many postoperative complications after liver resection are due to bleeding and bile leakage.[25] Effective sealing of blood vessels and biliary radicals with these adjunctive treatments may reduce these postoperative complications,[25] although this remains to be confirmed in clinical trials. A randomized, single-blind, controlled, multicentre trial was undertaken to compare the haemostatic efficacy of the fibrin sealant Crosseal with that of a control agent (a standard US FDAapproved topical haemostatic agent) in patients (aged 18 years; mean 59.3 years) who required liver resection (see table III for study design details).[25] All staff, including data analysts, were blinded to treatment as far as possible, but the surgeon could not be blinded due to nature of the treatments being compared. In an attempt to maintain blinding, the fibrin sealant was sprayed at the end of the surgery when all major bleeding was controlled and only diffuse parenchymal oozing remained.[25] Crosseal was significantly more effective than standard topical haemostatic agents in reducing the time to achieve haemostasis after liver resection (table III).[25] In the Crosseal group relative to the control group, the mean time to haemostasis was reduced by an estimated 21.1%
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Table III. Haemostatic efficacy of Crosseal in adult patients (pts)a undergoing liver surgery in a randomized, single-blind, multicentre study.[25] If pts had generalized oozing from the cut surface of the liver after resection, and if the use a topical haemostatic agent was deemed necessary, pts were randomized to receive Crosseal or a control agent (standard haemostatic agents, including Gelfoam and Surgicel). Primary efficacy analyses were conducted in both the intent-to-treat population (ITT) [all randomized pts] and in the efficacy-evaluable population (EE) [which excluded 5 pts with major protocol violations] Treatmentb Crosseal Control TE (95% CI) a Mean time to haemostasis (sec)c,d ITT 318 462 -97.2 (23.4, 159)
*
Ptse (%) achieving haemostasis 5 min >5 to 10 min 91.4 69.8

**
Ptse (%) needing re-operation for complicationsf 17.2* 36.5 abdominal coll. 3.4* 14.3
g g
EE 282 468 -104.4 (33, 164.4)

***
>10 min 100 100
71 55
g g
Pts who required liver resection for any reason, except trauma, and who underwent no other major surgical intervention were included. Key exclusion criteria included occurrence of a coagulation disorder other than that resulting from liver disease, or previous contact with bovine thrombin. Crosseal was sprayed in short bursts (0.10.2 mL) onto the cut surface of the liver to form a thin, even layer. Control agents were used singly or in combination, and were applied as per recommendations in the package insert and the surgeons standard of care, with the latter taking precedence. Primary endpoint; defined as time between application of the product to the surface of the liver (after resection was completed and all discrete bleeding points were controlled by suture or cauterization) and the time when there was no further evidence of bleeding over a 1-min observation period. The ITT and EE populations comprised of 58 and 55 Crosseal recipients and 63 and 61 controls, respectively. Pt population not specified. Including re-operation for any reason, a diagnosis of abdominal fluid collections or bilious drainage. Estimated from a graph.
d e f g
Coll. = collections; TE = treatment effect; * p 0.05, ** p = 0.003, *** p = 0.006 vs control.
(ITT [intent-to-treat] population) or 22.4% (efficacyevaluable population) [table III; primary endpoints].[25] Cumulative distribution curves of the ITT and the efficacy evaluable populations showed that after the initial 3 minutes of observation, fewer patients in the Crosseal group than the control group were still bleeding (no statistical data were reported). In addition, significantly more patients in the Crosseal group than in the control group had achieved haemostasis within 10 minutes of randomization (table III).[25] Furthermore, significantly fewer patients in the Crosseal group required re-operation for any reason, a diagnosis of abdominal fluid collections or bilious drainage, or, when these complications were analysed individually, for abdominal collections (table III).[25] No significant betweengroup differences were observed in intraoperative blood loss, duration of operative bilious drainage, proportion of patients with bile loss, volume of drainage fluid or duration of drainage. Mean hospital stay also did not differ significantly between the two groups (9 vs 10.5 days; median 7 days in both groups).[25]
4.3 In Retroperitoneal and Intra-abdominal Surgery
Fibrin sealants are also effective as an adjunct to achieve haemostasis for bleeding in soft tissue during elective retroperitoneal or intra-abdominal surgery.[26] A phase III, randomized, controlled, multicentre trial evaluated the haemostatic efficacy of the fibrin sealant Evicel versus that of the absorbable haemostat Surgicel in adult patients (aged 2084 years; mean 59.3 years) undergoing elective retroperitoneal or intra-abdominal surgery (see table IV for study design details).[26] Surgeons were not blinded to treatment because of differences in the application procedures of the two sealants.[26] Evicel was significantly more effective than Surgicel as an adjunct to haemostasis for soft tissue bleeding.[26] A significantly greater proportion of Evicel than Surgicel recipients achieved haemostasis at 10 minutes (primary endpoint), as well as at 7 and 4 minutes post-randomization (table IV). The incidence of treatment failures was also significantly lower (table IV) and the
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mean time to haemostasis was significantly shorter (2.9 vs 3.7 minutes; p = 0.0026) in the Evicel than in the Surgicel group.[26] During the 10-minute observation period, no patients in the Evicel group had brisk bleeding requiring additional haemostatic measures, compared with 3.2% of patients in the Surgicel group who required additional intervention (relative risk 1.03 [95% CI 0.97, 1.12]).[26] In patients with mild bleeding (defined as small areas of capillary, arteriole or venule oozing in tissues), haemostasis was achieved within 10 minutes in 100% of Evicel recipients compared with 88.9% of Surgicel recipients. In patients with moderate bleeding (defined as either a larger area of bleeding of a magnitude similar to that of mild bleeding, or bleeding that was more pronounced, such as flowing or pulsatile, but not massive or from a large artery), 87.0% versus 73.1% of patients in the respective groups achieved haemostasis within 10 minutes. There was no significant between-group difference in the incidence of complications potentially related to bleeding (table IV).[26] Like Evicel, Quixil was also shown to be an effective haemostatic agent in patients undergoing a laparotomy (n = 35) or laparoscopy (n = 4)
in a prospective, uncontrolled, observational study conducted in a tertiary gynaecological oncology centre.[27] Satisfactory haemostasis was achieved within 5 minutes of sealant application in all patients who underwent a total of 26 operations for malignant disease and 13 procedures for benign indications.[27]
4.4 In Orthopaedic Surgery
Orthopaedic surgery may be associated with considerable intraoperative and postoperative blood loss, resulting in the need for blood transfusions.[28,29] However, there are serious risks associated with blood transfusion, such as transfusion reactions and infections (particularly HIV).[28,29] Although techniques such as hypotensive or regional anaesthesia and intra- or postoperative salvage of blood may be used to reduce blood loss, a better approach would be to minimize blood loss by enhancing local haemostasis.[28,29] Fibrin sealants, like Evicel and Quixil, may offer one such option for haemostasis and several clinical trials were undertaken to evaluate the haemostatic efficacies of these sealants in patients undergoing orthopaedic surgery (see table V for study details).
Table IV. Haemostatic efficacy of Evicel in adult patients (pts)a undergoing retroperitoneal or intra-abdominal surgery in a randomized, nonblind, multicentre study.[26] If conventional techniques (e.g. sutures, ligature and cautery) to control soft-tissue bleeding at the primary operative site were considered impractical or ineffective, pts were randomized to receive Evicel or absorbable haemostat (Surgicel) as an adjunct to haemostasis. Analyses were based on the intent-to-treat population (all randomized pts) Treatmentb [no. of pts] Evicel [62] Surgicel [62] RR (95% CI) a Pts achieving haemostasisc (%) at 4 min 7 min 74.2* 54.8 1.35 (1.04, 1.80) 90.3* 77.4 1.17 (1.00, 1.39) 10 mind 95.2* 82.3 1.16 (1.02, 1.35) Incidence (%) TFe complicationsf 4.8* 17.7 11.3 16.1 0.7 (0.29, 1.67)
Pts scheduled to undergo elective retroperitoneal or intra-abdominal surgery were included, while those undergoing an emergent procedure were excluded from the study. Procedures included urological (e.g. simple or radical nephrectomy), gynaecological (e.g. radical hysterectomy or primary tumour reduction surgery) and general (e.g. colectomy or abdominoperineal resection) surgeries. Evicel was dripped or sprayed onto the target bleeding site; Surgicel was applied directly to the bleeding site. Defined as the absence of bleeding and absence of treatment with other haemostatic measures at the time of assessment. Primary endpoint. Presence of bleeding at the target bleeding site 10 min post-randomization, or brisk bleeding that required the use of additional haemostatic measures during the 10-min period. Potentially related to bleeding, including anaemia and low haemoglobin levels, assessed 714 d after surgery.
b c d e f
RR = relative risk; TF = treatment failure; * p 0.05 vs Surgicel.
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Table V. Design details of a retrospective study (poster presentation),[30] and randomized[28,29,31-33] single-blind[33] or non-blind[28,29] trials assessing the efficacy of Evicel[30] or Quixil[28,29,31-33] in patients (pts) undergoing orthopaedic surgery. Where reported,[28-30,33] the average age of the pts ranged from approximately 63 to 73 y Study Majoras et al.[30] Key incl/excl criteria Incl: pts undergoing unilateral primary THA or TKA Treatmenta Evicel grp: exposed tissues after component insertion were treated with SHP followed by FS as a spray SHP grp: did not receive FS Quixil grp: pts were randomized to receive 10 mL of FS as a spray during the operation (until the time of femoral implant insertion; until the time of femoral implant insertion and also prior to wound closure; or after both components were cemented and the hip reduced) Control grp: did not receive FS Quixil grp: 1020 mL of FS was sprayed after the prosthesis had been inserted and prior to closure of soft tissues SC grp: pts received standard method of haemostasis alone Quixil grp: 10 mL of FS was sprayed before the prosthesis was inserted, after placement of the prosthesis and after closure of the capsule TA grp: pts received intravenous TA 500 mg 5 min before deflation of tourniquet and a repeat dose 3 h later Control grp: pts received no pharmacological intervention Quixil grp: 10 mL of FS was sprayed after cementing of the joint and before tourniquet deflation and wound closure Control grp: pts did not receive FS Quixil grp: SC + 10 mL of FS as a spray during the operation (after the femoral head was dislocated and femoral neck osteotomy was completed, after insertion of the prosthesis and prior to fascial closure) SC grp: pts received SC alone
Crawford et al.[28]
Incl: pts undergoing elective THA Excl: prior surgery to the operated hip; known bleeding disorders; use of anti-coagulants (e.g. aspirin) within 10 d of surgery
Levy et al.[29]
Incl: pts who had OA of the knee and were undergoing unilateral TKA Incl: pts undergoing primary TKA; Hb level of 13 g/dL at BL Excl: prior knee surgery (except meniscectomy); bleeding, platelet or BM disorders; history of thromboembolism Incl: pts with OA undergoing primary, unilateral TKA; Hb level of >11 g/dL at BL Excl: bleeding or metabolic-based haemolytic disorders Incl: pts aged >18 y with OA of the hip undergoing primary, unilateral THA; Hb level of 11 g/dL at BL Excl: bleeding, platelet or BM disorders; anti-coagulant or NSAID use within 7 d of surgery (aspirin 150 mg/d was permitted); prior exposure to FS; prior surgery requiring bone grafts; prior hip surgery
Molloy et al.[31]
Wang et al.[32]
Wang et al.[33]
Where reported, all pts received thromboprophylaxis (with aspirin,[28,31] low-molecular-weight heparin[29,32] or warfarin[33]) pre- and postoperatively[29,31,33] or only postoperatively.[28,32] In one study, all the operations were performed in a uniform manner,[29] while in another study, surgeons standardized technique was consistently maintained for all the surgeons own pts throughout the study.[33]
BL = baseline; BM = bone marrow; excl = exclusion; FS = fibrin sealant; grp = group; Hb = haemoglobin; incl = inclusion; OA = osteoarthritis; SC = standard care; SHP = standard haemostatic protocol; TA = tranexamic acid; THA = total hip arthroplasty; TKA = total knee arthroplasty.
4.4.1 Efficacy of Evicel
Limited data from a retrospective review of 131 patients who underwent total knee or hip arthroplasty over an 11-month period showed that there may be some benefit of treatment with Evicel.[30] Postoperatively (in the recovery room), there was less (p 0.03) change from baseline in haemoglobin levels (table VI) and haematocrit (mean 4.75 vs 6.10 g/dL) in the Evicel group than in the control group. However, mean intraoperative, postoperative and total blood loss (table VI) and the mean amount of blood transfusions (0.21 vs 0.34 units) did not differ significantly between the Evicel and control groups. There were also no differences between the groups
in terms of clinical outcomes or the rate of complications (no quantitative data available).[30]
4.4.2 Efficacy of Quixil
As with Evicel, there was some benefit of treatment with Quixil in patients undergoing orthopaedic surgery, but the results were not consistent across all trials (table VI). Four controlled trials showed that, where assessed, there was significant reduction in total (16%,[31] 24%[33] or 47%[28] reduction), postoperative (47%[33] and 59%[29]) and intraoperative (63%)[28] blood loss in the Quixil groups relative to the control groups (table VI). However, in two of these studies, the reduction in intraoperative blood loss (23%)[33]
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and postoperative blood loss (19%)[28] in the Quixil groups relative to the control groups was not significant (table VI). The percentage reduction in all types of blood loss in two studies was estimated from adjusted mean[28] or geometric mean[33] values. In an active comparator-controlled study,[31] like Quixil, treatment with tranexamic acid also reduced total blood loss (by 13%) relative to the control group (table VI); there was no significant difference between the Quixil and tranexamic acid groups in terms of total blood loss. In one study, there was 55.6% less drainage within 12 hours of the surgery in the Quixil group than in the control group (assessed after adjustment for the time that the drainage was measured).[32] Haemoglobin levels were reduced from baseline to a significantly lesser extent in the Quixil group than in the control group in two studies,[29,32] but there was no significant between-group dif-
ference in another study (table VI).[33] Similar results were also observed for blood transfusions, with fewer patients in the Quixil group than in the control group requiring transfusions in two studies,[28,29] but not in two other studies[31,32] (table VI). With regard to the duration of hospitalization, the mean duration did not differ significantly between the Quixil and control groups (4.9 vs 5.3 days) in one study;[33] in another study, the mean durations in the Quixil, tranexamic acid and control groups were 4.82, 5.10 and 5.86 days, respectively (significance not reported).[31]
4.5 In Nose and Throat Surgery
Endonasal surgeries, such as septoplasty and rhinoplasty, may be associated with bleeding and postoperative haematoma.[34] Traditionally, nasal
Table VI. Haemostatic efficacy of Evicel or Quixil in patients (pts) undergoing orthopaedic surgery. Results from a retrospective study,[30] and randomized[28,29,31-33] single-blind[33] or non-blind[28,29] trials in pts undergoing total hip[28,30,33] and/or knee arthroplasty[29-32] are presented (see table V for study design details). Where reported,[28,33] analyses were conducted in the intent-to-treat population (all randomized pts). Statistical comparisons for haemoglobin (Hb)[28,31] and blood transfusion (BT)[33] were not reported in three studies Study Efficacy of Evicel Majoras et al.[30]c Efficacy of Quixil Crawford et al.[28] Levy et al.[29] Molloy et al.
[31]
Treatment
No. of pts
Mean blood lossa (mL) intraop. postop. 251 333 302** 626 308 354 285 390 360**d 878d
total 559 687 587** 1016
Mean from BL in Hbb (g/dL [%]) [1.7*] [2.2] 2.3 2.6 2.5** 3.7
No. of pts receiving a BT
Evicel SHP Quixil Control SC + Quixil SC alone Quixil TA Control
75 56 13 12 29 29 50 50 50 25 28 38 43
0* 5 5** 16 7 5 11 9 14 11 18
1190* 1225* 1415
2.68 2.75 3.20 2.01**e 2.73
Wang et al.[32] Wang et al.[33] a b c d e
Quixil Control SC + Quixil SC alone
432.85 559.67
116.63** 219.07
626.25*d 818.57d
2.62 2.99
Adjusted geometric mean values reported in one study.[33] Where reported, Hb levels at BL were 12[31] or 13[32] g/dL. Poster presentation. Primary endpoint. Statistical significance was based on values adjusted for preoperative Hb levels.
BL = baseline; intraop. = intraoperative; postop. = postoperative; SC = standard care; SHP = standard haemostatic protocol; TA = tranexamic acid; indicates decrease; * p < 0.05, ** p 0.005 vs SHP, SC or control.
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Table VII. Haemostatic efficacy of Quixil in patients (pts)a undergoing endonasal surgery. Pts aged 34.4 y (mean)[38] or 1864 y (range)[34,35,39,40] received Quixil or nasal packing (NP) [Merocel foam] to facilitate haemostasis in randomized,[34,38-40] controlled[34,35,38-40] trials. Statistical comparisons between groups were conducted in one study[38] Study Vaiman et al.[35] Vaiman et al.[34] Surgeryb Variousf Variousf Sept+Conch Sept+Conch Sept+Conch Vaiman et al.[38] Sept+Conch Sept+Conch ESS ESS ESS+Sept/Conch ESS+Sept/Conch Vaiman et al.[39] Vaiman et al.[40]h a ESS ESS Sept and/or Conch Treatmentc [no. of pts] Quixil [77] NP [81] Quixilg Quixil+TSg NPg Quixil [157] NP [182] Quixil [43] NP [48] Quixil [32] NP [32] Quixil [32] NP [32] Quixilh [146] Postoperative bleeding (% [no.] of pts) scanty NPRd 0 [0] 21 [17] 0 [0] 0 [0] 26 [18] 0 [0] 16 [29] 0 [0] 17 [8] 0 [0] 19 [6] 0 [0] 19 [6] 0 [0] ser/sig NPRd 0 [0] 3 [2] 0 [0] 0 [0] 4 [3] 0 [0] 3 [6] 0 [0] 2 [1] 0 [0] 3 [1] 0 [0] 3 [1] 0 [0] through NPd 0 [0] 1 [1] 0 [0] 0 [0] 3 [2] 0 [0] 1 [2] 0 [0] 4 [2] 0 [0] 0 [0] 0 [0] 3 [1] 0 [0] latee 0 [0] 1 [1] 0 [0] 1 [1] 1 [1] 4 [6] 3 [6] 5 [2] 0 [0] 3 [1] 3 [1] 3 [1] 0 [0] 0.7 [1] ISH 0 [0] 1 [1] 0 [0] 0 [0] 1 [1] 0 [0] 1 [2] 0 [0] 0 [0] 0 [0] 0 [0] 0 [0] 0 [0] 0 [0] total 0 [0] 27 [22] 0 [0] 1 [1] 37 [25] 4 [6]* 25 [45] 5 [2]* 23 [11] 3 [1]* 25 [8] 3 [1] 25 [8] 0.7 [1]
Pts had various symptoms, including deviated nasal septum and hypertrophy of the inferior conchae as a result of chronic, vasomotor and allergic rhinitis.[34,35,38,40] One study included pts undergoing ESS who had excessive intraoperative and/or immediate postoperative bleeding.[39] In the Quixil group in two studies, additional TS was used to avoid intraseptal haematoma.[35,38] Quixil was sprayed as an aerosol in short bursts (0.10.2 mL) to produce a thin even layer. In pts receiving Quixil, there was no postoperative bleeding, therefore, NP was not required. Bleeding occurring, where reported, 2430 hours after NPR[34,35,38] or 3048 hours after surgery.[38,39] Including Conch (n = 145), Sept (n = 146) and Culdwell Luc operation (n = 10). The study enrolled 204 pts; no. of pts in the individual treatment groups was not reported. This study assessed the haemostatic efficacy and glue properties of Quixil. Pts were randomized to receive TS (group I) or Quixil (group II) for septal sealing; in addition, all pts received Quixil for haemostasis. Data for the overall haemostatic efficacy of Quixil in both groups are presented.
b c d e f g h
Conch = conchotomy; ESS = endoscopic sinus surgery; ISH = intraseptal haematoma 48 h after pack removal; NPR = after nasal pack removal; Sept = septoplasty; ser = serious; sig = significant; TS = transseptal suturing; * p < 0.05 vs NP.
packing has been used to control bleeding after surgery; however, its use is associated with other risks and complications, such as mucosal lesions, infections, pain and respiratory compromise.[35] Similarly, tonsillectomy is frequently associated with bleeding and postoperative morbidity,[36,37] and optimal parameters and techniques for recovery from tonsillectomy are still being sought.[36] Postoperative bleeding after tonsillectomy usually responds to local measures, including electrocautery, but bleeding can be life-threatening.[36,37] Moreover, electrocautery itself can lead to additional pain and trauma.[36] Fibrin sealants are another option for haemostasis in such proce 2011 Adis Data Information BV. All rights reserved.
dures and several studies have been undertaken to assess the efficacy of Quixil in nose and throat surgeries.
4.5.1 Endonasal Surgery
Several controlled trials evaluated the haemostatic efficacy of Quixil in patients undergoing endonasal surgery (see table VII for study details).[34,35,38-40] Assessments included the incidence of postoperative bleeding and occurrence of complications, which were assessed objectively by the surgeon (by using anterior rhinoscopy and/ or endoscopy of the nasal cavity) and subjectively by the patients at follow-up visits.[34,35,38-40]
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Quixil was an effective haemostatic agent in endonasal surgery.[34,35,38-40] Overall, postoperative bleeding occurred in 05% of patients in the Quixil groups compared with 2337% of patients in the nasal packing groups (table VII).[34,35,38,39] Statistical significance was assessed in one study, which showed that total bleeding was significantly lower with Quixil than with nasal packing (table VII).[38] In patients receiving Quixil (with[34,35,38,40] or without[34,40] transseptal suturing) there was no postoperative bleeding and, therefore, no nasal packing was required.[34,35,38-40] However, late bleeding (3048 hours after surgery[38,39]) was reported in 5% of patients (table VII).[34,38-40] There was good tissue approximation and complete resolution of the major symptoms in these patients, with no haematomas, swelling, bleeding, synechia, displacement or any other complications.[34,35,38-40] Where reported, patients left the hospital immediately after the surgery and did not complain of pain or other inconveniences, and did not require postoperative care;[35,38] patients also did not have mucous discharge.[35,39] In contrast, patients who received nasal packing had several reports of postoperative bleeding (table VII), as well as various complications of nasal packing.[34,35,38,39] Scanty bleeding after removal of nasal packing (which generally stopped spontaneously) was the most frequent type of postoperative bleeding (1626% of patients; table VII).[34,35,38,39] In addition, serious/significant bleeding after nasal pack removal (requiring replacement of nasal pack) and bleeding through the nasal pack occurred in 4% of patients, and late bleeding (2430 hours after pack removal, which stopped spontaneously[34,35,38]) occurred in 3% of patients.[34,35,38,39] Intraseptal haematomas were reported in 1% of patients in three studies (table VII),[34,35,38] while four patients in two of these studies (one[34] and three[38] patients) presented with postoperative synechia. In terms of other complications, patients receiving the nasal pack complained of disturbance of breathing during sleep (93100% of patients),[35,38,39] lacrimation (2648%),[35,38,39] and pain and intranasal pressure caused by nasal packing (4793%);[35,38,39] mucous discharge was also
usually observed in this group.[35,38,39] In one study, haemorrhage after nasal pack removal was reported in seven patients (21.9%) in the group that received the pack (p < 0.001 vs the Quixil group).[39] In contrast with nasal packing, the administration of antibacterial agents was not required with Quixil, as there was no foreign body in the nasal cavity.[34,38,39] In Quixil recipients, convalescence was rapid and nasal breathing was possible immediately after the surgery, whereas in the nasal packing group, nasal breathing was possible only after removal of the packing.[34,35,38,39] Additionally, as Quixil does not form a plaque, there was no danger of plaque aspiration and, since nasal packing was not required, patient discomfort and sinonasal secondary infections or other complications were avoided.[34,38,39] Aerosol spraying of Quixil helped to stop bleeding in all parts of the nasal cavity[34] and in all operated sinuses,[38,39] and the technique was relatively easy to perform.[34,35,38,39]
4.5.2 Tonsillectomy and Adenoidectomy
The haemostatic efficacy of Quixil was compared with that of electrocautery in a randomized, controlled study in patients (aged 2 years) undergoing: bilateral tonsillectomy for chronic tonsillitis or hypertrophy of tonsils; adenoidectomy for hypertrophy of adenoids; or both surgeries.[36] Haemostasis at the tonsillar fossa and adenoidectomy site was achieved with bipolar or needlepoint electrocautery (n = 91) or Quixil (n = 88); Quixil was sprayed on each tonsillar fossa and/ or on the adenoidectomy site (0.5 mL at each site).[36] Bleeding, swelling, pain and the condition of the operative site were assessed by clinical evaluation of symptoms, objective evaluation by the surgeon (by posterior nasopharyngoscopy in patients aged >5 years or fibre nasopharyngoscopy in patients aged 25 years) and subjective evaluation by the patients at follow-up visits.[36] Quixil was a more effective haemostatic sealant than electrocautery and provided good sealing with minimal surgical trauma.[36] Intraoperative blood loss and postoperative bleeding were significantly (p 0.01) less in Quixil recipients than
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5. Tolerability The tolerability data for Evicel and Quixil/ Crosseal were obtained from the studies discussed in section 4 and from the EU SPC[20] and the US prescribing information.[21]
5.1 Tolerability of Evicel
Incidence (% of patients)
in patients undergoing electrocautery (average intraoperative blood loss was 15 mL vs 29 mL with needle-point cautery and 33 mL with bipolar cautery). There were no reports of postoperative bleeding in Quixil recipients, whereas four patients who underwent tonsillectomy followed by electrocautery experienced postoperative bleeding (three cases of primary haemorrhage and one case of secondary haemorrhage); in all cases, bleeding was successfully stopped with bipolar electrocautery.[36] Additionally, patients in the Quixil group had good resolution of major symptoms, good tissue healing, and no swelling, inflammation, plaques or crusts.[36] In contrast, patients who underwent electrocautery had postoperative swelling, pain and slow wound healing.[36]
a 16 14 12 10 8 6 4 2 0
a nf ec tio n N au se C on a st ip at H io yp n ot en si on b om em /th r ed
Incidence (% of patients)
Evicel (n = 75) MC (n = 72)
ia m n bi lo og Vo m di ac U TI ae fa i
lu iti ng re
lo
ra
ra
ft i
Pe
rip
b 16 14 12 10 8 6 4 2 0
ia a a a a on ni em se m xi re m si au ae so Py ed en al ot Pr as ed D ec re N
Evicel (n = 63) Surgicel (n = 61)
lo
In
yp
ra
yp
Evicel was generally well tolerated in two pivotal trials in patients undergoing vascular (n = 147),[23] or retroperitoneal or intra-abdominal (n = 124)[26] surgery (see sections 4.1.1 and 4.3 for study design details). The overall incidence of treatment-emergent adverse events in the Evicel group was 64% (vs 71% in the manual compression group) in patients undergoing vascular surgery[23] and 71% (vs 69% in the Surgicel group) in patients undergoing retroperitoneal or intraabdominal surgery.[26] The incidences of individual treatment-emergent adverse events did not differ significantly between the Evicel groups and the control groups in either study (figure 1). In patients undergoing vascular surgery, the most common (incidence >5%) adverse events in Evicel recipients were graft occlusion/thrombosis and peripheral oedema (figure 1a).[23] Treatmentemergent adverse events that were considered possibly treatment-related occurred in 12% of Evicel recipients, while no event was considered
Fig. 1. The tolerability profile of Evicel as adjunctive therapy for haemostasis in surgery. Patients (pts) aged 18 y received Evicel,[23,26] manual compression (MC)[23] or Surgicel[26] as adjunctive therapy in (a) vascular surgery[23] or (b) retroperitoneal or intra-abdominal surgery[26] in two randomized, controlled, multicentre studies (see sections 4.1.1 and 4.3 for further study design details). The most common (incidence 5% in either group) treatmentemergent adverse events occurring up to 5 wk after surgery[23] or the most common (incidence >5% in the Evicel group) treatmentemergent adverse events occurring up to 2 wk after surgery[26] are presented. GO = graft occlusion; thromb = thrombosis; UTI = urinary tract infection; h indicates zero incidence.
probably or definitely treatment-related.[23] Treatment-emergent serious adverse events were reported in 23 patients (31 events) in the Evicel group and in 21 patients (29 events) in the manual compression group, including two deaths in either group.[6] Seven of these events were considered possibly related to Evicel (including graft thrombosis, incision site haemorrhage and respiratory failure); none of the events in the control group were thought to be treatment-related[6] as manual compression was considered a standard surgical
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he
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ok
ur
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he
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technique and no adverse events were ascribed to it.[23] In this study, graft occlusion/thrombosis occurred within 12 days of surgery in six (8%) patients in the Evicel group compared with one (1%) patient in the manual compression group; during 5-weeks follow-up, two (3%) patients in the Evicel group and five (7%) patients in the manual compression group were diagnosed with this complication.[6] Overall, seven (9%) patients in the Evicel group and three (4%) patients in the manual compression group required surgical intervention to resolve the complication. In patients undergoing retroperitoneal or abdominal surgery, the most frequent (incidence >10%) treatment-emergent adverse events in Evicel recipients were nausea, hypokalaemia and insomnia (figure 1b).[26] No treatment-emergent adverse event in the Evicel or control group was considered treatment-related;[26] however, three serious adverse events were considered possibly treatment-related, of which one event (abdominal abscess) occurred in the Evicel group and two events (one abdominal and one pelvic abscess) occurred in the control group.[20] One fatality because of air embolism was reported in postmarketing experience with Evicel, which may be attributed to use of the spray device at higher than recommended pressure and at closer than recommended distance from the site of application.[21,41] In addition, there was one report of a non-fatal air embolism resulting from the use of an unapproved spray device;[41] the manufacturers prescribing information has specific recommendations for pressure and distance of application of the sealant (section 6).[20,21] Other adverse events that may occur with the use of fibrin sealants, but have not been observed in clinical studies of Evicel, include hypersensitivity or allergic reactions (e.g. angioedema, burning and stinging at the application site and generalized urticaria) and the development of antibodies against components of fibrin sealant or haemostatic products.[20] There is also a risk of thromboembolic events or disseminated intravascular coagulation (because of inadvertent intravascular injection), and anaphylaxis with the use of fibrin sealants.[20] As with all human-derived biological
agents, there is a risk, albeit a low risk, of transmission of blood-borne diseases with the use of Evicel[2,42] (see also section 7).
5.2 Tolerability of Quixil/Crosseal
The previous-generation fibrin sealant Quixil/ Crosseal was also generally well tolerated in patients undergoing liver resection,[25] orthopaedic surgery,[28,29,31-33] endonasal surgery,[34,38,39] or tonsillectomy and/or adenoidectomy[36] (see section 4 for study design details). In patients undergoing liver resection (n = 121), although most patients reported treatmentemergent adverse events occurring up to 6 weeks post-surgery, these were consistent with the type of surgery and the patients underlying condition.[25] Apart from significantly (p < 0.05) fewer patients in the Crosseal group than the control group (patients receiving standard haemostatic agent) having dyspepsia (6.9% vs 20.6%) or gall bladder disorders (3.4% vs 17.5%), there were no significant between-group differences in the incidences of individual treatment-emergent adverse events. However, the clinical significance of these two adverse events and their relationship to study agents is unclear.[25] None of the treatment-emergent adverse events in this study were considered probably treatmentrelated; 33 events in nine Crosseal recipients were considered unlikely to be treatment-related, while the other adverse events in this group were considered unrelated to therapy.[25] Severe treatment-emergent adverse events occurred in 11 patients in each group. There was one death in the Crosseal group and six deaths in the control group; all deaths were considered unrelated to therapy.[25] In the largest study (n = 150) in patients undergoing orthopaedic surgery, one patient receiving Quixil developed a femoral deep-vein thrombosis and received warfarin therapy 25 days after surgery, while another patient in this group had a pulmonary embolism and received warfarin therapy 20 days after surgery; there were no deaths in Quixil recipients.[31] In another study (n = 81), moderate to severe treatment-emergent adverse events occurred in 81% of patients in the Quixil
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group compared with 82% of patients in the control group, and severe events occurred in 8% (three patients) and 21% (nine patients) of patients, respectively, during the 2-week, post-surgery observation period.[33] The most common (incidence >40% of patients) treatment-emergent adverse events in the Quixil and control groups in this study were pain (92% vs 93%), fever (66% vs 65%) and constipation (45% vs 49%); nausea was the only event that occurred in statistically fewer patients in the Quixil group than in the control group (37% vs 61%; p = 0.046).[33] In a third study (n = 58) in patients undergoing orthopaedic surgery, treatment-emergent adverse events occurred in 90% of patients in the Quixil group compared with 93% of patients in the control group. Most of these events (75% vs 67% of events in the respective groups) were considered mild in severity, and none of the events were considered treatment-related.[29] The most common treatment-emergent adverse event in the Quixil and control groups was fever, occurring in 79% versus 83% of patients in this study.[29] In two other smaller studies (n = 25[28] and 53[32]), two Quixil recipients had blistering around the wound, which was possibly treatment-related,[28] and one Quixil recipient had a haematoma (compared with four patients in the control group).[32] In patients undergoing endonasal surgery, or tonsillectomy and/or adenoidectomy, no allergic reactions[34,36,38,39] or other treatment-emergent adverse events[38] were observed in Quixil recipients. 6. Dosage and Administration In the US and EU, Evicel is indicated as supportive treatment in patients undergoing surgery when control of bleeding by standard surgical techniques (e.g. suture, ligature or cautery) is ineffective or impractical.[20,21] In the EU, it is also indicated as suture support for haemostasis in vascular surgery.[20] The active ingredients of Evicel are human clottable protein (containing mainly fibrinogen)[21] and human thrombin, available in two separate vials;[20,21] the two components have to be mixed and applied using an application device.[20,21]
Evicel is indicated for topical use and should be applied to the surface of bleeding tissue only.[20,21] The amount of product used depends on the area of tissue to be treated and the method of application, and should be individualized by the treating physician.[20,21] Evicel should be dripped or sprayed in short bursts (0.10.2 mL) onto the tissue to produce a thin even layer; a second layer may be applied if the haemostatic effect is incomplete after first application. Excessive use of Evicel to form a thick clot may negatively interfere with the products efficacy and the wound healing process. Evicel must not be administered intravascularly[20,21] and it should not be used for the treatment of severe or brisk arterial bleeding.[21] Unintentional intravascular application of Evicel may result in lifethreatening thromboembolic complications.[20,21] When applying Evicel with a spray device, the pressure and distance from which it is applied should be within the range recommended by the spray device manufacturer.[20,21] Air or gas embolisms have been reported with the use of spray devices, which appear to be related to the use of the device at higher than recommended pressure and in close proximity to the application site (section 5.1). It is recommended that, in the absence of specific recommendations, the pressure of the application device should not exceed 1.41.7 bars (2025 psi) and the sealant should not be sprayed closer than 1015 cm from the tissue surface.[20,21] Local prescribing information should be consulted for comprehensive information on dosage and administration, contraindications, precautions and warnings. 7. Place of Fibrin Sealant (Evicel [Quixil/Crosseal]) in the Management of Haemostasis in Surgery An ideal haemostatic agent is expected to have certain performance characteristics, such as ease of use, efficacy, safety and low cost.[1,5] Several topical haemostatic agents are available for use in surgery (table VIII); however, an ideal agent that meets all these criteria is currently not available.[1,5] The surgeons choice is dependent on factors such as the severity, location and type of
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bleeding, the agents mechanism of action, its interaction with the environment and cost, and the patients individual coagulation abnormalities.[2,5] For example, collagen-, cellulose- and gelatin-based haemostats rely on intact clotting mechanisms (table VIII) and are less effective in coagulopathic patients; therefore, agents such as fibrin sealants, which are independent of the patients clotting mechanism, may be more appropriate for these patients.[2] However, all these agents have safety issues, such as foreign-body reactions with haemostats, and the risk of transmission of blood-borne diseases and risks associated with the use of antifibrinolytics with the fibrin sealants (table VIII).[1,2,5] Depending on the type of surgery, experts in the field recommend the use of specific agents, such as: microfibrillar collagens to control wide areas of parenchymal bleeding (because of their ability to activate platelets); topically applied thrombin for surgical use to stop small-vessel bleeding (because of ease of use and fast action); cyanoacrylates to close small wounds and incisions (because of good cosmetic results and rapid application); and Coseal for cardiac and vascular surgeries (because of its rapid sealing ability) where swelling and expansion are not a concern (table VIII).[5] Similarly, fibrin sealants are considered well suited to control venous oozing from raw surfaces, such as the retroperitoneum,[5] and have been used in several surgeries, including thoracic, cardiovascular and dental surgeries.[2,4] Fibrin sealants mimic the final stages of the blood coagulation process (section 2.1) and, compared with synthetic agents, have the advantage of being biocompatible and biodegradable, while not being associated with adverse events, such as inflammation and foreign body reactions.[4] Several fibrin sealants are currently available, including homologous, fibrin sealants (applied as liquids [table IX] or as a medicated sponge/patch [Tachosil]),[2] and fibrin sealants that use the patients own plasma as a source of either fibrinogen (Vitagel; table VIII) or both thrombin and fibrinogen (Cryoseal).[1] Compared with the latter group of fibrin sealants, the homologous sealants have several advantages, including being independent of the patients clotting mechanism
and coagulation status, and being easier to use, as they do not require special machinery for production.[2,5] On the other hand, Cryoseal is entirely patient derived, eliminating the risk of hypersensitivity reactions, and its clot strength is similar to that of commercially produced agents; however, the concentrations of fibrinogen and thrombin produced and its clot stability are less than those of commercially produced agents.[1] Although all liquid fibrin sealants contain fibrinogen and thrombin as the two active components, they differ from each other in several respects, including their composition (table IX) and ease of use, with the former affecting the speed of haemostasis, the characteristics of the fibrin clot and the agents safety profile.[3] For example, the mechanical strength of the fibrin clot is determined by the concentration of fibrinogen, whereas the rapidity of clot formation and the tensile strength of the clot is determined by the concentration of thrombin.[2,5] Thus, higher fibrinogen concentrations tend to produce stronger, but slowly forming clots, while higher thrombin concentrations result in rapid clot formation, but the clot formed is not as strong.[2,5] Evicel and Quixil contain approximately double the amount of thrombin present in Tisseel and Beriplast P (table IX), which may account for the short bleeding time observed with Quixil (section 2.3). Furthermore, Evicel and Quixil are composed of only human products, which reduces the potential for hypersensitivity reactions, with Evicel having the additional advantage of not containing tranexamic acid, which is potentially neurotoxic[7] (table IX). Studies have shown that tranexamic acid contained in fibrin sealants induces hyperexcitability and convulsions in rats,[45] probably by blocking GABA-mediated inhibition in the CNS.[46] Tisseel contains synthetic aprotinin and Beriplast P contains bovine aprotinin, which may cause hypersensitivity reactions[47] (table IX). The fibrin sealants also differ in terms of the manufacture of fibrinogen, with Tisseel and Beriplast P using the Schwartz method, which produces purified fibrinogen.[3,48] On the other hand, Evicel and Quixil use the Martinowitz method, which produces a biologically active component containing cross-linked fibrinogenDrugs 2011; 71 (14)
Table VIII. Key properties of some common, commercially prepared haemostatic agents[1,2,5] Class (e.g.) Haemostats and sealants Fibrin sealants (Evicel, Tisseel) THR (Thrombin-JMI, Evithromb, Recothrom) Human THR with bovine gelatin (Floseal) A: several applications, e.g. for dural sealing, splenic injuries and in re-operative cardiac surgery; Human THR and FIB are mixed at the site of application, allowing THR to cleave FIB to fibrin effective in heparinized pts; good for venous oozing from raw surfaces; easy to use D: risk of BB disease transmission; added antifibrinolytics may cause adverse events that forms clots Converts FIB in blood to fibrin to form clots and A: controls SV bleeding when pressure or ligature is insufficient; easy application; fast acting activates clotting factors D: may coagulopathy and thrombosis; requires contact with blood for FIB; bovine THR may induce immune response and allergic rxns; risk of viral disease transmission with human THR THR haemostatic effect and the gelatin granules cross-linked into the matrix swell on contact with blood to induce a tamponade-like effect Bovine collagen and THR are combined with pts plasma as a source of FIB and PLTs A: controls moderate arterial bleeding better than fibrin sealants due to gelatin granule tamponade effect; good for heavy bleeding; effective in heparinized pts D: requires contact with blood as a source of FIB; can swell 20% within 10 min; risk of allergic rxns and BB disease transmission A: PLTs from pts strengthen the clot; may be used in e.g. orthopaedic and hepatic procedures D: need for centrifugation and pre-use processing; potential for infection; decreased activity if lack of FIB in pts blood; may cause FB rxns A: better clot than collagen-based agents; controls SV bleeding; nonantigenic; neutral pH D: swells up; may embolize; may cause FB rxns Mechanism of action Potential advantages (A) and disadvantages (D)
1910
Platelet gel (Vitagel)
Haemostats Gelatin foams (Gelfoam) Microfibrillar collagen (Avitene, Instat, Helistat) Thought to provide physical matrix for clot initiation
Provide a matrix for clot formation and enhance A: haemostasis within 15 min; controls wide areas of parenchymal bleeding; no significant platelet adherence and activation swelling; effective despite heparinization D: less effective in pts with thrombocytopenia; may cause FB rxns and bind to neural structures
Oxidised cellulose (Surgicel) Several mechanisms, including blood A: low pH may contribute to haemostasis and antimicrobial effect; good handling properties absorption, surface interactions with PLTs and D: should not be used with other biological agents due to low pH; low pH may inflammation; proteins, and activation of intrinsic and extrinsic swells up; possibility of FB rxns pathways Polysaccharide spheres (Arista AH) Have a dehydrating effect, concentrating the solid components of blood, increasing barrier formation and helping the normal activity of PLTs and blood clotting proteins Two synthetic PEG polymers that mix and cross-link to each other and contacting tissue A: reduces SV bleeding; usually absorbed in 2448 h D: swells up (500%); avoid use of >50 g in diabetic patients as may glucose load; may embolize
Sealants PEG hydrogel (Coseal) A: polymerizes quickly (requires 60 sec); good mechanical sealant for vascular reconstructions; is not exothermic; does not potentiate bacterial infection or cause inflammation D: swells 4 times the initial volume after 1 d and can continue swelling A: maximum bonding in 2.5 min; may be used as replacement for sutures for wounds on the face, extremities and torso D: difficult to use in jagged lacerations; not for mucosal surfaces, axilla or perineum A: maximum bonding within 23 min; effective for reinforcing suture lines in cardiac surgery; independent of pts clotting mechanism and coagulation status D: GLU may cause nerve, sinoatrial node or conduction system injury; may cause end-organ injury from glue emboli; risk of hypersensitivity or mutagenicity
Adhesives Cyanoacrylates (Omnex, Histoacryl) GLU cross-linked albumin (Bioglue) Liquid monomers rapidly polymerize in the presence of water, gluing adjacent surfaces GLU forms covalent bonds with albumin and proteins on the tissue surface, thereby cross-linking the two
Dhillon
BB = blood borne; FB = foreign body; FIB = fibrinogen; GLU = gluteraldehyde; PEG = polyethylene glycol; PLTs = platelets; pts = patients; rxn(s) = reaction(s); SV = small vessel; THR = thrombin; indicates increase.
1911
Table IX. Commonly available homologous, liquid fibrin sealantsa Sealant (appr. in) Evicel (USb, EU) Composition (per mL) Comp. 1: mainly hu FIB and FIN (5090 mg) Comp. 2: hu THR (8001200 IU) Comp. 1: mainly hu FIB and FIN (4060 mg); TA (85100 mg) Comp. 2: hu THR (8001200 IU) Comp. 1: hu FIB (67106 mg); synthetic APR (22503750 KIU) Comp. 2: hu THR (400625 IU) Available as Frozen solutions and an application device Frozen solutions and an application device Comments Less potential for hypersensitivity as contains only hu products; thawed, unopened vials can be refrigerated for up to 30 d; comps are stable at room temp. for 24 h Less potential for hypersensitivity as contains only hu products; potentially neurotoxic due to the presence of TA; thawed, unopened vials can be refrigerated for up to 30 d APR may cause hypersensitivity reactions; freeze-dried comps require prior preparation; thawed, unopened liquid comps can be stored for up to 48 h at room temp; reconstituted comps or open vials should be used within 4 h APR may cause hypersensitivity reactions; comps require prior preparation; reconstituted comps can be stored for up to 8 h at room temp.
Quixil (Mexico and some countries in Europe) Tisseel (US, UK)
Prefilled syringe (frozen) or freeze-dried comps with or without application system Powders and solvents, with application system
Beriplast P (EU)
Comp. 1: FIB (HPPF; 90 mg); coagulation factor XIII (HPPF; 60 u); bovine lung APR (1000 KIU) Comp. 2: THR (HPPF; 500 IU)
a b
Composition was obtained from the latest prescribing informations.[8,20,21,43,44] Evicel has replaced Crosseal in the US.[10]
Appr. = approved; APR = aprotinin; Comp. = component; FIB = fibrinogen; FIN = fibronectin; HPPF = human plasma protein fraction; hu = human; KIU = Kallikrein Inactivator Unit; TA = tranexamic acid; temp. = temperature; THR = thrombin.
fibronectin multimers and other naturally occurring adhesive glycoproteins.[3,48] The presence of these multimers may improve the adhesion of the fibrin clot to the extracellular matrix, as the multimers increase the strength of the bond between the clot and collagen.[3,48] The haemostatic efficacy of fibrin sealants in surgery has been assessed in several trials, but few of these were comparative trials.[2] A Cochrane review suggested that fibrin sealants (including Quixil, Tisseel and Beriplast P) were generally effective in reducing postoperative blood loss and perioperative exposure to blood transfusions during surgery (such as orthopaedic, cardiac and liver surgeries), although there was heterogeneity between surgeries in terms of the size of the effect.[49] Evicel and the previous-generation fibrin sealant Crosseal were effective as supportive treatment for haemostatis in three pivotal studies in patients undergoing vascular (section 4.1), liver (section 4.2), or retroperitoneal or intra-abdominal (section 4.3) surgeries. In these studies, the fibrin sealant was significantly more effective than control treatment (conventional methods or other haemostatic agents) in terms of the mean time to achieve haemostasis or the proportion of patients achieving haemostasis.
In the pivotal study assessing the haemostatic efficacy of Crosseal in patients undergoing liver resection (section 4.2), although the sealant was applied only at the end of the surgery, the study authors suggested that it may also prove useful as adjunctive treatment during the early stages of surgery, as there may be occasions when bleeding may occur earlier during liver surgery, sometimes resulting in critical situations.[25] Quixil was also an effective haemostat in endonasal surgeries (section 4.5.1) and more effective than electrocautery in tonsillectomies and/ or adenoidectomies (section 4.5.2). Endonasal surgery using Quixil was a convenient and simple method to avoid nasal packing, with aerosol spraying of the agent useful for applying the sealant to small surfaces and unreachable sites.[38,40] In addition, with Quixil, there was no need to use antibacterial agents during endonasal surgeries, and in endonasal surgeries and tonsillectomies and/or adenoidectomies, patients had better outcomes than those observed with the comparators (sections 4.5.1 and 4.5.2). Some benefit was also observed with the use of Evicel or Quixil in patients undergoing orthopaedic surgery, although the results were not consistent across the trials (section 4.4). Significant
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Dhillon
reductions in total, intra- and/or postoperative blood loss, transfusions and the decrease in haemoglobin levels were observed in some studies, but not in others (section 4.4), which may be due to differences in study design[31] (e.g. when the fibrin sealant was applied during surgery; table V) or due to the small number of patients enrolled in the studies.[31,33] Total knee arthroplasty is associated with a high risk of thromboembolism and it is thought that most deep-vein thromboses are formed during the operation.[29] Consequently, preoperative thromboprophylaxis was thought to be better than postoperative thromboprophylaxis alone[29] and was used in three studies.[29,31,33] Results from one of these studies showed that there were significant reductions in postoperative blood loss, need for blood transfusions and the decrease in haemoglobin levels despite preoperative thromboprophylaxis,[29] suggesting that Quixil may allow the use of full-dose preoperative thromboprophylaxis without increasing the risk of postoperative bleeding.[29,32] The decrease in blood loss and postoperative extravasation of blood into the tissues with the use of Quixil may reduce the need for transfusions and prevent haematoma, which may reduce the rate of infection and promote healing.[29,33] It was suggested that one reason for the effectiveness of Quixil in reducing blood loss in this surgery may be because of its ability to seal and plug the bone-marrow sinusoids, thereby preventing oozing of blood.[29] Further, well designed studies are needed to confirm the benefit of Evicel or Quixil treatment in patients undergoing orthopaedic surgery. The efficacy studies discussed above were conducted, where reported, in a non-blind[26,28,29] or single-blind[25,33] manner, as it was difficult to mask the application of the sealant or because of different application procedures for the treatments. Moreover, only two[25,26] studies compared the haemostatic efficacy of Evicel[26] or Crosseal[25] with that of other topical haemostats (section 4); additional, well designed, head-to-head comparative studies with haemostats, including other fibrin sealants, would be useful. In addition to these studies, two small studies in patients undergoing rhytidectomy (n = 9)[50] or
lateral osteotomy in rhinoplasty (n = 10)[51] suggested that Crosseal[50] and Evicel,[51] respectively, were effective in reducing bruising and swelling. Larger, well designed studies would help to confirm these observations. Moreover, several studies have also assessed the efficacy of Evicel[52] or Quixil[53-55] as treatment for epistaxis,[53,54] as glue for conjunctival closure[55] and for aerostasis in patients undergoing pulmonary resection;[52] however, discussion of these trials is beyond the scope of this review. Evicel and Quixil/Crosseal were generally well tolerated as haemostatic agents in patients undergoing various types of surgeries. In the three pivotal trials in patients undergoing vascular,[23] liver,[25] or retroperitoneal or abdominal surgery,[26] there were generally no significant differences in the incidences of treatment-emergent adverse events between the Evicel[23,26] or Crosseal[25] groups and the control groups (sections 5.1 and 5.2). Quixil was also generally well tolerated in patients undergoing orthopaedic surgeries, or nose and throat surgeries (section 5.2). In patients undergoing vascular surgery, although the overall incidence of graft occlusion/ thrombosis did not differ significantly between Evicel recipients and manual compression recipients, the risk of experiencing this complication within the first 12 days of surgery and need for surgical intervention to resolve the issue appeared to be higher in the Evicel group than in the manual compression group (no statistical data reported; section 5.1).[6] As with all human-derived biological agents, there is a risk of transmission of blood-borne diseases with the use of fibrin sealants.[2] Although the manufacturing processes of all four liquid fibrin sealants discussed in this section include steps to reduce the risk of disease transmission, such as screening of donors, testing of pooled plasma and inactivation/removal of viruses, the risk of transmission cannot be excluded.[8,20,21,43,44] For Evicel, the manufacturing steps employed are considered effective for enveloped viruses (e.g. HIV, hepatitis B and C viruses) and nonenveloped hepatitis A virus, but may be of limited value against non-enveloped viruses such as parvovirus B19, which may seriously affect pregnant
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or immunocompromised patients.[20] A study that assessed the safety margins for several viruses in Evicel and Tisseel showed that the residual risk of transmission of HIV or hepatitis A, B and C viruses was low (calculated risk per vial was <1 in 10-15 for both the fibrinogen and thrombin components).[42] However, because of the greater quantities of parvovirus B19 that may be present and its thermal stability, the risk of transmission of this virus (calculated risk per vial was 1 in 5 105 for fibrinogen and 1 in 107 for thrombin) was higher than that of other viruses; despite this, parvovirus transmissions are expected to be rare.[42] The cost of the fibrin sealant may also be important in determining the choice of therapy in patients undergoing surgery. One cost analysis conducted from the UK National Health Service perspective and based on data from two[29,32] clinical trials in patients undergoing total knee replacement estimated that use of a 5 mL dose of Quixil with conventional haemostatic treatment was cost saving relative to conventional treatment alone, and reduced the expected cost by d296 per procedure (costs for blood transfusion and the surgery were based on 2003/04 values and Quixil costs were based on 2007 values).[56] However, use of a 10 mL dose increased the expected cost by d94 per procedure.[56] A threshold analysis further suggested that Quixil remained cost saving when up to 75% of patients received a 10 mL dose and up to 25% of patients received a 5 mL dose, with an estimated cost saving of d3 per procedure.[56] Additional, well designed pharmacoeconomic analyses are required to assess whether Evicel and Quixil are cost-effective treatment options in surgery. In conclusion, Evicel and its previousgeneration formulation (Quixil/Crosseal) were generally well tolerated and effective haemostatic agents for adjunctive use in various types of surgeries. The fibrin sealants were significantly more effective than control treatment (conventional methods or other haemostatic agents) in achieving haemostasis in patients undergoing vascular, liver, or retroperitoneal or intra-abdominal surgeries in randomized studies. In addition, these sealants were effective in reducing bleeding in nose and throat surgeries, with some benefit also
observed in orthopaedic surgery. Evicel is easy to use and has the added advantage of not containing the antifibrinolytic agent tranexamic acid, which is potentially neurotoxic; in addition, the lack of synthetic or bovine aprotinin reduces its potential for hypersensitivity reactions. Although additional comparative studies with other haemostatic agents would help to definitively position Evicel with respect to these agents, current evidence suggests that Evicel is useful in surgeries and for improving haemostasis where standard techniques are insufficient. Disclosure
The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agents under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the Adis author on the basis of scientific and editorial merit.
References
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27. Papacharalabous EN, Giannopoulos T, Tailor A, et al. Intraoperative haemostasis with new fibrin surgical sealant (Quixil) in gynaecological oncology. J Obstet Gynaecol 2009 Apr; 29 (3): 233-6 28. Crawford RW, Giangrande P, Murray D. Fibrin sealant reduces blood loss in total hip arthroplasty. Hip Int 1999; 9 (3): 127-32 29. Levy O, Martinowitz U, Oran A, et al. The use of fibrin tissue adhesive to reduce blood loss and the need for blood transfusion after total knee arthroplasty: a prospective, randomized, multicenter study. J Bone Joint Surg Am 1999 Nov; 81 (11): 1580-8 30. Majoras N, Fabi D, Patel P, et al. Use of novel fibrin sealant in total hip and knee arthroplasty [poster no. 16]. 28th Annual Meeting of the Mid-America Orthopaedic Association; 2010 Apr 21-24; Lost Pines (TX) 31. Molloy DO, Archbold HAP, Ogonda L, et al. Comparison of topical fibrin spray and tranexamic acid on blood loss after total knee replacement: a prospective, randomised controlled trial. J Bone Jt Surg Ser B 2007; 89 (3): 306-9 32. Wang GJ, Hungerford DS, Savory CG, et al. Use of fibrin sealant to reduce bloody drainage and hemoglobin loss after total knee arthroplasty: a brief note on a randomized prospective trial. J Bone Joint Surg Am 2001 Oct; 83-A (10): 1503-5 33. Wang GJ, Goldthwaite Jr CA, Burks S, et al. Fibrin sealant reduces perioperative blood loss in total hip replacement. J Long-Term Eff Med Implants 2003; 13 (5): 399-411 34. Vaiman M, Eviatar E, Segal S. The use of fibrin glue as hemostatic in endonasal operations: a prospective, randomized study. Rhinology 2002 Dec; 40 (4): 185-8 35. Vaiman M, Eviatar E, Segal S. Effectiveness of secondgeneration fibrin glue in endonasal operations. Otolaryngol Head Neck Surg 2002 Apr; 126 (4): 388-91 36. Vaiman M, Eviatar E, Shlamkovich N, et al. Effect of modern fibrin glue on bleeding after tonsillectomy and adenoidectomy. Ann Otol Rhinol Laryngol 2003 May; 112 (5): 410-4 37. Baugh RF, Archer SM, Mitchell RB, et al. Clinical practice guideline: tonsillectomy in children. Otolaryngol Head Neck Surg 2011 Jan; 144 Suppl. 1: S1-30 38. Vaiman M, Sarfaty S, Shlamkovich N, et al. Fibrin sealant: alternative to nasal packing in endonasal operations. A prospective randomized study. Isr Med Assoc J 2005 Sep; 7 (9): 571-4 39. Vaiman M, Eviatar E, Shlamkovich N, et al. Use of fibrin glue as a hemostatic in endoscopic sinus surgery. Ann Otol Rhinol Laryngol 2005 Mar; 114 (3): 237-41 40. Vaiman M, Sarfaty S, Eviatar E. The use of fibrin sealant as a glue for septoplasty and conchotomy. Rhinology 2009 Sep; 47 (3): 297-300 41. Center for Biologics Evaluation and Research. 1-year postapproval adverse event review [online]. Available from URL: http://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/PediatricAdvisoryCommittee/ UCM192059.pdf [Accessed 2011 Aug 10] 42. Horowitz B, Busch M. Estimating the pathogen safety of manufactured human plasma products: application to fibrin sealants and to thrombin. Transfusion (Paris) 2008 Aug; 48 (8): 1739-53 43. Baxter Healthcare Corporation. Tisseel (fibrin sealant): US prescribing information [online]. Available from URL:
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51. Pryor SG, Sykes J, Tollefson TT. Efficacy of fibrin sealant (human) (Evicel) in rhinoplasty: a prospective, randomized, single-blind trial of the use of fibrin sealant in lateral osteotomy. Arch Facial Plast Surg 2008 Sep-Oct; 10 (5): 339-44 52. Tempesta BJ, Gharagozloo F, Schwartz A, et al. Aerostasis with human fibrin sealant (Evicel) in patients undergoing pulmonary resection [abstract]. Chest 2007; 132 (4 Suppl.): 661S 53. Vaiman M, Segal S, Eviatar E. Fibrin glue treatment for epistaxis. Rhinology 2002 Jun; 40 (2): 88-91 54. Vaiman M, Martinovich U, Eviatar E, et al. Fibrin glue in initial treatment of epistaxis in hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber disease). Blood Coagul Fibrinolysis 2004 Jun; 15 (4): 359-63 55. Bahar I, Weinberger D, Dan G, et al. Pterygium surgery: fibrin glue versus vicryl sutures for conjunctival closure. Cornea 2006 Dec; 25 (10): 1168-72 56. Steuten L, Vallejo-Torres L, Bastide P, et al. Analysing uncertainty around costs of innovative medical technologies: the case of fibrin sealant (Quixil) for total knee replacement. Health Policy 2009 Jan; 89 (1): 46-57
Correspondence: Sohita Dhillon, Adis, a Wolters Kluwer Business, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand. E-mail: demail@adis.co.nz
Drugs 2011; 71 (14)
Drugs 2011; 71 (14): 1917-1946 0012-6667/11/0014-1917/$55.55/0
Fenofibrate
A Review of its Use in Dyslipidaemia
Kate McKeage and Gillian M. Keating
Various sections of the manuscript reviewed by: D. Bhatnagar, Diabetes Centre, The Royal Oldham Hospital, Oldham, UK; M.B. Elam, Department of Pharmacology and Medicine, University of Tennessee Health Sciences Center, Memphis, TN, USA; M. Farnier, Rond Point de la Nation, Point Medical, Dijon, France; S.M. Mohiuddin, The Creighton Cardiac Center, Omaha, NB, USA.
Data Selection Sources: Medical literature (including published and unpublished data) on fenofibrate was identified by searching databases since 1996 (including MEDLINE and EMBASE and in-house AdisBase), bibliographies from published literature, clinical trial registries/databases and websites (including those of regional regulatory agencies and the manufacturer). Additional information (including contributory unpublished data) was also requested from the company developing the drug. Search strategy: MEDLINE, EMBASE and AdisBase search terms were fenofibrate and (hyperlipidaemia or hyperlipidemia or dyslipidaemia or dyslipidemia). Searches were last updated 17 August 2011. Selection: Studies in patients with dyslipidaemia who received fenofibrate. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included. Index terms: Fenofibrate, dyslipidaemia, metabolic syndrome, pharmacodynamics, pharmacokinetics, therapeutic use, type 2 diabetes mellitus.
Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Effects on Lipids and Apolipoproteins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Other Effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Special Patient Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Potential Drug Interactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Monotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1 Comparisons with Placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2 Comparisons with Gemfibrozil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.3 Comparisons with Statins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.4 Comparison with Niacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1 In Combination with a Statin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2 In Combination with Ezetimibe with or without a Statin . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.3 Other Combinations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Monotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1918 1918 1919 1919 1920 1921 1922 1922 1923 1923 1923 1927 1928 1928 1929 1929 1932 1933 1934 1934 1935
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6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1936 7. Place of Fenofibrate in the Management of Dyslipidaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1936
Abstract
Fenofibrate is a fibric acid derivative indicated for the treatment of severe hypertriglyceridaemia and mixed dyslipidaemia in patients who have not responded to nonpharmacological therapies. The lipid-modifying effects of fenofibrate are mediated by the activation of peroxisome proliferator-activated receptor-a. Fenofibrate also has nonlipid, pleiotropic effects (e.g. reducing levels of fibrinogen, C-reactive protein and various pro-inflammatory markers, and improving flow-mediated dilatation) that may contribute to its clinical efficacy, particularly in terms of improving microvascular outcomes. Fenofibrate improves the lipid profile (particularly triglyceride [TG] and highdensity lipoprotein-cholesterol [HDL-C] levels) in patients with dyslipidaemia. Compared with statin monotherapy, fenofibrate monotherapy tends to improve TG and HDL-C levels to a significantly greater extent, whereas statins improve low-density lipoprotein-cholesterol (LDL-C) and total cholesterol levels to a significantly greater extent. Fenofibrate is also associated with promoting a shift from small, dense, atherogenic LDL particles to larger, less dense LDL particles. Combination therapy with a statin plus fenofibrate generally improves the lipid profile to a greater extent than monotherapy with either agent in patients with dyslipidaemia and/or type 2 diabetes mellitus or the metabolic syndrome. In the pivotal FIELD and ACCORD trials in patients with type 2 diabetes, fenofibrate did not significantly reduce the risk of coronary heart disease events to a greater extent than placebo, and simvastatin plus fenofibrate did not significantly reduce the risk of major cardiovascular (CV) events to a greater extent than simvastatin plus placebo. However, the risk of some nonfatal macrovascular events and the incidence of certain microvascular outcomes were reduced significantly more with fenofibrate than with placebo in the FIELD trial, and in the ACCORD trial, patients receiving simvastatin plus fenofibrate were less likely to experience progression of diabetic retinopathy than those receiving simvastatin plus placebo. Subgroup analyses in the FIELD and ACCORD Lipid trials indicate that fenofibrate is of the greatest benefit in decreasing CV events in patients with atherogenic dyslipidaemia. Fenofibrate is generally well tolerated when administered alone or in combination with a statin. Thus, in patients with dyslipidaemia, particularly atherogenic dyslipidaemia, fenofibrate is a useful treatment option either alone or in combination with a statin.
1. Introduction Cardiovascular disease (CVD) remains the leading cause of death worldwide.[1] Of the estimated 17.1 million deaths from CVD in 2004, 7.2 million resulted from coronary heart disease (CHD) and 5.7 million were due to stroke. Elevated low-density lipoprotein-cholesterol (LDL-C) levels are a major predictor of CVD, and LDL-C continues to be the primary target of
cholesterol-lowering therapy.[2,3] Other lipid risk factors or markers include low levels of high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein (Apo)AI, and elevated levels of triglycerides (TG), lipoprotein(a), ApoB, homocysteine, fibrinogen, C-reactive protein (CRP) and very lowdensity lipoprotein-cholesterol (VLDL-C).[2,4] The goal of cholesterol-lowering treatment varies according to the risk of a CHD event.[2,5] Non-HDL-C (i.e. the combination of LDL-C
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and TG-enriched lipoproteins) is considered a secondary treatment target in patients with TG levels >2.3 mmol/L.[2] The prevalence of obesity, the metabolic syndrome and type 2 diabetes mellitus is increasing in the developed world, posing a threat to the reduction in CHD risk achieved over recent decades.[6,7] Diabetes mellitus is considered a CHD risk equivalent, and patients with pre-existing CHD and type 2 diabetes mellitus or the metabolic syndrome are considered to be at very high risk of a CHD event.[2] The metabolic syndrome is characterized by atherogenic dyslipidaemia (comprises the triad of elevated TG levels, low HDL-C levels and small dense LDL particles), abdominal obesity, raised blood pressure, prothrombotic and proinflammatory states, and insulin resistance.[2] Both atherogenic dyslipidaemia and the metabolic syndrome are common features of type 2 diabetes, and patients with diabetes are at risk of both macrovascular complications (e.g. CHD, peripheral vascular disease and cerebrovascular disease) and microvascular complications (e.g. retinopathy, nephropathy and neuropathy).[6,7] Improving lipid levels in patients with dyslipidaemia is important in order to reduce the risk of CVD, and pharmacological therapy is frequently indicated together with therapeutic lifestyle changes.[2] Lipid-modifying agents include the HMG-CoA reductase inhibitors (statins), the fibric acid derivatives (fibrates), the bile acid sequestrants (e.g. colesevelam), nicotinic acid (niacin), the cholesterol absorption inhibitors (e.g. ezetimibe) and omega-3 fatty acids.[2] Statins are usually the first-line option for lowering LDL-C levels, and fibrates are effective for modifying atherogenic dyslipidaemia and particularly for lowering serum TG.[2] Fenofibrate is a fibric acid derivative that has been available worldwide for many years for the treatment of dyslipidaemia.[8] Recently, in the EU, the label of fenofibrate (100, 300, 67, 200, 250 mg capsules and 160 and 145 mg film-coated tablets) was amended, and the drug is now indicated as an adjunct to diet and other non-pharmacological measures (e.g. exercise, weight reduction) for the treatment of severe hypertriglyceridaemia with or
without low HDL-C, mixed hyperlipidaemia when a statin is contraindicated or not tolerated, and in addition to a statin in patients with mixed hyperlipidaemia at high cardiovascular risk when TGs and HDL-C are not adequately controlled (see also section 6).[9-12] Since fenofibrate was introduced, many formulations have been developed in order to optimize bioavailability, including micronized tablets and capsules, which should be taken with food, and nanoparticle tablets, which may be taken without regard to food. The micronized fenofibrate 200 mg capsules and 160 mg film-coated tablets and the nanoparticle fenofibrate 145 mg film-coated tablets are all bioequivalent.[9-11] This article focuses on the efficacy of fenofibrate in improving lipid profiles and cardiovascular outcomes, and focuses particularly on its use in combination with a statin in patients with dyslipidaemia, including those with type 2 diabetes and the metabolic syndrome. Throughout the article, lipid levels are reported in mmol/L; to convert to mg/dL, total cholesterol (TC), LDL-C and HDL-C values should be multiplied by 38.7 and TG values should be multiplied by 88.6. 2. Pharmacodynamic Properties
2.1 Effects on Lipids and Apolipoproteins
Fenofibrate is converted into the pharmacologically active metabolite fenofibric acid (section 3).[13] The lipid-modifying effects of fenofibrate are mediated by its activation of the nuclear transcription factor peroxisome proliferator-activated receptor-a (PPARa).[14,15] Activated PPARa forms a heterodimer with another nuclear receptor, retinoid X receptor, which then binds to specific peroxisome proliferator response elements, thereby modulating the expression of genes regulating lipid metabolism.[13-16] Activation of PPARa results in increased lipolysis and plasma clearance of atherogenic TGrich lipoproteins via the activation of lipoprotein lipase and ApoAV and reduced production of the lipoprotein lipase inhibitor ApoCIII.[15,17-21] Fenofibrate also promotes the b-oxidation of fatty acids, thus reducing the availability of free fatty
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acids for TG synthesis.[17,21,22] De novo fatty acid synthesis is also inhibited with fenofibrate via reductions in acetyl-CoA carboxylase and fatty acid synthase activity; this also reduces the availability of fatty acids for TG synthesis.[21,22] ApoB and VLDL production and secretion are also reduced with fenofibrate.[21,22] Fenofibrate increases LDL clearance and reduces small dense LDL.[23-26] Larger, less dense LDL particles have a high binding affinity for cellular LDL receptors, and are less susceptible to oxidation.[15,17,23,24] PPARa activation also increases the synthesis of the major proteins in HDL, ApoAI and ApoAII,[21,22,27,28] as well as enhancing expression of adenosine triphosphate-binding cassette transporter A1 and scavenger receptor-B1, which results in HDL-mediated cholesterol efflux from macrophages.[13,16,17,29,30] Fenofibrate reduces cholesteryl ester transfer protein (CETP) activity;[17,23,31,32] the reduction in CETP-mediated transfer of lipid from HDL to VLDL may also contribute to the observed increase in HDL-C levels.[17,23,33] In keeping with the above-mentioned mechanisms, fenofibrate has beneficial effects on the lipid profile, particularly in terms of reducing TG levels and increasing HDL-C levels (see section 4). Fenofibrate was also associated with significant (p < 0.05 vs baseline or placebo) increases in ApoAI and ApoAII levels and/or reductions in non-HDL-C, ApoCIII and ApoB levels in patients with primary dyslipidaemia,[25,34-53] the metabolic syndrome[54-60] or type 2 diabetes.[61-65]
2.2 Other Effects
As well as regulating lipid metabolism, PPARa appears to modulate various other processes, including inflammation and thereby atherosclerosis.[16] Various pro-inflammatory cytokines (e.g. tumour necrosis factor [TNF]-a, interleukin-6 and -1b, and monocyte chemoattractant protein-1) contribute to the early development of atherosclerotic lesions. Vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 recruit leukocytes and monocytes to the atherosclerotic region.[16,66] Increased levels
of fibrinogen, plasminogen activator inhibitor-1 and CRP have also been linked with an increased risk of atherosclerosis.[66] Fenofibrate generally demonstrated beneficial effects on these markers in patients with dyslipidaemia, as well as in patients with the metabolic syndrome or type 2 diabetes (although the effects of fenofibrate on VCAM-1 and ICAM-1 were mixed) [table I]. Lipoprotein-associated phospholipase A2 (LpPLA2) activity is predictive of atherosclerosis; Lp-PLA2 oxidatively modifies LDL and generates pro-inflammatory byproducts.[82,96] Fenofibrate reduced total Lp-PLA2 activity in patients with dyslipidaemia and reduced Lp-PLA2 mass in patients with the metabolic syndrome (table I). Impaired vasoreactivity precedes the development of atherosclerosis;[41,72] fenofibrate improved flow-mediated dilatation in patients with dyslipidaemia or type 2 diabetes (table I). In addition, fenofibrate reduced postprandial blood viscosity in patients with the metabolic syndrome (table I). Raised uric acid and homocysteine levels have also been implicated in atherosclerosis.[87] Although fenofibrate reduced uric acid levels in patients with dyslipidaemia or type 2 diabetes, increased homocysteine levels were seen with fenofibrate in both patient groups (table I). Paraoxonase (PON1), an enzyme present on HDL, is thought to have an antioxidant effect,[67] and adiponectin is thought to have antiinflammatory effects, as well as improving insulin sensitivity.[43] Increased PON1 activity and adiponectin levels were seen in patients with dyslipidaemia who received fenofibrate (table I). Mixed results were seen in terms of the effect of fenofibrate on insulin sensitivity and glucose metabolism. Among patients with dyslipidaemia, improvements in insulin sensitivity were seen in some studies,[45] but not in others.[85] Improved glucose metabolism was seen in patients with mixed dyslipidaemia[80] or the metabolic syndrome[57,94] who had impaired fasting glucose and/or impaired glucose tolerance, although no improvement in glucose metabolism was seen in patients with the metabolic syndrome and insulin resistance.[54] Glycaemic control was unaltered in patients with type 2 diabetes who received fenofibrate (see also section 4.1.1).[61,65,99]
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Table I. Nonlipid effects of fenofibrate in patients (pts) with dyslipidaemia, the metabolic syndrome or type 2 diabetes mellitus In pts with dyslipidaemia plasma/serum levels of fibrinogen,[35-39,41-43,45,52,67-71] PAI-1,[41,68] (high-sensitivity[25,42,43,45,52,67,71-74] ) CRP,[25,42,43,45,48,52,67,71-75] IL-6,[71,74-76] IL-1b,[72,76] TNFa[41,45,75,77] and MCP-1[74,76,78,79] monocyte release of IL-1b[80] and MCP-1[79-81] in vitro plasma soluble ICAM-1 levels in some[78] but not all[74] studies total and non-HDL Lp-PLA2 activity and HDL Lp-PLA2 activity[82] serum PON1 activity[49,67,83,84] plasma/serum (high molecular weight[85]) adiponectin levels[42,43,45,85] Improved (p < 0.05 vs PL or baseline) flow-mediated dilatation,[41-43,45,72,77] but not the dilator response to nitroglycerin[41-44,72] Improved (p < 0.05 vs PL) forearm blood flow in response to acetylcholine, nitroprusside or verapamil[86] plasma/serum uric acid levels[34,35,38,46,48,51,75,87-89] plasma/serum homocysteine levels[48,87,90-93] In pts with the metabolic syndrome circulating levels of fibrinogen,[57,94] high-sensitivity CRP,[54,57,95] IL-6[54] and PAI-1[57] LPS-stimulated production of MCP-1, IL-1b, and MIP-1a[95] and monocyte release of IL-1b, IL-6, MCP-1 and TNFa[57] circulating levels of VCAM-1 and ICAM-1 in some studies,[58] but not others[54] Lp-PLA2 mass[96] plasma adiponectin levels in some studies,[95] but not others[54] postprandial blood viscosity[97] In pts with type 2 diabetes plasma/serum fibrinogen,[61,65,98] high-sensitivity CRP[98] and uric acid[65,98] levels Improved (p < 0.05 vs PL) brachial artery flow-mediated dilatation, but not the dilator response to nitroglycerin[65,99] plasma homocysteine levels[64,100] CRP = C-reactive protein; HDL = high-density lipoprotein; ICAM-1 = intercellular adhesion molecule-1; IL = interleukin; Lp-PLA2 = lipoproteinassociated phospholipase A2; LPS = lipopolysaccharide; MCP-1 = monocyte chemoattractant protein-1; MIP-1a = macrophage inflammatory protein-1a; PAI-1 = plasminogen activator inhibitor-1; PL = placebo; PON1 = paraoxonase 1; TNFa = tumour necrosis factor-a; VCAM-1 = vascular cell adhesion molecule-1; indicates significantly (p < 0.05 vs PL or baseline) reduced; indicates significantly (p < 0.05 vs PL or baseline) increased.
When fenofibrate was co-administered with simvastatin, the lymphocyte-suppressing, but not the monocyte-suppressing, effect on the release of pro-inflammatory cytokines was greater than when either agent was administered alone (p < 0.05) in patients with type 2 diabetes and mixed dyslipidaemia.[101] Results of in vitro[102-106] and animal[105] studies suggest additional mechanisms by which fenofibrate may exert its beneficial effects. For example, fenofibrate activated adenosine monophosphateactivated protein kinase (AMPK) in vitro.[102-104] AMPK activation contributed to the anti-apoptotic effects of fenofibrate seen in human retinal endothelial cells[104] and human glomerular microvascular endothelial cells;[102] the anti-apoptotic effect of fenofibrate appeared to be independent of PPARa
activity.[102,104] The activation of AMPK by fenofibrate also resulted in increased nitric oxide production and reduced expression of adhesion molecule genes.[102,103] In addition, fenofibrate inhibited endothelial cell proliferation and migration in vitro, as well as inhibiting angiogenesis in mice.[105] 3. Pharmacokinetic Properties Fenofibrate is rapidly absorbed following oral administration and converted by esterases to its active metabolite fenofibric acid.[107] After administration of a micronized fenofibrate 200 mg capsule, the mean plasma concentration of fenofibric acid was 15 mg/mL and the maximum plasma concentration (Cmax) occurred a mean of
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5 hours after dosing.[10] Multiple doses of the film-coated suprabioavailable tablet formulation of micronized fenofibrate 160 mg/day (bioequivalent to the 200 mg capsule[108]) resulted in a steadystate mean fenofibric acid Cmax of 12.2 mg/mL, reached in a time (tmax) of 3.5 hours.[9,107] The mean trough plasma concentration of fenofibric acid was 4.1 mg/mL.[107] The absorption of fenofibrate from the micronized capsule and film-coated tablet formulations is less efficient when administered in a fasting state.[9] For example, the extent of absorption of the film-coated tablet of micronized fenofibrate is increased by 35% in the fed versus fasting state.[107] By contrast, Cmax and overall exposure to the nanoparticle formulation of fenofibrate 145 mg film-coated tablets is independent of food intake.[11] The 145 mg nanoparticle formulation has a tmax of 24 hours,[11] and showed bioequivalence, in terms of Cmax and the area under the plasma concentration-time curve (AUC), when it was administered in the fasting state or with a low- or high-fat meal.[107] Fenofibrate does not accumulate with repeated administration, and fenofibric acid is >99% bound to plasma albumin.[9,10] Following oral administration of fenofibrate and its metabolism to fenofibric acid, no unchanged fenofibrate was detectable in plasma.[9] The drug was mainly excreted in the urine as fenofibric acid and its glucuronide conjugate.[9,10] Approximately 70% of the fenofibrate dose was detected in the urine after 24 hours, with 88% of the dose detected within 6 days; total excretion in the urine and faeces at 6 days was up to 93%.[9,10] Fenofibric acid has an elimination half-life of 20 hours.[9,10]
3.1 Special Patient Populations
cronized fenofibrate and the 145 mg nanoparticle film-coated tablets[11] are contraindicated in children. Fenofibrate has not been studied in patients with hepatic impairment.[9] Micronized fenofibrate is contraindicated in patients with severe renal dysfunction (section 6), and dose reduction may be needed in patients with less severe renal impairment.[12] In addition, the 160 mg micronized film-coated tablet and the 145 mg nanoparticle film-coated tablet are not recommended in patients with renal impairment; alternative formulations that allow a lower dosage of the active ingredient are recommended.[9,11] For example, two 67 mg capsules of micronized fenofibrate should be administered to patients with a creatinine clearance (CLCR) of <60 mL/min (<3.6 L/h) and one 67 mg capsule of micronized fenofibrate should be administered to patients with a CLCR of <20 mL/min (<1.2 L/h), according to UK prescribing information.[12]
3.2 Potential Drug Interactions
No dosage adjustment is recommended in the elderly for micronized fenofibrate capsules (as long as patients do not have renal impairment),[10] micronized film-coated tablets,[9] or nanoparticle film-coated tablets.[11] One 67 mg capsule of micronized fenofibrate per day may be administered to children,[12] although 200[10] and 267[109] mg capsules and 160 mg film-coated tablets[9] of mi 2011 Adis Data Information BV. All rights reserved.
Fenofibrate has a low potential for drug interactions, and in in vitro studies in human liver microsomes, it did not inhibit cytochrome P450 (CYP) isozymes CYP3A4, CYP2D6, CYP2E1 or CYP1A2.[9] Fenofibrate showed mild to moderate inhibition of CYP2C9 and weak inhibition of CYP2C19 and CYP2A6.[9] Dosage adjustment may be needed in patients receiving fenofibrate in combination with CYP2C19, CYP2A6 and CYP2C9 substrates.[9] Coadministration of fenofibrate plus simvastatin[110] or rosuvastatin[111] did not affect the pharmacokinetics of either drug to a clinically significant extent. Moreover, fenofibrate did not have a clinically significant effect on the pharmacokinetics of atorvastatin[112] or fluvastatin,[113] and had only modest effects on the exposure of pravastatin and its active metabolite 3a-hydroxy-isopravastatin.[114] The pharmacokinetics of fenofibrate were not altered to a significant extent by the concomitant administration of pravastatin.[115] Coadministration of ezetimibe did not have a significant effect on the pharmacokinetics of fenofibrate in healthy volunteers[116] or patients with primary hypercholesterolaemia.[117] Although feDrugs 2011; 71 (14)
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nofibrate increased ezetimibe exposure, this effect was not considered of clinical significance.[116,117] Concomitant administration of colesevelam did not have a significant effect on the bioavailability of fenofibrate.[118] Fenofibrate did not have a significant effect on the pharmacokinetics of the meglitinide analogue repaglinide.[119] The UK summary of product characteristics does not recommend the concomitant administration of fenofibrate and oral anticoagulants, given that fenofibrate has been shown to potentiate the anticoagulant effect.[9] Whole-blood concentrations of ciclosporin were significantly (p = 0.03) reduced in heart transplant patients receiving concomitant fenofibrate, and serum creatinine levels were significantly (p = 0.003) increased.[120] Thus, coadministration of the two agents may increase the inherent nephrotoxicity of ciclosporin. 4. Therapeutic Efficacy This section focuses on well designed clinical studies in adults. Most included a drug-free or placebo run-in period, in addition to dietary control, prior to commencing active treatment. Dietary restrictions were generally maintained for the duration of each study. Selected studies include those administering micronized capsule or tablet formulations of fenofibrate or the nanoparticle tablet formulation. Trial abbreviations and acronyms are defined in table II.
4.1 Monotherapy
Table II. Trial abbreviations/acronyms and definitions Abbreviation/ acronym ACCORD DAIS DIACOR FIELD SAFARI Definition Action to Control Cardiovascular Risk in Diabetes Diabetes Atherosclerosis Intervention Study Diabetes and Combined Lipid Therapy Regimen Fenofibrate Intervention and Event Lowering in Diabetes Study of simvastatin plus fenofibrate for combined hyperlipidaemia
years, and the duration of studies primarily evaluating changes in lipid levels ranged from 6 to 24 weeks. Patient baseline characteristics, study design details and lipid entry criteria for cardiovascular outcome trials are summarized in table III, and study design details and lipid entry criteria for other trials are summarized in subsequent tables. Across all trials, the mean patient age ranged from about 46[127] to 62[121] years.
4.1.1 Comparisons with Placebo The FIELD Trial
The efficacy of fenofibrate compared with placebo,[36,46,58,121,122] gemfibrozil[38,123] or statins[48,124-128] in patients with type 2 diabetes mellitus and/or dyslipidaemia (including metabolic syndrome) has been reviewed previously.[129,130] This section summarizes results presented previously, focusing on the large FIELD trial[121] that primarily evaluated cardiac outcomes. All trials discussed in this section were randomized, and efficacy analyses were conducted in intent-to-treat or modified intent-to-treat populations. The duration of studies primarily evaluating cardiac outcomes was >3[122] and 5[121]
The FIELD study primarily evaluated cardiac outcomes in fenofibrate-treated patients with type 2 diabetes (key study design details and patient characteristics are presented in table III).[121] While patients were considered to be at increased risk of CHD, they generally had no clear indication for lipid-lowering therapy and their glycaemic control was generally good.[121] The drop-out rate averaged over 5 years was 11% in fenofibrate recipients and 10% in placebo recipients. The incidence of CHD events (primary endpoint) or CHD mortality did not differ significantly between fenofibrate and placebo recipients; however, there was a significant 24% relative reduction in nonfatal myocardial infarction (MI) with fenofibrate versus placebo (table IV).[121] Fenofibrate reduced the risk of several macrovascular and microvascular outcomes to a significantly greater extent than placebo, and achieved significant relative reductions of 11% in total CVD events and 20% in coronary revascularization or all revascularization compared with placebo (table IV). There was no significant difference between fenofibrate and placebo recipients in the
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Table III. Features of large randomized trials evaluating the effect of fenofibrate (FEN) on cardiovascular outcomes in patients (pts) with type 2 diabetes mellitus (T2DM). FIELD[121] and DAIS[122] were of double-blind design. In ACCORD Lipid,[131] simvastatin (SIM) was administered to all pts in an open-label manner, whereas administration of FEN and placebo (PL) was blinded. The duration of follow-up was 5 y in FIELD,[121] up to 57 mo in DAIS,[122] and a mean 4.7 y for the primary endpoint in ACCORD Lipid (5.0 y for total mortality)[131] FIELD[121] FEN 200 mg od (n = 4895) Baseline characteristics males (% of pts) mean age (y) median diabetes duration (y) median (mean) HbA1c [%] dyslipidaemia (% of pts) previous CVD or CHD (% of pts) retinopathy (% of pts) Inclusion criteria
b
1924
DAIS[122,132] PL (n = 4900) 63 62.2 5 6.9 37 22 8.4 T2DM; age 4065 y; HbA1c 170% of ULN; TC : HDL-C ratio 4 plus either LDL-C 3.54.5 mmol/L and TG 5.2 mmol/L, or TG 1.75.2 mmol/L and LDL-C 4.5 mmol/L 48 47 (7.5) (7.6) FEN 200 mg od (n = 207) 72 57.4 PL (n = 211) 74 56.3
ACCORD Lipid[131,133]a SIM + FEN (n = 2765) 69.2 62.2 10 8.1 (8.3) SIM + PL (n = 2753) 69.4 62.3 9 8.1 (8.3)
63 62.2 5 6.9 39 22 8.2
36.5 46.8[134]
36.6 49.4[134]
T2DM; age 5075 y; TC 3.06.5 mmol/L plus TC : HDL-C ratio 4 or TG 1.05.0 mmol/L
T2DM; HbA1c 7.5%; age 4079 y with clinical CVD or age 5579 y with subclinical CVD or at least 2 additional CV risk factors; LDL-C 1.554.65 mmol/L; HDL-C <1.42 mmol/L (women and Black pts) or <1.29 mmol/L (other pts); TG <8.5 mmol/L if not receiving lipidlowering therapy and <4.5 mmol/L if receiving lipid-lowering therapy Significant hypoglycaemia;c serum creatinine >1.5 mg/dL in past 2 mo; active liver disease or transaminase level >2 ULN; CV event/procedure or hospitalization for unstable angina pectoris in past 3 mo; symptomatic heart failure, history of NYHA class III or IV heart failure, ejection fraction <0.25. Major CV event (nonfatal MI, nonfatal stroke, or death from CV cause)
Selected exclusion criteria
Significant renal impairment; chronic liver disease; symptomatic gallbladder disease; CV event in past 3 mo
Major coronary event or angiogram in past 6 mo; ejection fraction <0.30 or active treatment for CHF; lipid-lowering medication in past 4 wk; pts expected to require CABG or PTCA in the next 6 mo; significant renal disease
Primary endpoint
Initially, CHD death; subsequently amended to total CHD events (i.e. CHD death or non-fatal MI)
Angiographic progression of diffuse coronary atherosclerosis (assessed using mean segment diameter)
a b c
Initially the FEN dosage was 160 mg/day; subsequently it was adjusted according to the glomerular filtration rate. The SIM dosage was modified over time according to changing treatment guidelines (average SIM dosage during follow-up was 22.3 mg/day in the FEN group and 22.4 mg/day in the PL group). Dyslipidaemia defined as HDL-C <1.03 mmol/L in men and <1.29 mmol/L in women and TG >1.7 mmol/L. Hypoglycaemic coma/seizure within past 12 mo or hypoglycaemia requiring third-party assistance in past 3 mo, with glucose <3.3 mmol/L.
McKeage & Keating
CABG = coronary artery bypass graft surgery; CHD = coronary heart disease; CHF = congestive heart failure; CV = cardiovascular; CVD = CV disease; HbA1c = glycosylated haemoglobin; HDL-C = high-density lipoprotein-cholesterol; LDL-C = low-density lipoprotein-cholesterol; MI = myocardial infarction; NYHA = New York Heart Association; od = once daily; PTCA = percutaneous transluminal coronary angioplasty; TC = total cholesterol; TG = triglyceride; ULN = upper limit of normal.
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Table IV. Effect of micronized fenofibrate (FEN) 200 mg/day on cardiovascular outcomes in patients (pts) with type 2 diabetes mellitus. Results of the randomized, double-blind, multicentre FIELD trial.[121,135,136] The mean duration of follow-up was 5 y. Further study design details and pt characteristics at baseline are shown in table III Endpoint Primary outcome CHD events CHD mortality nonfatal MIa Secondary outcomes Total CVD eventsb CVD mortality Total mortality Total stroke Coronary revascularization All revascularizationc Tertiary outcomes First amputation Minor first amputation Major first amputation Minor first amputation, without large-vessel disease Minor or major first amputation, with large-vessel disease First laser therapy for any retinopathy First laser therapy for any maculopathy First laser therapy for proliferative retinopathy a b c 0.9 0.6 0.5 0.4 0.7 3.4 2.4 1.5 1.4 1.1 0.5 0.7 0.9 4.9 3.4 2.2 0.64 (0.44, 0.94) 0.54 (0.34, 0.85) 0.93 (0.53, 1.62) 0.53 (0.30, 0.94) 0.81 (0.52, 1.28) 0.69 (0.56, 0.84) 0.69 (0.54, 0.87) 0.70 (0.52, 0.93) 0.02 0.007 0.79 0.027 0.37 0.0002 0.002 0.015 12.5 2.9 7.3 3.2 5.9 7.8 13.9 2.6 6.6 3.6 7.4 9.6 0.89 (0.80, 0.99) 1.11 (0.87, 1.41) 1.11 (0.95, 1.29) 0.90 (0.73, 1.12) 0.79 (0.68, 0.93) 0.80 (0.70, 0.92) 0.035 0.41 0.18 0.36 0.003 0.001 5.2 2.2 3.2 5.9 1.9 4.2 0.89 (0.75, 1.05) 1.19 (0.90, 1.57) 0.76 (0.62, 0.94) 0.16 0.22 0.01 Incidence (% of pts) FEN (n = 4895) PL (n = 4900) Hazard ratio (95% CI) p-Value
A diagnosis of MI required at least two of the following: ECG changes, ischaemic symptoms and raised cardiac enzymes (i.e. it excluded silent MI). Includes CHD events, total stroke, other cardiovascular deaths, and coronary and carotid revascularization. Includes coronary, carotid and peripheral revascularization.
CHD = coronary heart disease; CVD = cardiovascular disease; MI = myocardial infarction; PL = placebo.
incidence of CVD mortality, total mortality or total stroke. Over 5 years, 70 patients would need to be treated with fenofibrate to prevent at least one CVD event in one patient.[121] It has been suggested that a higher rate of statin use among placebo recipients in the FIELD trial may partly explain the lack of a significant between-group difference in the total incidence of CHD events.[121] In the trial, 17% of placebo recipients and 8% of fenofibrate recipients received additional lipid-lowering therapy (p < 0.0001) [averaged over the 5-year study period].[121] The additional lipid-lowering therapy was a statin in 93% of placebo recipients and 94% of fenofibrate recipients.[121] A subsequent analysis adjusted for
the potential effect of active nonstudy medications found that the relative reduction in the risk of total CHD events improved from 11% (p = 0.16) to 16% (p = 0.06), and the relative reduction in the risk of total CVD events improved from 11% (p = 0.04) to 15% (p = 0.008) with fenofibrate versus placebo.[137] Fenofibrate appeared to have the greatest effect among patients with marked hypertriglyceridaemia or marked dyslipidaemia at baseline, according to a post hoc subgroup analysis.[138] The adjusted hazard ratio (HR) for the 5-year CVD event rate in fenofibrate versus placebo recipients was 0.77 (95% CI 0.63, 0.94) in patients with marked hypertriglyceridaemia (TG level of
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2.3 mmol/L; 25% of patients in each group) and 0.73 (95% CI 0.58, 0.91) in patients with marked dyslipidaemia (TG level of 2.3 mmol/L and low HDL-C; 20% in each group).[138] Among patients meeting National Cholesterol Education Program Adult Treatment Panel III (ATP III)[2] criteria for the metabolic syndrome (83% in each group), the adjusted HR for the 5-year CVD event rate in fenofibrate versus placebo recipients was 0.89 (95% CI 0.79, 1.00).[138] For CVD events, the number needed to treat was 23 among patients with marked dyslipidaemia versus 143 among patients without marked dyslipidaemia.[138] Additional analysis revealed that the incidence of all MIs (i.e. clinical or silent MI) was significantly lower with fenofibrate than with placebo (5.8% vs 7.2%) [HR 0.81; 95% CI 0.69, 0.94].[139] Although the incidence of silent MI (2.5% vs 2.9%) or fatal MI (0.4% vs 0.5%) did not significantly differ between fenofibrate and placebo recipients, the incidence of CVD events after a silent MI was significantly lower with fenofibrate than with placebo (8.9% vs 34.5%) [HR 0.22; 95% CI 0.08, 0.65].[139] The risk of a first amputation, a minor first amputation or a minor first amputation without large-vessel disease (considered to be related to microvascular disease) was significantly lower in patients receiving fenofibrate than in those receiving placebo, although there was no significant between-group difference in the incidence of major first amputation, or minor or major first amputation with large-vessel disease (table IV).[136] With regard to additional microvascular outcomes, the incidence of first laser therapy for any retinopathy, any maculopathy or proliferative retinopathy was significantly lower in fenofibrate recipients than in placebo recipients (table IV).[135] For first laser therapy, the number needed to treat was 17 among patients with a history of retinopathy versus 90 among patients without a history of retinopathy. An ophthalmology substudy (n = 1012) revealed that in the overall population, the proportion of patients experiencing 2-step progression of retinopathy grade did not significantly differ between fenofibrate and placebo recipients (9.6% vs 12.3%) [primary substudy endpoint]; however, among patients with
pre-existing retinopathy, fenofibrate recipients were significantly less likely than placebo recipients to experience 2-step progression (3.1% vs 14.6%; p = 0.004).[135] Furthermore, fenofibrate appeared to preserve the estimated glomerular filtration rate (GFR) and reduce albuminuria progression.[140] The mean annual decline in estimated GFR was 1.19 mL/min/ 1.73 m2 with fenofibrate and 2.03 mL/min/1.73 m2 with placebo (p < 0.001), and the fall in the albumin : creatinine ratio was 23.7% with fenofibrate and 11.5% with placebo (p < 0.001).[140] Further analysis suggested that lower estimated GFR and albuminuria were independent risk factors for total CVD events.[141] The effects of fenofibrate therapy on lipid levels in patients in the FIELD trial are shown in table V.[121] Fenofibrate was associated with significantly greater improvements in TG, TC, LDL-C and HDL-C levels than placebo. The fenofibrateinduced improvement in HDL-C levels diminished over time; the between-group difference favoured fenofibrate by 0.05 mmol/L after 4 months therapy and by 0.01 mmol/L at study end.[121] Fenofibrate also reduced large VLDL particles and increased LDL particle size to a significantly (p < 0.001) greater extent than placebo.[64] Glycaemic control was not altered to a clinically significant extent in fenofibrate recipients in the FIELD trial.[121] At study end, median glycosylated haemoglobin (HbA1c) values in fenofibrate and placebo recipients were 7.0% and 6.9% (see for table III for baseline values).
The DAIS Trial
The DAIS study primarily evaluated atherosclerosis progression in fenofibrate-treated patients with type 2 diabetes (key study design details and patient characteristics are presented in table III).[122] As in the FIELD trial, patients did not have substantial dyslipidaemia at baseline. There was no significant difference between fenofibrate and placebo recipients in the change from baseline in the primary endpoint of mean segment diameter (reflecting diffuse disease) [-0.06 vs -0.08 mm]; however, fenofibrate did significantly slow the angiographic progression of focal coronary atherosclerosis.[122] The reduction in average
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Table V. Efficacy of monotherapy with fenofibrate (FEN) on lipid levels. Results of trials in patients (pts) with type 2 diabetes mellitus,[121,122] primary hypercholesterolaemia[38] or mixed dyslipidaemia[38,123,142] Study [design; duration] Lipid entry criteria (mmol/L) Treatment (mg/day) No. of pts Mean change from baseline in lipid level (% [baseline level; mmol/L]) TC Comparisons with PL DAIS[122]a [r, db, mc; 3 y] FIELD[121] [r, db, mc; 5 y] Duez et al.[123] [r, db, mc; 24 wk] See table III See table III FEN 200 PL FEN 200 PL FEN 200 GEM 1200 207 211 4895 4900 116 118 -9.6** [5.6] +0.4 [5.6] -16* [5.0] -9 [5.0] -5.9** [3.4] +0.4 [3.4] -21* [3.1] -15 [3.1] +7.4** [1.0] +1.5 [1.1] +3* [1.1] +2 [1.1] +16 [0.87] +12 [0.86] -28.5** [2.6] +1.1 [2.4] -25* [2.0] -3 [1.9] -39 [3.49] -41 [3.47] LDL-C HDL-C TG
Comparisons with GEM TC : HDL-C 6 (men) or 5.6 (women), TG 2.25.6 LDL-C >4.1, TG <2.3 mmol/L TG 1.75.6, HDL-C <1.2
Insua et al.[38] [r, db, co; 6 wk] Wi et al.[142] [r, ol, sc; 24 wk] a b
FEN 200 SR GEM 900 FEN 160 NIA XR 1500b
21 21 80 60
-22* [7.63] -15 [7.63] -6.4 [5.3] -13.3** [5.1]
-27* [5.21] -16 [5.21] +8.5 [2.7] -11.6** [2.7]
+9 [1.57] +9 [1.57] +24* [1.0] +19 [1.0]
-54 [2.28] -47 [2.28] -57* [3.1] -45 [3.1]
Comparison with NIA XR
Percentage changes were estimated from a graph. Dosage started at 500 mg/day, then titrated up at wk 5 and 9.
co = cross over; db = double blind; GEM = gemfibrozil; HDL-C = high-density lipoprotein-cholesterol; LDL-C = low-density lipoproteincholesterol; mc = multicentre; NIA XR = niacin extended release; ol = open-label; PL = placebo; r = randomized; sc = single centre; SR = slow release; TC = total cholesterol; TG = triglyceride; * p < 0.05, ** p < 0.001 vs comparator.
minimum lumen diameter was 40% less in fenofibrate recipients than in placebo recipients (-0.06 vs -0.10 mm; p = 0.029), and progression in the percentage diameter stenosis was reduced by 42% (+2.11% vs +3.65%; p = 0.02).[122] According to a subgroup analysis (n = 314), fenofibrate had a significant (p = 0.031) beneficial effect on progression to albuminuria.[143] Among fenofibrate and placebo recipients, progression of albuminuria occurred in 8% versus 18%, regression occurred in 13% versus 11%, and there was no change in albuminuria in 79% versus 71%.[143] With regard to improvements in lipid levels, fenofibrate was associated with significantly greater improvements in TG, TC, LDL-C and HDL-C levels than placebo (table V).[122] Fenofibrate therapy did not alter glycaemic control to a clinically significant extent.
Other Trials
dyslipidaemia (-27% to -46% vs -4% to +14%) [including hypertriglyceridaemia,[36] mixed dyslipidaemia[46] and metabolic syndrome[58]], according to results of relatively small (n = 40207), randomized, double-blind trials that primarily evaluated lipid profiles. Lipid entry criteria included TG levels >2.36,[36] <3.99,[46] and 1.7 and <6.9[58] mmol/L; LDL-C levels <5.0[36] and >4.65[46] mmol/L; and patients with 2 of the ATP III criteria[2] for the metabolic syndrome.[58] Moreover, improvements in TC,[36,46] LDLC[46] and/or HDL-C[36] levels were significantly (p < 0.05) greater with fenofibrate than placebo in some trials in these patient populations.
4.1.2 Comparisons with Gemfibrozil
TG levels were consistently reduced from baseline to a significantly (p < 0.05) greater extent with fenofibrate than with placebo in patients with
The improvements seen in TG and HDL-C levels did not significantly differ between fenofibrate and gemfibrozil recipients in two randomized, double-blind trials[38,123] in patients with primary hypercholesterolaemia[38] or mixed dyslipidaemia[38,123] (table V). Where reported, TC and LDL-C levels were reduced from baseline to
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a significantly greater extent with fenofibrate than with gemfibrozil[38] (table V). In one trial, a significantly greater increase from baseline in ApoAI levels occurred with fenofibrate than with gemfibrozil (+9% vs +2%; p < 0.001).[123]
4.1.3 Comparisons with Statins
Fenofibrate 200 mg/day was consistently associated with significantly greater improvements than those achieved with statins in TG (-30% to -53% vs -32% to +25%),[48,124-128] and HDL-C (+10% to +18% vs -1% to +15%)[48,124-126,128] levels in most studies in patients with primary hypercholesterolaemia[124,126-128] or mixed dyslipidaemia[48,124-128] (table VI). In contrast, reductions from baseline in
TC (-12% to -19% vs -25% to -28%) and LDL-C (-8% to -21% vs -34% to -39%) levels were generally significantly less with fenofibrate than with statins (table VI).[48,124,125,128] A shift in the LDL profile towards larger, less atherogenic particles was seen in fenofibrate recipients (with a higher proportion of LDL 2 and 3 particles and a lower proportion of LDL 4 and 5 particles following treatment), whereas the distribution of LDL particles was essentially unaltered in atorvastatin recipients.[124]
4.1.4 Comparison with Niacin
Fenofibrate improved TG and HDL-C levels more effectively than niacin, and niacin improved
Table VI. Efficacy of monotherapy with fenofibrate (FEN) compared with HMG-CoA reductase inhibitors (statins) in patients (pts) with primary dyslipidaemia Study [design; duration] Lipid entry criteria (mmol/L) Treatment (mg/day) No. of pts Mean change from baseline in lipid level (% [mean baseline level; mmol/L]) TC Comparisons with ATO Ansquer et al.[124] [r, ol, mc; 12 wk] Despres et al.[125] [r, ol, mc; 12 wk] LDL-C 4.1, TG 1.74.5 LDL-C >3.2, HDL-C <1.2 (women) and <1.1 (men), TG <4.5 TC >6.2, TG >1.5 FEN 200 ATO 10 FEN 200 ATO 10 84 81 79 86 -16.5 [7.4] -27.0** [7.5] -15 [6.3] -28*** [6.1] -17.3 [5.0] -35.4** [5.2] -16 [4.2] -39*** [4.2] +10.4- [1.2] +4.6 [1.2] +13---a [0.9] +5a [0.9] -37.2--- [2.6] -20.2 [2.5] -30-- [2.5] -15 [2.3] LDL-C HDL-C TG
Malik et al.[48] [r, sb, co; 10 wk] Comparison with PRA Ducobu et al.[126] [r, db, mc; 3 mo]
FEN 200 ATO 10 FEN 200 PRA 20
29 29 75 76
-12 [7.6] -28*** [7.6] -18 [7.6] -15 [7.6]
-8 [4.4] -34*** [4.4] -18a [5.2] -17a [5.3]
+13-- [1.3] -1 [1.3] +13-- [1.1] +6 [1.0]
-50-- [5.4] -32 [5.4] -39---b [2.0] -12b [2.2]
IIa TC 6.5, TG <2.3; IIb TC >6.5, TG 2.34.5 IIa TC 6.2, LDL-C 4.1, TG <1.5 IIb TC 6.2, TG 1.55.2
Comparisons with SIM Farnier et al.[127]c [r, db, co, sc; 3 mo] FEN 200 SIM 20 FEN 200 SIM 20 FEN 200 SIM 20 15 16 11 10 66 64 -27 [8.3] -28 [8.8] -23 [7.8] -21 [7.6] -19 [7.6] -25* [7.6] -33 [6.4] -36 [6.9] -25 [5.6] -29 [5.1] -21 [5.5] -35** [5.4] +1.3 [1.5] +1.4 [1.4] +25 [1.1] +15 [1.1] +18- [1.0] +15 [0.9] -36--- [1.0] -1 [1.0] -53--- [2.6] +25 [3.1] -41--- [2.4] -17 [2.9]
Steinmetz et al.[128] [r, db, mc; 12 wk] a b c Primary endpoint.
IIa and IIb TC >6.5, LDL-C 4.77.8
Primary endpoint in the subgroup of pts with type IIb dyslipidaemia. Pts were randomized to FEN for 3 mo followed by SIM for 3 mo or vice versa. Because of the absence of a washout period between the first and second treatment periods, the changes in lipid levels are only reported for the first 3 mo treatment period.
IIa/b = Fredrickson classification type IIa/b; ATO = atorvastatin; co = crossover; db = double-blind; HDL-C = high-density lipoproteincholesterol; LDL-C = low-density lipoprotein-cholesterol; mc = multicentre; ol = open-label; PRA = pravastatin; r = randomized; sb = singleblind; sc = single centre; SIM = simvastatin; TC = total cholesterol; TG = triglyceride; * p < 0.05, ** p < 0.001, *** p < 0.0001 vs FEN; - p < 0.05, -- p < 0.01, --- p < 0.001 vs statin.
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TC and LDL-C levels more effectively than fenofibrate (table V) in an open-label, single-centre trial in patients with mixed dyslipidaemia.[142] The reduction from baseline in the ApoB : AI ratio at week 16 (primary endpoint) was not significantly different between treatment groups.[142]
4.2 Combination Therapy
This section summarizes the efficacy of fenofibrate in combination with other lipid-lowering therapies and, in particular, statins. Fenofibrate (100, 300, 67, 200, 250 mg capsules and 160 and 145 mg film-coated tablets) is approved in Europe for the treatment of severe hypertriglyceridaemia with or without low HDL-C, mixed hyperlipidaemia when a statin is contraindicated or not tolerated, and for use with a statin in patients with mixed hyperlipidaemia at high cardiovascular risk when TG and HDL-C are not adequately controlled.[10] Discussion includes the large, longterm (a mean of 4.7 year follow-up for the primary endpoint) ACCORD Lipid trial that primarily evaluated cardiac outcomes (patient baseline characteristics, study design details and lipid entry criteria are summarized in table III), and trials of 212 months duration that primarily evaluated lipid profiles. Study design details and lipid entry criteria for these trials are summarized in respective tables. All trials discussed in this section were randomized, and efficacy analyses were generally conducted in intent-to-treat or modified intentto-treat populations.
4.2.1 In Combination with a Statin The ACCORD Lipid Trial
The ACCORD trial recruited patients (n = 10 251) with type 2 diabetes who were at high risk of CVD events.[133] Of these patients, 5518 were included in the ACCORD Lipid trial[131,134] and were randomized in a double-blind manner to fenofibrate or placebo in combination with open-label simvastatin (table VII). At study end, 77.3% of fenofibrate recipients and 81.3% of placebo recipients were taking their assigned medication; 80% of patients in each group were still taking simvastatin.[131] There was no significant difference between fenofibrate plus simvastatin or placebo plus sim 2011 Adis Data Information BV. All rights reserved.
vastatin treatment groups in the incidence of the primary endpoint of major cardiovascular events (i.e. nonfatal MI, nonfatal stroke or death from cardiovascular cause; primary endpoint) [table VII]. Moreover, there were no significant differences between treatment groups in the incidence of secondary endpoints, including the composite endpoint of major cardiovascular events, revascularization or hospitalization for congestive heart failure; major CHD events; nonfatal MI; stroke; all-cause mortality; cardiovascular mortality; or fatal or nonfatal congestive heart failure (table VII). Subgroup analysis revealed a significant (p = 0.01) treatment interaction according to gender, with the primary endpoint in men occurring in 11.2% of fenofibrate plus simvastatin recipients and 13.3% of placebo plus simvastatin recipients (p = 0.037), and in women, the incidence in corresponding groups was 9.1% and 6.6% (p = 0.069).[131,144] In a prespecified subgroup analysis among patients with a TG level within the top third (2.30 mmol/L) and an HDL-C level in the bottom third (0.88 mmol/L) [n = 941; 17% of the overall ACCORD Lipid study cohort], the primary endpoint was reported in 12.4% of fenofibrate plus simvastatin recipients and 17.3% of placebo plus simvastatin recipients (p = 0.057 for interaction),[131] corresponding to a 31% relative reduction in the risk of the primary endpoint (p = 0.032) and a 4.95% reduction in terms of absolute risk.[145] Among this cohort, there was no evidence of the heterogeneity by gender observed in the overall ACCORD Lipid cohort.[145] Among patients in ACCORD Lipid who were also enrolled in the ACCORD Eye trial, patients receiving fenofibrate plus simvastatin were 40% less likely than those receiving placebo plus simvastatin to experience progression of diabetic retinopathy at 4 years (primary endpoint in the ACCORD Eye trial), although there was no significant between-group difference in the incidence of moderate vision loss (table VII).[134] In ACCORD Lipid, the post-randomization incidence of microalbuminuria and macroalbuminuria was significantly (p < 0.05) lower with fenofibrate plus simvastatin than with placebo plus simvastatin (see also section 5).[131]
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Table VII. Effect of fenofibrate (FEN) plus simvastatin (SIM) on cardiovascular outcomes. Results of the randomized, placebo (PL)-controlled, multicentre ACCORD Lipid trial in patients (pts) with type 2 diabetes mellitus; the administration of FEN and PL was double-blind and the administration of SIM was open-label.[131,134] The mean duration of follow-up was 4.7 y for the primary outcome, and 5 y for total mortality. Further study design details and pt baseline characteristics are shown in table III Endpoint Primary outcome Major CV event (nonfatal MI, nonfatal stroke or death from CV cause) Secondary outcomes Primary outcome plus revascularization or hospitalization for CHF Major CHD eventb Nonfatal MI Stroke All-cause mortality CV mortality Fatal or nonfatal CHF Other outcomes Progression of diabetic retinopathyc Moderate vision loss a
e
Incidence (% of pts) [annual rate; %] SIM + FENa (n = 2765) 10.5 [2.24] SIMa + PL (n = 2753) 11.3 [2.41]
Hazard ratio (95% CI)
p-Value
0.92 (0.79, 1.08)
0.32
23.2 [5.35]
24.2 [5.64]
0.94 (0.85, 1.05)
0.30
12.0 [2.58] 6.3 [1.32] 1.8 [0.38] 7.3 [1.47] 3.6 [0.72] 4.3 [0.90] 6.5 23.7
12.8 [2.79] 6.8 [1.44] 1.7 [0.36] 8.0 [1.61] 4.1 [0.83] 5.2 [1.09] 10.2 24.5
0.92 (0.79, 1.07) 0.91 (0.74, 1.12) 1.05 (0.71, 1.56) 0.91 (0.75, 1.10) 0.86 (0.66, 1.12) 0.82 (0.65, 1.05) 0.60 (0.42, 0.87)d 0.95 (0.79, 1.14)f
0.26 0.39 0.80 0.33 0.26 0.10 0.006 0.57
Initially the FEN dosage was 160 mg/day; subsequently it was adjusted according to the glomerular filtration rate. The SIM dosage was modified over time according to changing treatment guidelines (average SIM dosage during follow-up was 22.3 mg/day in the FEN group and 22.4 mg/day in the PL group). Defined as a fatal CHD event, nonfatal MI or unstable angina pectoris. Endpoint assessed at 4 y in 806 FEN recipients and 787 PL recipients from ACCORD Lipid who were also enrolled in ACCORD Eye. Adjusted odds ratio. Endpoint assessed in 956 FEN recipients and 950 PL recipients from ACCORD Lipid who were also enrolled in ACCORD Eye. Adjusted hazard ratio.
b c d e f
CHD = coronary heart disease; CHF = congestive heart failure; CV = cardiovascular; MI = myocardial infarction.
Fenofibrate plus simvastatin was associated with significantly greater improvements in TC, HDL-C and TG levels than placebo plus simvastatin (table VIII).[131]
Other Trials
Fenofibrate plus a statin generally improved lipid levels to a greater extent than monotherapy with either agent in patients with type 2 diabetes and/or dyslipidaemia (tables IX and X).[43,61,131,146-153] For example, in the SAFARI trial in patients with mixed dyslipidaemia, fenofibrate 160 mg/day plus simvastatin 20 mg/day improved TC, LDL-C, HDL-C and TG levels to a significantly greater extent than simvastatin 20 mg/day alone (table IX).[153]
Similarly, in patients with type 2 diabetes and mixed dyslipidaemia, the combination of fenofibrate plus rosuvastatin (varying dosages; table VIII) improved TG to a significantly greater extent than rosuvastatin or fenofibrate alone and improved TC and LDL-C to a significantly greater extent than fenofibrate alone.[148] Similar effects on individual lipid parameters were observed when fenofibrate was combined with atorvastatin, fluvastatin or pravastatin (table VIII and table IX). The change in levels of non-HDL-C was the primary endpoint in three 12-week studies.[147,150,151] Two of these studies included a 6-[147] (table VIII) or 8-week[151] (table IX) run-in period, in which all patients received statin monotherapy. Eligible patients (i.e. those who did not achieve their lipid goals)
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Table VIII. Efficacy of fenofibrate (FEN) plus a HMG-CoA reductase inhibitor (statin) in patients (n > 40) with type 2 diabetes mellitus and mixed dyslipidaemia Study [design; duration] In combination with ATO Athyros et al.[61] [r, ol; 24 wk] TC >5.7, LDL-C >3.4, TG 2.34.5, HDL-C <1.04 FEN 200 ATO 20 ATO 20 + FEN 200 40 40 40 -16 [6.5] -31 [6.5] -37*- [6.6] -15 [4.2] -40 [4.2] -46*- [4.2] +16 [0.9] +9 [0.9] +22* [0.9] -41 [3.2] -30 [3.1] -50*- [3.1] Lipid entry criteria (mmol/L) Treatment (mg/day) No. of pts Mean change from baseline in lipid level (% [mean baseline level; mmol/L]) TC LDL-C HDL-C TG
In combination with FLU Derosa et al.[146] [r, db; 12 mo] TC 5.2, LDL-C 2.6, TG 1.7 FLU ER 80 FLU ER 80 + FEN 200 23 25 -20a [6.7] -26a [6.8] -25a [4.8] -35*a [4.9] +14a [1.1] +34*a [1.1] -17a [1.7] -32*a [1.8]
In combination with PRA Farnier et al.[147]b [r, db, mc; 12 wk] non-HDL-C 3.4, LDL-C 2.6, TG 1.76.8 SIM 20 FEN/PRA 160/40c 145 144 -5.2 [5.5] -8.7* [5.5] -6.8 [3.3] -5.3 [3.3] +1.8 [1.1] +6.3** [1.2] +5.0 [3.1] -28.6*** [3.0]
In combination with ROS Durrington et al.[148] [r, mc; 24 wk] TC 5.2, TG 2.39.0 PL - FEN 67201 PL - ROS 1040 ROS 5 - ROS 5 + FEN 67201 ROS 10 - ROS 10 + FEN 67201 49 51 60 53 -7.5 [6.3] -36.6-- [6.2] -31.0-- [6.5] -36.3-- [6.4] +0.7 [3.7] -46.7-- [3.7] -34.1-- [3.9] -42.2-- [3.9] +9.2 [1.0] +6.4 [1.0] +10.8 [1.1] +11.7 [1.0] -33.6a [4.2] -30.3a [3.6] -40.9a [3.5] -47.1***--a [3.5]
In combination with SIM ACCORD Study Group[131] [r, pb, mc; 5 y] Muhlestein et al.[149] [DIACOR trial; r, db; 12 wk] a b c d Primary endpoint. Prior to eligibility assessment, SIM 20 mg/day was administered in a 6-wk run-in period. Fixed-dose combination. Median values. See table III SIM + PL SIM + FEN 2753 2765 -12.5 [4.5] -13.5* [4.5] -20.9 [2.6] -18.9 [2.6] +6.0 [1.0] +8.4** [1.0] -8.7 [2.1] -22.2*** [2.1] -38.2*d [3.1] -24.8d [2.6] -49.4*d [3.2]
LDL-C 2.6, HDL-C <1.0, TG 2.3
FEN 160 SIM 20 SIM 20 + FEN 160
100 100 100
-13.3 [5.8] -26.2- [5.9] -27.1- [6.0]
-10.1 [3.5] -34.1- [3.7] -29.1- [3.5]
+13.7 [0.9] +7.4 [1.0] +13.0 [0.9]
ATO = atorvastatin; db = double-blind; ER = extended release; FLU = fluvastatin; HDL-C = high-density lipoprotein-cholesterol; LDL-C = low-density lipoprotein-cholesterol; mc = multicentre; ol = open-label; pb = partial-blind; r = randomized; PRA = pravastatin; ROS = rosuvastatin; SIM = simvastatin; TC = total cholesterol; TG = triglyceride; * p < 0.05, ** p = 0.01, *** p 0.001 vs statin monotherapy (corresponding dose); - p < 0.05, -- p 0.001 vs FEN monotherapy; p 0.001 vs ROS 5 + FEN 67201.
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Table IX. Efficacy of fenofibrate (FEN) plus an HMG-CoA reductase inhibitor (statin) in patients (pts) [n > 50] with mixed dyslipidaemia[43,150-153] or primary hypercholesterolaemia.[152] A proportion of pts (1627%) in each study, except for two,[150,152] had type 2 diabetes mellitus Study [design; duration] Lipid entry criteria (mmol/L) Treatment (mg/day) No. of pts Mean change from baseline in lipid level (% [mean baseline level; mmol/L]) TC In combination with ATO Davidson et al.[150] TG 1.75.6, HDL-C >3.4 FEN 145 ATO 40 ATO/FEN 40/100 Koh et al.[43]b [r, db, co; 2 mo] TC 5.2, TG 2.39.0 FEN 200 ATO 10 ATO 10 + FEN 200 63 70 67 56 56 56 -10.4 [6.5] -32.8 [6.6] -33.9 [6.5] -13 [6.0] -29- [6.3] -29- [6.2]
--
LDL-C -13.9 [4.3] -43.1 [4.3] -42.3 [4.0] -6 [3.4] -40- [3.5] -30- [3.3]
--
HDL-C +18.2a [1.0] +6.5 [1.1] +19.7

**a a
TG -27.8a [2.6] -28.9a [3.0] -49.1**--a [3.0] -55* [3.8] -25 [3.4] -57* [3.6]
[1.1]
+23* [1.1] +0 [1.2] +15* [1.2]
In combination with FLU Farnier and Dejager[152] [r, db, mc; 16 wk] LDL-C 4.9, TG 3.9 FEN 200 FLU 20 + FEN 200 FLU 40 + FEN 200 In combination with PRA Farnier et al.[151]c [r, db, dd, mc; 12 wk] In combination with SIM Grundy et al.[153] [SAFARI trial; r, db, mc; 12 wk] a b c d Primary endpoint. Prior to each treatment switch, there was a 2-mo washout period. Prior to eligibility assessment, PRA 40 mg/day was administered in a 8-wk run-in period. Median value. LDL-C >3.4, TG 1.75.6 SIM 20 SIM 20 + FEN 160 207 411 -20.3 [6.6] -26.3*** [6.6] -25.8 [4.2] -31.2*** [4.2] +9.7 [1.1] +18.6*** [1.1] -20.1a,d [2.6] -43.0***a,d [2.6] LDL-C 2.6, TG 1.74.5 PRA 40 PRA 40 + FEN 160 119 120 -4.4 [6.0] -9.9** [6.0] -5.9 [3.6] -11.7* [3.6] +2.3 [1.2] +6.5** [1.2] -2.0 [2.7] -22.6*** [2.7] 32 33 31 -19 [9.1] -27 [9.7] -35 [9.2] -21a [7.1] -32a [7.6] -41a [7.1] +4 [1.2] +14 [1.3] +3 [1.4] -29 [1.8] -39 [1.8] -40 [1.6]
ATO = atorvastatin; co = crossover; db = double-blind; dd = double dummy; FLU = fluvastatin; HDL-C = high-density lipoprotein-cholesterol; LDL-C = low-density lipoprotein-cholesterol; mc = multicentre; PRA = pravastatin; r = randomized; SIM = simvastatin; TC = total cholesterol; TG = triglyceride; * p < 0.05, ** p 0.01, *** p 0.001 vs statin monotherapy (corresponding dose); - p < 0.05, -- p 0.001 vs FEN monotherapy; p < 0.05, p < 0.001 (analysis of variance F test for the comparison of the three treatment groups).
were then randomized to continue monotherapy or receive combination therapy in a double-blind manner.[147,151] In these studies, the combination of pravastatin 40 mg plus fenofibrate 160 mg per day[151] (or the fixed-dose combination of fenofibrate/pravastatin 160 mg/40 mg per day[147]) reduced mean non-HDL-C from baseline (i.e. following statin monotherapy run-in) more than pravastatin 40 mg/day alone (14.1% vs 6.1%; p = 0.002)[151] and more than simvastatin 20 mg/day alone (12.9% vs 6.8%; p = 0.008; figure 1).[147] In a third study, the mean percentage reduction from baseline in non-HDL-C was significantly greater with atorvastatin/fenofibrate 40 mg/100 mg than with fenofibrate 145 mg alone (44.8% vs 16.1%; p < 0.001), but was not significantly dif 2011 Adis Data Information BV. All rights reserved.
ferent from that with atorvastatin 40 mg alone (44.8% vs 40.2%).[150] In a 12-month study of patients with type 2 diabetes, hyperlipidaemia and CHD, HbA1c levels were significantly reduced from baseline with fluvastatin plus fenofibrate but not with fluvastatin alone (12% vs 7%; p < 0.05).[146]
4.2.2 In Combination with Ezetimibe with or without a Statin
The addition of fenofibrate to the combination of a statin plus the cholesterol absorption inhibitor ezetimibe further improved the lipid profile in a 12-week study in patients with mixed dyslipidaemia.[154] Mean values of HDL-C and median values of TG were improved to a significantly greater
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4.2.3 Other Combinations
The efficacy of fenofibrate has also been assessed in combination with various other drugs in well designed studies, including the bile acid sequestrant colesevelam,[158] the oral antidiabetic agent metformin[159] and the lipase inhibitor orlistat.[160] In patients with mixed dyslipidaemia, the addition of colesevelam 3.75 mg/day to fenofibrate 160 mg/day for 6 weeks resulted in significantly (p < 0.0001) greater reductions in mean levels of TC and LDL-C, but no additional improvement in levels of HDL-C or TG, compared with the continuation of fenofibrate alone.[158] In patients with the metabolic syndrome (n = 681), combination therapy with fenofibrate 160 mg/day plus metformin 1700 mg/day (the highest of four dosage regimens given in two divided doses) was more effective than monotherapy
Farnier et al.[155]
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HDL-C = high-density lipoprotein-cholesterol; LDL-C = low-density lipoprotein-cholesterol; PL = placebo; SIM = simvastatin; TC = total cholesterol; TG = triglyceride; ** p < 0.001 vs PL; - p < 0.01, -- p < 0.001 vs FEN; p < 0.01, p < 0.001 vs EZE/SIM or EZE alone.
extent from baseline with fenofibrate 160 mg plus ezetimibe/simvastatin 10 mg/20 mg than with the ezetimibe/simvastatin (table X).[154] Fenofibrate plus ezetimibe/simvastatin also achieved significantly greater improvements in TC, LDL-C and TG than fenofibrate alone. The combination of fenofibrate plus ezetimibe was associated with significantly greater improvements from baseline in TC and LDL-C levels than monotherapy with either agent alone in two trials in patients with mixed dyslipidaemia (table X).[155,156] However, improvements in HDL-C and TG achieved with fenofibrate plus ezetimibe were not significantly different to those achieved with fenofibrate alone.[155,156] One trial reported a shift to a larger LDL size pattern in 64% of patients receiving fenofibrate plus ezetimibe, 62% receiving fenofibrate monotherapy, 22% receiving ezetimibe monotherapy and 12% receiving placebo.[155] At baseline, 70% of patients in each treatment group had a pattern B LDL phenotype.[155] A 12-month double-blind extension phase of this study, during which patients received fenofibrate plus ezetimibe (n = 340) or fenofibrate alone (n = 236), demonstrated greater improvements from baseline of the core study with combination therapy than with monotherapy (mean values of LDL-C were reduced by 22% vs 9%; p < 0.001).[157]
Table X. Efficacy of combination therapy with fenofibrate (FEN) plus ezetimibe (EZE) with or without a HMG-CoA reductase inhibitor (statin) in patients (pts) with mixed dyslipidaemia. Results of randomized, double-blind, multicentre, 12-week trials. A proportion of pts (10%[154] and 15%[155]) in two studies had type 2 diabetes mellitus (T2DM)
-9.2 [2.9] -43.2** [3.2]
-38.3b [2.5]
-44.0** [3.1]
-38.3b [2.3] -10.4b [2.4]
-50.0*- [2.6]
-41.3* [2.6]
-11.1 [3.1]
-3.1 [2.6] -28.6* [2.5]
Mean change from baseline in lipid level (% [mean baseline level; mmol/L])
TGa
+3.2 [1.1] +18.8** [1.1]
+19.0** [1.1]
+18.2* [1.2]
+3.9 [1.1]
-20.4**--b [4.2]
-3.5a,b [4.2] -47.1*-a,b [4.3]
LDL-C
-13.4b [4.1]
+0.2b [4.2] -5.5b [4.3]
-27.9-- [7.6]
-22.4**-- [6.8]
-1.0a [6.6] -35.4*-a [6.7]
No. of pts
TC
61 179
175
180
-14.7*a [6.6]
-18.9 [7.5] -17.1 [7.4]
173
60 179
FEN 145 + EZE 10
FEN 160 + EZE 10
PL EZE/SIM 10/20c
Treatment (mg/day)
FEN 145 EZE 10
PL FEN 160
EZE 10
Lipid entry criteria (mmol/L)
LDL-C 3.45.7 (2.64.6 in pts with
LDL-C 3.45.7, TG 2.35.7
FEN 160
EZE/SIM 10/20c + FEN 160
180
58 56
59
-38.7*-a [6.4]
+0.2 [6.7] -10.8** [6.9]
-11.8** [6.7]
-45.8*-a,b [4.1]
-36.2-- [5.1]
-15.7*a,b [4.2]
-22.4 [5.0] -22.8 [5.0]
+18.7* [1.1]
11.5b [1.4]
+1.1 [1.2] +9.3* [1.2]
HDL-C
7.9b [1.3] 2.2b [1.3]
b Primary endpoint. c Fixed-dose combination.
LDL-C >4.1, TG 1.74.6
T2DM), TG
1.75.7
Ansquer et al.[156]
Study
Farnier et al.[154]
Median values.
p < 0.01,
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10 Change from level recorded after statin monotherapy run-in (%) 5 0 5 10 15 20 25 30 35 Non-HDL-C HDL-C TC LDL-C ** * **
FEN/PRA SIM
5.1 Monotherapy
***
TG
Fig. 1. Efficacy of fenofibrate/pravastatin (FEN/PRA) combination therapy versus HMG-CoA reductase inhibitor (statin) monotherapy in patients with type 2 diabetes mellitus and mixed dyslipidaemia previously treated with statin monotherapy.[147] Results of a randomized, double-blind, multicentre study in which patients (n = 289) not at lipid goals following a 6-wk run-in period during which they received simvastatin (SIM) 20 mg/day were randomized to FEN/PRA 160 mg/40 mg per day or SIM 20 mg/day for 12 wk. HDL-C = highdensity lipoprotein-cholesterol; LDL-C = low-density lipoproteincholesterol; TC = total cholesterol; TG = triglycerides; * p < 0.05, ** p < 0.01, *** p < 0.001 vs SIM 20 mg/day.
with either agent alone (p 0.01 for both) in terms of normalising biochemical abnormalities in a 3-month study.[159] Also in patients (n = 86) with the metabolic syndrome, fenofibrate, alone or in combination with orlistat improved metabolic parameters.[160] After 3 months therapy, 48% of patients receiving monotherapy with fenofibrate 200 mg/day, 44% receiving monotherapy with orlistat 120 mg three times daily and 50% receiving fenofibrate 200 mg/day plus orlistat 120 mg three times daily no longer fulfilled the criteria for the metabolic syndrome (all p < 0.0001 vs baseline); there were no significant between-group differences.[160] 5. Tolerability Tolerability data on fenofibrate discussed in this section are derived primarily from clinical trials discussed in section 4 in patients with dyslipidaemia and/or type 2 diabetes or the metabolic syndrome. In all trials, fenofibrate administered alone or in combination with statins was generally well tolerated, including in studies following patients for periods of up to 5 years.[121,131]
The most common (incidence >1% and <10%) adverse events associated with fenofibrate monotherapy included gastrointestinal signs and symptoms (e.g. abdominal pain, nausea, vomiting, diarrhoea and flatulence) and increased transaminase levels, according to a pooled analysis of data from placebo-controlled clinical trials (n = 2344).[9] Uncommon (incidence >0.1% and <1%) adverse events included headache, thromboembolism, pancreatitis, cholelithiasis, cutaneous hypersensitivity (e.g. rashes, pruritus and urticaria), muscle disorders (e.g. myalgia, myositis, muscular spasms and weakness), sexual dysfunction and increased blood creatinine levels.[9] Fenofibrate was generally well tolerated in the longer-term, according to the results of the placebo-controlled FIELD trial, in which patients with type 2 diabetes and no clear indication for lipid-lowering therapy (n = 9795) were followed for 5 years.[121] Possible serious adverse reactions were reported in 0.8% of fenofibrate recipients and 0.5% of placebo recipients. Although low, the incidence of pancreatitis (0.8% vs 0.5%; p = 0.031) or pulmonary embolism (1.1% vs 0.7%; p = 0.022) was significantly higher in fenofibrate recipients than in placebo recipients. Other clinically important adverse events included deep vein thrombosis (1.4% of fenofibrate recipients vs 1.0% of placebo recipients) and renal disease needing dialysis (0.3% vs 0.4%).[121] Rhabdomyolysis was reported in three fenofibrate recipients (0.06%) and one placebo recipient (0.02%); none of the patients were receiving a statin and all cases fully resolved.[121] Myositis was reported in 0.04% of fenofibrate recipients and 0.02% of placebo recipients.[121] With regard to laboratory abnormalities reported in the FIELD trial, creatine phosphokinase (CPK) levels of 510 or >10 the upper limit of normal (ULN) or ALT levels of 35 or >5 ULN were reported in <1% of fenofibrate or placebo recipients.[121] In most cases, elevations in transaminase levels were transient, minor and asymptomatic.[9] Indeed, a subsequent analysis of FIELD trial data found that, although ALT levels initially rose among fenofibrate recipients, the risk
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of elevated ALT levels was significantly lower with fenofibrate than with placebo at 12 months (odds ratio [OR] 0.71; 95% CI 0.60, 0.84) and at the end of the trial (OR 0.71; 95% CI 0.58, 0.86).[161] Increases in plasma creatinine levels were seen among fenofibrate recipients in the FIELD study, with a median plasma creatinine level at study end of 91 mmol/L in fenofibrate recipients and 80 mmol/L in placebo recipients (p < 0.001).[121] A subgroup analysis in patients (n = 661) in whom creatinine levels were reassessed 8 weeks after stopping the study drug revealed that median plasma creatinine levels had fallen from 92 to 77 mmol/L among fenofibrate recipients and from 82 to 79 mmol/L among placebo recipients.[121] Further prespecified analyses of FIELD trial data suggest that, given the rapid reversion of plasma creatinine levels to pretreatment levels among fenofibrate recipients, fenofibrate therapy did not result in permanent renal injury.[140] Moreover, in the longer term, fenofibrate appeared to preserve the estimated GFR and reduce albuminuria progression (section 4.1.1).[140] In the single study comparing fenofibrate with niacin (n = 201), adverse events were less common (9 vs 44 patients; p < 0.001), and led to treatment discontinuation less often (5 vs 27 patients; p < 0.001) in the fenofibrate group.[142] The most common adverse events associated with niacin were pruritis and skin flushing, which each occurred in 11 patients.
5.2 Combination Therapy
In the ACCORD Lipid trial,[131] in which patients received fenofibrate or placebo against a background of simvastatin therapy and were followed for 5 years (n = 5518), there was no significant difference between fenofibrate plus simvastatin recipients and placebo plus simvastatin recipients in the incidence of serious myopathy, myositis or rhabdomyolysis (0.1% vs 0.1%). Serum creatinine elevations occurred in significantly more fenofibrate plus simvastatin than placebo plus simvastatin recipients (27.9% vs 18.7% among women and 36.7% vs 18.5% among men; p < 0.001 for both), although the post-randomization incidence of microalbuminuria (38.2% vs 41.6%) and
macroalbuminuria (10.5% vs 12.3%) was significantly (p < 0.05) lower with fenofibrate plus simvastatin than with placebo plus simvastatin.[131] A similar pattern was reported in other trials in which fenofibrate was co-administered with a statin in patients with dyslipidaemia, with no significant differences between combination therapy and monotherapy groups in the incidence of treatmentrelated serious or severe adverse events.[61,146-153] After 12 weeks of treatment in the SAFARI trial (n = 618),[153] the frequency and type of clinical adverse events was similar in patients receiving fenofibrate 160 mg plus simvastatin 20 mg or simvastatin 20 mg alone. Treatment-related adverse events occurred in 1.5% of combination therapy recipients (myalgia, arthralgia, musculoskeletal pain and gastrointestinal complaints) and 1.4% of simvastatin monotherapy recipients (myalgia, arthralgia and headache).[153] There were no cases of rhabdomyolysis or muscle symptoms with CPK levels >10 ULN in either group. Increases in AST and ALT to >3 ULN occurred in 3.2% and 2.5% of patients, respectively, in the combination therapy group, and in no patients receiving simvastatin alone.[153] Four patients receiving combination therapy and no patients receiving simvastatin monotherapy discontinued treatment due to elevated ALT and/or AST.[153] A recent US retrospective cohort study assessed safety among 584 784 new users of fibrates, statins or fibrate plus statin combination therapy between 2004 and 2007; during the follow-up period, 32 769 patients received only fenofibrate, 9986 received only gemfibrozil, 484 345 received only statins, 36 319 received statins plus fenofibrate and 7967 received statins plus gemfibrozil.[162] Among patients receiving fenofibrate, gemfibrozil, a statin, a statin plus fenofibrate, or a statin plus gemfibrozil, the incidence rate per 100 000 patient-years for rhabdomyolysis was 2.8, 9.6, 3.3, 15.0 and 20.7, respectively; for renal impairment it was 147.9, 183.0, 108.9, 226.4 and 249.6, respectively; for hepatic injury it was 13.9, 0, 8.6, 11.3 and 20.7, respectively; and for pancreatitis it was 125.4, 86.5, 45.8, 157.9 and 83.1, respectively.[162] Fenofibrate was generally well tolerated when combined with ezetimibe with or without a statin.[154-156] In a 12-week study of patients with
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mixed dyslipidaemia, elevations in ALT and/or AST 3 ULN occurred in 3% of patients in each of the groups receiving fenofibrate 160 mg plus ezetimibe/simvastatin 10 mg/20 mg (n = 183) or fenofibrate 160 mg alone (n = 184) and no patients receiving ezetimibe/simvastatin 10 mg/20 mg (n = 184) or placebo (n = 60).[154] The incidence of myalgia was not significantly different between the active treatment groups (4.4%, 3.3% and 3.8%, respectively). 6. Dosage and Administration As previously mentioned, there are several formulations of fenofibrate available worldwide. This section focuses on formulations most commonly used in clinical trials. Local prescribing information should be consulted for full details regarding indications, dosages, contraindications, warnings and precautions. In Europe, micronized fenofibrate (67[12] and 200[10] mg capsules, 160 mg film-coated tablets[9]) and the nanoparticle formulation (145 mg filmcoated tablets)[11] are indicated as an adjunct to diet and other nonpharmacological therapies (e.g. exercise, weight reduction) for the treatment of severe hypertriglyceridaemia with or without low HDL-C, mixed hyperlipidaemia when a statin is contraindicated or not tolerated, and mixed hyperlipidaemia in patients at high cardiovascular risk in addition to a statin when TG and HDL-C are not adequately controlled. In the US, fenofibrate is indicated as an adjunct to diet and other nonpharmacological therapies in patients with hypercholesterolaemia and hypertriglyceridaemia alone or combined (i.e. Fredrickson type IIa, IIb, III, IV or V dyslipidaemia[163]) and in patients with persisting secondary hyperlipoproteinaemia despite prior treatment of the underlying disease.[8] The recommended initial dosage in adults is one tablet or capsule once daily.[9-11] No dose adjustment is needed in patients switching between the 200 mg micronized capsule,[10] the 160 mg micronized film-coated tablet[9] and the 145 mg nanoparticle film-coated tablet.[11] Formulations of micronized fenofibrate should be taken with food,[9,10] but fenofibrate nano 2011 Adis Data Information BV. All rights reserved.
particle film-coated tablets[11] may be administered without regard to food. Fenofibrate is contraindicated in patients with severe hepatic or renal insufficiency or gallbladder disease (see section 3.1).[9-11] 7. Place of Fenofibrate in the Management of Dyslipidaemia In patients with dyslipidaemia, the intensity of cholesterol-lowering intervention is based on the degree of associated risk for CHD events.[2] Current treatment guidelines identify LDL-C as the primary target of therapy, based on evidence that lowering LDL-C levels reduces the risk for major coronary events.[2,3,5] When LDL-C levels are above the goal for a specific risk category, management includes judicious use of therapeutic lifestyle changes (e.g. dietary changes and increased physical activity) and drug therapies.[2,3,164] Statins are generally the first-line option for reducing LDL-C levels based on their proven benefit in reducing cardiovascular morbidity and mortality in clinical trials.[3,164-166] Although reducing LDL-C levels is the primary goal of therapy, other lipid parameters are also risk factors for CHD, including low levels of HDL-C and elevated TG.[2] The co-existence of these three lipid risk factors constitutes atherogenic dyslipidaemia, which constitutes one component of the metabolic syndrome.[2] Patients with elevated TG also usually have an increase in atherogenic VLDL remnants, which can be evaluated by measuring VLDL-C. Thus, non-HDL cholesterol (i.e. the combination of LDL-C and TG-enriched lipoproteins) is a secondary target of therapy in these patients.[2] While statins effectively reduce LDL-C levels, they have a more limited effect on improving levels of TG and HDL-C. Fenofibrate, a PPARa activator (section 2.1), is particularly associated with improvements in TG and HDL-C levels (table XI).[2,167] In clinical trials in patients with dyslipidaemia, including those with type 2 diabetes and the metabolic syndrome (section 4.1), fenofibrate monotherapy consistently decreased TG levels to a significantly greater extent than placebo and achieved signifDrugs 2011; 71 (14)
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icantly greater improvements in HDL-C, LDL-C and/or TC levels in some trials. Monotherapy with fenofibrate or gemfibrozil had generally similar effects on TG and HDL-C levels, although in one trial, TC and LDL-C levels were reduced to a significantly greater extent with fenofibrate than with gemfibrozil (section 4.1.2). Compared with statin monotherapy, fenofibrate monotherapy tended to improve TG and HDL-C levels to a significantly greater extent, whereas statins decreased LDL-C and TC levels to a significantly greater extent than fenofibrate (section 4.1.3). In a single study, fenofibrate improved TG and HDL-C levels more effectively than niacin, whereas niacin improved TC and LDL-C levels more effectively (section 4.1.4). In patients with atherogenic dyslipidaemia, fenofibrate was also associated with promoting a shift from small, dense, atherogenic LDL particles to larger, less dense LDL particles (sections 4.1.1 and 4.1.3), which have a higher affinity for the LDL receptor, leading to more rapid catabolism.[167] The lipid-modifying effect of fenofibrate is largely influenced by baseline lipid levels.[168] For example, the beneficial effect on TG and HDL-C levels usually increases as baseline levels worsen.[168] However, the effect of fenofibrate on LDL-C levels varies according to the type of dyslipidaemia (e.g. LDL-C levels are decreased to a greater extent in patients with normal TG levels at baseline than in those with mixed dyslipidaemia). An increase in LDL-C levels following fenofibrate therapy in patients with severe hypertriglyceridaemia and low LDL-C levels is thought to result from an accelerated catabolism of TGTable XI. Main lipid effects of lipid-lowering drugs[2] Drug class Fibrates HMG-CoA reductase inhibitors Nicotinic acid (niacin) Bile acid sequestrants a LDL-C (%) 520a 1855 525 1530 HDL-C (%) 1035a 515 1535 35 TG (%) 2050 730 2050
May be increased in hypertriglyceridaemic individuals.
HDL-C = high-density lipoprotein-cholesterol; LDL-C = low-density lipoprotein-cholesterol; TG = triglyceride; indicates an increase; indicates a decrease.
rich lipoproteins, leading to increased LDL conversion and an increase in LDL particle size.[168] In addition to improving the lipid profile, fenofibrate also has beneficial effects on emerging risk factors such as ApoB, ApoAI, fibrinogen and CRP levels (sections 2.1 and 2.2). Fenofibrate also improved other markers of inflammation and atherosclerosis (section 2.2), and these nonlipid effects may also contribute to its clinical efficacy.[16] Fenofibrate can lead to raised levels of homocysteine (section 2.2), which has been implicated in atherosclerosis,[87] but this did not appear to attenuate the improvement in focal coronary atherosclerosis progression seen with fenofibrate in the DAIS trial (section 4.1.1). As stated, statins are usually the first-line option for lowering LDL-C levels;[2] however, fenofibrate monotherapy has a role in patients with mixed dyslipidaemia who cannot receive a statin because of tolerability issues or contraindications.[168] The ATP III guidelines recommend fibrate monotherapy as an option in patients with CHD who have low LDL-C levels and atherogenic dyslipidaemia and in patients with very high TG levels (to reduce the risk of acute pancreatitis).[2] In the FIELD trial in patients with type 2 diabetes, fenofibrate monotherapy did not significantly reduce the risk of CHD events despite improving the lipid profile and the risk of several macrovascular and microvascular outcomes (section 4.1.1). One possible reason for this finding is the higher rate of concomitant statin use among placebo recipients than fenofibrate recipients. Furthermore, fewer than 40% of patients in the FIELD trial were considered to have dyslipidaemia at study entry, and further subgroup analysis in patients with marked hypertriglyceridaemia (TG level of 2.3 mmol/L) or marked dyslipidaemia (TG level of 2.3 mmol/L and low HDL-C) revealed a significant reduction in the CVD event rate among fenofibrate recipients.[138] Subgroup analyses of primary (Helsinki Heart Study[169,170] ) and secondary (Bezafibrate Infarction Prevention,[171-173] Veterans Affairs HDL-C Intervention Trial[174,175] ) prevention trials support results from the FIELD study. These studies provide collective evidence that fibrate therapy
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has the greatest benefit in patients with high TG and/or low HDL-C levels, suggesting that fibrates may improve CVD outcomes in patients with the metabolic syndrome or type 2 diabetes who also have atherogenic dyslipidaemia. The microvascular benefits associated with fenofibrate therapy in the FIELD trial (section 4.1.1) may result from mechanisms besides its lipid-lowering effect.[135,136,140,176] Possible mechanisms include the various pleiotropic effects of fenofibrate discussed in section 2 (e.g. improved endothelial function, anti-inflammatory effects, reduced blood viscosity, prevention of retinal cell apoptosis, reduced angiogenesis). Thus, there may be a potential role for fenofibrate in the management of microvascular complications, particularly in patients with type 2 diabetes who are at high risk of amputation, diabetic eye disease and renal morbidity.[136,140,177] Results of an observational cohort study suggest that fenofibrate may also protect against diabetic peripheral sensory neuropathy,[178] although more data are needed. Fenofibrate is also indicated as add-on therapy with a statin when the treatment goal is not achieved and TG levels remain elevated.[2,164] Some dyslipidaemic patients, particularly those with diabetes or the metabolic syndrome, have residual CHD risk despite receiving optimum statin therapy.[166,168] Moreover, some patients remain at risk of CVD despite achieving target LDL-C levels.[168] Recent evidence indicates that abnormalities of the triglyceride-HDL axis, in particular, are associated with adverse CV outcomes.[168] A post hoc analysis of the Treating to New Targets trial demonstrated that among patients with CHD treated with statins, those with persisting low HDL-C levels had greater CVD risk.[179] Furthermore, while raised TG levels are not considered directly atherogenic, they are indicative of atherogenic remnant particles and are an important biomarker of CVD risk.[167] In clinical trials in patients with dyslipidaemia, including some trials where a run-in period of statin monotherapy had not achieved non-HDL-C and LDL-C goals, combination therapy with a statin plus fenofibrate generally improved the lipid profile to a significantly greater extent than monotherapy (section 4.2.1).
In ACCORD Lipid, which was designed to establish if combination therapy with simvastatin plus fenofibrate would result in additional cardiovascular benefit in patients with type 2 diabetes who were at high risk of CVD events,[180] there were no significant differences between patients receiving simvastatin plus fenofibrate and those receiving simvastatin plus placebo for any of the primary or secondary cardiovascular outcomes (section 4.2.1). The reason that ACCORD Lipid failed to demonstrate a significant difference in cardiac outcomes in favour of combination therapy, despite significantly improved lipid profiles, is thought to reflect the fact that most patients did not meet the criteria for fenofibrate add-on treatment, i.e. hypertriglyceridaemia and mixed dyslipidaemia. Indeed, in a predefined subgroup analysis of patients with a TG level within the top third and an HDL-C level in the bottom third, adding fenofibrate to simvastatin reduced the relative risk of a major CV event by 31% (section 4.2.1). Therefore, although the results of ACCORD Lipid do not support the use of simvastatin plus fenofibrate in all patients with type 2 diabetes, combination therapy appears beneficial, with respect to cardiovascular outcomes, in selected patients.[181,182] Indeed, in a discussion of ACCORD Lipid results, the Residual Risk Reduction Initiative state that adding fenofibrate to a statin can provide additional reduction in CV risk in patients with type 2 diabetes with persisting atherogenic dyslipidaemia, i.e. both elevated TG and low HDL-C plasma levels.[181] It is also worthy of note that, in keeping with the results of the FIELD trial, the ACCORD Eye trial demonstrated significantly slower progression of diabetic retinopathy with simvastatin plus fenofibrate than with simvastatin plus placebo (section 4.2.1). ACCORD Lipid demonstrated a significant interaction effect between treatment and gender, with the possibility of an increased risk of a major cardiovascular event in women treated with simvastatin plus fenofibrate compared with men (section 4.2.1). However, no such interaction was seen in the subgroup with raised TG levels and low HDL-C levels[131] or in the total population of the FIELD trial, which included more than
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twice the number of women that were in ACCORD Lipid.[121] Other combination regimens including statins and fenofibrate have also shown some promise in patients with atherogenic dyslipidaemia. Adding fenofibrate to a statin plus ezetimibe further improved the lipid profile compared with a statin plus ezetimibe (section 4.2.2), and fenofibrate plus metformin resulted in better normalization of biochemical abnormalities than either agent alone (section 4.2.3). Fenofibrate is generally well tolerated in patients with dyslipidaemia (section 5). The most common adverse events include gastrointestinal signs and symptoms and increased transaminase levels, which are generally transient, minor and asymptomatic. Increases in creatinine levels, a class effect of fibrates, are also seen in fenofibrate recipients, although these increases resolve when treatment is discontinued indicating that fenofibrate is not likely to be associated with permanent renal injury (section 5).[183] Indeed, after long-term use (5 years) in the FIELD trial, fenofibrate was associated with beneficial renal effects (section 4.1.1). Creatinine should be monitored during the first 3 months of fibrate treatment and periodically thereafter, and transaminase levels should be monitored at 3-monthly intervals during the first 12 months of treatment and periodically thereafter.[10] Myopathy is the most serious potential adverse effect associated with fibrate monotherapy or combination therapy, but it is rare.[183] Patients who have predisposing factors for myopathy and/ or rhabdomyolysis (e.g. age >70 years, renal impairment, hypothyroidism, a personal or family history of hereditary muscular disorders, or high alcohol intake) may be at increased risk of rhabdomyolysis, and the benefits versus the risk of fenofibrate therapy should be carefully considered in such patients.[10] Although the risk of muscle toxicity may be increased if fibrates and statins are administered concomitantly, the risk appears higher with coadministration of gemfibrozil and a statin than with fenofibrate and a statin (section 5.2),[162] possibly reflecting differences between the pharmacokinetics of gemfibrozil and fenofibrate.[113,183,184] In ACCORD
Lipid, the combination of simvastatin plus fenofibrate was generally well tolerated over 5 years, with no significant difference between patients receiving fenofibrate plus simvastatin and those receiving placebo plus simvastatin in the incidence of serious myopathy, myositis or rhabdomyolysis (section 5.2). In conclusion, fenofibrate improves the lipid profile (particularly TG and HDL-C levels) in patients with dyslipidaemia. In the pivotal FIELD and ACCORD Lipid trials in patients with type 2 diabetes, fenofibrate monotherapy did not reduce the risk of CHD events to a greater extent than placebo, and fenofibrate plus simvastatin did not reduce the risk of major CV events to a greater extent than simvastatin plus placebo. However, the risk of some nonfatal macrovascular events and certain microvascular outcomes was reduced significantly more with fenofibrate than with placebo in the FIELD trial, and in the ACCORD Lipid trial, patients receiving fenofibrate plus simvastatin were less likely to experience progression of diabetic retinopathy than those receiving simvastatin plus placebo. Subgroup analyses in the FIELD and ACCORD Lipid trials suggest that fenofibrate is of the greatest benefit in decreasing cardiovascular events in patients with atherogenic dyslipidaemia. Fenofibrate is generally well tolerated when administered alone or in combination with a statin. Thus, in patients with dyslipidaemia, particularly atherogenic dyslipidaemia, fenofibrate is a useful treatment option either alone or in combination with a statin. Disclosure
The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the Adis authors on the basis of scientific and editorial merit.
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135. Keech AC, Mitchell P, Summanen PA, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007 Nov 17; 370 (9600): 1687-97 136. Rajamani K, Colman PG, Li LP, et al. Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial. Lancet 2009 May 23; 373 (9677): 1780-8 137. Simes J, Voysey M, OConnell R, et al. A novel method to adjust efficacy estimates for uptake of other active treatments in long-term clinical trials [published erratum appears in: PLoS One 2010; 5 (1)]. PLoS One 2010 Jan; 5 (1): e8580 138. Scott R, OBrien R, Fulcher G, et al. Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care 2009 Mar; 32 (3): 493-8 139. Burgess DC, Hunt D, Li L, et al. Incidence and predictors of silent myocardial infarction in type 2 diabetes and the effect of fenofibrate: an analysis from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Eur Heart J 2010 Jan; 31 (1): 92-9 140. Davis TME, Ting R, Best JD, et al. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetologia 2011; 54 (2): 280-90 141. Drury PL, Ting R, Zannino D, et al. Estimated glomerular filtration rate and albuminuria are independent predictors of cardiovascular events and death in type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetologia 2011 Jan; 54 (1): 32-43 142. Wi J, Kim J-Y, Park S, et al. Optimal pharmacologic approach to patients with hypertriglyceridemia and low highdensity lipoprotein-cholesterol: randomized comparison of fenofibrate 160 mg and niacin 1500 mg. Atherosclerosis 2010; 213 (1): 235-40 143. Ansquer JC, Foucher C, Rattier S, et al. Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study (DAIS). Am J Kidney Dis 2005 Mar; 45 (3): 485-93 144. Lovato LC, Elam MB, Byington RP, et al. Effect of feofibrate therapy on cardiovascular disease in men versus women with type 2 diabetes in the ACCORD-Lipid trial [abstract no. 20114]. American Heart Association Scientific Sessions; 2010 Nov 13-17; Chicago (IL) 145. Elam M, Lovato LC, Ginsberg H. Role of fibrates in cardiovascular disease prevention, the ACCORD-Lipid perspective. Curr Opin Lipidology 2011; 22 (1): 55-61 146. Derosa G, Cicero AE, Bertone G, et al. Comparison of fluvastatin + fenofibrate combination therapy and fluvastatin monotherapy in the treatment of combined hyperlipidemia, type 2 diabetes mellitus, and coronary heart disease: a 12-month, randomized, double-blind, controlled trial. Clin Ther 2004 Oct; 26 (10): 1599-607 147. Farnier M, Steinmetz A, Retterstol K, et al. Fixed-dose combination fenofibrate/pravastatin 160/40 mg versus simvastatin 20 mg monotherapy in adults with type 2 diabetes and mixed hyperlipidemia uncontrolled with
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Correspondence: Kate McKeage, Adis, a Wolters Kluwer Business, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand. E-mail: demail@adis.co.nz
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ERRATUM
Drugs 2011; 71 (14): 1820 0012-6667/11/0014-1820
Article Corrected Kontzias A, Efthimiou R. Adult-onset Stills disease: pathogenesis, clinical manifestations and therapeutic advances. Drugs 2008; 68 (3): 319-337 Corrections Made Page 324, table II, column 2, last row: The entry, which previously read: 6. Glycosylated ferritin 20% has now been corrected as follows: 6. Glycosylated ferritin <20% Note All online versions of this article have been updated to reflect this correction.

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Antiplatelet Therapy in Patients with Coronary Stents Undergoing Non-Cardiac Surgery

ATP = adenosine triphosphate.

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Antiplatelet Therapy in Patients with Coronary Stents Undergoing Non-Cardiac Surgery

Polymer-free stents Biodegradable stents

Antiplatelet Therapy in Patients with Coronary Stents Undergoing Non-Cardiac Surgery

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Neuraxial Morphine and Respiratory Depression

Neuraxial Morphine and Respiratory Depression

Neuraxial Morphine and Respiratory Depression

IV-PCA vs E 4 mg every 1624 h 3 vs IT 0.2 mg E 24 mg + PCEA vs IV-PCA IT 0.20.8 mg E 36 mg + infusion

General General General

2696 5969 245

Prospective Prospective Prospective

E bolus 2 mg with 0.05% bupivacaine + infusion IT 0.2 mg E 25 mg E 5 mg

856 4880 1000

Prospective Retrospective Prospective

0.9 0.25 0.4

Andrieu et al. (2009)[79]

Retropubic prostatectomy TAH Donor right hepatectomy Orthopaedics

Massicotte et al. (2009)[80] Ko et al. (2009)[81] Gehling et al. (2009)[82]

Yes Yes Yes

PSF CD Laminectomy Abdominal surgery THA CD

Naloxone requirement Not disclosed

Yes Yes Yes Yes Yes Yes

RR <10 RR <8 RR <10

Neuraxial Morphine and Respiratory Depression

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Neuraxial Morphine and Respiratory Depression

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Biomarkers of Therapeutic Response in Patients with Chronic Obstructive Pulmonary Disease

Yoon & Sin

Yoon & Sin

Yoon & Sin

Yoon & Sin

Pulmonary neutrophilic inflammation COPD, cystic fibrosis

Smoke; LPS; PM10 Alveolae

MCP-1 IL-8, IL-6 SP-D CC-16

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