Protocol for Oral Antiplatelet Therapy

Approved by the All Wales Medicine Strategy Group (AWMSG) on 12 August 2009 Clinical setting
Primary prevention of vascular events in high-risk groups

First line therapy

Aspirin 75mg daily provided blood pressure is controlled (< 145/90 mmHg) (1) A Cochrane review concluded that for primary prevention in patients with elevated blood pressure antiplatelet therapy with aspirin cannot be recommended since the magnitude of the benefit, reduced myocardial infarctions, is similar to the magnitude of harm, increased major haemorrhagic events (2) Further trials are in progress. High-risk groups are those with a 10 year CVD risk 20% and aged over 50 years, patients with diabetes 50 years of age, those who have had diabetes > 10 years and patients with diabetes who are receiving antihypertensive treatment(1) A recent trial found that aspirin was ineffective for the primary prevention of cardiovascular events in patients with diabetes and asymptomatic peripheral arterial disease. However studies with sufficient power are required to confirm these findings a small absolute benefit may remain a possibility.(3) Current evidence does not support the use of a combination of aspirin and clopidogrel. The CHARISMA study(4) concluded that in a high-risk population overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of MI, stroke or death from cardiovascular causes. Aspirin 300mg daily should be commenced within 48hours of ischaemic stroke and continued for at least 14 days(5). MR-Dipyridamole 200mg twice daily PLUS aspirin 75mg daily for a period of 2 years (based on 2 year trial evidence from the ESPS-2 study) from the most recent event. Thereafter, or if MR dipyridamole not tolerated, preventative therapy should revert to standard care (including long-term treatment with low dose aspirin 50325mg daily) (6) In practice, aspirin 75mg daily is generally used in the UK. The decision to continue or discontinue dipyridamole beyond 2 years should be made after appropriate assessment of risks and benefits on an individual basis. Note-NICE intends to conduct a review of TA 90. The ESPRIT trial (7) (aspirin versus combination aspirin and dipyridamole) where patients were followed for a mean of 3.5 years and the PRoFESS trial (8) (combination aspirin

Aspirin intolerance
No clinical evidence to support the use of other antiplatelet drugs for primary prevention and they are not licensed for this indication.

Acute ischaemic stroke/ Transient ischaemic attack (TIA) (NOT associated with atrial fibrillation)

Clopidogrel 75mg daily(6) evidence for its use in recurrent TIAs where resistance to aspirin is suspected is still awaited. SPC states: clopidogrel cannot be recommended in acute ischaemic stroke. Initiate from 7 days until less than six months after the ischaemic stroke.

Protocol for Oral Antiplatelet Therapy

and dipyridamole versus clopidogrel) have been published since the original appraisal. For patients intolerant to dipyridamole: Aspirin 75mg daily(6). There is no consensus on the best approach for patients who continue to have TIAs or have a further ischaemic stroke. Current evidence does not support the use of a combination of aspirin and clopidogrel (9) (or of MRdipyridamole alone, or standard-release dipyridamole aspirin). Such patients should be investigated fully for potential causes of further ischaemic strokes or TIAs. Peripheral arterial disease (symptomatic) Atrial fibrillation Aspirin 75mg daily(6) Warfarin is highly effective in the prevention of stroke in atrial fibrillation, with a 64% risk reduction compared with 22% for aspirin (10). However for patients at low-risk of stroke or thromboembolism (less than 65yrs of age with no moderate or high risk factors): Aspirin 75mg to 300mg daily (11) if no contraindications. Consider anticoagulation or aspirin in patients at moderate risk ( 65 years of age or older with no high risk factors or age less than 75 years with hypertension, diabetes or vascular disease) Consider aspirin for moderate or high risk patients who have contraindications to warfarin. No clinical evidence for the combination of clopidogrel and aspirin in preference to warfarin for the prevention of vascular events in patients with AF at high risk of stroke the ACTIVE-W study (12) was stopped early due to a significant difference in efficacy in favour of warfarin. For patients with rheumatic mitral valve disease not candidates for warfarin: Aspirin 75mg daily In combination with warfarin, for specific indications, according to the analysis of the benefit and the increased risk of major bleeding (13). Aspirin(14) 75mg daily commonly prescribed There is no evidence to support the long-term use of antiplatelet agents in patients with a bioprosthesis who do not have an indication other than the presence of the bioprosthesis itself. (14) In people who are at moderate to high risk of MI or death: With or without PCI: Initially 300mg clopidogrel and 150mg (-325mg) aspirin as stat doses then, clopidogrel 75mg daily PLUS aspirin 75-325mg daily for up to twelve months after the most recent episode of NSTEMI ACS, thereafter aspirin 75-325mg daily(15) unless there are other indications to continue dual antiplatelet therapy.(N.B. Aspirin 75mg daily is generally used in UK) Initiate, during the first 24 hours after the MI ,clopidogrel 300mg stat (in patients less than 75 years of age) and then 75mg daily in combination with aspirin 300mg stat and then 75mg daily and continue for at least four weeks
(16)

Clopidogrel 75mg daily

(6).

No clinical evidence to support the use of other antiplatelet drugs for primary prevention and they are not licensed for this indication.

Valve disease Valve surgery

MR-Dipyridamole 200mg twice daily

Acute coronary syndromes (ACS) without persistent STsegment elevation (NSTEMI)

Clopidogrel monotherapy should be considered as an alternative treatment.

ST elevation MI (STEMI)

Clopidogrel monotherapy should be considered as an alternative treatment.

Page 2 of 10

Protocol for Oral Antiplatelet Therapy

Thereafter, standard treatment including low-dose aspirin should be given, unless there are other indications to continue dual antiplatelet therapy e.g. coronary stenting
(17).

For patients intolerant to clopidogrel and have a low risk of bleeding, treatment with aspirin and moderate-intensity warfarin (INR 23) combined should be considered (17) see information on page 4 on co-prescribing Post-CABG Aspirin 300mg daily for first 12 months then aspirin (75325mg) daily continued indefinitely (18)

For patients unable to tolerate either aspirin or clopidogrel, treatment with moderate-intensity warfarin (INR 23) should be considered for up to four years, and possibly longer(17). Clopidogrel 75mg daily (19) (OFF LABEL use)

Post-carotid endarterectomy Elective PCI (without recent acute coronary syndrome) NOTE: Do not discontinue combination early except in exceptional circumstances.

Aspirin 75mg daily continued indefinitely Both types of stent (Bare Metal and Drug Eluting) require the use of an antiplatelet drug in addition to aspirin (20): Bare Metal Stent (BMS) Aspirin (75mg - 300mg daily for one month then 75mg daily (lifelong) PLUS clopidogrel 300mg stat at least 6 hours before PCI then 75mg daily for one month. (if patient has bare metal stent and NSTEMI ACS then the latter takes precedence i.e. patient will be on clopidogrel for twelve months) Drug Eluting Stent (DES) Aspirin 300mg daily for one month reducing to 75mg daily thereafter (lifelong) PLUS clopidogrel 300mg stat at least 6 hours before PCI then 75mg daily for twelve months.(see part review of NICE TAG 71 (Final appraisal determination) Dosage and duration of antiplatelet therapy may vary amongst interventional cardiologists depending on complexity of coronary intervention/type of stents patients will have detailed instructions as to recommendations. Antiplatelet therapy should not be stopped earlier than recommended (particularly with DESs) without discussing the case with a cardiologist first.

There is little evidence to support advice on how best to manage patients who have both AF and a DES who also require anticoagulation (21) All existing patients with a history of prior stroke/TIA, MI and those with chronic stable angina should be on aspirin 75mg daily, as a minimum, unless contraindicated.

Prescribing points
Aspirin For full prescribing information consult the Summary of Product Characteristics (SmPC).

Page 3 of 10

Protocol for Oral Antiplatelet Therapy

Aspirin intolerance is defined by NICE as either: a proven hypersensitivity to aspirin-containing medicines or a history of severe dyspepsia caused by low-dose aspirin (6). Intolerance to antiplatelet doses of aspirin can take many forms, but four types of reaction are commonly cited: Gastrointestinal (GI), haemorrhage, allergy and bronchospasm. For patients experiencing gastrointestinal symptoms with aspirin: Ensure 75mg dose is being taken and that medication is taken with food. Consider co-prescribing a proton pump inhibitor (PPI) e.g. lansoprazole 15mg or omeprazole 20mg daily (check outcome) Evidence from two studies supports this approach: The combination of aspirin (80mg daily) plus esomeprazole (20mg twice daily) (n=159) was superior to clopidogrel (75mg daily) (n=161) in preventing recurrent ulcer bleeding at 12 months (22). Patients with aspirin- induced peptic ulcer (low to moderate risk of bleeding or rebleeding) were randomised to either a combination of aspirin 100mg plus omeprazole 20mg daily or a combination of clopidogrel 75mg plus omeprazole 20mg daily with no difference in GI outcomes at eight weeks (23). Summary of contra-indications/special precautions that apply to clopidogrel and aspirin: Active pathological bleeding (e.g. peptic ulceration) History of peptic/duodenal ulcer Clotting/bleeding disorders (e.g. haemophilia) Aspirin allergy (e.g. rash) History of asthma Under 16 years old Breast-feeding Use aspirin? No Recent studies(22,23) suggest use cautiously with PPI No No Caution No No Use clopidogrel? No Caution - patients should be followed carefully for any signs of bleeding Caution - patients should be followed carefully for any signs of bleeding Yes - note rash still seen with clopidogrel (uncommon >1/1,000, <1/100) Yes Unlicensed in children and adolescents No

Recurrent vascular events in patients taking aspirin have many possible causes (24). Prescribers should be aware of the potential for ibuprofen to reduce the effectiveness of aspirin, although the evidence from observational studies does not yet confirm a clinically important effect. Consideration can be given to taking the aspirin and ibuprofen at different times of the day(25)

Aspirin and warfarin in combination For patients already on aspirin commencing warfarin for atrial fibrillation:

Page 4 of 10

Protocol for Oral Antiplatelet Therapy

Start low dose warfarin and stop aspirin at the same time (the advice to GP to stop aspirin once INR reaches 2 is considered probably unnecessary and may risk inadvertent coprescribing in Primary Care) Patients admitted to secondary care on aspirin for AF generally stay on aspirin until the INR is therapeutic.

For patients with recent coronary events with an additional indication for long-term anticoagulation: The decision to co-prescribe aspirin and warfarin will depend on the perceived risk of future coronary events according to non-invasive +/- angiography data by the physician in Secondary Care. Combination therapy was associated with a significant reduction in the combined risk of death, non-fatal MI or thromboembolic stroke in the WARIS II study (26). Rate ratio as compared with aspirin = 0.71 (95% CI, 0.60 to 0.83; P=0.001). Patients with recent coronary events with an additional indication for long-term anticoagulation (e.g. AF, previous DVT or prosthetic heart valve) will be likely candidates. Patients should be counselled at initiation on the increased risk of bleeding. Consideration should be given to prescribing a prophylactic PPI. Clopidogrel (Plavix) For full prescribing information consult the Summary of Product Characteristics (SmPC) (16). Indications: The prevention of atherothrombotic events in: Patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease. Patients suffering from non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction) including patients undergoing a stent placement following percutaneous coronary intervention in combination with aspirin 75mg daily. -ST segment elevation acute MI in combination with aspirin in medically treated patients eligible for thrombolytic therapy. The indication and duration of clopidogrel should be clearly recorded and, where relevant, communicated between secondary and primary care. The duration of treatment of clopidogrel should be documented and flagged on GP clinical system for patients with unstable angina/ACS or stents. Patients should be advised to inform other practitioners/prescribers that they are taking clopidogrel. For elective surgical/dental procedures, in which an antiplatelet effect is not required clopidogrel should be discontinued 7 days before surgery.

Is clopidogrel safer/better tolerated than aspirin? In the CAPRIE study (27) clopidogrel was compared head-to-head with aspirin. Although all reported GI haemorrhage was less common with clopidogrel (1.99% vs. 2.66%, P < 0.05) the dose of aspirin used was 325mg daily. Severe rash was more common with clopidogrel (0.26% vs. 0.1%, P = 0.017) than with aspirin although one of the trials exclusion criteria was a history of aspirin sensitivity. Yellow Card submissions for suspected adverse reactions for clopidogrel (to the MHRA up to November 2008) indicate that GI haemorrhage is the most frequently reported event. Rash, pruritis and urticaria have also been commonly reported (see
Page 5 of 10

Adverse event GI haemorrhage Contusion/brusiin g Haematemesis Rash Pruritis Urticaria

No. 100 97 83 71 74 66

Protocol for Oral Antiplatelet Therapy

table at right). Haematological effects have also been reported; most notably neutropenia and thrombocytopenia (32 and 45 reports respectively). Current evidence does not support using clopidogrel in combination with a PPI. There have also been preliminary reports, currently being investigated by the manufacturers, that PPIs may make clopidogrel less effective (28) The following advice was issued recently from MHRA and CHM (29) Review the need for PPI therapy in patients who are also taking clopidogrel and avoid concomitant use of these medicines unless considered essential. Prescribe PPIs in line with their licensed indications wherever possible. Consider whether another gastrointestinal therapy would be more suitable Check whether patients who are taking clopidogrel are buying over-the-counter omeprazole. Is the combination of aspirin and clopidogrel safe? Results from the CLARITY-TIMI 28 and COMMIT studies suggest that short-term concomitant use (up to 16 days) is not associated with an increase in bleeding complications. However, three longer-term studies (CURE (30), MATCH (9), and CHARISMA (4)) found statistically significant increases in bleeding associated with the combination of clopidogrel plus aspirin (compared to either clopidogrel or aspirin used alone): Trial MATCH CURE CHARISMA Event Life-threatening bleed Major bleeding Moderate bleeding Rate with Clopidogrel +Aspirin 2.6% 3.7% 2.1% Rate with Aspirin alone Rate with Clopidogrel alone 1.3% P value <0.0001 0.001 <0.001

2.7% 1.3%

Patients taking aspirin and clopidogrel should be advised of the risks. When co-prescribed with clopidogrel, the total daily dose of aspirin should not exceed 100mg.

Dipyridamole 200mg M/R (Persantin Retard) For full prescribing information consult the Summary of Product Characteristics (SmPC) Indication: Secondary prevention of ischaemic stroke and transient ischaemic attacks either alone or in conjunction with aspirin. (NOTE the 25mg and 100mg preparations of dipyridamole do not have this indication although Asasantin does) An adjunct to oral anti-coagulation for prophylaxis of thromboembolism associated with prosthetic heart valves. The only contraindication to Persantin Retard is hypersensitivity to any of its constituents. It should be used with caution in patients with bleeding disorders.

Page 6 of 10

Protocol for Oral Antiplatelet Therapy

In the large (n = 6602) European Stroke Prevention Study(31) found that bleeding episodes (any site) were significantly more frequent in the MR-dipyridamole plus aspirin (8.7%) and the aspirin alone (8.2%) groups compared with the MR-dipyridamole alone (4.7%) and placebo (4.2%) groups. As an indication of frequency of adverse events with dipyridamole (all preparations including Asasantin) the table below lists the Yellow Card submissions for suspected adverse reactions to the MHRA up to November 2008) in order of frequency: Adverse event Headache Diarrhoea Dizziness Rash Vomiting No. 142 50 48 33 39

Dipyridamole acts as a potent vasodilator. It should therefore be used with caution in patients with severe coronary artery disease including unstable angina and/or recent MI, left ventricular outflow obstruction or haemodynamic instability (e.g. decompensated heart failure). Peri-operative management of anti-platelets Although some surgery can be completed without suspension of clopidogrel, most surgeons would prefer a 5-7 day dose-free period prior to any elective surgery. The SPC for clopidogrel states that if a patient is to undergo elective surgery and antiplatelet effect is not necessary,clopidogrel should be discontinued 7 days prior to surgery. However it is extremely important that due consideration is given to the indication for clopidogrel and aspirin use. Decisions on when to stop antiplatelets are needed on a caseby-case basis based on patient-and procedure-related risk factors for thrombosis and bleeding, weighing up anti-platelet indications (e.g. primary prevention, high or low risk secondary prevention) against timing and type of surgery(32). If given for primary prevention of cardiovascular disease aspirin can generally be discontinued 10 days before surgery and clopidogrel can be discontinued 7 days before surgery (32) . Serious thrombotic risks are associated with the discontinuation of these agents when used as secondary prevention of vascular disease or after coronary revascularisation(32). Patients requiring elective surgery and who are receiving dual antiplatelet therapy should ideally, have surgery postponed until the recommended duration of clopidogrel is finished. If such a delay is unacceptable the cardiologist, the surgeon and the anaesthetist should consider the balance of perioperative risk (for example stent thrombosis) compared with the possibility of increased surgical bleeding related to the procedure.

Page 7 of 10

Protocol for Oral Antiplatelet Therapy

Relative costs of oral antiplatelet therapy

Primary care costs of 28 days treatment with oral antiplatlets (Drug Tariff July 2009)
Aspirin disp 75mg od Aspirin disp 75mg od and omeprazole 20mg od Aspirin disp 75mg od and dipyridamole MR 200mg bd Aspirin disp 75mg od and omeprazole 20mg bd Clopidogrel 75mg od 0 5 10 15 20 Value() 25 30 4.3 33.92 35 40 0.82 2.56 7.82

Page 8 of 10

Protocol for Oral Antiplatelet Therapy

References: 1. National Library for Health. Available at: www.cks.library.nhs.uk/antiplatelet treatment (accessed 11/03/09) 2. Lip GYH, Felmeden DC. Antiplatelet agents and anticoagulants for hypertension. Cochrane Database of Systematic Reviews 2004, Issue 3. 10.1002/14651858.CD003186.pub2. 3. Belch Je t al The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo-controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 2008;337:a1840. 4. Bhatt DL et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events (CHARISMA study) New Engl J Med 2006;354:17061717 5. Anon. Management of patients with stroke or TIA SIGN 2008 Guideline No 108 6. Anon. Clopidogrel and modified-release dipyridamole in the prevention of occlusive vascular events. NICE Technology Appraisal90 May 2005 www.nice.org.uk/Guidance/TA90 Note NICE is currently conducting a review of TA 90 7. The ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. The Lancet 2006;367:1665-1673. 8. Sacco RL et al (for the PRoFESS Study Group) Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Eng J Med 2008: 359:1238-1251 9. Diener H-C et al (the MATCH Investigators). Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high risk patients (MATCH):randomised, double-blind, placebo-controlled trial. Lancet 2004;364:331337 10. Hart RG et al. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857-867. 11. Anon 2006 NICE Clinical Guideline 36 Atrial fibrillation. 2006 (http://www.nice.org.uk/guidance/CG36) 12. Connolly S et al Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. The ACTIVE Investigators. Lancet 2006; 367: 1903-1912. 13. Vahanian A et al (The Task Force on the Management of Valvular Heart Disease of the European Society Cardiology) Eur Heart J 2007;. 28: 230-268. 14. Little SH, Massel DR. Antiplatelet and anticoagulation for patients with prosthetic heart valves. Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No.: CD003464. DOI: 10.1002/14651858.CD003464. 15. Anon. NICE TA080 Clopidogrel in the treatment of non-ST-segment-elevation acute coronary syndrome. NICE Technology Appraisal 80 July 2004 (http://www.nice.org.uk/guidance/TA80) 16. Plavix. Summary of product characteristics (www.emc meds.org.uk)-last updated 28/09/07 17. Anon. NICE CG048 MI: secondary prevention. NICE Clinical Guideline 48 May 2007 18.Lim E et al. Indirect comparison meta- analysis of aspirin therapy after coronary surgery. BMJ ;327:1309-1313. 19.Bhatt DL et al. Superiority of clopidogrel versus aspirin in patients with prior cardiac surgery Circulation 2001;103:363-368. 20. Anon. Drug-eluting stents for the treatment of coronary artery disease NICE Technology Appraisal 71 2003NICE TA071 Ischaemic heart disease - coronary artery stents. 2003. Note NICE is currently conducting a part review of TA71. (http://www.nice.org.uk/guidance/TA71)

Page 9 of 10

Protocol for Oral Antiplatelet Therapy

21.Silber S et al. ESC Guidelines for Percutaneous Coronary Interventions. European Heart Journal 2005 http://www.bcis.org.uk/resources/documents/esc_pci2005.pdf) 22. Chan FKL et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding N Engl J Med 2005;352:238-244. 23. Ng FH et al. Clopidogrel plus omeprazole compared with aspirin plus omeprazole for aspirininduced symptomatic peptic ulcers / erosions with low to moderate bleeding / re-bleeding risk a single-blind, randomized controlled study. Alimentary Pharmacology and Therapeutics 2004; 19(3): 359365. 24. Hankey, GJ Eikelboom JW Aspirin resistance BMJ 2004;328:477-479 25. Anon. Cardiovascular and gastrointestinal safety of NSAIDs .MeReC Extra Issue 2008: No 30:1-6 26.Hurlen M et al. Warfarin, aspirin or both after myocardial infarction N Engl J Med 2002;347:969-974. 27.CAPRIE Steering Committee. A randomised ,blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) Lancet 1996;348:1329-1339 28. Anon NPCi Blog. FDA investigates possible safety concerns over clopidogrel http://www.npci.org.uk/blog/?p=271 29.Anon. Clopidogrel and proton pump inhibitors: interaction. Drug Safety Update 2009:2(12)2-3 30.The CURE Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502. 31. Diener H-C et al. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. (ESPS-2) J Neurol Sci 1996;142:1-13. 32. Thachil J et al Management of surgical patients receiving anticoagulation and antiplatelet agents. British Journal of Surgery 2008 ;95 :1437-1448 Further Information MeReC Bulletin Volume 15, Number 6 (July 2005) Prescribing antiplatelet drugs in primary care. http://www.npc.co.uk/MeReC_Bulletins/2004Volumes/Vol15no6.pdf WeMeReC Bulletin Volume 11, Number 1 (February 2004) Prescribing clopidogrel. http://www.wemerec.org/Documents/bulletins/14clpdgl.pdf MeReC Bulletin Volume 14, Number 2 (August 2003) Antiplatelet agents for stroke patients. http://www.npc.co.uk/MeReC_Bulletins/2003Volumes/Vol14no2.pdf Update: National Clinical Guidelines for Stroke , 3rd edition , RCP, & Clinical Effectiveness and Evaluation Unit . Page 67

The All Wales Prescribing Advisory Group (AWPAG) wish to acknowledge the contribution of Jonathan Simms, Stuart Evans, Trevor Batt and Robert McArtney in the development of this document.

Page 10 of 10