Antiplatelet Drugs

Pharmacology & Therapeutics 127 (2010) 95107
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Pharmacology & Therapeutics

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p h a r m t h e r a
Current strategies in antiplatelet therapy Does identication of risk and adjustment of therapy contribute to more effective, personalized medicine in cardiovascular disease?
Tobias Geisler a,b,, Meinrad Gawaz b, Steven R. Steinhubl c, Deepak L. Bhatt d, Robert F. Storey e, Marcus Flather a
a
Clinical Trials and Evaluation Unit, Royal Brompton and Hareeld NHS Foundation Trust, Sydney Street, London SW3 6NP, United Kingdom Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Universittsklinikum der Eberhard-Karls-Universitt Tbingen, Tbingen, Germany c The Medicines Company, 8058 Zurich-Flughafen, Switzerland and the Geisinger Clinic, Danville, PA, USA d VA Boston Healthcare System, Brigham and Women's Hospital, and Harvard Medical School, Boston, USA e Department of Cardiovascular Science, University of Shefeld, Shefeld, United Kingdom
b
a r t i c l e
i n f o
a b s t r a c t
There is a wide consensus that intensied antiplatelet therapy contributes to the reduction of major atherothrombotic complications in cardiovascular (CV) disease. In the setting of PCI (percutaneous coronary intervention) and acute coronary syndromes, dual antiplatelet therapy at optimal dosing and timing has signicantly lowered the risk of thrombotic complications. There is a growing body of evidence that there is variability in response to antiplatelet treatments and this represents a potentially important clinical problem. Understanding the mechanisms underlying this phenomenon is important in improving patient care, but due to the diversity of factors involved, a clear predictive model for responsiveness to antiplatelet therapy is still missing. Attempts have been made to characterize the efcacy of antiplatelet therapy using platelet function testing but based on current information, its routine use is not recommended particularly as costs and cost effectiveness have not been established and agreement between laboratory methods is lacking. Hence, it is necessary to identify risk factors for decreased efcacy of standard antiplatelet drug treatment. It may be useful to adjust antiplatelet therapy based on individual risk assessment, especially as new platelet inhibitors are being introduced or are in development including prasugrel as well as the non-thienopyridines, ticagrelor, elinogrel, the ATP analog cangrelor, and thrombin receptor antagonists. This article focuses on antiplatelet therapy in patients at high risk for cardiovascular events and discusses the options for individual risk assessment and strategies to personalize therapy in the light of the large number of recent developments. 2010 Elsevier Inc. All rights reserved.
Keywords: Antiplatelet therapy Platelets Drugs Cardiovascular disease Percutaneous coronary intervention
Contents 1. 2. 3. 4. 5. 6. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antiplatelet treatment in different risk groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . Identication of optimal timing of clopidogrel cessation dependent on individual risk . . . . . . . . . . Evidence for variability in platelet responsiveness limitations for one-size-ts-all antiplatelet approach How can new treatments change current practise efcacy and safety of novel antiplatelet substances . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 . 96 . 96 . 96 97 . 101 96 . 104 97
Abbreviations: ACC, American College of Cardiology; ACS, Acute Coronary Syndrome; ADP, Adenosine Diphosphate; AHA, American Heart Association; ASA, Acetylic Salicylic Acid; ATP, Adenosine Triphosphate; AUC, Area Under the Curve; BMS, Bare Metal Stent; CAD, Coronary Artery Disease; COX1, Cyclooxygenase-1; CV, Cardiovascular; CYP, Cytochrome P450; DES, Drug Eluting Stent; ESC, European Society of Cardiology; GWAS, Genome Wide Association Studies; GPIIb/IIIa, Glycoprotein IIb/IIIa; LTA, Light Transmittance Aggregometry; MEA, Multiple Electrode Aggregometry; NSAIDS, Nonsteroidal Antiinammatory Drugs; NSTE-ACS, Non ST elevation ACS; NSTEMI, Non ST elevation Myocardial Infarction; NICE, National Institute of Health and Clinical Excellence; PCI, Percutaneous Coronary Intervention; PAR, Protease activated receptor; PFA-100, Platelet Function Analyser100; PRU, Platelet Reactivity Units; RPA, Residual Platelet Aggregation; STEMI, ST Elevation Myocardial Infarction. Corresponding author. Clinical Trials and Evaluation Unit, Royal Brompton and Hareeld NHS Foundation Trust, Sydney Street, London SW3 6NP, United Kingdom. Tel.: +44 207 351 8866; fax: +44 207 351 8829. E-mail address: t.geisler@rbht.nhs.uk (T. Geisler). 0163-7258/$ see front matter 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.pharmthera.2010.04.017
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T. Geisler et al. / Pharmacology & Therapeutics 127 (2010) 95107
Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 97 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 98
1. Introduction There is a progressive shift towards questioning the one-size-tsall concept of antiplatelet therapy for secondary prophylaxis in cardiovascular (CV) disease. This is due to the following major issues: 1. Increasing information exists that there are some patient subgroups in whom the efcacy of dual antiplatelet therapy does not meet expectations. 2. Monitoring of antiplatelet drug responsiveness has gained attention and a link between the observed variability of responsiveness to antiplatelet agents and adverse cardiovascular outcome has been established. Prompted by this guidelines allow for the consideration of the use of platelet function testing in patients at high risk for stent thrombosis. Although previous studies generally support that drug efcacy might be inuenced by a broad interindividual response variability affected by several mechanisms, monitoring of platelet function has certain limits to its integration into routine therapeutic decision making. In particular, there is no consensus regarding the most appropriate cut-off value for any one single method to predict major CV risk and there is only a moderate correlation between different assays. 3. The use of percutaneous coronary interventions has increased throughout the last several years. Additionally, the overall risk of interventionally treated cardiovascular patients has signicantly changed and with this the risk for stent thrombosis and major ischemic events after PCI. Thus, more intensied antiplatelet and antithrombotic regimens are needed, but with them comes the potential costs of increased bleeding rates. A careful weighing of benets and risk is therefore warranted to improve the individual net outcome.
2. Antiplatelet treatment in different risk groups 2.1. Dual antiplatelet therapy for primary and secondary prevention in patients without recent PCI There was no benet of dual antiplatelet therapy with clopidogrel and aspirin over aspirin alone in the primary prevention cohort of the CHARISMA trial, and subgroup analysis revealed a higher mortality and bleeding risk with the addition of clopidogrel to aspirin therapy in asymptomatic patients (Bhatt et al., 2006; Wang et al., 2007). The CHARISMA primary prevention cohort also comprised a high percentage of diabetics. Thus, for the moment there is no evidence for a benet of dual antiplatelet therapy in diabetics for primary prevention. However, there was a signicant effect on risk reduction for recurrent cardiovascular events in the subgroup of patients with established cardiovascular disease enrolled in the CHARISMA study (Bhatt et al., 2007). These results suggest that appropriate patients with established cardiovascular disease might benet from a more aggressive antiplatelet regimen for chronic treatment. This may be the addition of clopidogrel to aspirin as demonstrated in the symptomatic cohort of patients from CHARISMA or even clopidogrel alone instead of aspirin as shown in the CAPRIE trial (reference) (CAPRIE Steering Committee, 1996), or the use of new antiplatelet agents either instead of or in combination with aspirin for long-term protection. 2.2. Antiplatelet therapy in PCI Long-term dual antiplatelet therapy as well as sufcient pretreatment with clopidogrel has been shown to reduce subsequent
cardiovascular events after PCI (Mehta et al., 2001; Steinhubl et al., 2002). Current guidelines advocate a dual antiplatelet therapy with aspirin and clopidogrel for up to 12 months depending on type of stent and acuity of disease and favour continuation beyond this time period according to individual risk assessment (King et al., 2008). More rapid acting and reversible novel antiplatelet substances might show particular advantage in the setting of acute coronary syndromes (ACS). There has been no discussion in the use of GPIIbIIIa inhibitors which are a mainstream class of anti-platelet therapy used in ACS and PCI patients. The rationale for general peri-procedural administration of glycoprotein (GP) IIb/IIIa inhibitors in the era of high dose thienopyridines has been called into question by the results of some trials. In the ISAR-REACT 2 trial the benet of peri-interventional GP inhibition with abciximab was restricted to higher risk non-ST-elevation ACS patients presenting with signicant elevation of cardiac markers (Kastrati et al., 2006). Additionally, GPI treatment showed a benet mainly in patients with ACS undergoing PCI (Rof et al., 2002) rather than in conservatively treated patients (Simoons et al., 2001). Thus the current practice guidelines provide support for the use of GPIIb/IIIa inhibitors in addition to aspirin and heparin rather than aspirin and heparin alone in high risk ACS patients undergoing PCI. The bleeding risk of this combination is particularly noteworthy and the net clinical benet of heparin and GPI treatment has been shown to be lower compared to single treatment with the direct thrombin inhibitor bivalirudin in high risk non-ST elevation ACS and STEMI patients undergoing primary PCI (Stone et al., 2006, 2008). Optimal timing of GPI administration is a further issue to be resolved. Recent studies have evaluated the benets of pre-hospital and pre-angiography administration of GPIIb/IIIa-inhibitors. The ON-TIME 2 (Ongoing Tiroban in Myocardial Infarction Evaluation) study evaluated the effects of early provisional treatment with tiroban given to STEMI patients in the ambulance. As results, high-bolus dose tiroban was associated with increased ST-segment resolution and better clinical outcome after PCI (Van't Hof et al., 2008) According to the results of the FINESSE, EARLY-ACS and ACUITY-timing trials there is currently no evidence of a benet of upstream GPIIb/IIIa antagonism in NSTE-ACS patients who receive guideline adherent treatment, before the coronary anatomy is known and a decision upon PCI is made (Ellis et al., 2004; Ellis, 2007; Stone et al., 2007; Giugliano et al., 2009).
3. Identication of optimal timing of clopidogrel cessation dependent on individual risk Duration of treatment with dual antiplatelet therapy (aspirin and a thienopyridine) is frequently determined by the perceived individual risk for stent thrombosis. The critical role of maintaining adequate durations of dual antiplatelet therapy is highlighted by the large number of studies identifying premature discontinuation of antiplatelet therapy as a major driver for stent thrombosis. Compared with bare-metal stents (BMS), drug-eluting stents (DES) result in markedly reduced neointima formation and late lumen loss but also in delayed endothelialisation and increased inammation which might prolong the window of susceptibility to stent thrombosis (Joner et al., 2006). Thus, the FDA along with the American Heart Association/ American College of Cardiology (AHA/ACC) recently updated PCI guidelines and empirically recommended the use of clopidogrel for at least 12 months in patients without increased bleeding risk, on a Class I, Level of Evidence B indication. Clopidogrel use beyond 1 year was conferred a Class IIb, Level of Evidence C indication. There does appear to be an important relationship between the duration of dual
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antiplatelet therapy, cessation of an antiplatelet agent and stent thrombosis. In an analysis of 3021 PCI patients treated with DES, the highest stent thrombosis rate was found in patients taking dual antiplatelet medication for less than 6 months with the thrombotic event occurring within a median of 13.5 days (IQR 4.2 to 25.7 days) after discontinuation of thienopyridine treatment (Airoldi et al., 2007). These results were mostly inuenced by the occurrence of early stent thrombosis in patients prematurely stopping clopidogrel. The occurrence of late and very late DES thrombosis is less related to the transition from dual to single antiplatelet therapy (Eisenberg et al., 2009). The possibility of a clopidogrel rebound effect has been suggested in some clinical studies and studies involving platelet function testing. Rebound describes a transitory reverse effect on platelet function resulting in platelet hyper-aggregability and increased thrombotic risk after cessation of the drug. A prothrombotic rebound was discussed previously after cessation of thrombin inhibitors (Gold et al., 1993). There is no evidence of a classical rebound after discontinuation of GPIIb/IIIa antagonists (Lauer et al., 2001), however prothrombotic effects under therapy were described due to partial agonism and integrin receptor clustering induced activation (Peter et al., 1998; Cox et al., 2000). Concerning clopidogrel one study suggested a possible clinical effect of a rebound phenomenon by the observation that the majority of PCI-patients developed recurrent CV-events after a short term period i.e. less than 90 days after discontinuation of dual antiplatelet therapy (Ho et al., 2008). On the other hand in a subgroup analysis of the CHARISMA trial there was no adverse effect of study drug withdrawal in patients randomized to clopidogrel compared to those randomized to placebo in patients with established cardiovascular disease. The ndings suggest that a possible effect might only be relevant in patients with high risk coronary artery disease (e.g. PCI in the short term) (Collet et al., 2009a). Some authors suggest that a possible rebound effect might become relevant in patients with high platelet reactivity to aspirin treatment and in different subgroups of patients with increased platelet turnover (like diabetics) (Angiolillo et al., 2006; Lordkipanidz et al., 2009). The ONSET/OFFSET trial did not demonstrate a classical rebound effect within 10 days after stopping clopidogrel 75 mg/day (Gurbel et al., 2009a). Nor did the ISAR-CAUTION trial identify rebound as measured by two different platelet function tests (Sibbing et al., 2010c). In conclusion, although one observational clinical study did suggest a clinical rebound, this nding has been unable to be duplicated clinically or mechanistically suggesting that rebound is unlikely to be a real phenomenon in the early period after clopidogrel discontinuation in PCI-patients.
4. Evidence for variability in platelet responsiveness limitations for one-size-ts-all antiplatelet approach 4.1. Methods to assess platelet responsiveness There have been tremendous efforts to characterize antiplatelet drug effects with the help of platelet function tests. These tests use different principles: most common are the agonist induced assays that try to simulate a certain platelet activating pathway which ideally is blocked by a platelet inhibitor affecting that particular pathway (Table 1). A few of the tests have been evaluated for bedside, point-ofcare use. Nearly all tests are able to detect the activity of oral platelet inhibitors compared to untreated healthy controls and they all demonstrate variability in residual platelet aggregability and activation in treated patients (Fig. 1). Response to aspirin is generally adequate when using assays specic for COX1 activity (e.g. arachidonic induced platelet aggregation, enzyme-linked immunoassays determining stable metabolites of thromboxane A2 in serum and urine). Thus aspirin low-response often refers to results from non-specic assays of platelet reactivity (e.g. ADP- and collagen-induced platelet aggregation, platelet function analyser (PFA)-100). On the other hand, variability of clopidogrel response is a better dened phenomenon related to level of P2Y12 receptor blockade, which in turn is mainly dependent on active metabolite levels. Recently the terminology non-, low or poor response has emerged to describe efcacy of aspirin and clopidogrel and has appropriately replaced the absolute term of resistance. When talking about response, one has to differentiate between failure of the drug to show laboratory or clinical effects. In past literature non-response to clopidogrel has been reported with a prevalence of 530% and for aspirin up to a prevalence of 60% depending on the disease setting (i.e. stable cardiovascular disease, ACS, stroke, diabetes). Several mechanisms have been considered that inuence drug efcacy (Table 2). Some tests (light transmittance aggregometry, Multiplate, VerifyNow) have reproducibly demonstrated the ability to predict recurrent atherothrombotic events including stent thrombosis in clopidogreltreated patients (Gurbel et al., 2005; Geisler et al., 2006; Hochholzer et al., 2006; Sibbing et al., 2010a) and adjustment of drug dosage based on platelet function testing has become more common in clinical practise in specialized centres, although the clinical data supporting this are extremely limited (Depta et al., 2009). An important limitation to the interpretation of the many studies is the overall
Table 1 Overview of available platelet function tests. Test Turbidometry/light-transmittance aggregometry (LTA) Principle of method, measured parameter % platelet-aggregation (maximum, nal), Inhibition of aggregation Flow cytometry, measurement of platelet reactivity index (PRI): difference between PGE1 und PGE1 +ADP induced VASP-P concentration Area under the aggregation curve (AUC) Turbidimetric method using Microbead agglutination P2Y12 Reaction Units Aspirin Reaction Units Platelet activation Units (Iso-TRAP as activator) Quantitative measurement of Agonist-induced platelet activation by cell counting Quantication of clot strength after agonists stimulation or addition of antiplatelet substances Whole blood assay, allowing for platelet aggregation under physiological shear stress condition Sensitivity for antiplalelet substances Aspirin (agonists: arachidonic acid, collagen, epinephrine), clopidogrel (agonist: ADP, ADP/PGE1); other agonists (e.g. TRAP, TXA2) Clopidogrel
Vasodilator-stimulated phosphoprotein (VASP) assay Impedance aggregometry (Multiplate Analyzer, Dynabyte, Munich) VerifyNow (Accumetrics Inc, San Diego) P2Y12 assay Aspirin assay GPIIb/IIIa assay Plateletworks (Helena Labs; Beaumont, Texas) Thrombelastogram (Haemoscope Corporation, Niles, Illinois) Impact Cone and Plate(let) Analyzer (DiaMed, Cressier, Switzerland )
Aspirin, clopidogrel, GPIIb/IIIa Inhibitors
Clopidogrel Aspirin GPIIbIIIa inhibitors Aspirin, clopidogrel, GPIIb/IIIa inhibitors Aspirin, clopidogrel, GPIIb/IIIa Inhibitors Aspirin, clopidogrel monitoring of platelet function disorders
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Fig. 1. Variability in clopidogrel responsiveness in a population of 544 patients as determined by changes in maximal ADP-induced aggregation before and after clopidogrel therapy. A high inter-individual variability almost conforming to normal distribution was observed.
agreement between the various methods, thus making a comparison of results difcult (Lordkipanidz et al., 2008). Platelet aggregation studies performed in whole blood (WB) are considered to have technical qualitative advantages over those done in platelet-rich plasma (PRP) due to a smaller blood volume requirement, minimal sample manipulation and inclusion of physiological blood compounds contributing to platelet activation and aggregation.
about the optimal cut-off value of platelet inhibition for identifying patients at high thrombotic risk and the important relationship between measured results and bleeding risk need further investigation. In this context, the correlation between platelet function and major bleeding events is not entirely clear (Sibbing et al., 2009a; Serebruany et al., 2010). Another major drawback of the majority of available platelet function assays (e.g. agonist-induced aggregation and ow cytometry) is based on the non-physiological, static principle of measuring platelet function not taking into account the effects of shear stress and platelet/endothelial interaction. In the past, ex-vivo platelet function testing attributed antiplatelet effects to non-aspirin NSAIDs in contrast to their potential prothrombotic effects in-vivo caused by inhibition of endothelium derived prostacyclin. Taken together, a general implementation of platelet function analysis into treatment algorithms is currently not practical and has not been included in present international guidelines on a high evidence level (Kuliczkowski et al., 2009; Kushner et al., 2009). However, monitoring of clopidogrel response is reasonable in high risk patients. The results of ongoing studies to evaluate the effects of tailoring therapy based on platelet function testing will provide more insights to help dene whether optimal thresholds for efcacy and bleeding exist for pointof-care assessment and adjustment of antiplatelet therapy (Bhatt, 2008). Several small studies have addressed the question of whether tailored antiplatelet therapy can improve platelet inhibition and prognosis of clopidogrel poor responders (Bonello et al., 2008; Fontana et al., 2008). Larger randomized studies are currently underway to further deal with this issue (GRAVITAS, ARCTIC, and TRIGGER-PCI) and denitely identify whether altering therapy improves clinical outcomes.
4.2. Limitations of platelet function testing and potential scope 4.3. Assessment of responsiveness in terms of clinical/therapeutic efcacy Risk stratication based on platelet function analysis currently has some limitations: There have been a wide variety of platelet function tests used in the past ranging from measurement of intracellular signalling pathways like the VASP-assay, to detection of platelet surface activation markers to various aggregation studies including light transmittance aggregometry, whole blood impedance aggregometry, Plateletworks, multiple electrode aggregometry (Multiplate) and the VerifyNow cartridge based system. However, several methods only show a moderate correlation with each other, making their general use more difcult. Even for one single method there have been inconsistent denitions for poor-responsiveness to antiplatelet therapy. The majority of these tests need to be carried out by experienced laboratory staff using the appropriate equipment. The lack of consensus
Table 2 Reported mechanisms affecting responsiveness to aspirin and clopidogrel. Mechanisms Genetic polymorphisms Aspirin response Polymorphic variants of cyclooxygenase 1, von Willebrand Factor, glycoprotein GPIIIa collagen receptor NSAIDs Compliance Hyperglycemia Diabetes Stroke reduced gastrointestinal absorption Increased extraplatelet metabolism of aspirin Clopidogrel response CYP2C19*2 genotype Poor metabolizer genotype (CYP2C19*2, non-CYP2C19*17), polymorphisms of multidrug resistance gene-1 (ABCB1) Ca-antagonists, statins, proton-pump-inhibitor (in particular substrates of CYP2C19), phenprocoumon Compliance Diabetes Acute coronary syndrome Impaired left ventricular function/acute heart failure Renal failure Older age Body mass index Sepsis Reduced gastrointestinal absorption Increased fractalkine levels Accelerated platelet turnover Up-regulation of P2Y1 and/or P2Y12 activation pathway
4.3.1. Prediction of atherothrombotic risk by monitoring antiplatelet drug effects Studies have shown a relationship between the degree of clopidogrel dependent platelet inhibition measured by ADP-induced LTA and the occurrence of major CV events: Mller et al. found that stent thrombosis occurred in subjects with very low platelet inhibition (Mller et al., 2003) and Matetzky et al. described a potential relationship of platelet inhibition during clopidogrel treatment and major CV events within 6-month follow-up in 60 patients undergoing PCI with stenting for acute ST-elevation myocardial infarction (STEMI) (Matetzky et al., 2004). Whether platelet inhibition or post-treatment platelet aggregation (Gurbel et al., 2003; Samara et al., 2005) is the more useful measure remains unclear, but there has been
Drugdrug interactions Clinical factors
Cellular factors
Over-expression of COX-2 mRNA Accelerated platelet turnover Increased levels of norepinephrine Increased formation of 8-Iso-PGF2a
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growing experience with the acquisition of one single post-treatment (residual) platelet aggregation value as being more practical and relevant to characterize the atherothrombotic risk after PCI. Several publications based on analysis of a large single-centre data-set of patients treated with dual antiplatelet therapy after coronary intervention found a relationship between residual platelet aggregation and events including stent thrombosis (Table 3) (Gurbel et al., 2005; Cuisset et al., 2006; Hochholzer et al., 2006; Geisler et al., 2010). These effects have also been conrmed by rapidly processing platelet function assays using VerifyNow or multiple electrode whole blood aggregometry (Multiplate) (Price et al., 2008; Sibbing et al., 2009b). These observational data indicate that the strongest relationship between the intensity of platelet aggregation and outcome was found for the occurrence of short-term cardiovascular events especially early stent thrombosis rather than long-term events after PCI (Geisler et al., 2010; Sibbing et al., 2010a) supporting observations of wide variations in platelet function tests within individuals over time and that single point platelet function tests do not really carry a long-term prognostic value (Fig. 2). Although the recently published prospective POPULAR-trial also demonstrated an association between agonist (ADP) induced assays (but not shear stress simulating assays such as PFA-100 and cone and plate analyzer) and the occurrence of 1-year MACE, this effect was due to higher event rate at 6 months onwards in patients with high platelet reactivity (Breet et al., 2010). 4.3.2. Identication of risk markers for low responsiveness On-treatment measured platelet reactivity is a multi-factorial phenomenon. Comorbidities and risk factors for coronary heart disease seem to inuence platelet reactivity and individual response to dual antiplatelet therapy especially clopidogrel (Bhatt, 2004; Wang et al., 2006). Risk factors like diabetes have been attributed to poor platelet response to both aspirin and clopidogrel. Antiplatelet effects after a 300-mg clopidogrel loading dose (LD) were attenuated in diabetics compared to non-diabetics up to 24 h (Angiolillo et al., 2005), and this has also been observed in diabetics receiving 600 mg clopidogrel LD in the setting of PCI (Geisler et al., 2007). These observations are consistent with recent data from a sub-analysis of the TRITON-TIMI 38 trial which demonstrated a higher net clinical benet of prasugrel in diabetic patients compared to non-diabetics (Wiviott et al., 2008). The impact of
Table 3 Association of post-treatment platelet reactivity and events in different PCI-patient groups. Patient cohort 192 patients undergoing PCI Denition of high residual platelet Endpoints aggregation
renal function on antiplatelet drug responsiveness has been addressed in only a few studies. An impact of chronic kidney disease on responsiveness to clopidogrel treatment has been observed in small studies (Deray et al., 1998; Price et al., 2008; Park et al., 2009). Post hoc analyses from the CREDO and CHARISMA trials showed that randomization to clopidogrel was associated with either harm or less benet based on decreasing renal function (Best et al., 2008; Dasgupta et al., 2009). A relationship between older age and clopidogrel low-responsiveness as described by high post-treatment platelet reactivity or low percentage of inhibition has also been reported in different clinical collectives (Prabhakaran et al., 2008; Cuisset et al., 2009). Patients with ACS exhibit decreased response to standard clopidogrel therapy in the very early phase after the event (Matetzky et al., 2004; Geisler et al., 2008a). This association might be caused by a higher degree of platelet aggregation and activity preceding the coronary event (Ault et al., 1999; Bigalke et al., 2008). Decreased drug metabolization due to hemodynamic instability or cardiogenic shock in the setting of ACS can contribute to decreased drug efcacy (Ibrahim et al., 2008; Osmancik et al., 2009). Left ventricular dysfunction affects clopidogrel responsiveness possibly by means of impaired metabolism (Marcucci et al., 2007; Geisler et al., 2008b). Concurrent medication use might interfere with clopidogrel dependent platelet inhibition. Some reports suggested that high doses of calcium-channel blockers and proton-pump-inhibitors (PPI) inuencing CYP2C19 and CYP2C9-dependent metabolism possibly affects response to clopidogrel (Gurbel et al., 2003; Gilard et al., 2008; Siller-Matula et al., 2008; Ho et al., 2009). Most of these reports use data from nonrandomized observational studies with platelet function or clinical endpoints investigating the effects of co-medication on clopidogrel efcacy. The only randomized study which was designed to investigate the effect of concomitant treatment with the PPI omeprazole on clinical outcome was the Clopidogrel and the Optimization of Gastrointestinal Events (COGENT) -1 trial which was terminated early due to lack of funding before reaching the calculated sample size. However, analysis of the available data that included over 3600 patients with a median follow-up of 133 days did not support an adverse inuence of concomitant omeprazole treatment on the clinical efcacy of clopidogrel (Bhatt D. Presented at: Transcatheter Cardiovascular Therapeutics; Sept. 2115, 2009; San Francisco). Furthermore, a recent subanalysis from the randomized TRITON-TIMI-38 and PRINCIPLE-TIMI-44 study also did not
Hazard/odds ratios OR: 4.23 (upper quartile versus lower quartile) HR (95%CI): 3.7 (1.0812.69; P = 0.037) OR (95% CI) 22.4 (4.6109) quartile 4 vs. 1, 2, 3 OR 5.22 (HPR versus NPR)
Reference Gurbel et al., 2005 Geisler et al., 2006
LTA: ADP(20Mol/L)-induced PA in the upper quartile (N67%) 379 patients with PCI for symptomatic LTA: ADP(20Mol/L)-induced coronary artery disease PA N70% 106 NSTE ACS consecutive patients undergoing PCI 100 consecutive patients receiving chronic antiplatelet therapy undergoing non-urgent stenting 380 patients undergoing PCI with sirolimus-eluting stents 1019 patients undergoing coronary intervention for symptomatic coronary artery disease 215 consecutive patients were treated with DES for unprotected left main disease 1608 consecutive patients with coronary artery disease and elective drug-eluting stent implantation LTA: ADP-induced platelet aggregation in the upper quartile LTA: ADP (5 Mol/l ADP)-induced platelet aggregation 50% VerifyNow 235 PRU
Post-discharge ischemic events within 6 months Combined ischemic events (CV-death, myocardial infarction, ischemic stroke) within 3 months CV events
Cuisset et al., 2006 Bliden et al., 2007
LTA: ADP (20Mol/L) induced platelet aggregation in the upper tertile (N42.5%) LTA: ADP (10 Mol/L) induced platelet aggregation N70%
Death, myocardial infarction, stent thrombosis, stroke, or ischemia requiring a hospital stay within 12 months Out-of-hospital CVHR: 6.5 death, non-fatal MI, or stent thrombosis within 6 months Stent thrombosis within 3 months OR (95% CI) 2.21 (1.313.73); P b 0.01 CV-death and stent thrombosis during a median follow-up of 19.3 months Denite Stent thrombosis within 30 days Cardiac death: HR (95% CI): 3.82 (1.38 to 10.54) P = 0.01 and stent thrombosis: 3.69; (1.12 to 12.09); P = 0.031 OR (95% CI): 9.4; (3.1 to 28.4); P b 0.001
Price et al., 2008
Geisler et al., 2010
Migliorini et al., 2009
MEA: Upper quintile of ADPinduced aggregation
Sibbing et al., 2009b
LTA: light transmittance aggregometry; MEA: multiple electrode aggregometry; OR: odds ratio; HR: hazard ratio; CI: condence interval; CV: cardiovascular; HPR: high platelet reactivity; NPR: normal platelet reactivity.
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Fig. 2. Hazard for early stent thrombosis increases with higher post-treatment platelet aggregation.
nd any relationship between PPI treatment and outcomes in thienopyridine treated patients (O'Donoghue et al., 2009). Thus, there is to date inadequate clinical evidence supporting a general recommendation to alternate antiplatelet or GI prophylaxis regimen in patients who are at risk for peptic ulcer. Concerning interaction of statins and clopidogrel there have been cumulative data from large clinical endpoint studies (Saw et al., 2003; Serebruany et al., 2004; Saw et al., 2007) that did not conrm the initial observation derived from well-founded pharmacodynamic studies (Lau et al., 2003). In fact, a benet in CV risk reduction has been found with concomitant standard dosing of statins in addition to clopidogrel irrespective of the particular statin (Geisler et al., 2008c). Cigarette smoking enhances CYP1A2 activity and may therefore lead to increased conversion of clopidogrel into its active metabolite. Initial studies hint towards a possible effect on clopidogrel dependent platelet inhibition (Bliden et al., 2008; Motovska et al., 2009). In support of the potential clinical importance of this interaction a retrospective analysis of the CHARISMA study found a signicant benet of clopidogrel on mortality in the subgroup of current cigarette smokers only (Berger et al., 2009a). The impact of clinical, non-genetic factors on the degree of residual platelet aggregation (RPA) in clopidogrel-treated patients has also been estimated in an observational study of 1092 patients. Increased age (N65 years), ACS, reduced left ventricular function, and presence of diabetes mellitus and renal failure (creatinine N1.5 mg/dl) could be identied as independent determinants for a high RPA. After weighing these variables according their degree of inuence a clinical score (PREDICT-Score) was developed that allowed for the estimation of the probability of a high RPA and the risk for short-term thromboischaemic events from easily available clinical data (Geisler et al., 2008b; Gawaz & Geisler, 2009). Further investigations are needed, to evaluate such clinical scores for identication of patients who might benet from alternative antiplatelet therapies. 4.3.3. Genetic risk associated with decreased drug efcacy Recently, there has been a large amount of data indicating that a relevant part of the observed variability to clopidogrel treatment might be attributed to genetic inheritance. A number of recent reports have investigated different candidate genes involved in enteric and hepatic metabolism of clopidogrel. These include polymorphisms of
cytochrome P450 (CYP450) isoenzymes and polymorphisms and of the Multidrug Resistance Protein 1 (MDR1) coding gene (ABCB1). Most of the association between clopidogrel pharmacokinetics and drug efcacy has been described for polymorphisms of the gene encoding for CYP2C19 isoenzyme. There are a number of different single nucleotide polymorphisms described for CYP2C19 which have been considered showing functional impact by predicting poormetabolizer (e.g. *2) or ultra-rapid metabolizer (e.g. *17) phenotype. The genetic variant CYP2C19*2 has been primarily linked to platelet inhibitory effects of clopidogrel and clinical prognosis in different settings of cardiovascular risk patients (Fig. 3) (Collet et al., 2009b; Mega et al., 2009a; Shuldiner et al., 2009; Simon et al., 2009). Although, it appears that CYP2C19*2 polymorphism is associated with outcome in clopidogrel treated patients, it is currently unclear to which degree the single allele contributes to prognostic effects as in some studies subjects heterozygous for a single variant did not differ from the wildtype in terms of clinical prognosis (Simon et al., 2009). The homozygous allele frequency of CYP2C19*2 is relatively rare (about 2%) in the white Caucasian population (in contrast to Asian and Afro-American populations) which makes it difcult to assess the true clinical importance of this mutation. Therefore, some studies have evaluated a risk genotype by identication of at least 1 reducedfunction CYP2C19 allele being associated with poor clopidogrel metabolism (Mega et al., 2009a). In a consecutive population of 237 patients undergoing PCI it was suggested that CYP2C19 variant genotypes function as an additional risk factor for poor response to clopidogrel besides established non-genetic risk factors. Patients with a high PREDICT-score value indicating increased probability for low clopidogrel dependent platelet inhibition based on non-genetic factors and additionally with a variant CYP2C19*2 genotype were most likely to be identied as having poor response to clopidogrel (Geisler et al., 2008d). In contrast to CYP2C19*2 variant, the CYP2C19*17 allele has been reported to result in a putatively increased enzyme function of CYP2C19 (Sim et al., 2006). The functional role of this less-common genotype on platelet inhibition and outcomes is not yet clear (Frre et al., 2009; Mega et al., 2009a,b; Simon et al., 2009; Sibbing et al., 2010b). In the future genome wide association studies (GWAS) are warranted to identify candidate genes and variant clusters linked to antiplatelet drug response and outcome. Thus, Shuldiner et al. recently demonstrated by using a GWAS approach that only single-nucleotide polymorphisms on chromosome 10q24 within the CYP2C18CYP2C19CYP2C9CYP2C8 cluster could inuence clopidogrel response (Shuldiner et al., 2009). 4.3.4. Assessment and prognostic impact of bleeding risk In the last decade, the importance of minimizing bleeding has become increasingly recognized. Due to the growing number of patients undergoing PCI and coronary artery bypass grafting (CABG) and the use of a myriad of antithrombotic strategies, especially in the setting of ACS, the risk of bleeding continues to increase. Furthermore, it represents an independent predictor of cardiovascular mortality in patients who have an indication for antiplatelet therapy (Rao et al., 2005; Eikelboom et al., 2006). The risk of bleeding correlates with dosage, intensity, timing and combination of antiplatelet and anticoagulant agents. Retrospective analysis of aspirin trials suggest that higher dosage is associated with unfavourable effects on bleeding rates (Manoukian et al., 2007) especially when used in combination with clopidogrel (Steinhubl et al., 2009). This relationship could not be conrmed by the recent CURRENT-OASIS results showing no bleeding excess in the higher aspirin (300325 mg) arm for at least a treatment period of 30 days after randomization (presented at the annual meeting of the ESC 2009, clinical trials NCT00335452, Study Design: Mehta et al., 2008). Higher bleeding risk has been observed with long-term dual antiplatelet therapy compared with aspirin alone in large randomized PCI and non-PCI studies. The net clinical benet of long-term dual
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Fig. 3. Overview of recent evidence of the prognostic impact of CYP2C19 polymorphism in cardiovascular patients. Cumulative data indicate an effect of CYP2C19 polymorphism on long-term outcome in clopidogrel-treated patients.
antiplatelet therapy with clopidogrel and aspirin over aspirin alone in the setting of PCI was documented by the CREDO and PCI-CURE trials. According to the CURRENT-OASIS 7 results, a 600 mg LD followed by short-term high maintenance dose treatment (7 days of 150 mg/day followed by 75 mg/day) signicantly reduced the primary efcacy endpoint in the PCI treated subgroup compared with the standard 300 mg LD followed by 75 mg daily. Whereas the intensied dosing did not lead to an increase in TIMI major or fatal bleeding, a higher major bleeding event rate according to CURRENT denitions was observed. There have been several attempts to develop risk score models to predict major bleeding events in patients receiving dual antiplatelet therapy. These risk models mainly derive from ACS registries that are inuenced by additional antithrombotic treatment regimens in the analysed cohorts. However, these data may help to identify patient subgroups in which a more pronounced antiplatelet therapy might be more hazardous than benecial. Thus, analysis from the Global Registry of Acute Coronary Events (GRACE) registry revealed that there are independent predictors, including older age, renal failure, female gender, history of bleeding, the use of GP-receptor antagonists and right-side heart catheterization for increased risk of bleeding (Moscucci et al., 2003). In the CRUSADE registry baseline hematocrit b36%, creatinine clearance, heart rate, extremes of systolic blood pressure, female gender, congestive heart disease, prior vascular disease, and diabetes were associated with severe bleeding and were included in a score model to predict bleeding risk in ACS patients (available at www.crusadebleedingscore.org) (Subherwal et al., 2009). Since these risk models include some established risk factors which are relevant for atherothrombotic complications, it suggests that there is only a thin line between efcacy and safety of the antiplatelet and anticoagulant strategies. There are several existing bleeding classications (TIMI, GUSTO-, CURRENT, ACUITY, STEPPLE, PLATO,) which are based on more and less objective criteria, but due to the large number of varying denitions it is difcult to generalize results across the different studies supporting the need for a common denition of bleeding outcomes. Prospective studies are needed to weigh the bleeding against the
protective effects of different antiplatelet regimens and to identify individual risk factors for major bleedings effects. 5. How can new treatments change current practise efcacy and safety of novel antiplatelet substances Novel antiplatelet drugs have been recently evaluated in clinical trials. Multimodal approaches taking into account various risk factors and the benets and risk of novel drugs could be a key to personalized therapeutic approaches (Fig. 4). 5.1. Possible strategies to overcome response variability and delayed onset of action in acute coronary events? 5.1.1. Prasugrel Prasugrel is a 3rd generation thienopyridine that, like clopidogrel, needs biotransformation into its active compound. However, the differences in metabolism allow for greater bioavailability of prasugrel's active metabolite compared to clopidogrel's. Thus, a major part of clopidogrel is inactivated by esterases and only a smaller part is further metabolized by two cytochrome P450 (CYP) dependent oxidization steps to its active metabolite (Hagihara et al., 2009). On the contrary, prasugrel is partly activated by esterases and only a single CYP metabolization step is necessary for conversion into the active form (Rehmel et al., 2006). Thus, prasugrel achieves greater levels of the active metabolite and therefore enhanced platelet inhibition (Fig. 5) (Wallentin et al., 2008). In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) the effectiveness of prasugrel was proven for the treatment of patients with ACS undergoing PCI. Thirteen thousand six hundred and eight patients with either STEMI (26%) or unstable angina and non-STEMI (74%) were randomized to prasugrel (60 mg LD, 10 mg daily MD) or clopidogrel (300 mg LD, 75 mg daily MD) for a median duration of 14.5 months. There was a signicant reduction of the primary endpoint (CV death, non-fatal myocardial infarction and stroke) in the prasugrel treated arm (9.9% versus 12.1% in
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Fig. 4. Multimodal approach and emerging factors for current and future decision on antiplatelet drug treatment in CAD patients. The atherothrombotic risk increases with the acuity of the disease and the therapeutic approach (interventional vs. non-interventional). Additional factors inuence the risk for thrombotic complications. A therapeutic decision should be considered in the future to take atherothrombotic risk factors and bleeding risk factors (red arrow) into account to determine the optimal antiplatelet strategy. Additionally, bleeding risk associated with more effective antiplatelet therapy should be carefully taken into consideration in patients who are at transitory or permanent high bleeding risk.
the clopidogrel arm, P b 0.001; number needed to treat 46). Additionally, stent thrombosis was decreased by 50% in prasugrel treated patients which was mainly due to a reduction of early stent thromboses. On the other side, there was a signicantly higher incidence of TIMI major, nonCABG associated bleedings (1.4 versus 0.9%, P = 0.01) and bleedings with fatal outcome (0.4 versus 0.1%; P = 0.002), that was most marked in subgroups of patients with a previous cerebrovascular event, older patients (75 years) and patients with a body weight of less than 60 kg, although even after excluding all of these patients treatment with prasugrel was still associated with a signicant increase in TIMI major
+ minor bleeding. However, the net clinical net benet (TIMI major bleeding plus CV death, non-fatal myocardial infarction and stroke) remained in favour of prasugrel treatment, except in those subgroups (Wiviott et al., 2007). One limitation of the study was the relative underdosing of the active comparator (e.g. 300 mg) and the fact, that 72% of the patients in the clopidogrel-arm received rst study medication during PCI and only 27% at any time prior to PCI. Furthermore, the excess of recurrent MI in the clopidogrel group was mostly due to an increase in cardiac enzyme rather than clinically overt infarction. Nevertheless, the US Food and Drug Administration (FDA) approved prasugrel for clinical
Fig. 5. Comparison of onset of platelet inhibition and antiplatelet effects under maintenance dose therapy between prasugrel and clopidogrel.
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use based on the TRITON data, stating that the efcacy of prasugrel outweighs the bleeding risk due to the low frequency of fatal bleedings. At the same time, they recommended that prasugrel should be considered only after careful weighing of the individual bleeding risk (Unger, 2009). In the UK the National Institute of Health and Clinical Excellence (NICE) has supported the use of prasugrel for STEMIpatients, diabetics with ACS undergoing PCI and those with stent thrombosis (National Institute of Health & Clinical Excellence, 2009). 5.1.2. Prasugrel in different subgroups 5.1.2.1. Diabetics. There are data from subgroup analysis suggesting that diabetics experience a more pronounced platelet inhibition resulting in improved outcome under prasugrel compared to clopidogrel. However, this effect might be due to higher concentrations of the active metabolite of prasugrel compared to clopidogrel rather than platelet P2Y12 receptor abnormalities (Erlinge et al., 2008). The OPTIMUS-3 trial showed in a small cohort of patients that a higher degree of platelet inhibition could be achieved after loading dose and under maintenance dose with prasugrel compared to clopidogrel (600 mg LD, 150 mg MD) treated type-2 diabetics (presented at the American Heart Association Meeting 2009, clinicaltrials.gov NCT00642174). Concerning clinical efcacy, the net benet with prasugrel was greater for diabetics (14.6% versus 19.2%; HR, 0.74; P = 0.001) compared to non-diabetics DM (11.5% versus 12.3%; HR, 0.92; P = 0.16, P(interaction)= 0.05) in a sub-analysis of the TRITON-TIMI 38 cohort (Wiviott et al., 2008). Thus, there is some evidence that diabetics benet from increased platelet inhibition by prasugrel especially in ACS, however more prospective studies in diabetic patients are needed to conrm this effect on net clinical outcome of the patients. 5.1.2.2. Genetic risk groups. According to recent studies, the metabolism and action of prasugrel seems not to be affected by CYP polymorphisms. A retrospective analysis of the TRITON-TIMI 38 cohort revealed no effects of SNPs in the genes for CYP2C19, CYP2C9, CYP2B6, CYP3A5 or CYP1A2 in the prasugrel treated arm, however, efcacy of clopidogrel was reduced in carriers of polymorphic CYP2C19 loss-offunction variants (Mega et al., 2009a,b). Thus, the present data favour the application of prasugrel in patients with CYP2C19-polymorphism, however, it is premature to recommend genetic testing in all patients anticipated to require thienopyridine treatment as a guide to therapeutic adjustments at this time (Bhatt, 2009a). Additional work is also needed to determine if the benets are present in both heterozygotes and homozygotes. 5.1.2.3. Interactions. Recently proposed interference of thienopyridine drug metabolization with the use of proton pump inhibitors (PPI) was not apparent for the combination of prasugrel and PPI in a retrospective data analysis of a randomized trial. However, there were observations of a salt-to-base conversion within the prasugrel tablets which might be relevant for drug efcacy in a high-pH gastric environment inuenced by PPI use. There is currently no evidence of a clinical importance of this observation. 5.1.3. Ticagrelor Ticagrelor is a cyclopentyl-triazolo-pyrimidine that is orally active and reversibly inhibits the P2Y12 receptor on platelets with rapid peaking of plasma levels (1.53 h). In the Dose Conrmation Study Assessing Anti-Platelet Effects of AZD6140 Versus Clopidogrel in NSTEMI (DISPERSE-2) study, a randomized phase 2 study, ticagrelor (90 mg or 180 mg twice daily) was compared to clopidogrel (300 mg LD, 75 mg daily MD) for 412 weeks in 990 patients with ACS (Cannon et al., 2007). Overall, there was no signicant difference in bleeding rates between clopidogrel and ticagrelor. In the subset of 84 patients who underwent coronary artery bypass surgery bleeding rates in patients randomized to ticagrelor were numerically lower
among patients undergoing CABG within 15 days after their last dose of study drug (36% versus 64% for clopidogrel users) suggesting the use of ticagrelor as a reversible agent may provide more exibility for the timing of surgery than the irreversible thienopyridines. With regard to side effects, ticagrelor was associated with a dosedependent greater incidence of persistent dyspnea: 6% of patients in the ticagrelor group versus 2% of clopidogrel-users. The cause of dyspnea is not fully understood yet but might be related to effects of ticagrelor on adenosine reuptake. Additionally, clinically relevant but mostly asymptomatic ventricular pauses N2.5 s as well as mild increase in uric acid levels were observed in the ticagrelor group. The recent PLATO (Platelet Inhibition and Patient Outcomes) trial compared ticagrelor to clopidogrel in a phase 3 trial in 18,624 patients with ACS (STEMI and Non-STEMI) (Wallentin et al., 2009). Ticagrelor given as 180 mg LD followed by a 90 mg MD twice a day was associated with a signicant reduction of the primary endpoint (composite of CV death, myocardial infarction and or stroke) at 12 months (9.8 versus 11.7) and no difference in PLATO-or TIMI-dened (however more Non-CABG related) bleedings compared to a standard clopidogrel dosing regimen (300600 mg LD at discretion followed by 75 mg daily MD). These results could be further conrmed in an analysis of the cohort intended for invasive management at randomization (Cannon et al., 2010). Data from the recently published ONSET/OFFSET trial revealed a faster onset and a higher maximum level of platelet inhibition after loading, greater suppression of platelet function under maintenance dose therapy and a faster recovery of platelet function after cessation of therapy with ticagrelor compared to clopidogrel (600 mg LD/75 mg MD) (Fig. 6). Pharmacogenomic analysis from the genetic data obtained in PLATO should provide further information whether there are particular benets of ticagrelor over clopidogrel in patients exhibiting genetic variants that affect clopidogrel efcacy (Bhatt, 2009b). 5.1.4. Cangrelor Cangrelor is a short-acting, intravenous ADP receptor antagonist. The CHAMPION PCI trial did not demonstrate superiority of this agent compared with 600 mg of clopidogrel initiated within 20 min of the start of PCI for the primary endpoint, but it did demonstrate noninferiority (Harrington et al., 2009). CHAMPION PLATFORM did not demonstrate superiority for cangrelor over placebo for the primary endpoint, but the secondary endpoints of stent thrombosis and mortality were reduced (Bhatt et al., 2009). If proven efcacious there may be a role for this agent in patients who cannot take oral drugs, such as those who are intubated although further studies are needed. 5.1.5. Elinogrel Elinogrel is a novel, direct acting, reversible, intravenous (IV) and oral P2Y12 ADP receptor antagonist (Gretler et al., 2007) which is currently being evaluated for its effectiveness and safety in phase 2 studies. The ERASE MI was a randomized, double blind, placebo controlled, dose escalating safety trial that evaluated the effects of additional IV elinogrel bolus administration in a total of 70 patients with STEMI. The primary safety endpoint of the study was TIMI major and minor in hospital bleedings, GUSTO severe and moderate inhospital bleedings and 30-day intracerebral hemorrhage. No difference in bleeding frequency was seen between the placebo arm and across the different elinogrel dosing arms (Berger et al., 2009b). The currently recruiting INNOVATE-PCI study is a multi-centre, randomized, double-blind, triple-dummy, clopidogrel-controlled study of IV and oral elinogrel compared to clopidogrel in patients undergoing non-urgent PCI. Patients will be randomized to clopidogrel or to one of three dose levels of elinogrel (clinicaltrials.gov NCT00751231). Early data show that elinogrel might provide additional platelet inhibition on top of standard dual antiplatelet therapy independently from CYP2C19 polymorphism (Gurbel et al., 2009b). However, larger studies are needed to prove in the clinical setting.
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Fig. 6. Comparison of onset and offset of platelet inhibition between ticagrelor and clopidogrel. Ticagrelor shows a faster onset and a higher maximum level of platelet inhibition after loading, greater suppression of platelet function under maintenance dose therapy and a faster recovery of platelet function after offset compared to clopidogrel.
5.1.6. Thrombin receptor antagonists Protease activated receptors are a subfamily encompassing four described G-protein coupled receptors which are activated by serine proteases like thrombin (PAR-1, 3 and 4) or trypsin (PAR-2). The major receptors for thrombin on platelets are PAR-1 and PAR-4. PAR-1 has a high afnity for attracting alpha-thrombin serving as a possible moderator between platelet activation, thrombin formation and endothelial-platelet interaction (Kahn et al., 1999). There are emerging data supporting that blocking the PAR-1 receptor prevents ischaemic events without an increase in bleeding risk (Becker et al., 2009). Vorapaxar (SCH 530348), a PAR-1 antagonist derived from the natural product himbacine, is being evaluated in phase III clinical trials for efcacy and safety in acute coronary syndromes and secondary prevention on top of standard antiplatelet therapy (Morrow et al., 2009; TRA*CER Executive & Steering Committees, 2009). Another PAR-1 antagonist, E5555 targeting the tethered ligand-binding epitope site, has been shown to effectively inhibit platelet aggregation and activation (Serebruany et al., 2009) and has entered the clinical trial program. The advantages of these novel drugs for an individualized antiplatelet strategy will have to be evaluated in future trials. 6. Conclusions Current strategies for dual antiplatelet drug therapy have been shown to lack clinically useful antiplatelet effect in a considerable number of patients undergoing PCI. Variability in responsiveness may be a major cause for the increased risk being observed in particular subgroups of patients. Although potentially suitable for guiding therapy in certain risk groups of patients such as patients at high risk for stent thrombosis, a general recommendation to adjust therapy based on platelet function monitoring cannot be strongly supported until data from ongoing randomized trials are available to demonstrate the effects of a tailored approach. GPIIb/IIIa inhibitors, while showing early promise, are now restricted to use in the cardiac catheter laboratory for patients undergoing higher risk PCI. Several novel antiplatelet substances including new P2Y12 inhibitors and thrombin receptor antagonists are in development and may help to solve the issue of response variability. However, the unrestricted use of these drugs might not be favourable due to increased bleeding risk in some patients as well as nancial constraints. Thus, individual atherothrombotic and bleeding risk has to
be clearly dened as well as factors that determine therapeutic response to antiplatelet therapy. Optimizing antiplatelet treatment will undoubtedly require the use of multiple strategies based on clinical, genetic and laboratory information leading to a tailored approach for individual patients as well as accurate measurement of antiplatelet effect.
Disclosures Dr. Geisler: speaker fees: the Medicines Company. Dr. Gawaz: Speaker fees and advisory boards from: the Medicines Company, Bayer Vital, AstraZeneca, Eli Lilly, Daichii Sankyo. Dr. Steinhubl: Full-time employee of The Medicines Company. Dr. Storey: Speaker fees, consultancy and/or institutional research grants from: AstraZeneca, Eli Lilly, Daiichi Sankyo, Schering Plough, Novartis, Teva and The Medicines Company and GSK. Dr. Bhatt: Research Grants to the institution for studies in which he served as PI Astra Zeneca, Bristol-Myers Squibb, Eisai, Ethicon, Heartscape Technologies, Sano Aventis, The Medicines Company. Dr. Flather: Speaker fees and advisory boards from: Eli Lilly, Daiichi Sankyo, Sano Aventis, Bristol Myers Squibb, Novartis, Boehringer Ingelheim, Eisai.
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Pharmacology & Therapeutics 127 (2010) 95107

Contents lists available at ScienceDirect

Pharmacology & Therapeutics

T. Geisler et al. / Pharmacology & Therapeutics 127 (2010) 95107

Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 97 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 98

T. Geisler et al. / Pharmacology & Therapeutics 127 (2010) 95107

Aspirin, clopidogrel, GPIIb/IIIa Inhibitors

T. Geisler et al. / Pharmacology & Therapeutics 127 (2010) 95107

Drugdrug interactions Clinical factors

T. Geisler et al. / Pharmacology & Therapeutics 127 (2010) 95107

Reference Gurbel et al., 2005 Geisler et al., 2006

Cuisset et al., 2006 Bliden et al., 2007

Price et al., 2008

Geisler et al., 2010

Migliorini et al., 2009

MEA: Upper quintile of ADPinduced aggregation

Sibbing et al., 2009b

T. Geisler et al. / Pharmacology & Therapeutics 127 (2010) 95107

T. Geisler et al. / Pharmacology & Therapeutics 127 (2010) 95107

T. Geisler et al. / Pharmacology & Therapeutics 127 (2010) 95107

T. Geisler et al. / Pharmacology & Therapeutics 127 (2010) 95107

T. Geisler et al. / Pharmacology & Therapeutics 127 (2010) 95107

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