Inhibition of platelet aggregation for the secondary prevention after ACS: when clopidogrel instead of ASA, when clopidogrel and ASA?

Long-term inhibition of platelet aggregation is essential for the secondary prevention after acute coronary syndromes (ACS). Inhibition of platelet aggregation with acetylsalicylic acid (ASA) has been established as a safe and effective therapy in this indication already end of the eighties in the preceding century. A decade later, with the introduction of the thieno-pyridines, combined platelet aggregation inhibition became possible. This opened the door for new treatment strategies in interventional cardiology. The first substance, ticlopidine was more or less replaced by the newer substance clopidogrel, which has improved pharmacological properties and less side effects. Low dose ASA (75 mg/d) is still regarded as the standard therapy for secondary prevention after ACS. However, large clinical trials established clopidogrel as at least as effective and safe as ASA in this indication. Following PCI with bare metal stent implantation, a combined therapy of ASA and clopidogrel should be given for at least 4 weeks. After ACS with non-ST-elevation myocardial infarction the combined therapy with ASA and clopidogrel gives a better outcome than ASA alone. Recently published clinical trials show superiority of this strategy in patients with ST-elevation myocardial infarction, too. If a combined long-term platelet aggregation inhibition with ASA and clopidogrel will be safe and more effective for secondary prevention is discussed.     

Ticagrelor (Brilinta)--better than clopidogrel (Plavix)?

The FDA has approved ticagrelor (Brilinta-AstraZeneca), an oral antiplatelet drug, for use with low-dose aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It will compete with clopidogrel (Plavix) and prasugrel (Effient) for such use. Clopidogrel is expected to become available generically in the US within the next few months.     

Interaction between statins and clopidogrel: is there anything clinically relevant?

Since their introduction several years ago, the 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors-the statins-have been widely used for hyperlipidemia and for the primary/secondary prevention of cardiovascular diseases. They have been shown to be safe as well as efficacious in a number of different clinical trials; however, studies have suggested that they can interact with other co-administered therapies. More recently, the thienopyridines have been successfully integrated with the conventional medical treatment of coronary disease as they showed effectiveness in reducing platelet activity both in stable and unstable settings. They also improve the outcome of patients treated with percutaneous coronary intervention. The potential interaction of statins and thienopyridines is a matter of concern. Despite some preclinical data suggesting an interaction between statins metabolized by the liver cytochrome P3A4-such as atorvastatin, lovastatin and simvastatin-and clopidogrel, there is no compelling clinical evidence to stop their co-administration.     

Interpreting the CHARISMA study. What is the role of dual antiplatelet therapy with clopidogrel and aspirin?

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study (N Engl J Med 2006; 354:1706-1717, J Am Coil Cardiol 2007; 49:1982-1988) assessed the effect of dual antiplatelet therapy with clopidogrel (Plavix) and aspirin in patients at risk of atherothrombotic events. At a median of 28 months, the rate of the primary efficacy end point (a composite of myocardial infarction, stroke, and death from cardiovascular causes) was not significantly lower in the group receiving clopidogrel plus aspirin than in the group receiving placebo plus aspirin. However, one subgroup may have derived some benefit from the combination: those at higher risk owing to a history of myocardial infarction, ischemic stroke, or symptomatic peripheral arterial disease.     

Response variability to clopidogrel: is tailored treatment,based on laboratory testing,the right solution?

Summary. Clopidogrel is an antithrombotic prodrug, whose active metabolite inhibits platelet function by irreversibly binding to the platelet receptor for adenosine diphosphate, P2Y₁₂. Wide inter‐individual variability of response to clopidogrel has been reported in several studies: a significant proportion of treated patients (about one‐third) exhibit a suboptimal inhibition of platelet function. Genetic and environmental factors that influence the absorption and/or the extent of metabolism of clopidogrel to its active metabolite account for the observed variability of response. Tailored treatment based on the results of laboratory tests of platelet function has been proposed as a solution to this problem, which has important clinical implications. Although it is often considered a desirable evolution of modern medicine, tailored treatment based on laboratory tests is actually an old remedy (of yet unproven efficacy, in the case of antiplatelet therapy) for the problem of response variability to antithrombotic drugs with unpredictable bioavailability. When possible, the use of alternative drugs with more uniform and predictable bioavailability, and with favourable profiles in terms of risk/benefit and cost‐benefit ratios should be preferred. Moreover, tailored treatment with laboratory tests must be validated in randomized clinical trials before its implementation can be recommended. We still need to identify and standardize the laboratory test for this purpose, as well as answer basic questions on its clinical utility and cost‐effectiveness, before tailoring clopidogrel therapy based on laboratory tests can be recommended in clinical practise.     

PON1 Q192R and clopidogrel: a case of the winner's curse or inadequate replication?

The antiplatelet drug clopidogrel is one of the most commonly prescribed drugs in the world, but there is wide interpatient variability in its antiplatelet effects. The majority of this variation is due to genetic effects, but there is controversy over which genetic variants are important and their relative contribution. This controversy may stem from the genetic association research paradigm, which casts the "winner's curse."     

Role of CYP2C19 genotype testing in clinical use of clopidogrel: is it really useful?

Introduction: P2Y12 inhibitors, including clopidogrel have become an integral part of treatment for patients receiving coronary stent placement as a result of stable coronary artery disease or acute coronary syndromes (ACS) and also for medically managed ACS patients.

Areas covered: Clopidogrel efficacy can be significantly modified by polymorphism of CYP2C19 genotype (more than 25 allelic variants) involved in its metabolism that can adversely affect its anti-platelet activity. As a result, a substantial number of patients (20–30%) with ACS show an inadequate response to clopidogrel despite a standardized dosing regimen.

Experts commentary: Currently, there is conflicting evidence in regards to the use of CYP2C19 genotyping to identify poor responders to clopidogrel in clinical practice. ACC/AHA guidelines do not recommend routine use of CYP2C19 in clinical practice, whereas Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend its use to identify poor/intermediate metabolizers of Clopidogrel and suggest alternative P2Y12 inhibitors among ACS patients undergoing percutaneous coronary intervention. This review article will look at the literature evidence for the use of CYP2C19 genotyping in clinical practice.