Does the use of statins compromise the effectiveness of platelet inhibition by clopidogrel?

Antiplatelet drugs are now firmly established in the secondary prevention of myocardial infarction and stroke in patients with cardiovascular and peripheral arterial disease. 1–4 Other essential uses include providing short-term cover for surgical procedures that carry a high risk of thrombosis or embolism, such as angioplasty or the placing of stents. The thienopyridine derivatives, ticlopidine and clopidogrel, are prodrugs that are metabolised in the liver to active compounds that inhibit the P2Y12 ADP receptor on platelets. The occasional incidence of neutropenia or thrombotic thrombocytopenic purpura with ticlopidine has led to clopidogrel becoming the preferred drug. 5 Because of the important physiological role of ADP in platelet activation and aggregation, and in particular the amplification of activation induced initially by other agonists, clopidogrel is effective in inhibiting aggregation induced by a number of different stimuli. 6 Unlike other classes of ADP receptor, P2Y12 appears to be confined to platelets and neural cells thus improving the specificity of action of its antagonists. Several large controlled clinical trials have yielded remarkable results with clopidogrel, whether administered alone or in combination with aspirin. It should be borne in mind that these relative risk reductions take place in addition to the significant benefits that are associated with aspirin treatment alone. 7 The CAPRIE study was a randomised blinded trial of Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events in which 19 185 patients with recent ischaemic stroke, recent myocardial infarction or peripheral arterial disease were assigned to treatment with aspirin (325 mg once daily) or clopidogrel (75 mg once daily) and followed for 1–3 years. Clopidogrel was significantly more effective than aspirin in reducing the composite risk of stroke, myocardial infarction or vascular death, with a relative risk reduction of 8.7%. 8 In the CURE trial (Clopidogrel in Unstable angina to prevent Recurrent Events) a combination of 75 mg clopidogrel with aspirin resulted in a 20% relative risk reduction in cardiovascular deaths, non-fatal myocardial infarction and stroke, compared with aspirin alone, in patients with acute coronary syndrome. 9 The authors reported that ‘minimal increased side effects’ were associated with the combined therapy, although patients who received both drugs and subsequently underwent coronary artery bypass grafting were more likely to have major bleeding during or after surgery. The CREDO (Clopidogrel for the Reduction of Events During Observation) trial consisted of 2116 patients selected for percutaneous coronary intervention (PCI) who received either pretreatment with clopidogrel at least 6 h before PCI followed by a year of clopidogrel therapy, or no pre-treatment followed by 1 month on clopidogrel. 10 A 26.9% relative reduction in the composite outcome of death, myocardial infarction or stroke was reported in the former group. These data give strong support for continuing the use of clopidogrel beyond the immediate high-risk period