Response to clopidogrel is variable, and in some patients the anti-platelet effect is dose-dependent. In one study, in which 96 patients undergoing elective coronary stenting received a 300mg loading dose of clopidogrel, the incidence of nonresponsiveness to the drug was 31% when measured at five days post-procedure.¹ In another study, where a 600mg loading dose of clopidogrel was compared with a 300mg loading dose of clopidogrel in 192 patients undergoing elective coronary stenting, the incidence of nonresponsiveness significantly declined from 32% with the 300mg loading dose to 8% with the 600mg loading dose.² Lack of response to clopidogrel appears to be dose dependent. In the first and second Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) trials, the 600mg loading dose of clopidogrel was well tolerated,^3,4 but this loading dose still requires further investigation as the new standard for antiplatelet therapy. In the Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty (AMMYDA-2) study, 255 patients were randomised to a pre-procedural loading dose of 300mg or 600mg of clopidogrel.⁵ Treatment with the higher loading dose in this trial was associated with a significant reduction in the 30- day composite end-point of death, myocardial infarction (MI) and target vessel revascularisation. In particular a 600mg loading dose of clopidogrel resulted in a relative reduction of approximately 50% in the occurrence of early MI (odds ratio 0.48, P=0.044). As yet, however, there has been no large-scale randomised study powered to determine the clinical efficacy of the 300mg loading dose compared with that of the 600mg loading dose.

Lack of response to clopidogrel appears to be due to inadequate generation of the active drug metabolite required to inhibit the P2Y12 receptors. The primary mechanism of this variability lies in the hepatic CYP3A4 pathway. The variability of response to clopidogrel may be caused by polymorphisms of CYP3A4, drug–drug interactions (for example, with statins),⁶ or differences in the rate of intestinal absorption of clopidogrel.⁷ Whether newer generation P2Y12 platelet receptor antagonists that are metabolised differently than clopidogrel are as clinically safe and effective as clopidogrel in patients undergoing percutaneous coronary revascularisation is an issue being examined in on-going clinical trials.

Preliminary data link non-responsiveness to clopidogrel with a higher risk for thromboses. However, only a few small trials have explored the clinical relevance of an inadequate platelet response to clopidogrel.⁸ In the Clopidogrel Effect on Platelet Reactivity in Patients with Stent Thrombosis (CREST) study, post-treatment platelet reactivity was higher in patients who suffered from subacute stent thrombosis than in patients without, despite the use of clopidogrel therapy in both groups.⁹ The results strongly suggested that the P2Y12 receptor was not adequately inhibited by clopidogrel in a large percentage of patients experiencing subacute stent thrombosis. Matetzky and colleagues found, in a prospective study of 60 consecutive patients with ST-segment elevation MI who underwent angioplasty and stenting, that those patients in the lowest quartile in terms of responsiveness to clopidogrel were at an increased risk for a recurrent cardiovascular event during a six-month follow-up.¹⁰ Similarly, in a prospective study of 105 patients undergoing percutaneous stenting, Muller and colleagues found that the two patients who developed stent thrombosis did not respond to clopidogrel.¹¹

Testing is currently impractical. There is no single and validated platelet function assay to measure the antiplatelet effect of clopidogrel and there is a need for significant prospective data before recommending routine screening on all patients undergoing stenting. Additionally, there are no current therapeutic alternatives to clopidogrel.