Dual antiplatelet therapy with aspirin and thienopyridines (clopidogrel or ticlopidine) has become increasingly important in the management of patients with ischemic vascular disease. The combination of aspirin and clopidogrel has become the standard for the prevention of sub-acute stent thrombosis and protection against ischemic events in a variety of clinical scenarios including acute coronary syndromes (ACS) and ST-elevation myocardial infarctions (MIs).^1–6 However, clinical experience with clopidogrel and aspirin suggests that some patients do not exhibit the expected response and recurrent events on aggressive therapy are common. In fact, in the recently reported Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa inhibitors (SYNERGY) trial, more than 10% of patients presenting with high-risk ACS treated with ‘triple antiplatelet therapy’ (aspirin, clopidogrel, and glycoprotein IIb/IIIa inhibition) and with intensive antithrombin therapy suffered a recurrent MI at 30 days.⁷ The concept that some patients might be resistant to the effects of aspirin and/or clopidogrel has been advanced to explain the high recurrent event rate noted in trials such as SYNERGY. Unfortunately, there remains no clear definition of antiplatelet ‘resistance’. There is an accumulation of evidence, largely from studies performed ex vivo, that suggests significant interpatient and temporal variability in response to these agents. In this article, ex vivo and clinical evidence regarding clopidogrel resistance is reviewed and potential mechanisms for this phenomenon summarized.

Ex-vivo Evaluation of the Antiplate let Effects of Clopidogrel

A variety of techniques have been employed to quantify the variability in platelet inhibition associated with clopidogrel therapy. In these small studies, the percentage of patients found to exhibit at least some degree of resistance to clopidogrel varied dramatically with the type of assay, definition of resistance, and the length of follow-up (see Table 1). Results from a recent trial serve to illustrate the difficulty in translating results from ex vivo analyses to clinical practice. Lebarthe et al. measured the effect of clopidogrel therapy on platelet activation using optical platelet aggregometry in platelet-rich plasma, the current gold standard for such studies. Employing traditional methods, and applying common criteria for clopidogrel resistance (<10% inhibition of peak platelet aggregation), a group of patients with stable angina were screened for resistance to clopidogrel. Thirty-five per cent of these patients were found to be non-responsive to clopidogrel after seven days of therapy; results comparable with those from other groups.^8–10 In this study, however, the analysis was repeated with a more physiologic platelet agonist (rhiruden and D-Phenylanalyl-prolyl-arginine chloromethyl ketone), and the percentage of patients found to be non-responsive to clopidogrel fell to 12%. Furthermore, it has been argued that focusing on peak platelet aggregation (one minute after addition of the agonist) is less physiologic than measuring ‘late’ platelet aggregation (six minutes after the addition of the agonist).¹¹ When the analysis was repeated using the more physiologic agonist and late aggregation, the number of non-responsive patients fell to 6%, more consistent with recurrent event rates in clinical trials.⁸

Clinical Evidence for Clopidogrel Resistance

Ex vivo measurements of platelet activity have traditionally been difficult to relate to clinical events.¹² There are two small trials examining clinical outcomes in the setting of an inadequate response to clopidogrel. Matetzky and colleagues evaluated response to clopidogrel therapy among 60 patients undergoing percutaneous coronary intervention (PCI) in the setting of ST segment elevation MI. Platelet activity was assessed before and after clopidogrel administration via optical aggregometry, and by a cone and platelet analyzer. In the six months following enrollment, there were eight cardiovascular events that occurred in seven patients. Seven of these events (88%) occurred among patients described as clopidogrel non-responders.¹³

In a larger study, Gurbel et al. randomized 120 patients scheduled to undergo elective PCI to treatment with 300mg of clopidogrel, 600mg, or the same doses in patients also receiving the glycoprotein (GP) IIb/IIIa inhibitor eptifibitatide. Using the ex vivo measurements of platelet activity, platelet inhibition was more complete among patients treated with higher doses of clopidogrel and higher still among patients randomized to receive adjuvant GP IIb/IIIa inhibition. Most importantly, patients receiving more intensive antiplatelet therapy were less likely to exhibit post-procedural elevation in serum troponin levels. Because baseline platelet activity was related to responsiveness to clopidogrel it was recommended that complete platelet inhibition should become a ‘therapeutic target’ in PCI.¹⁴