Potential Mechanisms for Clopidogrel Resistance

Numerous mechanisms could explain the observed variability in response to clopidogrel (see Table 2). Gurbel et al. noted that elevated baseline platelet activity was related to an inhibited response to clopidogrel in one study and increased post-procedural MI in another.^9,14 Variability in the serum concentrations of compounds known to modulate platelet activity, such as adenosine diphosphate, nitric oxide, thrombin, tissue factor, or thromboxane A2, may explain an inadequate response to clopidogrel. Muller et al. found that clopidogrel did not inhibit platelet aggregation in response to thrombinrelated activating peptide, suggesting that elevated serum thrombin levels could overwhelm the effects of thienopyridines.¹⁵ Reponse to clopidogrel may be related to bioavailability as well. Significant correlations between inhibition of ADP-induced platelet aggregation and plasma levels of clopidogrel, its active metabolite, and its inactive carboxyl metabolite have been identified among 10 healthy volunteers.¹⁶ Higher doses of clopidogrel have been shown to be more effective in achieving complete inhibition of platelet activity, perhaps by providing higher concentrations of the active metabolite.¹⁴

Genetic polymorphisms of many proteins may modulate response to thienopyridine therapy. In particular, variation in the density of the platelet receptor that binds clopidogrel (the P2Y12 receptor), or genetic polymorphisms in the receptor itself, could affect the response to clopidogrel. Fontana et al. have described variations in the structure of the P2Y12 receptor that were associated with higher maximal platelet aggregation and more commonly found among patients with peripheral arterial disease.^17,18 Other groups have characterized P2Y12 receptor polymorphisms but have not consistently demonstrated increased platelet aggregation or a relationship to adverse events.^19,20

An important potential mechanism contributing to a lack of uniformity in response to clopidogrel is variability in cytochrome P450 3A4 activity. Cytochrome P450 oxidation is central to the generation of the active metabolite of clopidogrel. Lau and colleagues investigated this hypothesis in a study of 35 healthy patients and 35 patients undergoing elective PCI. Platelet aggregation studies were performed before and after treatment with clopidogrel, and cytochrome P450 3A4 activity was measured using the erythromycin breath test. A highly significant inverse correlation was found between cytochrome P450 activity and clopidogrel non-responsiveness in healthy volunteers and those undergoing PCI. In addition, coadministration of rifampin, an inducer of the cytochrome P450 3A4 isoenzyme, and clopidogrel resulted in improved inhibition of platelet aggregation in a group of healthy volunteers.²¹

Additional evidence in favor of this mechanism was put forward by Matetzky et al., who noted that patients resistant to clopidogrel were less likely to be cigarette smokers than patients who responded as expected.The authors noted that nicotine and the aromatic hydrocarbons found in cigarette smoke, activate the cytochrome P450 isoenzymes.¹³ Furthermore, in a separate study, Lau et al. demonstrated in vitro that atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation, via competition for cytochrome P450 3A4 isoenzyme binding.22 On the other hand, in the Interaction of Atorvastatin and Clopidogrel Study (INTERACTION) no interaction between the antiplatelet effects of clopidogrel and statin therapy was identified using a variety of ex vivo methods to characterize platelet activity.²³ Perhaps most importantly, no evidence for increased risk of adverse events was detected among patients treated with statins and clopidogrel in retrospective analyses of data from several clinical trials.^24–26 Most notably, in the Clopidogrel for the Reduction of Events During Observation (CREDO) trial were previously published as part of MedscapeCREDO trial, Saw and colleagues found no increase in the event rate among patients enrolled in CREDO concomitantly treated with CYP3A4-metabolized statins (i.e. atorvastatin) and clopidogrel.²⁵

Clopidogrel Resistance?

The term ‘clopidogrel resistance’ has been used to describe patients who demonstrate a relatively poor response to clopidogrel ex vivo. It appears there are a significant number of patients who fail to respond to clopidogrel as expected. Additionally, there is evidence that a failure to respond appropriately is associated with an increased risk of adverse clinical events. Several of the proposed mechanisms for clopidogrel are reasonable and would predict and explain the wide inter-patient variability noted in some trials of ex vivo platelet response. However, whether use of the term ‘clopidogrel resistance’ is appropriate deserves further study and consideration. Large-scale studies that carefully correlate baseline platelet activity with the degree of inhibition by aspirin and/or clopidogrel and with clinical events are necessary to validate the concept of antiplatelet resistance and shed light on the mechanism(s) involved.