Clopidogrel-statin interaction: A mountain or a mole hill?
Article Outline
In late 2002, Lau et al1 first reported their results of an ex vivo study showing that atorvastatin, one of several statins metabolized through the cytochrome P450 3A4 (CYP3A4) system, attenuated the antiplatelet effects of clopidogrel in a dose-dependent fashion. In an elegant set of mechanistic experiments, they further demonstrated that other drugs that were substrates of the CYP3A4 system (erythromycin and troleandomycin) had a similar effect whereas drugs that were inducers of CYP3A4 (rifampin) increased clopidogrel's effects as measured by a whole blood single-platelet counting method. Based on these ex vivo studies, they concluded that patients treated with clopidogrel should not be treated with CYP3A4-metabolized statins, not only atorvastatin but also simvastatin and lovastatin. Reaction throughout the medical and lay community after this report was swift. The coprescribing of atorvastatin and clopidogrel generated an automated warning of a “potential harmful interaction” at pharmacies and many patients changed their cholesterol-lowering therapies or antiplatelet treatments based on news stories in the lay press. Over the ensuing months and years, with the publication of a number of conflicting reports, the initial furor died down and practice patterns returned to normal. However, now a full 3 years later, the question of a clopidogrel-statin interaction remains unresolved in many clinician's and researcher's minds as demonstrated by the number of studies that continue to be published on the topic. The question is, of course, a critical one. First, CYP3A4 is responsible for the metabolism of ~60% of currently known drugs including many cardiovascular drugs such as antiarrhythmics and calcium-channel blockers.2 Therefore, the implications of any potential interaction could be extremely far-reaching and influence patient treatment decisions well beyond statins alone. Secondly, because both clopidogrel and statins have been shown to significantly decrease major adverse cardiac events, they are very commonly coadministered, and therefore, any potential interaction would influence the treatment of tens of millions of patients. If all statins were of equivalent benefit in all patients, the question of a potential interaction might be less important, but in at least one head-to-head trial, a CYP3A4-metabolized statin (atorvastatin) was found to be superior to a non–CYP3A4-metabolized statin (pravastatin) in the reduction of ischemic cardiovascular events.3 So, with so much at stake, why does the clinical importance of this remain unclear?
First, much of the data exploring this issue are based on the ex vivo determination of platelet function. Although some measure of the inhibition of agonist-induced platelet aggregation has served as a biomarker for the clinical efficacy of antiplatelet agents for decades, there are actually surprisingly few data demonstrating that any ex vivo measure of the platelet inhibitory effects of clopidogrel correlates with clinical outcome. In the studies of a potential clopidogrel-statin interaction, a wide range of platelet function tests have been utilized: light-transmittance aggregometry, flow cytometric determination of ADP-induced expression of platelet surface markers of activation (eg, P selectin), whole blood single-platelet counting, various point of care tests (PFA-100, Ultegra), and others. None of these can be considered a proven criterion standard, and not only have different tests provided conflicting results, but even the same tests in different laboratories have lead to contradictory conclusions. As highlighted in Table I, although some studies have concluded that CYP3A4-metabolized statins decrease clopidogrel's effect on platelets, a similar number of studies have found that they actually enhance the antiplatelet effects of clopidogrel. Most studies, however, including the largest that involved almost 1400 patients, found no influence of statin therapy on platelet function.6 Although others have tried to rationalize these disparate findings based on differences in clopidogrel dosing or the type of platelet function testing used, no clear pattern seems to exist to support this contention. The results do, however, highlight the severe limitations in translating ex vivo platelet testing results to clinical practice and cardiovascular outcomes.
Table I. Ex vivo studies of clopidogrel-statin interaction
| Study | Patients | Clopidogrel dose | Platelet function study | Effect of CYP3A4 statin on clopidogrel's antiplatelet effect |
|---|---|---|---|---|
| Lau et al1 | 44 | 300 mg load, then 75 mg daily | WBSPC | Attenuates |
| Neubauer et al4 | 47 | 300 mg load, then 75mg daily | Flow cytometry | Attenuates |
| Mach et al5 | 21 | 75 mg daily | LTA | No effect by atorvastatin, attenuated by simvastatin |
| Hochholzer et al6 | 1397 | 600 mg load, then 75mg daily | LTA | No effect |
| Flow cytometry | ||||
| Mitsios et al7 | 45 | 375 mg load, then 75 mg daily | LTA | No effect |
| Flow cytometry | ||||
| Serebruany et al8 | 75 | 300 mg load, then 75 mg daily | LTA | No effect |
| Flow cytometry | ||||
| Muller et al9 | 77 | 600 mg load | LTA | No effect |
| Gorchakova et al10 | 180 | 600 mg load | LTA | No effect |
| Flow cytometry | ||||
| Smith et al11 | 58 | 300 mg load, then 75 mg daily | LTA | No effect |
| Flow cytometry | ||||
| WBSPC | ||||
| Ultegra | ||||
| Zsamboki et al12 | 48 | 300 mg load, then 75 mg daily | LTA | Increases |
| Piorkowski et al13 | 49 | 300 mg load, then 75 mg daily | Flow cytometry | Increases |
| Vinholt et al14 | 66 | Chronic 75 mg daily | LTA | Increases |
| PFA-100 |
With uncertainty regarding the meaning of ex vivo studies, several investigators, including Brophy et al19 in this issue of the Journal, have turned to a variety of clinical data sets to help answer the question (Table II). Before the current study, all previous evaluations attempting to identify an important clinical interaction between clopidogrel and CYP3A4 statins have been unable to find one.15, 16, 17, 18 However, as with all retrospective or post hoc analysis, all of these previous studies had limitations. For similar reasons, so does the current pharmacoepidemiology analysis. The investigators analyzed the administrative databases of the universal health insurance program in Quebec to identify 2927 patients undergoing a percutaneous coronary intervention with a stent between January 1999 and November 2000, all of whom were prescribed clopidogrel.19 From this data set, they found 727 patients who were prescribed atorvastatin and compared their 30-day outcomes with a control group of 2200 patients not prescribed atorvastatin. Surprisingly, only a little >50% of the patients in this control group were prescribed any lipid-lowering therapy, and of these, nearly half received a CYP3A4-metabolized statin. In all, 42% of the control cohort was being treated with a known CYP3A4 inhibitor. Still, a significant difference in 30-day clinical outcomes was found favoring the control group. Importantly, no dose-effect of atorvastatin was identified, and in fact, higher doses were associated with a trend toward better outcomes—the opposite of what would be expected based on the original data of Lau et al.1 The authors also appropriately point out that it is possible that the ∼25% of patients in their study population who were deemed to require treatment with atorvastatin by their physician may represent a higher-risk cohort. Although they attempted to control for this through an analysis adjusting for the covariants available to them, the nature of the administrative database almost certainly limited their ability to do so effectively. Finally, the large percentage of patients in the control group receiving a CYP3A4 inhibitor would suggest that if the relationship between atorvastatin and outcomes were a real one, it would be unlikely to be mediated through its effect on the CYP3A4 system. So based on the results of the current analysis, along with those of earlier clinical studies, it seems that the most appropriate conclusion to be drawn from the available clinical data is that there is no significant influence of the choice of statin on the efficacy of clopidogrel and that studies suggesting either a helpful or a harmful influence are likely due to chance.
Table II. Studies of clinical outcomes in patients treated with clopidogrel and statins
| Study | Type of study | Patients | Effect of statin on clopidogrel's clinical benefit |
|---|---|---|---|
| Mukherjee et al15 | Prospective single-center cohort | 1651 with ACS | None |
| CREDO16 | Post hoc analysis of a prospective, randomized, placebo-controlled trial | 2116 undergoing a non-urgent percutaneous coronary intervention | None |
| MITRA PLUS17 | Prospective multicenter registry | 1576 with ACS | None |
| GRACE18 | Prospective multicenter registry | 15 693 with ACS | Synergistic |
| Brophy et al19 | Retrospective analysis of a population-based database | 2927 undergoing a percutaneous coronary intervention | Detrimental |
Of course, the optimal way to definitely answer the question regarding any clopidogrel-statin interaction would be to carry out a prospective, blinded randomized trial of a high-dose CYP3A4-metabolized statin (such as 80 mg of atorvastatin, a dose that would presumably completely prevent any antiplatelet effects of clopidogrel) and a non–CYP3A4-metabolized statin such as pravastatin, which would have no impact at all on the clinical benefit of clopidogrel. Ideally, such a trial would involve a large population of patients in whom clopidogrel has been proven effective such as an acute coronary syndrome population. The PROVE IT–TIMI 22 trial comes very close to meeting these criteria.3 In this trial, >4000 patients with an acute coronary syndrome within the previous 10 days were randomized to double-blinded therapy with pravastatin 40 mg or atorvastatin 80 mg daily. Although clopidogrel was not mandated, >72% of patients did receive clopidogrel, presumably for at least 1 month because 69% of patients had undergone a percutaneous coronary intervention. By 1 year, 20% of patients were still on clopidogrel. Overall, randomization to atorvastatin was associated with a 24% relative reduction in the primary end point at a mean follow-up of 24 months. However, even by 30-days, when most patients were still receiving clopidogrel, randomization to 80 mg of atorvastatin compared with 40 mg of pravastatin was associated with a significant 28% relative reduction in the primary end point.20 It is almost impossible to explain these results if it were true that only those patients randomized to pravastatin were receiving the proven early benefit of clopidogrel.21
The time is past due to move on from asking whether CYP3A4-metabolized statins interfere with the clinical benefit of clopidogrel. The overwhelming evidence, in particular the clinical evidence, establish that they do not. What remains extremely intriguing is why some, or even most, ex vivo measures of platelet function seem to give us results that have little to no bearing on the clinical efficacy of antiplatelet agents. The answer to this question has implications well beyond the clopidogrel-statin debate as it impacts the development of new antiplatelet agents and the optimization of old ones. Now there is a real mountain.
References
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PII: S0002-8703(06)00051-2
doi:10.1016/j.ahj.2006.01.001
© 2006 Mosby, Inc. All rights reserved.
