EDITORIAL COMMENT
Clopidogrel–Statin InteractionMyth or Reality?*
Dominick J. Angiolillo, MD, PhD, FACC, FESC ,*,1 and
Fernando Alfonso, MD, PhD, FESC
Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida
Interventional Cardiology, San Carlos University Hospital, Madrid, Spain.
* Reprint requests and correspondence: Dr. Dominick J. Angiolillo, Division of Cardiology, University of Florida-Shands Jacksonville, 655 West 8th Street, Jacksonville, Florida 32209. (Email: dominick.angiolillo{at}jax.ufl.edu).
Variability in individual responsiveness to clopidogrel is an emerging clinical problem (1). Numerous mechanisms have been implied in this phenomenon, among which a "clopidogrel–statin interaction" has been highly speculated (1–4). In particular, lipophilic statins, which are metabolized by cytochrome P450 (CYP) 3A4 and share the same metabolic pathway as clopidogrel, have been suggested to potentially reduce the clinical benefit of clopidogrel (1–4). However, there are conflicting opinions on the existence of a clopidogrel–statin interaction. To address this, both prospective studies and post-hoc assessments of large-scale clinical trials have been performed (5–9). In most cases, however, as in a post-hoc analysis of the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial published in this issue of the Journal (10), no evidence of a negative clinical interaction was shown. In this commentary, we address the current knowledge of ex vivo platelet function assessments, as well as clinical studies evaluating the implications of clopidogrel-statin coadministration.
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Clopidogrel–statin interaction: ex vivo findings and potential clinical implications
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Clopidogrel is a prodrug requiring oxidation by the hepatic CYP system to generate an active metabolite, which irreversibly blocks the platelet P2Y12 receptor. The degree of metabolic activity of CYP3A4, the dominant metabolic pathway of clopidogrel (11), has been associated with different levels of clopidogrel-induced antiplatelet effects (12). Clopidogrel response variability may be attributed to clinical, cellular, or genetic factors (1). Some of these can affect the activity of the CYP3A4 system, thus interfering with the hepatic conversion of clopidogrel into its active metabolite and leading to variations in the antiplatelet effects achieved (Table 1).
In 2003, Lau et al. (2) reported an interaction between a CY3A4 metabolizing statin, atorvastatin, and clopidogrel. In this preliminary ex vivo study performed in 44 subjects, a dose-dependent attenuation of clopidogrel-induced antiplatelet effects was observed. These results rapidly led to overwhelming concern over the potential harmful consequences of coadministration of these drugs. Results of another small ex vivo analysis using another CYP3A4 metabolizing statin (simvastatin) corroborated the presence of a clopidogrel–statin interaction (3). Despite the ex vivo nature of these small studies and the lack of evidence of clinical consequences, many patients requiring concomitant clopidogrel and statin therapy were switched from a CYP3A4-metabolizing to a non–CYP3A4-metabolizing statin. This approach also generated dispute, given that these findings paralleled in time with the observation that atorvastatin was superior to pravastatin, a non-CYP3A4-metabolizing statin, in reducing cardiovascular events (13). In this study,  70% of patients received clopidogrel for at least 1 month, and, at 30 days, those treated with atorvastatin (80 mg) had a 28% relative reduction in the primary end point compared with patients treated with pravastatin (40 mg). It would thus be unlikely that these results would have been obtained if only patients treated with pravastatin were receiving the early benefit of clopidogrel (14).
Recently, there has been accumulating evidence on the prognostic implications of inadequate clopidogrel-induced antiplatelet effects (1). This has inevitably led to further investigation of the clopidogrel–statin interaction phenomenon. Experimental studies, including several prospective analyses and a plethora of post-hoc assessments, mostly reject the hypothesis of a clopidogrel–statin interaction (1,15). Clinical studies have corroborated these laboratory findings (5–8,10). To date, only 1 report showed a negative clinical interaction between clopidogrel and a CYP3A4-metabolizing statin (9). In addition, this study showed that other CYP3A4-metabolized drugs also increased the risk of adverse cardiac events after stenting (9). These findings should not be undervalued, because >50% of all drugs (including many cardiovascular medications) require CYP3A4 (16). However, all other clinical analyses failed to find a negative clopidogrel–statin interaction (Table 2).
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Clopidogrel–statin interaction: insights from the CHARISMA trial
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In 2003, Saw et al. (5) demonstrated the lack of a clopidogrel–statin interaction in a post-hoc analysis of the CREDO trial. The unsettled debate on this potential interaction led the same investigators to perform a similar post-hoc analysis in another large-scale, randomized, placebo-controlled trial: CHARISMA (10). This analysis considered >10,000 patients on the basis of their baseline use of a statin (65% of the overall study population) (10). Of these, 80% were treated with CYP3A4-metabolizing statins. This is the largest study assessing the theoretical concerns of a clopidogrel–statin interaction in which, once more, no interaction was found. Nevertheless, some observations from this post-hoc analysis should be made.
First, it is important to remember that the primary end point of the CHARISMA trial was not met, making this an overall negative trial (17). Thus, in this setting, it is quite difficult to anticipate the identification of any potential "reduction in clinical efficacy" as the result of an interaction of clopidogrel with another drug. Second, the CHARISMA trial had a combined primary end point, and data on the potential influence of statin therapy on each component of the primary end point would be illustrative. In fact, some events (myocardial infarction) may be interpreted as the result of increased platelet aggregation, whereas others (fatal bleeding) may have a completely different pathogenesis, thus canceling the net effects and obscuring the potential drug interaction. Third, the CHARISMA trial patients treated with CYP3A4-metabolizing statins had adverse baseline characteristics (10). However, in the "higher risk" patient group requiring statins, the primary end point was less frequent (5.9% clopidogrel vs. 6.6% placebo) than in the complete study cohort (6.8% clopidogrel vs. 7.3% placebo). This finding appears to be counterintuitive and deserves further investigation. Fourth, numerous other cardiovascular medications are metabolized by the CYP3A4 system and may confound this post-hoc assessment (37% of patients were receiving calcium antagonists). Finally, more encouraging conclusions would come from analyses performed in the highest risk patients in whom clopidogrel is known to be particularly effective, such as in the "CAPRIE-like" cohort of patients enrolled in the CHARISMA trial.
Despite these caveats, overall, the large number of patients included in the present study, the elegant analysis performed, and the consistent results observed in most subgroups provide robust evidence excluding any potential clinical implication of the disputed clopidogrel–statin interaction.
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Clopidogrel–statin interaction: a critical appraisal
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To date, most laboratory findings reject the hypothesis of a clopidogrel–statin interaction. This inevitably warrants critical analyses of the studies suggesting the contrary. First, there are numerous methods to measure clopidogrel-induced antiplatelet effects (1). Some of these, however, such as light transmittance aggregometry and assessment of intraplatelet vasodilator-stimulated phosphoprotein, are more validated and have been associated with clinical outcomes (1). In the few studies demonstrating the presence of a negative clopidogrel–statin interaction, these methodologies were not used (2,3). Second, inadequate platelet inhibition is more common in the early phases of clopidogrel treatment, which is when the studies showing a negative clopidogrel–statin interaction were performed (2,3). Clopidogrel responsiveness improves with length of therapy, and there is no evidence that statins negatively influence clopidogrel effects in the steady-state phase of treatment (1,18). Third, high clopidogrel dosing improves responsiveness (1). In studies showing a clopidogrel–statin interaction, standard clopidogrel doses were used (2,3). However, Lau et al. (2) did observe a dose-dependent effect of CYP3A4-metabolizing statins on clopidogrel-induced antiplatelet effects. Alternatively, relatively low doses of statins have been used in previous studies. Accordingly, it remains possible that mild inhibitory effects of atorvastatin may have been overlooked by such study designs.
The paucity of evidence supporting a negative clopidogrel–statin interaction may question the rationale per se of this dilemma. Although the CYP3A4 system represents the major metabolic pathway for clopidogrel (11), other CYP isoenzymes (e.g., 3A5, 2C9, 2C19, 2B6, or 1A2) may be implied (1). Similarly, metabolism of lipophilic statins also includes auxiliary CYP isoenzymes (16). This suggests that alternative CYP isoenzymes may become more relevant in patients concomitantly treated with multiple CYP3A4-metabolized drugs. Moreover, it cannot be excluded that a clopidogrel–statin interaction may be observed only in specific patient subgroups, such as those with low CYP3A4 metabolic activity (12) or with up-regulation of the P2Y12 pathway (19). Genetic profiling and studies in specific patient subsets may be useful to unravel this dilemma. Ultimately, the presence of an extrahepatic origin of a clopidogrel–statin interaction should not be underestimated. In fact, CYP3A4-metabolizing statins have inhibitory effects on the multidrug transporter P-glycoprotein located on intestinal epithelial cells, and recent findings have shown that clopidogrel absorption and active metabolite formation are diminished by P-glycoprotein mediated efflux (16,20).
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Conclusions
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Data currently available suggest that clopidogrel response variability is clinically more important than the possibility of interaction with other CYP3A4-metabolized drugs. Therefore, clinicians should continue to prescribe clopidogrel and statins where clinically indicated and disregard selecting statins on the basis of CYP3A4 metabolism. Nevertheless, prospective studies are still required to fully elucidate the potential clinical impact of coadministration of CYP3A4-metabolized drugs, including clopidogrel and lipophilic statins. Patients in whom these drugs have clearly proven to be clinically effective should be targeted for these studies, which should be integrated with standardized biological assessments. With the ever-increasing length of dual antiplatelet therapy required after the use of drug-eluting stents (21), any potential drug interaction with clopidogrel warrants further investigation. Given the widespread use of these medications in patients with cardiovascular disease, even a significantly marginal effect may be extremely far reaching, translating into a large number of clinical events in routine clinical practice.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
1 Dr. Angiolillo has served as a consultant/speaker’s bureau member for Bristol-Myers Squibb and Sanofi-Aventis.
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References
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