Recently, there have been concerns that certain statins may inhibit the activity of clopidogrel by competing for the cytochrome P450 CYP3A4 enzyme that metabolizes clopidogrel. Atorvastatin, lovastatin, and simvastatin are also metabolized by CYP3A4, whereas pravastatin, fluvastatin, and rosuvastatin are not metabolized by CYP3A4 and would not be expected to alter clopidogrel activation.

Clopidogrel, however, is an inactive prodrug that also requires in vivo conversion in the liver by the CYP3A4 enzyme to an active metabolite to exert its antiplatelet effect.

Last year, a study published in Circulation and previously reported by heartwire indicated that the antiplatelet action of clopidogrelas measured by the Plateletworks^TM (Helena Laboratories Corp, Beaumont, TX) aggregometerwas inhibited by the lipid-lowering drug atorvastatin, but not pravastatin.1 Another German study, also reported by heartwire and published in the European Heart Journal, suggested that atorvastatin and simvastatin may interfere with the activity of clopidogrel.2

Dr Nazheem Wahab

However, these previous study results have been disputed, and many of the leading investigators in the major clopidogrel clinical trials such as CREDO and CURE believe the findings of an interaction between certain statins and clopidogrel are not clinical relevant.

Lead investigator of this most recent study, Dr Nazheem Wahab (Dalhousie University, Halifax, NS), said that in this clinical setting, any blunting of the antiplatelet effect of clopidogrel would be expected to result in an increased thrombotic event rate.

"The clinically relevant question is if the reduced antiplatelet activity translates into patients coming back with more symptoms requiring repeat revascularization and recatheterization based on symptoms," Wahab told heartwire. "Based on this, we were not able to demonstrate any kind of increase in clinically adverse events."

Investigators used the registry of the ongoing Improving Cardiovascular Outcomes in Nova Scotia (ICONS) initiative to identify 1537 patients who underwent PCI between January 1, 2000 and December 31, 2001.

Investigators sought to determine whether the interaction between clopidogrel and the various statinsmost important, atorvastatin and simvastatin, the two statins expected to compete for CYP3A4 with clopidogrelused in the study lead to differential clinical outcomes in patients at higher risk for thrombosis. The 30-day and 180-day composite end point of unstable angina, acute MI, and death was selected as the primary outcome. Repeat revascularization by PCI or CABG was also analyzed.

In patients undergoing PCI, nearly 95% received a stent and the loading dose of clopidogrel was 300 mg followed by 75-mg administration for 28 days following PCI. The mean statin dose was 25 mg.

Based on univariate and multivariate analysis, there was no significant difference in event outcomes between any of the statins or control group at 30 days. There was also no significant difference in event rates across the statin and control groups at 180 days.

Dr Jafna L Cox

According to senior author Dr Jafna L Cox (Dalhousie University, Halifax, NS), the fact that investigators did not see any of theoretic blunting of the antiplatelet benefit of clopidogrel highlights the importance of clopidogrel in real-world clinical practice.

"From a practical perspective, it's in that one month following stent implantation when the patient is at biggest risk for a thrombotic occlusion that we've historically treated people with a double antiplatelet agent, more recently with aspirin and clopidogrel," Cox told heartwire. "The goal is to protect the stent during that one-month period so endothelialization can occur."

Cox added, "Whatever the guys in the lab might be showing, the people who are looking at this from a real-world perspective are not seeing any clinical adverse outcomes."