In a viewpoint published on June 19 in the Journal of the American Medical Association (JAMA), the authors look at several large-scale clinical trials that have led to the dominant use of clopidogrel in the treatment of high-risk patients with cardiovascular disease.

However, the authors note that "evidence from these same studies consistently support less or no clinical efficacy from clopidogrel therapy among patients who do not smoke."

The authors analyzed the following clinical trials:

• Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events (CAPRIE)
• Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE)
• Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction 28 (CLARITY-TIMI 28)
• Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA)
• Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events – Seventh Organization to Assess Strategies in Ischemic Symptoms (CURRENT-OASIS 7) trial.

In the CAPRIE trial, "patients in the clopidogrel-treated nonsmoker group had no reduction in the incidence of the primary outcome of ischemic stroke, myocardial infarction, or vascular death compared with the aspirin-treated nonsmoker group."

The authors note that an abstract based on the CURE trial reported that, "the largest smoking status subgroup – never smokers – clopidogrel treatment was not associated with a significant reduction in the primary outcome compared with never smokers treated with placebo."

In the CLARITY-TIMI 28 trial the authors observe that "clopidogrel-treated patients who smoked zero cigarettes per day or less than one-half pack per day had no significant benefit in 30-day clinical end point occurrence compared with patients treated with placebo."

Similarly in the CHARISMA trial, authors note that "no reduction in all-cause mortality was reported for clopidogrel relative to placebo therapy for either never smokers or former smokers."

The CURRENT-OASIS 7 trial indicated that "there was no reduction in the primary composite end point of cardiovascular death, myocardial infarction, and stroke for nonsmokers treated with high-dose clopidogrel."

The authors' observations "raise concerns about the costs and potential risks incurred by treating nonsmokers with clopidogrel.” They add that the, “clopidogrel-smoking interaction deserves further scrutiny and may be related to the influence of cigarette smoking on CYP activity."

They conclude noting that the "influence of smoking status on clopidogrel metabolism is currently being evaluated in a prospective study."

"It is important to recall that this analysis of post-hoc subgroup analyses is only a hypothesis-generating study," said Christopher Cannon, MD, FACC, editor-in-chief of the Science and Quality section of CardioSource. "It is a reasonable hypothesis: that greater efficacy of clopidogrel exists in smokers due to induction of the CYP 2C19 enzyme that could increase the amount of active metabolite, and thereby have a greater level of antiplatelet effect and clinical effect. We all look forward to seeing the data from the author's completed platelet function study. However, the clinical implications would need to be prospectively confirmed in a large clinical outcomes trial."

"However, to say that all the benefits of clopidogrel (as seen in so many large trials) derive only from benefit in 1/3 of patients who are smokers seems unlikely," Cannon added. "I do not know of other cardiovascular therapies that only work in 1/3 of patients, that have multiple positive Phase III outcomes trials in all comers. Thus, this viewpoint raises an interesting idea, but we should wait before doing anything differently until there are other prospective large clinical trials on this topic."

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