Clopidogrel is a prodrug that requires metabolic activation to attain its active form. Cigarette smoking induces the cytochrome P450 isoenzyme 1A2, a key enzyme involved in activation. Some authors have hypothesized that smoking therefore increases the availability of the active metabolite of clopidogrel, thus enhancing its efficacy. In addition, subgroup analyses of randomized controlled trials have raised the question of whether the efficacy of clopidogrel occurs primarily among smokers. This systematic review, meta-analysis, and series of indirect comparisons aimed to quantify the efficacy of clopidogrel separately in smokers and nonsmokers and to compare the efficacy of newer antiplatelet agents (prasugrel and ticagrelor) in these groups of patients. A total of nine high-quality randomised controlled trials (n= 74,489; 29% smokers) with follow up ranging from 30 days up to three years, met the inclusion criteria.
In smokers, clopidogrel reduced the risk of the composite clinical endpoint (cardiovascular death, myocardial infarction, and stroke) by 25% (relative risk 0.75, 95% confidence interval 0.67 to 0.83). However, there was only an 8% reduction among nonsmokers (0.92, 0.87 to 0.98). In an indirect comparison of antiplatelet agents among smokers, the relative risk was 0.71 (0.61 to 0.82) for prasugrel compared with clopidogrel and 0.83 (0.68 to 1.00) for ticagrelor compared with clopidogrel. Corresponding relative risks were 0.92 (0.83 to 1.01) and 0.89 (0.79 to 1.00) among nonsmokers.
The authors note that although the exact mechanism by which smoking might enhance the activity of antiplatelet agents is not known, the results were considered to be robust – there was statistical heterogeneity among results in each subgroup, results were consistent across sensitivity analyses and there was no strong evidence for potential publication bias. They add that if the findings of this study are confirmed, there could be important risk-benefit considerations for antiplatelet drugs in smokers and nonsmokers. Furthermore, while smokers might be more likely to benefit from treatment, the enhanced antiplatelet effect might also increase the risk of bleeding. Future studies are also required to investigate whether different doses should be used in smokers and nonsmokers.