RECENT ANALYSES OF LARGE-SCALE TRIALS SUGGEST either a reduced or complete lack of clinical benefit from clopidogrel therapy in nonsmokers. Importantly, this observation is not explained by an enhanced prothrombotic state (a condition in which P2Y12 inhibitor therapy may be expected to be most effective) in smokers relative to nonsmokers as evidenced by variable event rates in smokers and nonsmokers treated with placebo. Cigarette smoking induces the activity of cytochrome P450 (CYP) 1A2, an isoenzyme involved in the metabolic activation of clopidogrel but less recognized in importance than CYP2C19. Nonsmokers have greater platelet reactivity than smokers during clopidogrel treatment. A recent additional important analysis of the CAPRIE (Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events) trial revealed a significant interaction based on smoking status (P=.01 for interaction). Specifically, patients in the clopidogrel-treated nonsmoker group (a combination of the neversmoker group and former-smoker group) had no reduction in the incidence of the primary outcome of ischemic stroke, myocardial infarction (MI), or vascular death compared with the aspirin-treated nonsmoker group (10.4% vs 10.6%, respectively; hazard ratio [HR], 0.98 [95% CI, 0.88-1.09]), whereas patients in the clopidogrel-treated currentsmoker group had a significantly lower incidence of the primary outcome compared with the aspirin-treated currentsmoker group (8.3% vs 10.8%, respectively; HR, 0.76 [95% CI, 0.64-0.90]). To our knowledge, the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events [N=12 562]) trial investigators have not presented a similar adjusted analysis of nonsmokers and smokers. However, an abstract based on CURE trial data reported that in the largest smoking status subgroup—never smokers—clopidogrel treatment was not associated with a significant reduction in the primary outcome (a composite of death from cardiovascular causes, nonfatal MI, or stroke) compared with never smokers treated with placebo (10.2% vs 10.9%, respectively; HR, 0.93 [95% CI, 0.79-1.11]), whereas current smokers treated with clopidogrel had a significantly lower incidence of the primary outcome compared with placebo (6.1% vs 9.4%, respectively; HR, 0.63 [95% CI, 0.48-0.83]). In the CREDO (Clopidogrel for the Reduction of Events During Observation) trial, there was no difference in the occurrence of the primary composite end point (1-year death, MI, and stroke) in clopidogrel-treated nonsmokers relative to placebo-treated nonsmokers, whereas a significant benefit was observed in clopidogrel-treated smokers compared with placebo-treated smokers (6.3% vs 13.8%, respectively; HR, 0.44 [95% CI, 0.23-0.83]). Desai et al attempted to refine the relation between smoking status and clinical outcomes based on previous pharmacodynamic findings. These investigators conducted a post hoc analysis of patients with ST-segment elevation MI, based on the quantification of the number of cigarettes smoked at baseline, in the Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis In Myocardial Infarction 28 (CLARITY-TIMI 28) trial. They reported an adjusted analysis based on smoking status for both the primary end point (angiographic outcome) and the secondary end point (30-day clinical outcome), revealing a significant smoking status interaction for both end points (P=.04 and P=.006, respectively, for interaction in patients who smoked at least 10 cigarettes/d). In that trial, clopidogrel therapy was associated with an overall 36% and 20% reduction in the rate of the primary and secondary end points, respectively, relative to placebo. The reduction in the primary end point was enhanced among clopidogrel-treated patients who smoked 10 or more cigarettes per day relative to placebo (adjusted odds ratio [OR], 0.49; P .0001). In addition, clopidogreltreated 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 (13.7% vs 14.3%, respectively; OR, 0.98 [95% CI, 0.75-1.28]), whereas clopidogrel-treated patients who smoked 10 or more cigarettes per day exhibited a 46% reduction in the 30-day clinical end point relative to the placebo group (8.0% vs 14.3%, respectively; OR, 0.54 [95% CI, 0.38-0.76]).