Interaction between cigarette smoking and clinical benefit of clopidogrel

Abstract

Objectives: The aim of this study was to examine the interaction between cigarette smoking and the clinical efficacy of clopidogrel in ST-segment elevation myocardial infarction (STEMI).

Background: Cigarette smoking induces cytochrome P450 (CYP)1A2, which converts clopidogrel into its active metabolite, and prior studies suggest greater inhibition of platelet aggregation by clopidogrel in smokers of > or =10 cigarettes/day.

Methods: The effect of clopidogrel compared with placebo on angiographic and clinical outcomes was examined in 3,429 STEMI patients in the CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis In Myocardial Infarction 28) randomized trial stratified by smoking intensity as follows: not current smokers (n = 1,732), and smokers of 1 to 9 (n = 206), 10 to 19 (n = 354), 20 to 29 (n = 715), and > or =30 cigarettes/day (n = 422). Logistic regression was used to adjust for other baseline characteristics and interaction terms to test for effect modification.

Results: Although clopidogrel reduced the rate of the primary end point of a closed infarct-related artery or death/myocardial infarction before angiography in the CLARITY-TIMI 28 trial, the benefit was especially marked among those who smoked > or =10 cigarettes/day (adjusted odds ratio [OR]: 0.49, 95% confidence interval [CI]: 0.37 to 0.66; p < 0.0001) compared with those who did not (adjusted OR: 0.72, 95% CI: 0.57 to 0.91; p = 0.006; p(interaction) = 0.04). Similarly, clopidogrel was significantly more effective at reducing the rate of cardiovascular death, myocardial infarction, or urgent revascularization through 30 days among those who smoked > or =10 cigarettes/day (adjusted OR: 0.54, 95% CI: 0.38 to 0.76; p = 0.0004) compared with those who did not (adjusted OR: 0.98; 95% CI: 0.75 to 1.28; p = 0.87; p(interaction) = 0.006).

Conclusions: Cigarette smoking seems to positively modify the beneficial effect of clopidogrel on angiographic and clinical outcomes. This study demonstrates that common clinical factors that influence the metabolism of clopidogrel might impact its clinical effectiveness.

Figure 1. Benefit of Clopidogrel on Primary Endpoint by Smoking Status

The primary efficacy endpoint was a composite of Thrombolysis in Myocardial Infarction (TIMI) flow grade 0 or 1 on angiography or death or recurrent myocardial infarction prior to angiography. Odds ratios (OR) are adjusted for age, sex, region, hypertension, diabetes, infarct location, time to fibrinolytic therapy, and type of fibrinolytic. For each subgroup, the size of the box is proportional to the number of individuals included in the analysis. The horizontal lines represent the 95 percent confidence intervals (CI).

Figure 2. Benefit of Clopidogrel on 30-Day Clinical Endpoint by Smoking Status

The 30-day clinical endpoint was a composite of death from cardiovascular causes, recurrent myocardial infarction, or recurrent ischemia leading to the need for urgent revascularization. Odds ratios (OR) are adjusted for age, sex, region, hypertension, diabetes, infarct location, time to fibrinolytic therapy, and type of fibrinolytic. For each subgroup, the size of the box is proportional to the number of individuals included in the analysis. The horizontal lines represent the 95 percent confidence intervals (CI).