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CLINICAL RESEARCH: ANTIPLATELET THERAPY

Interaction Between Cigarette Smoking and Clinical Benefit of Clopidogrel

Nihar R. Desai, MD, MPH^_*, Jessica L. Mega, MD, MPH, Songtao Jiang, MPH, Christopher P. Cannon, MD and Marc S. Sabatine, MD, MPH^,_*

^_* Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts
TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts
Harvard Clinical Research Institute, Boston, Massachusetts

Manuscript received September 21, 2008; revised manuscript received December 9, 2008, accepted December 16, 2008.

^_* Reprint requests and correspondence: Dr. Marc S. Sabatine, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115 (Email: msabatine{at}partners.org).

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 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 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 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 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.

Key Words: clopidogrel • cytochrome P450 • smoking

Abbreviations and Acronyms   ACS = acute coronary syndrome(s)   ADP = adenosine diphosphate   CI = confidence interval   CYP = cytochrome P450   MI = myocardial infarction   OR = odds ratio   STEMI = ST-segment elevation myocardial infarction   TFG = Thrombolysis In Myocardial Infarction flow grade   TIMI = Thrombolysis In Myocardial Infarction

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