Response to Letter Regarding Article, “Smoking, Clopidogrel, and Mortality in Patients With Established Cardiovascular Disease”
As noted by Dr Aboyans and colleagues, no interaction was noted in the effect of clopidogrel versus placebo on the composite outcome of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial.1 However, in our recently published study,2 we demonstrated a significant interaction of the effect of clopidogrel versus placebo on all-cause mortality and cardiovascular mortality. Dr Aboyans et al suggest that the definition of current smoking may have differed between the 2 studies and that this may account for the difference in results. However, both the randomized trial and our recently published article used smoking ≥1 cigarette a day as the definition of current smoking. When the original randomized trial refers to smoking >15 cigarettes a day, that is referring to the definition of an atherothrombotic risk factor as a study inclusion criterion. As discussed in our recently published article, because smoking status was also used as an entry criterion for inclusion in the study for patients without established cardiovascular disease, patients without established cardiovascular disease were excluded from the smoking analysis. Nevertheless, our findings remained consistent whether we modified the definition of current smoking to ≥1, >5, >10, or >15 cigarettes a day.
Aboyans and colleagues raise the hypothesis that the antiplatelet effect of clopidogrel may be more pronounced in patients resistant to aspirin secondary to smoking. Because we have no data on the platelet response to aspirin or clopidogrel in this analysis, we are unable to confirm or refute this theory. Finally, Aboyans et al suggest that the increased bleeding complications in patients taking clopidogrel may be related to the higher rate of gastrointestinal complications noted in smokers undergoing dual antiplatelet therapy. Although clopidogrel was associated with a numerically greater incidence of major bleeding in current smokers, the interaction between smoking status and the effect of clopidogrel on major bleeding failed to reach statistical significance. Therefore, any hypotheses emerging from this finding require prospective testing in future studies. The source of serious bleeding in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial was gastrointestinal in a little more than half of all bleeding episodes. Although cancer mortality was significantly higher in current smokers, there was no interaction between smoking status and the effect of clopidogrel on cancer mortality, suggesting no significant identification bias.
Dr Berger reports receiving research support from AstraZeneca and has received honoraria for advisory board participation from The Medicines Co. Dr Bhatt has received research grants (to the institution) from AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi-Aventis, and The Medicines Co. Dr Steinhubl is currently a full-time employee of The Medicines Co and as such has stock options in the company. Dr Topol has served as a consultant to Daiichi-Sankyo, Portola Pharmaceuticals, and Sanofi-Aventis. Dr Steg reports receiving research support from Sanofi-Aventis and honoraria as a consultant to or speaker for AstraZeneca, Astellas, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Endotis, GlaxoSmithKline, Merck Sharpe Dohme, Medtronic, Nycomed, Sanofi-Aventis, Servier, Takeda, and The Medicines Co. Dr Fox reports receiving grants and honoraria from Sanofi-Aventis, Glaxo-SmithKline, and MSD during the prior 2 years. Dr Lincoff reports receiving research funding (to the institution) from Sanofi-Aventis, AstraZeneca, Bristol-Myers Squibb, The Medicines Co, Eli Lilly, Johnson and Johnson, Schering-Plough, Scios, Takeda, and Daiichi-Sankyo. Dr Hacke reports having received consulting and lecture fees from Sanofi-Aventis and Bristol-Myers Squibb. Dr Montalescot reports that his institution has received research grants from Bristol-Myers Squibb, Sanofi-Aventis Group, Eli Lilly, Guerbet Medical, Medtronic, Boston Scientific, Cordis, Stago, Centocor, Fondation de France, INSERM, Fédération Françcaise de Cardiologie, and Société Françcaise de Cardiologie; consulting fees from Sanofi-Aventis, Eli Lilly, Bristol-Myers Squibb, The Medicines Co, and Schering-Plough; and lecture fees from Sanofi-Aventis, Eli Lilly, Bristol-Myers Squibb, Merck Sharpe & Dohme, Cordis, GlaxoSmithKline, and Schering-Plough. Dr Berger served as a consultant to PlaCor, Accumetrics, and Lilly/Daiichi Sankyo.
Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006; 354: 1706–1717.
Berger JS, Bhatt DL, Steinhubl SR, Shao M, Steg PG, Montalescot G, Hacke W, Fox KA, Lincoff AM, Topol EJ, Berger PB. Smoking, clopidogrel, and mortality in patients with established cardiovascular disease. Circulation. 2009; 120: 2337–2344.