Letter by Aboyans et al Regarding Article, “Smoking, Clopidogrel, and Mortality in Patients With Established Cardiovascular Disease”
To the Editor:
Berger and colleagues1 are commended for their interesting and hypothesis-generating posthoc analysis of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial published recently in Circulation. To better understand the potential pathways leading to an enhanced protective effect of clopidogrel in smokers, several issues need further discussion and analysis.
First, the protective effect of clopidogrel in smokers in this report contrasts with the lack of interaction between smoking and antiplatelet strategies in the subgroups analysis in the first Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial report.2 This difference might be explained by a different definition of smoking in the current article1 (≥1 cigarette a day) compared with the original publication (>15 cigarettes a day). The authors should explain why they changed their definition and whether the number of cigarettes smoked daily may affect the beneficial effects of clopidogrel, as suggested recently by others.3
Second, the authors repeatedly called the 2 therapeutic arms of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial the “clopidogrel” group and the “placebo” group, even though both groups were also taking low-dose (75 to 160 mg) aspirin. Another hypothesis that has not been considered by the authors is that the protective effect observed in smokers in the “aspirin plus clopidogrel” group (compared with the “aspirin alone” group) might be related to the antiplatelet effect of clopidogrel in patients resistant to aspirin, the latter condition being strongly associated with smoking.4
Last, the authors report higher rates of bleeding in smokers taking clopidogrel plus aspirin, but they did not detail the different localizations of bleeding. Smoking (along with aspirin) is a risk factor for gastrointestinal ulcers and their hemorrhagic complications.5 The higher rates of bleeding while taking clopidogrel in smokers versus nonsmokers not only might be related to a greater platelet inhibition by this drug in smokers, as suggested by the authors, but also may be due to an increased incidence of smoking-related gastrointestinal complications revealed by dual antiplatelet therapy. Similarly, the higher incidence of different types of cancers in smokers may contribute to this increased hemorrhagic risk.
Berger JS, Bhatt DL, Steinhubl SR, Shao M, Steg PG, Montalescot G, Hacke W, Fox KA, Lincoff AM, Topol EJ, Berger PB, for the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) Investigators. Smoking, clopidogrel, and mortality in patients with established cardiovascular disease. Circulation. 2009; 120: 2337–2344.
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, for the CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006; 354: 1706–1717.