Impact of smoking on long-term outcomes in patients with atherosclerotic vascular disease treated with aspirin or clopidogrel: insights from the CAPRIE trial (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events).
OBJECTIVE
The goal of this study was to investigate the differential efficacy of clopidogrel or aspirin monotherapy according to smoking status in patients with atherosclerotic vascular disease.


BACKGROUND
Smoking enhances clopidogrel-induced platelet inhibition, which may explain the higher relative benefit among smokers observed in trials evaluating dual antiplatelet therapy. Whether smoking has an impact on clinical outcomes in patients requiring a single antiplatelet agent remains unknown.


METHODS
This was a post-hoc analysis of the CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trial that compared clopidogrel and aspirin monotherapy in patients (N = 19,184) with atherosclerotic vascular disease.


RESULTS
Current smokers (n = 5,688) had an increased risk of ischemic events compared with never smokers (n = 4,135; hazard ratio [HR]: 1.24 [95% confidence interval (CI): 1.08 to 1.42]) and ex-smokers (n = 9,381; HR: 1.32 [95% CI: 1.18 to 1.47]) (p < 0.001). Clopidogrel was associated with a reduction in ischemic events among current smokers (8.3% vs. 10.8%; HR: 0.76 [95% CI: 0.64 to 0.90]), whereas no benefit over aspirin was seen in the combined group of ex-smokers/never-smoked patients (10.4% vs. 10.6%; HR: 0.99 [95% CI: 0.89 to 1.10]; p = 0.01 for interaction). Among current smokers, clopidogrel also reduced myocardial infarction, vascular death, and death from any cause compared with aspirin. No interaction between smoking status and study treatment was observed for bleeding events.


CONCLUSIONS
In a post-hoc analysis of the CAPRIE population, current smokers appeared to have enhanced benefit with clopidogrel therapy for secondary prevention compared with aspirin. These results should be considered hypothesis generating for future prospective studies assessing the impact of specific platelet-inhibiting strategies according to smoking status.
University of Florida College of Medicine-Jacksonville, Jacksonville, Florida; Heart Diseases Institute, Hospital Universitari de Bellvitge-IDIBELL, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
José L
JL
Ferreiro
VA Boston Healthcare System, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
Deepak L
DL
Bhatt
University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
Masafumi
M
Ueno
Department of Biostatistics, Sanofi, Bridgewater, New Jersey.
Deborah
D
Bauer
University of Florida College of Medicine-Jacksonville, Jacksonville, Florida. Electronic address: dominick.angiolillo@jax.ufl.edu.
Dominick J
DJ
Angiolillo
D001241:Aspirin / Q000627:therapeutic use*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000453:epidemiology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000453:epidemiology; D000077144:Clopidogrel; D005260:Female; D006801:Humans; D008297:Male; D012307:Risk Factors; D016037:Single-Blind Method; D012907:Smoking / Q000188:drug therapy* / Q000453:epidemiology; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin
antiplatelet agents; clopidogrel; smoking; smoking paradox