Of the 12,152 patients included in this analysis, 2419 (19.9%) were current smokers, 6260 (51.5%) were former smokers, and 3473 (28.6%) never smoked. The median time of quitting smoking for former smokers was 11 years (range, 0 to 69 years; mean 14.3 ±13.4 years). shows the baseline characteristics of the study participants by smoking status. Compared with never smokers, current smokers were younger, less frequently female and more likely to be Caucasian. Current smokers were less likely to have a history of hypertension, diabetes, heart failure, or prior revascularization, but were more likely to have peripheral arterial disease.
Baseline demographics by smoking status
All-cause mortality significantly differed according to smoking status: current smoker – 6.1%, former smoker – 4.6%, never smoker – 4.3%, P=0.001 (). After multivariable adjustment, current smokers had an increased hazard of all-cause mortality (hazard ratio (HR) 2.58, 95% confidence interval (CI) 1.85 – 3.60, P<0.01) compared with never smokers; whereas the hazard associated with former smokers compared with those who never smoked did not reach statistical significance (HR 1.25, 95% CI 0.93 – 1.68, P=0.14) (). In multivariable adjusted modeling, cardiovascular mortality (HR 2.26, 95% CI 1.48 – 3.45, P<0.01) and cancer mortality (HR 3.56, 95% CI 1.96 – 6.46, P<0.001) were elevated in current smokers compared with never smokers. Former smokers compared with never smokers were at increased hazard for cardiovascular mortality (HR 1.29, 95% CI 0.90 – 1.84, P=0.17) and cancer mortality (HR 2.08, 95% CI 1.24 – 3.49, P<0.01), although the former was not statistically significant.
Kaplan-Meier curves of cardiovascular events stratified by smoking status
Hazard Ratios for death and cardiovascular events according to smoking status
The incidence of cardiovascular events (MI/stroke/cardiovascular death) was 8.4% in current smokers, 7.1% in former smokers and 7.3% in never smokers (P=0.05). Compared with those who never smoked, current smokers had an increased adjusted hazard of cardiovascular events (HR 1.49, 95% CI 1.21 – 1.82, P<0.01). No excess hazard was seen for former smokers (HR 1.00, 95% CI 0.84 – 1.17, P=0.95). Current smokers had a greater hazard of stroke (HR 1.56, 95% CI 1.16 – 2.10, P<0.01); for MI, the excess risk did not reach statistical significance (HR 1.37, 95% CI 0.96 – 1.95, P=0.08). No significant difference was observed between former smokers and never smokers for MI or stroke ().
Severe or moderate bleeding occurred in 3.1% of current smokers, 3.0% of former smokers and 3.3% of never smokers (P=0.64). After multivariable adjustment, current smokers had a higher hazard of severe or moderate bleeding (adjusted HR 1.48, 95% CI 1.09 – 2.00, P=0.01) compared with never smokers. No statistically significant increased hazard for severe or moderate bleeding was observed for former smokers (HR 1.06, 95% CI 0.83 – 1.34, P=0.64).
Current versus former smokers
After removing all patients who never smoked from the analysis, we performed multivariable adjustments to compare current versus former smokers. Current smokers were at increased risk for all-cause mortality (HR 1.72, 95% CI 1.39 – 2.12, P<0.01), cardiovascular mortality (HR 1.62, 95% CI 1.23 – 2.13, P<0.01), cancer mortality (HR 1.69, 95% CI 1.21 – 1.82, P<0.01), cardiovascular events (HR 1.56, 95% CI 1.31 – 1.86, P<0.01), MI (HR 1.39, 95% CI 1.03 – 1.882, P=0.03), stroke (HR 1.56, 95% CI 1.18 – 2.05, P<0.01), and severe or moderate bleeding (HR 1.38, 95% CI 1.05 – 1.83, P=0.02) compared with former smokers ().
Adjusted hazard ratio for the cardiovascular endpoints in current smokers versus former smokers
Finally, we assessed whether smoking status had any influence on the effect of clopidogrel. In the overall cohort, all-cause mortality was 4.6% with clopidogrel and 5.0% with placebo (HR 0.91, 95% CI 0.78 – 1.07, P=0.27). A significant interaction existed between current smokers and clopidogrel use for the outcome of all-cause mortality (P=0.018). Among current smokers, clopidogrel was associated with a reduction in all-cause mortality (HR 0.68, 95% CI 0.49 – 0.94). No reduction in all-cause mortality was noted for either former smokers (HR 0.95, 95% CI 0.75 – 1.19) or patients who never smoked (HR 1.14, 95% CI 0.83 – 1.58). Similarly, a significant interaction existed between current smokers and clopidogrel for the outcome of cardiovascular mortality (P for interaction =0.037) (). As would be expected, no significant interaction was noted for cancer mortality (P=NS).
Subgroup analysis of clopidogrel versus placebo on a) all-cause mortality, b) cardiovascular mortality, and c) cancer mortality by smoking status
The effect of clopidogrel on reducing cardiovascular events (MI/stroke/cardiovascular death) did not differ according to smoking status (P for interaction=NS). Clopidogrel was associated with a non-significant reduction in cardiovascular events in current smokers (HR 0.93, 95% CI 0.71 – 1.22), former smokers (HR 0.83, 95% CI 0.69 – 1.00), and never smokers (HR 0.92, 95% CI 0.72 – 1.17). Although no significant interaction was noted, the benefit of clopidogrel versus placebo on the risk of cardiovascular death or MI was greater in current smokers (HR 0.82, 95% CI 0.58 – 1.15) than in former smokers (HR 0.92, 95% CI 0.74 – 1.15) or those who never smoked (HR 1.01, 95% CI 0.74 – 1.37).
The relationship between clopidogrel versus placebo on severe or moderate bleeding is illustrated in . The risk of severe or moderate bleeding was increased in all smoking categories. However, despite the lack of a significant interaction between smoking and bleeding (P for interaction = NS), the magnitude of the risk of severe or moderate bleeding with clopidogrel seemed to be related to smoking status. Specifically, clopidogrel was associated with a statistically significant increase in the risk of bleeding in current smokers (HR 1.62, 95% CI 1.02 – 2.58, P=0.04). Among those who never smoked, however, the increase in risk associated with clopidogrel was not statistically significant (hazard ratio, 1.31, 95% CI 0.90 – 1.90, P=0.15).
Hazard ratio of severe or moderate bleeding in randomized assignment to clopidogrel versus placebo therapy according to smoking status