Context Previous findings regarding the relationship between smoking and clopidogrel effects were considerably discrepant.

Objective To assess the impact of smoking on clinical and pharmacodynamic response to clopidogrel.

Data sources Medline, EMBASE and the Cochrane Library through January 2013 were searched. Reference lists of pertinent literatures and abstracts of major cardiovascular conferences were screened.

Study selection Clinical and laboratory studies, which reported major adverse cardiovascular events and on-clopidogrel platelet reactivity categorised by smoking status respectively, were selected.

Data extraction Descriptive and quantitative data were extracted. The main analyses were performed under a random-effects model. For clinical studies, HR estimates were synthesised according to smoking status; for laboratory studies, standardised mean difference (SMD) of on-clopidogrel platelet reactivity and OR for high on-clopidogrel platelet reactivity were pooled. Heterogeneity was quantified by computing I² statistic.

Results Of the 1869 citations retrieved, seven clinical studies and 12 laboratory studies involving 111 132 patients with established cardiovascular disease and 6658 patients with acute coronary syndrome and/or stent deployment, respectively, were included for meta-analysis. Pooled clinical results showed that an intensified antiplatelet regimen involving clopidogrel was associated with 10% reduced risk for major adverse cardiovascular events among non-current smokers (HR 0.90; 95% CI 0.85 to 0.96), while this clinical benefit was enhanced by 2.9-fold among current smokers (HR 0.71; 95% CI 0.62 to 0.80). Pooled analysis of laboratory studies revealed that current smokers had significantly lower on-clopidogrel platelet reactivity (SMD −0.30; 95% CI −0.46 to −0.15) but, notably, there was considerable inter-study heterogeneity (I² 76.2%; p=0.000). The analysis based on four studies (n=1423) suggested a significantly lower odds of high on-clopidogrel platelet reactivity among current smokers than those among never smokers (OR 0.33; 95% CI 0.22 to 0.43).

Conclusions Smoking appears to positively modify the relative clinical efficacy and pharmacodynamic effects of clopidogrel.