The impact of smoking on clinical efficacy and pharmacodynamic effects of clopidogrel: a systematic review and meta-analysis.

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 I(2) 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 (I(2) 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.