The effect of smoking on residual platelet reactivity to clopidogrel: a systematic review and meta-analysis

Abstract

Cigarette smoking is an important cardiovascular risk factor, causing morbidity and mortality. There are many original studies on the impact of smoking, but its influence on platelet ADP-P2Y12 receptor inhibitors lack consistency. Thus, we conducted a systematic review and meta-analysis of already existing data/studies to further explore this issue. PubMed, Web of science, EMBASE, Clinical Trials, and the Cochrane Library were searched from inception to March 2018. Studies investigating the residual platelet reactivity categorized by smoking status and patients treated with platelet ADP-P2Y12 receptor inhibitors qualified the inclusion criteria. The primary outcome was P2Y12 reaction unit (PRU) value measured by VerifyNow P2Y12 assay, compared with different smoking status in ADP-P2Y12 receptor inhibitors treatment groups. Secondary outcome was post-treatment with 5 μmol/L ADP-inhibition of platelet aggregation (ADP-IPA) measured by light transmittance aggregometry (LTA). Of the 4954 citations retrieved, 12 studies involving 16 296 patients with acute coronary syndrome and/or stent deployment using platelet ADP-P2Y12 receptor inhibitors were included for meta-analysis. Pooled analysis revealed that PRU values of current smokers were 25.70 lower than nonsmokers (95% CI −38.81 to −12.60, p = 0.0001), getting better effects of antiplatelet treatment. In the smoking extent subgroup analysis, patients smoking >10 cigarettes/day shown about 46.49 lower of PRU values than patients smoking <10 cigarettes/day (p < 0.00001). Racial subgroup analyses found that smokers had increased platelet inhibition in the Caucasian population. Further, pooled analysis of ADP-IPA values for 1658 patients from five studies showed a significantly lower residual platelet reactivity in current smokers compared to that in nonsmokers (MD = −4.19; 95% CI −6.55 to −1.83; p = 0.0005). This systematic review and meta-analysis suggested that smokers have increased platelet inhibition and lower aggregation in response to clopidogrel than nonsmokers. These residual platelet reactivity observations may help to explain differential clinical outcomes in smokers vs. nonsmokers in large scale clinical trials.

Keywords:

• Meta-analysis
• platelet aggregation inhibitors
• residual platelet reactivity
• smoking

Statement of Contribution

Yimin Cui and Qian Xiang conceived and designed the study. Zhiyan Liu and Guangyan Mu searched the databases and checked these according to the eligible criteria and exclusion criteria. Yanjun Gong and Jie Jiang helped develop search strategies. Zining Wang, Qiufen Xie, and Shuang Zhou extracted the quantitative data. Zhiyan Liu, Shuqing Chen, and Kun Hu analyzed the data. Zhiyan Liu wrote the draft of the paper. All authors contributed in writing, reviewing, or revising the paper.

Acknowledgments

The authors would like to acknowledge the support of Yanjun Gong and Jie Jiang for early encouragement and assistance with our literature review.

Additional information

Funding

This study was supported by grants from the National Natural Science Foundation (No. 81673509 and No. 81573504) of PR China, Beijing Municipal Natural Science Foundation (No.7171012), National Key R&D Program of China No.2016YFC0904900, and National Science and Technology Major Projects for “Major New Drugs Innovation and Development” of China (No.2017ZX09304028 and No. 2017ZX09101001).