The effect of statins on cardiovascular outcomes by smoking status: A systematic review and meta-analysis of randomized controlled trials


Sorin Ursoniu | Dimitri P. Mikhailidis | Maria-Corina Serban | Peter Penson | Peter P. Toth | Paul M. Ridker | Kausik K. Ray | Kees Hovingh | John J. Kastelein | Adrian V. Hernandez | JoAnn E. Manson | Jacek Rysz | Maciej Banach | Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group

First published: August 2017 |


Smoking is an important risk factor for cardiovascular disease (CVD) morbidity and mortality. The impact of statin therapy on CVD risk by smoking status has not been fully investigated. Therefore we assessed the impact of statin therapy on CVD outcomes by smoking status through a systematic review of the literature and meta-analysis of available randomized controlled trials (RCTs). The literature search included EMBASE, ProQuest, CINAHL and PUBMED databases to 30 January 2016 to identify RCTs that investigated the effect of statin therapy on cumulative incidence of major CVD endpoints (e.g. non-fatal myocardial infarction, revascularization, unstable angina, and stroke). Relative risks (RR) ratios were calculated from the number of events in different treatment groups for both smokers and non-smokers. Finally 11 trials with 89,604 individuals were included. The number of smokers and non-smokers in the statin groups of the analyzed studies was 8826 and 36,090, respectively. The RR for major CV events was 0.73 (95% confidence interval [CI]: 0.67–0.81; p < 0.001) in nonsmokers and 0.72 (95%CI: 0.64–0.81; p < 0.001) in smokers. Moderate to high heterogeneity was observed both in non-smokers (I2 = 77.1%, p < 0.001) and in smokers (I2 = 51.6%, p = 0.024) groups. Smokers seemed to benefit slightly more from statins than non-smokers according to the number needed to treat (NNT) analysis (23.5 vs 26.8) based on RRs applied to the control event rates. The number of avoided events per 1000 individuals was 42.5 (95%CI: 28.9–54.6) in smokers and 37.3 (95%CI: 27.2–46.4) in non-smokers. In conclusion, this meta-analysis suggests that the effect of statins on CVD is similar for smokers and non-smokers, but in terms of NNTs and number of avoided events, smokers seem to benefit more although non-significantly.

Section snippets


Currently, smoking is a cause of 5 million premature deaths globally each year with 50% of smokers being middle age persons [1], [2]. According to the World Health Organization (WHO) the deaths caused by smoking will increase to as many as 8 million persons/year [3]. Cigarettes contain >5000 carcinogenic, toxic and mutagenic chemicals, stable and unstable free radicals, and reactive oxygen that substantially increase the morbidity and mortality from pulmonary disease and a wide array of cancers 


We followed the guidelines of the 2009 preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement [16]. Due to the study design (meta-analysis) neither Institutional Review Board (IRB) approval, nor patient informed consent were needed or obtained

Search results and trial flow

The search initially identified 2712 full text articles. After excluding duplicates, the titles and abstracts of 2612 papers were screened, from which 2571 papers were excluded. Among the remaining 41 full text articles assessed for eligibility, 30 studies were excluded for not having data results reported separately for smokers and non-smokers. After final assessment, 11 eligible RCTs achieved the inclusion criteria and were selected for the final meta-analysis (Fig. 1)

Search results and trial flow

Characteristics of included studies


This meta-analysis did not suggest any significant difference between smokers and non-smokers regarding the effect of statins on CV outcomes. In terms of NNTs and number of avoided events, the smokers seem to benefit more, although non-significantly. There was no suggestion of substantial difference between smokers and non-smokers analyzing the results from primary and secondary prevention trials, however primary prevention patients seem to benefit more from the statin therapy irrespective on

Conflict of interest disclosures



This meta-analysis was written independently; no company or institution supported it financially.


Maciej Banach (M.B.) had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. S.U. contributed to the study concept and design, data acquisition, data analysis and interpretation, and drafting of the manuscript; D.P.M. contributed to the study concept and design, and critical revision of the manuscript; M.C-S. contributed to the data acquisition, drafting and critical revision of the manuscript; P.M.R

Declaration of interest

Maciej Banach: speakers bureau: Abbott/Mylan, Abbott Vascular, Actavis, Akcea, Amgen, KRKA, MSD, Sanofi-Aventis and Valeant; consultant to Abbott Vascular, Amgen, Daichii Sankyo, Esperion, Lilly, MSD, Resverlogix, Sanofi-Aventis; Sorin UrsoniuMaria-Corina Serban, Adrian V. Hernandez, JoAnn E. Manson, and Jacek Rysz have nothing to declare; Peter Penson owns four shares in AstraZeneca PLC; Dimitri P. Mikhailidis: has given talks and attended conferences sponsored by MSD, AstraZeneca and

Additional information

Two authors (M.B., J.R.) have been partially supported by the Healthy Ageing Research Centre project of Medical University of Lodz, Lodz, Poland (REGPOT-2012-2013-1, 7FP)

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