Mills EJ, Thorlund K, Eapen S, et al.
Circulation. 2013 Dec 9. [Epub ahead of print]

Background

Early cessation of smoking is associated with increases in life expectancy, improved quality of life, and reduced health care costs for smoking associated conditions [1]. One of the major health benefits of smoking cessation is improved cardiovascular (CV) health [2,3].
Clinical practice guidelines recommend the use of smoking cessation pharmacotherapies for those interested in quitting, unless contraindicated [4,5]. Three classes of first-line therapy have been approved in the US, namely nicotine replacement therapy (NRT), bupropion, an antidepressant, and varenicline, a nicotine receptor partial agonist. Although many studies have shown that these agents are effective in promoting smoking cessation [6,7], concerns have been raised about potential negative CV effects. Conflicting results about the safety of smoking cessation pharmacotherapies have been published thus far.
Using network analysis that can examine both direct (head-to-head RCTs) and indirect evidence, the aim of this work was to examine the comparative safety of NRT, bupropion and varenicline, focussing on all-CVD events and major adverse cardiovascular events (MACE) in smokers with and without pre-existing CVD. In total, 63 RCTs were considered eligible, encompassing data on 30508 patients.
The median treatment duration was 12 weeks (IQR: 8-12 weeks), and median duration of follow-up was 12 months (IQR: 6-12 months).

Main results

• In the network analysis, a significantly increased risk of any CVD event was seen for NRT in comparison with placebo (RR: 2.29, 95%cRi: 1.39-3.82) and bupropion (bupropion vs. NRT: RR: 0.43, 95%cRi: 0.19-0.91). Restriction to only MACE gave wider CIs, thus NRT was no longer significantly associated with harm.
• Results for bupropion suggested a protective direction of the effect for MACE in comparison with both NRT (RR: 0.23, 95%CrI: 0.08-0.63) and varenicline (RR: 0.33, 95%CrI: 0.16-0.87) .
• No differences in relative risk was seen for varenicline in the network analysis.
• Limiting the analysis to RCTs that enrolled high-risk populations, the direction of effect was similar to the analysis of all trials, but none of the comparisons reached statistical significance.
• Sensitivity analysis by removing MACE revealed that heart palpitations were the most commonly reported adverse event with NRT.
• A sensitivity analysis that excluded studies with follow-up shorter than 12 months, gave highly similar results to the main analysis for both bupropion and varenicline in comparison with placebo, while the increased risk for all CVD events of NRT was more pronounced and statistically significant.

Conclusion

None of the three smoking cessation pharmacotherapies were harmful with respect to MACE, and bupropion even appears to have a protective effect. NRT is however associated with an increase in CVD events, an effect that was driven by lower risk events, typically tachycardia; a known benign effect of NRT. No evidence was seen for specific harm with any of the therapies in high-risk patients.
Naturally, concerns about adverse events need to be balanced with the consistent evidence for the benefit of smoking cessation. Patients need to be educated on possible adverse events that may stem from smoking cessation therapy, and which may be associated with withdrawal from cigarettes, or existing disease.

Editorial comment [8]

Understanding the mechanism by which nicotine may contribute to increasing CVD risk, such as endothelial cell function, prothrombotic effects, oxygen demand and atherosclerosis, does not easily explain the increased risk after NRT, as these effects are not anticipated to extend beyond the period of NRT therapy. Neither can the decreased risk for MACE with bupropion be readily interpreted by its biological mechanism.
The pooling of 63 trials provided only an imprecise and uncertain picture of the potential adverse consequences of pharmacotherapy for smoking cessation. Trial data are not ideal for identifying adverse events . Thus, this evidence is not of sufficient strength to warrant reconsideration of guidelines.
Furthermore, smoking cessation has benefits for population health that extend beyond CVD, thus increased risk for CVD associated with smoking cessation need to be viewed in that context. Clinical experience indicates that therapy should be tailored for individuals, thus either one of the three pharmacotherapies may be deemed best for particular smokers.

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