Cardiovascular Events Associated With Smoking Cessation Pharmacotherapies A Network Meta-Analysis

Stanford Prevention Research Center, Stanford University, Stanford, CA & University of Ottawa, Ottawa, Canada.
Circulation (Impact Factor: 14.43). 12/2013; 129(1). DOI: 10.1161/CIRCULATIONAHA.113.003961
Source: PubMed


Stopping smoking is associated with many important improvements in health and quality of life. Use of cessation medications is recommended to increase the likelihood of quitting. However, there is historical and renewed concern that smoking cessation therapies may increase the risk of cardiovascular disease (CVD) events associated within the quitting period. We aimed to examine whether the three licensed smoking cessation therapies: nicotine replacement therapy (NRT); bupropion, and; varenicline and were associated with an increased risk of CVD events using a network meta-analysis.
We searched ten electronic databases, and made communication with authors of published randomized clinical trials (RCT), and accessed internal US Food and Drug Administration (FDA) reports. We included any RCT of the 3 treatments that reported on CVD outcomes. Among 63 eligible RCTs involving 21 NRT RCTs, 28 bupropion RCTs and 18 varenicline RCTs, we found no increase in the risk of all-CVD events with bupropion (RR 0.98, 95% Confidence Intervals [CIs], 0.54-1.73) or varenicline (RR 1.30, 95% CI, 0.79-2.23). There was an elevated risk associated with NRT that was predominantly driven by less serious events (2.29, 95% CI, 1.39-3.82). When we examined major adverse cardiovascular events (MACE) events, we found a protective effect with bupropion (RR 0.45, 95% CI, 0.21-0.85) and no clear evidence of harm with varenicline (RR 1.34, 95% CI, 0.66-2.66) or NRT (RR 1.95, 95% CI, 0.26-4.30).
Smoking cessation therapies do not appear to raise the risk of serious CVD events.

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    ABSTRACT: Smoking cessation benefits health and lengthens life expectancy at any age.(1, 2) With that rationale, smoking cessation figures centrally in comprehensive tobacco control initiatives, including the recommendations of the US Preventive Services Task Force and the World Health Organization.(3, 4) The population of the United States has recognized the personal benefits of stopping smoking and, at present, the majority of those who have ever smoked cigarettes have stopped.(2, 5) Public health benefits have been realized. Smoking cessation is a powerful driver of the decline in cardiovascular mortality over the last 4 decades and also of the more recent declines in rates of smoking-caused cancers among men.(2, 6, 7.)
    Circulation 12/2013; 129(1). DOI:10.1161/CIRCULATIONAHA.113.006928 · 14.43 Impact Factor
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    ABSTRACT: It has been suggested that varenicline-induced activation of nicotinic acetylcholine receptors (nAChRs) could play a role in the cardiovascular (CV) safety of varenicline. However, since preclinical studies showed that therapeutic varenicline concentrations have no effect in models of CV function, this study examined in vitro profiles of varenicline and nicotine at nAChR subtypes possibly involved in CV control. Concentration-dependent functional effects of varenicline and nicotine at human α3β4, α3α5β4, α7, and α4β2 nAChRs expressed in oocytes were determined by electrophysiology. The proportion of nAChRs predicted to be activated and inhibited by concentrations of varenicline (1mg b.i.d.) and of nicotine in smokers was derived from activation-inhibition curves for each nAChR subtype. Human varenicline and nicotine concentrations can desensitize and inhibit nAChRs but cause only low-level activation of α3β4, α4β2 (<2%), α7 (<0.05%), and α3α5β4 (<0.01%) nAChRs, consistent with literature data. Nicotine concentrations in smokers are predicted to inhibit larger fractions of α3β4 (48%) and α3α5β4 (10%) nAChRs than therapeutic varenicline concentrations (11% and 0.6%, respectively) and to inhibit comparable fractions of α4β2 nAChRs (42%-56%) and α7 nAChRs (16%) as varenicline. Nicotine and varenicline concentrations in patients and smokers are predicted to cause minimal activation of ganglionic α3β4* nAChRs, while their functional profiles at α3β4, α3α5β4, α7, and α4β2 nAChRs cannot explain that substituting nicotine from tobacco with varenicline would cause CV adverse events in smokers who try to quit. Other pharmacological properties that could mediate varenicline-induced CV effects have not been identified.
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