Dataset Information

Use of varenicline for smoking cessation and risk of serious cardiovascular events: nationwide cohort study.

ABSTRACT:

Objective

To investigate whether varenicline is associated with an increased risk of serious cardiovascular events compared with another drug used for smoking cessation, bupropion.

Design

Nationwide historical cohort study.

Setting

Denmark, 2007-10.

Participants

New users of varenicline (n = 17,926) and bupropion (n = 17,926).

Main outcome measures

Individual level data on dispensed drug prescriptions, cardiovascular events, and potential confounders were linked between registries. Cox regression was used to estimate hazard ratios of cardiovascular events in analyses matched for propensity score. The primary outcomes at six months after start of treatment were acute coronary syndrome, ischaemic stroke, and cardiovascular death analysed individually and as a composite of any major event.

Results

There were 57 major cardiovascular events among varenicline users (6.9 cases per 1000 person years) compared with 60 events among bupropion users (7.1 cases per 1000 person years); the hazard ratio for any major event was 0.96 (95% confidence interval 0.67 to 1.39). Varenicline use was not associated with an increased risk of acute coronary syndrome (1.20, 0.75 to 1.91), ischaemic stroke (0.77, 0.40 to 1.48), and cardiovascular death (0.51, 0.13 to 2.02). In subgroup analyses, the risk of any major cardiovascular event was not significantly different between patients with and without a history of cardiovascular disease (1.24 (0.72 to 2.12) and 0.83 (0.51 to 1.36), respectively; P=0.29).

Conclusions

This cohort study found no increased risk of major cardiovascular events associated with use of varenicline compared with bupropion for smoking cessation. On the basis of the upper confidence limit, the data allowed the exclusion of a 40% increased risk of the composite outcome of any major cardiovascular event. While the estimates were less precise for specific outcomes, any differences would be small in absolute terms.

SUBMITTER: Svanstrom H

PROVIDER: S-EPMC3493624 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:To examine the risk of treatment emergent, cardiovascular serious adverse events associated with varenicline use for tobacco cessation.Meta-analysis comparing study effects using four summary estimates.Medline, Cochrane Library, online clinical trials registries, and reference lists of identified articles.We included randomised controlled trials of current tobacco users of adult age comparing use of varenicline with an inactive control and reporting adverse events. We defined treatment emergent, cardiovascular serious adverse events as occurring during drug treatment or within 30 days of discontinuation, and included any ischaemic or arrhythmic adverse cardiovascular event (myocardial infarction, unstable angina, coronary revascularisation, coronary artery disease, arrhythmias, transient ischaemic attacks, stroke, sudden death or cardiovascular related death, or congestive heart failure).We identified 22 trials; all were double blinded and placebo controlled; two included participants with active cardiovascular disease and 11 enrolled participants with a history of cardiovascular disease. Rates of treatment emergent, cardiovascular serious adverse events were 0.63% (34/5431) in the varenicline groups and 0.47% (18/3801) in the placebo groups. The summary estimate for the risk difference, 0.27% (95% confidence interval -0.10 to 0.63; P = 0.15), based on all 22 trials, was neither clinically nor statistically significant. For comparison, the relative risk (1.40, 0.82 to 2.39; P = 0.22), Mantel-Haenszel odds ratio (1.41, 0.82 to 2.42; P = 0.22), and Peto odds ratio (1.58, 0.90 to 2.76; P = 0.11), all based on 14 trials with at least one event, also indicated a non-significant difference between varenicline and placebo groups.This meta--analysis--which included all trials published to date, focused on events occurring during drug exposure, and analysed findings using four summary estimates-found no significant increase in cardiovascular serious adverse events associated with varenicline use. For rare outcomes, summary estimates based on absolute effects are recommended and estimates based on the Peto odds ratio should be avoided.

Project description:Background and aimsVarenicline effectiveness may be related to the level of adherence, which might be reduced by adverse effects such as nausea. The aim of the study was to test a possible effect of nausea on smoking cessation outcomes mediated by adherence.DesignMediation path analysis.SettingMultiple sites within Canada and the United States.ParticipantsTreatment-seeking smokers receiving varenicline from two smoking cessation clinical trials: Quit2Live (NCT01836276; n = 449) and Pharmacogenetics of Nicotine Addiction Treatment (PNAT) (NCT01314001; n = 421).MeasurementsNausea severity was collected through self-report and adherence was biologically assessed using varenicline concentrations (Quit2Live, plasma sample at week 4; PNAT, saliva sample at week 2). In Quit2Live, the end-points were cotinine-verified abstinence at weeks 4, 12 and 26. In PNAT, the end-points were carbon monoxide-verified abstinence at weeks 2, 12 and 26.FindingsEarly nausea was not directly associated with abstinence [odds ratio (OR) ranging from 0.73-1.28; P ? 0.26]. However early nausea was indirectly associated with lower cessation rates at multiple timepoints (ORs ranging from 0.92-0.94; 95% CI between 0.83-0.99) in a relationship mediated by reduced varenicline adherence (assessed by plasma varenicline concentrations) in the primary trial (Quit2Live). This relationship between nausea, adherence and cessation was similar in direction but weaker in effect size (ORs ranging from 0.98-0.99; 95% CI between 0.90-1.03) in a secondary trial (PNAT), where adherence was assessed using salivary varenicline concentrations.ConclusionsThese data suggest that early nausea during varenicline treatment may be indirectly associated with lower likelihood of smoking cessation through reducing varenicline adherence. Differences in robustness between the trials may be due to the different biological matrices (plasma vs. saliva) and/or timing used to assess varenicline adherence. The results of the first study suggest that improved management of early nausea during varenicline treatment may positively impact smoking cessation success through increasing varenicline adherence.