Risk of Cardiovascular Serious Adverse Events With Varenicline
Risk of Cardiovascular Serious Adverse Events With Varenicline
Our systematic review entailed computer based searches of Medline, the Cochrane Library, and online clinical trials registries (ClinicalTrials.gov and the industry sponsored Clinical Study Results registry) to identify randomised controlled trials evaluating varenicline for tobacco cessation. The search covered January 2005 (the year when articles on varenicline were first published) to September 2011, and included articles available online ahead of print publication. The search strings were “varenicline and randomised” in Medline and “SR-tobacco and varenicline” in the Cochrane Central Register of Controlled Trials. We manually searched bibliographies of relevant research and review articles.
Studies included in the meta-analysis met the following criteria: randomised controlled design, study sample of current tobacco users of adult age, comparing use of varenicline with that of an inactive control, and reporting adverse events. Exclusion criteria included use of a quasi-experimental or crossover design, laboratory studies with no follow-up, studies with adolescents, studies of non-smokers, studies in which all participants received varenicline, and comparisons of varenicline with another active drug (for example, nicotine replacement). Study inclusion criteria, data extraction, and methods of the analysis were specified in advance and documented in a protocol.
Two reviewers independently conducted article data extraction and quality assessment for each study meeting the inclusion criteria. Data extraction included descriptive characteristics of the study samples; varenicline dose; duration of drug treatment; study duration; sample attrition; and the number of participants with treatment emergent, cardiovascular serious adverse events in the inactive and active drug conditions. For comparability, we used the same primary outcome as Singh and colleagues, defining cardiovascular serious adverse events as 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 obtained details on timing of the cardiovascular serious adverse events from the study publications; the online clinical trials registries; the Chantix product label; and for three trials, for which the information was not publicly available, we contacted the medical adviser for varenicline at Pfizer or the study lead author directly. For one additional study, we contacted the lead author to confirm that no serious adverse events had occurred in the trial because only adverse events were reported. Discrepant findings between reviewers were settled by discussion, further review of the article, and (if necessary) consultation with a third reviewer.
We assessed study quality using a three item method developed by Jadad and colleagues that evaluated adequacy of randomisation, concealment of randomisation, and completeness of follow-up. We assessed two additional items, relevant to the area of interest: adequate reporting and adjudication of the cardiovascular serious adverse events. No quality scoring system has proven to correlate consistently with treatment outcomes, and it is recognised that general quality scales often need to be supplemented with more problem specific items for each particular meta-analysis.
We described trial characteristics in terms of publication date; sample size and allocation; and participants’ exposures to tobacco, cardiovascular disease, and study treatments. For each trial included in the meta-analysis, we cross classified study participants by treatment group and by any occurrence of a treatment emergent, cardiovascular serious adverse event. For trials that examined multiple doses of varenicline, we combined the active treatment groups.
Using Comprehensive Meta-Analysis (version 2 professional edition; Biostat) and fixed effects estimation, we summarised evidence of an increased risk of cardiovascular serious adverse events associated with varenicline use via four summary statistics: the Mantel-Haenszel versions of the risk difference, relative risk, and odds ratio; and the Peto odds ratio. For each statistic, we reported the mean effect, 95% confidence interval, P value testing the null hypothesis of no effect, and I statistic estimating heterogeneity across trials. We confirmed all results using the “metan” and “funnel” routines added to Stata version 11. The three relative statistics excluded trials in which event counts were zero in both arms. For trials in which one event count was equal to zero, both software packages (Stata and Comprehensive Meta-Analysis) added 0.5 to each of the four cell counts before estimating the relative risk or Mantel-Haenszel odds ratio.
We planned to do random effects meta-analyses and subgroup analyses if levels of heterogeneity exceeded 50%. We plotted the cumulative evidence by date of trial publication and examined asymmetry in a funnel plot as an indicator of publication bias. Finally, we compared the four summary statistics at the trial level grouping the studies by presence (v absence) of events and equal (v unequal) numbers of events, ordering the groups by increasing evidence of a varenicline effect. We expected this comparison would provide insight into the most suitable summary statistic in the present setting.
Methods
Literature Search
Our systematic review entailed computer based searches of Medline, the Cochrane Library, and online clinical trials registries (ClinicalTrials.gov and the industry sponsored Clinical Study Results registry) to identify randomised controlled trials evaluating varenicline for tobacco cessation. The search covered January 2005 (the year when articles on varenicline were first published) to September 2011, and included articles available online ahead of print publication. The search strings were “varenicline and randomised” in Medline and “SR-tobacco and varenicline” in the Cochrane Central Register of Controlled Trials. We manually searched bibliographies of relevant research and review articles.
Studies included in the meta-analysis met the following criteria: randomised controlled design, study sample of current tobacco users of adult age, comparing use of varenicline with that of an inactive control, and reporting adverse events. Exclusion criteria included use of a quasi-experimental or crossover design, laboratory studies with no follow-up, studies with adolescents, studies of non-smokers, studies in which all participants received varenicline, and comparisons of varenicline with another active drug (for example, nicotine replacement). Study inclusion criteria, data extraction, and methods of the analysis were specified in advance and documented in a protocol.
Data Extraction
Two reviewers independently conducted article data extraction and quality assessment for each study meeting the inclusion criteria. Data extraction included descriptive characteristics of the study samples; varenicline dose; duration of drug treatment; study duration; sample attrition; and the number of participants with treatment emergent, cardiovascular serious adverse events in the inactive and active drug conditions. For comparability, we used the same primary outcome as Singh and colleagues, defining cardiovascular serious adverse events as 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 obtained details on timing of the cardiovascular serious adverse events from the study publications; the online clinical trials registries; the Chantix product label; and for three trials, for which the information was not publicly available, we contacted the medical adviser for varenicline at Pfizer or the study lead author directly. For one additional study, we contacted the lead author to confirm that no serious adverse events had occurred in the trial because only adverse events were reported. Discrepant findings between reviewers were settled by discussion, further review of the article, and (if necessary) consultation with a third reviewer.
We assessed study quality using a three item method developed by Jadad and colleagues that evaluated adequacy of randomisation, concealment of randomisation, and completeness of follow-up. We assessed two additional items, relevant to the area of interest: adequate reporting and adjudication of the cardiovascular serious adverse events. No quality scoring system has proven to correlate consistently with treatment outcomes, and it is recognised that general quality scales often need to be supplemented with more problem specific items for each particular meta-analysis.
Statistical Analysis
We described trial characteristics in terms of publication date; sample size and allocation; and participants’ exposures to tobacco, cardiovascular disease, and study treatments. For each trial included in the meta-analysis, we cross classified study participants by treatment group and by any occurrence of a treatment emergent, cardiovascular serious adverse event. For trials that examined multiple doses of varenicline, we combined the active treatment groups.
Using Comprehensive Meta-Analysis (version 2 professional edition; Biostat) and fixed effects estimation, we summarised evidence of an increased risk of cardiovascular serious adverse events associated with varenicline use via four summary statistics: the Mantel-Haenszel versions of the risk difference, relative risk, and odds ratio; and the Peto odds ratio. For each statistic, we reported the mean effect, 95% confidence interval, P value testing the null hypothesis of no effect, and I statistic estimating heterogeneity across trials. We confirmed all results using the “metan” and “funnel” routines added to Stata version 11. The three relative statistics excluded trials in which event counts were zero in both arms. For trials in which one event count was equal to zero, both software packages (Stata and Comprehensive Meta-Analysis) added 0.5 to each of the four cell counts before estimating the relative risk or Mantel-Haenszel odds ratio.
We planned to do random effects meta-analyses and subgroup analyses if levels of heterogeneity exceeded 50%. We plotted the cumulative evidence by date of trial publication and examined asymmetry in a funnel plot as an indicator of publication bias. Finally, we compared the four summary statistics at the trial level grouping the studies by presence (v absence) of events and equal (v unequal) numbers of events, ordering the groups by increasing evidence of a varenicline effect. We expected this comparison would provide insight into the most suitable summary statistic in the present setting.
