Dataset Information

Cardiovascular adverse events in the drug-development program of bupropion for smoking cessation: A systematic retrospective adjudication effort.

ABSTRACT:

Background

In 2011, the US Food and Drug Administration requested that GlaxoSmithKline perform retrospective adjudication of cardiovascular (CV) events reported in the bupropion drug-development trials for smoking cessation.

Hypothesis

Retrospective adjudication of clinical trial data will not increase the identification of adverse events.

Methods

We performed a comprehensive retrospective analysis of adverse events in 19 previously completed controlled US clinical trials of bupropion marketed for the treatment of smoking cessation, yielding 9479 subjects (5290 bupropion, 2927 placebo, 1018 active control [ACT], and 244 treated concurrently with bupropion and ACT). All adverse events were sent to the Duke Clinical Research Institute for adjudication by Clinical Events Classification (CEC) physician reviewers. The primary endpoint was a composite of major adverse CV events: CV death, nonfatal myocardial infarction (MI), and nonfatal stroke.

Results

Overall, 416 nonfatal CV events in 366 subjects, and 22 deaths, were identified and processed for adjudication. Of these, 7 nonfatal MIs (4 bupropion, 3 placebo, 0 ACT), 5 nonfatal strokes (1 bupropion, 3 placebo, 1 ACT), and 9 CV deaths (4 bupropion, 4 placebo, 1 ACT) were confirmed by the CEC Committee. The primary endpoint occurred in 3/4297 (0.07%) subjects in the bupropion group and in 4/2927 (0.14%) subjects in the placebo group (log-rank P value: 0.613).

Conclusions

CV events in bupropion clinical trials for smoking cessation were uncommon, with no observed increase among subjects assigned to bupropion vs placebo. However, this effort was limited by a paucity of quality data.

SUBMITTER: Kittle J

PROVIDER: S-EPMC6490529 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Publications

Cardiovascular adverse events in the drug-development program of bupropion for smoking cessation: A systematic retrospective adjudication effort.

Kittle Jessie J Lopes Renato D RD Huang Mingyan M Marquess Marsha L ML Wilson Matthew D MD Ascher John J Krishen Alok A Hasselblad Vic V Kolls Brad J BJ Roe Matthew T MT McGuire Darren K DK Russell Stuart D SD Mahaffey Kenneth W KW

Clinical cardiology 20170612 10

<h4>Background</h4>In 2011, the US Food and Drug Administration requested that GlaxoSmithKline perform retrospective adjudication of cardiovascular (CV) events reported in the bupropion drug-development trials for smoking cessation.<h4>Hypothesis</h4>Retrospective adjudication of clinical trial data will not increase the identification of adverse events.<h4>Methods</h4>We performed a comprehensive retrospective analysis of adverse events in 19 previously completed controlled US clinical trials o ...[more]

PMID: 28605035

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Project description:BackgroundResearch on risk factors for neuropsychiatric adverse events (NAEs) in smoking cessation with pharmacotherapy is scarce. We aimed to identify predictors and develop a prediction model for risk of NAEs in smoking cessation with medications using Bayesian regularization.MethodsBayesian regularization was implemented by applying two shrinkage priors, Horseshoe and Laplace, to generalized linear mixed models on data from 1203 patients treated with nicotine patch, varenicline or placebo. Two predictor models were considered to separate summary scores and item scores in the psychosocial instruments. The summary score model had 19 predictors or 26 dummy variables and the item score model 51 predictors or 58 dummy variables. A total of 18 models were investigated.ResultsAn item score model with Horseshoe prior and 7 degrees of freedom was selected as the final model upon model comparison and assessment. At baseline, smokers reporting more abnormal dreams or nightmares had 16% greater odds of experiencing NAEs during treatment (regularized odds ratio (rOR) = 1.16, 95% credible interval (CrI) = 0.95 - 1.56, posterior probability P(rOR > 1) = 0.90) while those with more severe sleep problems had 9% greater odds (rOR = 1.09, 95% CrI = 0.95 - 1.37, P(rOR > 1) = 0.85). The prouder a person felt one week before baseline resulted in 13% smaller odds of having NAEs (rOR = 0.87, 95% CrI = 0.71 - 1.02, P(rOR < 1) = 0.94). Odds of NAEs were comparable across treatment groups. The final model did not perform well in the test set.ConclusionsWorse sleep-related symptoms reported at baseline resulted in 85%-90% probability of being more likely to experience NAEs during smoking cessation with pharmacotherapy. Treatment for sleep disturbance should be incorporated in smoking cessation program for smokers with sleep disturbance at baseline. Bayesian regularization with Horseshoe prior permits including more predictors in a regression model when there is a low number of events per variable.

Project description:BackgroundAlthough a relatively small proportion of women who become pregnant continue to smoke cigarettes, no smoking cessation medication has been shown to be effective for this subgroup of smokers. Bupropion, a nonnicotine-based medication, is approved for the promotion of smoking cessation in nonpregnant individuals. We chose to study it in pregnant smokers because, although pregnancy increases nicotine metabolism, it does not affect the metabolism of bupropion.ObjectiveWe evaluated the efficacy and safety of sustained-release bupropion for smoking cessation among pregnant women.Study designWe conducted a multiple site, placebo-controlled, randomized clinical trial of bupropion for tobacco use among pregnant women (N=129) (clinical trial number NCT02188459). We enrolled women during the second trimester and randomly assigned them to receive 10 weeks of treatment with either bupropion or placebo, accompanied by a total of 6 smoking cessation counseling sessions (4 during treatment and 2 postpartum). The primary outcome was 7-day point prevalence smoking abstinence, confirmed with breath carbon monoxide measurements, at the end of treatment (week 10) and at week 24. Group differences were assessed as a binary abstinence outcome using a repeated measure generalized estimating equations model with a logit link. Prolonged abstinence and smoking rates were secondary outcomes. Safety measures included maternal treatment-related adverse events, gestational age, the rate of overall and spontaneous preterm births and infant birthweight and size for gestational age, head circumference, and 5-minute Apgar scores.ResultsThere were no significant differences in the safety measures across the treatment arms and bupropion was not efficacious in promoting smoking cessation at the end of treatment (7-day point prevalence quit rates: bupropion, 11.0%; placebo, 18.5%) or week 24 (7-day point prevalence quit rates: bupropion, 9.4%; placebo, 21.5%) (P>.05). African American women and women with a lower severity of nicotine dependence had significantly higher quit rates overall and women with an opioid use disorder who were being treated with opioid agonist therapy had significantly lower quit rates overall, irrespective of the treatment group (all P values <.05).ConclusionAlthough bupropion use was not associated with an elevated risk for pregnancy complications when initiated in the second trimester, it did not increase the likelihood of smoking cessation in this cohort of pregnant women. Because smoking is the major preventable source of poor pregnancy outcomes and psychosocial interventions have only modest beneficial effects, additional studies are needed to identify safe and efficacious smoking cessation medications for pregnant women who continue to smoke.

Project description:BackgroundPre-treatment factors that increase smokers' risk of experiencing neuropsychiatric adverse events (NPSAEs) when quitting smoking are unknown.ObjectiveTo identify baseline smoker characteristics beyond the history of mental illness that predict which participants were more likely to experience moderate to severe NPSAEs in EAGLES.DesignA prospective correlational cohort study in the context of a multinational, multicenter, double-blind, randomized trial.ParticipantsSmokers without (N = 3984; NPC)/with (N = 4050; PC) histories of, or current clinically stable, psychiatric disorders including mood (N = 2882; 71%), anxiety (N = 782; 19%), and psychotic (N = 386; 10%) disorders.InterventionsBupropion, 150 mg twice daily, or varenicline, 1 mg twice daily, versus active control (nicotine patch, 21 mg/day with taper) and placebo for 12 weeks with 12-week non-treatment follow-up.Main measuresPrimary safety outcome was the incidence of a composite measure of moderate/severe NPSAEs. Associations among baseline demographic/clinical characteristics and the primary safety endpoint were analyzed post hoc via generalized linear regression.Key resultsThe incidence of moderate to severe NPSAEs was higher among smokers in the PC (238/4050; 5.9%) than in the NPC (84/3984; 2.1%). Three baseline characteristics predicted increased risk for experiencing clinically significant NPSAEs when quitting regardless of carrying a psychiatric diagnosis: current symptoms of anxiety (for every ~ 4-unit increase in HADS anxiety score, the absolute risk of occurrence of the NPSAE endpoint increased by 1% in both PC and NPC); prior history of suicidal ideation and/or behavior (PC, 4.4% increase; P = 0.001; NPC, 4.1% increase; P = 0.02), and being of White race (versus Black: PC, 2.9% ± 0.9 [SE] increase; P = 0.002; and NPC, 3.4% ± 0.8 [SE] increase; P = 0.001). Among smokers with psychiatric disorders, younger age, female sex, history of substance use disorders, and proxy measures of nicotine dependence or psychiatric illness severity also predicted greater risk. There were no significant interactions between these characteristics and treatment. Smokers with unstable psychiatric disorders or with current, active substance abuse were excluded from the study.ConclusionsIrrespective of cessation pharmacotherapy use, smokers attempting to quit were more likely to experience moderate to severe NPSAEs if they reported current anxiety or prior suicidal ideation at baseline and were White. In smokers with a psychiatric history, female sex, younger age, and greater severity of nicotine dependence were also predictive.Trial registrationClinicalTrials.gov Identifier: NCT01456936.

Project description:Cigarette smoking continues to be the leading cause of preventable death and is the main risk factor of major diseases such as chronic obstructive pulmonary disease (COPD). The best treatment to help smokers quit is a combination of behavioural support with pharmacotherapy. Varenicline is the newest drug on the market and has been shown to be effective in the general smoking population and in smokers with COPD. The safety profile of varenicline was initially established using standard approaches to pharmacovigilance, but postmarketing reports have raised concerns about a possible association between the use of varenicline and cardiovascular and neuropsychiatric events. Although recent studies have not confirmed such an association, further research is needed given the large number of smokers who are being prescribed varenicline, including important subgroups such as smokers with COPD who may be particularly vulnerable to side effects of drugs. The aim of this study is to assess the cardiovascular and neuropsychiatric safety of varenicline using data from the QResearch general practice (GP) database.We will conduct a retrospective cohort study in the QResearch GP database. Patients will be categorised into three exposure groups: prescription of (1) varenicline, (2) bupropion or (3) nicotine replacement therapy (NRT Rx; =reference group). We will separately consider major incident neuropsychiatric and cardiovascular outcomes that occur during 6?months of follow-up using Cox proportional hazards models, adjusted for confounders. Furthermore, propensity score analysis will be used as an analytical approach to account for potential confounding by indication.This work involves analysis of anonymised, routinely collected data. The protocol has been independently peer-reviewed by the QResearch Scientific Board and meets the requirements of the Trent research ethics committee. We plan to disseminate the results from this study via articles in international peer-reviewed journals and presentations at relevant national and international health conferences.

Dataset Information

Cardiovascular adverse events in the drug-development program of bupropion for smoking cessation: A systematic retrospective adjudication effort.

Background

Hypothesis

Methods

Results

Conclusions

Publications

Cardiovascular adverse events in the drug-development program of bupropion for smoking cessation: A systematic retrospective adjudication effort.

Similar Datasets

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