Resumen de Combination Varenicline and Bupropion SR for Tobacco-Dependence Treatment in Cigarette Smokers

Jon O. Ebbert, Dorothy K. Hatsukami, Ivana T. Croghan, Darrell R. Schroeder

• Importance Combining pharmacotherapies for tobacco-dependence treatment may increase smoking abstinence.

  Objective To determine efficacy and safety of varenicline and bupropion sustained-release (SR; combination therapy) compared with varenicline (monotherapy) in cigarette smokers.

  Design, Setting, and Participants Randomized, blinded, placebo-controlled multicenter clinical trial with a 12-week treatment period and follow-up through week 52 conducted between October 2009 and April 2013 at 3 midwestern clinical research sites. Five hundred six adult (≥18 years) cigarette smokers were randomly assigned and 315 (62%) completed the study.

  Interventions Twelve weeks of varenicline and bupropion SR or varenicline and placebo.

  Main Outcomes and Measures Primary outcome was abstinence rates at week 12, defined as prolonged (no smoking from 2 weeks after the target quit date) abstinence and 7-day point-prevalence (no smoking past 7 days) abstinence. Secondary outcomes were prolonged and point-prevalence smoking abstinence rates at weeks 26 and 52. Outcomes were biochemically confirmed.

  Results At 12 weeks, 53.0% of the combination therapy group achieved prolonged smoking abstinence and 56.2% achieved 7-day point-prevalence smoking abstinence compared with 43.2% and 48.6% in varenicline monotherapy (odds ratio [OR], 1.49; 95% CI, 1.05-2.12; P = .03 and OR, 1.36; 95% CI, 0.95-1.93; P = .09, respectively). At 26 weeks, 36.6% of the combination therapy group achieved prolonged and 38.2% achieved 7-day point-prevalence smoking abstinence compared with 27.6% and 31.9% in varenicline monotherapy (OR, 1.52; 95% CI, 1.04-2.22; P = .03 and OR, 1.32; 95% CI, 0.91-1.91; P = .14, respectively). At 52 weeks, 30.9% of the combination therapy group achieved prolonged and 36.6% achieved 7-day point-prevalence smoking abstinence compared with 24.5% and 29.2% in varenicline monotherapy (OR, 1.39; 95% CI, 0.93-2.07; P = .11 and OR, 1.40; 95% CI, 0.96-2.05; P = .08, respectively). Participants receiving combination therapy reported more anxiety (7.2% vs 3.1%; P = .04) and depressive symptoms (3.6% vs 0.8%; P = .03).

  Conclusions and Relevance Among cigarette smokers, combined use of varenicline and bupropion, compared with varenicline alone, increased prolonged abstinence but not 7-day point prevalence at 12 and 26 weeks. Neither outcome was significantly different at 52 weeks. Further research is required to determine the role of combination therapy in smoking cessation.

  Trial Registration clinicaltrials.gov Identifier: http://clinicaltrials.gov/show/NCT00935818 Smoking accounts for 62% of deaths among female smokers and 60% of deaths among male smokers.1 Innovative pharmacotherapeutic approaches to tobacco-dependence treatment need investigation to reduce smoking-related death and disability.

  Bupropion SR (sustained-release) and varenicline are nonnicotine pharmacotherapies indicated for tobacco-dependence treatment. Bupropion SR may mediate effects through noradrenergic and dopaminergic systems2 with a competitive inhibitory effect on nicotinic acetylcholine receptors.3Varenicline is a partial agonist that binds with high affinity and selectivity at α4β2 neuronal nicotinic acetylcholine receptors.4,5 Opportunities exist for additive or synergistic therapeutic effects from combination therapy with these 2 medications.

  Combination pharmacotherapy for treating tobacco dependence may increase smoking abstinence compared with monotherapy. A combination of bupropion SR and the nicotine patch is more effective than nicotine patch therapy alone,6 suggesting that an additive benefit is achieved by combining therapies. In an open-label pilot study evaluating combination therapy with varenicline and bupropion SR, the combination was well tolerated with smoking abstinence rates exceeding those observed in prior trials with either drug as monotherapy.7 If proven to be more effective than single-drug therapy, this therapeutic approach may have important clinical implications for tobacco-dependence treatment. Exploration of combination therapy with existing drugs may provide the best opportunity to advance treatment in the absence of any new pharmacotherapies for tobacco dependence.

  To investigate the efficacy of combination pharmacotherapy with varenicline and bupropion SR for smoking cessation, compared with varenicline monotherapy, we conducted a multicenter, randomized, phase 3 clinical trial.