Twelve weeks of combined treatment with bupropion and varenicline was more effective than varenicline alone at helping people quit smoking, according to a report published online Jan. 7 in JAMA.
However, 38% of study participants dropped out by 12 weeks, and combined therapy showed no significant advantage over varenicline alone when smoking abstinence was measured 1 year later, said Dr. Jon O. Ebbert of the Nicotine Dependence Center, Mayo Clinic, Rochester, Minn., and his associates (JAMA 2014;311:155-63).
The findings highlight the stubborn public health challenge smoking still presents 50 years after the U.S. Surgeon General’s groundbreaking report on smoking and health debuted in January 1964.
Dr. Ebbert and his colleagues compared the efficacy of the two treatment approaches in a phase III, double-blind clinical trial involving 506 adults treated for 12 weeks at three medical centers during 2009-2013. All the study participants smoked at least 10 cigarettes per day at baseline.
The patients were randomly assigned to receive for 12 weeks either up to 300 mg bupropion SR per day plus up to 2 mg per day of varenicline (249 patients) or varenicline alone (257 patients).
They all attended 11 clinic visits at which they received brief behavioral counseling, were assessed for smoking abstinence using exhaled-air carbon monoxide measurement, and completed assessments of tobacco craving and nicotine withdrawal. The patients also received a follow-up phone call on their target quit date and two more calls during 1 year of follow-up.
The dropout rate was high, at 38%, but did not differ significantly between the two treatment groups. A total of 158 patients (63%) in the combination-therapy group and 157 patients (61%) in the varenicline-only group completed the study.
The study’s primary endpoint was the rate of smoking abstinence at week 12, confirmed by CO testing. The rate was 53% with combination therapy, significantly higher than the 43% rate with varenicline alone. Similarly, the rate of smoking abstinence at week 26 was significantly higher with combination therapy (36.6%) than with varenicline alone (27.6%).
The smoking abstinence rates were no longer significantly different between the two groups at 1 year: 30.9% with combination therapy, compared with 24.5% with varenicline alone.
Weight gain after smoking cessation was slightly lower with combination therapy (1.1 kg) than with varenicline alone (2.5 kg) at 12 weeks, but that difference disappeared by 26 weeks (3.4 kg vs 3.8 kg). At 1 year, weight gain again was lower after combination therapy (4.9 kg) than after monotherapy (6.1 kg). That finding suggests that combination therapy may be the preferred option for patients who are concerned about weight gain, especially those "for whom weight gain may undermine smoking cessation" attempts, Dr. Ebbert and his associates said.
There were no significant differences between the two study groups at any time point in symptoms of nicotine withdrawal or craving.
The only adverse events deemed to be possibly related to treatment were significant increases in the rate of anxiety (7.2%) and depressive symptoms (3.6%) among patients receiving combination therapy, compared with those receiving monotherapy (3.1% and 0.8%, respectively). However, tobacco withdrawal itself has been linked to symptoms of both anxiety and depression, the investigators noted.
"All patients being treated with pharmacotherapy for tobacco dependence should be monitored for changes in anxiety and mood," which is standard clinical practice, the researchers cautioned.
Exploratory analyses showed that treatment effects did not differ according to patient age or sex. However, combination therapy appeared to be slightly more effective than monotherapy among patients who smoked heavily (20 or more cigarettes per day) and those with higher levels of nicotine dependence, as measured by the Fagerstrom Test for Nicotine Dependence.
The study is the first to show that a combination approach with varenicline could top monotherapy. "Prior to the current study, no combination therapies with varenicline have been shown to be effective for increasing smoking abstinence rates, compared with varenicline monotherapy," Dr. Ebbert noted in an interview. Other research has indicated that bupropion combined with the nicotine patch may be more beneficial than using the nicotine patch alone, he added.
Alone or in combination, drug therapy must be part of a wider approach to smoking cessation, Dr. Ebbert emphasized. "Behavioral treatment is a critical piece, and it should be a component of all treatment for tobacco use."
The study was supported in part by the National Institutes of Health. Pfizer provided the varenicline used in the study. Dr. Ebbert reported ties to GlaxoSmithKline, JHP Pharmaceuticals, Orexigen, and Pfizer. His associates reported ties to Nabi Biopharmaceuticals and Pfizer.