Varenicline vs. Placebo on Smoking Cessation - Varenicline vs. Placebo on Smoking Cessation


The goal of the trial was to evaluate treatment with varenicline, a nicotine acetylcholine receptor agonist, compared with placebo for maintenance of smoking abstinence.

Study Design

Study Design:

Patients Screened: 2,416
Patients Enrolled: 1,210
Mean Follow Up: 52 weeks
Mean Patient Age: Mean age 45 years
Female: 51

Patient Populations:

Age 18-75 years, smoked at least 10 cigarettes per day for the past year with no period of abstinence longer than 3 months, and motivated to quit smoking


Serious or unstable disease within 6 months; required treatment for depression within 12 months; history of panic disorder, psychosis, or bipolar disorder; severe chronic obstructive pulmonary disease, history of cancer, evidence or history of clinically significant allergic reactions, laboratory abnormalities, cardiovascular disease within 6 months, uncontrolled hypertension, or a history of drug or alcohol abuse or dependence within 12 months; used a smoking cessation product within the previous month; used tobacco products other than cigarettes or marijuana within the past month and did not agree to abstain from use of these products during study participation; had a body mass index of <15 or >38; or used any of the following medications: nicotine replacement therapy (NRT), antidepressants, antipsychotics, mood stabilizers/anticonvulsants, naltrexone, steroids, or insulin

Primary Endpoints:

Continuous abstinence rate (carbon dioxide confirmed) during weeks 13-24

Secondary Endpoints:

Continuous abstinence rate (carbon dioxide confirmed) during weeks 13-52

Drug/Procedures Used:

Patients were treated with open-label varenicline (1 mg bid) during a 12-week open-label phase (n = 1,927). Among the subjects who did not smoke or use tobacco during the last of the 12-week run-in, 1,210 were randomized in a double-blind manner to an additional 12 weeks of treatment with varenicline (n = 603) or placebo (n = 607). Patients were followed for an additional 40 weeks after randomization.

Principal Findings:

Mean duration of smoking was 28 years, and the average number of cigarettes per day smoked in the past month was 20.7. The majority of patients had ≥1 previous serious attempts to quit (85%).

The primary endpoint of 4-week continuous quit rate during weeks 13-24 was higher in the varenicline group compared with the placebo group (70.5% vs. 49.6%, odds ratio [OR] 2.48, p < 0.001). The secondary endpoint of continuous abstinence rate during weeks 13-52 was also higher in the varenicline group (43.6% vs. 36.9%, OR 1.34, p = 0.02), although the abstinence rate declined notably in the varenicline group following the end of the active double-blind treatment phase (from 70.5% at 24 weeks to 59.9% at 28 weeks, 50.7% at 36 weeks, and 46.4% at 44 weeks).

Adverse events resulting in study drug discontinuation occurred in 11.9% of the open-label run-in phase. There was no difference in the frequency of adverse events leading to discontinuation in the double-blind phase between the varenicline and placebo groups (1.7% vs. 1.3%). Nausea was the main adverse event (3.2% during the run-in phase).


Among long-term smokers who achieved smoking abstinence for at least 7 days during open-label treatment with varenicline, an additional 12 weeks of treatment with varenicline was associated with higher rates of continuous smoking abstinence compared with placebo.

Smoking is a leading, preventable cause of cardiovascular morbidity and mortality. Varenicline is a nicotine acetylcholine receptor agonist that has the potential to relieve nicotine cravings and withdrawal symptoms and reduce the nicotine reinforcement associated with smoking. The present study, along with two other studies by the same group, showed improvements in both smoking cessation as well as continued abstinence with varenicline.

While adverse events were higher with varenicline, the events were generally mild. There was a noticeable decline in abstinence once patients discontinued the active double-therapy with varenicline, suggesting that long-term maintenance may be needed to prevent/postpone relapse. Given the narrowing of the treatment effect by 1 year, longer follow-up is warranted.


Tonstad S, Tonnesen P, Hejek P, Williams KE, Billing CB, Reeves KR. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. JAMA 2006;296:64-71.

Clinical Topics: Heart Failure and Cardiomyopathies

Keywords: Nausea, Odds Ratio, Follow-Up Studies, Recurrence, Nicotinic Agonists, Substance Withdrawal Syndrome, Quinoxalines, Tobacco Use Disorder, Receptors, Cholinergic, Smoking Cessation, Benzazepines

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