Dallas, TX - Smokers treated with an oral nicotine-receptor blocker for 12 weeks were significantly more likely to get off and stay off cigarettes for up to a year than those who received bupropion (Zyban, GlaxoSmithKline), a currently used antismoking drug, or those who received placebo, according to three complementary, prospective studies reported here at the American Heart Association (AHA) Scientific Sessions 2005. The treatment was augmented by a continuous motivational support program.

Dr Serena Tonstad

Varenicline (Champix, Pfizer) showed "robust and superior efficacy" out to one year and was safe and well tolerated, Dr Serena Tonstad (Ulleval University Hospital, Oslo, Norway) said when presenting the trio of studies. Two of them followed the same protocol but were conducted at different times and at different research centers, with the goal of seeing whether the second study would replicate the findings of the first, she said. The third was a completely separate maintenance study testing the value of a second course of the drug. Tonstad and her colleagues described the outcomes as "demonstrating a new order of effectiveness in smoking-cessation therapy."

After Tonstad's presentation, discussant Dr Erika S Froelicher (University of California, San Francisco) said the studies weren't conclusive and didn't address every issue that would need to be clarified before the drug could enter general use. However, they showed that varenicline was indeed safe and effective and that, while awaiting further trials, healthcare professionals "can feel confident that help is on the way."

Varenicline is a nicotine-receptor partial agonist with multiple effects on nicotine addiction, according to Tonstad. It puts a halt to "all the downstream effects of nicotine," including dopamine surges and stimulation of the brain's reward centers. "So this breaks the cycle of addiction," Tonstad said at a presentation for the medical press. But it also has a partial activation effect on nicotine receptors that helps to curb withdrawal symptoms, although cravings persist, she said.

In the two three-arm studies, 1025 and 1027 smokers, respectively, were randomized in a double-blind fashion to receive varenicline 1 mg twice daily, bupropion 150 mg twice daily, or placebo, with dosages titrated to those levels over the first week, during which smoking was allowed. They were instructed to quit on the eighth day; therapy continued out to 12 weeks, and follow-up went out to one year. The participants went to a clinic weekly for formal motivational support sessions throughout the study periods.

In all studies, patients were considered to have fallen off the wagon if they had even one puff of a cigarette. Continued abstinence from smoking was confirmed by regular measurements of breath carbon-monoxide concentrations.

In the first study, "the odds of being smoke-free were quadrupled on varenicline compared with placebo . . . and doubled compared with bupropion," Tonstad said, results that were "almost exactly duplicated" in the identical second study.

Rates of continuous smoking abstinence, weeks 9 to 12 (primary end point) and weeks 9 to 52 (secondary end point) in studies 1 and 2

Parameter	Varenicline	Bupropion	Placebo
Study 1	n=349	n=329	n=344
Weeks 9-12: Rate (%), odds ratio, p*	44.4	29.5, 1.96, <0.0001	17.7, 3.91, <0.0001
Weeks 9-52: Rate (%), odds ratio, p*	22.1	16.4, 1.45, 0.064	8.4, 3.13, <0.0001
Study 2	n=343	n=340	n=340
Weeks 9-12: Rate (%), odds ratio, p*	44.0	30.0, 1.89, <0.0001	17.7, 3.85, <0.0001
Weeks 9-52: Rate (%), odds ratio, p*	23.0	15.0, 1.72, <0.0001	10.3, 2.66, <0.0001

In the third study, testing maintenance therapy, 1236 other smokers took the drug at the same dosage but on an open-label basis for 12 weeks; they were told to quit cigarettes completely before day 8. The 1206 people from that group who successfully abstained to week 12 and complied with the motivational support sessions were then randomized to the active drug or placebo.

A second 12-week course of varenicline "was more beneficial than placebo in maintaining abstinence from smoking to both the end of treatment and one year after the start of treatment," Tonstad said.

Rates of continuous smoking abstinence, weeks 13 to 24 (primary end point) and weeks 13 to 52 (secondary end point) in the maintenance study

Parameter	Varenicline, n=602	Placebo, n= 604	P
Weeks 13-24: Rate (%)	70.6	49.8	<0.0001
Weeks 13-52: Rate (%)	44.0	37.1	0.0126

Observed side effects in the two three-arm studies that were markedly more common in the varenicline group included mild-to-moderate nausea and abnormal dreams. The dreams were usually described as vivid, Tonstad said. But the rate of withdrawal because of side effects in the first two trials was similar for all three groups.

Rates of the most common adverse effects of varenicline

Adverse effect	Varenicline (%)	Bupropion (%)	Placebo (%)
Study 1
Nausea*	28.1	12.5	8.4
Abnormal dreams	10.3	5.5	5.5
Study 2
Nausea*	29.4	7.4	9.7
Abnormal dreams	13.1	5.9	3.5

Dr Timothy Gardner

At a press conference on the trials, Dr Timothy Gardner (Christiana Care Health Services, Wilmington, DE), the current AHA program-committee chair, praised the three trials but had a caveat as well. He said the absolute numbers of participants who benefited from varenicline "were perhaps a little disappointing." Although the drug appeared to be superior to bupropion, the studies suggested that it may help keep less than half of smokers off cigarettes for up to 12 weeks and less than one quarter for 12 months.

Tonstad described the absolute numbers as a testament to nicotine's powerfully addictive effects.

The three trials were funded by Pfizer. Tonstad reported that she has consulted for and received lecture honoraria from GlaxoSmithKline and Pfizer.