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Increasing the dosages of varenicline (Chantix) or combined nicotine replacement therapy (CNRT), or switching from CNRT to varenicline, improved abstinence from smoking, a randomized clinical trial showed.

Among participants who were treated with varenicline but were not abstinent, the end-of-treatment abstinence rate was 20% for those who increased their varenicline dosage, 0% for those who switched to CNRT, and 3% for those who continued their initial varenicline dose, with a more than 99% posterior probability that continuing varenicline at the initial dosage was worse than switching to a higher dosage, reported Paul M. Cinciripini, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and co-authors.

For those who were treated with CNRT but were not abstinent, the end-of-treatment abstinence rate was 14% for those who increased their dosage, 14% for those who switched to varenicline, and 8% for those who continued at their initial dosage, with a more than 99% posterior probability that the first two strategies conferred benefit over continuing the initial dosage, they noted in .

Only increased dosages of varenicline and CNRT led to continuous abstinence at 6 months compared with continuation of initial treatment dosages.

"Continuing was really the control here because that's normally what clinicians might do -- 'Well, you didn't succeed, let's just leave you on the medication for a longer period of time.' Whereas switching to a new medication or increasing the dose, those are the options that we were trying to test," Cinciripini said during an interview for JAMA's .

"So, it turns out that our study really makes that contribution of, again, what to do when people fail. If they succeed initially, they're going to have a really good chance of staying abstinent to the end of treatment, but if they fail, you need to do something different," he added.

The authors noted that the "probability of abstinence at the end of phase 1 was 22% for those in CNRT group and 36% for those in the varenicline group. This was unexpected."

Abstinence among those in the CNRT group was lower than that reported in a previous randomized trial -- about 36% for both varenicline and CNRT groups at 4 weeks, they pointed out. Other studies, including a and also showed "slightly higher abstinence rates among those taking varenicline compared with CNRT at similar times; however, a showed a small advantage for varenicline over a full course of medication."

have shown that almost 70% of smokers want to quit, with 55% reporting a serious attempt to do so. However, only 7.5% actually succeed, the authors noted. Those who do succeed often require multiple attempts, despite evidence that smoking cessation is associated with a reduced cancer risk in the long run, particularly when quitting was sustained and occurred prior to middle age. Both counseling and pharmacotherapy are recommended, but just 4.7% of smokers actually receive that care.

Glen B. Chun, MD, of the Icahn School of Medicine at Mount Sinai in New York City, described varenicline to MedPage Today as "probably the most effective single drug, as opposed to just a single NRT treatment."

"Ultimately, it's one of these situations where if there is a more optimal dose for patients using varenicline, and that was sort of the most interesting thing for me -- that it didn't have any significant side effects or any significant complications associated with the higher dose. I think that's very reassuring and very encouraging," he said.

For this double-blind study conducted from June 2015 through October 2019, 490 volunteers (mean age 48, 43% women, 58% white) from a Texas tobacco treatment clinic were randomized to receive 6 weeks of varenicline or CNRT. Nonabstainers were then rerandomized to continue, switch, or increase medication dosage for 6 additional weeks.

Participants in this study smoked an average of 20 cigarettes a day. Exclusion criteria included previous use of other smoking treatments or medications that were contraindicated for varenicline or CNRT and presence of substance use disorder, among others.

Initial treatments were varenicline 2 mg/day or the combined replacement therapy of a 21-mg patch plus 2-mg lozenge. The rerandomized participants either continued with their initial therapies, switched between varenicline and CNRT, or increased dosages to either 3 mg or more of varenicline or a 42-mg patch and lozenges.

There were no significant differences in adherence to the drug or the patch. The mean prescribed dosage taken averaged 82% or higher for active varenicline and 77% or higher for the active CNRT patch. Active lozenge count was more variable, ranging from a median of 40 lozenges to 76 lozenges across phases.

All volunteers were provided with counseling -- two in-clinic visits and three over the telephone during phase 1, and two in-clinic visits and one telephone call during phase 2. All counseling sessions were 15 minutes in length.

There were no adverse events for which group differences were above 2% that were linked to medication, except for nausea. Nausea was greater among participants in the phase 1 varenicline group versus the CNRT group. Three serious adverse events were observed and were deemed to be unrelated to treatment.

Cinciripini and team noted that not all phase 1 nonabstainers returned for rerandomization, which was an important limitation to the study. Others included the small sample size; the use of 2-mg lozenges as opposed to 4-mg lozenges, which may have limited the effectiveness of the CNRT approach for heavier smokers; and the fact that adding a second 21-mg nicotine patch would technically be considered "off-label prescribing."`

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