Combining treatments, extending therapy duration did not increase quit rates

Combination treatment with varenicline and nicotine patch therapy did not lead to improved smoking abstinence among adults smoking at least five cigarettes a day, regardless of whether treatment was carried out for 12 or 24 weeks, researchers found.

Some research has reported significant increases in smoking cessation when varenicline is used in combination with a nicotine replacement therapy (NRT), leading the American Thoracic Society to “conditionally recommend varenicline plus nicotine patch combination therapy over varenicline monotherapy for smoking cessation,” Timothy B. Baker, PhD, of the Center for Tobacco Research and Intervention at the University of Wisconsin School of Medicine and Public Health in Madison, Wisconsin, and colleagues wrote in JAMA. However, most guidelines did not follow suit, either recommending monotherapies or combination therapy using different types of NRT.

There is also some evidence suggesting that extending the duration of anti-smoking pharmacotherapy increases its efficacy, but whether or not this applies to treatment with varenicline has not been thoroughly evaluated.

To assess whether adding an NRT to varenicline or increasing varenicline treatment duration had any impact on smoking cessation rates, Baker and colleagues conducted a 52-week double-blind, 2 × 2 factorial randomized clinical trial among adults who expressed an interest in quitting, assigning participants to one of four treatment groups: varenicline monotherapy for 12 weeks, varenicline plus nicotine patch for 12 weeks, varenicline monotherapy for 24 weeks, or varenicline plus nicotine patch for 24 weeks.

The authors found that, among adults smoking five cigarettes a day or more, “there were no statistically significant differences in 7-day point prevalence abstinence at 52 weeks among those treated with combined therapy of varenicline pills plus nicotine patch versus varenicline monotherapy, or among those treated with varenicline monotherapy for 24 weeks versus 12 weeks. No statistically significant interactions were observed for these 2 treatment factors of medication type and medication duration. Furthermore, no statistically significant effects were obtained when the group receiving 12 weeks of varenicline monotherapy was compared with each of the other 3 treatment groups… These findings do not support recommendations that combination therapy with varenicline plus the nicotine patch be used in clinical care or that extended duration varenicline therapy be used during quit attempts.”

Baker and colleagues conducted their analysis through two Wisconsin research clinics, one in Madison and one in Milwaukee. Participants were included if they spoke English; smoked at least five cigarettes a day during the past six months; had an exhaled carbon monoxide (CO) level of 5 ppm or more; were at least 18 years old; expressed a desire to quit smoking; were not currently undergoing smoking cessation treatment; reported no other use of tobacco products (pipe tobacco, cigars, snuff, e-cigarettes, or chewing tobacco) within the preceding 30 days; had phone access; were willing and able to use both the nicotine patch and varenicline; were able to attend clinic visits over the next 12 months; and were not pregnant and were willing to use an acceptable birth control method during the study period.

Study medication was dispensed at the first clinical visit (week −2) and visit two (target quit day) and mailed to participants at week 8. For all groups, varenicline treatment was initiated one week before the target quit day (week −1) and nicotine patch treatment began 2 weeks before the target quit day (week −2). Active varenicline treatment lasted either 12 or 24 weeks, while nicotine patch treatment lasted 14 to 26 weeks due to the different medication start and stop times.

The four treatment groups were:

  • Varenicline monotherapy for 12 weeks: active varenicline for week −1 to week 11 and placebo varenicline from week 12 to week 23; placebo patch from week −2 to week 24.
  • Varenicline plus nicotine patch for 12 weeks: active varenicline for week −1 to week 11 followed by placebo varenicline from week 12 to week 23; active nicotine patch from week −2 to week 12 and placebo patch from week 13 to week 24.
  • Varenicline monotherapy for 24 weeks: Active varenicline from week −1 to week 23; placebo patch from week −2 to week 24.
  • Varenicline plus nicotine patch for 24 weeks: active varenicline from week −1 to week 23; active nicotine patch from week −2 to week 24.

Participants also received six 15-minute counseling sessions at study visits during week −2, target quit day, and week 2, as well as sessions over phone at weeks −1, 4, and 8. These sessions “focused on instructions for medication use, support, coping skills, and motivation to quit,” the study authors explained.

The study’s primary outcome was self-reported 7-day point prevalence abstinence at 52 weeks after the target quit day, biochemically confirmed by exhaled CO levels ≤5 ppm.

The authors randomized a total of 1,251 patients (mean age 49.1 years; 675 [54.0%] women), of whom 751 (60.0%) completed treatment and 881 (70.4%) provided final follow-up.

“For the primary outcome, there was no significant interaction between the 2 treatment factors of medication type and medication duration (odds ratio [OR], 1.03 [95% CI, 0.91 to 1.17]; P=0.66),” Baker and colleagues reported. “For patients randomized to 24-week vs 12-week treatment duration, the primary outcome occurred in 24.8% (154/622) versus 24.3% (153/629), respectively (risk difference, −0.4% [95% CI, −5.2% to 4.3%]; OR, 1.01 [95% CI, 0.89 to 1.15]). For patients randomized to varenicline combination therapy versus varenicline monotherapy, the primary outcome occurred in 24.3% (152/625) versus 24.8% (155/626), respectively (risk difference, 0.4% [95% CI, −4.3% to 5.2%]; OR, 0.99 [95% CI, 0.87 to 1.12]). Nausea occurrence ranged from 24.0% to 30.9% and insomnia occurrence ranged from 24.4% to 30.5% across the four groups.”

The analysis did not identify any subgroups for whom the various treatment options varied significantly, the study authors added.

In an editorial accompanying the study, Rajat S. Barua, MD, PhD, and Mohinder Vindhyal, MD, MEd, both of the University of Kansas Medical Center in Kansas City, Kansas, pointed out several strengths to the study by Baker et al, including the cohort size, long-term follow-up, and stratification by sex, race, treatment size, and tobacco dependence.

That being said, they noted that the current study had lower smoking cessation rates in the varenicline plus nicotine patch groups (24.4% at 12 weeks and 25.1% at 24 weeks) compared with other previous studies, which Baker and colleagues also acknowledged, saying that it was “unclear why standard varenicline combination therapy or extended varenicline monotherapy produced some positive effects in prior trials but showed little evidence of enhanced effectiveness in the present study.”

Barua and Vinhyal hypothesized that this difference might be related to the study authors using a lower exhaled CO cutoff (5 ppm or less) to confirm smoking cessation; most other studies used cutoffs of <9 ppm to 10 ppm. This lower cutoff, “along with the higher dropout rate and failure to follow-up, may have translated into the finding of lower cessation rates across all groups in the study by Baker et al,” they wrote.

Barua and Vindhyal also noted that a substantial number of smokers go through phases of abstinence and relapse

And, they added, this cycle of abstinence and relapse means that “clinicians need to use a chronic disease management approach, which involves monitoring tobacco use over time and making frequent efforts to encourage and assist cigarette smokers in quitting tobacco products. As outlined in the clinical recommendations, all patients should have a tobacco use assessment at each visit, and based on their readiness to quit tobacco, the level of dependence, past quit attempts, and personal preferences, a stepwise tailored approach is needed to achieve successful tobacco cessation.”

Barua and Vindhyal noted that future studies on this subject should assess the impact of granting participants a flexible quit date—a tactic that has shown some success in previous trials—on smoking cessation, and that more effort should be made to assess the efficacy of combination treatment and longer therapy duration among Black cigarette smokers, who tend to have significantly lower quit rates than White smokers.

Study limitations included that a small proportion of patients couldn’t have their abstinence biochemically confirmed due to Covid-19 restrictions; the decline in medication adherence over the course of the study; and the loss of roughly 23% of the sample to follow-up, with an additional 9% withdrawing from the study prior to completion.

  1. Combination varenicline and nicotine patch therapy did not improve smoking cessation compared to varenicline monotherapy.

  2. Extending pharmacological treatment for smoking cessation from 12 weeks to 24 weeks did not lead to improved smoking cessation rates, regardless of whether varenicline was given as monotherapy or in combination with nicotine patch therapy.

John McKenna, Associate Editor, BreakingMED™

Pfizer supplied the study with free active and placebo varenicline as per an investigator-initiated research agreement. This research was supported by grants from the National Heart, Lung, and Blood Institute and from the National Cancer Institute (both awarded to the University of Wisconsin Center for Tobacco Research and Intervention).

Baker reported receiving personal fees from the National Cancer Institute (NCI) for editing a monograph and grants from NCI. Coauthors Bolt and Fiore disclosed grants and personal fees, respectively, from NCI.

Barua and Vindhyal had no relevant relationships to disclose.

Cat ID: 489

Topic ID: 89,489,730,143,489,925