Smoking Cessation After Initial Treatment Failure With Varenicline or Nicotine Replacement: A Randomized Clinical Trial

Abstract

Importance: Most people who smoke do not quit on their initial attempt.

Objective: To determine the best subsequent strategy for nonabstinence following initial treatment with varenicline or combined nicotine replacement therapy (CNRT).

Design, setting, and participants: Using a double-blind, placebo-controlled, sequential multiple assignment randomized trial, 490 volunteers were randomized to receive 6 weeks of varenicline or CNRT. After 6 weeks, nonabstainers were rerandomized to continue, switch, or increase medication dosage for 6 additional weeks. The study was conducted from June 2015 through October 2019 in a Texas tobacco treatment clinic.

Interventions: The initial treatment was 2 mg/d of varenicline 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 either to 3-mg or more of varenicline or to a 42-mg patch and lozenges. All received weekly brief counseling.

Main outcomes and measures: Biochemically verified 7-day point prevalence abstinence at the end of treatment at 12 weeks.

Results: The 490 randomized participants (210 female [43%], 287 non-Hispanic White [58%], mean age, 48.1 years) smoked an average of 20 cigarettes per day. After the first phase, 54 participants in the CNRT group were abstinent and continued their therapy; of the 191 who were not abstinent, 151 were rerandomized, and the 40 who did not return for rerandomization were assigned to continue their initial CNRT condition in phase 2. The end-of-treatment abstinence rate for the 191 phase 1 nonabstainers was 8% (95% credible interval [CrI], 6% to 10%) for the 90 (47%) who continued at the dosage condition, 14% (CrI, 10% to 18%) for the 50 (33%) who increased their dosage, and 14% (95% CrI, 10% to 18%) for the 51 (34%) who switched to varenicline (absolute risk difference [RD], 6%; 95% CrI, 6% to 11%) with more than 99% posterior probability that either strategy conferred benefit over continuing the initial dosage. After the first phase, 88 participants in the varenicline group were abstinent and continued their therapy; of the 157 who were not abstinent, 122 were rerandomized and 35 who did not return for rerandomization were assigned to continue with the varenicline condition. The end-of-treatment abstinence rate for the 157 phase 1 nonabstainers was 20% (95% CrI, 16% to 26%) for the 39 (32%) who increased their varenicline dosage, 0 (95% CrI, 0 to 0) for the 41 (34%) who switched CNRT, and 3% (95% CrI, 1% to 4%) for the 77 (49%) who were assigned to the continued varenicline condition (absolute RD, -3%; 95% CrI, -4% to -1%) with more than 99% posterior probability that continuing varenicline at the initial dosage was worse than switching to a higher dosage. Furthermore, increasing the varenicline dosage had an absolute RD of 18% (95% CrI, 13% to 24%) and a more than 99% posterior probability of conferring benefit. The secondary outcome of continuous abstinence at 6 months indicated that only increased dosages of the CNRT and varenicline provided benefit over continuation of the initial treatment dosages.

Conclusions and relevance: For individuals who smoked but did not achieve abstinence after treatment with varenicline, increasing the dosage enhanced abstinence vs continuing, whereas for nonabstainers initially treated with CNRT, a dosage increase or switch to varenicline enhanced abstinence and may be viable rescue strategies.

Trial registration: ClinicalTrials.gov Identifier: NCT02271919.

Figure 1.. Sequential Multiple Assignment Randomized Trial Design

Study participants were initially randomized to receive either active varenicline or an active nicotine patch plus lozenges (combined nicotine replacement therapy [CNRT]) and were assessed for abstinence from smoking at week 6. Abstainers continued the same medication. Nonabstainers were rerandomized to continue the same medication, switch to the alternate medication, or increase the current dosage.

Figure 2.. The Flow Diagram Depicting Participant Flow Through the Trial

^aRandomization in phase 1 used minimization to balance gender and race. ^bParticipant was assigned to the wrong phase 2 condition and was excluded from all analyses. ^cConsistent with an intent-to-treat approach, participants were imputed into the continuation condition in phase 2. ^dAbstinence was 7-day point prevalence biochemically verified; continuous abstinence was measured 30 days after treatment and 6 months after the target quit date.

Figure 3.. Posterior Probability Distributions for Abstinence at End of Treatment (12 Weeks)

Each distribution is a probability density with an area under the curve equal to 1. The height of the density is scaled to permit full depiction of each distribution. The phase 1 dose for the combined nicotine replacement therapy (CNRT) was a 21-mg patch and 2-mg lozenges and the varenicline dose was 2 mg/d. The phase 2 CNRT dose increased to 2 patches and lozenges remained at 2 mg, and the varenicline dose increased to 3 mg/d. The color brown indicates participants who had abstained after 6 weeks; lighter blue, nonabstainers who switched treatment; orange, nonabstainers whose dosages were increased; and darker blue, nonabstainers who continued phase 1 treatment.