ImportanceMost people who smoke do not quit on their initial attempt.ObjectiveTo determine the best subsequent strategy for nonabstinence following initial treatment with varenicline or combined nicotine replacement therapy (CNRT).Design, Setting, and ParticipantsUsing 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.InterventionsThe 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 MeasuresBiochemically verified 7-day point prevalence abstinence at the end of treatment at 12 weeks.ResultsThe 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 RelevanceFor 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 RegistrationClinicalTrials.gov Identifier: NCT02271919

中文翻译：

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伐尼克兰或尼古丁替代疗法初次治疗失败后戒烟

重要性大多数吸烟者在初次尝试时不会戒烟。目的确定采用伐尼克兰或联合尼古丁替代疗法 (CNRT) 初始治疗后不戒烟的最佳后续策略。设计、设置和参与者使用双盲、安慰剂对照、序贯试验在多项分配随机试验中，490 名志愿者被随机分配接受 6 周的伐尼克兰或 CNRT。 6 周后，非戒毒者被重新随机分组，继续、转换或增加药物剂量，持续 6 周。该研究于 2015 年 6 月至 2019 年 10 月在德克萨斯州的一家烟草治疗诊所进行。 干预措施 初始治疗为 2 毫克/天的伐尼克兰或 21 毫克贴剂加 2 毫克含片的联合替代疗法。重新随机分组的参与者要么继续最初的治疗，在伐尼克兰和 CNRT 之间切换，要么将伐尼克兰的剂量增加到 3 毫克或更多，或者增加到 42 毫克的贴剂和含片。所有人都接受每周简短的咨询。主要结果和措施在 12 周治疗结束时通过生化验证 7 天点流行率戒断。结果 490 名随机参与者（210 名女性 [43%]，287 名非西班牙裔白人 [58%]，平均年龄，48.1岁）平均每天吸20支烟。第一阶段结束后，CNRT 组中有 54 名参与者戒酒并继续治疗；在 191 名未戒烟的患者中，151 名被重新随机分组，40 名未返回重新随机分组的患者被分配在第 2 阶段继续其初始 CNRT 条件。191 名第 1 阶段非戒烟者的治疗结束戒烟率为 8% （95% 可信区间 [CrI]，6% 至 10%）对于继续维持剂量条件的 90 名（47%）来说，对于 50 名（33%）增加剂量的人来说是 14%（CrI，10% 到 18%）剂量，以及 51 名 (34%) 转用伐尼克兰的 14%（95% CrI，10% 至 18%）（绝对风险差 [RD]，6%；95% CrI，6% 至 11%）后验概率超过 99% 表明任一策略都比继续初始剂量有益处。第一阶段结束后，伐尼克兰组的 88 名参与者戒酒并继续治疗；在 157 名未戒烟的患者中，122 名被重新随机分组，35 名未返回重新随机分组的患者被分配继续接受伐尼克兰治疗。 157 名 1 期非戒断者的治疗结束戒断率为 20%（95% CrI，16% 至 26%），而 39 名（32%）增加伐尼克兰剂量的患者为 0（95% CrI，0 至 0） ）对于转为 CNRT 的 41 名（34%），对于被分配到继续伐尼克兰条件的 77 名（49%）为 3%（95% CrI，1% 至 4%）（绝对 RD，-3%；95 % CrI，-4% 至 -1%），超过 99% 的后验概率表明，继续使用伐尼克兰初始剂量比改用更高剂量更糟糕。此外，增加伐尼克兰剂量的绝对 RD 为 18%（95% CrI，13% 至 24%），并且带来益处的后验概率超过 99%。6 个月时持续戒烟的次要结果表明，只有增加 CNRT 和伐尼克兰的剂量才比继续初始治疗剂量有益处。结论和相关性对于吸烟但在伐尼克兰治疗后未实现戒烟的个体，增加剂量可增强戒烟效果与继续治疗相比，对于最初接受 CNRT 治疗的非戒断者来说，增加剂量或改用伐尼克兰可增强戒断效果，并且可能是可行的救援策略。 试验注册ClinicalTrials.gov 标识符：NCT02271919