Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial
Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial
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DOI：
10.1016/s0140-6736(16)30272-0
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发表时间：
2016-06-18
期刊：
影响因子：
168.9
通讯作者：
Evins, A. Eden
中科院分区：
文献类型：
--
作者：
Anthenelli, Robert M.;Benowitz, Neal L.;Evins, A. Eden
背景：人们对戒烟药物伐尼克兰和安非他酮的神经精神安全性提出了实质性的担忧。相对于尼古丁贴片，它们的有效性主要依赖于间接比较，而且关于精神疾病吸烟者的安全性和有效性的信息有限。在有和没有精神疾病的吸烟者中，我们比较了伐尼克兰和安非他酮与尼古丁贴片和安慰剂的相对神经精神安全风险和疗效。方法：2011年11月30日至2015年1月13日，我们在16个国家的140个中心（临床试验中心、学术中心和门诊诊所）进行了一项随机、双盲、三哑、安慰剂对照和主动对照（尼古丁贴片，21mg /天，逐渐减少）的伐尼克兰（1mg /天两次）和安非他酮（150mg /天两次）为期12周的试验，并进行了12周的非治疗随访。参与者在每次访问时接受简短的戒烟咨询，有或没有精神疾病的吸烟者都被激励戒烟。随机化由计算机生成（1:1:1:1比例）。参与者、调查人员和研究人员按治疗任务分组。主要终点是中度和重度神经精神不良事件的复合测量发生率。主要疗效终点是生物化学证实的9-12周的持续禁欲。所有随机分配的参与者被纳入疗效分析，接受治疗的参与者被纳入安全性分析。该试验已在ClinicalTrials.gov上注册（编号NCT01456936），现已关闭。研究结果：8144名受试者被随机分配，其中4116名进入精神科队列（4074名纳入安全性分析），4028名进入非精神科队列（3984名纳入安全性分析）。在非精神病学队列中，990名参与者中有13名（1.3%）报告了瓦伦尼克兰组中度和重度神经精神不良事件，989名参与者中有22名（2.2%）报告了安非他酮组不良事件，1006名参与者中有25名（2.5%）报告了尼古丁贴片组不良事件，999名参与者中有24名（2.4%）报告了安慰剂组不良事件。中度和重度神经精神不良事件的瓦伦尼克林安慰剂和安非他酮安慰剂的风险差异（RDs）分别为-1.28 （95% CI -2.40 ~ -0.15）和-0.08 (-1.37 ~ 1.21)；与尼古丁贴片比较，RDs分别为-1.07（-2.21 ~ 0.08）和0.13（-1.19 ~ 1.45）。在精神科队列中，1026名参与者中有67名（6.5%）报告了中度和重度神经精神不良事件，1017名安非他酮组有68名（6.7%），1016名尼古丁贴片组有53名（5.2%），1015名安慰剂组有50名（4.9%）。伐尼克林安慰剂和安非他酮安慰剂的RDs分别为1.59 （95% CI -0.42 ~ 3.59）和1.78 (-0.24 ~ 3.81)；与尼古丁贴片相比，RDs分别为1.22（-0.81 ~ 3.25）和1.42（-0.63 ~ 3.46）。伐尼克林治疗的受试者戒断率高于安慰剂组（优势比[OR] 3.61, 95% CI 3.07至4.24）、尼古丁贴片（1.68,1.46至1.93）和安非他酮（1.75,1.52至2.01）。安非他酮组和尼古丁贴片组的戒断率高于安慰剂组（OR分别为2.07[1.75 ~ 2.45]和2.15[1.82 ~ 2.54]）。在所有队列中，治疗组最常见的不良事件是恶心（伐尼克兰，25%[2016年参与者511人]）、失眠（安非他酮，12%[2006年参与者245人]）、异常梦（尼古丁贴片，12%[2022年参与者251人]）和头痛（安慰剂，10%[2014年参与者199人]）。不同队列的疗效治疗比较无差异。研究没有显示与尼古丁贴片或安慰剂相比，伐尼克兰或安非他酮导致的神经精神不良事件显著增加。在帮助吸烟者戒烟方面，伐尼克兰比安慰剂、尼古丁贴片和安非他酮更有效，而安非他酮和尼古丁贴片比安慰剂更有效。
Background Substantial concerns have been raised about the neuropsychiatric safety of the smoking cessation medications varenicline and bupropion. Their efficacy relative to nicotine patch largely relies on indirect comparisons, and there is limited information on safety and efficacy in smokers with psychiatric disorders. We compared the relative neuropsychiatric safety risk and efficacy of varenicline and bupropion with nicotine patch and placebo in smokers with and without psychiatric disorders.Methods We did a randomised, double-blind, triple-dummy, placebo-controlled and active-controlled (nicotine patch; 21 mg per day with taper) trial of varenicline (1 mg twice a day) and bupropion (150 mg twice a day) for 12 weeks with 12-week non-treatment follow-up done at 140 centres (clinical trial centres, academic centres, and outpatient clinics) in 16 countries between Nov 30, 2011, and Jan 13, 2015. Participants were motivated-to-quit smokers with and without psychiatric disorders who received brief cessation counselling at each visit. Randomisation was computer generated (1: 1: 1: 1 ratio). Participants, investigators, and research personnel were masked to treatment assignments. The primary endpoint was the incidence of a composite measure of moderate and severe neuropsychiatric adverse events. The main efficacy endpoint was biochemically confirmed continuous abstinence for weeks 9-12. All participants randomly assigned were included in the efficacy analysis and those who received treatment were included in the safety analysis. The trial is registered at ClinicalTrials.gov (number NCT01456936) and is now closed.Findings 8144 participants were randomly assigned, 4116 to the psychiatric cohort (4074 included in the safety analysis) and 4028 to the non-psychiatric cohort (3984 included in the safety analysis). In the non-psychiatric cohort, 13 (1.3%) of 990 participants reported moderate and severe neuropsychiatric adverse events in the varenicline group, 22 (2.2%) of 989 in the bupropion group, 25 (2.5%) of 1006 in the nicotine patch group, and 24 (2.4%) of 999 in the placebo group. The varenicline-placebo and bupropion-placebo risk differences (RDs) for moderate and severe neuropsychiatric adverse events were -1.28 (95% CI -2.40 to -0.15) and -0.08 (-1.37 to 1.21), respectively; the RDs for comparisons with nicotine patch were -1.07 (-2.21 to 0.08) and 0.13 (-1.19 to 1.45), respectively. In the psychiatric cohort, moderate and severe neuropsychiatric adverse events were reported in 67 (6.5%) of 1026 participants in the varenicline group, 68 (6.7%) of 1017 in the bupropion group, 53 (5.2%) of 1016 in the nicotine patch group, and 50 (4.9%) of 1015 in the placebo group. The varenicline-placebo and bupropion-placebo RDs were 1.59 (95% CI -0.42 to 3.59) and 1.78 (-0.24 to 3.81), respectively; the RDs versus nicotine patch were 1.22 (-0.81 to 3.25) and 1.42 (-0.63 to 3.46), respectively. Varenicline-treated participants achieved higher abstinence rates than those on placebo (odds ratio [OR] 3.61, 95% CI 3.07 to 4.24), nicotine patch (1.68, 1.46 to 1.93), and bupropion (1.75, 1.52 to 2.01). Those on bupropion and nicotine patch achieved higher abstinence rates than those on placebo (OR 2.07 [1.75 to 2.45] and 2.15 [1.82 to 2.54], respectively). Across cohorts, the most frequent adverse events by treatment group were nausea (varenicline, 25% [511 of 2016 participants]), insomnia (bupropion, 12% [245 of 2006 participants]), abnormal dreams (nicotine patch, 12% [251 of 2022 participants]), and headache (placebo, 10% [199 of 2014 participants]). Efficacy treatment comparison did not differ by cohort.Interpretation The study did not show a significant increase in neuropsychiatric adverse events attributable to varenicline or bupropion relative to nicotine patch or placebo. Varenicline was more effective than placebo, nicotine patch, and bupropion in helping smokers achieve abstinence, whereas bupropion and nicotine patch were more effective than placebo.