Pharmacotherapy for smoking cessation: Effects by subgroup defined by genetically informed biomarkers
Schuit, Ewoud; Panagiotou, Orestis A; Munafò, Marcus R; Bennett, Derrick A; Bergen, Andrew W.; David, Sean P
(2017) Cochrane Database of Systematic Reviews, volume 2017, issue 9
(Article)
Abstract
Background: Smoking cessation therapies are not effective for all smokers, and researchers are interested in identifying those subgroups of individuals (e.g. based on genotype) who respond best to specific treatments. Objectives: To assess whether quit rates vary by genetically informed biomarkers within pharmacotherapy treatment arms and as compared with placebo.
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To assess the effects of pharmacotherapies for smoking cessation in subgroups of smokers defined by genotype for identified genome-wide significant polymorphisms. Search methods: We searched the Cochrane Tobacco Addiction Group specialised register, clinical trial registries, and genetics databases for trials of pharmacotherapies for smoking cessation from inception until 16 August 2016. Selection criteria: We included randomised controlled trials (RCTs) that recruited adult smokers and reported pharmacogenomic analyses from trials of smoking cessation pharmacotherapies versus controls. Eligible trials included those with data on a priori genome-wide significant (P < 5 × 10-8) single-nucleotide polymorphisms (SNPs), replicated non-SNPs, and/or the nicotine metabolite ratio (NMR), hereafter collectively described as biomarkers. Data collection and analysis: We used standard methodological procedures expected by Cochrane. The primary outcome was smoking abstinence at six months after treatment. The secondary outcome was abstinence at end of treatment (EOT). We conducted two types of meta-analyses- one in which we assessed smoking cessation of active treatment versus placebo within genotype groups, and another in which we compared smoking cessation across genotype groups within treatment arms. We carried out analyses separately in non-Hispanic whites (NHWs) and non-Hispanic blacks (NHBs). We assessed heterogeneity between genotype groups using T2, I2, and Cochrane Q statistics. Main results: Analyses included 18 trials including 9017 participants, of whom 6924 were NHW and 2093 NHB participants. Data were available for the following biomarkers: nine SNPs (rs1051730 (CHRNA3); rs16969968, rs588765, and rs2036527 (CHRNA5); rs3733829 and rs7937 (in EGLN2, near CYP2A6); rs1329650 and rs1028936 (LOC100188947); and rs215605 (PDE1C)), two variable number tandem repeats (VNTRs; DRD4 and SLC6A4), and the NMR. Included data produced a total of 40 active versus placebo comparisons, 16 active versus active comparisons, and 64 between-genotype comparisons within treatment arms. For those meta-analyses showing statistically significant heterogeneity between genotype groups, we found the quality of evidence (GRADE) to be generally moderate. We downgraded quality most often because of imprecision or risk of bias due to potential selection bias in genotyping trial participants. Comparisons of relative treatment effects by genotype For six-month abstinence, we found statistically significant heterogeneity between genotypes (rs16969968) for nicotine replacement therapy (NRT) versus placebo at six months for NHB participants (P = 0.03; n = 2 trials), but not for other biomarkers or treatment comparisons. Six-month abstinence was increased in the active NRT group as compared to placebo among participants with a GG genotype (risk ratio (RR) 1.47, 95% confidence interval (CI) 1.07 to 2.03), but not in the combined group of participants with a GA or AA genotype (RR 0.43, 95% CI 0.15 to 1.26; ratio of risk ratios (RRR) GG vs GA or AA of 3.51, 95% CI 1.19 to 10.3). Comparisons of treatment effects between genotype groups within pharmacotherapy randomisation arms For those receiving active NRT, treatment was more effective in achieving six-month abstinence among individuals with a slow NMR than among those with a normal NMR among NHW and NHB combined participants (normal NMR vs slow NMR: RR 0.54, 95% CI 0.37 to 0.78; n = 2 trials). We found no such differences in treatment effects between genotypes at six months for any of the other biomarkers among individuals who received pharmacotherapy or placebo. Authors' conclusions: We did not identify widespread differential treatment effects of pharmacotherapy based on genotype. Some genotype groups within certain ethnic groups may benefit more from NRT or may benefit less from the combination of bupropion with NRT. The reader should interpret these results with caution because none of the statistically significant meta-analyses included more than two trials per genotype comparison, many confidence intervals were wide, and the quality of this evidence (GRADE) was generally moderate. Although we found evidence of superior NRT efficacy for NMR slow versus normal metabolisers, because of the lack of heterogeneity between NMR groups, we cannot conclude that NRT is more effective for slow metabolisers. Access to additional data from multiple trials is needed, particularly for comparisons of different pharmacotherapies.
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Keywords: General Medicine, Pharmacology (medical), Journal Article, Review
ISSN: 1469-493X
Publisher: John Wiley and Sons Ltd
Note: Funding Information: Health education plus NRT gum (N = 189) Motivational interviewing plus NRT gum (N = 189) Health education plus placebo gum (N = 189) Motivational interviewing plus placebo gum (N = 188) Participants were assigned randomly to 1 of 4 study arms: 2 mg nicotine gum plus health education (HE); 2 mg nicotine gum plus motivational interviewing (MI); placebo gum plus HE; and placebo gum plus MI Primary outcomes: cotinine-verified 7-day abstinence at week 26, defined as having smoked no cigarettes - not even a puff - on the previous 7 days A salivary cotinine cutoff of ≤ 20 ng/mL was used to verify abstinence at 26 weeks; a cutoff of ≤ 10 ppm was used for CO Secondary outcomes: Secondary outcome was 7-day abstinence at week 8. Process measures included counseling attendance at randomisation and at weeks 1, 3, 6, and 8; and 16 counseling visits and self-reported gum usage in the past 7 days at weeks 1, 3, and 8 (end of gum treatment) This project was supported by the National Cancer Institute at the National Institutes of Health (R01 CA091912). GlaxoSmithKline provided study medication but played no role in design or conduct of the study nor in interpretation and analysis of data Funding Information: N = 925 Recruited from 26 general practice clinics in Buckinghamshire and Oxfordshire, UK Inclusion criteria: current smokers, age ≥ 18, smoked ≥ 10 cigarettes/d Exclusion criteria: contraindications to nicotine replacement therapy (NRT) Basic support (N = 469) Weekly support (N = 456) Participants were randomised to behavioural support provided by practice nurse before quitting, telephoned around quit day, and seen 1 and 4 weeks after the initial appointment (basic support) vs basic support plus weekly support - additional telephone call at 10 days and 3 weeks after the initial appointment, and an additional visit at 2 weeks to motivate adherence to nicotine replacement and to renew quit attempts. 15 mg/16 h nicotine patches were given to all participants Primary outcomes: confirmed sustained abstinence at 1, 4, 12, and 26 weeks from quit day. Sustained abstinence was defined as self-reported total abstinence after a 14-day grace period from quit date confirmed by expired air carbon monoxide (CO) < 10 ppm Secondary outcomes: not indicated “This study was funded by a programme grant from Cancer Research UK (trial registration ISRCTN 05689186). United Pharmaceuticals supplied the nicotine patches for the study free to be given without charge to the participants.” “PA has received free nicotine replacement products from Novartis and nortriptyline from King Pharmaceuticals for distribution to trial participants; personal income for advice to Xenova, a biotechnology company investigating a nicotine vaccine; small gifts and had numerous meals paid for by drug companies, including those producing medications for smoking cessation; and travel grants to attend conferences from the Society for Research in Nicotine and Tobacco. KB, CS, and AA have received small gifts and had meals paid for by drug companies, including those manufacturing medications for smoking cessation. M Munafó has received fees for invited lectures from the National Health Service, GlaxoSmithKline, Novartis, the Moffitt Cancer Research Center, and the Karolinska Institutet; benefits in kind (hospitality, etc.) from various pharmaceutical companies; research and travel support from the European Research Advisory Board, GlaxoSmithKline, Pfizer Consumer Healthcare and Novartis; and he has acted as a consultant to the European Commission, The American Institutes for Research, the National Audit Office, and G-Nostics Ltd. EJ has received consultancy income from the European Network for Smoking Prevention. M Murphy has received consultancy income from the European Network for Smoking Prevention and has provided scientific consultancy services through the University of Oxford ISIS Innovation to the National Audit Office and Funding Information: G-Nostics Ltd. The Childhood Cancer Research Group and the Cancer Research UK General Practice Research Group have received unrestricted educational grants, research project grants, and consultancy fees from Ciba Geigy/Novartis, GlaxoSmithKline, Phar-macia/Pfizer, Ares-Serono, Sanofi-Synthelabo, Third Wave Technologies, Astra Zeneca, and G-Nostics.” This paper did not report analyses of pharmacogenetics. However, DNA was collected from all trial participants and analyses of pharmacogenetics were reported in subsequent papers (David 2008; David 2011; Munafò 2008;Munafò 2009; Munafò 2011; Munafò 2012;Spruell 2012; Uhl 2010). Funding Information: This research was supported by a Junior Investigator Award from the National Alliance for Research on Schizophrenia and Depression (NARSAD) (AR) and was partially supported by Phillip Morris USA and Phillip Morris International Funding Information: This study was funded in part by US Public Health Service grants HL32318, DA08511, CA84719, and DA14276, and by GlaxoSmithKline, Inc., which provided study medication Funding Information: SPD is a scientific advisor with BaseHealth and participated in a 1-day workshop with Pfizer. MRM has received research support from Pfizer and GlaxoSmithKline. CL has served as a consultant and has received research funding from Astra Zeneca, Glaxo-SmithKline, and Pfizer DNA was collected after start of trial, resulting in genotyping for 59% of trial participants. Participants contributing DNA were significantly more likely to be female (51% vs 40%) and older (45.4 vs 43.2 years), and had been smoking longer (27.1 vs 24.8 years) . Analyses of pharmacogenetics were reported in subsequent papers from the original study sample (PMID: 17654295, PMID: 18058343). An additional 60 participants were recruited, randomised to bupropion vs placebo, and administered the same ST behavioural treatment following completion of the original trial. Analyses of the larger sample were reported in additional publications (David 2013a; Leventhal 2012; Uhl 2008). Funding Information: N = 147 Participants were smokers recruited from the Houston, Texas, metropolitan area via newspaper, radio, and TV advertisements and public service announcements Inclusion criteria: smoking ≥ 10 cigarettes/d at baseline, between 18 and 75 years old Exclusion criteria: taking smoking cessation treatment; taking psychoactive medication; or having any uncontrolled systemic illness, contraindications for taking venlafaxine or the nicotine patch, current substance abuse, or other psychiatric disorders Venlafaxine (n = 71) Placebo (n = 76) 21 weeks of active venlafaxine or placebo. After a 1-week no-medication baseline (3 weeks before the quit date), participants began antidepressant therapy 2 weeks before quitting at an initial dose of 75 mg/d (37.5 mg/d twice daily). The dose was increased up to 150 mg/d during the week just before participants were to quit. During each subsequent week, the dose was raised in 37.5-mg increments up to a maximum 225 mg/ d. Two weeks before the end of treatment, the dose was decreased by 37.5 mg every 2 to 3 days. The medication cycle was completed 18 weeks after quitting. All participants also used the nicotine patch (Prostep, 22 mg) for 6 weeks, beginning on their quit date, and received smoking cessation counseling Outcomes: Abstinence was assessed on the quit date and at post quit weeks 1, 3, 6, 18 (end of treatment), 26, and 52. Abstinence was verified in person by expired air carbon monoxide ≤ 10 ppm or by a saliva cotinine sample of < 15 ng/µL at 26 or 52 weeks Support for this research was provided by grants from the MD Anderson Cancer Center (PRS), the National Cancer Institute (P50CA70907), and the National Institute on Drug Abuse (R01DA1182-01) to Paul M. Cinciripini. Study medication was provided by Wyeth-Ayerst Laboratories Funding Information: “The Kick It at Swope III (KIS-III) study is a federally funded registered clinical trial (ClinicalTrials.gov identifier: NCT00666978) from the grant “Enhancing Tobacco Use Treatment for African American Light Smokers”.” Funding Information: Research was supported by National Institute on Drug Abuse Grant R01 DA12289 awarded to David G. Gilbert and by nicotine and placebo patches from GlaxoSmithKline Funding Information: chronic obstructive pulmonary disease. These relationships include serving as a consultant for Adams, Almirall, Altana, Array Biopharma, AstraZeneca, Aventis, Biolipox, Centocor, Dey, Critical Therapeutics, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis,OnoPharma, Otsuka, RJ Reynolds, Roche, Sankyo, Schering-Plough, Scios, and Wyeth; advising regarding clinical trials for Altana, AstraZeneca, Aventis, Cento-cor, GlaxoSmithKline, Novartis, Pfizer, and Philip Morris; and speaking at continuing medical education programs and performing funded research at both basic and clinical levels for Altana, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Novartis. Dr Nides reports having received research grants, consulting fees, and honoraria from Pfizer, Sanofi-Aventis, and GlaxoSmithKline. Dr Oncken reports having received research grants, consulting fees, and honoraria from Pfizer; receiving, at no cost, nicotine replacement and placebo products from GlaxoSmithKline for smoking cessation studies; and receiving honoraria from Pri-Med. Drs Azoulay, Watsky, Gong, Williams, and Reeves and Mr Billing report owning Pfizer stock or having stock options in Pfizer Funding Information: Randomised double-blind placebo-controlled trial of smoking cessation with a 2 × 2 factorial design (the “Patch Trial”) Study period: June 1991 to March 1992 N = 1686 Recruited from 19 general practice clinics in Oxfordshire, UK Inclusion criteria: current smokers, age ≥ 18 and ≤ 65 years, smoked ≥ 15 cigarettes/ d Exclusion criteria: (a) known skin hypersensitivity to nicotine, (b) severe skin condition likely to make patch use impossible, (c) untreated peptic ulcer, (d) life-threatening arrhythmia, (e) active cancer, (f) cerebrovascular or cardiovascular event within past 6 months, (g) lactation, and (h) existing or planned pregnancy. Patients were warned that they should not use other forms of nicotine, such as cigars, pipes, or nicotine chewing gum, during the trial, and that medication with centrally acting alpha activity (such as clonidine) was contraindicated 16-Page booklet plus nicotine patch (N = 422) 46-Page booklet plus nicotine patch (N = 420) 16-Page booklet plus placebo patch (N = 422) 46-Page booklet plus placebo patch (N = 422) Participants were randomised to 1 of 4 treatment groups: (a) nicotine patch with a standard, 16-page Health Education Authority pamphlet on smoking cessation; (b) nicotine patch with a 46-page booklet giving specific and more detailed information on smoking cessation with the help of patches; (c) placebo patch with a standard, 16-page Health Education Authority pamphlet on smoking cessation; or (d) placebo patch with a 46-page booklet giving specific and more detailed information on smoking cessation with the help of patches. Patches were delivered 21 mg/d × 4 weeks, followed by 14 mg/ d × 4 weeks, then 7 mg/d × 4 weeks Primary outcomes: biochemically verified point prevalence abstinence at 1 and 4 weeks (CO ≤ 10 ppm), and at 12, 24, and 52 weeks by cotinine ≤ 20 ng/mL or CO ≤ 10 ppm. Non-attenders were assumed to be smoking Abstinence at follow-up in 1999 to 2000 was confirmed by a plasma cotinine level ≤ 20 ng/mL Secondary outcomes: withdrawal symptoms The Patch Trial was supported by Ciba-Geigy Pharmaceuticals, which also supplied the nicotine and placebo patches. The Patch II Study was funded by the Imperial Cancer Research Fund and Cancer Research UK. “Personal funding to SPD provided by DA027331; National Institute for Health Research fellowship (to PA); and the UK Centre for Tobacco Control Studies (UKCTCS to P.A. and M.M.). The UKCTCS gratefully acknowledges funding from British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, and the Department of Health, Funding Information: The clinical trial was supported by a grant from the National Institute on Drug Abuse (R01DA015732, Maintaining Abstinence in Chronic Smokers, PI: Sharon M Hall) Funding Information: Clinical trial and publications (portion related to this trial) were supported by grants from the National Institute on Drug Abuse (R01 DA02538, K05 DA016752, K23 DA018691 and P50 DA 09253, and R01 DA15732) Funding Information: The clinical trial was sponsored by Pfizer Inc., which provided funding, study drug and placebo, and monitoring. Drs Azoulay, Watsky, Williams, Gong, and Reeves, and Mr Billing, employees of Pfizer Inc., were involved in all elements of this study. In addition, the database containing findings of the 14 investigator sites was maintained by Pfizer Inc. , and statistical analyses were performed at Pfizer Inc. by Mr Billing and Ann Pennington, MS. Independent analysis was performed to verify the findings of Pfizer Inc Dr Jorenby reported receiving research support from Pfizer, Nabi Biopharmaceutical, and Sanofi-Aventis, and consulting fees from Nabi Biopharmaceutical. Dr Hays reported receiving a research grant from Pfizer. Dr Rigotti reported receiving research grant funding and consulting fees from GlaxoSmithKline, which markets smoking cessation medications, and from Pfizer and Sanofi-Aventis, which are developing smoking cessation medications. Dr Rigotti also reported receiving consulting fees from Merck, which is developing smoking cessation medications Funding Information: N = 143 Participants were in recovery from alcohol problems and were recruited from a residential substance abuse treatment programme and from the community Inclusion criteria: smoked ≥ 10 cigarettes/d, history of alcohol abuse or dependence, and between 2 and 12 months of abstinence from alcohol Exclusion criteria: older than age 70; diagnosis of schizophrenia; current psychotic episode; cardiac problems in the past 3 months; uncontrolled hypertension; history of seizure; history of head injury with neurological sequelae or prolonged loss of consciousness; and use of medications that lower the seizure threshold Bupropion + nicotine patch (n = 73) Placebo + nicotine patch (n = 70) Participants were taking study medication for 8 weeks. They began study medication (bupropion 150 mg SR tablets or placebo) 1 week before their quit day. Participants were instructed to take 1 tabletd for 3 days, then one 150-mg tablet twice per day for the remainder of the treatment phase of the study All participants received a nicotine patch for 7 weeks, starting 1 week after starting study medication on their quit day. They received a 21-mg patch for 4 weeks, a 14-mg patch for 2 weeks, and a 7-mg patch for 1 week Outcomes: 7-day point prevalence smoking abstinence at week 7 (end of treatment) , week 11, and week 24. At week 7, smoking abstinence was defined via self-report (complete abstinence during the 7 days before the time of assessment) and biochemical verification (CO reading < 8 ppm). At week 11 and week 24, smoking abstinence was defined via self-report and biochemical verification (salivary cotinine levels ≤ 15 ng/mL) Study was sponsored through personal funding by David Kalman: NIDA R01-DA11713-01; Peter Monti: NIAAA K05 Senior Scientist Award; and Marc Mooney: NIDA K01-DA-019446. NIDA and NIAAA had no further role in study design; in collection, analysis, and interpretation of data; in writing of the report; or in the decision to submit the paper for publication No conflicts were declared. None of the review authors have any connection with the tobacco, alcohol, pharmaceutical, or gaming industries or with any body substantially funded by 1 of these organizations Funding Information: Primary outcome: point prevalence abstinence rates at 25-week and 52-week follow-up Secondary outcomes: repeated point prevalence abstinence; continuous abstinence; craving and withdrawal symptoms; physiological measurements; adverse events; medication compliance Support was provided solely by National Cancer Institute Grant CA 090300 awarded to Joel D. Killen. Nicotine patches and bupropion were kindly provided by GlaxoSmithK-line Funding Information: Support was provided solely by a grant from the National Institute on Drug Abuse Funding Information: Study medication for the bupropion trial was provided by GlaxoSmithKline. This research was supported by grants from the National Cancer Institute and the National Institutes of Drug Abuse, P50CA/DA84718 and RO1CA 63562 Funding Information: Primary outcomes: continuous abstinence measured at end of treatment and at 6 months after cessation Secondary outcomes: short-term quit rates using 7-day and 30-day point prevalence 76% and 72% of participants reporting abstinence at end of treatment and at 6 months provided a CO sample for verification This work was supported by a Transdisciplinary Tobacco Use Research Center Grant from the National Cancer Institute and the National Institute on Drug Abuse P5084718, and the Abramson Cancer Center and Annenberg Public Policy Center (CL), and PHS grants P60DA005186 (WB), DA02277, DA12393, CA078703, and the UCSF Comprehensive Cancer Center (NB), and Public Health Services Research Grant M01-RR0040 from the National Institutes of Health. Nicotine nasal spray was provided by Pharmacia, Helsingborg, Sweden Funding Information: Primary outcome: biochemically verified 7-day point prevalence abstinence at end of treatment Secondary outcomes: side effects, withdrawal symptoms, 6-month and 12-month quit rates This work was supported by a grant from the National Institute on Drug Abuse, the National Cancer Institute, the National Human Genome Research Institute, and the National Institute on General Medical Sciences (U01-DA20830) to CL and RFT; funding from the Abramson Cancer Center at the University of Pennsylvania (P30 CA16520) and a grant from the Commonwealth of Pennsylvania Department of Health was provided to CL; a grant from the Canadian Institutes of Health Research (CIHR TMH109787), an endowed Chair in Addiction for the Department of Psychiatry, CAMH Foundation, the Canada Foundation for Innovation (#20289 and #16014), and the Ontario Ministry of Research and Innovation were given to RFT. The Pennsylvania Department of Health disclaims responsibility for analyses, interpretations, or conclusions. Pfizer provided varenicline and placebo pills at no cost CL received study medication and placebo, and support for medication packaging, from Pfizer; she has also consulted for Gilead, and has been a paid expert witness in litigation against tobacco companies. PC served on the scientific advisory board of Pfizer Pharmaceuticals, presented educational talks sponsored by Pfizer on smoking cessation from 2006 to 2008, and has received grant support from Pfizer. RAS received medication and placebo free of charge from Pfizer for a different project, and has consulted for Pfizer and GlaxoSmithKline. TPG has received both investigator-initiated and industry-sponsored grants from Pfizer in the past 12 months, and serves on a data monitoring committee for Novartis. NIB has served as a consultant to several pharmaceutical companies that market smoking cessation medications and has been a paid expert witness in litigation against tobacco companies. RFT has acted as a consultant to pharmaceutical companies, primarily on smoking cessation. The remaining authors declare no competing interests. Funding Information: Primary outcomes: adherence to prescription of NRT over 28 days, motivation to make further quit attempts Secondary outcomes: adherence to prescription of NRT over 7 days, 6-month abstinence “This study was funded as part of a grant from the Medical Research Council, UK (Risk communication in preventive medicine: Optimising the impact of DNA risk information; G0500274 PI: TMM). The trial protocol was peer reviewed by the Council. PA is funded by a personal award from the National Institute of Health Research (NIHR) and by the UK Centre for Tobacco Control Studies (UKCTCS). PA and MRM are members of UKCTCS, a UKCRC Public Health Research Centre of Excellence. Funding from British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, and National Institute for Health Research, under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged. The sponsors and funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.” “PA has done consultancy and research on smoking cessation for pharmaceutical companies. The remaining authors declare that they have no conflicts of interest.” Funding Information: Primary outcomes: electronic diary and retrospective report of lapse and of relapse (7 days) with 7-day point prevalence abstinence confirmed via CO at each office visit and cotinine testing at end of treatment; 7-day point prevalence abstinence at 6 and 12 months with CO testing Secondary outcomes: prolonged abstinence outcomes at end of treatment, at 6 and 12 months This work was supported by Transdisciplinary Tobacco Use Research Center grants CA084724 from the National Cancer Institute and DA19706 from the National Institute on Drug Abuse. GlaxoSmithKline provided complimentary active and placebo medication used in this study. GlaxoSmithKline was not involved in the design, data collection, analysis, or reporting of this study DEJ has received research support from Nabi Biopharmaceutical and Pfizer, Inc., and consulting fees from Nabi Biopharmaceutical. SS serves as consultant to GlaxoSmithK-line Consumer Healthcare on an exclusive basis regarding over-the-counter smoking cessation products and is a partner in a company that is developing a new nicotine medication. He is a cofounder of invivodata, Inc., which provides electronic diary services for clinical research. In 1998 the University of Wisconsin appointed MCF to a named Chair made possible by an unrestricted gift to the university from GlaxoWellcome This work did not report analyses of pharmacogenetics, but these were reported in Bergen 2013. Funding Information: disease. These relationships include serving as a consultant (for Adams, Almirall, Altana, Array Biopharma, AstraZeneca, Aventis, Biolipox, Centocor, Dey, Critical Therapeutics, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Ono Pharma, Otsuka, RJ Reynolds, Roche, Sankyo, Schering-Plough, Scios, and Wyeth), advising regarding clinical trials (Altana, AstraZeneca, Aventis, Centocor, GlaxoSmithKline, Novartis, Pfizer, and Philip Morris), speaking at continuing medical education programs and performing funded research at both basic and clinical levels (Altana, AstraZeneca, Boehringer Ingel-heim, GlaxoSmithKline, and Novartis). He does not own any stock in any pharmaceutical companies. Dr Nides has received research grants, consulting fees, and honoraria from Pfizer, Sanofi-Avenits, and GlaxoSmithKline. Drs Watsky and Reeves and Messrs Billing and Anziano are employees of Pfizer and own Pfizer stock or hold Pfizer stock options Funding Information: This work was supported by Transdisciplinary Tobacco Use Research Center grants CA084724 from the National Cancer Institute and DA019706 from the National Institute on Drug Abuse Dr Fiore neither consults for nor accepts honoraria from the pharmaceutical industry, effective 1 January 2006. In 1998 the University of Wisconsin appointed Dr Fiore to a named chair, made possible by an unrestricted gift to the university from GlaxoWellcome. Dr Baker has received monies from pharmaceutical companies (Nabi, Glaxo, Pfizer, Sanofi) to conduct clinical trials; he has received no personal remuneration from these companies Funding Information: Primary outcome: 7-day point prevalence abstinence at 1 week post quit, at end of treatment, and at 6 months post quit, confirmed via CO (breath) analysis Secondary outcomes: initial cessation, days to lapse, days to relapse, latency to relapse after lapse This research was conducted at the University of Wisconsin-Madison and was supported by grant P50 DA019706 from the National Institute on Drug Abuse and by grant M01 RR03186 from the General Clinical Research Centers Program of the National Center for Research Resources. Dr Piper was supported by an Institutional Clinical and Translational Science Award, University of Wisconsin-Madison (KL2 grant 1KL2RR025012-01). Medication was provided to participants at no cost under a research agreement with GlaxoSmithKline Study authors report the following potential conflicts of interest for the past 5 years: Dr Smith has received research support from Elan Corporation. Dr Baker has served as an investigator on research projects sponsored by pharmaceutical companies, including Sanofi-Synthelabo, Pfizer Inc., and Nabi Biopharmaceuticals. Dr Jorenby has received research support from the National Institute on Drug Abuse, the National Cancer Institute, Pfizer Inc., Sanofi-Synthelabo, and Nabi Biopharmaceuticals. He has received support for educational activities from the National Institute on Drug Abuse and the Veterans Administration, and consulting fees from Nabi Biopharmaceuticals. Dr Fiore has received honoraria from Pfizer. He has served as an investigator on research studies at the Funding Information: University of Wisconsin that were funded by Pfizer, Sanofi-Synthelabo, GlaxoSmithK-line, and Nabi Biopharmaceuticals. In 1998, the University of Wisconsin appointed Dr Fiore to a named chair funded by an unrestricted gift to University of Wisconsin from Glaxo Wellcome This work did not report analyses of pharmacogenetics, but these were reported in Bergen 2013. Funding Information: National Institutes of Health (NIH), Intramural Research Program, National Institute on Drug Abuse, Department of Health and Social Services; grant to Duke University Funding Information: Transdisciplinary Tobacco Use Research Center Grant from the National Cancer Institute and the National Institute on Drug Abuse at the National Institutes of Health Dr Lerman has served as a consultant to GlaxoSmithKline - one company that manufactures the nicotine patch. She has also served as a consultant for or has received research funding from AstraZeneca, Pfizer, and Novartis. Financial support for this study was not provided by an industry sponsor. Dr Lerman had full access to the data and had full responsibility for the decision to submit for publication Funding Information: National Natural Science Foundation of China; Training Program Foundation for Excellent Talents by the Beijing Municipal Government, China; Stanley Medical Research Institute; Department of Veterans Affairs, Mental Illness Research, Education and Clinical Center (MIRECC); US National Institutes of Health Funding Information: Primary outcome: self-reported 7-day and 30-day point prevalence abstinence at 3 months and at 6 months after the targeted quit day Secondary outcomes: probable side effects (6) and probable abstinence effects (9) at 3 months after the targeted quit day This work was supported by Grant R01CA071358 from the National Cancer Institute. Pfizer provided varenicline and nominal support for recruiting participants Funding Information: SMZ owns stock in Free & Clear, Inc.; GES received financial support from Pf zer to attend a 1-day advisory meeting in 2008, and a small grant from Pf zer to support recruitment and study intake This paper did not provide analyses of pharmacogenetics, but these were reported in Bergen 2013. Funding Information: Research was supported by the UEM 03-2006 Internal Project of European University of Madrid and by the 035-2006 Project of the Spanish Lung Foundation (SEPAR) Funding Information: Blinding of participants and personnel (performance bias) All outcomes bupropion SR, 150 mg once daily, for days 1 through 6, followed by 150 mg twice daily for days 7 through 84; (2) nortriptyline, 25 mg once daily, for days 1 through 3, followed by 50 mg once daily for days 3 through 7, then 75 mg once daily for days 8 through 84; or (3) placebo. At the baseline visit, the target quit date (TQD) was set for the second week, usually day 11 from the start of medication Primary outcomes: prolonged abstinence from smoking from week 4 to week 26 after the target quit date. Prolonged abstinence was defined as a participant’s report of 0 cigarettes/d (not even a puff ) during weeks 4 through 26, confirmed by urinary cotinine values ≤ 60 ng/mL at weeks 4, 12, and 26 after TQD. Participants were allowed to miss 1 in-person visit but not the last follow-up visit Secondary outcomes: prolonged abstinence during weeks 4 through 12 and 7-day point prevalence abstinence (defined as having smoked 0 cigarettes, not even a puff, for the previous 7 days) at weeks 4, 12, and 26, confirmed by urinary cotinine levels ≤ 60 ng/ mL This work has been supported by a grant from the Netherlands Organization for Health Research and Development (ZonMW, The Hague; Project no. 50-50101-96-404). The original trial was funded by grants of the Dutch Asthma Foundation (NAF grant no. 3.2. 00.21) and the Health Research and Development Council (ZorgOnderzoek Nederland, grant no. 2200.0111), the Netherlands. Lundbeck B.V. provided active nortriptyline free of charge. Lundbeck B.V. as well as GlaxoSmithKline B.V. did not play a role in the design and conduct of the study, nor in interpretation and analysis of the data and the decision to submit for publication “CPVS has received financing (grants, consultancy and/or travel/accommodation costs) from AstraZeneca, Boehringer Ingelheim, and Pfizer, unrelated to this study. DSP has received financing (grants, consultancy, and/or travel/accommodation costs) from Chiesi, GlaxoSmithKline, AstraZeneca, Nycomed, and Boehringer Ingelheim, unrelated to this study. MQ, EJW, FJVS declare no conflict of interest.” The original study did not report pharmacogenetic outcomes. 214/255 (84%) participants in the original clinical trial were genotyped. Results were published in a subsequent pharmacogenetic paper (Quaak 2012). Funding Information: Study was conducted through a grant from the Foundation of Scientific Research (FWO number G.0604.06), Vlaamse Liga tegen Kanker, and an independent research grant from McNeil AB, Helsingborg, Sweden Funding Information: MRM: has received grant funding from Pfizer through its Investigator Initiated Research programme. Funding Information: • Netherlands Organisation for Scientific Research, Netherlands. ES acknowledges past support from the Netherlands Organisation for Scientific Research grant 825.14.001. • NIH, USA. AWB acknowledges past support from NIH grants DA020830, DA028793, DA033813 and DA041211, and a Visiting Professorship at the University of Bristol. Publisher Copyright: © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.
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