title: Flexible, dual-form nicotine replacement therapy or varenicline in comparison with nicotine patch for smoking cessation: a randomized controlled trial.
abstract: BACKGROUND
  Extended use of combined pharmacotherapies to treat tobacco dependence may increase smoking abstinence; few studies have examined their effectiveness. The objective of this study was to evaluate smoking abstinence with standard nicotine patch (NRT), extended use of combined formulations of nicotine replacement therapy (NRT+), or varenicline (VR).
  
  
  METHODS
  A total of 737 smokers, including those with medical and psychiatric comorbidities, were randomly assigned to one of the above three treatment conditions. The NRT group received 10 weeks of patches (21 mg daily maximum); the NRT+ group received patches (35 mg daily maximum) and gum or inhaler for up to 22 weeks; and the VR group received 1 mg twice daily for up to 24 weeks (22 weeks post target quit date). All participants also received six standardized 15-minute smoking cessation counseling sessions by nurses experienced in tobacco dependence treatment. The primary outcome was carbon monoxide-confirmed continuous abstinence rates (CAR) from weeks 5-52. Secondary outcomes were: CAR from weeks 5-10 and 5-22, and carbon monoxide-confirmed 7-day point prevalence (7PP) at weeks 10, 22, and 52. Adjusted and unadjusted logistic regression analyses were conducted using intention-to-treat procedures.
  
  
  RESULTS
  The CARs for weeks 5-52 were 10.0 %, 12.4 %, and 15.3 % in the NRT, NRT+, and VR groups, respectively; no group differences were observed. Results with 7PP showed that VR was superior to NRT at week 52 (odds ratio (OR), 1.84; 97.5 % Confidence Interval (CI), 1.04-3.26) in the adjusted intention-to-treat analysis. Those in the VR group had higher CAR at weeks 5-22 (OR, 2.01; CI, 1.20-3.36) than those in the NRT group. Results with 7PP revealed that both NRT+ (OR, 1.72; CI, 1.04-2.85) and VR (OR, 1.96; CI, 1.20-3.23) were more effective than NRT at 22 weeks. As compared to NRT monotherapy, NRT+ and VR produced significant increases in CAR for weeks 5-10 (OR, 1.52; CI, 1.00-2.30 and OR, 1.58; CI, 1.04-2.39, respectively); results were similar, but somewhat stronger, when 7PP was used at 10 weeks (OR, 1.57; CI, 1.03-2.41 and OR, 1.79; CI, 1.17-2.73, respectively). All medications were well tolerated, but participants in the VR group experienced more fatigue, digestive symptoms (e.g., nausea, diarrhea), and sleep-related concerns (e.g., abnormal dreams, insomnia), but less dermatologic symptoms than those in the NRT or NRT+ groups. The frequency of serious adverse events did not differ between groups.
  
  
  CONCLUSIONS
  Flexible and combination NRT and varenicline enhance success in the early phases of quitting. Varenicline improves abstinence in the medium term; however, there is no clear evidence that either varenicline or flexible, dual-form NRT increase quit rates in the long-term when compared to NRT monotherapy.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifier: NCT01623505 ; Retrospectively registered on July 13, 2011.
authors.affiliation: Division of Prevention and Rehabilitation, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON, K1Y 4 W7, Canada. hetulloch@ottawaheart.ca.|Faculty of Medicine, University of Ottawa, Ottawa, Canada. hetulloch@ottawaheart.ca.|School of Psychology, University of Ottawa, Ottawa, Canada. hetulloch@ottawaheart.ca.
authors.forename: Heather E
authors.initials: HE
authors.lastname: Tulloch
authors.affiliation: Division of Prevention and Rehabilitation, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON, K1Y 4 W7, Canada.|Faculty of Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Pipe
authors.affiliation: Department of Psychiatry, 1E1 Walter Mackenzie Health Sciences Centre, University of Alberta, Edmonton, AB, T6G 2R7, Canada.
authors.forename: Charl
authors.initials: C
authors.lastname: Els
authors.affiliation: Division of Prevention and Rehabilitation, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON, K1Y 4 W7, Canada.|School of Psychology, University of Ottawa, Ottawa, Canada.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Clyde
authors.affiliation: Division of Prevention and Rehabilitation, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON, K1Y 4 W7, Canada.|Faculty of Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Reid
mesh_terms: D037001:Directive Counseling / Q000379:methods*; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D012907:Smoking / Q000188:drug therapy* / Q000523:psychology; D016540:Smoking Cessation / Q000379:methods*; D000074606:Smoking Prevention; D061485:Tobacco Use Cessation Devices; D014029:Tobacco Use Disorder / Q000188:drug therapy* / Q000517:prevention & control / Q000523:psychology; D016896:Treatment Outcome; D000068580:Varenicline / Q000627:therapeutic use*
chemical_list: D018722:Nicotinic Agonists; D000068580:Varenicline
keywords: Efficacy; Extended treatment; Intervention; RCT; Smoking cessation