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Research

Original Investigation

Efficacy of Varenicline Combined With Nicotine Replacement
Therapy vs Varenicline Alone for Smoking Cessation
A Randomized Clinical Trial
Coenraad F. N. Koegelenberg, MD, PhD; Firdows Noor, MD; Eric D. Bateman, MD, PhD;
Richard N. van Zyl-Smit, MD, PhD; Axel Bruning, MD; John A. O’Brien, MD; Clifford Smith, MD;
Mohamed S. Abdool-Gaffar, MD; Shaunagh Emanuel, MD; Tonya M. Esterhuizen, MSc; Elvis M. Irusen, MD, PhD

Related article page 180
IMPORTANCE Behavioral approaches and pharmacotherapy are of proven benefit in assisting Supplemental content at
smokers to quit, but it is unclear whether combining nicotine replacement therapy (NRT) with jama.com
varenicline to improve abstinence is effective and safe.

OBJECTIVE To evaluate the efficacy and safety of combining varenicline and a nicotine patch
vs varenicline alone in smoking cessation.

DESIGN, SETTING, AND PARTICIPANTS Randomized, blinded, placebo-controlled clinical trial
with a 12-week treatment period and a further 12-week follow-up conducted in 7 centers in
South Africa from April 2011 to October 2012. Four hundred forty-six generally healthy
smokers were randomized (1:1); 435 were included in the efficacy and safety analyses.

INTERVENTIONS Nicotine or placebo patch treatment began 2 weeks before a target quit
date (TQD) and continued for a further 12 weeks. Varenicline was begun 1 week prior to TQD,
continued for a further 12 weeks, and tapered off during week 13.

MAIN OUTCOMES AND MEASURES Tobacco abstinence was established and confirmed by
exhaled carbon monoxide measurements at TQD and at intervals thereafter up to 24 weeks.
The primary end point was the 4-week exhaled carbon monoxide–confirmed continuous
abstinence rate for weeks 9 through 12 of treatment, ie, the proportion of participants able to
maintain complete abstinence from smoking for the last 4 weeks of treatment, as assessed
using multiple imputation analysis. Secondary end points included point prevalence
abstinence at 6 months, continuous abstinence rate from weeks 9 through 24, and adverse
events. Multiple imputation also was used to address loss to follow-up.

RESULTS The combination treatment was associated with a higher continuous abstinence
rate at 12 weeks (55.4% vs 40.9%; odds ratio [OR], 1.85; 95% CI, 1.19-2.89; P = .007) and 24 Author Affiliations: Stellenbosch
weeks (49.0% vs 32.6%; OR, 1.98; 95% CI, 1.25-3.14; P = .004) and point prevalence University, Cape Town, South Africa
abstinence rate at 6 months (65.1% vs 46.7%; OR, 2.13; 95% CI, 1.32-3.43; P = .002). In the (Koegelenberg, Noor, Esterhuizen,
Irusen); University of Cape Town,
combination treatment group, there was a numerically greater incidence of nausea, sleep Cape Town, South Africa (Bateman,
disturbance, skin reactions, constipation, and depression, with only skin reactions reaching van Zyl-Smit); Gatesville Melomed
statistical significance (14.4% vs 7.8%; P = .03); the varenicline-alone group experienced Hospital, Cape Town, South Africa
(Bruning); Christiaan Barnard
more abnormal dreams and headaches.
Memorial Hospital, Cape Town, South
Africa (O’Brien); Rochester Place
CONCLUSIONS AND RELEVANCE Varenicline in combination with NRT was more effective than Medical Centre, Johannesburg, South
varenicline alone at achieving tobacco abstinence at 12 weeks (end of treatment) and at 6 Africa (Smith); Kingsway Medical
Centre, Durban, South Africa
months. Further studies are needed to assess long-term efficacy and safety. (Abdool-Gaffar); Synopsis Research
Unit, Cape Town, South Africa
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01444131 (Emanuel).
Corresponding Author: Coenraad F.
N. Koegelenberg, MD, PhD, Division
of Pulmonology, Department of
Medicine, Stellenbosch University
and Tygerberg Academic Hospital,
PO Box 19063, Tygerberg,
7505 Cape Town, South Africa
JAMA. 2014;312(2):155-161. doi:10.1001/jama.2014.7195 (coeniefn@sun.ac.za).

155

Copyright 2014 American Medical Association. All rights reserved.

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etc) in the past 6 months been studied to date.com/ by a World Health Organization User on 07/14/2014 . An History of or currently experiencing psychosis.5 kg weeks. Previous enrollment in a study that included varenicline tablished at the TQD and at 1. smoking cessation. The primary end point was the 4-week History of clinically significant endocrine disorders or gastrointesti- continuous abstinence rate during weeks 9 through 12 of va- nal diseases.jamanetwork. stroke. History of drug or alcohol abuse or dependence within the past tine patch. myocardial infarction. lead. 8. Smoking status was es. and 24 weeks there- Use of nicotine replacement therapy within the last 6 months after. naltrexone. coronary artery bypass graft. The study was conducted in ever is longer) before the baseline visit or within 30 days of study compliance with the ethical principles of the Declaration of Hel. Downloaded From: http://jama.9. Written informed consent was obtained from all partici- Use of other investigational drugs within 30 days or 5 half-lives (which- pants prior to enrollment.9 Nicotine from nicotine replacement weeks before the TQD) into 1 of the 2 groups of the study in a therapy (NRT) acts on this cholinergic receptor (as well as other 1:1 ratio using centrally generated block randomization within receptor subtypes. cutaneous and systemic allergic reactions) ceive varenicline plus placebo patch or varenicline plus nico. Participants aged 18 to 75 years who sought assistance with lar diseases and cancer.3-7 tives were provided. and clinically significant conduction abnormalities The aim of this study was to evaluate the efficacy of com- Uncontrolled hypertension or a systolic blood pressure greater than bining varenicline and a nicotine patch vs varenicline alone as 150 mm Hg or diastolic pressure greater than 95 mm Hg at screening an aid to smoking cessation in a double-blind study design in Clinically significant neurological disorders or cerebrovascular dis- a larger group and with a longer assessment period than has eases (eg. All rights reserved. livery is significantly slower. including bu- lines on Good Clinical Practice. Participants had to be prepared to attend clinic vis- is believed to be the princ ipal mediator of nicotine its. 156 JAMA July 9. and the protocol was approved propion. percutaneous addition of nicotine patches. or insulin search ethics committee of Stellenbosch University.2 Encouraging smoking cessa. the human re. mood stabilizers. and the in- dependent review board of each center. and active peptic ulcer Significant hepatic or renal impairment or other clinically significant abnormal laboratory test values (performed at the discretion of the investigator) Methods History of cancer (cured basal cell or squamous cell carcinoma of the A randomized. severe April 2011 to October 2012. 4. criteria are summarized in the Box.10 and a randomized controlled trial sug- gested that the efficacy of varenicline was not enhanced by the Clinically significant cardiovascular disease in the past 6 months. or bi- observational study found no differences in outcome be- polar disorder tween a cohort of participants receiving various NRT prod- Severe chronic obstructive pulmonary disease ucts and varenicline. panic disorder. ste- by the South African Medicines Control Council. eg. Participants were randomized to re. although the pharmacokinetic de. roids (inhaled and topical steroids were permitted). Exclusion dependence.7 The nicotinic cho.1. nadotropin). transient ischemic attack. The combination of had had no period of smoking abstinence longer than 3 months behavioral approaches and pharmacotherapy are of proven in the past year were eligible for the study.10 mia.9 Both studies found the combi- transluminal coronary angioplasty. Both tine from tobacco smoke. and priority for all health care professionals. Johannesburg. completion sinki and the International Conference on Harmonization guide- Use of prohibited medications: any antidepressants. through 30 days after the last dose of study medication.3 Past or present depression or treatment with antidepressants within Previous studies have evaluated combining varenicline and the past 12 months NRT as a potential means for increasing abstinence rates. had smoked at least 10 cigarettes/d dur- tion and supporting smokers who want to quit should be a ing the previous year and the month prior to screening. serious arrhyth- nation to be safe and well tolerated. finity than nicotine. trolled hyperthyroidism. Only 1 participant per household was allowed. had a and addiction results from the development of tolerance and negative test for pregnancy (urinary β–human chorionic go- mechanisms that reinforce dependance. Participant Selection and Randomization bidity and mortality from respiratory and cardiovascu. 16. uncon- renicline treatment. the investigators and the participants were blinded. and tapered off during week 13.com Copyright 2014 American Medical Association. blocking nicotine effects but also acting Eligible participants were randomized at a second visit (2 as a partial agonist. and specifically the α4β2 receptor subtype. continued for a further 12 45. Number 2 jama. double-blind trial was conducted at 7 centers (in skin allowed) Cape Town. Women of child-bearing potential were The pharmacologic effects of nicotine are mediated via allowed to enroll provided they agreed to avoid pregnancy nicotinic receptors on the surface of cells throughout the body. 2014 Volume 312. antipsychotic agents. Exclusion Criteria ing to complex pharmacodynamics. 2.8. varenicline may in theory block the direct agonist effects of nicotine. Research Original Investigation Varenicline and Nicotine Replacement Therapy for Smoking Cessation T obacco use is the foremost preventable cause of mor.7 Varenicline targets this receptor with higher af. Varenicline was A body mass index less than 15 or greater than 38 or a weight less than up-titrated 1 week before the TQD. 12. unstable angina. each site (blocks of 4 with 2 active and 2 placebo patches). and agreed to use an effective birth control linergic receptor. including insulin-dependent diabetes mellitus. No financial incen- benefit in assisting smokers to quit. Patches were commenced 2 weeks before a target quit 12 months date (TQD) and continued for a further 12 weeks. including α3β4) in a similar way to nico.9 As a partial agonist. method. Box. and Durban) in South Africa from History of clinically significant allergic reactions to drugs (eg.

4-6 However. treatment. to determine point prevalence.com/ by a World Health Organization User on 07/14/2014 .com JAMA July 9. difference. domization. A logit model was used to impute the outcome Outcome Measures for participants who did not attend their 12. participants are summarized in Table 1. The primary end point was the 4-week con. titrated to 0. con. 16. and t tests on con- (and packaging) to active patches. 2014 Volume 312. body mass took at least 1 dose of varenicline while using the randomized index. we required a further 40 participants.jamanetwork. missed a visit were considered to be smokers at that point in ducted at weeks 13 (telephonic). Number 2 157 Copyright 2014 American Medical Association. of week 13 (0. Varenicline and Nicotine Replacement Therapy for Smoking Cessation Original Investigation Research Study Procedures and Assessment surement greater than 10 ppm at weeks 12. resulting in domization visit. StataCorp). medical and smoking history (past attempts to quit smoking Participants who discontinued the study or were lost to fol- and lifetime cigarette use) and a physical examination. ceed 10%.13 for clinical relevance to 14%. in the Supplement). 435 ered to be smokers in the calculation of point prevalence ab. One week before the TQD. Downloaded From: http://jama.5 mg once analyses (which included all randomized participants). Using this value. years smoked.5 mg IBM). at a 5% signifi- cance level and 80% power (2-tailed. and 12 both the primary and secondary end points. continuous abstinence in weeks 9 through 12 was estimated cluding tobacco craving were assessed by means of the Wis.and 24-week The efficacy analysis population consisted of participants who follow-up visits. during the pre- ceding 7 days (eMethods 1 in the Supplement). An additional post hoc firmed with end-expiratory exhaled carbon monoxide mea. ie. Par. based on the parameters of age.6 Exhaled car. Descriptive statistics and χ2 or Fisher exact tests were per- plied by the same manufacturer and were similar in appearance formed on dichotomous categorical variables. 0. Analyses were conducted using SPSS software (version 21. the continuous abstinence rate from week 9 through 24. 14 weeks). mean [SD] age. the proportion of participants who were able to Bivariable logistic models were then fitted with the imputed val- maintain complete abstinence from cigarette smoking and ues using treatment group as the predictor variable for com- other nicotine use for the last 4 weeks of treatment. Statistical Aspects bon monoxide was measured at each visit using a Micro IV The efficacy of varenicline to achieve the primary outcome of Smokerlyzer (Bedfont Scientific). to be 45%. Of these. to account for missing data using Stata software (version 13. and 24 were all Participants completed the Fagerström Test for Nicotine De. parison with the per-protocol analysis. A post hoc multiple imputation analysis was performed in the evenings for 3 days. and all participants who were followed up at least ous abstinence by reporting the use of cigarettes and other nico.05). considered not to have achieved continuous abstinence at 6 pendence on enrollment. last contact and. Par- ticipants who answered yes to any of the NUI questions per- Results taining to the preceding 7 days or who had an exhaled carbon A total of 446 participants (171 males. Follow-up visits were con. tinuous data in both the per-protocol and intention-to-treat all participants began taking varenicline (Pfizer).9] monoxide measurement greater than 10 ppm were all consid. 46. til week 12 (total duration. Varenicline was tapered off and stopped at the end able. total duration. and our initial assumption was that a 12% further consin Scale for Withdrawal Symptoms (eMethods 2 in the increase in the 4-week abstinence rate in the NRT active group Supplement) at randomization and up to 4 weeks after the would represent a clinically relevant treatment outcome TQD. the sample size Study Medication was calculated at 199 per group (total sample size of 398).11 Further assessment included a months. Five imputations were performed. and 24 during the non. Withdrawal symptoms in. Placebo patches were sup. logistic mixed model analysis was also performed (eMethods 3 surements of 10 ppm or less at week 12. daily average nicotine patch. α = . jama. Ten minutes of smoking cessation counseling. 2 weeks before the TQD. an estimated sample size of 438 participants.5 mg twice daily for 4 days. a subsequent study combining vareni- vere). 4. treatment period.3 [11. cigarettes smoked. and the incidence of adverse events. As- Active 15-mg nicotine patches (Nicorette. 14 weeks).14 Accordingly. pack-years smoked. Fagerström test score.5 mg twice daily for days 4 to 7 logistic regression model was fitted to the primary binary end and then to the maintenance dose of 1 mg twice daily through point and included treatment center as an independent vari- week 12. Secondary end points included the point prevalence ab- stinence at 6 months. A daily for 3 days.12 Each subscale ranges from 0 (no symptoms) to 4 (se. Demographic characteristics and smoking history of the NUI questions or who had an exhaled carbon monoxide mea. previous attempts to tinuous abstinence rate for weeks 9 through 12 of varenicline quit. whereas participants who answered yes to any of the ses. were included in the per-protocol efficacy and safety analy- stinence. low-up were considered smokers in the per-protocol and in- ticipants were followed up weekly from randomization until tention-to-treat calculations of continuous abstinence rates of the TQD (2 weeks later) and subsequently at 1. the per-protocol analysis. sex. 2. 8. McNeil) or placebo suming the attrition rate at the end of treatment would not ex- patches were administered for 16 h/d beginning at the ran. Participants who weeks during the treatment period. and continued un. All rights reserved. Participants were asked at each clinic visit All adverse events were recorded at each visit after ran- to complete a Nicotine Use Inventory (NUI) to assess continu. in abstinence. once after the initiation of any study medication were in- tine-containing products (other than that provided) since the cluded in the safety analysis. years) were enrolled and randomized (Figure). and treatment group. based on cline with a nicotine gum reported a 16% additional increase the 2008 update of the US Public Health Service guidelines. followed by 0. 16. we increased our required value was provided to all participants at each visit.

Baseline Characteristics of All Participants Randomized (N=446) Abstinence Rates and Craving for Cigarette Smoking The continuous and the point prevalence abstinence rates for Mean (SD) the per-protocol and multiple imputation analyses are pre- Varenicline sented in Table 2.6 (11.6%.5 (1.1 (6.3) 4. P = . 216 Included in 12-wk multiple imputation analysis 219 Included in 12-wk multiple imputation analysis d Two hundred seventy-eight 179 Completed treatment periodc 173 Completed treatment periodc participants completed the 24-wk 37 Imputed datac 46 Imputed datac follow-up and 155 imputations were 216 Included in 24-wk multiple imputation analysis 217 Included in 24-wk multiple imputation analysis 144 Completed study periodd 134 Completed study periodd performed. P = .8) numbers needed to treat (NNT) to achieve 1 additional suc- Cigarettes.com Copyright 2014 American Medical Association.5) cebo NRT and varenicline. Continuous abstinence score denotes greater dependency.6%. 27.2) 26. 158 JAMA July 9. Research Original Investigation Varenicline and Nicotine Replacement Therapy for Smoking Cessation Figure.3 (14. a Calculated as weight in kilograms divided by height in meters squared.37 (0-15) prevalence abstinence at 24 weeks was 18. The difference observed in point Previous quit attempts. at 12 weeks was observed in 99 of 222 participants (44.8) 27.2%-25. 1.8) 21. P = . a All participants randomized were 179 Completed treatment period (12 wk)c 173 Completed treatment period (12 wk)c included in the intention-to-treat 18 Withdrew consent 15 Withdrew consent analysis. y 46. respectively.9%) and the NNT.0% vs 32.4 (14. Table 1. mean (SD).1 (11.1 (4.8%) at 12 Smoking history weeks and 16.1) 7 (95% CI. The differences observed in con- Fagerström scoreb 4.7%. 5-20) and Pack-years 21. 6 (95% CI.5 (5. 13 Lost to follow-up 19 Lost to follow-up 6 Withdrawn because of adverse events 11 Withdrawn because of adverse events b All participants who took ⱖ1 dose of 1 Withdrawn because of protocol violation varenicline while using the randomized nicotine patch were 144 Completed study period (24 wk)d 134 Completed study period (24 wk)d included in the per-protocol 28 Withdrew consent 28 Withdrew consent analysis. (%) 87 (39. No. Participants who received active NRT and and Active Varenicline and Nicotine Patch Placebo Patch varenicline were more likely to achieve continuous absti- Characteristic (n = 222) (n = 224) nence at 12 weeks (55.5% (95% CI.4) tinuous abstinence were 14.5 (6. Downloaded From: http://jama.8 (11. No.5) 24 weeks (65. 9./d 15.004) and point prevalence abstinence at Male.0 (11.002) than those receiving pla- Body mass indexa 27. Results of the intention-to-treat analysis of the primary b The Fagerström score for nicotine dependence ranges from 0 to 10. 4-11).5 (1.1% vs 46. 7 Lost to follow-up 11 Lost to follow-up c Three hundred fifty-two participants completed the 12-wk 216 Included in per-protocol efficacy and safety analysisb 219 Included in per-protocol efficacy and safety analysisb follow-up and 83 imputations were 222 Included in intention-to-treat analysisa 224 Included in intention-to-treat analysisa performed.9%.4% vs 40.9) 46.9) (49.007) and 24 weeks Age. 7. Number 2 jama.4% (95% CI.com/ by a World Health Organization User on 07/14/2014 . 72 Imputed datad 83 Imputed datad e Data for 2 participants were 2 Excluded due to insufficient datae insufficient to perform the multiple imputation analysis at 24 weeks. 5.5%- mean (range).55 (0-11) 1. Participant Flow Through the Study 692 Individuals screened 246 Excluded 73 History of psychiatric condition 70 Use of prohibited medication 21 History of recent significant disease or previous cancer 20 Unwilling to commit to follow-up 17 Older than 75 y 15 Smoked <10 cigarettes/d 14 Body mass index too high 8 Not motivated to stop smoking and use medication 5 Residing too far from study site 3 Other household member in study 446 Participants enrolled and randomized 222 Randomized to receive NRT patch and vareniclinea 224 Randomized to receive placebo patch and vareniclinea 216 Received treatment as randomizedb 219 Received treatment as randomizedb 3 Withdrew consent (prior to using varenicline) 4 Withdrew consent (prior to using varenicline) 2 Lost to follow-up (prior to using varenicline) 1 Lost to follow-up (prior to using varenicline) NRT indicates nicotine replacement 1 Excluded (concomitant psychiatric medication) therapy. All rights reserved.jamanetwork.5%) at 24 weeks. and the Years smoked 26. 4-14).9) cessful attempt at smoking cessation were 7 (95% CI.4% (95% CI. No.8) 16. 2014 Volume 312.2) 84 (37.2%-23. a higher end point provided similar results.

41).58 (1.50.90) . respectively. All rights reserved. 1. P = . ization (2.3-3.30) . P = . for the main outcome of continued abstinence (weeks 9-12). 2.22 (0.9) 1. Safety.43 Any skin reactions 31 (14. 25.9) 22 (10.02-2.8) 1.003 9-16 24 wk Weeks 71 (32.08-2.83) .79) .58) .66) .78.43-1.68 4 wk Week 4 110 (50.8 kg) in the placebo NRT groups.13 (1.001 141 (65.84) . 2014 Volume 312.4) .55-2.66. 95% CI.20-2.85 (1.58) .5) 96 (43.23-2. no change in the effect was observed.com/ by a World Health Organization User on 07/14/2014 .6) 13 (5.43) . Data for 2 a Calculated mean proportional values (numbers rounded) derived from data of participants (in the placebo group) were insufficient to perform the multiple participants who completed follow-up to 12 and 24 weeks.0) 1.0%%-51.1) .4) 95 (43.25-3. any time during the treatment phase or follow-up are sum- consin Scale for Withdrawal Symptoms (range.32.0 kg (95% CI.9) 112 (51.35 2 wk Week 2 98 (45. nor did it differ at the TQD (2.73.4) 76 (34. tively (P = .95 vs 1. and the differences re. No significant differences in the other variables of the bust standard errors.04 5-8 12 wk Weeks 99 (45.19-2.002 Abbreviations: OR. 1.9) 56 (25. did not marized in Table 3.jamanetwork.7) 2.7) 1. 2. Adverse Events Reported in at Least 2% of Participants per Study Group No.3%-37. respectively (OR.59.02 24 wk Week 24 94 (43.9) 35 (15.32) . The The mean weight gain in those who completed 6 months of post hoc logistic mixed model analysis also confirmed signifi.63.007 9-12 16 wk Weeks 84 (38.50a χ2 test). Table 3. P < . did not attend their 12.19) or at 4 weeks after the TQD (1.54 Headaches 17 (7.8) .08-2. P = .66. Continuous Abstinence and Point Prevalence Abstinence Rates (n=435) Per-Protocol Analysis Multiple Imputation Analysis of Main Outcomes No.74-1. 2.1) 101 (46.7) 87 (39. 95% CI. Other adverse events that were observed at The craving for cigarette smoking.com JAMA July 9.53 Insomnia and disturbed sleep 43 (19.48-2. (%)a Varenicline Varenicline and Active Varenicline and and Active Time Since Time Nicotine Patch Placebo Patch Nicotine Patch Varenicline and TQD Period (n = 216) (n = 219) OR (95% CI) P Value (n = 216) Placebo Patchb OR (95% CI) P Value Continuous Abstinence 8 wk Weeks 96 (44. (%) No. Number 2 159 Copyright 2014 American Medical Association.8%) randomized to receive the addition of P = . follow-up was 3. 95% CI.2 kg (95% CI.8) 1.3) 3 (1. respec- groups (eResults in the Supplement).08 (0.91 (1.31 (0.9) 61 (27. NRT patch group included localized erythema (n = 21) or jama.81-1. as measured by the Wis.02 8 wk Week 8 109 (50.1) 6 (2.9) 87 (39.80 (1.8) 70 (32.70 vs 2.9) 42 (19.5) 63 (28.03 16 wk Week 16 104 (48.7-2.4) 1. and.66) .32 vs NRT vs placebo.18 Abnormal dreams 10 (4.76 (1.6) 1.07-2.21) . 95% CI. 38.03 a Constipation 9 (4.68 (1. 95% CI.0) . 2. 0-4).9) . 1.003 138 (63. (%) Varenicline and Active Varenicline and Nicotine Patch Placebo Patch Adverse Event (n = 216) (n = 219) P Value Nausea 59 (27.20.52-1. Tolerability.51) among par- When considering site as a clustering variable and mod.85 (1.7) 1.6) 1.003 120 (55. 5 sets of imputed values for the participants who n = 219 at 12 wk and n = 217 at 24 wk.4%) vs 70 of 224 participants (31.3) 54 (24. 95% CI.4) 90 (40. Downloaded From: http://jama. 1.001 106 (49. 95% CI. 1.77. and Compliance mained significant (OR. 7 days.30-2.84.2) 1.004 9-24 Point Prevalence Abstinence Rates 1 wk Week 1 69 (31. 95% CI.18-2. 2. 2.7) 1.57 (1.32-3. Varenicline and Nicotine Replacement Therapy for Smoking Cessation Original Investigation Research Table 2.80.89) .06 (1.8 kg) in the active and cant differences in rate of abstinence over time between the 2 2.7) . odds ratio. logistic regression analysis showed that scale were observed. Skin reactions reported in the active differ between the active and placebo NRT groups at random. ticipants who abstained from smoking during the preceding eling the effect with clustering by site adjusted for using ro.22) . TQD.98 (1. target quit date.and 24-week follow-up visits (Figure). b to account for missing data.2) 2.20-2.7) .0) 71 (32. 1.43.17 12 wk Week 12 116 (53.3%.4) 17 (7.08-2.09).33-3.0) 1.50 (1. imputation analysis at 24 weeks. 95% CI.22-2.42 Fisher exact probability test (all other P values were calculated with Depression 5 (2.14) .004).1) 81 (37.9) 1.90-1. 1.28-2. 95% CI.001).

patches. cally important higher continuous abstinence rate at 12 and 24 there was a numerically greater incidence of nausea. P = .19 Hajek et al9 also reported a favorable safety pro- 1. 1.72. Cutaneous adverse events in the pla.2% sality seems unlikely given the mechanism of action of the drug vs 31.38-2. 95% CI.7%) participants randomized to receive the introduction of varenicline 1 week after NRT or tapering of placebo patch. given the rela.39). with only vivid dreams being reported more frequently mulations (OR. P = .3% of ran- of varenicline and NRT patch.5%.13). P = . abstinence at 12 weeks was self-reported (not bio.42. cacy analysis. only a single double-blind randomized con. patch). ment period (12 weeks) showed at least an 80% adherence with for example. 1. 7. P = . Five other unrelated may bind to different (additional) receptors involved in nico- SAEs were reported during follow-up: 4 among participants tine dependency. Had the pretreatment with NRT been responsible for the superior abstinence rate.9 Hajek et al9 found that the com. this would have been expected to wane over time. 140 (78. 1. chemically validated). but not more effective than a combination of NRT for. P = .48) in increasing the in the combination group (20.8%. 1. is slower than that of nicotine from smoking or varenicline and the patch.12.20.14). participants in the varenicline-alone group re- firmed that varenicline was more effective than nicotine ported more abnormal dreams and headaches. varenicline might in some way have improved the effective- ness of the combination. Other strengths vitis (n = 1).28.5%) did not take 1 dose of varenicline abstinence rates at 1 and 4 weeks after the TQD compared with and were excluded from the per-protocol analyses. as well as a higher point prevalence abstinence rate at turbance. We limited our study population to relatively Moreover.7 gave birth to an infant with Down syndrome (confirmed tri. respectively. compared with varenicline alone. mild generalized dermatitis (n = 3).91) or self-reported abstinence rates at 12 weeks protocol abstinence rates when compared with earlier re- (36% vs 29%. One pregnancy was anembryonic and considered an The additive efficacy of combining the 2 drugs is not eas- unrelated serious adverse event (SAE). and up to 5 lapses were permitted. and 60% attrition rate may be a reason for the relatively modest per- vs 59%. The ized reactions and a single participant reported worsening present study’s larger sample size.51. nicotine replacement was considered a possibly related SAE. and the use of a rigorous definition of abstinence (includ- cebo NRT patch group included localized erythema (n = 11) ing regular monitoring of nicotine use and exhaled carbon mon- or itch (n = 2). However. Number 2 jama. of our study are its blinded design and multiple-center com- Two women became pregnant during the treatment ponents.3 Finally. skin reactions. whereas 3 patients experienced mild general. Research Original Investigation Varenicline and Nicotine Replacement Therapy for Smoking Cessation itch (n = 6).18 treatment with NRT.2%) and 137 (76. we found no evidence that randomized to receive the active patch and 1 to receive the combination therapy decreased craving for nicotine.17. file. There rate all α4β2 nicotine receptors in the brain. Moreover. P = .4% vs A recent Cochrane analysis covering 267 studies con. of skin reactions was comparable with reported figures for NRT 95% CI. Only 62. Another participant ily explained. to our knowledge the largest study to date ex. oxide) may account for the different results. The authors acknowledged that their ported figures5 but does not account for the differences ob- study may have been inadequately powered to reject the null served. 1. There is currently also no evidence that quit rates In this study. as our post hoc multiple imputation analysis confirmed hypothesis (no benefit in the combination). Alternatively. up.87).03).5%) participants random. association. agonism. and other NRT (OR. ther possibility is that the different pharmacokinetics of the Overall. 1. it is possible that the phased (80. compared with 139 that of varenicline.15 Of note.9%.21 trolled trial has compared varenicline with the combination Our study had potential limitations. 95% CI. The birth odds of quitting. healthy smokers because the potential for unexpected ad- 160 JAMA July 9. that the missing outcomes did not bias the per-protocol effi- tively small sample size (n = 117) and short follow-up (12 weeks). safety and tolerability end points. 2 components provide a more favorable onset of receptor ized to receive the NRT patch and who completed the treat. Ebbert randomized to receive the placebo patch was reported as pos- et al16 reported that the combined use of varenicline and sibly drug related owing to the category C status of vareni- bupropion. 0. A fur- placebo patch.06). constipation. All rights reserved. with 6 months. which may have increased heterogeneity among par- phase (both were randomized to receive the placebo NRT ticipants. 1. only skin reactions reaching statistical significance (14. sleep dis- weeks. Interestingly. and depression. given that both target α4β2 nicotine receptors. cau- increase the point prevalence abstinence at 26 weeks (38.15 In a recent study.com/ by a World Health Organization User on 07/14/2014 . The opposite was Discussion observed.79).06. It is possible that neither varenicline nor nicotine fully satu- somy 21) with associated congenital heart defects. 2014 Volume 312.3%) and 143 (82.75-1. Downloaded From: http://jama. we have found the combination treat. did not cline and the temporal relationship to treatment. The high varenicline and placebo patch (69% vs 59%. 11 ran- bination treatment did not improve biochemically validated domized participants (2.com Copyright 2014 American Medical Association.22-1. nicotine gum (OR. are higher with gradual reduction in smoking compared with amining the efficacy and safety of supplementing varenicline abrupt quitting. domized participants completed the study.7% vs 8. and it the action of the other. leaving room for was no family history of chromosomal abnormalities. combination NRT also outper. of an infant with Down syndrome (trisomy 21) in a participant formed single-formulation NRT. 95% CI. and gingi.16 and the absence to date in postmarketing research of this To date. The incidence patch (OR. The present study was not adequately powered to assess ment to be associated with a statistically significant and clini. The onset of action of nicotine released from NRT.jamanetwork. longer duration of follow- of preexisting acne. In the combination group.

Lindson-Hawley N. JAMA.310(1):91-92. Novartis. ARTICLE INFORMATION York. Burke MV. New jama. Jorenby DE.11:140. 11. Nicotine addiction. Future studies should Varenicline in combination with NRT was more effective than include a broader range of smokers. Jha P. design. Bateman. 2006. 1. Navigant Consulting.36(suppl 54):462s. Tonstad S. vs sustained-release bupropion and smokers: a randomized trial. Perera R. Further studies are needed to assess long- parisons with alternative therapies.296(1):47-55. may differ from the everyday practice and limit the generalizability of our findings. 17. Koegelenberg reported receiving grants for studies 4. New York. Hays JT. 2013. 16. 13. collection. 1999. Irusen. Emanuel.86(9): Koegelenberg. Boehringer Ingelheim. Clinical experience from a Koegelenberg. and McNeil. Lancaster T. Guerrero AC. Number 2 161 Copyright 2014 American Medical Association. combination of varenicline and nicotine patch more 2014]. Lindson-Hawley N. Varenicline 10. Irusen. Wetter DW.1155/2014 Boehringer Ingelheim. Tønnesen P. Prochaska JJ. Pharmacoepidemiol Drug reported receiving grants for studies (for his serious adverse events associated with varenicline Saf. Takeda Aeras. Olgac Dündar N. Pharmacological interventions for smoking completed and submitted the ICMJE Form for 3. Abdool-Gaffar. sustained-release bupropion for smoking cessation: Gradual reduction vs abrupt cessation as a smoking IMS Consulting Group. O’Brien. Gonzales D. Kozlowski LT. effective in helping smokers quit than varenicline /263981. Fernandez MI.9(9): 15. Mahoney MC. JAMA. Disclosure of Potential Conflicts of Interest. Esterhuizen. vs placebo or 18. 2. Strategies to help a smoker who is cessation: an overview and network meta-analysis. Landsman V. et al. van Zyl-Smit reported receiving grants for studies 56-63.22(10):1086-1092. Astra Zeneca. Merck Sharp and Dohme. Public Health Service. Esterhuizen. Bolliger. Zeneca. Obtained funding: Noor. GlaxoSmithKline. Jiménez-Ruiz CA. 2009. Reeves KR.296(1): cessation strategy in smokers who want to quit. Hatsukami DK. McRobbie H. analysis.11: Novartis. Study concept and design: Koegelenberg. Br J Addict. Conflict of Interest Disclosures: All authors have 655-664. McNeil. from Pfizer and GlaxoSmithKline. Case Rep Obstet Gynecol. 19. 5. Noor. Cochrane Database Syst Rev. Critical revision of the manuscript for important for the study. N Engl J Med. Dr Smith reported varenicline during pregnancy: a prospective receiving personal fees from Pfizer. Nides M. an Combination varenicline and bupropion SR for GlaxoSmithKline and personal fees from alpha4beta2 nicotinic acetylcholine receptor partial tobacco-dependence treatment in cigarette AstraZeneca. and decision to submit the manuscript Tolerance Questionnaire. Fiore MC. or approval of the Dependence: a revision of the Fagerström Acquisition. N Engl J Med. et al. 2013. 2012. Varenicline. and Varenicline Phase 3 Study Group. data. Sall D. (for his institution) from Pfizer and personal fees 6. and Nycomed. varenicline. Baker TB. other forms of NRT. Emanuel. reported receiving grants for studies (for his controlled trial. The Fagerström Test for Nicotine Irusen. Noor. management. Welsch SK.311(2):155- studies (for her institution) from Pfizer. for publication. Noor. 368(4):341-350. Adverse effects with use of nicotine reported receiving grants for studies (for his Group. JAMA. Aveyard P. Paterson H. et al. Rockville. and 6 months. receptor partial agonist. technical. Benowitz NL. institution) from Pfizer and McNeil. Rennard SI.11(5):572-576. MD. Croghan IT. Heatherton TF. Aveyard P. Avoidable global cancer deaths and total gum. Varenicline Phase 3 Study Cummings KM. Hays JT. Napp Pharma. Dr Bruning Billing CB. Varenicline and Nicotine Replacement Therapy for Smoking Cessation Original Investigation Research verse events was unknown. Forest. 2006. 2012. Dr struggling to quit. Eur Respir J. Efficacy of want to quit. Noor. BMJ.jamanetwork. Hughes JR. 7. Bruning. Ebbert JO. Kaplan YC. Pregnancy outcome after varenicline exposure in Boehringer Ingelheim and personal fees from Merck 9. smokers clinic combining varenicline and nicotine O’Brien. 2013. the Wisconsin Smoking Withdrawal Scale. accuracy of the data analysis. JAMA. and both active and placebo Combination treatment with varenicline and access to all of the data in the study and takes NRT patches were supplied by McNeil. 2008. Astra 2010. an alpha4beta2 nicotinic acetylcholine CD008033. Sharp and Dohme. MD: US Dept of Health Statistical analysis: Koegelenberg. O’Brien. 1119-1127. Astra Zeneca. or interpretation of data: manuscript. and placebo for smoking cessation: a randomized 163. Smith. Noor. Dr Noor reported receiving grants for agonist. Downloaded From: http://jama. Nat Rev Cancer. Additional Contributions: We acknowledge with 12. Smith. and interpretation of the Fagerström KO. All rights reserved. term efficacy and safety. Nicotine Tob Res. analysis. grants for studies (for his institution) from Actelion. preparation. JAMA. BMC Med. Jorenby DE. Hajek P. GlaxoSmithKline. Baker TB. Williams KE. as well as the spe- cific timing of initiation of both interventions and the taper. Merck. Boehringer Ingelheim. Stevens S. PhD (1950-2012). Abdool-Gaffar. nicotine replacement therapy. Irusen. and ICON. Funding/Support: This study was supported by 2013. and Human Services. Dr O’Brien varenicline on smoking cessation: a randomized Nicotine Tob Res. Ulibarri Administrative. Pfizer. Jaén CR. intellectual content: van Zyl-Smit. design and conduct of the study. Development and validation of Drafting of the manuscript: Koegelenberg. Fiore MC. Bateman. gratitude the contribution of Chris T. Tobacco Use and Dependence: Quick Reference REFERENCES Guide for Clinicians. No other disclosures were reported. Author Contributions: Dr Koegelenberg had full was supplied by Pfizer. review. van Zyl-Smit. Almirall. 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