Vareniclina e riscos cardiovasculares


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Vareniclina e riscos cardiovasculares

  1. 1. Early release, published at on July 4, 2011. Subject to revision. CMAJ ResearchRisk of serious adverse cardiovascular events associatedwith varenicline: a systematic review and meta-analysisSonal Singh MD MPH, Yoon K. Loke MBBS MD, John G. Spangler MD MPH, Curt D. Furberg MD PhDSee related commentary by Hays at Abstract Competing interests: Background: There have been postmarketing adverse events asociated with the use of Curt Furberg was paid by varenicline. plaintiffs for expert reports of adverse cardiovascular events asso- testimony on Pfizer’s ciated with the use of varenicline, a widely COX-2 inhibitors. No used smoking cessation drug. We conducted a Results: We analyzed data from 14 double- competing interests declared systematic review and meta-analysis of ran- blind randomized controlled trials involving by the other authors. domized controlled trials to ascertain the seri- 8216 participants. The trials ranged in duration from 7 to 52 weeks. Varenicline was associated This article has been peer ous adverse cardiovascular effects of vareni- reviewed. cline compared with placebo among tobacco with a significantly increased risk of serious users. adverse cardiovascular events compared with Correspondence to: placebo (1.06% [52/4908] in varenicline group Dr. Sonal Singh, Methods: We searched MEDLINE, EMBASE, v. 0.82% [27/3308] in placebo group; Peto odds the Cochrane Database of Systematic Reviews, ratio [OR] 1.72, 95% confidence interval [CI] CMAJ 2011. DOI:10.1503 websites of regulatory authorities and reg- 1.09–2.71; I2 = 0%). The results of various sensi- /cmaj.110218 istries of clinical trials, with no date or lan- tivity analyses were consistent with those of guage restrictions, through September 2010 the main analysis, and a funnel plot showed no (updated March 2011) for published and un- publication bias. There were too few deaths to published studies. We selected double-blind allow meaningful comparisons of mortality. randomized controlled trials of at least one week’s duration involving smokers or people Interpretation: Our meta-analysis raises safety who used smokeless tobacco that reported concerns about the potential for an increased on cardiovascular events (ischemia, arrhyth- risk of serious adverse cardiovascular events mia, congestive heart failure, sudden death associated with the use of varenicline among or cardiovascular-related death) as serious tobacco users.V arenicline is one of the most widely prod uct label was updated: “Post marketing used drugs for smoking cessation. It is a reports of myocardial infarction and cerebrovas- partial agonist at the α4–β2 nicotinic cular accidents including ischemic and hemor-acetylcholine receptors and a full agonist at the rhagic events have been reported in patients tak-α7 nicotinic acetylcholine receptor.1,2 The drug ing Chantix.”6 There are published reports ofmodulates parasympathetic output from the cardiac arrest associated with varenicline.7brainstem to the heart because of activities of the Cardiovascular disease is an important causeα7 receptor.3 Acute nicotine administration can of morbidity and mortality among tobacco users.induce thrombosis. 4 Possible mechanisms by The long-term cardiovascular benefits of smok-which varenicline may be associated with car- ing cessation are well established.8 Although onediovascular disease might include the action of statistically underpowered trial reported a trendvarenicline at the α7 receptor in the brainstem or, toward excess cardiovascular events associatedsimilar to nicotine, a prothrombotic effect.2–4 with the use of varenicline,9 a systematic review At the time of its priority safety review of of information on the cardiovascular effects ofvarenicline in 2006, the US Food and Drug varenicline is unavailable to clinicians.Administration (FDA) noted that “[t]he serious We conducted a systematic review and meta-adverse event data suggest that varenicline may analysis of randomized controlled trials (RCTs)possibly increase the risk of cardiac events, both to ascertain the serious adverse cardiovascularischemic and arrhythmic, particularly over effects of varenicline compared with placebolonger treatment period.”5 Subsequently, the among tobacco users.© 2011 Canadian Medical Association or its licensors CMAJ 1
  2. 2. Research Methods Data abstraction We scanned all titles and abstracts of studies Literature search identified through our searches and excluded We initially searched MEDLINE and EMBASE articles that clearly did not meet the selection in September 2010 using free text and indexing criteria. We evaluated full-text versions of the terms for “varenicline” and “clinical trials.” At remaining articles for their eligibility to be the same time, we identified unpublished studies included in the review. We evaluated trials listing from the websites of regulatory authorities (the adverse events and recorded numerical data on FDA and the European Medicines Agency), as adverse cardiovascular events and specific de- well as results of clinical trials of varenicline scriptions of cardiovascular events in the studies included in the Results Data- up to the completion of the specified follow-up base ( and period. We collected information on the study the industry-sponsored Clinical Study Results design, the phase of the trial, the location of the Database ( study, any exclusions from enrolment of patients In March 2011, we conducted an updated search with cardiac conditions and significant cardiac using an optimized filter for MEDLINE and an risk factors, the dose of varenicline, the patients’ RCT filter for EMBASE; we also searched the mean age, the proportion of patients who were Cochrane Central Register of Controlled Trials. men, the ethnicity, the duration of tobacco use We evaluated the bibliographies of included tri- and relevant outcomes. To avoid potential dupli- als and recent systematic reviews, Cochrane cation, we reconciled studies published in jour- reviews1 and meta-analyses for relevant RCTs. nals with trial reports from the manufacturer and We did not have any language restrictions. regulatory authorities. Details of our search strategy appear in Appen- dix 1 (available at Assessment of risk of bias /doi:10.1503/cmaj.110218/-/DC1). We evaluated the studies for adequacy of We selected double-blind RCTs with at least sequence generation, allocation concealment, one week of follow-up that evaluated varenicline blinding of participants and personnel, reporting as the intervention drug versus a placebo among of withdrawals and loss to follow-up, and report- tobacco users and that reported on cardiovascu- ing of adverse outcomes.12 Two of us (S.S. and lar events (including no events). We excluded J.G.S. or Y.K.L.) were independently involved in RCTs involving non-tobacco users and observa- all stages of study selection, data extraction and tional studies. quality assessment. All discrepancies were re- We chose the minimum follow-up period of solved after rechecking the source papers and one week to ascertain the early cardiovascular further discussion among the reviewers, with effects of varenicline, because the half-life of the arbitration by a third reviewer (C.D.F) and full drug is about 24 hours and at least five half-lives consensus before inclusion. are needed to reach a steady state.10 Our primary analysis focused on double-blind placebo- Data synthesis controlled trials, because blinding is critical to We used Review Manager (RevMan version the adequate ascertainment of serious adverse 5.025; Nordic Cochrane Center, Copenhagen, events and because placebo-controlled trials pro- Denmark) to conduct the meta-analysis. The unit vide unconfounded estimates of treatment effect. of analysis was individuals with adverse cardio- In addition, nicotine replacement therapy may be vascular events. Analysis was by intention to associated with cardiovascular risk.11 Open-label treat and included all participants, including trials and trials of varenicline and active com- dropouts, to minimize bias due to differences in parators were systematically identified and eval- dropout numbers between groups. We used the uated in a sensitivity analysis. Peto method to calculate odds ratios (ORs) and 95% confidence intervals (CIs) because this Outcome measures method provides the best confidence interval The primary outcome was any ischemic or coverage and is more powerful and relatively arrhythmic adverse cardiovascular event (myocar- less biased than the random-effects analysis dial infarction, unstable angina, coronary revascu- when dealing with low event rates.13 Statistical larization, coronary artery disease, arrhythmias, heterogeneity was assessed using the I2 statistic, transient ischemic attacks, stroke, sudden death or with values of 50% or more indicating a substan- cardiovascular-related death, or congestive heart tial level of heterogeneity.14 Statistical signifi- failure) reported by the investigators during the cance was set at two-sided α of 0.05. In trials double-blind period of the trial. We evaluated all- that had more than two intervention groups, we cause mortality as a secondary outcome. preserved randomization but collapsed the multi-2 CMAJ
  3. 3. Researchple intervention arms (e.g., varenicline 0.25 mg ciline was 1 mg twice daily. Three trials reportedtwice daily and 0.5 mg twice daily) into single on lower doses of varenicline.21,23,24treatment arms.12 Details of the risk-of-bias assessment appear in To account for potential imbalance in trial size Table 2 and Appendix 3 (available at www.cmaj.caand in the number of studies with zero events, pre- /lookup/suppl/doi:10.1503/cmaj.110218/-/DC1).specified sensitivity analyses were conducted Nine RCTs were judged to be at low risk of biasusing the fixed Mantel–Haenszel test.14,15 Prespeci- (adequate sequence generation, allocation con-fied sensitivity analyses were also conducted to cealement and double blinding, and clear reportingdetermine the influence on effect size of the of withdrawal rates);9,18–23,26,27 the remaining fivechoice of comparators (placebo v. active controls), RCTs were at unclear risk of bias owing to incom-and of the role of individual trials by excluding plete reporting of randomization.16,17,24,25,28 The open-the most influential trial.9 To maintain similarity of label trial had an unclear risk of bias.29 Loss to fol-investigator-reported definitions of cardiovascular low-up ranged from as low as none (in a treatmentevents across the trials, we conducted sensitivityanalyses to determine the robustness of effect size Articles identified through literature searchwhen unadjudicated cardiovascular events were n = 351added from the trial that reported adjudicated • Electronic databases n = 286events.9 We evaluated the effects of limiting our • Registry at n = 41 • Industry-sponsored registry atanalysis to trials that used a similar dose of vareni- n = 24cline (1 mg twice daily) or to trials that reportedonly on specific cardiovascular outcomes ofmyocardial infarction, stroke and cardiovascular-related death. Publication bias was estimated via Screening of titles and abstractsexamination of asymmetry in a funnel plot. n = 351 The protocol is available on request from the Excluded n = 306corresponding author. • Reviews, commentaries, letters without original data relevant toResults population or intervention n = 206 • Duplicates n = 63 • Not an RCT n = 29Study characteristics • No comparison group n = 6 • Crossover study n = 1The selection of studies included in our review is • Animal study n = 1summarized in Figure 1. Fourteen double-blindplacebo-controlled trials were included in the Full-text articles reviewedmeta-analysis.9,16–28 An additional open-label trial for eligibilityof varenicline versus nicotine replacement ther- n = 45apy was included in the sensitivity analysis.29 Characteristics of the trials are summarized in Excluded n = 30 • Review articles n = 11Table 1 and Appendix 2 (available at www • No serious cardiovascular or deaths n = 9 • Crossover trial n = 4/-/DC1). The 14 double-blind placebo-controlled • No relevant comparators n = 4trials enrolled a total of 8216 patients (4908 in • Study population not relevantthe varenicline arms, 3308 in the placebo arms). (healthy volunteers) n = 1 • Study ended early n = 1The sample sizes ranged from 250 to 1210. Theduration of treatment ranged from 7 weeks to 52weeks, and the total duration of study, including RCTs included in qualitative synthesistreatment and follow-up, ranged from 24 to 52 n = 15weeks. All but one of the trials enrolled smokers;the remaining trial enrolled people who usedsmokeless tobacco.18 The primary outcome wasthe continuous abstinence rate in 12 trials,9,16–25,27 RCTs included in meta-analysisthe long-term quit rate in 1 trial26 and long-term n = 14 RCTs included in sensitivity analysessafety in 1 trial.28 All but one of the trials ex - n = 15*cluded patients with a history of cardiovasculardisease; the remaining trial included participantswith stable cardiovascular disease but excluded Figure 1: Selection of double-blind placebo-controlled randomized controlled trials (RCTs) for inclusion in the systematic review and meta-analysis of thethose with unstable cardiovascular disease.9 Two risk of serious adverse cardiovascular events associated with varenicline use.of the 14 RCTs also had a bupropion comparator *An additional open-label trial of varenicline versus nicotine replacement ther-group.19,20 In most of the trials, the dose of vareni- apy was included in the sensitivity analysis. CMAJ 3
  4. 4. Research Table 1: Characteristics of randomized controlled trials of varenicline included in the analysis of serious adverse cardiovascular events* Duration of Duration treatment, of study, Primary Cardiac No. of Age, yr, mean Males, Study wk wk outcome exclusions at enrolment Drug and dose participants (SD or range) % Protocol 12 26 Continous Clinically significant CVD Varenicline 1 mg bid 394 43.1 (18–69) 60.4 16 A3051080, 2010 abstinence rate in last 6 mo, systolic Placebo 199 43.9 (20–71) 60.4‡ BP > 150 mm Hg Protocol 12 24 Continous quit No serious or unstable Varenicline 1 mg bid 493 43.9 (18–75) 60.3 A3051095, 201017 rate, continous disease in last 6 mo Placebo 166 43.2 (18–72) 60.0 abstinence rate Fagerstrom 12 26 Continous quit Any serious Varenicline 1 mg bid 214 43.9 (12.0) 88.7 et al., 201018 rate medical condition Placebo 218 43.9 (12.0) 89.9 Gonzales et 12 52 Continous quit CVD within last 6 mo Varenicline 1 mg bid 352 42.5 (11.1) 50.0 19 al., 2006 rate Bupropion 150 mg bid 329 42.0 (11.7) 58.4 Placebo 344 42.6 (11.8) 54.1 Jorenby et al., 12 52 Continous quit Clinically significant CVD Varenicline 1 mg bid 344 44.6 (11.4) 55.2 200620 rate in last 6 mo Bupropion 150 mg bid 342 42.9 (11.9) 60.2 Placebo 341 42.3 (11.6) 58.1 Nakamura et 12 52 Continous Unstable CVD Varenicline 1 mg bid 156 40.1 (11.6) 79.2 al., 200721 abstinence rate Varenicline 0.5 mg bid 156 39.0 (12.0) 71.1 Varenicline 0.25 mg 153 40.2 (12.3) 72.7 bid Placebo 154 39.9 (12.3) 76 Niaura et al., 12 52 Continous History of CVD Varenicline 1 mg/d 160 41.5 (11.3) 50.3 22 2008 abstinence rate Placebo 160 42.1 (11.7) 53.5 Nides et al., 7 52 Continous History of CVD Varenicline 0.3 mg/d 128 41.9 (10.6) 50.0 23 2006 abstinence rate Varenicline 1 mg/d 128 42.9 (10.5) 43.7 Varenicline 1 mg bid 127 41.9 (9.8) 50.4 Bupropion 150 mg bid 128 40.5 (10.8) 45.2 Placebo 127 41.6 (10.4) 52.0 Oncken et al., 12 52 Continous History of CVD Varenicline 1 mg bid 130 42.2 (10.7) 48.5 24 2006 abstinence rate titrated Varenicline 1 mg bid 129 43.7 (10.0) 48.8 nontitrated Varenicline 0.5 mg bid 130 43.5 (10.5) 53.1 titrated Varenicline 0.5 mg bid 129 42.9 (10.1) 45.0 nontitrated Placebo 129 43.0 (9.4) 51.9 Rigotti et al., 12 52 Continous Excluded if unstable CVD Varenicline 1 mg bid 355 57.0 (8.6) 75.2 20109 abstinence rate in last 2 mo; included Placebo 359 55.9 (8.3) 82.2 with stable CVD§ Tashkin 12 52 Continous Unstable CVD or history Varenicline 1 mg bid 250 57.2 (35–83) 62.5 et al.,† 201025 abstinence rate of CVD in last 6 mo Placebo 254 57.1 (34–77) 62.2 Tonstad et al., 12 52 Long-term quit CVD within last 6 mo Varenicline 1 mg bid 603 45.4 (10.4) 50.2 200626 rate Placebo 607 45.3 (10.4) 48.3 Tsai et al., 12 24 Continous Unstable CVD Varenicline 1 mg bid 126 39.7 (9.3) 84.9 27 2007 abstinence rate Placebo 124 40.9 (11.1) 92.7 Williams et al., 52 52 Long-term Clinically significant CVD Varenicline 1 mg bid 251 48.2 (12.3) 50.6 28 2007 safety in last 6 mo Placebo 126 46.6 (12.1) 48.4 Aubin et al., 12 52 Continous Serious or unstable Varenicline 1 mg bid 378 42.9 (10.5) 48.4 200829 abstinence rate disease in last 6 mo Nicotine transdermal 379 42.9 (12.0) 50.0 patch Note: BP = blood pressure, CVD = cardiovascular disease, SD = standard deviation. 18 *All but one of the trials involved smokers; the study by Fagerstrom et al. involved users of smokeless tobacco. Additional study characteristics are available in Appendix 2 ( †Investigators enrolled smokers with mild to moderate chronic obstructive pulmonary disease. ‡The proportion of males in study overall; the proportion in each study arm was not reported. §The proportion of participants with cardiac disease in varenicline versus placebo groups was angina 53.2% v. 47.9%, myocardial infarction 45.9% v. 52.4%, prior coronary revascularization 46.2% v. 51.5%, and stroke 4.5% v. 6.7%.4 CMAJ
  5. 5. Researcharm24 and a placebo arm27) to as high as 28.6% (in Sensitivity analysesa placebo arm24); loss to follow-up was higher in Sensitivity analyses9,16–28 using the reciprocal ofthe placebo arm in most of the trials except three, the treatment arm with a continuity correctionin which it was higher in the varenicline arm.9,18,27 (fixed Mantel–Haenszel OR 1.67, 95% CI Thirteen trials did not use an objective defini- 1.06–2.64) or without a continuity correctiontion of cardiovascular events and evaluated such (fixed Mantel–Haenszel OR 1.77, 95% CIevents as serious if they resulted in hospital 1.09–2.88) showed results similar to those ofadmission, disability or death.16–28 Although the the primary analysis (Table 3). The sensitivityrole of adjudication of major clinical events analysis in which we included data for activeremains unclear,30 one trial adjudicated cardio- comparators (nicotine replacement therapy invascular events and reported on investigator- the open-label trial 29 and bupropion in tworeported cardiovascular events that did not reach placebo-controlled trials 19,20 ) showed resultsthe threshold for adjudication.9 All of the in- similar to those of the the primary analysiscluded trials reported on mortality.9,16–28 Data on (Peto OR 1.67, 95% CI 1.07–2.62).9,16–29 Whenadverse cardiovascular events and mortality are we excluded the most influential trial (whichshown in Appendix 4 (available at involved participants with stable cardiovascular/lookup/suppl/doi:10.1503/cmaj.110218/-/DC1). disease),9 the results were also similar to those of the primary analysis (Peto OR 2.54, 95% CIRisk of serious adverse cardiovascular 1.26–5.12).16–28 The same was true when weevents and death included investigator-reported cardiovascularThe meta-analysis showed a significantly in- events from a trial that did not meet the thresh-creased risk of serious adverse cardiovascular old for adjudication9 (Peto OR 1.91, 95% CIevents associated with varenicline compared 1.25–2.94)9,16–28 (Table 3).with placebo (Peto OR 1.72, 95% CI 1.09–2.71; In the sensitivity analysis in which we ex-I2 = 0%) (Figure 2).9,16–28 cluded data for varenicline doses less than 1 mg Only five trials reported deaths (7/4908 in the twice daily, the results were again similar tovarenicline group v. 7/3308 in the placebo those of the primary analysis (Peto OR 1.76,group.9,19,21,25,26 This precluded any pooling of such 95% CI 1.11–2.77).9,16–20,22,25–28 The data from thesparse data in a meta-analysis. treatment arms that used lower doses (0.5 mg Table 2: Risk-of-bias assessment of randomized controlled trials (RCTs) of varenicline included in the analysis of serious adverse cardiovascular events* Adequate Adequate Adequate Adequate Adequate blinding of reporting of reporting of sequence allocation personnel and withdrawals and serious adverse Study generation concealment participants loss to follow-up events Double-blind RCTs Protocol A3051080 16 Unclear Unclear Yes Yes Yes 17 Protocol A3051095 Unclear Unclear Yes Yes Yes Fagerstrom et al.18 Yes Yes Yes Yes Yes Gonzales et al.19 Yes Yes Yes Yes Yes Jorenby et al.20 Yes Yes Yes Yes Yes 21 Nakamura et al. Yes Yes Yes Yes Yes Niaura et al.22 Yes Yes Yes Yes Yes Nides et al.23 Yes Yes Yes Yes Yes 24 Oncken et al. Unclear Unclear Yes Yes Yes Rigotti et al.9 Yes Yes Yes Yes Yes Tashkin et al.25 Unclear Unclear Yes Yes Yes 26 Tonstad et al. Yes Yes Yes Yes Yes Tsai et al.27 Yes Yes Yes Yes Yes Williams et al.28 Unclear Unclear Yes Yes Yes Open-label RCT Aubin et al.29 Yes Unclear Yes Yes Yes *Details of the methodology of the studies are available in Appendix 3 ( CMAJ 5
  6. 6. Research twice daily, 0.3 mg/d and 0.25 mg twice daily) the primary outcome (see the funnel plot in were too sparse to be pooled in a meta-analysis. Appendix 5, available at Only five trials reported on specific outcomes /suppl/doi:10.1503/cmaj.110218/-/DC1). of myocardial infarction, stroke and cardiovascu- lar-related death;9,19,22,25,28 the sensitivity analysis Interpretation of these limited data yielded a Peto OR of 1.80 (95% CI 0.83–3.91) which did not reach statisti- The use of varenicline among tobacco users was cal significance. associated with a 72% increased risk of serious There was no evidence of publication bias for adverse cardiovascular events. The robustness of Cardiovascular events, n/N Decreased Increased Weight, risk with risk with Study Varenicline Placebo % Peto OR (95% CI) varenicline varenicline Protocol A305108016 1/394 0/199 1.2 4.50 (0.07–285.96) Protocol A305109517 1/493 0/166 1.0 3.81 (0.04–347.82) Fagerstrom et al.18 0/214 1/218 1.4 0.14 (0.00–6.95) Gonzales et al.19 2/352 2/344 5.4 0.98 (0.14–6.97) Jorenby et al.20 1/344 1/341 2.7 0.99 (0.06–15.88) Nakamura et al.21 1/465 0/154 1.0 3.79 (0.04–352.44) Niaura et al.22 2/160 0/160 2.7 7.44 (0.46–119.40) Nides et al.23 1/383 0/127 1.0 3.79 (0.04–352.09) Oncken et al.24 2/518 0/129 1.7 3.49 (0.11–112.44) Rigotti et al.9 25/355 20/359 57.3 1.28 (0.70–2.34) Tashkin et al.25 5/250 2/254 9.4 2.42 (0.55–10.74) Tonstad et al.26 4/603 0/607 5.4 7.48 (1.05–53.20) Tsai et al.27 1/126 0/124 1.4 7.27 (0.14–366.57) Williams et al.28 6/251 1/126 8.3 2.40 (0.49–11.67) Overall 52/4908 27/3308 100.0 1.72 (1.09–2.71) Heterogeneity: I² = 0% 0.05 0.2 1 5 20 Peto OR (95% CI)Figure 2: Meta-analysis of double-blind placebo-controlled randomized trials of the risk of serious adverse cardiovascular events associ-ated with the use of varenicline. An odds ratio (OR) greater than 1.0 indicates an increased risk of a serious adverse cardiovascularevent. CI = confidence interval. Table 3: Sensitivity analyses for the outcome of serious adverse cardiovascular events* Group; no. of events, n/N Statistical Sensitivity analysis model No. of RCTs Varenicline Control OR (95% CI) Placebo comparator Reciprocal of the treatment arm size Continuity correction Fixed (MH) 149,16–28 52/4908 27/3308 1.67 (1.06–2.64) 9,16–28 No continuity correction Fixed (MH) 14 52/4908 27/3308 1.77 (1.09–2.88) Use of unadjudicated cardiovascular event Peto OR 149,16–28 61/4908 29/3308 1.91 (1.25–2.94) data from one trial Exclusion of most influential study Peto OR 1316–28 27/4553 7/2949 2.54 (1.26–5.12) Placebo or active† comparator Peto OR 159,16–29 52/5286 30/4486 1.67 (1.07–2.62) Note: CI = confidence interval, OR = odds ratio, MH = Mantel–Haenszel test, RCT = randomized controlled trial. 2 *Statistical heterogeneity was I = 0% for all sensitivity analyses. †Bupropion or nicotine replacement therapy.6 CMAJ
  7. 7. Researchthe effect size to alternative statistical approaches varenicline in the United States.32 All smokingor comparators in various sensitivity analyses cessation therapies are approved for short-termsuggests that this safety signal deserves further use. Long-term efficacy and safety data are lack-investigation. Although one can never entirely ing for all currently approved therapies, includ-rule out chance occurrence, there are potential ing bupropion.alternative explanations for these findings. Onepossibility is that the participants in the placebo Limitationsarms experienced a lower rate of serious adverse The limitations of our meta-analysis stemcardiovascular events because of failure of ran- mainly from the quality of reported summarydomization. A systematic failure of randomi- data. The trials enrolled different populations,zation is unlikely, because the baseline character- evaluated different doses of varenicline and hadistics of the participants were well balanced different lengths of follow-up and proportionsbetween groups. However, despite achieving lost to follow-up. Our estimates are imprecisemore than twofold higher rates of abstinence in owing to the low event rates. None of the trialsthe trials, which should potentially induce a car- was adequately powered to detect individual dif-diovascular benefit, the participants taking ferences in cardiovascular events. Although thevarenicline experienced an increased risk of seri- included trials were double blinded, differencesous adverse cardiovascular events. in ascertainment mediated by the cardiac symp- Our finding needs to be interpreted in the con- toms of nicotine withdrawal is possible. In thetext of other studies and the overall benefit–risk absence of source data, we could not assess forprofile of varenicline. An earlier pooled analysis potential blinding failure, blinding biases or dif-of data from clinical trials identified 22 serious ferences in ascertainment, or determine whetherischemic and arrhythmic cardiac adverse events these events were immediate or delayed. 33 Theamong 3940 patients allocated to receive vareni- cardiovascular events were not prespecified.cline compared with 4 such events among 1209 Thus, we could not determine whether the diag-patients allocated to receive placebo (2.32 per noses were clinical diagnoses or confirmed100 patient exposure-years for varenicline v. by established diagnostic criteria. Finally, the1.63 per 100 patient exposure-years for placebo applicability of our findings to smokers withafter accounting for differences in exposure). 5 unstable cardiovascular disease remains uncer-Our meta-analysis extends the findings of this tain because these people were excluded fromanalysis: including the data from those studies the the data from several other published stud-ies, we found three times the number of serious Conclusionadverse cardiovascular events among partici- Our meta-analysis raises safety concerns aboutpants in the varenicline group (61/4908 for the potential for an increased risk of seriousvarenicline v. 29/3308 for placebo). adverse cardiovascular events associated with Varenicline increases the chances of a suc- the use of varenicline among tobacco users.cessful quit attempt by twofold compared with Despite the limitations of our analysis, our find-unassisted smoking cessation.1 However, at the ings have potential regulatory and clinical impli-population level, most smokers quit unassisted.31 cations. Drugs that receive priority review haveThe number needed to treat with varenicline for limited safety data at the time of approval.34 Theone additional person to successfully quit smok- initial safety signal regarding cardiovascularing is estimated to be 10 (95% CI 8–13). 1 events in people using varenicline was not fol-Assuming a baseline risk of serious adverse car- lowed up by an adequately powered safety trial.diovascular events of 5.57% per year (among Until such trials are conducted, clinicians shouldsmokers with stable cardiovascular disease),9 the carefully balance the risk of serious cardiovas-number needed to harm (the number needed to cular events and serious neuropsychiatric ad-cause one additional serious cardiovascular verse events associated with varenicline useevent) with varenicline is estimated to be 28 against the known benefits of the drug on smok-(95% CI 13 to 213) per year. The risk of addi- ing cessation.tional serious adverse events associated withvarenicline use includes the potential for serious Addendumneuropsychiatric symptoms such as depressed At the time of publication, the FDA announcedmood, agitation and suicidal thoughts.32 These the addition of a warning to the product label ofadditional risks associated with varenicline have Chantix (varenicline) about the small, increasedresulted in a boxed warning (the highest level of risk of certain adverse cardiovascular eventsFDA warning) in the medication guide and a associated with the use of varenicline amongRisk Evaluation and Mitigation Strategy for smokers with cardiovascular disease.35 CMAJ 7
  8. 8. Research References egy in adult smokers: a randomized controlled trial. Curr Med Res Opin 2008;24:1931-41. 1. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists 23. Nides M, Oncken C, Gonzales D, et al. Smoking cessation with for smoking cessation. Cochrane Database Syst Rev 2011;(2): varenicline, a selective alpha4beta2 nicotinic receptor partial CD006103. agonist: results from a 7-week, randomized, placebo- and bupro- 2. Mihalak KB, Carroll FI, Luetje CW. Varenicline is a partial ago- pion-controlled trial with 1-year follow-up. Arch Intern Med nist at alpha 4 beta 2 and a full agonist at alpha 7 neuronal nico 2006;166:1561-8. tinic receptors. Mol Pharmacol 2006;70:801-5. 24. Oncken C, Gonzales D, Nides M, et al. Efficacy and safety of 3. Wang J, Wang X, Irnaten M, et al. 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Use and avoidance of continuity corrections in meta-analysis of (Loke), University of East Anglia, Norwich, UK; and the sparse data. Stat Med 2004;23:1351-75. Department of Family and Community Medicine (Spangler) 16. Protocol A3051080. New York (NY): Pfizer; 2009. Available: and the Division of Public Health Sciences (Furberg), Wake Forest University School of Medicine, Winston-Salem, NC _0.pdf (accessed 2011 Apr. 14). 17. Protocol A3051095. New York (NY): Pfizer; 2009. Available: Contributors: Sonal Singh, John Spangler and Yoon Loke were responsible for the study concept and design and for the _0.pdf (accessed 2011 Apr. 14). acquisition of data. Sonal Singh and Yoon Loke performed 18. Fagerström K, Gilljam H, Metcalfe M, et al. Stopping smokeless the statistical analysis. Curt Furberg supervised the study. All tobacco with varenicline: randomised double blind placebo con- of the authors analyzed and interpreted the data, drafted the trolled trial. BMJ 2010;341:c6549. manuscript and critically revised the manuscript for impor- 19. Gonzales D, Rennard SI, Nides M, et al.; Varenicline Phase 3 Study Group. Varenicline, an alpha4beta2 nicotinic acetyl- tant intellectual content. Sonal Singh had full access to all of choline receptor partial agonist, vs sustained-release bupropion the data in the study, takes responsibility for the integrity of and placebo for smoking cessation: a randomized controlled the data and the accuracy of the data analysis and acts as trial. JAMA 2006;296:47-55. guarantor of the paper. 20. Jorenby DE, Hays JT, Rigotti NA, et al.; Varenicline Phase 3 Study Group. Efficacy of varenicline, an alpha4beta2 nicotinic Funding: Sonal Singh is supported by a grant from the acetylcholine receptor partial agonist, vs placebo or sustained- National Center for Research Resources (NCRR), a component release bupropion for smoking cessation: a randomized con- of the US National Institutes of Health (NIH), and the NIH trolled trial. JAMA 2006;296:56-63. Roadmap for Medical Research (grant no. 1KL2RR025006- 21. Nakamura M, Oshima A, Fujimoto Y, et al. Efficacy and tolera- 03). The design and conduct of the study; the collection, man- bility of varenicline, an alpha4beta2 nicotinic acetylcholine recep- agement, analysis and interpretation of the data; and the prepa- tor partial agonist, in a 12-week, randomized, placebo-controlled, dose-response study with 40-week follow-up for smoking cessa- ration, review and approval of the manuscript were independent tion in Japanese smokers. Clin Ther 2007;29:1040-56. of any sources of funding. The contents of the manuscript are 22. Niaura R, Hays JT, Jorenby DE, et al. The efficacy and safety of solely the responsibility of the authors and do not necessarily varenicline for smoking cessation using a flexible dosing strat- represent the official view of the NCRR or the NIH.8 CMAJ