1. Early release, published at www.cmaj.ca on July 4, 2011. Subject to revision.
CMAJ Research
Risk of serious adverse cardiovascular events associated
with varenicline: a systematic review and meta-analysis
Sonal Singh MD MPH, Yoon K. Loke MBBS MD, John G. Spangler MD MPH, Curt D. Furberg MD PhD
See related commentary by Hays at www.cmaj.ca/lookup/doi/10.1503/cmaj.110804
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 ssingh31@jhu.edu
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 of
modulates parasympathetic output from the cardiac arrest associated with varenicline.7
brainstem to the heart because of activities of the Cardiovascular disease is an important cause
α7 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 one
diovascular disease might include the action of statistically underpowered trial reported a trend
varenicline at the α7 receptor in the brainstem or, toward excess cardiovascular events associated
similar 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 of
varenicline 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 cardiovascular
ischemic and arrhythmic, particularly over effects of varenicline compared with placebo
longer treatment period.”5 Subsequently, the among tobacco users.
© 2011 Canadian Medical Association or its licensors CMAJ 1

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 ClinicalTrials.gov Results Data- up to the completion of the specified follow-up
base (www.clinicaltrials.gov/ct2/info/results) 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 (www.clinicalstudyresults.org/home). 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 www.cmaj.ca/lookup/suppl 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. Research
ple intervention arms (e.g., varenicline 0.25 mg ciline was 1 mg twice daily. Three trials reported
twice daily and 0.5 mg twice daily) into single on lower doses of varenicline.21,23,24
treatment 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.ca
and 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 bias
using 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 reporting
determine the influence on effect size of the of withdrawal rates);9,18–23,26,27 the remaining five
choice 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 treatment
events across the trials, we conducted sensitivity
analyses to determine the robustness of effect size
Articles identified through literature search
when unadjudicated cardiovascular events were n = 351
added from the trial that reported adjudicated • Electronic databases n = 286
events.9 We evaluated the effects of limiting our • Registry at www.ClinicalTrials.gov n = 41
• Industry-sponsored registry at
analysis to trials that used a similar dose of vareni- ClinicalStudyResults.org n = 24
cline (1 mg twice daily) or to trials that reported
only on specific cardiovascular outcomes of
myocardial infarction, stroke and cardiovascular-
related death. Publication bias was estimated via Screening of titles and abstracts
examination of asymmetry in a funnel plot. n = 351
The protocol is available on request from the
Excluded n = 306
corresponding author. • Reviews, commentaries, letters
without original data relevant to
Results population or intervention n = 206
• Duplicates n = 63
• Not an RCT n = 29
Study characteristics • No comparison group n = 6
• Crossover study n = 1
The selection of studies included in our review is • Animal study n = 1
summarized in Figure 1. Fourteen double-blind
placebo-controlled trials were included in the
Full-text articles reviewed
meta-analysis.9,16–28 An additional open-label trial for eligibility
of varenicline versus nicotine replacement ther- n = 45
apy was included in the sensitivity analysis.29
Characteristics of the trials are summarized in Excluded n = 30
• Review articles n = 11
Table 1 and Appendix 2 (available at www • No serious cardiovascular events
.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.110218 or deaths n = 9
• Crossover trial n = 4
/-/DC1). The 14 double-blind placebo-controlled • No relevant comparators n = 4
trials enrolled a total of 8216 patients (4908 in • Study population not relevant
the varenicline arms, 3308 in the placebo arms). (healthy volunteers) n = 1
• Study ended early n = 1
The sample sizes ranged from 250 to 1210. The
duration of treatment ranged from 7 weeks to 52
weeks, and the total duration of study, including RCTs included in qualitative
synthesis
treatment and follow-up, ranged from 24 to 52 n = 15
weeks. All but one of the trials enrolled smokers;
the remaining trial enrolled people who used
smokeless tobacco.18 The primary outcome was
the continuous abstinence rate in 12 trials,9,16–25,27 RCTs included in meta-analysis
the long-term quit rate in 1 trial26 and long-term n = 14
RCTs included in sensitivity analyses
safety in 1 trial.28 All but one of the trials ex - n = 15*
cluded patients with a history of cardiovascular
disease; the remaining trial included participants
with 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 the
those 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. 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 (www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.110218/-/DC1).
†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. Research
arm24 and a placebo arm27) to as high as 28.6% (in Sensitivity analyses
a placebo arm24); loss to follow-up was higher in Sensitivity analyses9,16–28 using the reciprocal of
the placebo arm in most of the trials except three, the treatment arm with a continuity correction
in 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 correction
tion of cardiovascular events and evaluated such (fixed Mantel–Haenszel OR 1.77, 95% CI
events as serious if they resulted in hospital 1.09–2.88) showed results similar to those of
admission, disability or death.16–28 Although the the primary analysis (Table 3). The sensitivity
role of adjudication of major clinical events analysis in which we included data for active
remains unclear,30 one trial adjudicated cardio- comparators (nicotine replacement therapy in
vascular events and reported on investigator- the open-label trial 29 and bupropion in two
reported cardiovascular events that did not reach placebo-controlled trials 19,20 ) showed results
the threshold for adjudication.9 All of the in- similar to those of the the primary analysis
cluded trials reported on mortality.9,16–28 Data on (Peto OR 1.67, 95% CI 1.07–2.62).9,16–29 When
adverse cardiovascular events and mortality are we excluded the most influential trial (which
shown in Appendix 4 (available at www.cmaj.ca 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% CI
Risk of serious adverse cardiovascular 1.26–5.12).16–28 The same was true when we
events and death included investigator-reported cardiovascular
The 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% CI
events 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 to
varenicline 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 the
sparse 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 (www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.110218/-/DC1).
CMAJ 5

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 www.cmaj.ca/lookup
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 cardiovascular
event. 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. Research
the effect size to alternative statistical approaches varenicline in the United States.32 All smoking
or comparators in various sensitivity analyses cessation therapies are approved for short-term
suggests 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. One
possibility is that the participants in the placebo Limitations
arms experienced a lower rate of serious adverse The limitations of our meta-analysis stem
cardiovascular events because of failure of ran- mainly from the quality of reported summary
domization. A systematic failure of randomi- data. The trials enrolled different populations,
zation is unlikely, because the baseline character- evaluated different doses of varenicline and had
istics of the participants were well balanced different lengths of follow-up and proportions
between groups. However, despite achieving lost to follow-up. Our estimates are imprecise
more than twofold higher rates of abstinence in owing to the low event rates. None of the trials
the trials, which should potentially induce a car- was adequately powered to detect individual dif-
diovascular benefit, the participants taking ferences in cardiovascular events. Although the
varenicline experienced an increased risk of seri- included trials were double blinded, differences
ous 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 the
text of other studies and the overall benefit–risk absence of source data, we could not assess for
profile 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 whether
ischemic and arrhythmic cardiac adverse events these events were immediate or delayed. 33 The
among 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 confirmed
100 patient exposure-years for varenicline v. by established diagnostic criteria. Finally, the
1.63 per 100 patient exposure-years for placebo applicability of our findings to smokers with
after 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 from
analysis: including the data from those studies the trials.
plus the data from several other published stud-
ies, we found three times the number of serious Conclusion
adverse cardiovascular events among partici- Our meta-analysis raises safety concerns about
pants in the varenicline group (61/4908 for the potential for an increased risk of serious
varenicline 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 have
The number needed to treat with varenicline for limited safety data at the time of approval.34 The
one additional person to successfully quit smok- initial safety signal regarding cardiovascular
ing 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 should
smokers 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 use
event) 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 with
varenicline use includes the potential for serious Addendum
neuropsychiatric symptoms such as depressed At the time of publication, the FDA announced
mood, agitation and suicidal thoughts.32 These the addition of a warning to the product label of
additional risks associated with varenicline have Chantix (varenicline) about the small, increased
resulted in a boxed warning (the highest level of risk of certain adverse cardiovascular events
FDA warning) in the medication guide and a associated with the use of varenicline among
Risk Evaluation and Mitigation Strategy for smokers with cardiovascular disease.35
CMAJ 7

8. Research
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17. Protocol A3051095. New York (NY): Pfizer; 2009. Available: Contributors: Sonal Singh, John Spangler and Yoon Loke
www.clinicalstudyresults.org/documents/company-study_10818 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