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- Correspondence to: J J Prochaska JProchaska@ucsf.edu
- Accepted 21 March 2012
Abstract
Objective
To examine the risk of treatment emergent, cardiovascular serious
adverse events associated with varenicline use for tobacco cessation.
Design Meta-analysis comparing study effects using four summary estimates.
Data sources Medline, Cochrane Library, online clinical trials registries, and reference lists of identified articles.
Review methods
We included randomised controlled trials of current tobacco users of
adult age comparing use of varenicline with an inactive control and
reporting adverse events. We defined treatment emergent, cardiovascular
serious adverse events as occurring during drug treatment or within 30
days of discontinuation, and included any ischaemic or arrhythmic
adverse cardiovascular event (myocardial infarction, unstable angina,
coronary revascularisation, coronary artery disease, arrhythmias,
transient ischaemic attacks, stroke, sudden death or cardiovascular
related death, or congestive heart failure).
Results
We identified 22 trials; all were double blinded and placebo
controlled; two included participants with active cardiovascular disease
and 11 enrolled participants with a history of cardiovascular disease.
Rates of treatment emergent, cardiovascular serious adverse events were
0.63% (34/5431) in the varenicline groups and 0.47% (18/3801) in the
placebo groups. The summary estimate for the risk difference, 0.27% (95%
confidence interval −0.10 to 0.63; P=0.15), based on all 22 trials, was
neither clinically nor statistically significant. For comparison, the
relative risk (1.40, 0.82 to 2.39; P=0.22), Mantel-Haenszel odds ratio
(1.41, 0.82 to 2.42; P=0.22), and Peto odds ratio (1.58, 0.90 to 2.76;
P=0.11), all based on 14 trials with at least one event, also indicated a
non-significant difference between varenicline and placebo groups.
Conclusions
This meta-analysis—which included all trials published to date, focused
on events occurring during drug exposure, and analysed findings using
four summary estimates—found no significant increase in cardiovascular
serious adverse events associated with varenicline use. For rare
outcomes, summary estimates based on absolute effects are recommended
and estimates based on the Peto odds ratio should be avoided.
Introduction
Tobacco
use accounts for 440 000 deaths in the United States every year,
killing nearly one in two long term smokers, with the leading cause of
death being cardiovascular disease.1 2 Quitting smoking has immediate cardiovascular benefits,3
reducing the risk of recurrence of coronary events to that of a
non-smoker within three years and reducing mortality after a heart
attack by up to 50% over three to five years.4 5 6
US
clinical practice guidelines for treating tobacco dependence recommend
the use of cessation pharmacotherapy for all smokers interested in
quitting, unless contraindicated.7
The US Food and Drug Administration has approved three first line
classes of cessation pharmacotherapy: nicotine replacement therapy;
bupropion (Zyban, Wellbutrin), an antidepressant; and the most recently
approved option, varenicline (Chantix, Champix), a partial agonist to
nicotine receptors. Varenicline binds with high affinity and selectivity
to α4β2 nicotinic acetylcholine receptors in neurones. The partial
agonist activity induces modest receptor stimulation that attenuates the
symptoms of nicotine withdrawal. In addition, by blocking the ability
of nicotine to activate α4β2 nicotinic acetylcholine receptors,
varenicline inhibits the surges of dopamine release that are believed to
be responsible for the reinforcement and reward associated with tobacco
use.8
Meta-analyses and comparative trials have demonstrated the
effectiveness of varenicline for quitting smoking and sustaining
abstinence relative both to placebo and to bupropion.9
For
smokers with cardiovascular disease, cessation offers critical health
benefits and yet has been a challenge to achieve, particularly in the
long term.10
A recent placebo controlled trial of varenicline in 714 smokers with
stable cardiovascular disease reported sustained abstinence of 47% at
the end of treatment and 19% at one year follow-up in the varenicline
group, compared with 14% and 7% in the placebo group, respectively; the
group difference was significant at both time points.11
Incidence of cardiovascular serious adverse events in the varenicline
group during the 52 week trial was low (7.0%) and the 95% confidence
interval ruled out an excess greater than 5% (1.4%, −2.3% to 5.0%).
Nonetheless, the FDA has called for systematic review of all randomised
clinical trials of varenicline for tobacco cessation to determine its
association with cardiovascular risk.12
Singh
and colleagues conducted a meta-analysis of the safety of varenicline
and concluded that the drug increased the risk of cardiovascular serious
adverse events by 72%.13 However, doubts about the researchers’ conclusions have been raised,14 15 16 17 18 19
owing to several methodological issues, namely, the inclusion of
adverse events well beyond the treatment period; exclusion of trials
with no events, thereby biasing findings against the null; and use of
the Peto odds ratio, which has shown bias under conditions of imbalanced
design and rare events, which were present in most of the reviewed
trials. Inclusion of the adverse events beyond the treatment period is
of concern, because of the elevated risk for cardiovascular disease
among study participants associated with their chronic use of tobacco
and because of differential drop out by condition. In all but one20
of the 14 studies reviewed by Singh and colleagues, retention was lower
in the placebo group than in the varenicline group, thereby reducing
the likelihood of detecting adverse events in the placebo arm.
We
conducted a systematic review and meta-analysis of treatment emergent,
cardiovascular serious adverse events in all published, randomised
controlled trials of varenicline for tobacco cessation. We defined these
events as occurring during drug treatment or within 30 days of
discontinuation. We chose a 30 day window because it was biologically
relevant for detecting a drug toxicity effect, while still being
conservative; the half life of varenicline is 24 hours, and any direct
pharmacological effect should be gone within seven days. Other reports
of serious adverse events to the FDA for drugs with a similar half life
have used a discontinuation period of seven days.21
In
consideration of the low event rate and imbalanced study designs, we
summarised the study effects with the risk difference, an estimate of
absolute effect. Summaries based on the risk difference are easily
interpretable and ideal for conveying the clinical effect of a
treatment. The risk difference provides an unbiased estimate of
treatment effect, has been shown to be particularly appropriate in
examining rare event data, and can accommodate trials with no events.22 23 For comparison, we also summarised the study effects with the relative risk, Mantel-Haenszel odds ratio, and Peto odds ratio.
Methods
Literature search
Our systematic review entailed computer based searches of Medline, the Cochrane Library, and online clinical trials registries (ClinicalTrials.gov
and the industry sponsored Clinical Study Results registry) to identify
randomised controlled trials evaluating varenicline for tobacco
cessation. The search covered January 2005 (the year when articles on
varenicline were first published) to September 2011, and included
articles available online ahead of print publication. The search strings
were “varenicline and randomised” in Medline and “SR-tobacco and
varenicline” in the Cochrane Central Register of Controlled Trials. We
manually searched bibliographies of relevant research and review
articles.
Studies included in the meta-analysis met the
following criteria: randomised controlled design, study sample of
current tobacco users of adult age, comparing use of varenicline with
that of an inactive control, and reporting adverse events. Exclusion
criteria included use of a quasi-experimental or crossover design,
laboratory studies with no follow-up, studies with adolescents, studies
of non-smokers, studies in which all participants received varenicline,
and comparisons of varenicline with another active drug (for example,
nicotine replacement). Study inclusion criteria, data extraction, and
methods of the analysis were specified in advance and documented in a
protocol.
Data extraction
Two
reviewers independently conducted article data extraction and quality
assessment for each study meeting the inclusion criteria. Data
extraction included descriptive characteristics of the study samples;
varenicline dose; duration of drug treatment; study duration; sample
attrition; and the number of participants with treatment emergent,
cardiovascular serious adverse events in the inactive and active drug
conditions. For comparability, we used the same primary outcome as Singh
and colleagues, defining cardiovascular serious adverse events as any
ischaemic or arrhythmic adverse cardiovascular event (myocardial
infarction, unstable angina, coronary revascularisation, coronary artery
disease, arrhythmias, transient ischaemic attacks, stroke, sudden death
or cardiovascular related death, or congestive heart failure).13
We
obtained details on timing of the cardiovascular serious adverse events
from the study publications; the online clinical trials registries; the
Chantix product label; and for three trials, for which the information
was not publicly available, we contacted the medical adviser for
varenicline at Pfizer11 24 or the study lead author directly.25
For one additional study, we contacted the lead author to confirm that
no serious adverse events had occurred in the trial because only adverse
events were reported.26
Discrepant findings between reviewers were settled by discussion,
further review of the article, and (if necessary) consultation with a
third reviewer.
We assessed study quality using a three item method developed by Jadad and colleagues27
that evaluated adequacy of randomisation, concealment of randomisation,
and completeness of follow-up. We assessed two additional items,
relevant to the area of interest: adequate reporting and adjudication of
the cardiovascular serious adverse events. No quality scoring system
has proven to correlate consistently with treatment outcomes, and it is
recognised that general quality scales often need to be supplemented
with more problem specific items for each particular meta-analysis.28
Statistical analysis
We
described trial characteristics in terms of publication date; sample
size and allocation; and participants’ exposures to tobacco,
cardiovascular disease, and study treatments. For each trial included in
the meta-analysis, we cross classified study participants by treatment
group and by any occurrence of a treatment emergent, cardiovascular
serious adverse event. For trials that examined multiple doses of
varenicline, we combined the active treatment groups.
Using
Comprehensive Meta-Analysis (version 2 professional edition; Biostat)
and fixed effects estimation, we summarised evidence of an increased
risk of cardiovascular serious adverse events associated with
varenicline use via four summary statistics: the Mantel-Haenszel
versions of the risk difference, relative risk, and odds ratio; and the
Peto odds ratio.29 30
For each statistic, we reported the mean effect, 95% confidence
interval, P value testing the null hypothesis of no effect, and I2 statistic estimating heterogeneity across trials.31
We confirmed all results using the “metan” and “funnel” routines added
to Stata version 11. The three relative statistics excluded trials in
which event counts were zero in both arms.32
For trials in which one event count was equal to zero, both software
packages (Stata and Comprehensive Meta-Analysis) added 0.5 to each of
the four cell counts before estimating the relative risk or
Mantel-Haenszel odds ratio.
We planned to do random
effects meta-analyses and subgroup analyses if levels of heterogeneity
exceeded 50%. We plotted the cumulative evidence by date of trial
publication33
and examined asymmetry in a funnel plot as an indicator of publication
bias. Finally, we compared the four summary statistics at the trial
level grouping the studies by presence (v absence) of events and equal (v
unequal) numbers of events, ordering the groups by increasing evidence
of a varenicline effect. We expected this comparison would provide
insight into the most suitable summary statistic in the present setting.
Results
Study characteristics
The
Medline search yielded 133 citations; of these, 21 met the inclusion
criteria, which were all published in 2006 or later (fig 1⇓).
We identified one additional unpublished study from the online clinical
trials registries. Searching in the Cochrane Central Register of
Controlled Trials yielded 83 results which, along with manual searches
of the bibliographies of relevant research and review articles, did not
yield any additional studies.
Fig 1 Literature search results and study selection
In
total, we identified 22 randomised controlled trials of varenicline use
for tobacco cessation; all were double blind and placebo controlled,
and collectively included 9232 participants (5431 randomised to
varenicline, 3801 to placebo; table 1⇓).
The median overall sample size was 404 (range 31-1210). Seven trials
had notable imbalances in sample size by condition—four allocated
participants to varenicline and placebo groups in a 2:1 ratio, and three
studied multiple varenicline doses or regimens. In 21 trials, the
varenicline dose was 1 mg twice daily; three of these trials also
studied lower doses of varenicline (table 1). The median duration of
study treatment was 12 weeks, the median duration of follow-up for
treatment emergent, cardiovascular serious adverse events was 16 weeks,
and the median duration of the study period after randomisation was 25
weeks.
View this table:
Table 1
Characteristics of randomised controlled trials of varenicline included in the meta-analysis
The samples tended to have a majority of male and white participants. Two trials studied smokeless tobacco users24 34
and 20 studied cigarette smokers. Among the trials of cigarette
smokers, participants averaged 21.5 cigarettes (standard deviation 1.9)
per day at study screening and 25.1 years (6.3) of tobacco use. Thirteen
trials included patients with current or past cardiovascular disease.
Of these trials, one was conducted among smokers admitted to hospital,
of whom 57% had an admitting diagnosis that was cardiovascular25; another was conducted specifically among people with stable cardiovascular disease11;
and 11 trials included people with a past cardiovascular event (table
1). Nine trials excluded people with any history of cardiovascular
disease or the timing for exclusion was not specified. Study quality was
strong overall, with all 22 trials being of double blind design and
providing adequate descriptions of randomisation, loss to follow-up, and
cardiovascular serious adverse events. However, only one trial
adjudicated the serious adverse events.11
Risk of treatment emergent, cardiovascular serious adverse events
Across
the 22 studies, the crude rates of treatment emergent, cardiovascular
serious adverse events were 0.63% (34/5431) for the varenicline group
and 0.47% (18/3801) for the placebo group. No events occurred in eight
trials, including three trials with more than 100 participants per arm.
The summary risk difference was 0.27% (−0.10% to 0.63%, P=0.15, I2=0%; fig 2⇓),
with no indication of publication bias in the funnel plot. For
comparison, based on 14 studies with at least one event, the relative
risk was 1.40 (0.82 to 2.39, P=0.22, I2=0%; table 2⇓), the Mantel-Haenszel odds ratio was 1.41 (0.82 to 2.42, P=0.22, I2=0%), and the Peto odds ratio was 1.58 (0.90 to 2.76, P=0.11, I2=0%).
Fig 2
Difference in risk of treatment emergent, cardiovascular serious
adverse events associated with varenicline use in 22 double blinded,
placebo controlled, randomised trials. Studies grouped by presence (v absence) of events and equal (v unequal) numbers of events with groups ordered by increasing evidence of a varenicline effect
View this table:
Table 2
Risk of treatment emergent, cardiovascular serious adverse events
associated with varenicline use in double blind, placebo controlled
randomised trials of tobacco cessation
Neither
the individual trials nor the summary estimates showed a significant
treatment effect; consequently, we did not calculate the number needed
to harm.35 We found no evidence of heterogeneity according to the I2 statistic or the cumulative estimated effect of varenicline on cardiovascular serious adverse events (fig 3⇓).
Fig 3
Cumulative estimated difference in risk of cardiovascular serious
adverse events attributable to varenicline use. Studies ordered by
publication year
We conducted four sensitivity analyses excluding trials of participants with active cardiovascular disease11 25 (risk difference 0.29% (95% confidence interval −0.04 to 0.62), I2=0%); trials of smokeless tobacco users24 34 (0.31% (−0.07 to 0.69), I2=0%);
one trial in which all participants were initially exposed to
varenicline and then randomised to placebo or to a 12 week maintenance
phase of varenicline36 (0.26% (−0.16 to 0.67, I2=0%)); and one unpublished trial40 (0.27% (−0.10 to 0.64, I2=0%)). All four sensitivity analyses differed minimally from the full analysis.
After grouping the trials by presence (v absence) of events and equal (v
unequal) numbers of events, we obtained five groups (table 2, fig 2).
Group 1 included the one trial with more cardiovascular serious adverse
events in the placebo arm than in the varenicline group. Group 2 had no
events in either arm. Group 3 had an equal number of events per arm.
Group 4 had one or more events in the varenicline arm but none on the
placebo arm. Finally, group 5 had events occurring in both arms, with
more occurring in the varenicline arm.
For group 2 (no
event on either arm; eight trials), “no effect” was estimated by a risk
difference of 0%, but not by relative effects equal to 1, because the
relative summary statistics exclude trials with no events. For groups 3
and 5 (at least one event on each arm; six trials), the evidence for and
against the null hypothesis of no treatment effect was similar across
the four statistics in group 3, but the Peto odds ratio seemed to
underestimate treatment effects in group 5.
For every
trial in groups 1 and 4 (eight trials), in terms of both mean effects
and confidence intervals, the Peto odds ratio was far stronger than the
relative risk, but the Mantel-Haenszel odds ratio was nearly identical
to the relative risk. In all eight trials, the Peto odds ratio exceeded
3.4 (or its inverse) despite very few events, large sample sizes, and
differences of only one to two events by arm. For example, the trial by
Bolliger and colleagues37
saw one event among 394 participants receiving varenicline (0.25%)
compared with no events among 199 participants receiving placebo (0%)
(risk difference 0.25%, relative risk of 1.52, Mantel-Haenszel odds
ratio of 1.52, Peto odds ratio of 4.50).
Discussion
This
meta-analysis included all published randomised, placebo controlled
trials of varenicline for tobacco cessation, examined events occurring
during drug exposure or within 30 days of discontinuation, and analysed
findings via four summary measures. None of these measures identified a
significantly elevated risk of treatment emergent, cardiovascular
serious adverse events with varenicline use, and the 95% confidence
interval of the risk difference excluded an increase larger than 0.63%.
In response to the FDA’s call for analysis of cardiovascular serious
adverse events attributed to varenicline use, this meta-analysis of 22
independent trials and more than 9000 individuals had high power to
detect a significant treatment effect and found negligible variation in
the evidence across the trials.
Study participants
tended to be chronic, heavy smokers, averaging more than one pack of
cigarettes a day for more than two decades, placing them at elevated
risk of serious adverse events related to cardiovascular disease. Most
trials included individuals with current (two trials) or past (11
trials) cardiovascular disease. More than a third of studies did not
observe a cardiovascular serious adverse event; among these trials, five
of eight included participants with past cardiovascular disease.34 40 41 44 46
Comparison with other studies
In
their meta-analysis of the safety of varenicline, Singh and colleagues
reported a Peto odds ratio of 1.72 (95% confidence interval 1.09 to
2.71) and concluded that “The use of varenicline among tobacco users was
associated with a 72% increased risk of serious adverse cardiovascular
events.” They questioned the safety of this medication,13 and in subsequent press interviews called for withdrawal of varenicline from the market.38
The researchers’ analysis of cardiovascular serious adverse events at
any time during the trial duration was, on average, twice the duration
of study drug exposure and did not account for longer follow-up in the
varenicline group than in the placebo group.
The
discrepancy between the conclusions of our meta-analysis and those of
Singh and colleagues’ study is explained not only by differing periods
over which events were collected but also by the choice of statistics
used to summarise the results, which affected the trials included in the
meta-analyses. For direct comparison in our study, we analysed data
from all 22 trials using the full study follow-up, because the
observation period of interest and the calculated risk difference was
0.47% (95% confidence interval 0.04 to 0.91), far less inflammatory than
the previous meta-analysis’s reported risk based on the Peto odds
ratio, yet still biased in favour of finding an effect due to the
differential inclusion of events related to disease and not just
treatment. By contrast, our calculated risk difference of treatment
emergent, cardiovascular serious events was 0.27% (−0.10 to 0.63).
Choice of summary statistics
When
study participants are selected by outcome status (for example, case or
control), an odds ratio must be used to summarise an association with
exposure status. However, when participants are selected by exposure
status (for example, active or placebo treatment), a risk difference or
relative risk can be used. These statistics are more natural choices for
randomised trials because they explicitly estimate and contrast effects
of interest—namely, event rates in the active and placebo arms.
Treatment effects based on relative risks always are as or less extreme
than those based on odds ratios.30
The (absolute) risk difference has a further advantage because it can
be calculated for trials in which zero events occur, whereas relative
statistics cannot be calculated for these trials and therefore can bias
summaries against the null hypothesis of “no effect.”
Furthermore,
relative statistics are unitless, which hides the fact that a low
response rate remains very low even when scaled up by a seemingly large
effect; by contrast, the risk difference retains the units of the
measurement scale, showing that a difference between low response rates
is itself very small. Vandermeer and colleagues’ comprehensive
reanalysis of findings from 1613 meta-analyses of safety data indicated
that the Peto odds ratio statistic was particularly biased.22
We further demonstrate that, regardless of sample size allocation, when
all events are in one study arm, Mantel-Haenszel odds ratios match
relative risks well whereas Peto odds ratios are far more extreme. For
clinical considerations and in the setting of rare events, the risk
difference most clearly conveys the relevant effect.22 23 39
Conclusions and clinical implications
Meta-analysis
is an important analytical technique for synthesising treatment effects
across trials for maximum power and is particularly useful for analysis
of serious adverse events, which can occur with low frequency. Bias in
methods, however, is a real concern. Our comparison of four summary
statistics identified conditions under which the Peto odds ratio
produced extreme estimates that did not reflect the underlying event
rates, and identified cases in which it produced smaller estimates than
it theoretically should have done. Our results accord with other reports
that the Peto statistic can lead to incorrect conclusions.22 29
The consequence of inflated risk estimates, such as those from Singh
and colleagues’ meta-analysis concerning the effect of varenicline on
serious adverse events related to cardiovascular disease,13
can be unnecessary public alarm and real harm, since patients may
discontinue their drug treatment out of fear of adverse effects and
clinicians may recommend cessation treatments of reduced efficacy or
discourage use of the drug treatment altogether.
Smoking
is the leading preventable cause of death worldwide. Half of long term
smokers die from their tobacco use, and smokers die from cardiovascular
disease more than from any other cause.1 2 3
Varenicline is a first line treatment for quitting smoking, and
quitting smoking is central to the prevention of cardiovascular disease.
Our meta-analysis of treatment emergent, cardiovascular serious adverse
events, with attention to bias and critical design issues, indicates
that the risk of these events associated with varenicline use is small,
and statistically and clinically insignificant.
What is already known on this topic
- There have been drug safety concerns about the use of varenicline for tobacco cessation and the emergence of cardiovascular serious adverse events
- However, this association has since been called into question, owing to less than optimal methodology used, and the US FDA has called for further analysis
What this study adds
- Our meta-analysis of all published, randomised controlled trials of varenicline use for tobacco cessation included 50% more studies than a previous meta-analysis by Singh and colleagues; used an unbiased summary estimate and compared findings with three other estimates; and examined events that occurred during drug treatment, which is more biologically relevant and obviates problems with differential drop out
- All four summary estimates indicated no significant increase in the risk of treatment emergent, cardiovascular serious adverse events attributed to varenicline use
Notes
Cite this as: BMJ 2012;344:e2856
Footnotes
- We thank Romina Kim for assistance with data abstraction and data entry with the systematic review.
- Contributors: JJP conceived of the study, conducted the literature search and systematic review, assisted with the analyses, and led writing of the manuscript. JFH led the data analyses and assisted with writing the manuscript. Both authors are study guarantors, and had full access to all of the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis.
- Funding: JJP is funded by the National Institute on Drug Abuse (P50 DA09253) and the State of California Tobacco-Related Disease Research Program (17RT-0077) for the submitted work. The funding agencies had no role in the conduct of the research or preparation of the manuscript.
- Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: this study received support from the National Institute on Drug Abuse and the State of California Tobacco-Related Disease Research Program; JJP is principal investigator on R01 MH083684 from the National Institute of Mental Health and an Investigator Initiated Research award from Pfizer (WS981308), and is a collaborator on R34 DA030538 from the National Institute on Drug Abuse and a Cahan Award from the Flight Attendant Medical Research Institute, all of which are tobacco control trials; JFH is coinvestigator on five randomised controlled trials funded by the National Institutes of Health and the Agency for Healthcare Research and Quality, none of which are relevant to the submitted work; JFH has had no relationship with any company that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
- Ethical approval: Not required.
- Data sharing: Statistical code and dataset available from the corresponding author.
This
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