Whilst findings were not uniform, based on the findings of these reviews, the risk of cardiovascular events associated with the use of varenicline is judged to be minimal and clinically insignificant.



Note: The recent changes to the service product characteristics (SPC) for varenicline do not substantially change the points raised in this briefing nor the advice that it is safe and effective

Shahab, L

English

UCL Discovery

Executive SummaryIn light of trials reporting on the incidence of cardiovascular serious adverse events among those usingvarenicline and a call to evaluate the association of cardiovascular serious adverse events with the useof varenicline, two recent meta-analyses have reviewed existing evidence. Whilst findings were notuniform, based on the findings of these reviews, the risk of cardiovascular events associated with theuse of varenicline is judged to be minimal and clinically insignificant. Given the effectiveness of vareniclinein helping smokers to stop smoking and the associated reduction in cardiovascular disease risk followingsmoking cessation, consensus recommendations indicate that the benefits of varenicline outweigh anypotential slight increase in cardiovascular events. Patients on varenicline should, as should anyone, seekimmediate medical attention if they experience symptoms of myocardial infarction and should contacttheir doctor if they experience new or worsening of any cardiovascular symptoms.Key points1. Background■ Smoking is a major risk factor for cardiovascular disease (CVD); the average smoker has aboutdouble the risk of developing heart disease prematurely than a non-smoker1 and CVD is aleading cause of death of smokers2 as well as a major comorbidity.3■ Varenicline is a highly effective smoking cessation aid, more than doubling the chances ofstopping smoking.4,5 When smokers stop smoking, the excess risk of CVD goes down by about50% after the first year6 and the risk of a recurrence of coronary events reverts to that of anon-smoker within three years.7■ Given the enormous benefits of smoking cessation in smokers with CVD, varenicline has beentrialled in this population and shown to be effective.8 However, given that a number of studieshave reported cardiovascular serious adverse events in participants using varenicline, there havebeen calls for systematic reviews to estimate the potential for varenicline to increase cardiovascularrisk.9 Two such reviews have now been published,10,11 reporting contradictory findings whichare discussed below.Cardiovascular diseaseand varenicline (Champix)© 2013 National Centre for Smoking Cessation and Training (NCSCT). Version 3: August 2013.Authors: Leonie S. Brose, Eleni Vangeli, Robert West and Andy McEwenEditor: Andy McEwen1www.ncsct.co.ukBriefing: 42. The evidence2.1 Review 201111■ The authors reviewed 14 double-blind randomised controlled trials; these studies comparedthe effectiveness of varenicline and a placebo in helping tobacco users to stop smoking.Most of the trials excluded tobacco users with CVD within the last six months; one trialincluded those with stable CVD.■ A total of 8,216 tobacco users were included in these studies: 4,908 used varenicline and 3,308used a placebo. The duration of treatment ranged from 7 to 52 weeks and participants werefollowed-up for between 24 and 52 weeks. In this time, 52 (1.06%) participants in the vareniclinegroup experienced a cardiovascular event and 27 (0.82%) in the placebo group. These includedany ischemic or arrhythmic adverse cardiovascular events. The difference between the groupswas statistically significant which means that, if the authors only looked at this outcome andno others were considered and not reported, there is less than a 1 in 20 chance that it couldhave occurred without some real underlying difference (Figure 1).■ The authors conclude that 1 in 28 smokers treated with varenicline would experience anadditional cardiovascular event. However, the difference in the occurrence of cardiovascularevents between the varenicline and placebo groups was 0.24% (1.06–0.82) whichtranslates into 1 in 417 smokers, not 1 in 28.■ An acknowledged source of bias is that the loss to follow-up rate was lower in the vareniclinegroup than the placebo group; so there was more opportunity for adverse events to be detectedin the varenicline group and a possibility that events were missed in the placebo group. It is alsoimportant to note that with events that are very rare, such as the cardiovascular events, andwith imbalanced design, Peto odds ratios, which the main conclusions of this review werebased upon, are likely to be biased.12Cardiovascular disease and varenicline (Champix)2www.ncsct.co.ukBriefing: 42.2 Review 201210■ A more recent systematic review and meta-analysis used a number of steps to address someof these concerns and provide a more accurate risk estimate:■ Since it would be less plausible that varenicline had an effect if the cardiovascular eventsoccurred substantially after the medication was no longer being used, the authors ofthis review restricted analysis to cardiovascular serious adverse events that occurredduring treatment and within 30 days of discontinuation.■ The authors used a more robust statistic, risk difference, which provides an estimate ofabsolute effect and has the advantage that (a) studies with no events can be included inanalysis and (b) is unbiased when interpreting rare events.13■ As this is a more recent analysis, several new trials of varenicline not covered in the previousreview could be included in the meta-analysis.■ The authors reviewed 22 double-blinded and placebo-controlled trials of varenicline in currenttobacco users which reported adverse events. Two of these included participants with activeCVD and the remaining trials excluded participants with recent manifestation of CVD.■ Trials included a total of 9,232 tobacco users, 5,431 used varenicline and 3,801 were providedwith a placebo. The duration of treatment ranged from 6 to 52 weeks with a median follow-up of 16 weeks. The review confirmed that the risk of cardiovascular events was extremely rarefor users of both varenicline and the placebo. Within 30 days of discontinuation, 34 (0.63%)participants in the varenicline group experienced a cardiovascular event and 18 (0.47%) in theplacebo group. These included any ischemic or arrhythmic adverse cardiovascular events.■ The risk difference in cardiovascular serious adverse events between the groups was very small(0.27%. 95% confidence interval -0.10–0.63, p=0.15) and not statistically significant or clinicallymeaningful, as the authors conclude. Thus, in contrast to the previous review, it is unlikely thatthere is real underlying difference in CVD risk between groups.■ Further sensitivity analysis, excluding studies on the basis of different methodology, confirmedthis result as did the use of different risk estimates, including Peto odds ratio (see Figure 1).Cardiovascular disease and varenicline (Champix)3www.ncsct.co.ukBriefing: 4Figure 1: Risk of cardiovascular serious adverse events associated with varenicline useSAE: Serious adverse event; Error bars indicated 95% confidence interval of estimate(if error bars cross dotted line, the observed effect is not statistically significant)2.3 Recent studiesTwo studies that have been published since the second review support its conclusion. One ofthem14 used data from trials of varenicline and calculated time to any major cardiovascular eventin varenicline compared with placebo groups during treatment and up to 30 days after the lastdose. There was a trend towards increased incidence of events in the varenicline group that didnot reach statistical significance (events: 26/4,190=0.62% in varenicline and 12/2,812= 0.43%;risk difference 0.010, 95% CI = -0.002 to 0.022, p= 0.11). The overall number of events waslow and the absolute risk of cardiovascular events with varenicline was small.The second study15 was a nationwide cohort study using Danish registry data on drugs dispensed,cardiovascular events and potential confounders. New users of varenicline and new users ofbupropion (total n=35,924) were matched for demographic and medical characteristics. Therewas no significantly increased risk of any cardiovascular event associated with the use of vareniclinecompared with bupropion, and the risk of cardiovascular events was not significantly differentfor those with and without a history of cardiovascular disease.Cardiovascular disease and varenicline (Champix)4www.ncsct.co.ukBriefing: 40.51.0Peto odds ratioReview 201110 Review 2012111.52.02.53.0CVD SAE*3. Conclusion■ Taking the findings of the reviews and the two more recent studies together, there is little reasonto avoid this medication on the grounds that use of varenicline increases the risk of cardiovascularevents. Based on a review that relied on a more robust methodology to mitigate the impactof biases in studying rare events, results indicate that the risk of such events is very small indeedand likely to be statistically and clinically insignificant.■ This view is in line with the European Medicines Agency that confirmed a positive benefit-riskbalance for varenicline and concluded that its benefits as a smoking-cessation medicine outweighany potential slight increase in cardiovascular events.16■ Nevertheless, the Summary of Product Characteristics for Champix now includes a statementthat patients should be instructed to notify their doctor of new or worsening cardiovascularsymptoms and to seek immediate medical attention if they experience signs and symptomsof myocardial infarction or stroke; advice that appears applicable to anyone, regardlessof medication.Cardiovascular disease and varenicline (Champix)5www.ncsct.co.ukBriefing: 4Conflict of interest statementsLeonie Brose and Eleni Vangeli have no conflicts of interest to declare. Lion Shahab has received anhonorarium for a talk and travel expenses from a pharmaceutical company that makes smoking cessationproducts to attend meetings and workshops. Robert West undertakes research and consultancy forcompanies that develop and manufacture smoking cessation medications (Pfizer, J&J, McNeil, GSK, Nabi,Novartis and Sanofi-Aventis). He also is a trustee of QUIT, a charity that provides stop smoking support.Andy McEwen has received travel funding, honoraria and consultancy payments from manufacturersof smoking cessation products (Pfizer, GSK and Novartis). He also receives payment for providing trainingto smoking cessation specialists and receives royalties from books on smoking cessation. Robert Westand Andy McEwen have shares in a patent for a novel nicotine delivery device.Cardiovascular disease and varenicline (Champix)6www.ncsct.co.ukBriefing: 4References1. Doll R, Peto R, Boreham J, Sutherland I. Mortality in relation to smoking: 50 years’ observations on male British doctors.BMJ (Clinical research ed 2004;328(7455):1519.2. Centers for Disease Control and Prevention. Smoking-attributable mortality, years of potential life lost, and productivity losses– United States, 2000–2004. MMWR Morb Mortal Wkly Rep 2008;57(45):1226–8.3. Hyland A, Vena C, Bauer J, Li Q, Giovino GA, Cummings KM, et al. Cigarette Smoking-Attributable Morbidity – United States, 2000. Morbidity and Mortality Weekly Report 2003;52(35):842–44.4. Brose LS, West R, McDermott MS, Fidler JA, Croghan E, McEwen A. What makes for an effective stop-smoking service?Thorax 2011;66(10):924–6.5. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane database of systematic reviews(Online) 2012;4:CD006103.6. Edwards R. The problem of tobacco smoking. BMJ (Clinical research ed 2004;328(7433):217–9.7. Critchley J, Capewell S. Smoking cessation for the secondary prevention of coronary heart disease. Cochrane database of systematicreviews (Online) 2004(1):CD003041.8. Rigotti NA, Pipe AL, Benowitz NL, Arteaga C, Garza D, Tonstad S. Efficacy and safety of varenicline for smoking cessation in patientswith cardiovascular disease: a randomized trial. Circulation 2010;121(2):221–9.9. Food and Drug Administration. FDA drug safety communication: Chantix (varenicline) may increase the risk of certain cardiovascularadverse events in patients with cardiovascular disease. Silver Spring: FDA, 2011.10. Prochaska JJ, Hilton JF. Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation:systematic review and meta-analysis. BMJ (Clinical research ed 2012;344:e2856.11. Singh S, Loke YK, Spangler JG, Furberg CD. Risk of serious adverse cardiovascular events associated with varenicline: a systematicreview and meta-analysis. CMAJ 2011.12. Vandermeer B, Bialy L, Hooton N, Hartling L, Klassen TP, Johnston BC, et al. Meta-analyses of safety data: a comparison of exactversus asymptotic methods. Statistical methods in medical research 2009;18(4):421–32.13. Bradburn MJ, Deeks JJ, Berlin JA, Russell Localio A. Much ado about nothing: a comparison of the performance of meta-analyticalmethods with rare events. Stat Med 2007;26(1):53–77.14. Ware JH, Vetrovec GW, Miller AB, Van Tosh A, Gaffney M, Yunis C, et al. Cardiovascular safety of varenicline: patient-levelmeta-analysis of randomized, blinded, placebo-controlled trials. Am J Ther 2013;20(3):235–46.15. Svanstrom H, Pasternak B, Hviid A. Use of varenicline for smoking cessation and risk of serious cardiovascular events: nationwidecohort study. BMJ (Clinical research ed 2012;345:e7176.16. European Medicines Agency. Press release: European Medicines Agency confirms positive benefit-risk balance for Champix. www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2011/07/news_detail_001314.jsp&murl=menus/news_and_events/news_and_events.jsp&mid=WC0b01ac058004d5c1 21.07.2011.Cardiovascular disease and varenicline (Champix)7www.ncsct.co.ukBriefing: 4

Cardiovascular disease and varenicline (Champix)

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Cardiovascular disease and varenicline (Champix)

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