Tools for Practice


#71 Varenicline and Cardiovascular Risk – Is the Cure Worse than the Affliction?


CLINICAL QUESTION
Does smoking cessation with varenicline (Champix) increase the risk of cardiovascular disease (CVD)?

BOTTOM LINE
Varenicline does not appear to increase the risk of cardiovascular events over placebo or other smoking cessation drugs. Smoking cessation is the most effective intervention to reduce CVD risk. Varenicline is at least as good as other medications for cessation and may be slightly better.  


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EVIDENCE
CMAJ:1 First meta-analysis of 14 randomized controlled trials (RCTs) of 8216 patients found statistically significant increase in CVD (Peto odds ratio 1.72, 95% CI 1.09-2.71)  
  • Pooled event rates: Varenicline 1.06%, placebo 0.82%. 
Subsequent meta-analyses2-5 including more studies found no statistically significant increase in CVD: 
  • Meta-analysis of 38 RCTs (12,706 patients):4 Relative risk 1.03, 0.72-1.49 
    • Pooled event rates: Varenicline 0.79% versus placebo 0.78%. 
  • Meta-analysis5 of CVD risk with smoking cessation therapies found \
    • No increase in major CVD events with bupropion, nicotine replacement therapy (NRT), or varenicline versus placebo 
    • An increased risk of CVD events of any severity with NRT (mostly low-risk events like transient tachycardia): NRT 2.8% versus placebo 1.6%. 
All meta-analyses limited by included studies: 
  • Few CVD events limiting power 
  • CVD outcomes not systematically recorded in most RCTs 
  • High drop-out rates (up to 30%). 
Three large observational studies6-8 (total 278,596 patients on varenicline) found no difference in CVD risk between smokers taking varenicline versus bupropion.  Context:  
  • RCT of smoking cessation (counselling plus bupropion or nicotine replacement) after coronary care unit admission:9 
    • 9% absolute reduction in mortality at 2 years despite <40% abstinent. 
  • Varenicline may be the most effective smoking cessation drug.10  Number needed to treat (NNT) for different meds after 1 year, based on 10% cessation with placebo versus placebo 
    • Varenicline NNT=8, Nortriptyline NNT=10, bupropion NNT=10 
  • Concerns were also raised about an association between varenicline and an increased risk of depression and self-harm 
    • Multiple RCTs and observational studies, including patients with stable psychiatric disoders,11 show no increased risk of adverse neuropsychiatric events.12,13 
August 13, 2012

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Author(s):

  • G. Michael Allan MD CCFP
  • Ricky D. Turgeon BSc(Pharm) ACPR PharmD

1. 1. Singh S, Loke YK, Spangler JG, et al. CMAJ. 2011; 183:1359-66.

2. 2. Prochaska JJ, Hilton JF. BMJ. 2012; 344:e2856.

3. 3. Ware JH, Vetrovec GW, Miller AB, et al. Am J Ther. 2013; 20:235-46.

4. 4. Sterling LH, Windle SB, Filion KB, et al. J Am Heart Assoc. 2016; 5:e002849.

5. 5. Mills EJ, Thorlund K, Eapen S, et al. Circulation. 2014; 129:28-41.

6. 6. Svanstrom H, Pasternak B, Hviid A. BMJ. 2012; 345:e7176.

7. 7. Toh S, Baker MA, Brown JS, et al. JAMA Intern Med. 2013; 173:817-9.

8. 8. Graham DJ, By K, McKean S, et al. Pharmacoepidemol Drug Saf. 2014; 23:1205-12.

9. 9. Mohiuddin SM, Mooss AN, Hunter CB, et al. Chest 2007;131:446-52.

10. 10. Allan GM, Els C. Tools for Practice #26. Available at: https://www.acfp.ca/wpcontent/uploads/tools-for-practice/1397763918_20140317_101006.pdf Last accessed: Dec 1, 2016.

11. 11. Anthenelli RM, Benowitz NL, West R, et al. Lancet. 2016; 387:2507-20.

12. 12. Thomas KH, Martin RM, Davies NM, et al. BMJ. 2013; 347:f5704.

13. 13. Thomas KH, Martin RM, Knipe DW, et al. BMJ. 2015; 350:h1109.

Authors do not have any conflicts of interest to declare.