Cardiovascular Safety of Varenicline, Bupropion, and Nicotine Patch in Smokers

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Benowitz NL, et al. “Cardiovascular Safety of Varenicline, Bupropion, and Nicotine Patch in Smokers”. JAMA Intern Med. 2018;178(5):622-631.

Clinical Question

In patients who use tobacco, do smoking cessation regiments (bupropion, varenicline, and nicotine patches) increase the incidence of major adverse cardiovascular events (MACE) compared to those who do not participate in a smoking cessation therapy?

Bottom Line

Among patients who use tobacco, smoking cessation therapies do not increase risk of major adverse cardiovascular events compared to patients not taking smoking cessation therapy medications. The pharmacotherapies observed lacked evidence to indicate otherwise.

Major Points

Smoking is associated with an increased risk of cardiovascular events and trying to quit is the single most important step a smoker can take to prevent exposure to CV diseases. However, many doctors are wary when prescribing smoking cessation medications because of concerns regarding adverse events and cardiovascular safety. Evaluating Adverse Events Global Smoking Cessation Study (EAGLES) and its extension study expanded their research to include CV event monitoring during and after treatment.

The multinational study includes a population of adult smokers who were interested in stopping smoking with the assistance of smoking cessation therapies (bupropion, nicotine patches, varenicline). It then compared their risk for major adverse cardiovascular events (MACE), such as CV death, nonfatal MI, and nonfatal stroke, to those who did not use smoking cessation therapies. Any other MACE with new-onset or worsening peripheral vascular disease were also included in the study.

The data collected from the study proved to be insignificant in connecting MACE with smoking cessation therapy. For the general population, the cardiovascular health benefits for those who stop smoking far outweighs any possible induced risk from the smoking cessation therapies.

Guidelines

The US Public Health Service Clinical Practice Guidelines recommends the combination of pharmacotherapy and behavioral support for patients who smoke because it significantly increases the success rate of achieving long-term tobacco abstinence. This also contributes to significantly lowered risk of cardiovascular events. However, as of April 2019, guidelines have not been published specifically on the relation between potential increased cardiovascular risk and smoking cessation medications.

Design

  • Double-blinded, randomized, triple-dummy, placebo- and active-controlled trial with its non-treatment extension trial conducted at 140 centers in various nations.
  • N = 8144 (11,186 screened)
    • 4028 participants randomized to non-psychiatric cohort
      • Varenicline n = 990 (1005 randomized)
      • Bupropion n = 989 (1001 randomized)
      • Nicotine Patch n = 1006 (1013 randomized)
      • Placebo n = 999 (1009 randomized)
    • 4116 participants randomized to psychiatric cohort
      • Varenicline n = 1026 (1032 randomized)
      • Bupropion n = 1017 (1033 randomized)
      • Nicotine Patch n = 10016 (1025 randomized)
      • Placebo n = 1015 (1026 randomized)
  • Setting: 140 multinational centers
  • Enrollment: 2011-2015
  • Follow-up Mean: 52 weeks
  • Analysis: intention-to-treat
  • Primary Outcome: the time it takes to notice any major adverse cardiovascular events after starting the initial therapy. MACE includes cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke

Population

Inclusion Criteria

  • Age 18-75
  • Smoked 10 or more cigarettes per day
  • Interested in quitting smoking
  • Participated and completed 24 week check-up in EAGLES
  • Persons person who did not complete the EAGLES medication study, but completed the EAGLES study visits were included.

Exclusion Criteria

  • Unstable psychiatric illness
  • Active substance abuse
  • CVD two months prior (e.g. MI or coronary artery bypass graft)
  • Cerebrovascular disease 2 months prior
  • Uncontrolled hypertension

Baseline Characteristics

  • Mean age: 46.5 years
  • Male to female ratio: 0.79:1
  • Race: 81.5% Caucasian

Interventions

  • Randomized to
    • Varenicline 1 mg twice daily
    • Bupropion hydrochloride 150 mg twice daily
    • Nicotine replacement therapy, 21-mg/day patch with tapering
  • Patients followed up for 12 weeks with an additional 28 week follow up.

Outcomes

Primary Outcomes

Time between initiation of therapy for smoking cessation and incidence of major adverse cardiovascular events.

MACE
Drug treatment period No. (%)
  • Varenicline 1 (<0.1)
  • Bupropion 2 (0.1)
  • NRT 1 (<0.1)
  • Placebo 4 (0.2)
MACE+
Drug treatment period No. (%)
  • Varenicline 5 (0.2)
  • Bupropion 4 (0.2)
  • NRT 2 (0.1)
  • Placebo 5 (0.2)

Secondary Outcomes

Occurrence of MACE and other important cardiovascular events.

MACE
Until 30-d follow-up No. (%)
    • Varenicline 1 (<0.1)
    • Bupropion 2 (0.1)
    • NRT 2 (<0.1)
    • Placebo 4 (0.2)
End of study No. (%)
    • Varenicline 3 (0.1)
    • Bupropion 9 (0.4)
    • NRT 6 (0.3)
    • Placebo 8 (0.4)
MACE+
Until 30-d follow-up No. (%)
    • Varenicline 5 (0.2)
    • Bupropion 4 (0.2)
    • NRT 3 (0.1)
    • Placebo 7 (0.3)
End of study No. (%)
    • Varenicline 10 (0.5)
    • Bupropion 15 (0.7)
    • NRT 10 (0.5)
    • Placebo 12 (0.6)
New-Onset or Worsening PVD Requiring Intervention
Drug treatment period No. (%)
    • Varenicline 0
    • Bupropion 1 (<0.1)
    • NRT 1 (<0.1)
    • Placebo 0
Until 30-d follow-up No. (%)
    • Varenicline 0
    • Bupropion 1 (<0.1)
    • NRT 1 (<0.1)
    • Placebo 2 (0.1)
End of study No. (%)
    • Varenicline 3 (0.1)
    • Bupropion 3 (0.1)
    • NRT 3 (0.1)
    • Placebo 2 (0.1)
CV Death
Drug treatment period No. (%)
    • Varenicline 0
    • Bupropion 1 (<0.1)
    • NRT 0
    • Placebo 1 (<0.1)
Until 30-d follow-up No. (%)
    • Varenicline 0
    • Bupropion 1 (<0.1)
    • NRT 0
    • Placebo 1 (<0.1)
End of study No. (%)
    • Varenicline 1 (<0.1)
    • Bupropion 2 (0.1)
    • NRT 0
    • Placebo 2 (0.1)
Nonfatal MI
Drug treatment period No. (%)
    • Varenicline 1 (<0.1)
    • Bupropion 1 (<0.1)
    • NRT 1 (<0.1)
    • Placebo 3 (0.1)
Until 30-d follow-p No. (%)
    • Varenicline 1 (<0.1)
    • Bupropion 1 (<0.1)
    • NRT 1 (<0.1)
    • Placebo 3 (0.1)
End of study No. (%)
    • Varenicline 2 (0.1)
    • Bupropion 4 (0.2)
    • NRT 3 (0.1)
    • Placebo 5(0.2)
Hospitalization for Unstable Angina
Drug treatment period No. (%)
    • Varenicline 1 (<0.1)
    • Bupropion 0
    • NRT 0
    • Placebo 0
Until 30-d follow-up No. (%)
    • Varenicline 1 (<0.1)
    • Bupropion 0
    • NRT 0
    • Placebo 0
End of study No. (%)
    • Varenicline 1 (<0.1)
    • Bupropion 2 (0.1)
    • NRT 0
    • Placebo 0

Comparisons are varencicline vs. bupropion and vs. placebo.

MACE
During Treatment Period
    • Varenicline vs placebo -5.54% vs 3.27% (HR, 0.29; 95% CI, 0.05-1.68)
    • Bupropion vs placebo -4.15% vs 2.88% (HR, 0.50; 95% CI, 0.10-2.50)
Until 30 Days of Follow-up
    • Varenicline vs placebo -5.60% vs 3.28% (HR, 0.29; 95% CI, 0.05-1.70)
    • Bupropion vs placebo -4.09% vs 2.84% (HR, 0.51; 95% CI, 0.10-2.51)
End of Study
    • Varenicline vs placebo -4.80% vs 2.82% (HR, 0.39; 95% CI, 0.12-1.27)
    • Bupropion vs placebo -2.63% vs 2.48% (HR, 1.09; 95% CI, 0.42-2.83)
MACE+
During Treatment Period
    • Varenicline vs placebo -3.36% vs 2.94% (HR, 0.98; 95% CI, 0.28-3.37)
    • Bupropion vs placebo -3.13% vs 2.85% (HR, 0.80; 95% CI, 0.22-2.95)
Until 30 Days of Follow-up
    • Varenicline vs placebo -3.35% vs 2.15% (HR, 0.70; 95% CI, 0.22-2.16)
    • Bupropion vs placebo -2.92% vs 2.14% (HR, 0.57; 95% CI, 0.10-1.86)
End of Study
    • Varenicline vs placebo -2.75% vs 1.80% (HR, 0.81; 95% CI, 0.35-1.86)
    • Bupropion vs placebo -2.04% vs 2.25% (HR, 1.21; 95% CI, 0.57-2.58)

Criticisms

  • The study focused on a primarily Caucasian population which does not proportionately represent the smoking populations ratio of ethnicities.
  • The study can be difficult to navigate. It states that e-table 4 is listed with the others in supplementary section 1, but was not easily located.

Funding

Pfizer and GlaxoSmithKline b. Both require Evaluating Adverse Events in Global Smoking Cessation Study and extensions of it.

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