Expert Review: Pharmacotherapy

Efficacy and Safety of Varenicline for Smoking Cessation in Patients With Cardiovascular Disease : A Randomized Trial

Expert Review: Efficacy and Safety of Varenicline for Smoking Cessation in Patients With Cardiovascular Disease : A Randomized Trial
Reviewer: Amelia Carro. Hospital Universitario Vall d’Hebrón. Universidad Autónoma de Barcelona, Barcelona, Spain.
Date: June 13th, 2013

First-line pharmacological interventions approved by the US Food and Drug Administration for treatment of tobacco dependence include bupropion, varenicline, and nicotine replacement therapy administered in different forms1. Pharmacological interventions are more effective when combined with counseling, and smokers trying to quit should receive both1.Varenicline
is the most recent addition to the repertoire of pharmacological interventions. In 2006, 3 clinical trials were published2-4, of which two2-3 included an active treatment comparison group. All trials involved a population of otherwise healthy volunteer smokers; had multiple exclusion criteria, thus limiting generalizability; and were conducted in academic centers. In 2006, the US Food and Drug Administration approved varenicline for the treatment of tobacco dependence.

Knowledge Gap
Some issues were left open by previous research:
a) The safety of the drug in cardiovascular patients. Because of its relative selectivity for α4β2 nicotinic acetylcholine receptors, varenicline is predicted to have no significant cardiovascular effects, but this has not been tested in people with cardiovascular disease (CVD).
b) The occurrence of psychiatric adverse events, a concern that had been raised with regard to this agent in the postmarketing period.

Aim of the Study
The study aimed to compare the efficacy and safety of varenicline with placebo for smoking cessation in smokers with stable CVD.
The primary study end point was the 4-week continuous abstinence rate (CAR) during the last 4 weeks of study drug treatment (weeks 9 to 12). The key secondary end point was the CAR from week 9 through 52. Other secondary end points were CAR for weeks 9 to 24 and 7-day point prevalence of tobacco abstinence at weeks 12 (end of drug treatment), 24, and 52.

This multicenter, double-blind, randomized clinical trial compared varenicline (2 mg/daily for 12 weeks) with placebo in 714 smokers with stable CVD. Follow-up duration was 1 year. Smokers in both arms received in-person counseling followed by phone calls up to week 44. An intention-to-treat analysis was used.
The authors used CO sampling to confirm abstinence

The continuous abstinence rate (CAR) at 9 to 12 weeks, confirmed by expired air carbon monoxide (CO), was 47.0% in the varenicline group versus 13.9% in the control group (OR, 6.11, CI 4.18, 8.93). The CAR at weeks 9 to 52 (secondary outcome) was more than twice the CAR in the placebo group (19.2% versus 7.2%). Varenicline is well tolerated and does not increase cardiovascular events or mortality. Rates of severe psychiatric adverse events were very low and similar in both groups.
With cessation of the medication, the prevalence of patients who were abstinent during the previous 7 days drops from 54.1% at the end of treatment to 34.9% at 24 weeks (a 35% decrease in 3 months) and to 27.9% at 52 weeks (a 48.4% decrease). In the control group, the point prevalence abstinence is lower, but more stable over time (18.1% to 15.9% at both 24 and 52 weeks), and this is consistent with the effect of psychosocial interventions. The effect at 1 year is lower than that generally reported in studies of psychosocial interventions: pooled OR of quitting versus usual care at 12 months=1.66 (CI 1.24, 2.21); quit rates=48.7% versus 38.4%5.

Varenicline was efficacious for smoking cessation among patients with stable CVD. Varenicline more than tripled the tobacco CAR after 12 weeks of treatment compared with placebo. Although many participants resumed smoking after treatment ended, the superiority of varenicline over placebo was maintained for 1 year. Varenicline was well tolerated and was not associated with increases in cardiovascular events, deaths, blood pressure, or heart rate. Rates of psychiatric adverse events were low and similar in the varenicline and placebo groups.

Clinical Impact
Varenicline is a useful drug for the treatment of tobacco dependence, and it seems to be reasonably safe in patients with chronic, stable CVD without a history of depression or psychiatric disease. However, trial size and duration preclude a definitive conclusion about the safety of varenicline. The rapid reduction in the risk of recurrence, disease progression, and cardiovascular complications argues for the priority of smoking cessation in the management of any smoking patient with CVD. The availability of effective pharmacotherapies for smoking cessation enhances the cardiovascular clinician’s ability to intercede successfully with this fundamental risk factor.

Corresponding author from original paper
Dr. Nancy Rigotti, MD, Massachusetts General Hospital, 50 Staniford St, 9th Floor, Boston, MA 02114.E-mail

1.- Fiore M, Jaen C, Baker T, Benowitz N, Curry S, Dorfman S, Froelicher E, Goldstein M, Healton C, Henderson P, Heyman R, Koh H, Kottke T, Lando H, Mecklenburg R, Mermelstein R, Dolan Mullen P, Tracy Orleans C, Robinson L, Stitzer M, Tommasello A, Villejo L, Wewers M. Treating Tobacco Use And Dependence: Clinical Practice Guideline. Rockville, MD: US Department of Health and Human Services; 2008.
2- Gonzales D, Rennard SI, Nides M, Oncken C, Azoulay S, Billing CB, Watsky EJ, Gong J, Williams KE, Reeves KR, for the Varenicline Phase 3 Study G. Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA. 2006;296:47–55.
3.- Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, Billing CB, Gong J, Reeves KR, for the Varenicline Phase 3 Study G. Efficacy of varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA. 2006;296:56–63.
4.- Tonstad S, Tonnesen P, Hajek P, Williams KE, Billing CB, Reeves KR, for the Varenicline Phase 3 Study G. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. JAMA. 2006;296:64 –71.
5.- Barth J, Critchley J, Bengel J. Efficacy of psychosocial interventions for smoking cessation in patients with coronary heart disease: a systematic review and meta-analysis. Ann Behav Med. 2006;32:10 –20.

Citation: Citation: Circulation. 2010;121:221-229

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