Response to Letter Regarding Article, “Efficacy and Safety of Varenicline for Smoking Cessation in Patients With Cardiovascular Disease: A Randomized Trial”
In their letter, Drs Smolderen and Pelle correctly point out that patients with cardiovascular disease (CVD) have a high rate of comorbid depression, that depressed patients have less success when they attempt to stop smoking, and that the exclusion of smokers with comorbid depression from our trial of varenicline in patients with CVD limits our ability to generalize the results of our study to all smokers with CVD, as we had noted in the original article.1 As they request, we clarify here why our trial excluded CVD patients with comorbid depression.
According to standard methodology used in testing new drugs, medications not specifically intended for psychiatric indications are first studied in patients without serious active medical or psychiatric problems. Subsequent trials extend the knowledge base to a wider spectrum of patients. The study protocol for the trial we reported was finalized and approved on August 25, 2005, and the first subject was screened on February 20, 2006. This was soon after completion of the initial phase III trials of varenicline in healthy smokers,2,3 before varenicline was approved by the US Food and Drug Administration in May 2006,4 and well before the first postmarketing reports about potential neuropsychiatric effects of varenicline in September 2007.5 At the time of its design, the trial aimed to extend information about the safety and efficacy of this investigational drug from healthy smokers to patients with stable CVD. The rationale for the study was the activity of varenicline as a partial agonist at the α4β2 nicotinic acetylcholine receptor. To minimize complications in interpreting efficacy and safety results, we chose to exclude subjects who had a diagnosis of depression within the previous 12 months, were taking antidepressant medication, or had a history of psychosis, anxiety disorder, panic disorder, or bipolar disorder.
We agree with Drs Smolderen and Pelle that future studies of varenicline in patients with CVD should include smokers with comorbid psychiatric disease so that the safety and efficacy of varenicline in this population can be determined. We note that the manufacturer of varenicline, Pfizer (New York, NY), is now conducting a randomized, placebo-controlled trial of 12 weeks of varenicline treatment for smoking cessation in smokers with depression receiving a stable dose of antidepressant treatment (www.ClinicalTrials.gov; unique identifier: NCT01078298).
Drs Rigotti, Pipe, Benowitz, and Tonstad have consulted for Pfizer. Dr Rigotti has been site principal investigator for clinical trials of smoking cessation medications funded by Pfizer, sanofi-aventis, and Nabi Biopharmaceuticals. Dr Pipe has received educational and research support in the past from Bristol-Myers Squibb, Johnson & Johnson, GlaxoSmithKline, and Merrell-Dow. Drs Benowitz and Tonstad served on the scientific planning committee for this study and have been paid consultants to Pfizer and other pharmaceutical companies that are developing and/or marketing smoking cessation medications. Dr Benowitz has been a paid expert witness in litigation against tobacco companies. His family owns a small amount of Pfizer stock. Dr Tonstad has been the site principal investigator for clinical trials of smoking cessation medication and other medications funded by Pfizer and other pharmaceutical companies. Dr Arteaga is a statistical director at Pfizer Inc, supporting the varenicline studies. Dr Garza is a senior medical director for clinical research and development at Pfizer, Inc and is the medical monitor for this study.
Rigotti NA, Pipe AL, Benowitz NL, Arteaga C, Garza D, Tonstad S. Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease: a randomized trial. Circulation. 2010; 121: 221–229.
Gonzales D, Rennard SI, Nides M, Oncken C, Azoulay S, Billing CB, Watsky EJ, Gong J, Williams KE, Reeves KR. 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.
Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, Billing CB, Gong J, Reeves KR. 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.
US FDA. News release: FDA approves novel medication for smoking cessation. May 2006. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108651.htm. Accessed May 10, 2010.
US FDA. Early communication about an ongoing safety review of varenicline (marketed as Chantix). November 2007. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm070765.htm. Accessed May 10, 2010.