Comment and Reply: A double-blind study evaluating the long-term safety of varenicline for smoking cessation

Smoking is the leading cause of preventable mortality in the US responsible for over 400 000 deaths annually. Although a number of treatment options exist for smoking cessation, the newest drug on the market, varenicline (Chantix, Pfizer) has generated considerable excitement because it has been shown to be more effective than bupropion, and by extension, likely to be more effective than nicotine replacement. In earlier studies, varenicline appeared to be safe and to date possesses no known drug–drug interactions. Aside from pregnancy, severe renal dysfunction is its only major precaution, although it also has not been studied in children. These facts increase the enthusiasm for its use. The recent study by Williams et al. published in the journal reports on longer-term safety and efficacy of this drug when used up to 52 weeks. A total of 251 subjects were randomized to varenicline and 126 to placebo. At week 52, the 7-day point prevalence abstinence rates were 36.7% (varenicline) and 7.9% (placebo). Unfortunately numerous adverse events emerged on active drug. Over half of the patients dropped out of the study due to an adverse event. Total adverse event rates were 65/251 (25.9%) for patients on varenicline and 13/126 (10.3%) for patients on placebo. This translates into a relative risk of 2.51 for any adverse event causing drop out (95% confidence interval (CI): 1.44–4.38). Of more concern, serious adverse event also occurred. On active drug, one patient developed bilateral subcapsular cataracts (deemed to be drug related by the investigators, including the investigator who actually examined the patient); and two patients developed coronary artery disease events. Subcapsular cataracts and heart disease events are listed as side effects on the package insert but are not discussed by the authors in this study. Total serious adverse event rates were also greater in the varenicline group than in the placebo group (15/251 vs. 3/126, respectively). This translates into a relative risk of about 2.5 (95% CI: 0.75–8.72). Although this relative risk is not statistically significant, clinically it is quite important in a study that purports drug safety. Further, the authors admit that they do not carry out inferential statistics comparing varenicline with placebo. Nonethe less they proceed to make the inferences that ‘[v]arenicline 1 mg BID can be safely administered for up to 1 year [and] was also a more effective smoking cessation aid than placebo throughout the study, supporting both its short(12-week) and longterm (52-week) efficacy’ [emphasis added]. Moreover, as listed on clinicaltrials.gov, this study was initiated as a safety trial, yet safety inferential statistics are not available, and, in any case, the study has extremely low power (31%) to detect the differences of serious events seen between varenicline (15/251) and placebo (3/126). According to the authors, ‘Many of [these] serious adverse events were cardiovascular conditions known to be comorbid with cigarette smoking and the medical histories of many of these subjects documented conditions that may have contributed to the events. ’ 5 Unfortunately, aside from mentioning the two activedrug cardiovascular (CV) events, the breakdown of other CV events by treatment group is not given, nor is a full list of the all types of serious adverse events. Oxidative stress is known to play a role both in subcapsular cataract formation as well as CV disease. Cigarette smoking, in turn, contributes to oxidative stress in both conditions. Thus, diminishing systemic CURREnt MEdICAL REsEARCh And OPInIOn® VOL. 24, NO. 2, 2008, 577–579