Reframing the varenicline question: have anecdotes and emotional filters clouded our decision making?
Authors: Frank T Leone, Robert Schnoll
Journal: The Lancet Respiratory Medicine (2015)

In searching for an appropriate way to begin describing our impressions of the retrospective cohort analysis by Daniel Kotz and colleagues,1Kotz D Viechtbauer W Simpson C van Schayck O West R Sheikh A Cardiovascular and neuropsychiatric risks of varenicline: a retrospective cohort study.Lancet Respir Med. 2015; 3: 761-768Summary Full Text Full Text PDF Scopus (78) Google Scholar published in The Lancet Respiratory Medicine, we were tempted to rely on worn but reliable observations regarding the magnitude of the tobacco epidemic. Smoking is the single most common cause of preventable death and disability, as the refrain goes. After reading Kotz and colleagues' report1Kotz D Viechtbauer W Simpson C van Schayck O West R Sheikh A Cardiovascular and neuropsychiatric risks of varenicline: a retrospective cohort study.Lancet Respir Med. 2015; 3: 761-768Summary Full Text Full Text PDF Scopus (78) Google Scholar on the cardiovascular and neuropsychiatric risks of varenicline, however, something about that oft-quoted phrase became quite a bit more discomfiting. Could a portion of the epidemic's persistence, we wondered, be attributable to the way clinicians, scientists, and individual smokers think about risk? What portion of preventable death and disability have we simply failed to prevent? Shortly after varenicline was introduced to American and European markets for the treatment of tobacco dependence, concerns regarding its potential adverse effects began to take form. Earliest post-marketing surveillance reports suggested that users were reporting various dangerous psychiatric side-effects, including hallucinations, memory loss, rage, depression, and suicidal behaviours. Soon thereafter, treatment with varenicline was used as a plausible defense in trials involving violent crimes. The European Medicines Agency (EMA) first alerted the US Food and Drug Administration (FDA) to concerns over varenicline's association with suicidality in May, 2007. Government regulators on both sides of the Atlantic adopted a justifiably protective stance, urging patients and clinicians to proceed cautiously with their treatment decisions.2US Food and Drug AdministrationChantix (varenicline) warning.http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021928s012s013lbl.pdfGoogle Scholar, 3European Medicines AgencyEuropean Medicines Agency concludes new advice to doctors and patients for Champix needed.http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2009/11/news_detail_000085.jsp&mid=WC0b01ac058004d5c1Google Scholar Several investigators went to work reporting results of sophisticated observational analyses, involving progressively larger cohorts of patients with sample sizes reaching the tens of thousands, with results suggesting that the initial concern might have been unwarranted.4Tonstad S Davies S Flammer M Russ C Hughes J Psychiatric adverse events in randomized, double-blind, placebo-controlled clinical trials of varenicline: a pooled analysis.Drug Saf. 2010; 33: 289-301Crossref PubMed Scopus (130) Google Scholar, 5Gibbons RD Mann JJ Varenicline, smoking cessation, and neuropsychiatric adverse events.Am J Psychiatry. 2013; 170: 1460-1467Crossref PubMed Scopus (103) Google Scholar Yet natural human preference for avoiding risk led to regulatory inaction and the persistence of anecdotal contraindications to treatment within the clinical community. Even prospective trials of the safety and efficacy of varenicline in patients with pre-existing serious mental illness seemed to be insufficient to overcome a powerful omission bias.6Williams JM Anthenelli RM Morris CD et al.A randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of varenicline for smoking cessation in patients with schizophrenia or schizoaffective disorder.J Clin Psychiatry. 2012; 73: 654-660Crossref PubMed Scopus (141) Google Scholar, 7Thomas KH Martin RM Knipe DW Higgins JPT Gunnell D Risk of neuropsychiatric adverse events associated with varenicline: systematic review and meta-analysis.BMJ. 2015; 350: h1109Crossref PubMed Scopus (109) Google Scholar, 8US Food and Drug AdministrationJoint meeting of the psychopharmacologic drugs and drug safety and risk management advisory committees.http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/psychopharmacologicdrugsadvisorycommittee/ucm434007.pdfGoogle Scholar So far, the available evidence does not seem to have yet risen to the level of certainty necessary to shake the fear adopted as a result of the initial anecdotal post-marketing surveillance reports. During the same period, in a remarkable example of surveillance déjà vu, reports of a connection between varenicline use and an increased risk for cardiovascular adverse events emerged. Although the numbers of events were small, and cardiovascular outcomes reported did not necessarily have a common pathophysiological mechanism, nagging concerns once again resulted in a regulatory position that reflected a better-safe-than-sorry stance, despite good data suggesting that the initial associations might have been overblown.9Prochaska JJ Hilton JF Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation: systematic review and meta-analysis.BMJ. 2012; 344: e2856Crossref PubMed Scopus (169) Google Scholar Again, comfort was found in the false security of waiting for more data. Hopefully, Kotz and colleagues' report1Kotz D Viechtbauer W Simpson C van Schayck O West R Sheikh A Cardiovascular and neuropsychiatric risks of varenicline: a retrospective cohort study.Lancet Respir Med. 2015; 3: 761-768Summary Full Text Full Text PDF Scopus (78) Google Scholar will help to clarify the signals that have been emerging for several years now. In a real-world practice setting across England, they compared validated follow-up data from more than 51 000 users of varenicline with data from nearly 107 000 patients prescribed nicotine and more than 6500 patients prescribed bupropion. Hazard ratios (HRs) for conditions of concern were raised in neither the propensity-matched varenicline group nor bupropion groups. In fact, varenicline seemed to have a protective effect for many of the adverse events analysed (eg, self-harm [HR 0·56, 95% CI 0·46–0·68], heart failure [0·61, 0·45–0·83], and cerebral infarction [0·62, 0·52–0·73]), perhaps as a function of its unique pharmacological effect. In a nice example of epidemiological precision, Kotz and colleagues calculated the effect that an uncaptured confounder would need to have to negate the primary analysis result. The observed effect was so persistent that an unanticipated confounder would have to have both a very strong effect and an extremely biased distribution within the sample, making the likelihood that such a confounder might actually exist virtually nil. The investigators did miss an important opportunity to present a complete picture by omitting comparator groups of non-smokers and untreated smokers. Although the incidence of events did not seem to be adversely related to treatment with varenicline, the observed event rates for depression and ischaemic heart disease seemed to be higher than expected in a general population.10WHOAge-standardized DALYs per 100,000 by cause, and member state.www.who.int/entity/healthinfo/global_burden_disease/gbddeathdalycountryestimates2004.xlsDate: 2004Google Scholar Reframing these observations, however, confirms what clinicians have known for decades: nicotine addiction represents a profound disturbance in brain biology, manifesting as a compulsive disorder with a wide array of predictable consequences. In other words, ischaemic events, depression, and other neuropsychiatric effects might be a function of tobacco dependence and recovery, rather than an effect of the drug choices made during treatment. Treating tobacco dependence involves a series of personal and professional calculations, sometimes messy and coloured by intense emotions. Against this backdrop, the implications of Kotz and colleagues' study go beyond its obvious points regarding varenicline side-effects. To understand the true relevance of this work requires placing it within historical context, and asking some difficult questions about our own risk-aversive nature. For the past decade, clinicians have been faced with opposing signals from the field. Are adverse events a function of the treatment or the disease? Exactly how safe does a safe medication need to be when weighed against the burden of illness caused by tobacco dependence? Should reliance on anecdotal case reports be allowed when making treatment decisions? How big do observational studies need to be before the guidance they provide can be trusted? Would the answers to these questions be different if the questions weren't about smoking? By providing precise risk estimates associated with the treatment options, Kotz and colleagues' study should allow us to move on comfortably, and begin to examine the nature of our internal calculus of risk with respect to what remains as the single greatest cause of premature death and disability around the world. RS has served as a consultant to GlaxoSmithKline and has received free medication (varenicline) and placebo from Pfizer for research purposes. FTL declares no competing interests. Cardiovascular and neuropsychiatric risks of varenicline: a retrospective cohort studyVarenicline does not seem to be associated with an increased risk of documented cardiovascular events, depression, or self-harm when compared with NRT. Adverse events that do not come to attention of general practitioners cannot be excluded. These findings suggest an opportunity for physicians to prescribe varenicline more broadly, even for patients with comorbidities, thereby helping more smokers to quit successfully than do at present. Full-Text PDF Open Access