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Smoking Cessation: The Urgent Need for Increased Utilization of Varenicline

Published:December 13, 2016DOI:https://doi.org/10.1016/j.amjmed.2016.11.015
      In the US, cigarette smoking causes 480,000 premature deaths annually, due mainly to a twofold increased risk of cardiovascular disease and a 20-fold increased risk of lung cancer.

      US Department of Health and Human Services. The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health 17 (2014). Available at: http://www.surgeongeneral.gov/library/reports/50-years-of-progress/full-report.pdf. Accessed November 16, 2016.

      Public health efforts and effective cessation treatments–including behavioral counseling and medications–have decreased US rates to approximately 14%; they are markedly increasing in most developing countries.

      Centers for Disease Control and Prevention. Current cigarette smoking among adults—United States, 2005-2014. MMWR Morb Mortal Wkly Rep. 2015;64(44):1233-1240. Available at: http://www.cdc.gov/tobacco/campaign/tips/resources/data/cigarette-smoking-in-united-states.html. Accessed December 7, 2015.

      Smoking and the emerging pandemic of obesity are the leading avoidable cause of premature deaths in most developed countries and rapidly becoming so in developing countries. Smoking and obesity are the major contributors to the worldwide increase in mortality from cardiovascular disease from #5 to #1.
      • Hennekens C.H.
      • Andreotti F.
      Leading avoidable cause of premature deaths worldwide: case for obesity.
      In people with serious mental illnesses such as schizophrenia, smoking rates reach 75%. Smoking is the chief contributor to these individuals dying, on average, about 20 years earlier than the general population. Although the risk of suicide is about 10-fold higher in people with serious mental illnesses than the general population rate of 1%, the majority of premature deaths are due to cardiovascular disease because it is so much more common.
      • Hennekens C.H.
      • Hennekens A.
      • Hollar D.
      • Casey D.E.
      Schizophrenia and increased risk of cardiovascular disease.
      Smoking cessation significantly reduces risks of cardiovascular disease, beginning within a matter of months and reaching the nonsmoker within a few years, even among older adults. For lung and other cancers, however, reductions are not observable for several years after quitting, and by 10 years achieve death rates only midway between the continuing smoker and the nonsmoker. Thus, to reduce risks of cardiovascular disease, it is never too late to quit, but to reduce risks of cancer, it is never too early.
      • LaCroix A.Z.
      • Lang J.
      • Scherr P.
      • et al.
      Smoking and mortality among older men and women in three communities.
      In 2006, varenicline, a selective α4β2 nicotinic acetylcholine receptor partial agonist, was approved by the US Food and Drug Administration (FDA), producing long-term cessation rates of approximately 20%, significantly greater than the other approved smoking cessation aids such as bupropion or nicotine replacement therapy.
      • Gonzales D.
      • Rennard S.I.
      • Nides M.
      • et al.
      Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial.
      In 2009 the FDA issued a black box warning for varenicline, resulting in a 76% decrease in the number of prescriptions dispensed, from a peak of approximately 2 million in the fourth quarter of 2007 to approximately 531,000 in the first quarter of 2014.

      US Food and Drug Administration (FDA). FDA briefing document, joint meeting of the Psychopharmacologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee. Chantix and Serious Neuropsychiatric Adverse Events October 16, 2014. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM418705.pdf. Accessed November 16, 2016.

      The black box warning was based on reports to the Adverse Event Reporting System, useful to formulate, but not test, hypotheses. They included serious neuropsychiatric symptoms (NPSs) of aggression, depression, suicidal ideation, and agitation. Interestingly, those with psychiatric histories comprised about half of the cases of suicidal ideation and behavior change, those taking psychotropic drugs approximately 42%, and those with depression approximately 42%.

      US Food and Drug Administration (FDA). FDA briefing document, joint meeting of the Psychopharmacologic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee. Chantix and Serious Neuropsychiatric Adverse Events October 16, 2014. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM418705.pdf. Accessed November 16, 2016.

      Thus, plausible alternative explanations for these uncontrolled, and not unexpected, case reports include prior psychiatric conditions as well as psychiatric correlates of smoking cessation, which are independent of varenicline usage.

      US Food and Drug Administration (FDA). FDA Drug Safety Newsletter Vol. 2, No. 1, 2009. The smoking cessation aids varenicline (marketed as Chantix) and buproprion (marketed as zyban) and generics: suicidal ideation and behavior (n.d.). Available at: http://www.fda.gov/downloads/Drugs/DrugSafety/DrugSafetyNewsletter/UCM107318.pdf. Accessed November 16, 2016.

      The reliable detection of small-to-moderate risks and benefits of drug therapies requires cogent data from large-scale randomized trials designed a priori to test the hypothesis.
      • Hennekens C.H.
      • DeMets D.
      The need for large scale randomized evidence without undue emphasis on small trials, meta-analyses or subgroup analyses.
      Until recently, the totality of randomized evidence on varenicline safety was restricted to 8 small trials. Two included patients with psychiatric conditions such as schizophrenia and schizoaffective disorder or major depressive disorder, and only 5 used the validated Columbia-Suicide Severity Rating scale for assessing suicidal ideation and behavior. All showed no significant association between varenicline and NPSs. In a meta-analysis of 18 small randomized trials, there was no significant association between varenicline and serious NPSs.
      • Gibbons R.D.
      • Mann J.J.
      Varenicline, smoking cessation, and neuropsychiatric adverse events.
      In 2011, the FDA sponsored 2 analyses of existing data sets containing information on varenicline use, both focusing on psychiatric hospitalizations. One was derived from the Department of Veterans Affairs Center for Medication Safety and the other from the Department of Defense's US Army Medical Commands Pharmacovigilance Center. Although also useful to formulate, not test, hypotheses, both demonstrated no statistically significant association between varenicline and psychiatric hospitalizations.
      • Thomas K.H.
      • Martin R.M.
      • Knipe D.W.
      • Higgins J.P.T.
      • Gunnell D.
      Risk of neuropsychiatric adverse events associated with varenicline: systematic review and meta-analysis.
      At the request of the FDA and with their consultation, a large, 8000-subject, randomized, double-blind, triple-dummy, placebo-controlled, and active-controlled (nicotine patch; 21 mg per day with taper) trial of varenicline (1 mg twice a day) and bupropion (150 mg twice a day) was conducted for 12 weeks.
      • Anthenelli R.M.
      • Benowitz N.L.
      • West R.
      • et al.
      Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomized, placebo-controlled clinical trial.
      Participants were long-term smokers and included equal subgroups of those with and without psychiatric disorders. The primary safety endpoint was a composite of moderate and severe NPSs. The primary efficacy endpoint was biochemically confirmed continuous abstinence for 12 weeks.
      The relative risk, 95% confidence interval (CI), and P-value comparing varenicline to placebo for NPSs was 1.08 (95% CI, 0.77-1.47; P = .62). For the subgroup without psychiatric symptoms, the values were 0.55 (95% CI, 0.28-1.07; P = .08). Further, 13 (1.3%) of 990 participants reported moderate and severe NPSs in the varenicline group, 22 (2.2%) of 989 in the bupropion group, 25 (2.5%) of 1006 in the nicotine patch group, and 24 (2.4%) of 999 in the placebo group. In the subgroup with psychiatric disorders, the values were 1.32 (95% CI, 0.93-1.89; P = .12). Moderate and severe NPSs were reported in 67 (6.5%) of 1026 participants in the varenicline group, 68 (6.7%) of 1017 in the bupropion group, 53 (5.2%) of 1016 in the nicotine patch group, and 50 (4.9%) of 1015 in the placebo group. Varenicline-treated participants achieved significantly higher abstinence rates at 12 weeks than those on placebo (3.61; 95% CI, 3.07-4.24), nicotine patch (1.68; 95% CI, 1.46-1.93), and bupropion (1.75; 95% CI, 1.52-2.01). Overall, the most frequent adverse events by treatment group were nausea (varenicline, 25% [511 of 2016]), insomnia (bupropion, 12% [245 of 2006]), abnormal dreams (nicotine patch, 12% [251 of 2022]), and headache (placebo, 10% [199 of 2014]).
      • Anthenelli R.M.
      • Benowitz N.L.
      • West R.
      • et al.
      Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomized, placebo-controlled clinical trial.
      Thus, this large randomized trial of adequate size and duration showed no significant increases in serious NPSs attributable to varenicline or bupropion relative to nicotine patch or placebo. For efficacy, varenicline was more effective than placebo as well as bupropion and the nicotine patch, although bupropion and the nicotine patch were more effective than placebo.
      • Anthenelli R.M.
      • Benowitz N.L.
      • West R.
      • et al.
      Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomized, placebo-controlled clinical trial.
      With 35 million smokers attempting to quit in the US, 7 million would have succeeded with varenicline. Prescription rates fell by 76%; about 5.3 million did not use varenicline and failed to quit. Rates of cardiovascular disease of nonsmokers are achieved within 3 to 5 years after quitting. There are approximately 350,000 annual deaths from cardiovascular disease. Thus, we estimate that approximately 17,000 annual premature deaths would have been avoided if prescription rates of varenicline had not dropped by 76% following the black box warning.

      National Institute of Drug Abuse (NIDA). Is nicotine addictive? 24 July 2016. Available at: https://www.drugabuse.gov/publications/research-reports/tobacco/nicotine-addictive. Accessed November 16, 2016.

      In conclusion, the existing totality of evidence suggests an urgent need to increase utilization of varenicline among the general population, as well as those with serious mental illness, to achieve smoking cessation among those attempting to quit. The relevant considerations should include, but not be limited to, removal of the black box warning by FDA.

      Acknowledgment

      We are indebted to A. Eden Evins and Robert Anthonelli for their expert advice and help.

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