Journal of the American College of Cardiology 2013 by the American College of Cardiology Foundation Published by Elsevier Inc.

Vol. 61, No. 5, 2013 ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2012.11.017

EDITORIAL COMMENT

Smoking Cessation After Acute Myocardial Infarction*

Neal L. Benowitz, MD, Judith J. Prochaska, PHD, MPH San Francisco and Stanford, California

Cigarette smoking produces endothelial dysfunction, constricts blood vessels, activates platelets, creates a chronic inammatory state, and causes dyslipidemia (1). These effects accelerate atherosclerosis, destabilize coronary artery plaques, and precipitate acute coronary events and sudden death. Smoking cessation substantially reduces the likelihood of recurrent myocardial infarction, stent or graft thrombosis, need for revascularization, and cardiovascular death. Smoking cessation is probably the most important thing a smoker with acute myocardial infarction can do to improve future health.
See page 524

Hospitalization for an acute cardiovascular event provides an important opportunity for quitting smoking. Smokers are often strongly motivated to quit because the risks of smoking are now personal. Furthermore, most hospitals are smoke-free, requiring smokers to stop smoking at least temporarily. The 2008 U.S. Clinical Practice Guidelines for Treating Tobacco Use and Dependence recommend counseling and medications to help all hospitalized tobacco users maintain abstinence and to treat withdrawal symptoms (2). However, smoking-cessation therapy in hospitalized patients offers a number of challenges. Many patients have used tobacco for many years and have continued to smoke despite having cardiovascular risk factors and being counseled to quit, indicating a high level of dependence. The duration of hospitalization for acute myocardial infarction is usually brief and the hospital stay is busy, so it is difcult to
*Editorials published in the Journal of the American College of Cardiology reect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Division of Clinical Pharmacology and Experimental Therapeutics, the Departments of Medicine and Bioengineering & Therapeutic Sciences, University of California, San Francisco, California; and the Department of Medicine, Stanford Prevention Research Center, Stanford University, Stanford, California. Dr. Benowitz is a paid consultant to pharmaceutical companies that market smoking-cessation medications, including Pzer, GlaxoSmithKline, and McNeil; and has served as a paid expert witness in litigation against tobacco companies. Dr. Prochaska is an ad hoc advisory board member, grant reviewer, and principal investigator on an investigatorinitiated research award with Pzer Inc.

gain the patients full attention for smoking-cessation counseling. Post-hospitalization, continuity of care for tobacco treatment, and patient adherence can be challenging, requiring coordination between inpatient and outpatient providers and facilities. A 2012 Cochrane review of 50 tobacco treatment trials for hospitalized patients found that intensive counseling, initiated during hospitalization with follow-up for at least 1 month after hospital discharge, signicantly increased quit rates (relative risk: 1.37; 95% CI: 1.27 to 1.48; 25 trials) (3). The Cochrane analysis did not nd a signicant benet for less intensive counseling. Adding nicotine replacement therapy to intensive counseling increased quitting compared with counseling alone (relative risk: 1.54; 95% CI: 1.34 to 1.79; 6 trials). Neither bupropion nor varenicline increased quit rates compared with counseling alone, although the number of trials was small (3 and 2, respectively), so statistical power was limited. Some clinicians are hesitant to add a smoking-cessation medication on top of a number of other medications that have been initiated or continued in the context of myocardial infarction and other medical conditions. In the trial by Eisenberg et al. (4) in this issue of the Journal, for example, a majority of the sample was prescribed 6 different heartrelated medications at hospital discharge. Clinicians also may be concerned about the safety of smoking-cessation medications in patients with heart disease. Nicotine medications increase heart rate, blood pressure, and myocardial contractility and have the potential to cause endothelial dysfunction and coronary vasoconstriction (1). Bupropion also has sympathomimetic activity and in higher doses can increase heart rate and blood pressure. Varenicline is a relatively selective nicotinic receptor agonist. It acts on the 42 nicotinic cholinergic receptor, which is thought to be most important in addiction, and has a lower afnity for the 34 receptor, which mediates cardiovascular effects. There is little evidence in animal or human experimental studies that varenicline has cardiovascular effects. However, a number of cases of cardiovascular events, such as myocardial infarction, arrhythmia, and syncope, in people taking varenicline have been reported to regulatory authorities. One meta-analysis of cardiovascular serious adverse events found a small but significant increase with varenicline versus placebo (5), whereas a subsequent larger meta-analysis found no signicantly increased risk (6). The study by Eisenberg et al. (4) is the rst published trial of pharmacotherapy for smoking cessation in a population composed entirely of patients hospitalized with acute myocardial infarction. This was a multicenter trial involving 392 smokers, two thirds from Canada and the remainder from Iran and India. Subjects received bupropion in standard doses or placebo, along with modest behavioral counseling. The 7-day point prevalence smoking-cessation rates at 1 year were 37.2% for bupropion versus 32% for placebo (p 0.33). The authors concluded that bupropion is ineffective for smoking cessation in patients after myocardial infarc-

Downloaded From: http://content.onlinejacc.org/ on 04/03/2013

534

Benowitz and Prochaska Smoking Cessation After AMI

JACC Vol. 61, No. 5, 2013 February 5, 2013:5335

tion. There were also no signicant differences in cessation rates when assessed at 3 or 6 months. The authors did nd that among persistent smokers cigarette consumption decreased substantially in both treatment groups, with a decrease on average from 22.8 to 8.4 cigarettes per day. The authors observed few cardiovascular events during the trial with no difference by condition. The ndings of the study by Eisenberg et al. (4) are similar to those of the 2 other published studies of smokers hospitalized for acute cardiovascular disease (CVD) treated with bupropion (7,8), both of which reported fairly high quit rates in the placebo group (21% and 33% at 1 year), with no signicant difference by condition. Small samples are common across these trials, and the trial by Eisenberg and colleagues (4) also is limited with regard to power. Eisenberg and colleagues trial achieved 20% of its registered recruitment goal, so it likely was underpowered for the intended evaluation of efcacy and certainly underpowered for safety. Had the reported cessation rates been observed with the intended sample size of N 1,500, the treatment differences would have been signicant at p 0.05 at all time points. From a public health perspective, a difference in quit rates of 5% at 1 year is meaningful in a patient population at high risk for future cardiovascular events associated with continued tobacco use. The ndings of the trial by Eisenberg et al. (4) and other studies in hospitalized patients are in contrast to the results of studies of bupropion and varenicline in outpatients with stable CVD. Tonstad et al. (9) studied 629 patients with stable CVD treated with bupropion for 7 weeks versus placebo and found signicantly higher quit rates with bupropion (point prevalence abstinence 27% vs. 11%, continuous abstinence 22% vs. 9%, p 0.001 at 1 year). Rigotti et al. (10) treated 714 smokers with stable CVD with varenicline or placebo for 12 weeks and found signicantly higher quit rates with varenicline (7-day point prevalence abstinence 28% vs. 16%; continuous abstinence of 19% vs. 7% at 1 year, both p 0.001). When comparing abstinence rates, why is it that the absolute differences in quit rates between bupropion (and perhaps varenicline) and placebo seem to be less in patients hospitalized with acute CVD compared with outpatients with stable CVD? Several factors may be involved. First, as Eisenberg et al. (4) acknowledged, having approximately one third of patients taking placebo quit smoking at 1 year is fairly high compared with many other trials, suggesting that patients who entered this trial were highly motivated to quit, and per study inclusion criteria, patients had to want to quit smoking to be enrolled. The nding that those who continued to smoke markedly reduced their cigarette consumption is also suggestive of high motivation to reduce health risks. It also may be that patients who experience a life-threatening event such as a myocardial infarction, are hospitalized, and are given a study medication are particularly susceptible to placebo effects. On the other hand, the observation that two thirds of the sample continued to smoke after a myocardial infarction is discouraging. It may
Downloaded From: http://content.onlinejacc.org/ on 04/03/2013

be that the acute nature of the hospitalization was insufcient for maximizing the utility of bupropion (i.e., patients were discharged before reaching therapeutic blood levels) and cessation counseling. The patient population is varied, with two thirds treated in Canada and one third treated in Iran or India. We know relatively little about smoking cessation in Iran and India, although the authors report that the results of the trial were not different when controlling for country site. Given the current studys ndings and the extant literature, what then is the role of cessation pharmacotherapy in hospitalized smokers? On the basis of the Cochrane 2012 review, there is evidence of benet from nicotine replacement therapy, but limited evidence to support the routine prescription of bupropion or varenicline for smoking cessation in hospitalized smokers. An issue separate from pharmacotherapys impact on long-term smoking cessation is the use of nicotine medication in the hospital setting to relieve withdrawal symptoms. Such treatment can reduce discomfort and enhance compliance with medical treatments and hospital-wide smoking bans. Further, and in need of greater study, it may be that individualizing pharmacotherapy according to patient preference and side effects will enhance long-term cessation. Given the signicant health consequences of smoking after myocardial infarction, we suggest a minimal goal of achieving 50% of smokers quitting at long-term follow-up. Our recommendations, based on available data and The Joint Commissions current recommended hospital-wide standards, are as follows: 1. Effective counseling in the hospital for all smokers, and not just the minority who are ready to quit. Hospitalbased cessation treatment needs to be proactive, tailored to readiness to quit, progressive in use of nicotine replacement for the management of withdrawal symptoms, and focused on gaining buy-in and building rapport for continued treatment and patient adherence post-hospitalization. 2. Effective transition from inpatient to outpatient smokingcessation treatment, with a minimum of 1-month follow-up and preferably longer. 3. Personalized prescription of medication, intended to relieve withdrawal symptoms in all patients and to support long-term cessation in patients motivated to quit. 4. Management of co-occurring mental health conditions, such as depression, that are known to be triggers to smoking relapse and predictive of mortality after cardiovascular events. A prospective observational study found that a majority of patients relapsed to smoking within 6 months after hospitalization for myocardial infarction (11). Patients treated at a hospital without a smoking-cessation program (odds ratio [OR]: 1.71) who were not referred for cardiac rehabilitation (OR: 1.80) and had greater depressive symptoms during hospitalization (OR: 1.75) were more likely to relapse to

JACC Vol. 61, No. 5, 2013 February 5, 2013:5335

Benowitz and Prochaska Smoking Cessation After AMI

535

tobacco. Treatments need to consider the holistic needs of patients presenting with heart disease, including smoking status, mental health, and other associated risk behaviors (sedentary, alcohol use). Beyond short-term, acute-care measures, we support smoking-cessation treatment consistent with a chronic disease model, similar to management of other diseases, such as hypertension and diabetes. In this type of approach, all patients are counseled with the expectation that sooner or later they will quit smoking as an essential element of their health care (12). Pharmacotherapy is prescribed in an individualized and exible way to initiate and sustain abstinence, with medications combined and/or doses adjusted to relieve withdrawal symptoms and minimize urges to smoke. Relapse to smoking is anticipated, and patients are counseled about both relapse prevention and re-engagement in the quitting process after relapse. The observation that cigarette consumption was substantially reduced in the trial by Eisenberg et al. (4) suggests that these smokers remained concerned about smoking as a health risk and may have lowered their level of tobacco dependence, making them more amenable to later smoking cessation within a chronic disease management program. A continuing care model for smoking-cessation intervention for patients hospitalized with CVD has been described in Canada, named the Ottawa Model (13). The Ottawa Model intervention begins with customized counseling and pharmacotherapy for all smokers while in the hospital. Post-hospitalization follow-up is done using an interactive voice-responsive telephone system, with automated phone calls at frequent intervals for up to 180 days after discharge. Relapse counseling is provided as needed. Counselors are available to respond to particular patient needs. This approach is reported to result in 29% continuous abstinence at 6 months across institutions and as high as 44% at one institution. In conclusion, the standard of care for managing patients after myocardial infarction should include not only blood pressure and lipid management but also smoking cessation. At present, the quit rates for smokers after myocardial infarction are higher than those for the general population of smokers, yet given the enormous health risks, still much too low. Increasing quit rates will likely require a combination of counseling and personalized medications, with a chronic disease management approach. Future studies of

smoking cessation in hospitalized patients should be conducted to test the effectiveness of such multicomponent interventions.
Reprint requests and correspondence: Dr. Neal L. Benowitz, Division of Clinical Pharmacology and Experimental Therapeutics, University of CaliforniaSan Francisco, Box 1220, San Francisco, California 94143-1220. E-mail: NBenowitz@MedSFGH.ucsf.edu
REFERENCES

1. Department of Health and Human Services PHS. How Tobacco Causes Disease: The Biology and Behavioral Basis for SmokingAttributable Disease. A Report of the Surgeon General. DHHS (CDC). Washington, DC: US Government Printing Ofce, 2010. 2. Tobacco Use and Dependence Guideline Panel. Treating tobacco use and dependence: 2008 update. In: Services; RMUDoHaH, editor. Available at: http://www.ahrq.gov/clinic/tobacco/treating_tobacco_ use08.pdf. Accessed December 14, 2012. 3. Rigotti NA, Clair C, Munafo MR, Stead LF. Interventions for smoking cessation in hospitalised patients. Cochrane Database Syst Rev 2012;5:CD001837. 4. Eisenberg MJ, Grandi SM, Gervais A, et al. Bupropion for smoking cessation in patients hospitalized with acute myocardial infarction: a randomized, placebo-controlled trial. J Am Coll Cardiol 2013;61: 524 32. 5. Singh S, Loke YK, Spangler JG, Furberg CD. Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis. CMAJ 2011;183:1359 66. 6. Prochaska JJ, Hilton JF. Risk of cardiovascular serious adverse events associated with varenicline use for tobacco cessation: systematic review and meta-analysis. BMJ 2012;344:e2856. 7. Rigotti NA, Thorndike AN, Regan S, et al. Bupropion for smokers hospitalized with acute cardiovascular disease. Am J Med 2006;119: 1080 7. 8. Planer D, Lev I, Elitzur Y, et al. Bupropion for smoking cessation in patients with acute coronary syndrome. Arch Intern Med 2011;171: 1055 60. 9. Tonstad S, Farsang C, Klaene G, et al. Bupropion SR for smoking cessation in smokers with cardiovascular disease: a multicentre, randomised study. Eur Heart J 2003;24:946 55. 10. Rigotti NA, Pipe AL, Benowitz NL, Arteaga C, Garza D, Tonstad S. Efcacy and safety of varenicline for smoking cessation in patients with cardiovascular disease: a randomized trial. Circulation 2010;121: 2219. 11. Dawood N, Vaccarino V, Reid KJ, Spertus JA, Hamid N, Parashar S. Predictors of smoking cessation after a myocardial infarction: the role of institutional smoking cessation programs in improving success. Arch Intern Med 2008;168:19617. 12. Joseph AM, Fu SS, Lindgren B, et al. Chronic disease management for tobacco dependence: a randomized, controlled trial. Arch Intern Med 2011;171:1894 900. 13. Reid RD, Mullen KA, Slovinec DAngelo ME, et al. Smoking cessation for hospitalized smokers: an evaluation of the Ottawa Model. Nicotine Tob Res 2010;12:11 8. Key Words: acute myocardial infarction y bupropion y randomized controlled trial y smoking cessation.

Downloaded From: http://content.onlinejacc.org/ on 04/03/2013