Author + information
- Ajay J. Kirtane, MD, SM∗ ( and )
- Christopher R. Kelly, MD
- Herbert and Sandi Feinberg Interventional Cardiology and Heart Valve Center at Columbia University Medical Center/New York-Presbyterian Hospital, and the Cardiovascular Research Foundation, New York, New York
- ↵∗Reprint requests and correspondence:
Dr. Ajay J. Kirtane, Columbia University Medical Center, Center for Interventional Vascular Therapy, 161 Fort Washington Avenue, Herbert Irving Pavilion, 6th Floor, New York, New York 10032.
Among behavioral risk factors for adverse health outcomes, smoking stands alone in its public health impact, accounting for nearly 500,000 (or 1 in 5) deaths in the United States annually (1). In the aftermath of many well-chronicled legal battles with the tobacco industry, the causality between smoking and adverse cardiovascular events became unquestionable, and smoking cessation is a major goal of guideline-directed medical therapy for both primary and secondary prevention of coronary heart disease.
Nonetheless, it is important to recognize a curious phenomenon published within the cardiovascular literature known as the “smoker’s paradox”: an intermittently observed association between smoking status and improved short-term outcomes in various cardiovascular disease states. The smoker’s paradox was first noted in early studies on the natural history of acute myocardial infarction (MI) (2) and later confirmed in studies of fibrinolysis, such as GUSTO-I (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) (3). More recent data suggest a similar phenomenon among patients with acute stroke (4) or cardiac arrest (5).
The smoker’s paradox often is used to illustrate the differences between association and causality in clinical epidemiology. For example, compared with nonsmokers, smokers presenting with acute MI are consistently younger and have fewer atherosclerotic risk factors and other comorbid conditions, such as diabetes and hypertension. Thus, some of the crude (unadjusted) association between smoking and improved outcomes is clearly attributable to confounding; when multivariable analyses account for known confounders, the apparent benefit of smoking is uniformly attenuated. Some observational studies, however, have found a residual survival advantage among smokers, even after multivariable adjustment. In GUSTO-I, for example, the odds of 30-day mortality were 25% lower among smokers even after adjusting for age, sex, blood pressure, time to therapy, and other covariates (3). A similar phenomenon associating smoking with improved in-hospital mortality was noted among nearly 300,000 patients in the National Registry of Myocardial Infarction database (6).
Of course, the marked increase in long-term mortality attributable to smoking would completely negate any modest improvement in short-term outcomes; smokers lose, on average, a full decade of life (7). Nonetheless, the smoker’s paradox raises interesting pathophysiologic questions: First, does it point to a mechanism by which smokers accrue some short-term benefit? Second, would such a mechanism be relevant in the era of modern-day antithrombotic therapies?
Regarding the first question, several studies have demonstrated that fibrinolytic therapy yields better epicardial vessel patency (8) and myocardial perfusion (9) among smokers compared with nonsmokers. Therefore, smoking may result in either coronary occlusion that is richer in clot and more amenable to fibrinolysis or, in some other way, enhance responsiveness to these medications. This mechanism is less relevant in the era of primary percutaneous coronary intervention (PCI) as the dominant reperfusion therapy for acute MI (10). However, recent data have demonstrated a specific pharmacodynamic enhancement of platelet inhibition by clopidogrel among smokers (11), which may hold important implications for patients treated with PCI, given that clopidogrel remains the dominant P2Y12 inhibitor in clinical practice.
In this issue of the Journal, Zhang et al. (12) examined smoking status and outcomes among the 1,800 patients in the SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) trial, which randomized patients with severe coronary artery disease (CAD) to PCI with paclitaxel-eluting stents or coronary artery bypass grafting (CABG). The authors found no effect of baseline smoking status on 5-year rates of death/MI/stroke in unadjusted analyses, suggesting that, at best, smokers had the same risk as nonsmokers, who were a decade older and more likely to have diabetes and hypertension. Unlike in prior studies, however, these investigators reported smoking status not only at baseline but also at 6 months and 1, 3, and 5 years. The dynamic nature of smoking status in this population of patients with complex multivessel CAD is alone noteworthy. At presentation, 20.2% of patients actively smoked. Over 5 years, most of these smokers quit, usually prior to 6-month follow-up, yet of those who reported cessation at 6 months, >25% resumed smoking during 5-year follow-up. These findings are sobering and emphasize that our efforts at smoking cessation for our patients with the most severe CAD need to be continuous, not myopically targeted only to the time of initial revascularization.
Because smoking cessation markedly attenuates mortality risk (7), especially among younger patients, the failure of earlier studies to include subsequent assessments of smoking status may have contributed to the apparent survival benefit among baseline smokers, who may have quit smoking after the index event and were younger and otherwise healthier than baseline nonsmokers. Indeed, when smoking was considered as a time-varying covariate in SYNTAX (allowing for smokers who quit to be analyzed as nonsmokers during the interval in which they quit), smoking was associated with a higher rate of death/MI/stroke at 5 years, an effect driven by an 86% greater hazard of MI. After adjusting for other baseline covariates, the association between smoking and death/MI/stroke became stronger and was evident as early as 6 months. Notably, the increased incidence of MI was present both among CABG- and PCI-treated patients, with no protective effect of smoking on stent thrombosis in this clopidogrel-treated patient population.
Importantly, the SYNTAX trial examined a population of patients with predominantly stable CAD. Therefore, these findings cannot be compared directly to the acute MI studies that first described the smoker’s paradox. Additionally, because smokers requiring revascularization typically have less extensive disease than nonsmokers (13), the smokers with multivessel disease included in the SYNTAX trial likely had worse outcomes than smokers in other trials. Nonetheless, this analysis provides compelling evidence that for patients undergoing coronary revascularization, continuing to smoke markedly increases the risk of subsequent adverse outcomes, especially MI.
In this SYNTAX cohort, smoking was more hazardous than a 10-year increase in age and had an adjusted hazard exceeding that of the primary study comparison (of PCI vs. CABG). These 2 observations are vitally important from a public health perspective. As scientists, we often focus on the relative merits of medical and device-based therapies, yet from a global perspective, the realized effects of these marginal differences is likely far less than what could be achieved through successful interventions that reduce the rate of smoking. It is encouraging in this regard that cigarette smoking among adults in the United States is lower than ever, with a decline from 20.9% in 2005 to 17.8% in 2013 (14), but we clearly have a long way to go. As clinicians treating individual patients, it is critical for us to put these data in perspective, continuing to focus assiduously on smoking cessation with all patients, and remembering that relapses are common, even in high-risk patients who have undergone multivessel coronary revascularization.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Kirtane has received institutional research grants (to Columbia University) from Medtronic Cardiovascular, Boston Scientific, Abiomed, Abbott Vascular, Vascular Dynamics, St. Jude Medical, and Eli Lilly. Dr. Kelly has reported that he has no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- ↵U.S. Health and Human Services. The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, CDC. Available at: http://www.surgeongeneral.gov/library/reports/50-years-of-progress/. Accessed November 2, 2014.
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