SYNTAX Analysis Disputes ‘Smoker’s Paradox’

Smoking worsens the long-term prognosis of patients with complex CAD who have undergone revascularization, particularly regarding the risk of recurrent MI. The findings, published in the March 24, 2015, issue of the Journal of the American College of Cardiology, come from an analysis of the SYNTAX trial that took into account not only smoking status at baseline but also shifting habits over time. Take Home: SYNTAX Analysis Disputes ‘Smoker’s Paradox’

A few past studies have suggested a phenomenon known as the “smoker’s paradox,” which refers to the observed association between smoking and better short-term outcomes for patients with cardiovascular disease. Some pharmacodynamics studies, such as the PARADOX trial, have found that smoking enhances the antiplatelet effect of clopidogrel.

For the current analysis, a team led by Patrick W. Serruys, MD, PhD, of Erasmus Medical Center (Rotterdam, the Netherlands), reviewed details on smoking history collected from 1,793 (99.6%) of the 1,800 SYNTAX patients at baseline; 6 months; and 1, 3, and 5 years.

Despite having extensive CAD that required intervention, 20.2% of patients reported smoking at baseline. That proportion decreased to 8.6% at 6 months and 8.7% at 1 year. After 1 year, however, some patients restarted smoking, particularly in the CABG arm. By 5 years, 10.8% of the CABG group and 8.7% of the PCI group said they were smokers.

Overall, 17.9% of patients had a change in smoking status over 5-year follow-up.

Baseline smoking status was associated with higher 5-year risk of recurrent MI but was not related to risks of MACCE (death, MI, stroke, or TVR) or the composite of death, MI, or stroke (primary endpoint).

Considering smoking status as a time-dependent variable, however, produced different results. Using this approach, smoking was associated with greater risk of both MACCE and the primary endpoint. The predominant effect of smoking was on recurrent MI, with neither death nor TVR being significantly increased at 5 years in smokers (table 1).

 Table 1. Five-Year Outcomes: Smoking vs Nonsmoking as a Time-Dependent Variable

On multivariable analysis with smoking as a time-dependent covariate, smoking independently predicted MACCE (adjusted HR 1.35; 95% CI 1.05-1.74) and death, MI, or stroke (adjusted HR 1.80; 95% CI 1.27-2.54).

The smoker’s paradox “does not exist for patients undergoing coronary revascularization,” the investigators conclude.

Importance of Cessation Efforts

“Abstinence from smoking may improve the outcomes achieved with coronary revascularization, and all patients undergoing PCI or CABG should be encouraged to stop smoking indefinitely before revascularization,” Dr. Serruys and colleagues advise.

That the number of smokers was halved between baseline and 6 months suggests that “most of the patients took the smoking cessation advice at the time of revascularization seriously,” they say. “The time of revascularization, therefore, presents a good opportunity to reinforce smoking cessation advice and to offer practical help.”

In an editorial accompanying the paper, Ajay J. Kirtane, MD, SM, and Christopher R. Kelly, MD, both of Columbia University Medical Center (New York, NY), point out that the findings that more than a quarter of patients in the trial who reported quitting at 6 months had resumed smoking by 5 years “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.”

The editorialists also delve into the “smoker’s paradox” observed in the short term and whether the phenomenon represents confounding or something more.

“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,” they write. “Nonetheless, the smoker’s paradox raises interesting pathophysiological 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?”

Concerns Remain About Smoking, Clopidogrel

According PARADOX investigator Paul A. Gurbel, MD, of Sinai Hospital of Baltimore (Baltimore, MD), “There is no question that there is a pharmacodynamic interaction of smoking with clopidogrel metabolism. Smoking enhances active metabolite generation and the resultant [pharmacodynamic] effect.”

In addition to the findings of PARADOX, he told TCTMD in an email, “All of the major clinical trials of clopidogrel, which were much larger than SYNTAX, clearly demonstrated that the treatment effect of [the drug] was largely, if not solely, driven by the response in smokers.”

Dr. Gurbel pointed out that the SYNTAX analysis does not provide information about clopidogrel use or its treatment effect.

“Smoking is bad for your health. If you smoke, you should stop,” he emphasized. “However, this study does not clear the air about or address the controversy surrounding a potential treatment benefit of P2Y12 blockers in smokers versus nonsmokers. Stopping smoking in the presence of clopidogrel therapy may lead to less platelet inhibition due to the effect of smoking on active metabolite generation.”

Dr. Gurbel said that ongoing studies are assessing what happens to clopidogrel’s pharmacodynamic effect when patients stop smoking.

 


Sources:
1. Zhang Y-J, Iqbal J, van Klaveren D, et al. Smoking is associated with adverse clinical outcomes in patients undergoing revascularization with PCI or CABG: the SYNTAX trial at 5-year follow-up. J Am Coll Cardiol. 2015;65:1107-1115.
2. Kirtane AJ, Kelly CR. Clearing the air on the “smoker’s paradox” [editorial]. J Am Coll Cardiol. 2015:65:1116-1118. 

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Disclosures
  • Drs. Serruys and Kelly report no relevant conflicts of interests.
  • Dr. Kirtane reports receiving institutional research grants (to Columbia University) from Abbott Vascular, Abiomed, Boston Scientific, Eli Lilly, Medtronic CardioVascular, St. Jude Medical, and Vascular Dynamics.
  • Dr. Gurbel reports receiving grants from Bayer, CSL, Daiichi Sankyo, Haemonetics, New Haven Pharmaceuticals, the NIH, and Sinnowa as well as honoraria from AstraZeneca, Daiichi Sankyo, Haemonetics, Merck, and New Haven Pharmaceuticals.

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