Debunking the ‘smoker’s paradox,’ once and for all

A pooled analysis of 18 randomized trials has allowed researchers to unravel the so-called “smoker’s paradox,” proving that lighting up is an important risk factor for adverse events after percutaneous coronary intervention (PCI).

The smoker’s paradox—a term coined more than 25 years ago after observational studies reported that atherosclerosis patients who smoked saw better short-term outcomes than non-smokers—has been a subject of debate for decades, Mayank Yadav, MD, and colleagues wrote in JACC: Cardiovascular Interventions Oct. 14. And as technology and practice have evolved over the years, a number of studies have upheld the idea of the paradox in the context of PCI.

“Although most of these studies were completed in the thrombolytic therapy and balloon angioplasty eras, and even though it has been three decades since the first description of this paradox, the reasons underlying this enigma remain unclear,” Yadav, of the Bronx Lebanon Hospital Center in New York, et al. wrote in the journal.

Yadav’s team pooled data from 18 prospective trials, including the RAVEL, E-SIRIUS, SIRIUS, C-SIRIUS, TAXUS IV and V, ENDEAVOR II to IV, SPIRIT II to IV, HORIZONS-AMI, COMPARE I and II, PLATINUM and TWENTE I and II trials, for a better picture of the smoker’s paradox in modern practice. Patients were stratified by smoking status at the time of their enrollment.

Among 24,354 patients with data about their smoking status, 27.6% were current smokers, the research team reported. Smokers were on average younger and less likely to present with concomitant diabetes, hypertension, hyperlipidemia or a history of MI, PCI or coronary artery bypass grafting. Angiographically, smokers had longer and more complex lesions and more occlusions but were less likely to exhibit moderate or severe calcification or tortuosity.

In a related editorial comment, Michael Joner, MD, and Salvator Cassese, MD, PhD, both of the Technical University of Munich, said many researchers have posited that the smoker’s paradox exists because smokers are, typically, younger at the time of their first CV event. Therefore, they exhibit fewer atherosclerotic risk factors and comorbidities than non-smokers and are more likely to see positive outcomes than their older, non-smoking counterparts.

Five years into follow-up, Yadav et al. reported smokers had significantly higher rates of MI (7.8% vs. 5.6% in non-smokers) and definite or probable stent thrombosis (3.5% vs. 1.8% in non-smokers). However, there weren’t any noticeable differences in rates of death, cardiac death, target lesion revascularization or composite endpoints. Ultimately, after adjustment for potential confounders, smoking was linked to an 86% increased risk of death, 68% higher risk of cardiac death, 38% greater likelihood of MI, 60% greater risk of stent thrombosis and 17% increased risk of target lesion failure (TLF).

“Without any doubt, this study helps clarify the ‘smoker’s paradox’ in an era of primary PCI using cutting-edge drug-eluting stent technology with adjunct pharmacotherapy in an unprecedented way, outdating most prior analyses on this topic,” Joner and Cassese wrote. 

“The strength of the present analysis lies in the fact that, by means of individual patient data, it was possible to show that smoking was associated with increased adjusted risk for death and TLF. We therefore observe with relief that previous hesitation to overcome this paradox has been conquered, while future medical education should clearly focus on establishing effective preventive measures, including dedicated smoking cessation programs for patients with CVD to reduce this significant and clinically relevant risk factor.”

There are a couple of limitations to Yadav and colleagues’ study, though, the editorialists said, including the fact that smoking status was only assessed at baseline. The authors’ study population also comprised predominantly stable and less complex patients with reduced acuity—of the 18 trials included, 13 enrolled patients with angina but no acute MI, and just one enrolled patients with ST-segment elevation MI.

Still, Joner and Cassese applauded the team for their work and underlined the fact that any smoke exposure, including that from newer tobacco products, carries significant risk.

“In an era of high-technology treatment of MI, the findings of this study also serve to remind us of the central role of effective preventive measures for cardiovascular health,” they wrote.