Smoker’s Paradox Debunked: Post-STEMI Outcomes Worse in Cigarette Smokers

New findings throw cold water on the so-called smoker’s paradox, the counterintuitive concept that smokers somehow fare better than nonsmokers after an acute myocardial infarction.  

In an analysis of 2,564 patients undergoing primary PCI for STEMI, smokers did have a lower unadjusted risk of all-cause mortality at 1 year, as well as a lower rate of death or hospitalization for heart failure (HF). However, smokers presenting to the hospital were 10 years younger than nonsmokers, and after adjusting for age and other risk factors, the rate of death/hospitalization for HF and the rate of recurrent MI was significantly higher among smokers. Additionally, the difference in mortality was not observed in the adjusted analysis.     

“We not only explained away the paradox, but we showed that smoking confers a worse prognosis in terms of death or heart failure hospitalization and reinfarction,” senior investigator Gregg Stone, MD (Icahn School of Medicine at Mount Sinai, New York, NY), told TCTMD. “Not only are patients 10 years younger, but their age and comorbidity-adjusted outcomes are worse than people who don’t smoke. Smoking is a really bad risk factor obviously, not only for the development of atherosclerosis and acute coronary syndrome, but it’s also associated with worse prognosis once you develop an acute coronary syndrome.”

Serena Tonstad, MD, PhD (Oslo University Hospital, Norway), a preventive cardiologist who has studied the smoker’s paradox previously, said the concept should now be discarded to the history bin given the size of the present study and quality of data.

“I think the idea should be completely buried,” she told TCTMD. While the counterintuitive finding that smokers fare better than nonsmokers after an MI has been puzzling given the known adverse cardiovascular effects of smoking, physicians and public health officials need to work as hard as ever to make sure people stop smoking. Debunking the smoker’s paradox is a step in the right direction, she said.

Kishore Harjai, MD (Geisinger Commonwealth School of Medicine, Wilkes-Barre, PA), another cardiologist who has looked into the phenomenon, said the present study “lays to rest any lingering suspicion of a smoker’s paradox [and] shows strong evidence that smoking worsens outcomes after STEMI, as most cardiologists have intuitively suspected.” He told TCTMD that, hopefully, the smoker’s paradox will be relegated to an urban myth, stressing: “The resounding message is that if you smoke, you will have your heart attack earlier in life and suffer worse consequences, especially heart failure and recurrent heart attacks.”

Paradox Not Completely Understood

Although smoking is the leading cause of preventable death—responsible for nearly half a million deaths in the United States alone, according to the Centers for Disease Control and Prevention—there have been multiple studies reporting that smokers have a better prognosis than nonsmokers after STEMI. Several potential mechanisms have been put forward, including the possibility that smoking may reduce infarct size as a result of ischemic preconditioning. Another possibility had been that smoking promoted the metabolism of clopidogrel into its active form, which would increase its efficacy and improve outcomes. 

The smoker’s paradox is controversial, however, with other studies, including the 5-year results of the SYNTAX trial comparing PCI versus CABG surgery, showing that smokers had worse clinical outcomes due to a higher incidence of recurrent MI in both intervention arms.

“The fact that smokers as a class always have had lower mortality than nonsmokers with ST-segment elevation MI has been widely accepted,” said Stone. While some studies adjusting for risk factors and age have tended to explain away the lower event rates in smokers, this hasn’t been the case in all analyses, he said. “It’s a paradox that is well accepted as being real and not being completely understood,” continued Stone.

The new study, published April 13, 2020, in the Journal of the American College of Cardiology, New York, NY), is a patient-level analysis of 10 randomized studies that looked at primary PCI for STEMI. Of the patients included in the analysis, 42.6% were smokers, the definition of which varied by trial and ranged from current smoking to smoking within 3 months of symptom onset. The mean age of smokers presenting with STEMI for primary PCI was 55.0 years, which was nearly a full decade younger than the nonsmokers (mean age 64.6 years). Smokers also had significantly lower rates of diabetes, hypertension, hyperlipidemia, and prior MI than nonsmokers.

In the adjusted and unadjusted analyses, infarct size assessed a median of 4 days after PCI and LVEF were similar between the smokers and nonsmokers. Additionally, microvascular obstruction, expressed as a percentage of LV mass, was similar between the two groups. Restoration of TIMI 3 flow was more common in smokers than nonsmokers, however.

[This paradox can be] relegated to the historical museum of observed oddities that we don’t have a good explanation for. Gregg Stone

At 1 year, the unadjusted rate of all-cause mortality was 2.9% in nonsmokers and 1.0% in smokers (P < 0.001), while the unadjusted rate of death or HF hospitalization was 5.1% and 3.3%, respectively (P = 0.009). After adjusting for age and other risk factors, however, there was no significant difference in the risk of death between smokers and nonsmokers (HR 0.92; 95% CI 0.46-1.84), but smokers had a significantly higher risk of death or HF hospitalization (HR 1.49; 95% CI 1.09-2.02) and a higher risk of reinfarction (HR 1.97; 95% CI 1.17-3.33).

Like Tonstad and Harjai, Stone said he believes the smoker’s paradox can now be “relegated to the historical museum of observed oddities that we don’t have a good explanation for.” There is absolutely no benefit to smoking, he stressed. While the smoker’s paradox has been debated and discussed for many years, Tonstad said it doesn’t have any real clinical implications because all physicians think smokers need to quit, even if there was suspect evidence they seemed to survive a heart attack better.

Nonetheless, Tonstad said the findings are good news and one of the work’s major strengths is the collaboration across 10 randomized trials. “It also shows the investigators were interested in this idea even though their studies were not directly designed to look at this question,” she said. “It’s really good data, and I was pleased to see the result.” Like the investigators, she said age is the powerful factor responsible for the differential findings in the unadjusted analysis.

Paradox Within a Paradox

In an editorial, Harvey White, MBChB, DSc (Green Lane Cardiovascular Services/Auckland City Hospital, New Zealand), suggests that the higher rates of TIMI 3 flow in the smokers is likely related to having thrombotic, rather than atherogenic, lesions resulting from the effects of smoking on platelets and endothelial function.

“The improvement in epicardial TIMI flow grade 3 in smokers compared with nonsmokers surprisingly did not translate into improved microcirculatory perfusion, reduced infarct size, reduced microvascular obstruction, or improved prognosis; this remains a paradox opposite to the previous smoker’s paradox,” he writes.

Stone said the difference in TIMI 3 flow after PCI was statistically significant, but pointed out the difference between smokers and nonsmokers was relatively small and unlikely to be clinically relevant. Like White, Stone said the difference might be related to the type of lesion, with smokers having more thrombotic lesions and less lipid-rich, atherosclerotic plaque. Other factors aside from TIMI 3 flow can affect infarct size, he noted.

White says the current study exposes some of the biases, flaws, and inconsistencies behind the smoker’s paradox. He also questions whether an observational study can truly debunk it, though, particularly since there are limitations to the analysis, such as the lack of data of on post-PCI smoking status and different definitions of current or recent smoking. Nonetheless, roughly 34 million US adults are still smoking, which is a “travesty,” he said, and these new data confirm the detrimental effects of smoking as evidenced by the fact smokers have MIs 10 years before nonsmokers.

Note: Stone and several co-authors of the paper are faculty or employees of the Cardiovascular Research Foundation, the publisher of TCTMD.