Smoking Worsens Outcomes in PAH, Especially for Men, in REVEAL Study

Disproportionate prevalence of smokers found among men with PAH in the US

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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Cigarette smoking in men newly diagnosed with pulmonary arterial hypertension (PAH) was associated with a faster time to in-patient hospitalization and death after diagnosis, according to an analysis of the REVEAL study in the U.S.

More men smoked than women, and ever-smoking status (someone who has been a cigarette smoker) was associated with worse lung function, reduced physical abilities, impaired kidney function, and older age at PAH diagnosis.

“This is the largest report of prevalence and associated outcomes of smoking in PAH patients in the United States,” the researchers noted.

The REVEAL analysis was published in The Journal of Heart and Lung Transplantation in the study “Smoking history and pulmonary arterial hypertension: demographics, onset, and outcomes.”

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Cigarette smoking increases risk of diseases that affect blood vessels

PAH is marked by high blood pressure, or hypertension, caused by the narrowing of the pulmonary arteries, the small blood vessels that transport blood through the lungs.

Cigarette smoking is a well-established risk factor for diseases affecting blood vessels, including those of the pulmonary arteries. However, studies examining the prevalence and associated outcomes of cigarette smoking in PAH are scarce and conflicting.

Recently, a European registry analysis suggested that worse outcomes in people with idiopathic PAH (without a known cause) were related to smoking history and a low DLCO — a measure of oxygen passing from the air sacs of the lungs into the blood.

To complement this work, researchers in the U.S. examined data from REVEAL (NCT00370214) — an observational study that included 3,515 adults with PAH in the U.S. who were followed for up to five years to assess early and long-term PAH management.

The team collected medical history, lung function tests, and other clinical data alongside smoking status, which was self-reported as either ever-smoked or never-smoked. Based on these data, REVEAL risk scores were calculated, with higher scores reflecting increased mortality risk.

Among 3,046 REVEAL participants, 1,427 (46.8%) were ever-smokers, which accounted for 49.8% of newly diagnosed and 45.8% of previously diagnosed patients. Compared to never-smokers, more ever-smokers were men (61.7%) than women, were older at diagnosis and REVEAL enrollment, and had a history of lung disease.

Overall, DLCO was similar between men and women. Across all patients, it was substantially lower in ever-smokers (newly and previously diagnosed) than in never-smokers.

This is the largest report of prevalence and associated outcomes of smoking in PAH patients in the United States

Smoking status linked to lower scores in lung function

The researchers assessed lung function using the FEV1:FVC ratio, where FEV1 reflects the amount of air forced from the lungs in one second, while FVC represents the total amount of air exhaled. According to this ratio, lung function at enrollment was significantly lower in men than women and in ever-smokers versus never-smokers. Similar results were found across newly versus previously diagnosed patients.

A significantly lower DLCO in newly diagnosed men who ever smoked was observed compared to newly diagnosed men who never smoked. Ever-smoking status was significantly associated with a reduced FEV1:FVC ratio in both men and women. In newly diagnosed ever-smokers, the FEV1:FVC ratio was lower in men than women.

Compared to never-smokers, ever-smokers walked a significantly shorter distance in six minutes (6MWD), had worse kidney function (estimated glomerular filtration rate, or eGFR), higher REVEAL scores (reflecting increased mortality risk), and lower mixed venous oxygen saturation, or the percentage of hemoglobin protein bound to oxygen within red blood cells. Higher REVEAL scores and lower eGFR were driven by newly diagnosed males.

At diagnosis and enrollment, both newly and previously diagnosed ever-smokers were older than never-smokers. REVEAL risk scores were higher in ever- versus never-smokers, which was driven by men. No differences were observed in 6MWD, eGFR, and REVEAL scores in female ever- versus never-smokers across all ages.

No differences between ever- and never-smokers were seen in medical history or PAH treatments.

The researchers found no link between clinical outcomes and cigarette pack-years — the number of packs smoked per day multiplied by the number of years smoked. Men ever-smokers had significantly higher exposure to smoke than women (mean 30.86 vs. 22.26 pack-years).

Adjusted calculations for risk and survival did not differ between ever- and never-smokers. However, mortality, the composite of time to lung transplant or death, as well as the time to first hospitalization, were worse in newly diagnosed ever-smokers versus never-smokers, driven mostly by men.

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In a secondary analysis that focused on idiopathic PAH patients with a low DLCO (less than 45%), at three years, there was worse survival, lower transplant-free survival, and earlier time to the first hospitalization in ever- versus never-smokers, also driven by men. The researchers noted that in this group, “the very small numbers of patients make these data difficult to interpret.”

“Further research is needed to elucidate the factors responsible for the negative association of smoking on outcomes in newly diagnosed male PAH patients,” the researchers wrote, and to investigate “the disproportionate prevalence of smoking in males diagnosed with PAH, and older age at diagnosis for ever- versus never-smokers in the REVEAL population.”

This study was sponsored by Actelion Pharmaceuticals, a Janssen Pharmaceutical Company of Johnson & Johnson, that markets PAH therapeutics.

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