Kate Johnson

November 09, 2014

ATLANTA — The risk for cardiovascular disease is higher in patients with severe asthma and chronic use of oral corticosteroids than in those with moderate asthma whose use of oral corticosteroids is periodic, new research shows.

"The more severe the asthma, the greater the cardiovascular risk," said Carlos Iribarren, MD, MPH, PhD, a research scientist from the Kaiser Permanente Medical Care Program in Oakland, California.

Findings from the study are "consistent with the literature suggesting a link between asthma and cardiovascular disease, but add important new evidence for a modifying effect of asthma severity," he told Medscape Medical News.

The researchers looked at patients from the Evaluating Clinical Effectiveness and Long-Term Safety in Patients With Moderate to Severe Asthma (EXCELS) study.

EXCELS was an industry-funded 5-year multicenter prospective observational cohort study of patients with moderate to severe persistent allergic asthma, in which 5007 patients were treated with omalizumab (Xolair, Genentech) and 2829 were not.

The more severe the asthma, the greater the cardiovascular risk.

A safety review of EXCELS earlier this year by the US Food and Drug Administration prompted a warning that omalizumab poses a slightly elevated but serious risk for heart attack and transient ischemic attack.

In their study, Dr Iribarren and his colleagues followed the EXCELS patients who were not treated with omalizumab for a mean of 3.5 years. Mean age was 46.2 years, and mean duration of asthma was 21 years.

Physician global assessment was used to classify the baseline asthma severity of each patient as moderate or severe. In addition, for each patient, the researchers examined prebronchodilator forced expiratory volume in 1 second (FEV₁), oral corticosteroid use, and severity-of-asthma score, which assessed asthma symptoms, asthma medication burden, and history of the use of emergency asthma medication.

"The severity-of-asthma score is a 13-item validated instrument predictive of death and asthma-related outcomes, but not previously used to specifically evaluate risk of cardiovascular outcomes," the researchers explain.

Scores range from 0 to 28, with higher scores indicating more severe asthma. Patients were divided into three categories of scores: 0 to 8, 9 to 12, and 13 or more.

Cardiovascular and cerebrovascular events were combined into a single end point, and defined as the first of the following events: cardiovascular death, myocardial infarction, ischemic stroke, transient ischemic attack, or unstable angina.

The researchers found that a higher asthma severity score was significantly associated with an increased risk for cardiovascular and cerebrovascular events after adjustment for tobacco history, education level, baseline body mass index, type 2 diabetes, hypertension, hypercholesterolemia, age, sex, race, and ethnicity.

For patients with a score of 9 to 12, compared with a score of 0 to 8, the hazard ratio (HR) was 2.4 (P = .02). For those with a score 13 or more, the HR was also 2.4 (= .03).

On adjusted analysis, the risk for a cardiovascular or cerebrovascular event was more than 2 times higher in patients whose use of oral corticosteroids was chronic rather than periodic (HR, 2.4; = .03).

"The interpretation of the finding is speculative at this point, and should stimulate further research to delineate the degree to which potential, not mutually exclusive, mechanisms play a role," said Dr Iribarren.

He described three of these mechanisms: "asthma itself, through inflammatory or allergic pathways; side effects of asthma medications, particularly systemic steroids; and comorbid conditions that are also associated with increased cardiovascular risk, including obesity, metabolic syndrome, diabetes, hypertension, and mood disorders such as depression and anxiety."

However, even after controlling for these comorbidities, an association between asthma severity and longitudinal cardiovascular and cerebrovascular events was observed, "suggesting potentially more direct causal pathways."

The findings provide "robust evidence" linking asthma severity with cardiovascular and cerebrovascular outcomes, although further work is needed to understand the connection, the researchers conclude.

A Weak Association, Stronger in Women?

But the association is weak, asserted Mario Cazzola, MD, professor and chief of the respiratory clinical pharmacology unit at the University of Rome Tor Vergata.

"We conducted a large population-based retrospective cross-sectional study in Italy and showed that the diagnosis of asthma is modestly associated with the diagnosis of different cardiovascular morbidities," he told Medscape Medical News (Respir Med. 2012;106:249-256).

The prevalence of cardiovascular and cerebrovascular disease in asthmatic patients is very low.

The study by Dr Iribarren's team "confirms that the prevalence of cardiovascular and cerebrovascular disease in asthmatic patients is very low (46 of 2829 patients, with a prevalence of 1.62%)," Dr Cazzola explained. "This low prevalence does not allow a solid conclusion; however, we believe the fact that, also in this study, asthma was only weakly associated with cardiovascular and cerebrovascular disease raises the question of the importance of systemic inflammation in asthma."

Nonetheless, he said, "the documentation that more severe asthma — as expressed by a higher severity-of-asthma score, a lower FEV₁, and the greater use of oral corticosteroids — was associated with a higher cardiovascular and cerebrovascular risk seems, to me, to be worthy of attention and deserves further research."

It will be particularly important to determine whether a specific subtype of asthma patient is predisposed to developing cardiovascular and cerebrovascular disease, Dr Cazzola pointed out. "It has been suggested that subjects with severe asthma, especially females, have a significant increased risk of ischemic heart disease. We noted that in patients with asthma, the association with acute or previous myocardial infarction and angina and coronary disease was stronger in women than in men. Age and smoking did not modify cardiovascular morbidities in these patients, compared with the general population."

This study was funded by Genentech, and EXCELS was funded by Genentech and Novartis Pharma AG. Editorial support for the poster was provided by Charlotte Kenreigh, from Excel Scientific Solutions, and was funded by Genentech and Novartis Pharmaceuticals.

Dr Iribarren and Dr Cazzola have disclosed no relevant financial relationships.

American College of Allergy, Asthma & Immunology (ACAAI) 2014: Abstract P45. Presented November 8, 2014.


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