Jim Kling

September 11, 2015

AMSTERDAM — For patients with moderate chronic obstructive pulmonary disease (COPD) and a history of or risk for cardiovascular disease, the combination of an inhaled corticosteroid and a long-acting beta-2 agonist provides no mortality benefit, a new study indicates.

"We were not successful," said lead researcher Jørgen Vestbo, DrMedSci, from the University of Manchester, United Kingdom.

The study aimed to show a mortality reduction of 30% with the combination of fluticasone furoate and vilanterol (Breo, GlaxoSmithKline). This was "perhaps ambitious," he acknowledged.

The results were released in a GlaxoSmithKline news release. Complete results will be presented at the upcoming European Respiratory Society (ERS) International Congress 2015.

This could put to rest a theory that sought to explain cardiovascular complications related to COPD.

Wrong Hypothesis or Wrong Anti-inflammatory?

It was hypothesized that lung inflammation leads to systemic inflammation, which raises the risk for atherosclerosis, stroke, and other cardiovascular comorbidities. But if inhaled corticosteroid delivery to the lungs has no effect on cardiovascular events, that theory could be wrong, at least in the general population.

"Maybe steroids aren't the right anti-inflammatory to use, or maybe lung inflammation and systemic inflammation aren't coupled at all. I think the latter is true," said Gerard Criner, MD, from the Temple University School of Medicine and director of the Temple Lung Center in Philadelphia.

Dr Criner said he bases his opinion in part on a study he and colleagues conducted last year, which showed that simvastatin lowered cholesterol but had no effect on the number of COPD exacerbations ( N Engl J Med. 2014;370:2201-2210).

"Two different agents coming from two different directions may challenge the hypothesis" that lung and systemic inflammation are linked, Dr Criner told Medscape Medical News.

SUMMIT Study

The Study to Understand Mortality and Morbidity in COPD (SUMMIT) involved 16,485 patients from 43 countries who had COPD with moderate airflow limitation, defined as forced expiratory volume in 1 second (FEV1) of 50% to 70% predicted, and either a history of or increased risk for cardiovascular disease.

Patients were randomly assigned to one of four groups: the combination of fluticasone furoate 100 µg and vilanterol 25 µg; fluticasone furoate 100 µg monotherapy; vilanterol 25 µg monotherapy; or placebo. Data have only been reported for the combination and placebo groups.

For severe COPD exacerbation or multiple moderate exacerbations, study participants could use albuterol (also known as salbutamol), a long-acting muscarinic antagonist, or a phosphodiesterase type 4 inhibitor. For short treatment of COPD exacerbations, they could use oral corticosteroids and antibiotics. Cardiovascular medications were also allowed, but inhaled corticosteroids and long-acting beta-2 agonists were not.

Mortality — the primary end point — was 12.2% lower in the combination group than in the placebo group, but it did not reach statistical significance (P = .137).

For the decline in lung function — a secondary end point — the reduction in FEV1 was a significant 8 mL/year less with the combination than with placebo (P = .019).

The risk for an on-treatment cardiovascular event (cardiovascular death, myocardial infarction, stroke, unstable angina, or transient ischemic attack) — another secondary end point — was 7.4% lower with the combination than with placebo, but this difference was not significant (P = .475).

The combination also led to significant improvements, compared with placebo, in other secondary end points (P ≤ .002 for each), including postbronchodilator FEV1, the rate of moderate or severe exacerbation, time to first moderate or severe exacerbation, time to first hospitalization for severe exacerbation, rate of hospitalization for severe exacerbation, health- related quality of life at 12 months, and health status at 12 months.

Adverse events were more common with the combination than with placebo.

Table. Frequent Adverse Events

Event Combination, % Placebo, %
Nasopharyngitis 8.9 7.5
Upper respiratory tract infection 6.3 4.8
Pneumonia 5.0 4.6
Back pain 4.3 3.5
Hypertension 3.9 3.3
Influenza 3.4 2.9

 

The incidence of on-treatment serious adverse events was also higher with the combination than with placebo (23.2% vs 22.2%).

Because complete results are not yet available, they are "difficult to evaluate," said Reinoud Gosens, PhD, from the University of Groningen in the Netherlands. Specifically, he said, he would like to see the absolute numbers.

"Of course, the result is somewhat disappointing, in that a 12% reduction and the nonsignificance of the reduction is not what we had hoped for," he told Medscape Medical News.

"But that doesn't mean at all that this study only has negative aspects," he pointed out. "It appears that some of the secondary end points show statistically significant differences, although because the primary end point wasn't met, it's difficult to make firm conclusions. There seems to be an effect on lung function decline, which is absolutely a clear effect."

In the end, the uncertainty over the role of inhaled corticosteroids in treating COPD continues. The patient group in which inhaled corticosteroids should be used to treat COPD "remains an open scientific question," said Dr Criner.

The study was funded by GlaxoSmithKline. Dr Vestbo reports receiving fees from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, and Novartis. Dr Gosens and Dr Criner have disclosed no relevant financial relationships.

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