ACE Inhibitor Blunts Exercise Benefit in Pulmonary Rehab

Damian McNamara

May 17, 2016

SAN FRANCISCO — For patients with chronic obstructive pulmonary disease (COPD), the addition of the ACE inhibitor enalapril to pulmonary rehabilitation does not significantly improve outcomes and, in fact, reduces response to exercise therapy, according to a randomized, double-blind, multicenter trial.

"Whereas the placebo group managed to increase peak power compared with their baseline, the ACE inhibitor group did not," said Michael Polkey, PhD, from Imperial College London in the United Kingdom.

Dr Polkey was involved in a previous study of 80 COPD patients that showed no significant differences in quadriceps strength, endurance, or incremental shuttle walk distance between patients taking the ACE inhibitor fosinopril and those taking placebo (Chest. 2014;146:932-940).

So why try again? "We know pulmonary rehabilitation is highly effective, but in general, most benefits are considered lost at 12 to 18 months. There certainly is a place for adjunct therapy to extend the benefits, especially for a drug that is safe and cheap," Dr Polkey said here at the American Thoracic Society 2016 International Conference.

 
ACE inhibitors and ARBS are widely used in the treatment of heart failure and high blood pressure; it would be very appealing if these were useful for muscle training.
 

"ACE inhibitors and ARBS are widely used in the treatment of heart failure and high blood pressure; it would be very appealing if these were useful for muscle training as well," he explained.

The fact that the renin–angiotensin system is a key determinant of muscle phenotype, partly through glucose handling and insulin-like growth factor (IGF)-1 signaling, is further rationale for the study.

Study Details

Dr Polkey and his colleagues evaluated 78 patients with moderate to severe COPD (GOLD stage II to IV) who were breathless enough to require pulmonary rehabilitation. All patients participated in an 8-week pulmonary rehabilitation program and were concurrently randomized to enalapril or placebo for 10 weeks.

The study was completed by 31 patients in the enalapril group and 34 patients in the placebo group.

Improvement in peak exercise capacity from baseline, the primary outcome, was significantly worse in the enalapril group than in the placebo group (P < .001). There were no significant differences between the two groups in any of the secondary outcomes, such as physical activity levels, quadriceps strength, or health-related quality of life.

 
ACE inhibitors actually blunt the response to pulmonary rehabilitation.
 

"Contrary to what we hypothesized, we found that ACE inhibitors actually blunt the response to pulmonary rehabilitation," Dr Polkey reported. "We speculated that a mechanism behind muscle training, angiogenesis, might be involved. Since ACE inhibitors block angiogenesis, we wonder if that could be why it doesn't work."

There were no significant differences in the rate of pulmonary exacerbation or other adverse events.

Blood pressure and levels of serum angiotensin-converting enzyme were lower in the enalapril group than in the placebo group, "which is reassuring," Dr Polkey said.

On the basis of these results, there is no reason to stop ACE inhibitors in patients with a pre-existing clinical indication. "We don't want to suggest patients stop an ACE inhibitor for other reasons, but we certainly cannot endorse them," he explained.

This is a "well-done study," in line with the previous work by Dr Polkey's team, which also had a negative result, said session moderator Thierry Troosters, PhD, from the Catholic University of Leuven in Belgium.

"It's interesting for the rehabilitation population. For patients on an ACE inhibitor, we may have to provide training differently," he told Medscape Medical News. "These patients may have to work harder to see the same effect."

Does Dose Matter?

Dr Polkey was asked by a member of the audience whether a different dose of ACE inhibitor could have made a difference. "We managed to reduce the blood pressure, so I think we chose the right dosage," he replied.

But Dr Troosters suggested that the dose of enalapril for blood pressure reduction might not be the optimal dose to improve pulmonary rehabilitation. The situation could be similar to aspirin, he explained, where a higher dose can address pain and a lower dose can confer cardioprotective benefits.

Dr Polkey said he has no plans to conduct a third trial of ACE inhibitor adjunct therapy in this population.

Dr Polkey and Dr Troosters have disclosed no relevant financial relationships.

American Thoracic Society (ATS) 2016 International Conference: Abstract 2619. Presented May 15, 2016.

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