Angiotensin-Converting Enzyme Inhibition as an Adjunct to Pulmonary Rehabilitation in Chronic Obstructive Pulmonary Disease

Abstract

Rationale: Epidemiological studies in older individuals have found an association between the use of angiotensin-converting enzyme (ACE) inhibition (ACE-I) therapy and preserved locomotor muscle mass, strength, and walking speed. ACE-I therapy might therefore have a role in the context of pulmonary rehabilitation (PR).

Objectives: To investigate the hypothesis that enalapril, an ACE inhibitor, would augment the improvement in exercise capacity seen during PR.

Methods: We performed a double-blind, placebo-controlled, parallel-group randomized controlled trial. Patients with chronic obstructive pulmonary disease, who had at least moderate airflow obstruction and were taking part in PR, were randomized to either 10 weeks of therapy with an ACE inhibitor (10 mg enalapril) or placebo.

Measurements and main results: The primary outcome measurement was the change in peak power (assessed using cycle ergometry) from baseline. Eighty patients were enrolled, 78 were randomized (age 67 ± 8 years; FEV₁ 48 ± 21% predicted), and 65 completed the trial (34 on placebo, 31 on the ACE inhibitor). The ACE inhibitor-treated group demonstrated a significant reduction in systolic blood pressure (Δ, -16 mm Hg; 95% confidence interval [CI], -22 to -11) and serum ACE activity (Δ, -18 IU/L; 95% CI, -23 to -12) versus placebo (between-group differences, P < 0.0001). Peak power increased significantly more in the placebo group (placebo Δ, +9 W; 95% CI, 5 to 13 vs. ACE-I Δ, +1 W; 95% CI, -2 to 4; between-group difference, 8 W; 95% CI, 3 to 13; P = 0.001). There was no significant between-group difference in quadriceps strength or health-related quality of life.

Conclusions: Use of the ACE inhibitor enalapril, together with a program of PR, in patients without an established indication for ACE-I, reduced the peak work rate response to exercise training in patients with chronic obstructive pulmonary disease.

Keywords: COPD; exercise; rehabilitation; renin–angiotensin system.

Figure 1.

Consolidated Standards of Reporting Trials recruitment diagram for enrollment and study completion. ACE-I = angiotensin-converting enzyme inhibitor; A₂RB = angiotensin II receptor blocker; GOLD = Global Initiative for Chronic Obstructive Lung Disease; PR = pulmonary rehabilitation.

Figure 2.

Alterations in blood pressure (BP) parameters (systolic BP [sBP] and diastolic BP [dBP]) from baseline to after pulmonary rehabilitation in the placebo (PL) and angiotensin-converting enzyme inhibitor (ACE-I) treatment arms. The box represents 25–75th percentiles, the solid line represents the median, and the whiskers represent minimum to maximum values. Comparisons were made using unpaired t tests, *P < 0.0001; ^†P = 0.0001.

Figure 3.

Change in serum angiotensin-converting enzyme (ACE) levels from baseline to after pulmonary rehabilitation in the placebo (PL) and ACE inhibitor (ACE-I) treatment arms. The box represents 25–75th percentiles, the solid line represents the median, and the whiskers represent minimum to maximum values. Comparison was made using an unpaired t test, *P < 0.0001.

Figure 4.

Change in peak workload achieved during incremental cycle ergometry from baseline to after pulmonary rehabilitation in the placebo (PL) and angiotensin-converting enzyme inhibitor (ACE-I) treatment arms. The box represents 25–75th percentiles, the solid line represents the median, and the whiskers represent minimum to maximum values. Comparison was made using an unpaired t test, *P = 0.001.