A randomized, crossover, placebo controlled, double-blind trial of the effects of tiotropium-olodaterol on neuromuscular performance during exercise in COPD

Abstract

Exercise intolerance in chronic obstructive pulmonary disease (COPD) is associated with dyspnea, reduced inspiratory capacity (IC) and occurs with a neuromuscular "power reserve," i.e., an acute ability to increase isokinetic locomotor power. This power reserve is associated with resting forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) suggesting that treatments to target pulmonary function may protect neuromuscular performance and extend whole body exercise in COPD. We, therefore, tested whether combination long-acting β-agonist and muscarinic antagonist bronchodilator therapy [long-acting muscarinic antagonist (LAMA) + long-acting β-agonist (LABA); Stiolto Respimat] would ameliorate the decline in neuromuscular performance and increase endurance time during constant power cycling at 80% peak incremental power. Fourteen patients with COPD (4 female; 64 [58, 72] yr; FEV1 67% [56%, 75%] predicted; median [25th, 75th percentile]) participated in a randomized, placebo-controlled crossover trial (NCT02845752). Pulmonary function and cardiopulmonary exercise responses were assessed before and after 1 wk of treatment, with 2 wk washout between conditions. Performance fatigue was assessed using an ∼4-s maximal isokinetic cycling effort at preexercise, isotime, and intolerance. Isotime was the shorter exercise duration of the two treatment conditions. Significance was assessed using ANOVA with treatment as fixed factor and subject as random factor. FEV1 was greater with LAMA + LABA versus placebo (1.81 [1.58, 1.98] L vs. 1.72 [1.29, 1.99] L; P = 0.006), but IC at isotime, performance fatigue at isotime, and constant power endurance time were not different between conditions (each P > 0.05). A modest (∼95 mL) increase in FEV1 following 1 wk of combination LAMA + LABA treatment did not alleviate neuromuscular performance fatigue or enhance cycle exercise tolerance in patients with mild-to-severe COPD with largely preserved "static" lung volumes.NEW & NOTEWORTHY Bronchodilation is known to increase forced expiratory volume in 1 s (FEV1) and reduce hyperinflation in COPD. In a randomized controlled trial, we investigated whether combined inhaled long-acting β-agonist and muscarinic antagonist would alleviate maximal voluntary neuromuscular performance fatigue or enhance maximal muscle activation during cycling in patients with COPD. Despite increased FEV1, combination bronchodilator therapy did not reduce neuromuscular performance fatigue or enhance muscle activity or exercise tolerance in patients with mild-to-severe COPD.

Keywords: bronchodilation; dynamic hyperinflation; exercise intolerance; fatigue; isokinetic dynamometry.

Conflict of interest statement

Harry Rossiter reports consulting fees from Omniox Inc. and is involved in contracted clinical research with GlaxoSmithKline, Novartis, AstraZeneca, Astellas, United Therapeutics, Genentech, and Regeneron. He received grant support from Boehringer-Ingelheim to the institution to conduct this study. William Stringer is a medical director for a pulmonary rehabilitation program and is involved with Data Safety Monitoring Boards that focus on COPD and various biologic therapies. Richard Casaburi discloses consultancy fees from Boehringer-Ingelheim, Regeneron, Genentech, Abbott, and Respinova. He is involved in contracted clinical research with GlaxoSmithKline, Novartis, AstraZeneca, Genentech, and Regeneron. Janos Porszasz and Robert Calmelat are involved in contracted clinical research with AstraZeneca, United Therapeutics, Genentech, and Regeneron. Min Cao, Peter Kierstead, and Nicolo Carraro have nothing to disclose.

Figures

Graphical abstract

Figure 1.

Study design. Assessments included spirometry (filled circle), incremental exercise test (open triangle), and constant power exercise test (open square). All exercise tests were terminated with a maximal voluntary isokinetic cycling power assessment. *Visit 5 (following treatment period 3) was conducted using the treatment that resulted in the longest endurance time. Participants either continued on to the same treatment arm as visit 4, or crossed-over to the opposite treatment arm after visit 4, depending on which treatment resulted in the longer the endurance time at visits 3 and 4. At visit 5, the constant power exercise test was terminated at isotime with a maximal voluntary isokinetic cycling power assessment. Isotime was the shorter of the two endurance time durations measured at visits 3 and 4.

Figure 2.

Difference in preexercise (posttreatment) FEV1 and inspiratory capacity at peak exercise (Peak IC) between LAMA + LABA versus placebo. Error bars a median and interquartile range. n = 14. FEV1, forced expiratory volume in 1 s; IC, inspiratory capacity; LAMA + LABA, long-acting β-agonist and muscarinic antagonist bronchodilator therapy.