Exercise training improves peak oxygen consumption and haemodynamics in patients with severe pulmonary arterial hypertension and inoperable chronic thrombo-embolic pulmonary hypertension: a prospective, randomized, controlled trial

Abstract

Aims: The impact of exercise training on the right heart and pulmonary circulation has not yet been invasively assessed in patients with pulmonary hypertension (PH) and right heart failure. This prospective randomized controlled study investigates the effects of exercise training on peak VO2/kg, haemodynamics, and further clinically relevant parameters in PH patients.

Methods and results: Eighty-seven patients with pulmonary arterial hypertension and inoperable chronic thrombo-embolic PH (54% female, 56 ± 15 years, 84% World Health Organization functional class III/IV, 53% combination therapy) on stable disease-targeted medication were randomly assigned to a control and training group. Medication remained unchanged during the study period. Non-invasive assessments and right heart catheterization at rest and during exercise were performed at baseline and after 15 weeks. Primary endpoint was the change in peak VO2/kg. Secondary endpoints included changes in haemodynamics. For missing data, multiple imputation and responder analyses were performed. The study results showed a significant improvement of peak VO2/kg in the training group (difference from baseline to 15 weeks: training +3.1 ± 2.7 mL/min/kg equals +24.3% vs. control -0.2 ± 2.3 mL/min/kg equals +0.9%, P < 0.001). Cardiac index (CI) at rest and during exercise, mean pulmonary arterial pressure, pulmonary vascular resistance, 6 min walking distance, quality of life, and exercise capacity significantly improved by exercise training.

Conclusion: Low-dose exercise training at 4-7 days/week significantly improved peak VO2/kg, haemodynamics, and further clinically relevant parameters. The improvements of CI at rest and during exercise indicate that exercise training may improve the right ventricular function. Further, large multicentre trials are necessary to confirm these results.

Keywords: Cardiac index; Cardiac output; Cardiac rehabilitation; Pulmonary hypertension; Right heart catheterization.

Figure 1

Study design. The flowchart shows the number of allocated patients for each treatment group, the number of patients valid for analysis, and the number and reasons for exclusion, respectively (original data).

Figure 2

Primary endpoint: change in peak oxygen uptake. Left graph: The abscissa shows peak VO₂/kg at baseline, and the ordinate shows change of peak VO₂/kg from baseline after 15 weeks for each patient. The solid points represent patients of the training group, and the circles represent patients of the control group. This graph shows equal distribution of baseline peak VO₂ in both groups as well as changes after 15 weeks of exercise training. Change in peak VO₂ did not correlate with baseline peak VO₂. Right graph: the boxplots at the right side show median change of VO₂ max in the control vs. training group after 15 weeks. A significant increase can be shown in the training group (P < 0.001), whereas the control group shows a small reduction in peak VO₂ after 15 weeks. Multiple imputations showed the same P-value.

Figure 3

Secondary endpoints: haemodynamic function. Results from RHC for mean pulmonary arterial pressure (A), pulmonary vascular resistance (B), cardiac output (C) and cardiac index (D) at rest. The graphs depict the change of each parameter in per cent from baseline to 15 weeks after exercise training/no training. The mean changes of the training group, compared with baseline and control, as absolute values are given at the top of each graph with corresponding P-values of the ANCOVA for original data and multiple imputations. The bars are representing two times standard error.

Figure 4

Haemodynamics during exercise. The distribution of absolute changes in CI during exercise (P < 0.001) is shown by a boxplot for each group. The training group improved CI by 19.5%, whereas the control group had a decrease of 4.3%. P-values are given for the ANCOVA for original data and multiple imputations.

Figure 5

6MWD. The figure shows the absolute changes in 6MWD for each patient: patients of the training group as solid lines and patients of the control group as dashed lines. Mean changes are given with darker lines, and error bars indicate ±1 standard error of the mean. Exercise training significantly improved 6MWD compared with baseline (P = 0.002). P-values are given for the ANCOVA for original data and multiple imputations.

Figure 6

QoL. Mean changes of QoL ± 2 standard errors of the mean and sample sizes below each bar. The bars of the control group are shown on the left side of each category. Exercise and respiratory training significantly improved the subscale score for vitality (P = 0.036), compared with the control group, in which this parameter slightly worsened. The subscales role limitations due to physical restrictions (P = 0.099), role limitations due to emotional restrictions (P = 0.09), and general health perception (0.091) were significant in trend in the original data, but showed inconsistent findings in multiple imputation.