Combined endurance and resistance exercise training in heart failure with preserved ejection fraction: a randomized controlled trial

Abstract

Endurance exercise training (ET) is an effective treatment in heart failure with preserved ejection fraction (HFpEF), but the efficacy of resistance training in this patient population has been only scarcely evaluated. In this multicenter, randomized trial, we evaluated the effects of combined endurance and resistance training over 12 months in patients with HFpEF. The primary endpoint was a modified Packer score, including all-cause mortality, hospitalizations classified as potentially related to heart failure or exercise and changes in peak oxygen consumption ( $\dot{V}{O}_2$ ), diastolic function (E/e'), New York Heart Association (NYHA) class and global self-assessment (GSA). In total, 322 patients (mean age, 70 years; 192 females (59.6%) and 130 males (40.4%)) were randomized (1:1) to ET or usual care (UC). At 12 months, the modified Packer score showed an improvement in 33 ET patients (20.5%) and in 13 UC patients (8.1%) and showed a worsening in 69 ET patients (42.9%) and in 71 UC patients (44.1%) (Kendall's tau-b = -0.073, P = 0.17). Although the primary endpoint was not met, clinically relevant differences favoring the ET group as compared to the UC group were observed for the following secondary endpoints: changes in peak $\dot{V}{O}_2$ (mean difference, 1.3 ml kg^-1 min^-1 (95% confidence interval (CI): 0.4-2.1)) and NYHA class (odds ratio = 7.77 (95% CI: 3.73-16.21)). No significant between-group differences were observed for other secondary endpoints, including change in E/e', change in GSA, time to cardiovascular hospitalization or all-cause mortality. In conclusion, 1 year of combined endurance and resistance ET did not result in a significantly better modified Packer score, but it did result in improvements in important clinical parameters, such as peak $\dot{V}{O}_2$ and NYHA class, as compared to UC. ISRCTN registration: ISRCTN86879094 .

Fig. 1. CONSORT diagram of the Ex-DHF trial.

Among 764 patients who were screened for eligibility, 322 were randomized to UC or ET. All randomized patients were included in the primary analysis (intention-to-treat).

Fig. 2. Results of the modified Packer score (primary endpoint) at 12 months.

Results are shown for the ET (left) and UC (right) groups. For the primary endpoint, a two-sided test of Kendall’s tau-b was performed. Values of the tau-b parameter range from −1 (all ET patients are in a better category than UC patients) to 1 (all UC patients are in a better category than ET patients). A value of 0 indicates that the distribution is identical between groups. For the pre-specified sensitivity analysis, as the assumption of proportional odds was not met, ordinal regression analyses were performed by comparing (1) ‘improved/unchanged’ versus ‘worsened’ and (2) ‘improved’ versus ‘unchanged/worsened’. The two-sided ordinal regression analyses were adjusted for randomization strata (baseline peak VO₂ less than versus equal to or higher than 20 ml kg⁻¹ min⁻¹; NYHA functional class II/III), without adjustment for multiple comparisons. ORs and 95% CIs define the odds of ET patients being in the favorable category.

Fig. 3. Results of secondary endpoints at 6 months and 12 months.

a–c, Results from two-sided linear mixed models with the respective baseline variable as covariate and treatment as factor are shown for peak VO₂ (a), septal E/e′ (b) and GSA (c). The tests were based on complete cases and were not adjusted for multiple comparisons. Dots represent the mean and error bars represent the 95% CI for each group. GSA is based on a seven-point Likert scale (higher score indicates better health status).

Fig. 4. Time to all-cause death or cardiovascular hospitalizations in the ET and UC groups.

The difference in time to events was evaluated using a two-sided Cox regression analysis.

Extended Data Fig. 1. Reasons for Worsening of the Modified Packer Score (MPS).

Reasons are shown separately for exercise training (left) and usual care (right) as absolute and relative frequency.

Extended Data Fig. 2. Adherence to exercise training.

Green dots represent individuals who performed an average of at least 2 supervised sessions/week between baseline and 12-months follow-up (N = 53). Red dots represent individuals who performed an average of less than 2 supervised (left) or overall (right) sessions/week between baseline and 12-months follow-up (N = 108). Medians are shown by thick vertical lines and box boundaries were determined by the first and third quartile. The whiskers were defined as the highest/smallest value that was within 1.5× interquartile range ± upper/lower box boundary. For supervised sessions, minimum and maximum adherence were 0 sessions/week and 2.96 sessions/week, respectively. For overall sessions, minimum and maximum were 0 sessions/week and 4.23 sessions/week.

Extended Data Fig. 3. Per-Protocol analysis of the primary endpoint (modified Packer score).

Patients who were lost to 12-months follow-up or who had a major protocol deviation were excluded. Results are shown for a two-sided test of Kendall’s tau-b and based on two-sided ordinal regression analyses, which were adjusted for randomization strata (baseline peak VO₂ less vs. equal or higher than 20 mL/kg/min; New York Heart Association functional class II / III). P-values were not adjusted for multiple comparisons. The exact P-value for the comparison of ‘improved vs. unchanged / worsened’ modified Packer score is P = 0.0003.

Extended Data Fig. 4. Win Ratio for the components of the primary endpoint.

In this post-hoc analysis, a two-sided win ratio (based on all 322 randomized patients) was calculated using a similar hierarchy as for the primary endpoint (all-cause death > number of hospitalizations due to worsening heart failure > change in peak $\dot{\mathrm{V}}{\mathrm{O}}_2$ > change of NYHA class > change in GSA > change in E/e’). The cutoffs used to categorize peak $\dot{\mathrm{V}}{\mathrm{O}}_2$, NYHA class, GSA and E/e’ are the same as the predefined cutoffs used for the primary endpoint (-2 = hard criterion for clinical worsening, -1 = mild criterion for clinical worsening, 0 = unchanged, +1 = criterion for clinical improvement; for details see Supplementary Fig. 1).

Extended Data Fig. 5. Subgroup analysis for the modified Packer score (A) and the change in peak oxygen consumption V˙O2 (B).

Subgroup analyses for the modified Packer score were based on two-sided ordinal regression analyses with tests for interaction between the respective variables and study group. Subgroup analyses for the change in peak VO₂ were based on two-sided mixed-linear regression models with tests for interaction between the respective variables and study group. P-values have not been adjusted for multiple comparisons.

Extended Data Fig. 6. Association between adherence to exercise training (ET) and the modified Packer score compared to usual care (UC).

Based on a two-sided Mantel-Haenszel test of trend in proportions, there was a significant association between exercise training frequency and the modified Packer score (P = 0.002). (UC = no exercise, ET = divided into three groups based on the adherence to the supervised exercise training).