Searching for the Optimal Exercise Training Regimen in Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is increasing in prevalence, associated with high morbidity and mortality, and continues to be refractory to available pharmacotherapies.¹ HFpEF is a multiorgan disease with complex pathophysiology that culminates in debilitating exercise intolerance as its essential clinical manifestation.² Exercise intolerance is preceded by an accelerated decline in exercise capacity, measured objectively as peak exercise oxygen consumption (peak $\stackrel{·}{\text{V}}{\text{o}}_2$),³ and manifests clinically as dyspnea, fatigue, and reduced quality of life (QoL). Accordingly, there is an increasing emphasis on developing therapeutic approaches to improve exercise capacity and QoL in patients with HFpEF.

Prior randomized clinical trials (RCTs) have demonstrated the efficacy of short-duration supervised aerobic exercise training for improving peak $\stackrel{·}{\text{V}}{\text{o}}_2$ and QoL in patients with HFpEF.^4–6 However, these studies have been limited by relatively small sample sizes, single-center design, short-term exercise training intervention, and lack of data on the optimal intensity and duration of exercise training intervention.

The OptimEx-Clin Study, published in this issue of JAMA,⁷ is an important study that addresses some of these critical questions regarding the role of exercise training in patients with HFpEF. This multicenter trial of exercise training in HFpEF, the largest to date, evaluated the efficacy of 3 different approaches to exercise training, moderate continuous training vs high-intensity interval training vs guideline-based physical activity counseling (control group) over 12 months in 180 outpatients with HFpEF. The intervention included 3 months of supervised exercise training, followed by 9 months of home-based exercise. The primary outcome for the trial was a change in peak $\stackrel{·}{\text{V}}{\text{o}}_2$ at 3 months. The study was powered to detect a “meaningful” difference in peak $\stackrel{·}{\text{V}}{\text{o}}_2$, as defined by a threshold of 2.5 mL/kg/min, between groups and the pairwise comparison of the moderate continuous training vs high-intensity interval training groups.

The OptimEx-Clin trial was rigorous, well-designed, and well-conducted. Exercise training trials are often fraught with several logistical challenges such as small sample size, lack of adequate control group or blinding, poor enrollment, and high attrition rates. The investigators successfully conducted a multicentered RCT recruiting 180 patients with HFpEF with a screening to enrollment ratio of 3:1 and more than 90% and 80% retention at 3-month and 12-month follow-ups, respectively. The OptimEx-Clin trial is also the first adequately powered RCT to test the efficacy of 2 different modalities of aerobic exercise training in HFpEF. Furthermore, the participants underwent extensive phenotyping, including assessing echocardiographic characteristics, biomarkers, QoL, and exercise parameters using standardized protocols and core lab-based assessment of study outcomes. This rigorous and detailed phenotyping provides insights into the mechanisms through which exercise training may affect patients with HFpEF. In addition, incorporating a home-based training phase allowed for testing the feasibility and efficacy of a potentially more pragmatic and generalizable exercise training intervention and for addressing the enhancement of longer-term adherence.

The primary results of the OptimEx-Clin trial demonstrated a statistically significant increase in peak $\stackrel{·}{\text{V}}{\text{o}}_2$ with both exercise training interventions (moderate continuous training: 1.6 mL/kg/min, high-intensity interval training: 1.1 mL/kg/min) vs controls (−0.6 mL/kg/min) at 3-month follow-up. However, this difference did not meet the a priori-defined threshold of improvement (which was overly ambitious because 1.0 mL/kg/min is traditionally accepted as a clinically meaningful improvement, particularly among patients with HF who have severely reduced baseline peak $\stackrel{·}{\text{V}}{\text{o}}_2$), was not significantly different between the moderate continuous training vs high-intensity interval training groups, and was not sustained over longer-term follow-up.

The OptimEx-Clin trial provides several important lessons. High-intensity interval training has been regarded as an attractive mode of exercise training because it may require fewer sessions per week and shorter session duration to obtain significant physical conditioning and, therefore, potentially more acceptable by patients. Among patients with cardiometabolic disease and HF with reduced ejection fraction, high-intensity interval training is more effective than moderate continuous training in improving peak $\stackrel{·}{\text{V}}{\text{o}}_2$.^8,9 However, in the present study, among patients with HFpEF, high-intensity interval training was not more effective than moderate continuous training for improvement in exercise capacity or other outcomes. Moreover, patients undergoing moderate continuous training but not high-intensity interval training had a significant improvement in QoL in longer-term follow-up.

The lack of greater efficacy of high-intensity interval training vs moderate continuous training in this study could be related to several factors. First, the exercise training intervention in the high-intensity interval training vs moderate continuous training groups were not isocaloric (equivalent in energy expenditure) and the high-intensity interval training participants did not receive an equivalent dose of exercise with fewer training sessions than the moderate continuous training group. Second, more adverse events occurred in the high-intensity interval training group than in the moderate continuous training group, which may have adversely affected the adherence and motivation of the high-intensity interval training participants. Third, patients with HFpEF are generally older, have greater functional limitations, have more frailty, and have more comorbidities and, thus, may be less amenable to high-intensity interval training. Given the extensive experience with moderate continuous training and the established efficacy of moderate continuous training in improving exercise capacity and QoL, these data suggest that moderate continuous training may be the preferred exercise training approach in older patients with HFpEF.¹⁰

The investigators also observed a significant attenuation in the beneficial effects of both exercise training interventions over long-term follow-up with the transition from supervised to home-based exercise training. This attrition in the treatment effect coincided with a substantial decline in adherence to exercise training over the long-term. Poor long-term adherence is a critical limitation of all exercise training interventions.¹¹ The present study provides the most comprehensive assessment of safety and long-term adherence to exercise training in patients with HFpEF and highlights certain key challenges that need to be considered in designing future trials.

Several approaches, which were not part of the OptimEx-Clin trial design, could be considered to improve long-term adherence to exercise training. These include incorporation of a range of behavioral approaches that can enhance long-term adherence, gradual transition from supervised to home-based exercise whereby the supervised sessions are gradually phased out, and more comprehensive real-time remote monitoring and feedback during the home-based exercise period.^11,12 Similarly, implementation of multidomain rehabilitation interventions targeting improvement in functional status, balance, and muscle strength in addition to aerobic capacity might have fewer adverse effects in these higher-risk patients.¹³ Future studies incorporating these approaches in the exercise training studies may ensure better long-term adherence and safety of exercise training among older patients with HFpEF. Furthermore, including complementary lifestyle interventions, such as dietary weight loss with exercise training, appears to significantly augment the improvement in peak VO₂ and QoL substantially.⁴ This is particularly relevant considering the high prevalence of obesity and its relationship with exercise intolerance in patients with HFpEF.¹⁴

The OptimEx-Clin trial also evaluated the effects of exercise training on cardiac structure, function, and N-terminal pro-brain natriuretic peptide levels to understand better the mechanisms of exercise-related benefits in HFpEF. There were no significant changes in these parameters with exercise training. The lack of improvement in cardiac parameters is consistent with observations from prior exercise training studies in patients with HF with reduced ejection fraction and HFpEF,^10,15 whereby most (>80%) exercise training-related improvement in peak $\stackrel{·}{\text{V}}{\text{o}}_2$ has been attributed to peripheral adaptations, such as vascular and or skeletal muscle function, which can have rapid, robust responses to exercise training.^15,16 Future exercise training studies should focus on optimizing improvements in peripheral determinants of peak $\stackrel{·}{\text{V}}{\text{o}}_2$ in response to exercise training to exercise to further enhance benefit.

The OptimEx-Clin trial published in this issue of JAMA is an important attempt to improve the effectiveness of exercise training, one of the only interventions proven to improve symptoms in the growing population of patients with HFpEF. Although high-intensity interval training was not found more effective than moderate continuous training, the trial results highlight important future directions: incorporating strategies to enhance long-term adherence and optimizing effects on extracardiac contributors to exercise intolerance.