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Randomized Controlled Trial
. 2021 Feb 9;325(6):542-551.
doi: 10.1001/jama.2020.26812.

Effect of High-Intensity Interval Training, Moderate Continuous Training, or Guideline-Based Physical Activity Advice on Peak Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial

Stephan Mueller  1   2 , Ephraim B Winzer  3 , André Duvinage  1   2 , Andreas B Gevaert  4   5 , Frank Edelmann  6   7 , Bernhard Haller  8 , Elisabeth Pieske-Kraigher  6   7 , Paul Beckers  4   5 , Anna Bobenko  6   7 , Jennifer Hommel  3 , Caroline M Van de Heyning  4   5 , Katrin Esefeld  1   2 , Pia von Korn  1   2 , Jeffrey W Christle  1   9 , Mark J Haykowsky  10 , Axel Linke  3 , Ulrik Wisløff  11 , Volker Adams  3 , Burkert Pieske  6   7 , Emeline M van Craenenbroeck  4   5 , Martin Halle  1   2 ; OptimEx-Clin Study Group
Affiliations
Randomized Controlled Trial

Effect of High-Intensity Interval Training, Moderate Continuous Training, or Guideline-Based Physical Activity Advice on Peak Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial

Stephan Mueller et al. JAMA. .

Abstract

Importance: Endurance exercise is effective in improving peak oxygen consumption (peak V̇o2) in patients with heart failure with preserved ejection fraction (HFpEF). However, it remains unknown whether differing modes of exercise have different effects.

Objective: To determine whether high-intensity interval training, moderate continuous training, and guideline-based advice on physical activity have different effects on change in peak V̇o2 in patients with HFpEF.

Design, setting, and participants: Randomized clinical trial at 5 sites (Berlin, Leipzig, and Munich, Germany; Antwerp, Belgium; and Trondheim, Norway) from July 2014 to September 2018. From 532 screened patients, 180 sedentary patients with chronic, stable HFpEF were enrolled. Outcomes were analyzed by core laboratories blinded to treatment groups; however, the patients and staff conducting the evaluations were not blinded.

Interventions: Patients were randomly assigned (1:1:1; n = 60 per group) to high-intensity interval training (3 × 38 minutes/week), moderate continuous training (5 × 40 minutes/week), or guideline control (1-time advice on physical activity according to guidelines) for 12 months (3 months in clinic followed by 9 months telemedically supervised home-based exercise).

Main outcomes and measures: Primary end point was change in peak V̇o2 after 3 months, with the minimal clinically important difference set at 2.5 mL/kg/min. Secondary end points included changes in metrics of cardiorespiratory fitness, diastolic function, and natriuretic peptides after 3 and 12 months.

Results: Among 180 patients who were randomized (mean age, 70 years; 120 women [67%]), 166 (92%) and 154 (86%) completed evaluation at 3 and 12 months, respectively. Change in peak V̇o2 over 3 months for high-intensity interval training vs guideline control was 1.1 vs -0.6 mL/kg/min (difference, 1.5 [95% CI, 0.4 to 2.7]); for moderate continuous training vs guideline control, 1.6 vs -0.6 mL/kg/min (difference, 2.0 [95% CI, 0.9 to 3.1]); and for high-intensity interval training vs moderate continuous training, 1.1 vs 1.6 mL/kg/min (difference, -0.4 [95% CI, -1.4 to 0.6]). No comparisons were statistically significant after 12 months. There were no significant changes in diastolic function or natriuretic peptides. Acute coronary syndrome was recorded in 4 high-intensity interval training patients (7%), 3 moderate continuous training patients (5%), and 5 guideline control patients (8%).

Conclusions and relevance: Among patients with HFpEF, there was no statistically significant difference in change in peak V̇o2 at 3 months between those assigned to high-intensity interval vs moderate continuous training, and neither group met the prespecified minimal clinically important difference compared with the guideline control. These findings do not support either high-intensity interval training or moderate continuous training compared with guideline-based physical activity for patients with HFpEF.

Trial registration: ClinicalTrials.gov Identifier: NCT02078947.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Mueller reported receiving grants from Deutsche Forschungsgemeinschaft (DFG) through the TUM International Graduate School of Science and Engineering during the conduct of the study. Dr Winzer reported receiving personal fees from Novartis (honoraria for lectures and advisory board activities), Boehringer Ingelheim (honoraria for advisory board activities), and CVRX (honoraria for lectures) outside the submitted work. Dr Duvinage reported receiving grants from Novartis outside the submitted work. Dr Van de Heyning reported receiving speaker fees from Abbott, Daiichi Sankyo, and Edwards Lifesciences outside the submitted work. Dr Linke reported receiving speaker fees from Abbott, Medtronic, Edwards Lifesciences, AstraZeneca, Boston Scientific, and Novartis; grants from Edwards Lifesciences and Novartis; advisory board fees from Transverse Medical, Picardia, Edwards Lifesciences, and Heart Leaflet Technology; and stock options from Claret Medical and Transverse Medical, and being a co-owner of Dresden Cardiovascular Research Institute and Core Laboratories outside the submitted work. Dr Pieske reported receiving personal fees from Bayer Healthcare (steering committee, lectures), Merck (steering committee, lectures), Novartis (steering committee, lectures), Servier, AstraZeneca (lectures), Bristol-Myers Squibb (lectures), and Medscape (lectures) outside the submitted work. Dr Van Craenenbroeck reported receiving grants from the Flemish Research Funds (FWO) during the conduct of the study. Dr Halle reported receiving grants from the TUM International Graduate School of Science and Engineering during the conduct of the study and grants from Novartis (principal investigator of the Activity Study in HFrEF) and personal fees from Bristol-Myers Squibb, Berlin Chemie-Menarini, Novartis, Daiichi-Sankyo, AstraZeneca, Roche, Abbott (advisory board on exercise and diabetes), Sanofi, Pfizer, Boehringer Ingelheim, and Bayer outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Patient Recruitment, Randomization, and Follow-up in the OptimEx-Clin Study
FEV1 indicates forced expiratory volume in first second of expiration; HF, heart failure; and HFpEF, heart failure with preserved ejection fraction. aNon-HFpEF causes for HF symptoms included significant valvular disease, coronary disease, uncontrolled hypertension or arrhythmia, or primary cardiomyopathies. bThe other reasons were signs of ischemia during cardiopulmonary exercise testing (n = 3), comorbidities that may influence 1-year prognosis (n = 3), upcoming planned surgery (n = 2), social reasons (n = 2), concerns about patient’s ability to adhere and compliance (n = 1), recurrent syncopes (n = 1), and planned travel (n = 1). cRemoved after blinded review of eligibility of all patients.
Figure 2.
Figure 2.. Changes in Peak Oxygen Consumption (V̇o2), Estimated Left Ventricular Filling Pressure (E/e′ Medial), N-Terminal Pro–Brain Natriuretic Peptide (NT-proBNP), and Kansas City Cardiomyopathy Questionnaire (KCCQ) Quality of Life (QoL) at 3 and 12 Months
Changes are calculated from baseline to 3 and 12 months of intervention within each group (solid lines connect the mean changes from baseline to 3 months and baseline to 12 months). In the KCCQ, higher scores indicate better QoL (score range, 0-100; minimal clinically important difference [MCID, dashed line], 5 points). aSignificant difference (P < .05) in change between high-intensity interval training and guideline control. bSignificant difference (P < .05) in change between moderate continuous training and guideline control. cOpen points are at 3586 pg/mL (moderate continuous training, change to 3 months), 4133 and 5783 pg/mL (guideline control, change to 3 months), 4134 and 7063 pg/mL (guideline control, change to 12 months).
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