Training in HFpEF-PH (TRAIN HFpEF)

Implementation, Safety, Tolerability and Effect of Exercise and Respiratory Training on 6-minute Walking Distance in Patients With Pulmonary Hypertension and Heart Failure With Preserved Ejection Fraction (HFpEF): a Randomized Controlled Multicenter Trial in European Countries.

Exercise interventions alone or as a component of a comprehensive cardiac rehabilitation program for patients with heart failure (HFrEF and HFpEF) have already shown to reduce the risk of hospitalisations due to HF and improved exercise capacity and health-related quality of life. Two meta-analyses have confirmed the beneficial effects in cardiorespiratory fitness and quality of life. The effects of exercise training on systolic and diastolic function remain inconclusive. Due to the positive results of exercise training in HFpEF, cardiac rehabilitation is recommended (Class I, level A) to be integrated into the overall provision of HF care. However, none of these studies focused on concomitant PH in HFpEF.

Exercise training in patients with pulmonary hypertension has already shown to improve exercise capacity, quality of life and peak oxygen consumption, which was confirmed by three meta-analyses and a Cochrane review. Though different diagnostic subgroups have already been enrolled in PH exercise training studies, they mainly included pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Data on combined PH and HFpEF is still lacking.

As recently pointed out by Arena et al. there may thus be an exercise training volume/intensity which may be detrimental to the RV in patients with HF and concomitant PH.

This study is sought to investigate whether a specialized training program is safe and tolerable and may improve exercise capacity, quality of life, hemodynamics, diastolic dysfunction and biomarkers in patients with PH and HFpEF.

Study Overview

• Status: Not yet recruiting
• Conditions: Heart Failure With Preserved Ejection Fraction; Pulmonary Hypertension Due to Left Heart Disease
• Intervention / Treatment: Other: Exercise rehabilitation; Other: Standard treatment

Detailed Description

During the 6th World Symposium of PH in Nice, three main entities of PH due to left heart disease (PH-LHD) were identified. 1. PH due to HFpEF, 2. PH due to HF with reduced EF (HFrEF) and 3. PH due to valvular disease. The hemodynamic criteria measured by right heart catheterisation (RHC) of PH-LHD include mean pulmonary arterial pressure (mPAP)>20 mmHg and pulmonary arterial wedge pressure (PAWP) >15 mmHg.

The hallmark of HFpEF is an elevation in left-sided filling pressures. In some patients this leads to elevation of mean pulmonary arterial pressure as secondary pulmonary hypertension (PH). Pulmonary arterial pressure is a marker of the severity and chronicity of pulmonary venous congestion in HFpEF and in case of presence of PH, symptoms are more severe and the outcome is poorer.

Recently, an updated diagnostic algorithm (HFA-PEFF) for HFpEF was published as consensus recommendation from the Heart Failure Association of the European Society of Cardiology.

In first step, a pre-test assessment is performed (P: Pretest). In case risk factors for HFpEF are existing electrocardiographic and echocardiographic evaluation as well as an exercise test are required.

If the 1st step is proved positive, a detailed echocardiography (E: echocardiography) should be performed.

A definite diagnosis of HFpEF can be made by right heart catheterization with PAWP ≥15mmHg or LVEDP ≥16mmHg at rest and/or PAWP ≥25mmHg during exercise in presence of preserved left ventricular function.

Exercise interventions alone or as a component of a comprehensive cardiac rehabilitation program for patients with heart failure (HFrEF and HFpEF) have already shown to reduce the risk of hospitalisations due to HF and improved exercise capacity and health-related quality of life . Two meta-analyses have confirmed the beneficial effects in cardiorespiratory fitness and quality of life. The effects of exercise training on systolic and diastolic function remain inconclusive. Due to the positive results of exercise training in HFpEF, cardiac rehabilitation is recommended (Class I, level A) to be integrated into the overall provision of HF care. However, none of these studies focused on concomitant PH in HFpEF.

Exercise training in patients with pulmonary hypertension has already shown to improve exercise capacity, quality of life and peak oxygen consumption, which was confirmed by three meta-analyses and a Cochrane review. Though different diagnostic subgroups have already been enrolled in PH exercise training studies, they mainly included pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Data on combined PH and HFpEF is still lacking.

In healthy subjects, intensive exercise has already shown to cause potentially deleterious remodeling of the RV. As recently pointed out by Arena et al. there may thus be an exercise training volume/intensity which may be detrimental to the RV in patients with HF and concomitant PH.

This study is sought to investigate whether a specialized training program is safe and tolerable and may improve exercise capacity, quality of life, hemodynamics, diastolic dysfunction and biomarkers in patients with PH and HFpEF.

• Study Type: Interventional
• Enrollment (Anticipated): 90
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ekkehard Grünig, MD; Phone Number: 1288 +496221396; Email: ekkehard.gruenig@med.uni-heidelberg.de
• Study Contact Backup: Name: Nicola Benjamin, MSc; Phone Number: 1288 +49 6221 396; Email: nicola.benjamin@med.uni-heidelberg.de

Study Locations

• Germany
  • Heidelberg, Germany, 69126
    • Centre for Pulmonary Hypertension at the Thoraxklinik Heidelberg, Heidelberg University Hospital
• Lithuania
  • Vilnius, Lithuania
    • Clinic of Cardiac and Vascular Diseases, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
    • Contact: Egle Paleviciute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Female and male patients ≥18 years
2. WHO/NYHA functional class II - IV

3. PH with HFpEF diagnosed by right heart catheterisation showing:

   mean pulmonary arterial pressure (mPAP) ≥25mmHg at rest; pulmonary arterial wedge pressure (PAWP) ≥15mmHg at rest or LVEDP ≥16mmHg and/or PAWP≥25 mmHg during exercise, and

4. Preserved left ventricular ejection fraction ≥50%
5. Patients receiving optimized therapy including intensified treatment with diuretics and who have been stable for 1 month before entering the study.
6. Except for diuretics, medical treatment should not be changed during the study period.
7. Able to understand and willing to sign the Informed Consent Form

Exclusion Criteria:

1. Pre-capillary pulmonary hypertension (Group I; Group III; Group IV; Group V according to PH guidelines)
2. Congenital or acquired severe valvular diseases (severe aortic stenosis or insufficiency, severe mitral valve stenosis or insufficiency)
3. Pregnancy or lactation
4. Walking disability
5. Subject who participates in an interventional study during the course of this study
6. Severe lung disease: FEV1/FVC <0.5 and total lung capacity <60% of the normal value
7. Active myocarditis, unstable angina pectoris, exercise induced ventricular arrhythmias, active liver disease, porphyria or elevations of serum transaminases >3 x ULN (upper limit of normal) or bilirubin >1.5 x ULN
8. Haemoglobin concentration less than 75% of the lower limit of normal
9. Systolic blood pressure <85 mmHg
10. History or suspicion of inability to cooperate adequately.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Exercise training	Other: Exercise rehabilitation; The initial phase of exercise training will be closely monitored and will be based on a three-weeks in-hospital stay to adjust and teach the exercise training which will be continued at home for 12 more weeks. In-hospital stays will be arranged country specific and hospitalization time may range. The rehabilitation program comprises of interval ergometer training (20 minutes 5 days per week), dumbbell training (30 minutes 5 days per week), respiratory therapy (30 minutes 5 days per week), mental training and guided walks for 2-5 times/week.
Placebo Comparator: Standard treatment (waiting group)	Other: Standard treatment; Standard treatment during study duration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
6-minute walking distance	baseline to 15 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
WHO functional class		baseline to 15 weeks
Quality of life physical component scale SF-36		baseline to 15 weeks
Quality of life mental component scale SF-36		baseline to 15 weeks
peak oxygen consumption		baseline to 15 weeks
peak oxygen consumption/kg body weight		baseline to 15 weeks
workload achieved during cardiopulmonary exercise testing		baseline to 15 weeks
NT-proBNP (N-terminal pro brain natriuretic peptide)		baseline to 15 weeks
Tricuspid annular plane systolic excursion	echocardiography	baseline to 15 weeks
Systolic pulmonary arterial pressure	echocardiography	baseline to 15 weeks
Right atrial area	echocardiography	baseline to 15 weeks
Right ventricular area	echocardiography	baseline to 15 weeks
Right ventricular pump function	echocardiography	baseline to 15 weeks
Left ventricular pump function	echocardiography	baseline to 15 weeks
Left ventricular eccentricity index	echocardiography	baseline to 15 weeks

Collaborators and Investigators

• Sponsor: Heidelberg University

Study record dates

Study Major Dates

• Study Start (Anticipated): February 1, 2023
• Primary Completion (Anticipated): December 1, 2025
• Study Completion (Anticipated): December 1, 2026

Study Registration Dates

• First Submitted: July 14, 2022
• First Submitted That Met QC Criteria: July 14, 2022
• First Posted (Actual): July 19, 2022

Study Record Updates

• Last Update Posted (Actual): September 16, 2022
• Last Update Submitted That Met QC Criteria: September 14, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Heart Failure; Heart Diseases; Hypertension; Hypertension, Pulmonary
• Other Study ID Numbers: 2019-04ET

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No