Clinical trial NCT05464238: Training in HFpEF-PH
Official title: 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.
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Pulmonary Hypertension Due to Left Heart Disease
Heart Failure With Preserved Ejection Fraction
Lead sponsor: Heidelberg University
Sponsor class: OTHER
First posted: 2022-07-19
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomised, controlled, parallel-group with crossover of the control group
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 6-minute walking distance
timeFrame: baseline to 15 weeks
Secondary outcomes:
measure: WHO functional class
timeFrame: baseline to 15 weeks
measure: Quality of life physical component scale SF-36
timeFrame: baseline to 15 weeks
measure: Quality of life mental component scale SF-36
timeFrame: baseline to 15 weeks
measure: peak oxygen consumption
timeFrame: baseline to 15 weeks
measure: peak oxygen consumption/kg body weight
timeFrame: baseline to 15 weeks
measure: workload achieved during cardiopulmonary exercise testing
timeFrame: baseline to 15 weeks
measure: NT-proBNP (N-terminal pro brain natriuretic peptide)
timeFrame: baseline to 15 weeks
measure: Tricuspid annular plane systolic excursion
timeFrame: baseline to 15 weeks
measure: Systolic pulmonary arterial pressure
timeFrame: baseline to 15 weeks
measure: Right atrial area
timeFrame: baseline to 15 weeks
measure: Right ventricular area
timeFrame: baseline to 15 weeks
measure: Right ventricular pump function
timeFrame: baseline to 15 weeks
measure: Left ventricular pump function
timeFrame: baseline to 15 weeks
measure: Left ventricular eccentricity index
timeFrame: baseline to 15 weeks
Other outcomes:
Locations:
city: Heidelberg
country: Germany
facility: Centre for Pulmonary Hypertension at the Thoraxklinik Heidelberg, Heidelberg University Hospital
city: Vilnius
country: Lithuania
facility: Clinic of Cardiac and Vascular Diseases, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
Study officials:
References: