Clinical trial NCT05487261: Pulmonary REsistance Modification Under Treatment With Sacubitril/valsartaN in paTients With Heart Failure With Reduced Ejection Fraction
Official title: Pulmonary REsistance Modification Under Treatment With Sacubitril/valsartaN in paTients With Heart Failure With Reduced Ejection Fraction - PRESENT HF Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Heart Failure
Lead sponsor: Clinical Hospital Heliodor Swiecicki of the Medical University of Karol Marcinkowski in Poznań
Sponsor class: OTHER
Collaborators: name: Medical Research Agency, Poland
name: Medical University of Bialystok
name: University of Opole
name: Medical University of Gdansk
name: Medical University of Silesia
First posted: 2022-08-04
Enrollment: 260
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: MAIN OBJECTIVE. Demonstration that use of sacubitril/valsartan influences parameters of right heart catheterization, including pulmonary artery pressure, and provokes changes in pulmonary circulation resistance in patients with heart failure with reduced left ventricular ejection fraction (HFrEF) and post-capillary pulmonary hypertension (PH): both isolated post-capillary (Ipc-PH) and combined post- and pre-capillary (Cpc-PH), which we predict could improve prognosis in this group of patients.

RESEARCH HYPOTHESIS. Sacubitril/valsartan used in patients with HFrEF accompanied by pulmonary hypertension due to HFrEF will reduce pulmonary artery pressure, pulmonary vascular resistance, and the incidence of secondary end-points as listed in the protocol.

STUDY OUTLINE. PRESENT-HF will show the effects of sacubitril/valsartan on pulmonary circulation pressure in patients with HFrEF and post-capillary pulmonary hypertension (PH): both isolated post-capillary (Ipc-PH) and combined post- and pre-capillary (Cpc-PH), which is expected to improve prognosis.

Detailed description: Non commercial, multicentre, randomised, double-blind, comparator-controlled clinical trial. Eligible patients were randomly assigned (1:1) using a secure, central, interactive, web-based response system, to intervention or comparator arm. Time of observation 13 months \[1months active up titration phase + 12 months follow up\].

Eligibility criteria: Inclusion Criteria:

1. Age ≥18 years of age who are able to complete and sign the informed consent form.
2. HF patients in NYHA functional class II-IV with a reduced left ventricular ejection fraction (LVEF) ≤40% -(HFrEF) (confirmed by an examination such as echocardiography or cardiac magnetic resonance within the last 6 months) in whom right heart catheterization (RHC) reveals post-capillary or mixed pulmonary hypertension (defined on the basis of the 2015 ESC (European Society of Cardiology) guidelines: mean pulmonary artery pressure (PAPm) ≥25 mmHg and pulmonary capillary wedge pressure (PCWP)\>15mmHg) were found, both of the isolated extracapillary PH (Ipc-PH) (defined on the basis of the 2015 ESC guidelines: DPG \< 7 mm Hg and / or PVR ≤ 3 WU) as well as complex extra-and pre-capillary PH (Cpc-PH) (defined on the basis of the 2015 ESC guidelines: DPG ≥ 7 mm Hg and / or PVR\> 3 WU).
3. Stable patients haemodynamics, which is defined as no change in diuretic use for at least 4 weeks prior to study entry.
4. HF during optimal treatment with ACE-I (angiotensin converting enzyme) /ARB (angiotensin receptor blocker), beta blocker, MRA (Mineralocorticoid Receptor Antagonists), SGLT2-I except in cases where the above-mentioned treatment was contraindicated or not tolerated.
5. Understanding and acceptance of the research assumptions and methods and signing the informed consent by the patient.

Exclusion Criteria:

1. Current treatment with S/V.
2. Cardiogenic shock.
3. Current treatment with sildenafil.
4. Patients ineligible or contraindicated for treatment with sacubitril-valsartan.
5. Patients with a history of angioedema.
6. Patients who have had a heart transplant or have had a circulatory support device.
7. Patient on the urgent list for heart transplant.
8. Isolated right HF secondary to lung disease.
9. Documented untreated significant ventricular arrhythmia with syncope within the previous 3 months.
10. Symptomatic bradycardia or second or third degree atrioventricular block not protected by a pacemaker.
11. Factors that prevent RHC testing (e.g. very serious condition of the patient that makes it impossible to lie down, cardiogenic shock, allergy to contrast agents, etc.).
12. Pregnant or lactating women.
13. Women of childbearing age, defined as the physiological possibility of becoming pregnant, unless using two methods of contraception.
14. Acute coronary syndrome, including myocardial infarction (STEMI, NSTEMI), a condition with carotid revascularization or major cardiovascular surgery in the last 30 days.
15. Stroke or transient cerebral ischemia (TIA) within the last 3 months.
16. Previous CRT (Cardiac Resynchronization Therapy) implantation in the last 3 months or planning for CRT implantation.
17. Life expectancy \<6 months.
18. Severe renal failure, eGFR (epidermal growth factor receptor) \<30 ml / min / 1.73 m2(calculated according to the MDRD formula).
19. Serum potassium\> 5.2 mEq/L.
20. Liver failure or elevated liver transaminases (total bilirubin\> 3 mg / dL and/or ALT (Aspartate transaminase) and/or AST (Aspartate Aminotransferase) ≥3x ULN).
21. A major surgery planned within 6 months of randomization.
22. Planned coronary angioplasty or pacemaker / ICD (implantable cardioverter defibrillator) / CRT implantation within the next 6 months.
23. Severe primary valve disease (NOT secondary mitral regurgitation) or obstructive hypertrophic cardiomyopathy.
24. The presence of a malignant neoplasm of any organ system, ie clinical signs or no stable remission for at least 3 years after the end of the last treatment, with the exception of non-invasive basal cell carcinoma, squamous cell carcinoma of the skin or cervical epithelial dysplasia.
25. Diseases that significantly reduce physical performance:

    1. severe COPD (chronic obstructive pulmonary disease) putting off oxygen therapy,
    2. severe asthma,
    3. morbid obesity (BMI\> 40 kg / m2),
    4. significant lower limb atherosclerosis with intense intermittent claudication.
26. Uncontrolled hypertension (SBP\> 170 mmHg and / or DBP\> 100 mmHg).
27. Symptomatic hypotension (SPB \<90 mmHg)
28. Any situation that may make it impossible to perform the research in accordance with the protocol or express written consent in the opinion of the researcher, including abuse of alcohol, drugs or other psychoactive substances.
29. Participation in a study with a device or medicinal product within 3 months prior to randomization or 5 half-lives, whichever is longer, prior to the screening visit.

Primary outcomes:
measure: mean pulmonary artery pressure
timeFrame: 0-13 month
measure: pulmonary vascular resistance
timeFrame: 0-13 month
Secondary outcomes:
measure: pulmonary wedge pressure
timeFrame: 0 -13 month
measure: diastolic pressure gradient
timeFrame: 0-13 month
measure: 6-minute walk test
timeFrame: 0-13 month
measure: spiroergometric test (CPET, Cardio-Pulmonary Exercise Test)
timeFrame: 0-13 month
measure: echocardiographic parameters
timeFrame: 0-13 month
measure: composite endpoint of MACCEs (major adverse cardiac and cerebrovascular events)
timeFrame: 0-13 month
measure: hospitalization or an unplanned visit to the Emergency Department
timeFrame: 0-13 month
measure: unplanned intravenous administration of diuretics and/or an unplanned hospitalization
timeFrame: 0-13 month
measure: quality of life measurements - Short Form 36 Health Survey (SF-36 questionnaire)
timeFrame: 0-13 month
measure: quality of life measurements - Kansas City Cardiomyopathy Questionnaire (KCCQ)
timeFrame: 0-13 month
measure: quality of life measurements - EuroQol-5 Dimensions-3 Level (EQ-5D-3L) questionnaire
timeFrame: 0-13 month
measure: quality of life measurements - The World Health Organization Quality of Life (WHOQOL)
timeFrame: 0-13 month
measure: the New York Heart Association functional classes
timeFrame: 0-13 month
measure: the World Health Organization functional classes
timeFrame: 0-13 month
Other outcomes:
Locations:
city: Białystok
country: Poland
facility: Medical University of Bialystok Clinical Hospital
city: Gdańsk
country: Poland
facility: University Clinical Centre in Gdańsk
city: Opole
country: Poland
facility: University Clinical Hospital in Opole
city: Poznań
country: Poland
facility: University Hospital in Poznan
city: Zabrze
country: Poland
facility: Specialist Hospital in Zabrze
Study officials:
affiliation: University Hospital in Poznan
name: Ewa Straburzyńska-Migaj, Prof. MD
role: PRINCIPAL_INVESTIGATOR
References: