Pulmonary REsistance Modification Under Treatment With Sacubitril/valsartaN in paTients With Heart Failure With Reduced Ejection Fraction

Heart Failure Clinical Trial

— PRESENT-HF  

Official title:

Pulmonary REsistance Modification Under Treatment With Sacubitril/valsartaN in paTients With Heart Failure With Reduced Ejection Fraction - PRESENT HF Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05487261
• Other study ID #: 2019/ABM/01/00078
• Status: Recruiting
• Phase: Phase 4
• Start date: December 13, 2022
• Est. completion date: November 2025

Study information

• Verified date: June 2023
• Source: Clinical Hospital Heliodor Swiecicki of the Medical University of Karol Marcinkowski in Poznan
• Contact: Marta Kaluzna-Oleksy, MD, PhD
• Phone: 502 896 932
• Email: marta.kaluzna[@]wp.pl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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].

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 260
• Est. completion date: November 2025
• Est. primary completion date: February 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Heart Failure

Intervention

Drug:
• Sacubitril-valsartan
level 1-24 / 26mg 2 times a day, level 2-49 / 51mg 2 times a day, level 3-97 / 103mg 2 times aday
• Enalapril
level 1-2.5 mg twice a day, level 2-5 mg twice a day, level 3-10 mg twice a day
• placebo
placebo matching for 24 / 26mg, 49 / 51mg, 97 / 103mg 2 of sacubitril/valsartan
• Placebo
placebo matching for 2.5 mg, 5 mg, 10 mg of enalapril

Locations

Country	Name	City	State
Poland	Medical University of Bialystok Clinical Hospital	Bialystok
Poland	University Clinical Centre in Gdansk	Gdansk
Poland	University Clinical Hospital in Opole	Opole
Poland	University Hospital in Poznan	Poznan
Poland	Specialist Hospital in Zabrze	Zabrze

Sponsors (6)

Lead Sponsor	Collaborator
Clinical Hospital Heliodor Swiecicki of the Medical University of Karol Marcinkowski in Poznan	Medical Research Agency, Poland, Medical University of Bialystok, Medical University of Gdansk, Medical University of Silesia, University of Opole

Country where clinical trial is conducted

Poland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	mean pulmonary artery pressure	change from baseline in mean pulmonary artery pressure (mPAP), measured invasively in Right Heart Catheterization (RHC)	0-13 month
Primary	pulmonary vascular resistance	change from baseline in pulmonary vascular resistance (PVR), calculated from data measured invasively in Right Heart Catheterization (RHC)	0-13 month
Secondary	pulmonary wedge pressure	change from baseline in pulmonary wedge pressure (PWP), measured invasively in Right Heart Catheterization (RHC)	0 -13 month
Secondary	diastolic pressure gradient	change from baseline in the diastolic pressure gradient (DPG; where DPG = diastolic mPAP -mean PWP)	0-13 month
Secondary	6-minute walk test	change in the 6-minute walk test (6MWT) - analysis of changes from the baseline	0-13 month
Secondary	spiroergometric test (CPET, Cardio-Pulmonary Exercise Test)	evaluation of the parameters of the spiroergometric test - analysis of changes in relation to the baseline	0-13 month
Secondary	echocardiographic parameters	assessment of echocardiographic parameters - analysis of changes in echocardiographic parameters assessed in transthoracic echocardiographic examination (TTE)	0-13 month
Secondary	composite endpoint of MACCEs (major adverse cardiac and cerebrovascular events)	The incidence of the composite endpoint of MACCEs such as death from all causes, cardiac death, hospitalization due to worsening/ decompensation of heart failure (HF), stroke/ transient ischemic attack (TIA), acute coronary syndrome (ACS), the need for a heart transplant (HT), the need for a left ventricular assist device (LVAD) or biventricular(BVAD)	0-13 month
Secondary	hospitalization or an unplanned visit to the Emergency Department	hospitalization or an unplanned visit to the Emergency Department or an unplanned outpatient visit related to HF	0-13 month
Secondary	unplanned intravenous administration of diuretics and/or an unplanned hospitalization	the need for unplanned intravenous administration of diuretics and/or an unplanned hospitalization, outpatient visit due to the need to administer intravenous diuretics or requiring an increase in the dose of diuretics >50% from baseline	0-13 month
Secondary	quality of life measurements - Short Form 36 Health Survey (SF-36 questionnaire)	assessment of quality of life - SF-36 questionnaire - change from the baseline, the minimum and maximum values: 0-100, higher scores mean a less disability.	0-13 month
Secondary	quality of life measurements - Kansas City Cardiomyopathy Questionnaire (KCCQ)	assessment of quality of life - KCCQ, the minimum and maximum values: 0-100, higher scores mean higher quality of life.	0-13 month
Secondary	quality of life measurements - EuroQol-5 Dimensions-3 Level (EQ-5D-3L) questionnaire	assessment of quality of life - EQ-5D-3L questionnaire - change from the baseline, the minimum and maximum values: 0-100, higher scores mean higher quality of life.	0-13 month
Secondary	quality of life measurements - The World Health Organization Quality of Life (WHOQOL)	assessment of quality of life - WHOQOL - change from the baseline, the minimum and maximum values: 0-100, higher scores mean higher quality of life.	0-13 month
Secondary	the New York Heart Association functional classes	assessment of the New York Heart Association (NYHA) functional classes - change from the baseline, the minimum and maximum values: 1-4, higher scores mean a worse outcome.	0-13 month
Secondary	the World Health Organization functional classes	assessment of the World Health Organization (WHO) functional classes - change from the baseline, the minimum and maximum values: 1-4, higher scores mean a worse outcome.	0-13 month