Pulmonary Artery Pressure Reduction With ENTresto (Sacubitril/Valsartan) (PARENT)

PARENT Trial Pilot Pulmonary Artery Pressure Reduction With ENTresto (Sacubitril/Valsartan)

This pilot study will assess the impact of sacubitril/valsartan (trade name Entresto) on the elevated pulmonary artery pressures in patients with heart failure with reduced ejection fraction, measured using a previously implanted hemodynamic monitoring device (CardioMEMS).

Study Overview

• Status: Terminated
• Conditions: Congestive Heart Failure
• Intervention / Treatment: Device: Implantable Hemodynamic Monitor; Drug: sacubitril/valsartan; Drug: Angiotensin-Converting Enzyme Inhibitor; Drug: Angiotensin II Type 1 Receptor Blocker

Detailed Description

Angiotensin-converting enzyme inhibitors (ACEi) have been a cornerstone treatment for patients with heart failure and reduced ejection fraction (HFrEF) for over 25 years. They are included in every major set of guidelines for HFrEF management. Angiotensin receptor blockers (ARB's, such as valsartan) have similarly been shown to decrease the mortality rate of patients with HFrEF for patients who are unable to tolerate ACEi therapy.

The newest neurohormonal therapy approved for heart failure (August 2015) is sacubitril/valsartan (trade name Entresto). This medication is the first of a new family of agents (ARNI = angiotensin receptor antagonist with neprilysin inhibitor), combining the approved angiotensin receptor blocker valsartan with sacubitril, an inhibitor of neprilysin, which is a neutral endopeptidase that degrades endogenous vasoactive peptides. Treatment with sacubitril increases circulating levels of natriuretic peptides, which have been shown to facilitate natriuresis and vasodilation. Although the precise mechanisms responsible for benefit in heart failure remain unclear, sacubitril/valsartan may reduce the fluid retention and vasoconstriction that contribute to heart failure symptoms, and may also decrease apoptosis and remodeling that lead to disease progression. There is limited data about the incremental acute and long-term hemodynamic effects of composite neprilysin/angiotensin-receptor inhibitors over enalapril, and these data may provide important mechanistic insights.

Progress in HF management outside the hospital has included validation of a strategy of ongoing monitoring of pulmonary artery pressures every day from home via a monitor implanted in a distal pulmonary artery, the CardioMEMS device. The information is transmitted to a website where it is reviewed by the HF team, who can intervene to adjust diuretics and other medications by phone to avert decompensation and re-hospitalization. The device received FDA approval in mid 2014, and is now being implanted in many cardiac catheterization laboratories, including at Brigham and Women's Hospital. The pressure information is reviewed regularly by the HF management team who are in regular contact with the patient to aid in management decisions.

In summary, this pilot study will assess the impact of sacubitril/valsartan, an approved drug for heart failure with reduced ejection fraction (HFrEF) on the elevated pulmonary artery pressures measured using an implanted monitoring device that is also approved for such patients. Both the medication and the device will be used according to approved indications.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospita

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. Patients able to provide written informed consent
2. Patients ≥18 years of age, male or female, in NYHA Class II- III HF, previously hospitalized for HFrEF with LVEF < 35% (measured within the past year), and who have no subsequent LVEF>35%.
3. Systolic BP > 95 mm Hg at most recent clinical assessment.
4. Stable, ambulatory patients without the need for change in diuretics and other HF drugs (RAS blockers, beta blockers or mineralocorticoid receptor blockers) during the past 5 days
5. CardioMEMS HF System implanted for NYHA Class III HF. Patient transmitting information regularly and system functioning appropriately.
6. NT-proBNP > 500 pg/ml within 90 days of CardioMEMS implantation.
7. Average PAPm >20mm Hg during the 7 days prior to enrollment, including at least 4 daily measurements.
8. Women of childbearing age must be on highly effective method of contraception

Exclusion Criteria:

1. Treatment with vasodilators (other than nitrates, hydralazine) and/or IV inotropic drugs.
2. Entresto taken within the past 30 days.
3. History of hypersensitivity, intolerance or angioedema to previous renin-angiotensin system (RAS) blocker, ACE inhibitor, ARB, or Entresto.
4. eGFR < 30 ml/min/1.73 m2 as measured by the simplified MDRD formula.
5. Serum potassium > 5.5 mmol/L.
6. Acute coronary syndrome, stroke, transient ischemic attack, cardiovascular surgery, PCI, or carotid angioplasty within the preceding 3 months.
7. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within 3 months after trial entry.
8. Non-cardiac condition(s) as the primary cause of dyspnea.
9. Implantation of a cardiac resynchronization therapy device (CRT/D) within the pr preceding 3 months or intent to implant a CRT/D, which may alter the pressures during the course of the study.
10. History of heart transplantation, placement of an LVAD, listing for Status IA for cardiac transplantation or planned placement of an LVAD within 3 months following randomization.
11. Documented untreated ventricular arrhythmia with syncopal episodes within the prior 3 months.
12. Symptomatic bradycardia or second or third degree heart block without a pacemaker.
13. Hepatic dysfunction, as evidenced by total bilirubin > 3 mg/dl.
14. Pregnancy
15. Women who are breastfeeding
16. Chronic lithium use

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
Experimental: Group A; Group A will receive sacubitril/valsartan + placebo for weeks 1-12. and then sacubitril/valsartan only for weeks 13-32. All subjects in Group A will also receive longitudinal pulmonary artery pressure monitoring using a previously placed implantable hemodynamic monitor (CardioMEMS device).	Device: Implantable Hemodynamic Monitor; The CardioMEMS device is an implantable pulmonary artery pressure monitor that is FDA-approved for use in patients with symptomatic heart failure and previous heart failure hospitalization. Patients eligible for this study are those with an already implanted CardioMEMS device.; Other Names: CardioMEMS; Drug: sacubitril/valsartan; Angiotensin-neprilysin inhibitor that is now FDA-approved and guideline-directed therapy for patients with symptomatic heart failure and reduced ejection fraction despite treatment with an ACE-inhibitor/Angiotensin-Receptor Blocker; Other Names: Entresto
Active Comparator: Group B; Group B will receive an Angiotensin-Converting Enzyme Inhibitor (ACEi) or Angiotensin II Type 1 Receptor Blocker (ARB) + placebo for weeks 1-6 (depending on previous background therapy) and then switch to sacubitril/valsartan + placebo for weeks 7-12. Group B will then receive sacubitril/valsartan only for weeks 13-32. All subjects in Group B will also receive longitudinal pulmonary artery pressure monitoring using a previously placed implantable hemodynamic monitor (CardioMEMS device).	Device: Implantable Hemodynamic Monitor; The CardioMEMS device is an implantable pulmonary artery pressure monitor that is FDA-approved for use in patients with symptomatic heart failure and previous heart failure hospitalization. Patients eligible for this study are those with an already implanted CardioMEMS device.; Other Names: CardioMEMS; Drug: sacubitril/valsartan; Angiotensin-neprilysin inhibitor that is now FDA-approved and guideline-directed therapy for patients with symptomatic heart failure and reduced ejection fraction despite treatment with an ACE-inhibitor/Angiotensin-Receptor Blocker; Other Names: Entresto; Drug: Angiotensin-Converting Enzyme Inhibitor; Conventional, guideline-directed therapy for heart failure and reduced ejection fraction; Other Names: ACE inhibitor, ACEi; Drug: Angiotensin II Type 1 Receptor Blocker; Conventional, guideline-directed therapy for heart failure and reduced ejection fraction in ACE-inhibitor intolerant patients; Other Names: Angiotensin Receptor Blocker, ARB

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference Between Mean Change in Mean Pulmonary Artery Pressure (PAPm) With Sacubitril/Valsartan Compared to the Mean Change in PAPm With Continued ACEi/ARB	Change in mean PAP in group A versus group B	Baseline, 6 weeks
The Acute Change in PAPm After the First Administration of Sacubitril/Valsartan	Change in PAPm at 3 hours	Baseline, 3 hours (after first dose of sacubitril/valsartan)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in PAPm in Both Groups on Sacubitril/Valsartan	Change in PAPm from week 12-32	20 weeks (weeks 12 to 32 of the study)
The Difference Between Mean Change in PAPm From Baseline on Sacubitril/Valsartan Compared to ACEI/ARB	Change in PAPm on sacubitril/valsartan: Measured from baseline to week 6 (group A) and week 7-week 12 (Group B)	6 weeks (week 1-6 of the study for group A, weeks 7-12 for group B)
Determine the Change in Distance Walked During a Standard 6 Minute Walk Test From Baseline	Change in 6 minute walk distance in Group A vs. Group B at 6 weeks	Baseline, 6 weeks
Change in NT-proBNP	Change in NT-proBNP from baseline to 6 weeks	Baseline

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Relationship of Change in PAPm to Change in the Questions in the Kansas City Cardiomypathy Questionnaire (KCCQ) 3,7,8,9	Correlation between change in PAPm and change in KCCQ at 32 weeks	Baseline, 32 weeks (testing performed at intervals during study)
Mean Change in Total Daily Diuretic Dose While on Sacubitril/Valsartan	Mean change in total daily diuretic dose while on sacubitril/valsartan (32 weeks)	Baseline, 32 weeks (testing performed at intervals during study)

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: Novartis
• Investigators: Study Director: Lauren G Gilstrap, MD, Brigham & Womens' Hospital

Study record dates

Study Major Dates

• Study Start: September 1, 2016
• Primary Completion (Actual): November 9, 2018
• Study Completion (Actual): November 9, 2018

Study Registration Dates

• First Submitted: May 23, 2016
• First Submitted That Met QC Criteria: May 27, 2016
• First Posted (Estimate): June 2, 2016

Study Record Updates

• Last Update Posted (Actual): February 17, 2020
• Last Update Submitted That Met QC Criteria: February 3, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: heart failure; implantable hemodynamic monitor; neprilysin; angiotensin-converting enzyme inhibitor; angiotensin-receptor blocker
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Protease Inhibitors; Serine Proteinase Inhibitors; Vasoconstrictor Agents; Valsartan; Sacubitril and valsartan sodium hydrate drug combination; Enzyme Inhibitors; Angiotensin II; Giapreza; Angiotensinogen; Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists; Angiotensin II Type 1 Receptor Blockers
• Other Study ID Numbers: 2016P000831/MGH

Plan for Individual participant data (IPD)

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