Pulmonary Artery Pressure Reduction With ENTresto (Sacubitril/Valsartan)

Phase 4

Terminated

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

• Registration Number: NCT02788656
• Lead Sponsor: Brigham and Women's Hospital

Brief Summary

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).

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 Timeline

• Study First Submitted: 2016-05-23
• Study First Submitted QC: 2016-05-27
• Study First Posted: 2016-06-02
• Study Start: 2016-09
• Primary Completion: 2018-11-09
• Study Completion: 2018-11-09
• Status Verified: 2020-02
• Results First Submitted: 2020-02-03
• Results First Submitted QC: 2020-02-03
• Last Update Submitted: 2020-02-03
• Results First Posted: 2020-02-17
• Last Update Posted: 2020-02-17

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 4

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group A	Implantable Hemodynamic Monitor	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).
Group B	Implantable Hemodynamic Monitor	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).
Group B	Angiotensin-Converting Enzyme Inhibitor	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).
Group B	Angiotensin II Type 1 Receptor Blocker	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).
Group A	sacubitril/valsartan	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).
Group B	sacubitril/valsartan	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).

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Brigham and Women's Hospita; 🇺🇸 Boston, Massachusetts, United States