Comparison of ARNI to Alternate Oral Vasodilator Therapies in Patients With Low Cardiac Output (PARAVLO-HF)

Prospective Comparison of ARNI to Alternate Oral Vasodilator Therapies to Determine the Hemodynamic Profile and Relative Tolerability of (ARNIs) in Patients With Decompensated Heart Failure and Low Cardiac Output

This is a prospective, randomized, non-blinded, single-center efficacy study of acutely decompensated heart failure patients with reduced ejection fraction (HFrEF), low cardiac index (<2.2) as determined by pulmonary artery catheter (PAC) who have been hemodynamically stabilized and ready for transition to oral vasodilator therapy at the discretion of the clinician. The investigators would like to accomplish the following objectives with this study:

1. Establish the superiority of an upfront initiation strategy for sacubitril-valsartan at maintaining patients on ARNI therapy at one-month follow-up compared to usual care.
2. Establish the safety of initiating sacubitril-valsartan in an intensive care setting
3. Characterize the hemodynamic effect of sacubitril-valsartan on patients with low cardiac output
4. Expand the population of hospitalized patients that can be initiated on ARNIs and thus facilitate prior to hospital discharge patients who are on optimal goal-directed medical therapy (GDMT) for heart failure

Study Overview

• Status: Withdrawn
• Conditions: Cardiogenic Shock
• Intervention / Treatment: Drug: Sacubitril-Valsartan; Drug: Standard Oral Vasodilators

Detailed Description

This is a prospective, randomized, non-blinded, single-center efficacy study of acutely decompensated heart failure patients with reduced ejection fraction (HFrEF), low cardiac index (<2.2) as determined by pulmonary artery catheter (PAC) who have been hemodynamically stabilized and ready for transition to oral vasodilator therapy at the discretion of the clinician. The investigators would like to accomplish the following objectives with this study:

1. Establish the superiority of an upfront initiation strategy for sacubitril-valsartan at maintaining patients on ARNI therapy at one-month follow-up compared to usual care.
2. Establish the safety of initiating sacubitril-valsartan in an intensive care setting
3. Characterize the hemodynamic effect of sacubitril-valsartan on patients with low cardiac output
4. Expand the population of hospitalized patients that can be initiated on ARNIs and thus facilitate prior to hospital discharge patients who are on optimal goal-directed medical therapy (GDMT) for heart failure

In this pragmatic study, the primary endpoint will be establishing the superiority of sacubitril-valsartan as an oral vasodilator in maintaining ARNI therapy at one-month post hospital discharge as compared to usual care. Given the overall mortality and heart failure hospitalization benefit of ARNI over ACEI and other vasodilators has been established in large-scale clinical trials, establishing that upfront initiation of ARNI therapy in patients with low cardiac output is safe and can be maintained post-discharge would be of significant clinical benefit. Adverse events including symptomatic hypotension (requiring cessation of drug), development of worsening renal function (requiring cessation of drug), hyperkalemia [moderate (> 5.5 mmol/L) or severe (> 6 mmol/L)], or re-initiation of IV vasodilator or IV inotropic therapy will be monitored and tracked.

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic

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. Heart Failure with reduced ejection fraction (EF <40%) documented in past 1 year
2. Presence of low cardiac index ≤2.2 based on PA catheter measurement followed by stabilization and readiness to transition to oral vasodilator therapy
3. SBP > 90 and SVR >950 at the time of randomization or tolerating an adequate amount of IV vasodilator therapy i.e. sodium nitroprusside (clinician discretion) without symptomatic or sustained hypotension (>30 minutes)
4. Intention to maintain pulmonary artery catheter for hemodynamic directed optimization of therapy

Exclusion Criteria:

1. Acute kidney injury (increase in serum creatinine concentration of >0.5 mg per deciliter) and a decrease in the estimated GFR >25% in the preceding 24 hours
2. Documented intolerance to sacubitril, valsartan, or any ARBs, neprilysin inhibitors or any of the sacubitril/valsartan excipients, any history of angioedema
3. End-stage renal disease at screening, or estimated GFR <30mL/min/1.73m² by MDRD
4. Sustained Symptomatic hypotension after initiation of nitroprusside (Clinician Discretion or >30 minutes)
5. Acute Coronary Syndrome, Stoke, TIA, Cardiac, Carotid, or other major cardiovascular surgery, PCI, or carotid angioplasty within 3 months of screening
6. Hyperkalemia- Serum Potassium >5.5 mmol/L at randomization
7. Enrollment in concurrent clinical trials with investigational drugs
8. CAD likely to require surgical or percutaneous intervention within 3 months after screening
9. Implantation ofCRT, or upgrade of existing device or revision of the device leads within 1 month of screening
10. Heart Transplant or VAD or intent to transplant (on transplant list) or implant VAD in the next 6 months.
11. PI discretion regarding eligibility
12. Active infection/sepsis
13. Active use of temporary mechanical support

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ARNI therapy; Patient's randomized to this arm will receive sacubitril-valsartan per study protocol and titrated per titration guidelines.	Drug: Sacubitril-Valsartan; Patient's will be randomized to ICU initiation of sacubitril-valsartan vs. alternate oral vasodilator therapy in 1:1 fashion; Other Names: ARNI therapy
Active Comparator: Standard Oral Vasodilator; Patient's randomized to this arm will receive the oral vasodilator that the clinician chooses including angiotensin receptor blocker (ARB), isosorbide dinitrate, hydralazine, and angiotensin-converting enzyme inhibitor (ACEi).	Drug: Standard Oral Vasodilators; Patient's will be randomized to ICU initiation of sacubitril-valsartan vs. alternate oral vasodilator therapy in 1:1 fashion. Alternate vasodilators will include ARBs, hydralazine and isosorbide dinitrate, and ACEi; Other Names: Usual Care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients on ARNI therapy at one-month follow-up	This will be the proportion of patients randomized to each arm who remain on ARNI therapy at one-month follow-up. Reasons for discontinuation will be tracked.	1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of time of in the Intensive Care Unit	Length of time from admission to the cardiac intensive care unit to disposition.	Hospital discharge, 1 Month
Length of Hospital Stay	Length of time in days from hospital admission to discharge.	Hospital discharge, 1 Month
Change in NT-proBNP from admission at one-month follow-up	NT-proBNP value on admission and again drawn at the one-month follow-up visit.	1 Month
30 day HF readmissions	This includes 24 hr admits, IV therapy, ER visits for HF treatment that occur within 30 days of hospital discharge.	1 Month
180 day telephone follow up to determine: ARNI yes or no, hospitalizations, mortality, LVAD or transplant	180 day telephone follow up to determine: ARNI yes or no, hospitalizations, mortality, LVAD or transplant	180 days

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Investigators: Principal Investigator: Randall Starling, MD, MPH, The Cleveland Clinic

Study record dates

Study Major Dates

• Study Start (Actual): November 25, 2019
• Primary Completion (Actual): September 10, 2020
• Study Completion (Actual): September 10, 2020

Study Registration Dates

• First Submitted: December 11, 2019
• First Submitted That Met QC Criteria: December 18, 2019
• First Posted (Actual): December 20, 2019

Study Record Updates

• Last Update Posted (Actual): October 5, 2020
• Last Update Submitted That Met QC Criteria: October 1, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Cardiogenic Shock; ARNI; Sacubitril-Valsartan; Tailored Therapy; Cardiac Intensive Care
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Shock; Myocardial Infarction; Infarction; Shock, Cardiogenic; Cardiac Output, Low; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Valsartan; Sacubitril and valsartan sodium hydrate drug combination; Vasodilator Agents
• Other Study ID Numbers: 19-1133

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes