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

Sponsor

The Cleveland Clinic (Other)

Overall Status

Withdrawn

CT.gov ID

NCT04206865

Collaborator

(none)

Enrollment

Location

Arms

9.5

Actual Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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:

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.
Establish the safety of initiating sacubitril-valsartan in an intensive care setting
Characterize the hemodynamic effect of sacubitril-valsartan on patients with low cardiac output
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

Condition or Disease	Intervention/Treatment	Phase
Cardiogenic Shock	Drug: Sacubitril-Valsartan Drug: Standard Oral Vasodilators	Phase 4

Detailed Description

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.
Establish the safety of initiating sacubitril-valsartan in an intensive care setting
Characterize the hemodynamic effect of sacubitril-valsartan on patients with low cardiac output
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 Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Nov 25, 2019

Actual Primary Completion Date :

Sep 10, 2020

Actual Study Completion Date :

Sep 10, 2020

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Proportion of patients on ARNI therapy at one-month follow-up [1 month]
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.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Heart Failure with reduced ejection fraction (EF <40%) documented in past 1 year
Presence of low cardiac index ≤2.2 based on PA catheter measurement followed by stabilization and readiness to transition to oral vasodilator therapy
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)
Intention to maintain pulmonary artery catheter for hemodynamic directed optimization of therapy

Exclusion Criteria:

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