Comparison of ARNI to Alternate Oral Vasodilator Therapies in Patients With Low Cardiac Output

Phase 4

Withdrawn

• Conditions: Cardiogenic Shock
• Interventions: Drug: Sacubitril-Valsartan; Drug: Standard Oral Vasodilators

• Registration Number: NCT04206865
• Lead Sponsor: The Cleveland Clinic

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:

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

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 Timeline

• Study Start: 2019-11-25
• Study First Submitted: 2019-12-11
• Study First Submitted QC: 2019-12-18
• Study First Posted: 2019-12-20
• Primary Completion: 2020-09-10
• Study Completion: 2020-09-10
• Status Verified: 2020-10
• Last Update Submitted: 2020-10-01
• Last Update Posted: 2020-10-05

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ARNI therapy	Sacubitril-Valsartan	Patient's randomized to this arm will receive sacubitril-valsartan per study protocol and titrated per titration guidelines.
Standard Oral Vasodilator	Standard Oral Vasodilators	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).

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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.
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
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.

Trial Locations

Locations (1)

Cleveland Clinic; 🇺🇸 Cleveland, Ohio, United States