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

NCT ID: NCT04206865

Last Updated: 2020-10-05

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE4
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-11-25
• Study Completion Date: 2020-09-10

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.

Conditions

Cardiogenic Shock

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

ARNI therapy

Patient's randomized to this arm will receive sacubitril-valsartan per study protocol and titrated per titration guidelines.

Group Type: EXPERIMENTAL

Sacubitril-Valsartan

Intervention Type: DRUG

Patient's will be randomized to ICU initiation of sacubitril-valsartan vs. alternate oral vasodilator therapy in 1:1 fashion

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).

Group Type: ACTIVE_COMPARATOR

Standard Oral Vasodilators

Intervention Type: DRUG

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

Interventions

Sacubitril-Valsartan

Patient's will be randomized to ICU initiation of sacubitril-valsartan vs. alternate oral vasodilator therapy in 1:1 fashion

Intervention Type: 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

Intervention Type: DRUG

Other Intervention Names

ARNI therapy; Usual Care

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The Cleveland Clinic

OTHER

Sponsor Role: lead

Responsible Party

Randall C Starling MD MPH

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Randall Starling, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

The Cleveland Clinic

Locations

Cleveland Clinic

Cleveland, Ohio, United States

Countries

United States

Other Identifiers

19-1133

Identifier Type: -

Identifier Source: org_study_id