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

Study Overview
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Brief Summary
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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

Detailed Description
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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 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.

Official Title
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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

Conditions
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Cardiogenic Shock

Intervention / Treatment
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* Drug: Sacubitril-Valsartan
* Drug: Standard Oral Vasodilators


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARNI therapy<br>Patient's randomized to this arm will receive sacubitril-valsartan per study protocol and titrated per titration guidelines. | Drug: Sacubitril-Valsartan<br>* Patient's will be randomized to ICU initiation of sacubitril-valsartan vs. alternate oral vasodilator therapy in 1:1 fashion<br>* Other names: ARNI therapy;|
| Active Comparator: Standard Oral Vasodilator<br>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<br>* 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<br>* Other names: Usual Care;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ARNI, Sacubitril-Valsartan, Cardiogenic Shock, Tailored Therapy, Cardiac Intensive Care