Safety and Efficacy of ARNI After LVAD ImplanT (SEAL-IT) Study

Study Overview
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Brief Summary
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The purpose of the study is to evaluate how well tolerated and effective an angiotensin receptor-neprilysin inhibitor (sacubitril-valsartan) is in patients with contemporary durable continuous flow left ventricular assist device (CF-LVAD) implantation compared to usual care oral vasodilator therapy.

Detailed Description
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The aim of this pilot study is to prospectively determine the short-term (at 3 months) and long-term (at 6 and 12 months) safety and efficacy of an angiotensin receptor-neprilysin inhibitor (sacubitril-valsartan) in patients with contemporary durable continuous flow left ventricular assist device (CF-LVAD) implantation compared to standard-of-care (usual care) oral vasodilator therapy.

Official Title
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Safety and Efficacy of Angiotensin Receptor-neprilysin Inhibitor After Left Ventricular Assist Device ImplanT (SEAL-IT) Study

Conditions
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Stage D Heart Failure

Intervention / Treatment
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* Drug: Sacubitril-Valsartan
* Drug: Usual care (standard-of-care) arm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults (age ≥ 18 years) Durable CF-LVAD for any indication NYHA II to IV classification LVEF < 40% Written informed consent Exclusion Criteria: Inability to comply with the conditions of the protocol Any patient with durable CF-LVAD who has any one of the following: i. symptomatic hypotension or MAP < 60 mm Hg at randomization, ii. eGFR < 30 mL/min/1.73 m2 at randomization, iii. potassium > 5.4 mM at randomization, iv. history of angioedema at randomization, v. history of unacceptable side effects with ACE inhibitor, ARB, or sacubitril-valsartan therapy at randomization, vi. use of vasoactive agents (e.g., dobutamine, dopamine, epinephrine, norepinephrine, phenylephrine, vasopressin, nitroglycerin, nitroprusside, epoprostenol) or parenteral diuretics in 24 hours preceding randomization.

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: Sacubitril-valsartan study arm<br>Start medication-naïve patients on low-dose sacubitril-valsartan (24/26 mg PO BID) without a washout period per guideline and label recommendations. Switch patients to equivalent dose sacubitril-valsartan if on prior ACE inhibitor (after a 36 hour washout period) or ARB therapy (after discontinuing one day prior). If therapeutic range MAP (65 to 85 mm Hg), discontinue other oral vasodilator (e.g., hydralazine, isordil) or non-rate limiting dihydropyridine calcium channel blocker (non-DHP CCB, e.g., amlodipine) therapy on the day prior to sacubitril-valsartan initiation. If MAP > 85 mm Hg, low-dose sacubitril-valsartan will be added with or without discontinuation of other oral vasodilator or non-DHP CCB per physician's discretion based on drug tolerability and maintenance of therapeutic range MAP. Sacubitril-valsartan can be up-titrated every 2-4 weeks per standard practice guidelines per physician's discretion as above. | Drug: Sacubitril-Valsartan<br>* Sacubitril-valsartan at low or equivalent dose to be initiated or added to patients randomized to this arm, and titrated up every 2-4 weeks, per standard practice guidelines and label recommendations per physician's discretion.<br>* Other names: Entresto;|
| Active Comparator: Usual care (standard-of-care) arm<br>1. Continue current regimen of patients on oral vasodilator therapy (e.g., ACE inhibitor, ARB, hydralazine, isordil), allowing for up-titration of the drug every 2-4 weeks per standard practice guidelines in keeping with physician's discretion as above. 2. Start medication-naïve patients de novo on one of the oral vasodilators as below per guideline and label recommendations, allowing for up-titration of the drug every 2-4 weeks per standard practice guidelines in keeping with physician's discretion as above: i. ACE inhibitor: Enalapril 2.5 mg PO BID or Lisinopril 5 mg PO daily; ii. ARB: Valsartan 20 mg PO BID or Losartan 25 mg PO daily; iii. Other: Hydralazine 10 mg PO TID or Isordil 5 mg PO TID. | Drug: Usual care (standard-of-care) arm<br>* Other oral vasodilator therapy to be continued or initiated to patients randomized to this arm, and titrated up every 2-4 weeks, per standard practice guidelines and label recommendations per physician's discretion.<br>* Other names: Oral Vasodilator;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of drug discontinuation from drug-related adverse events due to sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 3 months | Incidence of drug discontinuation from drug-related adverse events due to sacubitril-valsartan versus standard-of-care oral vasodilator therapy evaluated at 3 months. Incidence of drug discontinuation is defined as the number of patients exposed to the drug with an adverse event over the total number of patients exposed to the drug. An adverse event is defined as any one of the following: acute kidney injury with eGFR decline > 25% from baseline, hyperkalemia with potassium > 5.5 mM, hypotension with mean arterial pressure (MAP) < 60 mm Hg, angioedema, dizziness, and/or cough. | 3 months | 
| Time-averaged proportional change in NT-proBNP concentration (pg/mL) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 3 months | Time-averaged proportional change in NT-proBNP concentration (pg/mL) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy evaluated at 3 months. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-averaged proportional change in NT-proBNP concentration (pg/mL) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 6 and 12 months | Time-averaged proportional change in NT-proBNP concentration (pg/mL) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy evaluated at 6 and 12 months. | 6 and 12 months | 
| Proportion of patients (%) with effective MAP control (65 to 85 mm Hg) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 3, 6 and 12 months | Proportion of patients (%) with effective MAP control (65 to 85 mm Hg) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy evaluated at 3, 6 and 12 months. | 3, 6 and 12 months | 
| Proportion of patients (%) on other cardiac medications with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 3, 6 and 12 months relative to baseline | Proportion of patients (%) on other cardiac medications (e.g., diuretics, aldosterone antagonists, beta-blockers, oral vasodilators, and anti-hypertensives) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy evaluated at 3, 6 and 12 months relative to baseline. | 3, 6 and 12 months | 
| Proportion of patients (%) in each New York Heart Association (NYHA) classification with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 3, 6 and 12 months relative to baseline | Proportion of patients (%) in each New York Heart Association (NYHA) classification (e.g., functional class I-IV) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy evaluated at 3, 6 and 12 months relative to baseline. | 3, 6 and 12 months | 
| Proportion of patients (%) with heart failure readmissions with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 6 and 12 months | Proportion of patients (%) with heart failure readmissions with sacubitril-valsartan versus standard-of-care oral vasodilator therapy determined at 6 and 12 months. | 6 and 12 months | 
| Absolute change in mean left ventricular end-diastolic dimension (mm) on echocardiogram with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 6 weeks and/or 3, 6 and/or 12 months | Absolute change in mean left ventricular end-diastolic dimension (mm) on echocardiogram with sacubitril-valsartan versus standard-of-care oral vasodilator therapy evaluated at 6 weeks and/or 3, 6 and/or 12 months. | 6 weeks and/or 3, 6 and/or 12 months | 
| Absolute change in mitral E/A ratio on echocardiogram with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 6 weeks and/or 3, 6 and/or 12 months | Absolute change in mitral E/A ratio on echocardiogram with sacubitril-valsartan versus standard-of-care oral vasodilator therapy evaluated at 6 weeks and/or 3, 6 and/or 12 months. | 6 weeks and/or 3, 6 and/or 12 months | 
| Absolute change in indexed left atrial volume (mL/m2) on echocardiogram with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 6 weeks and/or 3, 6 and/or 12 months | Absolute change in indexed left atrial volume (mL/m2) on echocardiogram with sacubitril-valsartan versus standard-of-care oral vasodilator therapy evaluated at 6 weeks and/or 3, 6 and/or 12 months. | 6 weeks and/or 3, 6 and/or 12 months | 
| Absolute change in indexed right atrial volume (mL/m2) on echocardiogram with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 6 weeks and/or 3, 6 and/or 12 months | Absolute change in indexed right atrial volume (mL/m2) on echocardiogram with sacubitril-valsartan versus standard-of-care oral vasodilator therapy evaluated at 6 weeks and/or 3, 6 and/or 12 months. | 6 weeks and/or 3, 6 and/or 12 months | 
| Absolute change in mean right atrial pressure (mm Hg) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 6 weeks and/or 3, 6 and/or 12 months | Absolute change in mean right atrial pressure (mm Hg) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy evaluated at 6 weeks and/or 3, 6 and/or 12 months. | 6 weeks and/or 3, 6 and/or 12 months | 
| Absolute change in mean pulmonary artery pressure (mm Hg) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 6 weeks and/or 3, 6 and/or 12 months | Absolute change in mean pulmonary artery pressure (mm Hg) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy evaluated at 6 weeks and/or 3, 6 and/or 12 months. | 6 weeks and/or 3, 6 and/or 12 months | 
| Absolute change in mean pulmonary artery diastolic pressure (mm Hg) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 6 weeks and/or 3, 6 and/or 12 months | Absolute change in mean pulmonary artery diastolic pressure (mm Hg) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy evaluated at 6 weeks and/or 3, 6 and/or 12 months. | 6 weeks and/or 3, 6 and/or 12 months | 
| Absolute change in mean pulmonary capillary wedge pressure (mm Hg) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 6 weeks and/or 3, 6 and/or 12 months | Absolute change in mean pulmonary capillary wedge pressure (mm Hg) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy evaluated at 6 weeks and/or 3, 6 and/or 12 months. | 6 weeks and/or 3, 6 and/or 12 months | 
| Absolute change in pulmonary artery pulsatility index with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 6 weeks and/or 3, 6 and/or 12 months | Absolute change in pulmonary artery pulsatility index with sacubitril-valsartan versus standard-of-care oral vasodilator therapy evaluated at 6 weeks and/or 3, 6 and/or 12 months. | 6 weeks and/or 3, 6 and/or 12 months | 
| Absolute change in pulmonary vascular resistance (Woods Unit) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 6 weeks and/or 3, 6 and/or 12 months | Absolute change in pulmonary vascular resistance (Woods Unit) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy evaluated at 6 weeks and/or 3, 6 and/or 12 months. | 6 weeks and/or 3, 6 and/or 12 months | 
| Absolute change in systemic vascular resistance (dynes-sec/cm5) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 6 weeks and/or 3, 6 and/or 12 months | Absolute change in systemic vascular resistance (dynes-sec/cm5) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy evaluated at 6 weeks and/or 3, 6 and/or 12 months. | 6 weeks and/or 3, 6 and/or 12 months | 
| Absolute change in cardiac index (L/min/m2) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 6 weeks and/or 3, 6 and/or 12 months | Absolute change in cardiac index (L/min/m2) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy evaluated at 6 weeks and/or 3, 6 and/or 12 months. | 6 weeks and/or 3, 6 and/or 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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continuous flow left ventricular assist device, sacubitril-valsartan, oral vasodilator, Heart failure