Safety and Efficacy of Angiotensin Receptor-neprilysin Inhibitor After Left Ventricular Assist Device ImplanT (SEAL-IT) Study
试验速览
- 阶段
- 4 期
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Time-averaged proportional change in NT-proBNP concentration (pg/mL) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 3 months
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adults (age ≥ 18 years)
- •Durable CF-LVAD for any indication
- •NYHA II to IV classification
- •LVEF < 40%
- •Written informed consent
排除标准
- •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.
研究组 & 干预措施
Sacubitril-valsartan study arm
- 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.
干预措施: Sacubitril-Valsartan (Drug)
Usual care (standard-of-care) arm
-
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.
-
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.
干预措施: Usual care (standard-of-care) arm (Drug)
结局指标
主要结局
Time-averaged proportional change in NT-proBNP concentration (pg/mL) with sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 3 months
时间窗: 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.
Incidence of drug discontinuation from drug-related adverse events due to sacubitril-valsartan versus standard-of-care oral vasodilator therapy at 3 months
时间窗: 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.
次要结局
- 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(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(6 weeks and/or 3, 6 and/or 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(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(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(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(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(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(6 weeks and/or 3, 6 and/or 12 months)
- 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(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(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(3, 6 and 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(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(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(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(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(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(6 weeks and/or 3, 6 and/or 12 months)
研究者
Jerry Estep MD
Principal Investigator
The Cleveland Clinic