Program of Angiotensin-Neprilysin Inhibition in Admitted Patients with Worsening Heart Failur

JRCT ID: jRCTs021210046

Registered date:15/11/2021

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Worsening heart failure with both signs of congestion and symptoms of heart failure
• Date of first enrollment: 27/12/2021
• Target sample size: 400
• Study type: Interventional

Intervention(s)

Participants will be randomized within 7 days of admission to either the sacubitril valsartan group or the control group (no sacubitril valsartan group). They will then begin protocol treatment during hospitalization within 48 hours of enrollment and allocation, followed by 8 weeks of observation and testing. Participants in the sacubitril valsartan group will start sacubitril valsartan medication on or after the day after baseline NT-proBNP is collected, and will be treated from that day until 8 weeks later. In the control group, the protocol treatment will start from the day after the baseline NT-proBNP sampling and end 8 weeks later. After the start of the protocol treatment, the study participants will be shifted to outpatient clinics according to their condition, and will be followed-up until 8 weeks later.
Participants in the sacubitril valsartan group will be switched from ACE inhibitors or ARBs that they were taking prior to allocation, and will begin oral sacubitril valsartan at a starting dose of 50 mg twice daily. The duration of treatment with the ACE inhibitor or ARB prior to allocation is irrelevant, but if the patient is switching from an ACE inhibitor, an interval of at least 36 hours must elapse since the last dose of the ACE inhibitor before starting sacubitril valsartan.
In the control group, standard treatment for heart failure, including ARB, an ACE inhibitor that the patient was taking before allocation, with drugs other than sacubitril valsartan.

Outcome(s)

• Primary Outcome: Group ratio of percent change in geometric mean NT-proBNP from baseline to 8 weeks after protocol treatment initiation

Secondary Outcome

1.Group ratio of percent change in geometric mean NT-proBNP from baseline to 4 weeks after protocol treatment initiation
2.Percentage of patients with at least a 50% reduction in NT-proBNP levels at 8 weeks after protocol treatment initiation compared with baseline
3.Percentage of patients with at least a 30% reduction in NT-proBNP levels at 4 weeks after protocol treatment initiation compared with baseline
4.Percentage of patients with at least a 40% reduction from baseline in mean NT-proBNP at 4 and 8 weeks after protocol treatment initiation
5.Amount of change and percent change in cardiac troponin T, CRP, GDF-15, soluble ST2, glucoalbumin, and 1,5-AG at 8 weeks after protocol treatment initiation compared with baseline
6.Amount of change and percent change in weight, BMI, blood pressure, heart rate, clinical laboratory test values, and NYHA class at 4 and 8 weeks after protocol treatment initiation compared with baseline
7.Amount of change and percent change in echocardiographic indices of cardiac function (LVEDV, LVESV, LVEF, septal e', lateral e', flow velocity pattern through the mitral orifice (E), E/e', LVMI, LAVI, LVOT, LVOT-VTI, TR velocity, IVC diameter, GLS, and left atrial strain (2-chamber view and 4-chamber view)) and percentage of patients with at least a 50% respiratory variation in IVC diameter at 8 weeks after protocol treatment initiation compared with baseline
8.Amount of change in KCCQ-12 score and percentage of patients with at least a 5-point increase in score at 8 weeks after protocol treatment initiation compared with baseline
9.Time to first occurrences of the composite event of all-cause death or worsening heart failure event, defined as i) unplanned rehospitalization, ii) initiation of intravenous treatment (vasodilator or positive inotropic agent) for heart failure (during hospitalization: excludes at rehospitalization), iii) urgent visit due to heart failure requiring intravenous treatment (vasodilator, positive inotropic agent, or diuretic), or iv) initiation of oral diuretic (loop diuretic, thiazide-type diuretic, or tolvaptan) or at least a 50% increase in its dose (outpatient)
10.Total number and incidence of occurrences of the composite event of all-cause death or worsening heart failure events (including recurrent event)
11.Total number and incidence of occurrences and time until occurrence of individual components of the following events: first and recurrent worsening heart failure events (i, ii, iii, and iv), all-cause mortality, and cardiovascular death
12.Total number of occurrences and time until occurrence of specific adverse events, including decreased renal function (at least a 50% increase in serum Cr or at least a 30% decrease in eGFR), hyperkalemia (serum potassium: 5.5 mEq/L or more), symptomatic hypotension, and angioedema
13.Number of occurrences of other serious adverse events

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1)Patients must provide written informed consent themselves to participate in this study
2)Aged 20 or older at consent (male or female)
3)Hospitalized due to worsening heart failure with both signs of congestion (such as edema, moist rales, and congestion on chest X-ray) and symptoms of heart failure (such as dyspnea on mild exertion or at rest) (any level of left ventricular ejection fraction)
4)NYHA class II-IV
5)Taking an ACE inhibitor or an ARB
6)Can undergo randomization within 7 days of current hospitalization
7)Patients who meet the following criteria of hemodynamic stability
I.Systolic blood pressure >100 mm Hg
II.No dose increase of intravenous diuretic within 6 hours before randomization
III.No intravenous administration of vasodilator (such as carperitide or nitrates) or positive inotropic agent
8)Patients who meet the following reference range for natriuretic peptide level from 48 hours before current hospitalization to the time of eligibility determination
NT-proBNP >-1200 pg/mL or BNP >-300 pg/mL

Exclude criteria

1)Currently taking oral sacubitril valsartan or have taken it within 30 days prior to randomization
2)History of hypersensitivity to ingredients in ARB, ACE inhibitor, or sacubitril valsartan; or expected to be contraindicated for or intolerant to any of these drugs
3)History of angioedema
4)Severe renal dysfunction (<eGFR 30 mL/min/1.73m2), on maintenance dialysis, or known bilateral renal artery stenosis (in patients with solitary kidney, known renal artery stenosis in the residual kidney)
5)Severe liver dysfunction (Child-Pugh class C)
6)Diabetic patients who are currently taking aliskiren fumarate
7)Serum potassium >5.3 mEq/L or more
8)Cardiogenic shock
9)On cardiopulmonary support, with a left ventricular assist device, or on a ventilator
10)Onset of stroke or acute coronary syndrome within 30 days prior to randomization
11)History of surgical or percutaneous treatment of cardiovascular disease within 30 days prior to randomization
12)Patients with an advanced plan for surgical or percutaneous treatment of cardiovascular disease or for coronary artery revascularization during an observation period
13)Patients with an advanced plan for pacemaker implantation, cardiac resynchronization therapy, or electrical cardioversion during an observation period
14)History or comorbidity of hypertrophic obstructive cardiomyopathy or infiltrative cardiomyopathy such as amyloidosis or sarcoidosis
15)Active pericardial disease
16)History of or awaiting heart transplant
17)Severe chronic respiratory disease or active infectious disease
18)Patients who are or might become pregnant or who are breastfeeding
19)Patients whom a study investigator determined to be unsuitable for the study (such as patients with comorbid active malignancy)

Related Information

• Primary Sponsor: Node Koichi
• Source(s) of Monetary Support: Novartis Pharma K.K.
• Secondary ID(s): NCT05164653