Effective Study of ARNI on Ventricular Arrhythmia in HFrEF Patients With ICD or CRT-D (RHYTHM)

Study Overview
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Brief Summary
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The purpose of this study is to generate effectiveness data of ARNI, in the Chinese HFrEF patients with implanted ICD or CRT-D. This will be a multicenter, interventional, open-label, and prospective single-arm study to evaluate the effect of ARNI on VAs in approximately 219 HFrEF patients receiving ICD or CRT-D in China.

Detailed Description
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The rationale of this study is to compare the effect of ACEI/ARB with the effect of ARNI on VA events for HFrEF patients with ICD or CRT-D, thus a multicenter, interventional, open-label, and prospective single-arm study was considered. Study design:This will be a multicenter, interventional, open-label, and prospective single-arm study to evaluate the effect of ARNI on VAs in approximately 219 HFrEF patients receiving ICD or CRT-D in China. After the patient is informed and asked to sign an informed consent form, baseline data will be collected. Device data of patients will be collected for 12 months. ACEI/ARB will be given to the patient for 6 months. Dosage of ACEI/ARB will be based on investigator's discretion and up titrated after 2-4 weeks to the maximum dosage the patients can tolerate and according to product label.After 6 months, patients using ACEI need to undergo a 36-hr washout period (36-hr washout period is not needed for patients using ARB at month 6). Patients will then receive ARNI (sponsored by Novartis only for this study) while the dosage of ARNI will be according to investigator's discretion and up titrated to the maximum dosage the patient can tolerate or 200 mg bid as per guideline.All patients will be followed up for 6 months for each treatment. After patients finalize the trial, the investigator will evaluate all patients and produce a report. Primary objective of this study is to assess the proportion of patients with VA events over 6 months of ACEI/ARB and 6 months of ARNI treatment. Secondary Objectives include:To assess numbers of occurrences of VA events and ICD or CRT-D shocks over 6 months of ACEI/ARB and 6 months of ARNI treatment; To compare the changes in LVEF and NYHA level between ACEI/ARB and ARNI treatment; To compare the changes in the NT-proBNP level between ACEI/ARB and ARNI treatments; To compare the healthcare resource utilization of HF patients during ACEI/ARB and ARNI treatments;

Official Title
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A Multicenter, Interventional, Open-label and Single-arm Study to Investigate the Effect of ARNI on Ventricular Arrhythmia in HFrEF Patients With ICD or CRT-D

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: ACEI/ARB
* Drug: ARNI


Participation Criteria
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Eligibility Criteria
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Key Inclusion criteria: Male or female patients ≥18 and ≤80 years of age Implanted with an ICD or CRT-D within 2 weeks NYHA functional class II - IV LVEF ≤40% (measured by echocardiography) Signed informed consent must be obtained prior to participation in the study. Key Exclusion criteria History of hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes. Patient received target dose (≥200 mg/d) of ARNI for 2 weeks continuously within the 6-week period prior to study enrollment. Participation in other clinical studies 3 months prior to participating study. Advanced cancer or other significant comorbidities with life expectancy of <1 year. Previous history of angioedema associated with ACEI/ARB treatment, hereditary or idiopathic angioedema. Patients with renal artery stenosis history. Current stage D HF patients requiring vasoactive drugs. Symptomatic hypotension < 100/60 mmHg at visit 1 (screening) or Symptomatic hypotension < 90/60 mmHg in anti-hypertension drug treatment at visit 1 (screening). Serum potassium >5.4 mmol/L at visit 1 (screening). Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 as measured at visit 1 (screening). Pregnant or nursing (lactating) women. Other exclusion depend on investigator's discretion. Other protocol- defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ACEI/ARB treatment in 6 months/ARNI treatment in next 6 months<br>Angiotensin-converting enzyme inhibitor/Angiotensin receptor blockers treatment in the first 6 months Angiotensin receptor neprilysin inhibitor treatment in next 6 months | Drug: ACEI/ARB<br>* initative ACE/ARB drug for 6 months in this study<br>Drug: ARNI<br>* initative ARNI drug for next 6 months in this study<br>* Other names: Entresto;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with VA, ICD and ATP events over 6 months of ACEI/ARB and 6 months of ARNI treatment | Paired proportion of patients by occurrence of at least one Ventricular arrhythmia (VA), Implantable cardioverter defibrillator (ICD ) & Antitachycardia pacing (ATP) event over 6 months of Angiotensin-converting enzyme inhibitor/Angiotensin receptor blockers(ACEI/ARB) & Angiotensin receptor neprilysin inhibitor (ARNI) treatment respectively. VA events defined as: NSVT(Non-sustained ventricular tachycardia), SVT(Sustained ventricular tachycardia),PVC(Premature ventricular contraction), SVT is defined as: tachycardia with haemodynamic disorder or lasting for ≥30 seconds. NSVT is defined as: different ICD devices. PVC is defined as: early ventricular depolarization as determined by device. ICD events: Ventricular tachycardia occurrence in implantable cardioverter defibrillator (ICD) patients may result in shock delivery & is associated with increased morbidity & mortality. ATP events: Anti-tachycardia pacing is defined as a low-energy alternative to high-energy biphasic shocks. | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Numbers of NSVT, SVT, PVC, ICD shock and ATP experienced by patients | To assess the number of occurrences of Ventricular arrhythmia (VA) events and Implantable cardioverter defibrillator (ICD) or Cardiac resynchronization therapy-defibrillator (CRT-D) shocks over 6 months of ACEI/ARB and 6 months of ARNI treatment | baseline, 6 month, 12 month | 
| LVEF (%) | To compare the changes in Left Ventricular Ejection Fraction (LVEF) between ACEI/ARB and ARNI treatments | baseline, 6 month, 12 month | 
| NYHA level | To compare the changes in New York Heart Association (NYHA) level between ACEI/ARB and ARNI treatments | baseline, 6 month, 12 month | 
| NT-proBNP (pg/mL) level | To compare the changes in the N-Terminal prohormone of Brain Natriuretic Peptide(NT-proBNP) level between ACEI/ARB and ARNI treatments | baseline, 6 month, 12 month | 
| Number of hospitalizations for arrhythmia or HF related hospitalizations | To compare the healthcare resource utilization of Heart Failure (HF) patients during ACEI/ARB and ARNI treatments | baseline, 6 month, 12 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LCZ696, sacubitril/valsartan, Heart Failure, Heart failure with reduced ejection fraction, HFrEF, Ventricular arrhythmias, Implanted Device, Healthcare resource utilization