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

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

The purpose of this study was to generate effectiveness data of Angiotensin receptor neprilysin inhibitor (ARNI), in the Chinese Heart failure with reduced ejection fraction (HFrEF) patients with implantable cardioverted defibrillator (ICD) or Cardiac resynchronization therapy-defibrillator (CRT-D).

Study Overview

• Status: Terminated
• Conditions: Heart Failure
• Intervention / Treatment: Drug: ACEI/ARB; Drug: ARNI

Detailed Description

The rationale of this study was to compare the effect of angiotensin-converting enzyme inhibitor (ACEI) / Angiotensin receptor blockers (ARB) with the effect of ARNI on ventricular arrhythmia (VA) events for HFrEF patients with ICD or CRT-D, thus a multicenter, interventional, open-label, and prospective single-arm study was considered.

ACEI/ARB was given to the patient for 6 months. After 6 months, patients using ACEI needed to undergo a 36-hr washout period (36-hr washout period was not needed for patients using ARB at month 6). Patients then received ARNI (sponsored by Novartis only for this study).

• Study Type: Interventional
• Enrollment (Actual): 201
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Qingdao, China, 266000
    • Novartis Investigative Site
  • Tianjin, China, 300000
    • Novartis Investigative Site
  • An Hui
    • Hefei, An Hui, China, 230001
      • Novartis Investigative Site
  • Bei Jing
    • Bei Jing, Bei Jing, China, 100034
      • Novartis Investigative Site
  • Beijing
    • Beijing, Beijing, China, 100044
      • Novartis Investigative Site
  • Fujian
    • Fuzhou, Fujian, China, 350001
      • Novartis Investigative Site
  • Guangdong
    • Guangzhou, Guangdong, China, 510000
      • Novartis Investigative Site
    • Shenzhen, Guangdong, China, 518057
      • Novartis Investigative Site
  • Henan
    • Zhengzhou, Henan, China, 450000
      • Novartis Investigative Site
  • Hunan
    • Changsha, Hunan, China, 410011
      • Novartis Investigative Site
  • Jiangsu
    • Nanjing, Jiangsu, China, 210000
      • Novartis Investigative Site
    • Nantong, Jiangsu, China, 226000
      • Novartis Investigative Site
    • Wu XI, Jiangsu, China, 214023
      • Novartis Investigative Site
    • Xuzhou, Jiangsu, China, 221000
      • Novartis Investigative Site
  • Liaoning
    • Dalian, Liaoning, China, 116011
      • Novartis Investigative Site
    • Shenyang, Liaoning, China, 110011
      • Novartis Investigative Site
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Novartis Investigative Site
    • Shanghai, Shanghai, China, 200433
      • Novartis Investigative Site
  • Shanxi
    • Xian, Shanxi, China, 710061
      • Novartis Investigative Site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Novartis Investigative Site
    • Chengdu, Sichuan, China, 610031
      • Novartis Investigative Site
  • Xinjiang
    • Wulumuqi, Xinjiang, China, 830054
      • Novartis Investigative Site
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310014
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion criteria:

1. Male or female patients ≥18 and ≤80 years of age
2. Implanted with an ICD or CRT-D within 2 weeks
3. NYHA functional class II - IV
4. LVEF ≤40% (measured by echocardiography)
5. Signed informed consent must be obtained prior to participation in the study.

Key Exclusion criteria

1. History of hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes.
2. Patient received target dose (≥200 mg/d) of ARNI for 2 weeks continuously within the 6-week period prior to study enrollment.
3. Participation in other clinical studies 3 months prior to participating study.
4. Advanced cancer or other significant comorbidities with life expectancy of <1 year.
5. Previous history of angioedema associated with ACEI/ARB treatment, hereditary or idiopathic angioedema.
6. Patients with renal artery stenosis history.
7. Current stage D HF patients requiring vasoactive drugs.
8. Symptomatic hypotension < 100/60 mmHg at visit 1 (screening) or Symptomatic hypotension < 90/60 mmHg in anti-hypertension drug treatment at visit 1 (screening).
9. Serum potassium >5.4 mmol/L at visit 1 (screening).
10. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 as measured at visit 1 (screening).
11. Pregnant or nursing (lactating) women.
12. Other exclusion depend on investigator's discretion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ACEI/ARB treatment for 6 months/ARNI treatment the next 6 months; Patients received angiotensin-converting enzyme inhibitor/angiotensin receptor blockers treatment the first 6 months. The following 6 months patients received angiotensin receptor neprilysin inhibitor treatment.	Drug: ACEI/ARB; Oral ACE/ARB drug according to the investigator's discretion for the first 6 months in this study; Drug: ARNI; Oral sacubitril/valsartan at the dosage of investigators discretion, whit a target dose of 200mg bid for the next 6 months of this study; Other Names: Entresto

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Paired Patients With Ventricular Arrhythmia (VA) Events	VA events were measured through devices to determine sustained ventricular tachycardia (SVT), non-sustained ventricular tachycardia (NSVT) and premature ventricular contraction (PVC). SVT was defined as tachycardia lasting for ≥30 seconds or with hemodynamic disorder as determined by Holter and/or device. NSVT was defined as recorded by Holter and/or device. PVC was defined as an early ventricular depolarization as determined by the device, and/or detected by Holter. PVC data were not available for patients with single -lumen implantation type	Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
Proportion of Paired Patients Who Experienced at Least One ICD or CRT-D Shock and ATP Event	Once VA events were detected, implantable cardioverter defibrillator (ICD) could treat with high-energy shocks or Anti-tachycardia pacing (ATP). ATP consists of one or more trains of pacing stimuli, expressed as a percentage of the tachycardia cycle length for a given RR interval, from the onset of the preceding R wave. Patients with sustained VA events would receive ICD or cardiac resynchronization therapy-defibrillator (CRT-D) shock therapy.	Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pairwise Number of SVT, NSVT, PVC, ICD or CRT-D Shocks and ATP Events 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. PVC data were not available for patients with single-lumen implantation type	Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
Left Ventricular Ejection Fraction	To compare the changes in Left Ventricular Ejection Fraction (LVEF) between ACEI/ARB and ARNI treatments. LVEF is a measurement expressed as a percentage of how much blood in the left ventricle is pumped out with each contraction of the heart.	Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
New York Heart Association Classification	To compare the changes in New York Heart Association (NYHA) level between ACEI/ARB and ARNI treatments. NYHA classification is a subjective physician's assessment of heart failure patient's functional capacity and symptomatic status. Class I - No limitation of physical activity. Class II - Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea (shortness of breath). Class III - Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV - Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases.	Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
N-Terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Level	To compare the changes in the N-Terminal prohormone of Brain Natriuretic Peptide(NT-proBNP) level between ACEI/ARB and ARNI treatments. NT-proBNP are small proteins produced in large amounts when the heart senses it needs to work harder, such as in heart failure.	Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)
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	Up to 12 months (6 months of ACEI/ARB treatment and 6 months of ARNI treatment)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on www.novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): November 11, 2020
• Primary Completion (Actual): June 8, 2023
• Study Completion (Actual): June 8, 2023

Study Registration Dates

• First Submitted: June 22, 2020
• First Submitted That Met QC Criteria: July 28, 2020
• First Posted (Actual): July 29, 2020

Study Record Updates

• Last Update Posted (Actual): May 16, 2025
• Last Update Submitted That Met QC Criteria: May 14, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Heart Failure; Heart failure with reduced ejection fraction; Ventricular arrhythmias; Healthcare resource utilization; LCZ696; HFrEF; sacubitril/valsartan; Implanted Device
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Heart Failure; Arrhythmias, Cardiac; Molecular Mechanisms of Pharmacological Action; Angiotensin Receptor Antagonists; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: CLCZ696BCN04

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No