The Impact of Ivabradine on Left Ventricular Reverse Remodeling in Nonischemic Dilated Cardiomyopathy (NIDCM) on Current Medical Therapy Era

In non-ischemic dilated cardiomyopathy (NIDCM), left ventricular reverse remodeling (LVRR) can be achieved through guideline-directed medical therapy (GDMT). LVRR is defined as an increase in left ventricular ejection fraction (LVEF) of more than 10% in heart failure patients with a baseline LVEF of 40% or less, or an increase in LVEF of more than 40% at follow-up, which is classified as heart failure with improved EF (HFimpEF) according to current guidelines. Several studies have examined the prevalence and predictors of LVRR in NIDCM. However, there is a lack of research on LVRR in the context of contemporary pharmacotherapy. Studies have demonstrated the beneficial effects of ivabradine in heart failure with reduced ejection fraction (HFrEF), improving patients' prognosis. A sub-study of the SHIFT trial indicated that ivabradine may also contribute to cardiac remodeling reversal in patients with HFrEF. However, there is limited evidence exploring the relationship between ivabradine and LVRR, particularly in the context of NIDCM.

Consequently, this study is a retrospective, multi-center cohort study aiming to evaluate the impact of ivabradine on LVRR in patients with NIDCM in the current era of medical therapy. Furthermore, by conducting this study, we aim to gain insights into the potential role of ivabradine in promoting LVRR in NIDCM patients receiving contemporary drug therapy.

Study Overview

• Status: Active, not recruiting
• Conditions: Dilated Cardiomyopathy; Ventricular Remodeling; Heart Failure, Reduced Ejection Fraction

• Study Type: Observational
• Enrollment (Estimated): 500

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Severance Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Patients diagnosed with NIDCM with sinus rhythm

Description

Inclusion Criteria:

1. Diagnosed with non-ischemic dilated cardiomyopathy (NIDCM) by performing coronary artery imaging (coronary angiography, CT angiography, or SPECT scan) at the time of diagnosis of HFrEF
2. Sinus rhythm
3. Baseline LVEF of 40% or less (LVEF≤40%)

4. Patients containing baseline heart rate (HR)

   • In the Ivabradine group, baseline HR must be >75 bpm at the time of ivabradine dosing.

Exclusion Criteria:

1. Patients with confirmed ischemic cardiomyopathy (when stenosis of 75% or more of major coronary arteries is confirmed on coronary artery imaging or ischemic cardiomyopathy findings such as transmural LGE on cardiac MRI)
2. Heart failure with other etiologies (e.g., valvular heart disease, endocrine disease).
3. Previous recovery history of left ventricular systolic function (LVEF)
4. Cardiac resynchronization therapy (CRT) implantation
5. Persistent/permanent atrial fibrillation

7) Contraindication to the administration of ivabradine according to the Summary of Product Characteristics (SmPC)

• Hypersensitivity reactions
• Symptomatic bradycardia or resting heart rate < 75 bpm prior to treatment
• Cardiogenic shock, acute myocardial infarction, severe hypotension (< 90/50 mmHg), severe hepatic failure, sinus syndrome, atrial block, unstable or acute heart failure, pacemaker dependence (with pacing dominance), unstable angina, third degree atrioventricular block
• Cytochrome P450 3A4 inhibitors: Azole class antifungals (ketoconazole,itraconazole), Macrolide class antibiotics (clarithromycin, erythromycin per os, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir), nefazodone or any concomitant use with verapamil or diltiazem (moderate CYP3A4 inhibitors with heart rate reducing properties).

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
achieved HR ≥ 70 bpm without ivabradine; **Achieved HR : heart rate (HR) at 12 month follow up after the initiation of GDMT**
achieved HR < 70 bpm without ivabradine; **Achieved HR : heart rate (HR) at 12 month follow up after the initiation of GDMT**
achieved HR ≥ 70 bpm with ivabradine; **Achieved HR : heart rate (HR) at 12 month follow up after the initiation of GDMT**
achieved HR < 70 bpm with ivabradine; **Achieved HR : heart rate (HR) at 12 month follow up after the initiation of GDMT**

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence of of LVRR in patients with NIDCM	LVRR is characterized by an increase in left ventricular ejection fraction (LVEF) of more than 10% in heart failure patients with a baseline LVEF of 40% or less, or an increase in LVEF of more than 40% during follow-up, which is classified as heart failure with improved EF (HFimpEF). Furthermore, the initiation of guideline-directed medical therapy (GDMT) is defined as the timeframe for commencing treatment with an angiotensin-converting enzyme inhibitor (ACEi), angiotensin II receptor antagonist (ARB), or beta-blocker after the diagnosis of heart failure with reduced ejection fraction (HFrEF).	at 12 months after the initiation of GDMT

Secondary Outcome Measures

Outcome Measure	Time Frame
Prevalence of LVRR in NIDCM at 8 months after initiation of GDMT	at 8 months after GDMT initiation
Extent of LVRR (measured by LVEDD/LVESD, LAVI, E/e' in echocardiography) in NIDCM at 8 and 12 months after GDMT initiation	at 8 and 12 months after GDMT initiation
Clinical course of LVRR in NIDCM	at 8 and 12 months after GDMT initiation
Effect of targeted HR (HF <60 or 70/min) on LVRR in NIDCM at 8 and 12 months after GDMT initiation	at 8 and 12 months after GDMT initiation
Effect of degree of change in HR before and after GDMT on LVRR in NIDCM at 8 and 12 months after GDMT initiation	at 8 and 12 months after GDMT initiation
Impact of GDMT on LVRR in NIDCM at 8 and 12 months after GDMT initiation	at 8 and 12 months after GDMT initiation
Prevalence of symptomatic bradycardia, syncope, or any other adverse events with Ivabradine	at 8 and 12 months after GDMT initiation

Collaborators and Investigators

• Sponsor: Yonsei University
• Investigators: Principal Investigator: Seok-Min Kang, Division of Cardiology, Yonsei Cardiovascular Hospital, Yonsei University College of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2023
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: July 16, 2023
• First Submitted That Met QC Criteria: July 31, 2023
• First Posted (Actual): August 3, 2023

Study Record Updates

• Last Update Posted (Actual): August 3, 2023
• Last Update Submitted That Met QC Criteria: July 31, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Pathological Conditions, Anatomical; Cardiomegaly; Laminopathies; Heart Failure; Cardiomyopathies; Cardiomyopathy, Dilated; Heart Failure, Systolic; Ventricular Remodeling
• Other Study ID Numbers: 4-2022-1665

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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