Ivabradine in Cirrhotic Cardiomyopathy

Efficacy of Carvedilol + Ivabradine vs Carvedilol Alone for Left Ventricular Diastolic Dysfunction in Chronic Liver Disease Patients and Its' Impact on Morbidity and Mortality; a Prospective Randomized Controlled Trial.

A total of 130 patients with liver cirrhosis who fulfill the criteria of the study, and who have been found to have left ventricular diastolic dysfunction on a screening 2D echocardiography, will then be randomized by Block randomization technique, to two arms in a ratio 1:1(Group A) will receive carvedilol+ Ivabradine targeted therapy for heart rate reduction while Group B will receive Carvedilol alone; and the dosage of drug in the treatment arm will be titrated every week to achieve target heart rate of 50-60/ minute. Patients in the treatment arms, who are unable to tolerate carvedilol due to hypotension episodes, will be offered ivabradine alone to allow achievement of targeted heart rate reduction. All patients will be evaluated at 0,6, and 12 months. The end points will be clinical events, cardiac function improvement, renal function, and mortality.

Study Overview

• Status: Recruiting
• Conditions: Portal Hypertension; Cirrhosis, Liver; Left Ventricular Dysfunction; Cirrhotic Cardiomyopathy
• Intervention / Treatment: Drug: Betablocker + ivabradine; Drug: Betablocker

Detailed Description

The investigators have already demonstrated the role of targeted heart rate reduction in the management of LVDD in cirrhosis, but the previous study could not demonstrate the role of ivabradine alone in absence of betablocker therapy. This trial will be a validation cohort for the initial data obtained on this novel drug. The use of ivabradine can treat patients who do not tolerate betablocker therapy due to contraindications or adverse effects especially hypotension.

Diagnosis of CCM will be as per 2020 CCMC criteria. CCM is defined as systolic or diastolic dysfunction in the absence of alternative cardiac pathology in concordance with the Cirrhotic Cardiomyopathy Consortium (CCMC) criteria. 9 Systolic dysfunction was defined as an ejection fraction (EF) ≤50% or an absolute value of GLS <18%. CCM will defined as presence of 3 of the following 4 criteria: septal early diastolic mitral annular flow velocity (e') <7 cm/s, early diastolic transmitral flow to early diastolic mitral annular velocity (E/e') ≥15, left atrial volume index (LAVI) >34 mL/m2, tricuspid jet maximum velocity >2.8 m/s, in the absence of pulmonary hypertension and the presence of measurable early to late diastolic transmitral flow velocity (E/A) ratio (E/A >2 = grade 3 & E/A 0.8-2 = grade 2 LVDD). Persons meeting only 2 criteria will be termed as indeterminate for LVDD grade.

• Study Type: Interventional
• Enrollment (Estimated): 130
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Madhumita Premkumar, MD DM; Phone Number: 01722756344; Email: drmadhumitap@gmail.com

Study Locations

• India
  • Choose Any State/Province
    • Chandigarh, Choose Any State/Province, India, 160012
      • Recruiting
      • Postgraduate Institute of Medical Education and Research
      • Contact: Madhumita Premkumar

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age range of 18-65 years
• Cirrhosis, as diagnosed by histology or clinical, laboratory and USG findings,
• LV diastolic dysfunction on 2D echocardiography

Exclusion Criteria:

• Chronic renal disease
• Patient already on beta blocker
• Pregnancy and peripartum cardiomyopathy
• Hypertension
• Coronary artery disease
• Valvular heart disease
• Sick sinus syndrome/ Pacemaker
• Cardiac rhythm disorder
• Hypothyroidism
• Hyperthyroidism
• Portal vein thrombosis
• Transjugular intrahepatic porto systemic shunt (TIPS) insertion
• Hepatocellular carcinoma
• Anemia Hb < 8gm/dl in females, and < 9 gm/dl in males

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Carvedilol	Drug: Betablocker; Use of maximum tolerated dose of carvedilol to achieve targeted heart rate reduction (THR) to 55-65 beats per minute (responder) or inability to reach THR (non responder) with maximum dose of carvedilol, maintaining a minimum MAP of 70 mmHg.
Experimental: Carvedilol + Ivabradine	Drug: Betablocker + ivabradine; Use of maximum tolerated dose of carvedilol and ivabradine to achieve therapeutic heart rate reduction (THR) to 55-65 beats per minute

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival	All cause mortality to be assessed	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Episodes of Cirrhosis related events	New onset ascites, variceal bleeding,hepatorenal syndrome	12 months
Change in E/e' Ratio	Echo parameter to be documented	12 months
Change in renal function		12 months
Change in HRQoL		12 months
Change in neurohormonal markers- Brain natriuretic peptide, aldosterone, plasma renin activity		12 months

Collaborators and Investigators

• Sponsor: Postgraduate Institute of Medical Education and Research
• Investigators: Study Chair: Radha K Dhiman, MD DM, Postgraduate Institute of Medical Education and Research

Publications and helpful links

General Publications

• Izzy M, VanWagner LB, Lin G, Altieri M, Findlay JY, Oh JK, Watt KD, Lee SS; Cirrhotic Cardiomyopathy Consortium. Redefining Cirrhotic Cardiomyopathy for the Modern Era. Hepatology. 2020 Jan;71(1):334-345. doi: 10.1002/hep.30875. Epub 2019 Oct 11. Erratum In: Hepatology. 2020 Sep;72(3):1161.
• Premkumar M, Rangegowda D, Vyas T, Khumuckham JS, Shasthry SM, Thomas SS, Goyal R, Kumar G, Sarin SK. Carvedilol Combined With Ivabradine Improves Left Ventricular Diastolic Dysfunction, Clinical Progression, and Survival in Cirrhosis. J Clin Gastroenterol. 2020 Jul;54(6):561-568. doi: 10.1097/MCG.0000000000001219.
• Kaur H, Premkumar M. Diagnosis and Management of Cirrhotic Cardiomyopathy. J Clin Exp Hepatol. 2022 Jan-Feb;12(1):186-199. doi: 10.1016/j.jceh.2021.08.016. Epub 2021 Aug 21.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2020
• Primary Completion (Estimated): October 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: September 26, 2019
• First Submitted That Met QC Criteria: September 28, 2019
• First Posted (Actual): October 1, 2019

Study Record Updates

• Last Update Posted (Estimated): February 13, 2024
• Last Update Submitted That Met QC Criteria: February 12, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Ivabradine; Carvedilol; Cirrhotic cardiomyopathy; Left ventricular diatolic dysfunction
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Liver Diseases; Fibrosis; Liver Cirrhosis; Cardiomyopathies; Hypertension, Portal; Ventricular Dysfunction; Ventricular Dysfunction, Left; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Adrenergic beta-Antagonists
• Other Study ID Numbers: INT/IEC/2019/001617

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No