Ivabradine in Cirrhotic Cardiomyopathy

Portal Hypertension Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04111133
• Other study ID #: INT/IEC/2019/001617
• Status: Recruiting
• Phase: N/A
• Start date: January 1, 2020
• Est. completion date: December 2024

Study information

• Verified date: February 2024
• Source: Postgraduate Institute of Medical Education and Research
• Contact: Madhumita Premkumar, MD DM
• Phone: 01722756344
• Email: drmadhumitap[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 130
• Est. completion date: December 2024
• Est. primary completion date: October 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Cardiomyopathies
• Cirrhosis, Liver
• Cirrhotic Cardiomyopathy
• Hypertension, Portal
• Left Ventricular Dysfunction
• Liver Cirrhosis
• Portal Hypertension
• Ventricular Dysfunction
• Ventricular Dysfunction, Left

Intervention

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
• 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.

Locations

Country	Name	City	State
India	Postgraduate Institute of Medical Education and Research	Chandigarh	Choose Any State/Province

Sponsors (1)

Lead Sponsor	Collaborator
Postgraduate Institute of Medical Education and Research

Country where clinical trial is conducted

India, 

References & Publications (3)

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 — View Citation

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. — View Citation

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 Gastroentero — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Survival	All cause mortality to be assessed	12 months
Secondary	Change in E/e' Ratio	Echo parameter to be documented	12 months
Secondary	Change in renal function		12 months
Secondary	Change in HRQoL		12 months
Secondary	Change in neurohormonal markers- Brain natriuretic peptide, aldosterone, plasma renin activity		12 months
Secondary	Number of Episodes of Cirrhosis related events	New onset ascites, variceal bleeding,hepatorenal syndrome	12 months