Ivabradine in Cirrhotic Cardiomyopathy

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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.

Conditions
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Left Ventricular Dysfunction, Portal Hypertension, Cirrhotic Cardiomyopathy, Cirrhosis, Liver

Intervention / Treatment
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* Drug: Betablocker + ivabradine
* Drug: Betablocker


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carvedilol + Ivabradine<br> | Drug: Betablocker + ivabradine<br>* Use of maximum tolerated dose of carvedilol and ivabradine to achieve therapeutic heart rate reduction (THR) to 55-65 beats per minute<br>|
| Active Comparator: Carvedilol<br> | Drug: Betablocker<br>* 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.<br>|

What is the study measuring?
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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 |
| --- | --- | --- |
| 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 | 
| Number of Episodes of Cirrhosis related events | New onset ascites, variceal bleeding,hepatorenal syndrome | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cirrhotic cardiomyopathy, Left ventricular diatolic dysfunction, Carvedilol, Ivabradine