Clinical trial NCT04111133: Ivabradine in Cirrhotic Cardiomyopathy
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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Cirrhotic Cardiomyopathy
Left Ventricular Dysfunction
Cirrhosis, Liver
Portal Hypertension
Keywords: Cirrhotic cardiomyopathy
Left ventricular diatolic dysfunction
Carvedilol
Ivabradine
Lead sponsor: PGIMER
Sponsor class: UNKNOWN
First posted: 2019-10-01
Enrollment: 130
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Survival
timeFrame: 12 months
Secondary outcomes:
measure: Change in E/e' Ratio
timeFrame: 12 months
measure: Change in renal function
timeFrame: 12 months
measure: Change in HRQoL
timeFrame: 12 months
measure: Change in neurohormonal markers- Brain natriuretic peptide, aldosterone, plasma renin activity
timeFrame: 12 months
measure: Number of Episodes of Cirrhosis related events
timeFrame: 12 months
Other outcomes:
Locations:
city: Chandigarh
country: India
facility: Postgraduate Institute of Medical Education and Research
state: Choose Any State/Province
Study officials:
affiliation: Post Graduate Institute of Medical Education and Research, Chandigarh
name: Radha K Dhiman, MD DM
role: STUDY_CHAIR
References:
citation: 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.
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 Gastroenterol. 2020 Jul;54(6):561-568. doi: 10.1097/MCG.0000000000001219.
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.