Cardiometabolic Risk Factors, Cirrhosis, Cirrhotic Cardiomyopathy, Empagliflozin
Conditions
Keywords
Empagliflozin in cirrhosis, Carvedilol in Cirrhosis, SGLT-2 inhibitor, Ascites, Diastolic heart failure, heart failure with preserved ejection fraction
Brief summary
1. This proposed double-blind placebo controlled randomized controlled trial incorporates recent advances in management of heart failure and portal hypertension using the SGLT-2 inhibitor i.e. EMPAGLIFLOZIN. The drug has been found to be useful in large trials on heart failure with preserved ejection fraction in the general population with improvement in MASLD progression, with improvement in body weight and hepatic steatosis but no change in liver fibrosis. 2. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce the development and progression of heart failure in patients with type 2 diabetes and in those with heart failure and a reduced and preserved ejection fraction. In patients with cirrhosis safety of empagliflozin in a dose of 10 mg has been demonstrated. 3. Prevention of decompensation related events in cirrhosis is the key endpoint of any liver-directed therapy as the median survival in the compensated state exceeds 10 years but median survival in the decompensated state approximates 1.5 years. Previous data has demonstrated the risk of hepatic decompensation acute kidney injury and poor survival in patients with cirrhosis and heart failure with preserved ejection fraction (HFpEF) i.e. LVDD a large subset of whom meet criteria for CCM.
Detailed description
New diagnostic criteria for cirrhotic cardiomyopathy For the diagnosis of cirrhotic cardiomyopathy (CCM) we will use criteria proposed by the CCM consortium in 2020 with modification to take septal e' and E/e' readings. In accordance with the recent CCM criteria 'systolic dysfunction is defined as an ejection fraction (EF) of 50% or less or an absolute value of GLS \<18%. LVDD grade will be determined if 3 of the following 4 criteria are met: early diastolic trans mitral flow to early diastolic mitral annular velocity (E/e') ≥15 left atrial volume index (LAVI) \>34 mL/m2 septal early diastolic mitral annular velocity (e') \<7 cm/second or tricuspid regurgitation (TR) maximum velocity \>2.8 m/second in the absence of pulmonary hypertension (HTN) and the presence of measurable early to late diastolic trans mitral flow velocity (E/A) ratio (E/A \>2 = grade 3 E/A 0.8-2 = grade 2)'. LVDD will be classified as "of indeterminate grade" when only 2 of the 4 criteria are met. The supporting criteria for diagnosis of LVDD are changes in cardiac chamber sizes electrophysiological abnormalities increased biomarkers like N terminal pro-brain natriuretic peptide (NT-Pro BNP) and troponin I.
Interventions
DRUGEmpagliflozin + Carvedilol
Patient Recruitment: The study participants are all cirrhosis patients receiving treatment at PGIMER Chandigarh. Eligible participants meeting LVDD criteria per the CCM Consortium 2020 consensus. Carvedilol Dosing protocol in this study Patients will be given carvedilol in a starting dose of 3.125 mg twice daily. The dose will be titrated weekly to achieve a target heart rate of 50-60/ min taking care that side effects such as hypotension bronchospasm excessive bradycardia are not seen. The maximum dosage allowed as per prior trial data is 25 mg per day. Empagliflozin Dosing protocol in this Study: • All patients will receive a standard dose of Empagliflozin fixed dose of 10 mg per day in patients with or without diabetes.
DRUGCarvedilol
* Carvedilol: Starting dose of 3.125 mg twice daily targeted upwards q 7 days to achieve target heart rate 10 mg placebo pill * Standard Medical Therapy
Sponsors
Post Graduate Institute of Medical Education and Research, Chandigarh
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Double Blind Placebo controlled Randomized Controlled Trial
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Age range of 18-65 years * Cirrhosis as diagnosed by histology or clinical laboratory and USG findings * LVDD (with EF\>50%) on 2D echocardiography with TDI * Written informed consent.
Exclusion criteria
* Age \>65 years * Serum Creatinine\>2 mg/dl * History of urinary tract /genital infections in last 3 months * Patient on treatment with statin (one month before the study) * Advanced Cirrhosis (MELD\>20) * Coronary artery disease * Sick sinus syndrome/ Pacemaker valvular heart disease * Cardiac rhythm disorder Peripartum cardiomyopathy * Portopulmonary hypertension/ hepatopulmonary syndrome * Transjugular intrahepatic porto systemic shunt (TIPS) insertion * Hepatocellular carcinoma * Pregnancy or lactation * Patients with HIV or retroviral therapy * Anemia Hb \< 8gm/dl in females and \< 9 gm/dl in males * Acute variceal bleeding in last 6months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite end point of decompensation event and/or death | From enrolment through study completion, an average of 1 year | The primary outcome measure is defined as a composite end point of acute decompensation event (acute variceal bleeding new ascites or recurrence of previously controlled ascites episode of hepatic encephalopathy or acute kidney injury) OR all-cause death in patients with cirrhosis and LVDD |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Improvement in Cardiac Diastolic Function | From enrolment through study completion, an average of 1 year | Improvement in CCM parameters (left ventricular diastolic function) in either arm based on Echocardiography and Cardiac Imaging Septal E/e' ratio |
| Improvement in Cardiac Systolic Function | From enrolment through study completion, an average of 1 year | Improvement in Cardiac systolic function (Cardiac Index) in either arm based on Echocardiography and Cardiac Imaging |
| Hospitalization events | From enrolment through study completion, an average of 1 year | • Episodes warranting hospitalization |
| • Serum level of NT-proBNP | At enrolment | Cardiac biomarkers |
| • Serum level of Galectin-3 | At enrolment | Cardiac biomarkers |
| • Serum level of Galectin 3 | At 6 months from enrolment | Cardiac biomarkers |
| • Serum level of Aldosterone | At enrolment | Cardiac biomarkers |
Countries
India
Contacts
CONTACTMadhumita Premkumar, MD DM
CONTACTMadumita Premkumar
Outcome results
None listed