Cirrhosis and portal hypertension are associated with a hyperdynamic circulation and decompensation events, including development of ascites, variceal bleeding, acute kidney injury, and susceptibility to infections.
Rationale:
Cirrhosis and portal hypertension are associated with a hyperdynamic circulation and decompensation events, including ascites, variceal bleeding, acute kidney injury, and susceptibility to infections. CCM, present in 30-70% of patients, is characterized by structural and functional abnormalities in the heart, and is associated with progression of cirrhosis, impaired quality of life and poor survival. Statins play a crucial role in reducing proatherogenic LDL cholesterol levels, making them a cornerstone in managing diabetes and cardiovascular diseases (CVDs) with the aim of decreasing or reversing atherosclerosis. This trial aims to evaluate the impact and safety of simvastatin in cirrhotic cardiomyopathy.
Novelty: Simvastatin might be of special value in diastolic dysfunction through its hemodynamic and functional effects on LV remodeling and improve portal hemodynamics through the pleotropic effects of lipophilic statins.
Objectives:
The primary objective is to assess the combined effects of carvedilol and simvastatin in managing CCM vs carvedilol alone for a composite outcome to prevent decompensation and reduce all-cause mortality. We will comprehensively evaluate cardiac function, decompensation events and survival based on impact of simvastatin over the standard betablocker carvedilol.
Methods:
This is a double-blinded randomized placebo-controlled trial involving patients diagnosed with CCM. Clinical data, including cardiac imaging, cardiac biomarkers, and survival outcomes, will be assessed for either group.
Expected Outcome:
The investigators anticipate that the synergistic use of simvastatin and carvedilol will effectively reduce portal pressure, improve portal haemodynamic, and enhance cardiac remodelling. Successful reversal of LVDD can potentially prevent clinical events such as ascites, encephalopathy, and acute kidney injury (AKI).
Age range of 18-65 years
Compensated cirrhosis, as diagnosed by histology or clinical, laboratory and USG findings,
CCM (with EF>50%) on 2D echocardiography with TDI
Written informed consent.
Age >65 years
Serum Creatinine>2 mg/dl
Patient previously treated with statin (one month before the study)
Contraindications to statins
Parallel
Simvastatin 20mg
DrugSimvastatin fixed dose of 20 mg per day
Carvedilol 3.125 mg
DrugCarvedilol: Starting dose of 3.125 mg twice daily targeted upwards q 7 days to achieve target heart rate
Time to acute decompensation event
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 cirrhotic cardiomyopathy
All-cause Mortality
Any New decompensation event
New decompensation events are defined as decompensation event( ascites, hepatic encephalopathy, variceal bleeding) in a previously compensated patient with cirrhosis or further decompensation when a new event \[recurrence of ascites, hepatorenal syndrome-acute kidney injury (HRS-AKI), hepatic encephalopathy (HE), or acute variceal bleeding (AVB), spontaneous bacterial peritonitis (SBP)\] occurs in a patient with previously decompensated disease
Improvement in CCM parameters (left ventricular diastolic function) in either arm based on Echocardiography and Cardiac Imaging
Episodes warranting hospitalization
Number of hospital admissions on follow up.
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Post Graduate Institute of Medical Education and Research, Chandigarh
Lead sponsor
Indian Council of Medical Research
Collaborator
