Carvedilol + Simvastatin vs. Carvedilol Alone for Cirrhosis and Cirrhotic Cardiomyopathy and Impact on Hepatic Decompensation and Survival

Cirrhotic cardiomyopathy (CCM) in chronic liver disease is seen as a blunted contractile responsiveness to stress, and/or altered diastolic relaxation with electrophysiological abnormalities, in absence of known cardiac disease. Cirrhosis induces systemic inflammation, and oxidative stress leading to cardiac structural remodeling, including fibrosis, hypertrophy, and chamber dilation. CCM is associated with risk of LVDD which further lead to hepatorenal syndrome (HRS), septic shock. and peri transplant cardiac complications. Autonomic dysfunction, and neurohormonal imbalances, cardiac arrhythmias, overt heart failure are common features of CCM in advanced liver disease. Efforts to ameliorate the abnormalities associated with CCM are crucial and necessitate a significant evidence-based therapeutic intervention. We have tested the use of carvedilol in this population and found that it causes an improvement in survival.

CCM can be managed by reducing preload (though nitrates), and by ameliorating neurohormonal activation. Lowering the heart rate to 55-65 beats per minute (bpm), as done with β-blockers, is likely to help by improving myocardial oxygen demand and coronary perfusion time with independent effects on portal hypertension, and heart failure. β-blockers may reduce myocardial contractility and patients with cirrhosis have low tolerance to β-blocker dosages required to achieve a THR of 55-65 bpm. Ivabradine is useful in a subset with baseline tachycardia but does not offer survival benefit over carvedilol alone. Therefore, there is a great need to evaluate other agents that can achieve improvement in CCM related complications in cirrhosis.

• Furthermore, β-blockers might diminish myocardial contractility, and patients with cirrhosis may struggle to tolerate β-blocker doses necessary for attaining a target heart rate (THR) of 55-65 bpm. Hence, there's a critical necessity to assess alternative agents capable of ameliorating complications associated with cirrhotic cardiomyopathy (CCM).
• Early interventions to avert cardiovascular morbidity will prove to be cost effective in managing outcome, as they avert high cost of managing the public health burden of all-cause mortality in cirrhosis.
• Cardiovascular complications stand as the primary cause of mortality post-liver transplantation (LT), underscoring the need for thorough evaluation before LT.
• This study will systematically screen participants for coronary artery disease as an integral part of its screening process.
• Statins, particularly simvastatin, exert a favorable impact on vascular reactivity especially in cirrhosis. Simvastatin increases the production of nitric oxide(NO), leading to increased hepatic blood flow and reduced sinusoidal resistance, particularly upon short-term exposure. resistance.
• Simvastatin has an acceptable adverse event profile in decompensated Child B patients. There is no high-quality evidence specifically evaluating the role of simvastatin in cirrhotic cardiomyopathy, although there are data to suggest its efficacy in portal hypertension. The proposed project covers an area of overlap between cardiovascular and liver disease outcomes, which reflect as decompensation events, worsening in liver severity scores and all-cause mortality.