Ignite Creation Date:
2024-06-16 @ 11:49 AM
Last Modification Date:
2024-10-26 @ 3:30 PM
Study NCT ID:
NCT06431919
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-05-29
First Post:
2024-05-22
Brief Title:
Carvedilol Simvastatin vs Carvedilol Alone for Cirrhosis and Cirrhotic Cardiomyopathy and Impact on Hepatic Decompensation and Survival
Sponsor:
Post Graduate Institute of Medical Education and Research Chandigarh
Organization:
Post Graduate Institute of Medical Education and Research Chandigarh
Study Overview
Official Title:
Carvedilol Simvastatin vs Carvedilol Alone for Chronic Liver Disease and Cirrhotic Cardiomyopathy and Its Impact on Hepatic Decompensation and Survival a Double-blind Randomized Controlled Trial
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
CIRROSTAT
Brief Summary:
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
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
Detailed Description:
Cirrhotic cardiomyopathy CCM in chronic liver disease is seen as a blunted contractile responsiveness to stress andor 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 theres 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 oxideNO 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
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 theres 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 oxideNO 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None