Pentoxifylline Plus Carvedilol vs Carvedilol Monotherapy in Preventing New Decompensation in Stable Cirrhotic Patients With Prior Decompensation

• Study population: Cirrhotic patients with prior decompensation at least 3 months ago
• Study design: A Open label randomized controlled trial
• Sample size Assuming decompensation in Arm 1 as 25%, and 10% in Arm 2, alpha error- 5, power - 80, 160 patients, 10 % lost to follow up - 180, Each arm 90 patients.
• Intervention Arm 1 : Carvedilol Arm 2 : Pentoxiphylline plus Carvedilol
• Monitoring and assessment

At enrollment:

• - Complete history and physical examination
• Prior ascites, Hepatic encephalopathy, acute variceal bleed.
• Time to prior decompensation
• Pattern and number of prior decompensation
• Prior spontaneous bacterial peritonitis, hydrothorax, Acute on chronic liver failure, acute kidney injury
• Use of Non selective beta blockers, norfloxaxin, rifaximin and albumin
• Recent herbal/drugs intake
• History of EVL or other endotherapy
• History of hypertension, diabetes mellitus
• Fever , signs of sepsis
• Examination- Sarcopenia, fraility, icterus, pedal edema

At follow-up (at 3 month, 6 month, 9 month, 12 month): Physical (preferably)

• Complete history and physical examination
• New onset ascites, Hepatic encephalopathy, acute variceal bleed, clinical Jaundice
• Time to new decompensation from enrollment
• Pattern and number of new decompensation
• Other complications - Spontaneous bacterial peritonitis, hydrothorax, Acute on chronic liver failure, acute kidney injury.
• Recent herbal/drugs intake
• History of EVL or other endotherapy
• Hypertension, Diabetes control
• Fever , signs of sepsis
• Examination- Sarcopenia, fraility, icterus, pedal edema, ascites, Hepatic encephalopathy

Clinical evaluation

• Etiology of chronic liver disease (Baseline)
• Control of etiological factor (Baseline, 3 monthly) Alcohol - No relapse, if relapse - severity HBV - on antivirals, HBV DNA -ve HCV - HCV RNA -ve Metabolic risk factors control- DM, HT, weight etc.
• Severity of liver disease (Baseline, 3 monthly) MELD score, MELD-Na score, CTP score
• Complications (at 3 month, 6 month, 9 month, 12 month):

Overt Hepatic Encephalopathy, Portal hypertension related bleed, clinical jaundice, ascites, hyponatremia, Acute kidney injury, spontaneous bacterial peritonitis, Infections

Laboratory parametres

• Baseline (at enrollment) - Blood : KFT, LFT, CBC, INR, AFP, TNF-a, IL-6, CRP, VWF, ADAM TS 13 Imaging : USG abdomen, LSM, SSM, ECHO Hemodynamics : HVPG (not mandatory)
• At 3 and 6 month - Blood : KFT, LFT, CBC, INR Imaging : USG abdomen, LSM, SSM
• At 1 year (end of follow-up) Blood : KFT, LFT, CBC, INR, AFP, TNF-a, IL-6, CRP, VWF, ADAM TS 13 Imaging : USG abdomen, LSM, SSM Hemodynamics : HVPG ( not mandatory)
• STATISTICAL ANALYSIS:
• Data will be reported as mean + SD.
• Categorical variables will be compared using the chi-square test or Fisher exact test
• Normal continuous variables will be compared using the Student's t test
• Non normal continuous variables will be compared using the Mann-Whitney rank-sum test (unpaired data) or the Wilcoxon test (paired data).
• The actuarial probability of survival will be calculated by the Kaplan-Meier method and compared using the log-rank test.
• A Cox regression analysis will be performed to identify independent prognostic factors for survival.
• Univariate and multivariate analysis will be used whenever applicable. - Adverse effects Carvedilol - Bradycardia, hypotension, giddiness, diarrhea, insomnia, hyperglycemia, weight gain, increased BUN, increased nonprotein nitrogen (NPN), increased cough, abnormal vision.

Pentoxiphylline - Abdominal discomfort, bloating, diarrhea, Dizziness, headache, flushing, chest pain, arrhythmias, hypertension, dyspnea, tachycardia, and hypotension.

• Stopping rule If primary end point achieved or any adverse event due to drug