Propranolol, Carvedilol and Rosuvastatin in the Prevention of Variceal Bleeding in Cirrhotic Portal Hypertension

Study Overview
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Brief Summary
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Patients with hepatic cirrhosis and previous variceal bleeding will be randomly assigned to use propranolol or carvedilol. After 8 weeks, rosuvastatin or placebo will be blindly added to nonresponders (HVPG measurement > 12mmHg) for another 8 weeks and hemodynamic response will be assessed again. Surrogate serum markers of portal hypertension will be evaluated and correlated to HVPG values and to its variations.

Official Title
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Propranolol, Carvedilol and Rosuvastatin in the Prevention of Recurrent Variceal Haemorrhage in Patients With Cirrhotic Portal Hypertension

Conditions
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Cirrhosis, Portal Hypertension, Variceal Hemorrhage

Intervention / Treatment
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* Drug: Propranolol
* Drug: Carvedilol
* Drug: Rosuvastatin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hepatic cirrhosis of any etiology Previous variceal bleeding Endoscopic variceal eradication at least 2 weeks before Exclusion Criteria: Beta blocker or statin contraindications Model for End-Stage Liver Disease (MELD) score > 25 Child-Pugh score > 13 HVPG ≤ 12 mmHg Creatinine clearance < 50 mL/min Refractory ascites Hepatic encephalopathy stages 3 or 4 Alcohol use in the last 6 months Hepatitis C treatment in the last 6 months Changing or initiating a new hepatitis B treatment in the last 6 months Malignant neoplasms from any origin except basal cell carcinoma HIV infection Pregnancy Anticoagulation Recent or complete portal vein thrombosis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Phase 1: Propranolol (PPL)<br>Hepatic venous pressure gradient (HVPG) will be measured before and after 120 minutes of a loading dose of Propranolol (PPL) 80 mg PO. Thereafter, patients will receive maintenance therapy with Propranolol (40 to 320 mg / day) adjusted according to blood pressure and heart rate. After 28 days of reaching the maximum tolerated dose, a new HVPG measurement will be performed. | Drug: Propranolol<br>* 40mg to 320mg / day<br>|
| Active Comparator: Phase 1: Carvedilol (CVD)<br>HVPG will be measured before and after 120 minutes of a loading dose of Carvedilol (CVD) 12.5 mg PO. Thereafter, patients will receive maintenance therapy with Carvedilol (6.25 - 25 mg / day) adjusted according to blood pressure. After 28 days of reaching the maximum tolerated dose, a new HVPG measurement will be performed. | Drug: Carvedilol<br>* 6.25mg to 25mg / day<br>|
| Active Comparator: Phase 2: PPL non-responders/rosuvastatin<br>Patients treated with PROPRANOLOL (PPL) who do not reach HVPG fall below 12 mmHg will be randomized to receive the addition of ROSUVASTATIN 20 mg /day PO. HVPG will be measured again after 56 days. | Drug: Propranolol<br>* 40mg to 320mg / day<br>Drug: Rosuvastatin<br>* 20mg / day<br>|
| Placebo Comparator: Phase 2: PPL non-responders/placebo<br>Patients treated with PROPRANOLOL (PPL) who do not reach HVPG fall below 12 mmHg will be randomized to receive the addition of PLACEBO 1 tablet PO. HVPG will be measured again after 56 days. | Drug: Propranolol<br>* 40mg to 320mg / day<br>Drug: Placebo<br>* Placebo of rosuvastatin<br>|
| Active Comparator: Phase 2: CVD non-responders/rosuvastatin<br>Patients treated with CARVEDILOL (CVD) who do not reach HVPG fall below 12 mmHg will be randomized to receive the addition of ROSUVASTATIN 20 mg /day PO. HVPG will be measured again after 56 days. | Drug: Carvedilol<br>* 6.25mg to 25mg / day<br>Drug: Rosuvastatin<br>* 20mg / day<br>|
| Placebo Comparator: Phase 2: CVD non-responders/placebo<br>Patients treated with CARVEDILOL (CVD) who do not reach HVPG fall below 12 mmHg will be randomized to receive the addition of PLACEBO 1 tablet PO. HVPG will be measured again after 56 days. | Drug: Carvedilol<br>* 6.25mg to 25mg / day<br>Drug: Placebo<br>* Placebo of rosuvastatin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute hemodynamic response | A decrease in HVPG to 12 mmHg or lower | Two hours after a load dose of carvedilol or propranolol | 
| Full hemodynamic response to beta blockers | A decrease in HVPG to 12 mmHg or lower | Eight weeks of carvedilol or propranolol | 
| Full hemodynamic response to beta blockers plus rosuvastatin or placebo | A decrease in HVPG to 12 mmHg or lower | Eight weeks of beta blockers plus rosuvastatin or placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sufficient hemodynamic response to beta blockers plus rosuvastatin or placebo | A decrease in HVPG of at least 20% from baseline | Eight weeks of beta blockers plus rosuvastatin or placebo | 
| Partial hemodynamic response to beta blockers plus rosuvastatin or placebo | A decrease in HVPG of at least 10% from baseline | Eight weeks of beta blockers plus rosuvastatin or placebo |