Study About Simvastatin in Portal Hypertension in Compensated Cirrhosis

Study Overview
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Brief Summary
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The purpose of this study is to determine whether simvastatin is effective in the prevention of progression of porta hypertension in compensated cirrhosis patients.

Detailed Description
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Decompensation of cirrhosis is associated with a dramatic reduction of survival. Progression of portal hypertension (PHT) is the main determinant of decompensation that appears when portal pressure gradient (PPG) is ≥10mmHg (clinically significant HTP). 40% of compensated cirrhotic patients have mild PHT. However, with progression of disease 41% develop clinically significant PHT. In cirrhosis, PHT results from increased resistance to blood flow, with a dynamic component due to decreased nitric oxide (NO) bioavailability. In advanced disease increased portal venous inflow also contributes to PHT. Beta-blockers have not been useful in compensated cirrhosis with mild PHT. In early cirrhosis, vasodilators may be more adequate. Statins, drugs that inhibit the activity of HMG-CoA reductase, induce selective hepatic vasodilation due to an enhanced bioavailability of NO. Acutely, they decreases hepatic resistance, while with long-term use statins decreases PPG without deleterious effects on systemic circulation. This multicenter, randomized, double-blind placebo-controlled study is aimed at assessing whether treatment with simvastatin may prevent progression of mild PHT (with PPG between 6 and 10 mmHg) to clinically significant PHT. Patients with compensated cirrhosis, without previous decompensation, without esophageal varices at risk and with PPG between 6 and 10 mmHg will be included. The calculated sample size is 80 patients and the duration of the study 4 years (2 years including and a follow-up of at least 2 year).

Official Title
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Prevention of Progression of Portal Hypertension in Compensated Cirrhosis Using Selective Hepatic Vasodilators. A Double-blind, Multicenter,Randomized Controlled Trial

Conditions
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Portal Hypertension., Liver Cirrhosis

Intervention / Treatment
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* Drug: Simvastatin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Liver cirrhosis diagnosed by previous biopsy or by clinical, laboratory, ultrasound Portal hypertension gradient between6 mmHg and10 mmHg Absence of esophageal and gastric varices or small esophageal varices without red signs Absence previous episodes of gastrointestinal hemorrhage, ascites, encephalopathy or jaundice Written informed consent Exclusion Criteria: Age <18 and> 80 years, Presence or history of ascites, clinical or ultrasound, Previous decompensation of liver cirrhosis, ascites or SBP, bleeding varices, large varices, hepatic encephalopathy, jaundice, Thrombosis splenoportal, Hepatocellular carcinoma; Child-Pugh >7 point Any comorbidity that leads to a restriction therapy and / or a life expectancy <12 months Absolute contraindication to treatment with statins or allergy Simvastatin; Concomitant potent CYP3A4 inhibitors (eg., itraconazole, ketoconazole, protease inhibitors, HIV, erythromycin, clarithromycin, telithromycin and nefazodone), Pretreatment (<1 month) with simvastatin or other lipid-lowering, Previous episodes of rhabdomyolysis, Active alcoholic hepatitis, Refusal to participate in the study or the informed consent claim; Pre-treatment with beta blockers or nitrates, or endoscopic treatment for varicose veins or portosystemic derivations; Pregnancy and lactation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: simvastatin<br>The experimental group will take simvastatin 40mg for at least two years. | Drug: Simvastatin<br>* The experimental group will take 40 mg each 24 hours for at least two years.<br>|
| Placebo Comparator: placebo<br>the control group wiil take placebo pills for at least two years. | Drug: placebo<br>* the control group wiil take placebo pills for at least two years.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the treatment of portal hypertension with simvastatin may prevent progression of portal hypertension | The main objective is to assess whether, in patients with compensated cirrhosis and mild portal hypertension (GPP between 6 and 10mmHg), the treatment of portal hypertension with simvastatin may prevent progression of portal hypertension and prevent the development of clinically significant HTP (defined GPP by a ≥ 10 mmHg) | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Portal hypertension complications | Development of complications related to portal hypertension (gastrointestinal bleeding related to portal hypertension, ascites, hepatic encephalopathy). | four years | 
| Adverse effects |  | four years |