Hemodynamic Effect of Simvastatin With Beta Blockers in Clinical Portal Hypertension

Liver Cirrhosis Clinical Trial

— SIMBETA  

Official title:

Hemodynamic Effect of the Combination of Simvastatin With Non-cardioselective Beta Blockers in Patients With Cirrhosis and Clinically Significant Portal Hypertension

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT01282385
• Other study ID #: IIBSP-SIM-2010-04
• Status: Not yet recruiting
• Phase: Phase 4
• First received: January 21, 2011
• Last updated: January 24, 2011
• Start date: April 2011
• Est. completion date: April 2014

Study information

• Verified date: January 2011
• Source: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
• Contact: Candido Villanueva, PHD
• Phone: 0034 5565917
• Email: cvillanueva[@]santpau.cat
• Is FDA regulated: No
• Health authority: Spain: Spanish Agency of Medicines
• Study type: Interventional

Clinical Trial Summary

In the genesis and maintenance of PH associated with liver cirrhosis are two mechanisms that act synergistically. The first is an increase in hepatic vascular resistance, due in part to the disruption of liver structure inherent cirrhosis, and increased hepatic vascular tone is caused by the contraction of perivascular smooth muscle cells, myofibroblasts and hepatic stellate cells, which represents about 30% of global intrahepatic resistance and is believed to be due to the production Defective nitric oxide (NO). The second mechanism, which maintains and exacerbates HTP, is an increase of splanchnic blood flow caused by increased NO and other vasodilators at this level

In this regard, we believe that in patients with compensated liver cirrhosis, with portal pressure gradient> 10 mmHg, both acute responders betablockers test as non-responders, the association of antifibrotic drugs and / or vasodilators, chronic liver selective May be beneficial in the control of portal hypertension

Description:

This study was prospective, randomized, controlled, double blind, in which patients who met the inclusion criteria and give written consent to participate in the study underwent a baseline hemodynamic study to determine the portal pressure gradient (GPSH). During the event, will assess the acute response to intravenous administration of propranolol. It is considered good hemodynamic response to declining GPSH >20% from baseline or decrease to <12 mmHg. At the conclusion of the baseline hemodynamic study patients will be divided into 2 treatment groups:

a) patients responding to treatment with beta-blockers, in which she was treated with nadolol at doses of 40mg/24horas (increasing the dose every 2-3 days as tolerated, to a maximum of 240 mg / 24 hours. Subsequently randomized into two treatment arms, double-blind:

a.1: simvastatin 20 mg capsules, starting at doses of 20 mg / 24 hours, may increase to 40 mg according to clinical and laboratory tolerance.

a.2: placebo capsules with external characteristics similar to simvastatin.

b) non-responders to treatment with beta blockers, carvedilol receive treatment with an initial dose of 6.25 mg / 24 hours, may increase to 25mg/dia if good clinical tolerance (HR and BP monitoring) and analytical (renal function and electrolyte disturbances) . Subsequently randomized into two treatment arms, double-blind b.1: simvastatin 20 mg capsules, starting at doses of 20 mg / 24 hours, may increase to 40 mg according to clinical and laboratory tolerance.

b.2: placebo capsules with external characteristics similar to simvastatin.

In order to evaluate the long-term hemodynamic effect, patients will receive treatment for a month and hemodynamic study will be repeated to completion.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 60
• Est. completion date: April 2014
• Est. primary completion date: April 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Liver cirrhosis diagnosed by previous biopsy or by clinical, laboratory, ultrasound,

• PPG> 10 mmHg,

• Presence of large esophageal varices or small varices with red spots, varices of any size and Pugh C, and / or gastric fundic varices of any size, in a recent gastroscopy (<1 month)

• Absence of previous episodes of gastrointestinal bleeding

• Written informed consent.

Exclusion Criteria:

• Age <18 and> 80 years;

• Episode of variceal bleeding,

• Thrombosis splenoportal axis,

• Hepatocarcinoma,

• Terminal liver failure (Child-Pugh scale> 13 points);

• Any comorbidity involving a medical drugs and / or a life expectancy <12 months,

• Severe chronic renal insufficiency (creatinine> 150 g / L),

• Absolute contraindication or allergy treatment with statins to simvastatin;

• Concomitant potent inhibitors of CYP3A4 (eg., itraconazole, ketoconazole, inhibitors of HIV protease, erythromycin, clarithromycin, telithromycin and nefazodone),

• Pretreatment (<1 month) or other lipid-lowering with simvastatin,

• Previous episodes rhabdomyolysis;

• Contraindication to beta-blockers (COPD with bronchial hyperresponsiveness, aortic stenosis, AV block, intermittent claudication, severe psychosis, bronchial asthma),

• Hypersensitivity to beta blockers,

• Concomitant administration of potent inhibitors of cytochrome P-450 (quinidine, fluoxetine, paroxetine, and propafenone)

• 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 shunts;

• Pregnancy and lactation.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Hypertension
• Hypertension, Portal
• Liver Cirrhosis
• Portal Hypertension.

Intervention

Drug:
• Simvastatin
simvastatin 20 mg capsules, starting at doses of 20 mg / 24 hours, may increase to 40 mg according to clinical and laboratory tolerance
• placebo
placebo capsules with external characteristics similar to simvastatin administrated each 24 hours.

Locations

Country	Name	City	State
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona

Sponsors (1)

Lead Sponsor	Collaborator
Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau

Country where clinical trial is conducted

Spain, 

References & Publications (4)

Abraldes JG, Albillos A, Bañares R, Turnes J, González R, García-Pagán JC, Bosch J. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology. 2009 May;136(5):1651-8. doi: 10.105 — View Citation

Bosch J. Carvedilol for portal hypertension in patients with cirrhosis. Hepatology. 2010 Jun;51(6):2214-8. doi: 10.1002/hep.23689. — View Citation

Trebicka J, Hennenberg M, Laleman W, Shelest N, Biecker E, Schepke M, Nevens F, Sauerbruch T, Heller J. Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase. Hepatology. 2007 Jul;46(1):242-53. — View Citation

Tripathi D, Therapondos G, Lui HF, Stanley AJ, Hayes PC. Haemodynamic effects of acute and chronic administration of low-dose carvedilol, a vasodilating beta-blocker, in patients with cirrhosis and portal hypertension. Aliment Pharmacol Ther. 2002 Mar;16( — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	improvement of the hemodynamic response rate	The main objective is to assess whether, in patients with compensated cirrhosis, portal pressure greater than 10mmHg and esophageal varices at risk, the association of a liver selective vasodilator and simvastatin together with non-cardioselective beta blockers can improve the hemodynamic response rate.	1 month.	Yes
Secondary	Portal hypertension complications.	Development of complications related to portal hypertension (gastrointestinal bleeding related to portal hypertension, ascites, hepatic encephalopathy).	1 month	Yes
Secondary	Adverse effects	adverse effects related to medication	1 month	Yes