Hemodynamic Effect of Simvastatin With Beta Blockers in Clinical Portal Hypertension

NCT ID: NCT01282385

Last Updated: 2011-01-25

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-04-30
• Study Completion Date: 2014-04-30

Brief 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

Detailed 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.

Conditions

Liver Cirrhosis; Portal Hypertension.

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: DOUBLE

Study Groups

simvasatin

a) patients responding to treatment with beta-blockers, in which she was treated with nadolol 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, receive treatment with carvedilol.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.

Group Type: EXPERIMENTAL

Simvastatin

Intervention Type: DRUG

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

placebo

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

placebo capsules with external characteristics similar to simvastatin administrated each 24 hours.

Interventions

Simvastatin

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

Intervention Type: DRUG

placebo

placebo capsules with external characteristics similar to simvastatin administrated each 24 hours.

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

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

OTHER

Sponsor Role: lead

Responsible Party

Hospital de la Santa Creu i Sant Pau

Principal Investigators

Candido Villanueva, MD

Role: PRINCIPAL_INVESTIGATOR

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

Locations

Hospital de la Santa Creu i Sant Pau

Barcelona, Barcelona, Spain

Countries

Spain

Central Contacts

Candido Villanueva, PHD

Role: CONTACT

cvillanueva@santpau.cat

0034 5565917

Angela Puente, MD

Role: CONTACT

apuentesa@santpau.cat

00345565917

Facility Contacts

Candido Villanueva, mPHD

Role: primary

cvillanueva@santpau.cat

0034935565917

Angela Puente, PHD

Role: backup

apuentesa@santpau.cat

0034935565917

References

Bosch J. Carvedilol for portal hypertension in patients with cirrhosis. Hepatology. 2010 Jun;51(6):2214-8. doi: 10.1002/hep.23689. No abstract available.

Reference Type: BACKGROUND

PMID: 20513005 (View on PubMed)

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. doi: 10.1002/hep.21673.

Reference Type: BACKGROUND

PMID: 17596891 (View on PubMed)

Abraldes JG, Albillos A, Banares R, Turnes J, Gonzalez R, Garcia-Pagan 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: 10.1053/j.gastro.2009.01.043. Epub 2009 Jan 24.

Reference Type: RESULT

PMID: 19208350 (View on PubMed)

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(3):373-80. doi: 10.1046/j.1365-2036.2002.01190.x.

Reference Type: RESULT

PMID: 11876689 (View on PubMed)

Other Identifiers

IIBSP-SIM-2010-04

Identifier Type: -

Identifier Source: org_study_id