To Study the Safety and Efficacy of Simvastatin in Patients With Hepatopulmonary Syndrome in Cirrhosis- A Double Blind Randomized Controlled Trial-Superiority Trial

Methodology:

Studypopulation: All the consecutive patients of cirrhosis admitted to Hepatologydepartment of ILBS will be evaluated for inclusion.

 Study Design:Double Blind randomized control trial: Superiority trial. The study will beconductedin Department of Hepatology ILBS.

 Study period: 2years

Sample size:  Assuming 40% as the response rate tosimvastatin and 1% to standard medical treatment with α 5% , power 80% andsuperiority marging as 10% ,we need to enroll 36 cases 18 in each arm. Furtherconsidering 10% drop rate, decided to enroll 40 cases with 20 randomised to 2groups using block randomisation method taking block score of 4.It is decidedto allocate the cases in 2:1 ratio (Simvastatin 2: 1 Placebo) decided to enroll45 cases so that 30 in simvastatin arm and 15 in standard medical therapy. (Noton pentoxiphylline) arm with block  size15

Patients to bedivided into 2 groups. Group A-Simvastatin 40mg OD plus standard treatment . GroupB-Matched placebo plus standard treatment (excluding Pentoxiphylline)

Stopping-rule-Developmentof drug related side effects

Diseaseprogression (Increase in baseline MELD by 4 or >25)

 Monitoring andassessment

Patients withknown cirrhotics will be enrolled as per inclusion criteria and baselineroutine testing with complete blood count, liver and kidney function test,ultrasonography of the abdomen, lipid profile, total CPK, measurement of liverand splenic stiffness.Pulmonary blood at the time of HVPG for endothelin-1 andTNF alpha,Nitric oxide levels,S1P expression,KLF-2 levels.

Matched placebonot on pentoxiphylline are included.

MELD score andChild score, Arterial blood gas analysis, Pulmonary function test,6 minute walktest,Saline contrast 2D ECHO at baseline and at 6months.

Clinicalevaluation done monthly. Response at the end of 6months.

 Hepatic venouspressure gradient (HVPG): Prior to the HVPG measurement, a venous access wasperformed under ultrasonography after local anesthesia. The Seldinger techniquewas used to insert a catheter into the right brachial vein or the rightinternal jugular vein. An occlusion balloon catheter of 6 F was guided in abranch of the hepatic veins, usually the median or right vein, underfluoroscopic control and continuous electrocardiographic and pressuremonitoring.

After inflatingthe balloon at the catheter’s tip (maximum diameter ranges from 8.5–11.5 mm), avenous check was performed to demonstrate complete vessel occlusion. The wedgedhepatic vein pressure (WHVP) was measured in this condition. Following that,the free hepatic vein pressure (FHVP) was measured after deflating the balloonat the catheter’s tip. On a multi-channel recorder, a permanent trace wasobtained. Pressures were also achieved in the inferior vena cava and the rightatrium. According to the Baveno VI consensus, the HVPG-response was defined asa 20% or 12 mmHg reduction in HVPG after NSBB treatment.

HVPG= WHVP –FHVP (Normal is <5mm of Hg)

 Ultrasonographyof the abdomen:

dilated portalvein (>13 mm): non-specific

biphasic orreverse flow in portal vein (late stage): pathognomonic

recanalizationof paraumbilical vein: pathognomonic

portal-systemiccollateral pathways (collateral vessels/varices)

splenomegaly

ascites

The dampingindex (showing changes in the doppler hepatic vein waveform) corresponds withhemodynamically significant portal hypertension and HVPG values (together withHVPG changes after treatment)

splenicarterial resistive index

 Liver and splenic stiffness: A3.5-MHz ultrasound transducer probe is mounted on the axis of a vibrator in theFibroScan device. Mild amplitude, low-frequency (50 Hz) vibrations aretransmitted to the liver tissue, causing an elastic shear wave to propagatethrough the underlying tissue. If the success rate was greater than 60% and theinterquartile range (IQR) was greater than 30% of the median value, LS valueswere accepted.     Guidelines formeasuring SS is same as LS. SS was performed on a supine patient with maximalabduction of the left arm, with the probe positioned in an intercostal spacewhere the spleen was correctly visualized by US. Furthermore, in accordancewith the FibroScan’s technical features, patients with a splenic parenchymalthickness of >4 cm under the probe were excluded.

 -              STATISTICAL ANALYSIS: Forcomparison of parameters pretherapy and posttherapy, the Wilcoxon signed ranktest

was used. P.05was considered significant. SPSS version 15.0 statistical software (SPSS Inc,Chicago, Illinois) was used for analysis.

 -              Adverse effects:

-              1. Major Sideeffects ofSimvastatin

 -              Rhabdomyolysis(Raised Total CPK> 3ULN)

-              Bradycardia

-              Transaminitis (ALT >5ULN)

-              Headache

-              Constipation

-              Upper respiratory tract infection

 2. HVPG relatedcomplications

 -              Transient arrhythmias

-              Vagal reaction

-              Local access pain and bleeding

 -              Stopping rule : Development ofserious adverse effects leading to withdrawal of the drug or death from anycause. Disease progression  (Increase inbaseline MELD by 4 or >25)