To Study the Hemodynamic Response of Early Addition of Carvedilol to Terlipressin in Acute Variceal Bleed in Child's B and C Cirrhosis

Study Overview
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Brief Summary
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Management of Acute variceal bleeding includes endoscopic variceal ligation (EVL) along with vasoactive agents. Inspite of successful hemostasis, this is associated with high variceal rebleeding (VRB) in Child B and C cirrhosis and have higher 6-week mortality rates. Pre-emptive TIPS has shown to prevent rebleed and improve survival in child B and C patients but is associated with liver related complications in advanced disease. HVPG guided therapy and treatment response is known to improve rebleeding and associated with improved survival. This is based on achieving hemodynamic response defined as HVPG reduction of ≥20% from baseline or absolute reduction of HVPG </= 12 mmHg for secondary prophylaxis for prevention of rebleeding. Studies have shown the safety of giving terlipressin in patients receiving beta- blockers. We aim to achieve hemodynamic response with addition of carvedilol with vasoactive agent for reduction of portal blood flow to decreases rebleeding episodes and reduce mortality.

Detailed Description
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Aim and Objective To compare the hemodynamic response of early addition of carvedilol with terlipressin in patients with cirrhosis presenting with acute esophageal variceal bleeding. Primary objective • To study the hemodynamic response (HVPG reduction of ≥20% from baseline or absolute reduction of HVPG </= 12 mmHg) in the groups at 5-days. Secondary objective Rebleeding rate in the two groups at 5-days Rebleeding rate at 6-weeks Reduction of HVPG <16mm Hg in both groups at 5-days Salvage treatment, TIPS in both groups at 5-days and at 6-weeks Salvage treatment, SEMS, SB tube placement in-between groups at 5-days and at 6- weeks Survival at 6-weeks Liver related decompensation in-between groups at 6-weeks Adverse events between the groups at 6-weeks Methodology: Study population: Patients with Child's B and C cirrhosis who present with acute esophageal variceal bleed, between 18-75 years will be enrolled and randomized based on inclusion and exclusion criteria. Study design- Prospective open label RCT Study period - 1.5 years Sample Size:Sample size will be calculated assuming that baseline characteristics (22.2±5.0 mmHg) are same and HVPG reduction on 5th day with terlipressin is 19.1±5 mmHg [7] and estimating a further reduction of 15% with addition of carvedilol [14] (16.3±4.3 mmHg), with an alpha value equal to 5 % and power of 80%, we need to enrol 45 cases in both arms. Assuming an attrition rate of 10%, it was decided to enrol 100 cases, 50 in each group, randomly allocated by block randomization method with block size of 10. Intervention: All patients to receive Inj. Terlipressin, 1 mg at 4 hours along with standard management for acute variceal bleed as per institutional protocol Arm A- Carvedilol will be initiated on day 2, at a dose of 3.125mg twice a day (6.25mg/day), along with standard management as per institutional protocol for AVB. Arm B- Carvedilol will be initiated on day 6, at a dose of 3.125mg twice a day (6.25mg/day), along with standard management as per institutional protocol for AVB. - Monitoring and assessment: Patients will be admitted in GI-bleed ICU and will be randomized into the study groups after successful endoscopic control of the bleed. Each patient will be monitored as per the institutional protocol for management of upper GI bleed. A detailed clinical history will be taken, and blood investigations and other relevant investigations required will be done as mentioned in the table 2. Patient will undergo HCC surveillance as per the guideline. Once discharged, patient will be called for OPD visits and routine investigations as planned will be done. Patient will be assessed for the tolerance of carvedilol and dose escalation to a maximum dose of 6.25mg twice a day (12.5mg/day) will be achieved. Each patient will maintain a patient diary for ease in recording details. Table 2: Investigations Day 0-5 Complete physical evaluation Hemogram, Kidney function test, Liver function test, INR Ultrasound abdomen with spleno-portal axis doppler Fibroscan-liver and spleen Coagulation parameter, vWF, ADAMTS-13 2D-ECHO, ECG Rest investigation, monitoring, antibiotics as per hospital protocol HVPG on Day 1 and at Day 5 Planned OPD visits on day 7, 14, 28, 42 Hemogram, Kidney function test, Liver function test, INR Follow-up visits Repeat upper GI endoscopy every 3 weeks till variceal eradication Expected outcome of the project: HVPG guided treatment and achieving hemodynamic response post bleed will reduce rebleeding rates and will prevent further decompensation and reduce mortality in patients with Child B and C cirrhosis.

Official Title
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To Study the Hemodynamic Response of Early Addition of Carvedilol to Terlipressin in Acute Variceal Bleed in Child's B and C Cirrhosis- A Randomized Controlled Trial

Conditions
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Liver Cirrhosis

Intervention / Treatment
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* Drug: Carvedilol Day2
* Other: Standard Medical Treatment
* Drug: Carvedilol Day6


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cirrhosis with Acute Variceal Bleed Child's B and C cirrhosis (CTP ≤ 12) Patients age between 18 to 75 years Exclusion Criteria: Gastric variceal bleed Bleeding related to coagulopathy Other causes of portal hypertensive bleeding Acute on chronic liver failure Sepsis Shock(persistence of hypotension) Acute kidney injury (>1.5 mg%) Grade 3 Ascites Hyponatremia (Na < 125 mEq/L) Complete portal vein thrombosis Hepatocellular carcinoma (>3cm lesion) Tumoral portal vein thrombosis Chronic kidney disease Coronary artery disease Valvular heart disease Sick sinus syndrome/ Pacemaker Arrythmia Uncontrolled hypothyroidism and hyperthyroidism Pregnancy Failure to give consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carvedilol at Day2 + Standard Medical Treatment<br>Arm A- Carvedilol will be initiated on day 2, at a dose of 3.125mg twice a day (6.25mg/day), along with standard management as per institutional protocol for AVB. All patients to receive Inj. Terlipressin, 1 mg at 4 hours along with standard management for acute variceal bleed as per institutional protocol | Drug: Carvedilol Day2<br>* Carvedilol will be initiated on day 2, at a dose of 3.125mg twice a day (6.25mg/day), along with standard management as per institutional protocol for AVB.<br>Other: Standard Medical Treatment<br>* All patients to receive Inj. Terlipressin, 1 mg at 4 hours along with standard management for acute variceal bleed as per institutional protocol. Standard Medical Treatment<br>|
| Active Comparator: Carvedilol at Day6 + Standard Medical Treatment<br>Arm B- Carvedilol will be initiated on day 6, at a dose of 3.125mg twice a day (6.25mg/day), along with standard management as per institutional protocol for AVB. All patients to receive Inj. Terlipressin, 1 mg at 4 hours along with standard management for acute variceal bleed as per institutional protocol | Other: Standard Medical Treatment<br>* All patients to receive Inj. Terlipressin, 1 mg at 4 hours along with standard management for acute variceal bleed as per institutional protocol. Standard Medical Treatment<br>Drug: Carvedilol Day6<br>* Carvedilol will be initiated on day 6, at a dose of 3.125mg twice a day (6.25mg/day), along with standard management as per institutional protocol for AVB.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemodynamic response in both groups | Hemodynamic response (HVPG reduction of ≥20% from baseline or absolute reduction of HVPG </= 12 mmHg) in the groups at 5-days. | Day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rebleeding within 6-week in both groups |  | 6-weeks | 
| Death in both groups |  | 6-weeks | 
| Adverse Effects in both groups |  | 6 weeks | 
| Decompensation events (ascites) at 6-weeks in both groups | Ascites defined as either development of ascites during the follow-up or worsening of pre-existing ascites either in the form of increasing the dose requirement of diuretic or requirement of therapeutic paracentesis. | 6 weeks | 
| Decompensation events (Hepatic Encephalopathy) at 6-weeks in both groups | New onset of Hepatic Encephalopathy. Hepatic encephalopathy is defined based on clinical parameters as per the West-Haven criteria. | 6 weeks |