Carvedilol and Midodrine Versus Carvedilol Alone in Preventing Early Rebleed in Patients With Cirrhosis.

Carvedilol and Midodrine Versus Carvedilol Alone in Preventing Early Rebleed in Patients With Cirrhosis: A Randomized Controlled Trial.

Acute variceal bleeding (AVB) in cirrhosis occurs as a result of portal hypertension and carries a 6-week mortality rate of approximately 10-20%. Standard management includes a restrictive transfusion approach, vasoactive therapy, prophylactic antibiotics, and endoscopic band ligation. Despite this, early rebleeding within the first 5 days still occurs in about 10-20% of patients, and individuals at particularly high risk may benefit from pre-emptive TIPS. However, its real-world use remains limited; one study reported that only 6.7% of eligible patients actually underwent pre-emptive TIPS, primarily due to logistical challenges and limited interventional radiology availability for early, non-emergent TIPS procedures.

Midodrine, an oral and fast-acting selective α1-adrenergic agonist, has been shown to enhance the effectiveness of nonselective beta-blockers like propranolol by allowing higher tolerated doses and achieving greater reductions in portal pressure (HVPG), thereby reducing the risk of initial variceal bleeding. However, no studies have evaluated the combination of midodrine with carvedilol-currently a preferred agent-versus carvedilol alone in patients at high risk of rebleeding.

To address this gap, we propose a study comparing carvedilol plus midodrine with carvedilol alone for preventing early rebleeding in cirrhotic patients. Individuals with cirrhosis (Child-Pugh 8-13) presenting with hematemesis will be enrolled, stabilized according to APASL guidelines, and after 48 hours randomized to either combined midodrine-carvedilol therapy or carvedilol alone. Participants will be followed for 6 weeks to assess the incidence of early rebleeding.

Study Overview

• Status: Not yet recruiting
• Conditions: Liver Cirrhosis
• Intervention / Treatment: Drug: Carvedilol; Drug: Midodrine Oral Product

• Study Type: Interventional
• Enrollment (Estimated): 210
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Dr Chitranshu Vashishtha, DM; Phone Number: 01146300000; Email: chitranshuv@gmail.com
• Study Contact Backup: Name: Dr Meenakshi S Mann, DNB; Phone Number: 01146300000; Email: meenakshimann22@gmail.com

Study Locations

• India
  • National Capital Territory of Delhi
    • New Delhi, National Capital Territory of Delhi, India, 110070
      • Institute of Liver and Biliary Sciences
      • Contact: Dr Meenakshi Mann, DNB; Phone Number: 01146300000; Email: meenakshimann22@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Consecutive patients of cirrhosis with high-risk acute variceal bleed (Child-Pugh class B > 7 with active bleeding at initial endoscopy or Child-Pugh class C < 14 points).

Exclusion Criteria:

1. Age less than 18 years or > 75 years.
2. HR < 60/ min and BP < 100/60 mm Hg
3. Child-Pugh's score <8 and >13.
4. MELD score >30 and serum lactate >12mmol/L.
5. Refractory variceal bleed.
6. Preemptive TIPS or previous Porto-systemic shunt or TIPS.
7. Non-selective Beta blocker/carvedilol / midodrine treatment in last 5 days.
8. Acute kidney injury - HRS.
9. Uncontrolled Hypertension (BP > 140/90 mmHg), heart block, congestive heart failure.
10. Contraindication to NSBB (HR<60/min, BP<90/60mmHg, bronchial asthma).
11. Hepatocellular carcinoma (outside Milan criteria), extrahepatic malignancy.
12. Pregnant women.
13. Bleeding from isolated gastric or ectopic varices.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Midodrine+Carvedilol; Patients in Group I will receive carvedilol 3.125 mg twice daily along with midodrine starting at 5 mg three times daily, with blood pressure monitored every 12 hours; carvedilol will be up-titrated by 3.125 mg daily to a maximum of 6.25 mg twice daily, and midodrine will be increased by 5 mg daily to a maximum of 15 mg three times daily (45 mg/day), aiming for the highest tolerated carvedilol dose without adverse effects such as systolic blood pressure falling below 90 mmHg	Drug: Carvedilol; Carvedilol will be up-titrated by 3.125 mg daily to a maximum of 6.25 mg twice daily; Drug: Midodrine Oral Product; Midodrine will be increased by 5 mg daily to a maximum of 15 mg three times daily (45 mg/day).
Active Comparator: Carvedilol; Group II will receive carvedilol alone, starting at 3.125 mg twice daily and titrated in the same manner as in Group I.	Drug: Carvedilol; Carvedilol will be up-titrated by 3.125 mg daily to a maximum of 6.25 mg twice daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion of patients with early variceal rebleed in 6 weeks in both the groups.	6 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Liver transplant free survival at 6 weeks.	6 weeks
Blood products Transfusion at 6 weeks.	6 weeks
Need of rescue therapy at 6 weeks (Danis Ella stent / Sengstaken tube/ rescue TIPS).	6 weeks
Change in HVPG at 4 weeks.	4 weeks
New decompensation and further decompensation at 6 weeks	6 weeks
ICU stay and hospital stay duration.	6 weeks
Change in MELD score	6 weeks
Mean carvedilol dose in both groups at 6 weeks.	6 weeks
Adverse events at 6 weeks	6 weeks

Collaborators and Investigators

• Sponsor: Institute of Liver and Biliary Sciences, India

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2026
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): September 30, 2027

Study Registration Dates

• First Submitted: March 6, 2026
• First Submitted That Met QC Criteria: March 6, 2026
• First Posted (Actual): March 12, 2026

Study Record Updates

• Last Update Posted (Actual): March 12, 2026
• Last Update Submitted That Met QC Criteria: March 6, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Digestive System Diseases; Liver Diseases; Fibrosis; Pathological Conditions, Signs and Symptoms; Liver Cirrhosis; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Amines; Indoles; Alcohols; Propanolamines; Amino Alcohols; Propanols; Heterocyclic Compounds, 3-Ring; Carbazoles; Carvedilol
• Other Study ID Numbers: ILBS-Cirrhosis-76

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No