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Midodrine plus propranolol versus propranolol alone in preventing first bleed in patients with cirrhosis and severe ascites: a randomized controlled trial

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Abstract

Background

Propranolol, a non-selective beta-blocker, commonly used to prevent variceal bleed, but might precipitate circulatory dysfunction in severe ascites. Midodrine, an alpha-1 adrenergic agonist improves renal perfusion and systemic hemodynamics. Addition of midodrine might facilitate higher maximum tolerated dose (MTD) of propranolol, thereby less risk of variceal bleed in cirrhosis patients with severe ascites.

Methods

140 patients with cirrhosis and severe/refractory ascites were randomized- propranolol and midodrine (Gr.A,n = 70) or propranolol alone (Gr.B,n = 70). Primary outcome was incidence of bleed at 1 year. Secondary outcomes included ascites control, achievement of target heart rate (THR), HVPG response and adverse effects.

Results

Baseline characteristics were comparable between two groups. Cumulative incidence of bleed at 1 year was lower in Gr.A than B (8.5%vs.27.1%,p-0.043). The MTD of propranolol was higher in Gr.A (96.67 ± 36.6 mg vs. 76.52 ± 24.4 mg; p-0.01) and more patients achieved THR (84.2%vs.55.7%,p-0.034). Significantly higher proportion of patients in Gr.A had complete resolution of ascites [17.1%vs.11.4%,p-0.014), diuretic tolerance (80%vs.60%,p-0.047) at higher doses(p-0.02) and lesser need for paracentesis. Patients in Gr.A also had greater reduction in variceal grade (75.7%vs.55.7%;p-0.01), plasma renin activity (54.4% from baseline) (p = 0.02). Mean HVPG reduction was greater in Gr.A than B [4.38 ± 2.81 mmHg(23.5%) vs. 2.61 ± 2.87 mmHg(14.5%),p-0.045]. Complications like post-paracentesis circulatory dysfunction and spontaneous bacterial peritonitis on follow-up were higher in Gr.B than A (22.8%vs.51.4%,p = 0.013 and 10%vs.15.7%, p = 0.03, respectively).

Conclusion

Addition of midodrine facilitates effective use of propranolol in higher doses and greater HVPG reduction, thereby preventing first variceal bleed, reduced paracentesis requirements with fewer ascites- related complications in patients with cirrhosis with severe/refractory ascites.

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Data availability

Study related data is available on reasonable request.

Abbreviations

PICD:

Paracentesis-induced circulatory dysfunction

ACLF:

Acute-on-chronic liver failure

PHT:

Portal hypertension

NSBBs:

Non-selective beta-blockers

HVPG:

Hepatic venous pressure gradient

ILBS:

Institute of Liver and Biliary Sciences

AST:

Aspartate aminotransferase

ALT:

Alanine aminotransferase

INR:

International normalization ratio

UGIE:

Upper gastrointestinal endoscopy

THR:

Target heart rate

MTD:

Maximum tolerated dose

SBP:

Systolic blood pressure

WHVP:

Wedged hepatic venous pressure

FHVP:

Free hepatic venous pressure

HCC:

Hepatocellular carcinoma

AKI:

Acute kidney injury

AKIN:

Acute kidney injury network

HE:

Hepatic encephalopathy

MELD:

Model for end-stage liver disease

SD:

Standard deviation

IQR:

Interquartile range

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Author notes

  1. Abhijeet Ranjan, Ankur Jindal and Shiv K. Sarin have contributed equally and this manuscript has dual first authors.

Authors and Affiliations

  1. Department of Hepatology, Institute of Liver and Biliary Sciences, D – 1, Vasant Kunj, New Delhi, 110070, India

    Abhijeet Ranjan, Ankur Jindal, Rakhi Maiwall, Chitranshu Vashishtha, Rajan Vijayaraghavan, Vinod Arora & Shiv K. Sarin

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  1. Abhijeet Ranjan
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Contributions

AR, AJ, RM, CV,VA, and SKS – :conceptualization, review, analysis, and editing of manuscript. AR, and AJ – original draft preparation. SKS: – conceptualization, review and editing of manuscript.

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Correspondence to Shiv K. Sarin.

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Abhijeet Ranjan, Ankur Jindal, Rakhi Maiwall, Chitranshu Vashishtha, Rajan Vijayaraghavan, Vinod Arora, Shiv K Sarin: none.

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Ranjan, A., Jindal, A., Maiwall, R. et al. Midodrine plus propranolol versus propranolol alone in preventing first bleed in patients with cirrhosis and severe ascites: a randomized controlled trial. Hepatol Int (2024). https://doi.org/10.1007/s12072-024-10687-1

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