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

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.

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.

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).

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.