BOSTON, MA—Compared with carvedilol alone, adding simvastatin to carvedilol did not improve hemodynamic efficacy or reduce incidence of first bleed in patients with cirrhosis with varices without a prior bleed, preliminary results of an open-label randomized controlled trial reported at The Liver Meeting® 2016. 

In patients with large varices, however, the combination improved hemodynamic response (P=0.07), noted V. Rajan, Hepatology, Institute of Liver and Biliary Sciences, Delhi, India. 

Carvedilol, a non-selective beta-blocker, effectively reduces portal pressure in nearly 50% of patients with cirrhosis, while simvastatin has been shown to reduce portal pressure and improve survival when combined with a non-selective beta-blocker. 

Dr. Rajan and colleagues assessed the hemodynamic response to carvedilol plus simvastatin vs. carvedilol monotherapy in patients with cirrhosis with small or large esophageal varices who have never bled. Hemodynamic response was defined as a reduction in hepatic vein pressure gradient (HVPG) by >20% compared to baseline or HVPG reduction to <12mmHg after 3 months of treatment. 

All patients with chronic liver disease with small or large esophageal varices were included in the study, which was initiated May 2015 and will run through December 2016. 

Excluded were patients with cirrhosis with a history of variceal bleed, acute or chronic liver failure, hepatocellular carcinoma, on primary variceal ligation sessions as prophylaxis, or were on beta-blockers or were intolerant or had a contraindication for beta-blockers. 

A total of 220 cases were randomly assigned to receive carvedilol (group 1; n=110) or carvedilol plus simvastatin (group 2; n=110) for 3 months. In group 1, patients received a weekly dose escalation of carvedilol starting with 3.125mg twice daily to a maximum dose of 25mg/day. In group 2, patients received a weekly dose escalation of carvedilol with maximum dose of 25mg/day with simvastatin started at 20mg/day and escalated to 40mg/day on Day 15. 

The primary study endpoint was hemodynamic response at 3 months. At baseline and 3 months, biochemical tests, UGI endoscopy, liver stiffness, and HPVG were conducted. 

To date, of the 220 consecutive patients enrolled, 115 have completed the 3-month follow-up, 59 in group 1 and 56 in group 2. 

Etiology of varices included nonalcoholic steatohepatitis (NASH; 28 patients in group 1 and 31 in group 2) and alcohol misuse, 11 patients in group 1 and 16 in group 2. The HVPG was comparable between groups. 

At the 3-month follow-up, mean HPVG was reduced in both group 1 (17.35mmHg to 14.23mmHg; P<0.001) and group 2 (19.04mmHg to 15.26mmHg; P<0.001); mean HVPG reduction was 3.13 in group 1 and 2.78 in group 2 (P=0.35). 

The addition of simvastatin to carvedilol in comparison to carvedilol alone did not enhance portal pressure reduction in non bleeders, the study found, 18.01% vs. 15.41% (P=0.43). 

Among patients with large varices, more patients in the carvedilol plus simvastatin group had improved hemodynamic response, 68.18%, compared with 56.25% in the carvedilol alone arm. 

Two patients in the carvedilol alone arm and 1 in the combination arm bled during the study period, Dr. Rajan noted, and both underwent variceal ligation. Four patients in the carvedilol alone arm and 2 in the combination arm were intolerant to therapy. 

Two patients developed drug toxicity to simvastatin, and 7 had extreme lethargy and weakness that required dose reduction of simvastatin. 

The median tolerated dose of carvedilol in both groups was 21.875mg/day.