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  The International Liver Congress™
EASL - European Association for the
Study of the Liver
June 22-26 2022
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Simvastatin May Boost Beta Blocker Carvedilol Impact on Portal Hypertension, Modulates Systemic Inflammation
  EASL International Liver Congress 2022, London, June 22-26, 2022
Mark Mascolini
Simvastatin enhanced the impact of the beta blocker carvedilol on portal hypertension, according to results of an 82-person placebo-controlled trial in Barcelona [1]. Carvedilol-related drops in some proinflammatory cytokines and drivers of oxidative stress both proved greater with simvastatin plus carvedilol than with placebo plus carvedilol.
Researchers at Barcelona's Hospital Santa Creu i Sant Pau noted that beta blockers have found a role in preventing bleeding in people with cirrhosis and portal hypertension (high blood pressure in the portal vein system, the main veins leading to the liver). Carvedilol conferred significantly greater survival than propranolol or nadolol (two other beta blockers) in trials involving people with portal hypertension. Statins, the Barcelona team hypothesized, may boost the impact of beta blockers like carvedilol on portal hypertension because their antihypertensive mechanism differs from that of beta blockers. They proposed that adding simvastatin to carvedilol may improve hemodynamic and inflammatory factors in people with cirrhosis and clinically significant portal hypertension (CSPH) that did not respond to beta blockers alone.
Trial inclusion criteria included age from 18 through 80 years and cirrhosis diagnosed by liver biopsy or clinical/biochemical criteria including CSPH with high-risk varices. Participants could have no prior bleeding episodes. The trial excluded people with Child-Pugh score above 12, advanced liver cancer, and other indicators of advanced illness. Researchers included only people with acute nonresponse to intravenous beta blockers, that is, hepatic venous pressure gradient (HVPG) decrease below 20%. Participants got randomized to carvedilol plus simvastatin or carvedilol plus simvastatin placebo for 30 days.
Among 111 eligible trial candidates, 82 were beta-blocker nonresponders, of whom 41 got randomized to carvedilol plus placebo and 41 to carvedilol plus simvastatin. About two thirds in each treatment arm were men and age averaged 62 or 63 years. About 40% overall had previous hepatic decompensation, and about one quarter had ascites when starting the study. Body mass index averaged 27 kg/m2 in the placebo group and 28 kg/m2 in the simvastatin group (both values in the overweight range).
After 1 month HVPG fell significantly more with simvastatin plus carvedilol than with placebo plus carvedilol when figured as percent change (-16% vs -11%, P < 0.05) or absolute change (about -3 mmHg vs -2 mmHg, P < 0.05).
Pretreatment measures indicated similar inflammatory marker values in the placebo group and the simvastatin group. After 1 month percent decline in certain markers proved significantly greater with simvastatin plus carvedilol than with placebo plus carvedilol: IL-6, -39% vs -25%, P < 0.05; MDA, about -30% vs -18%, P < 0.01; MCP-1, about -15% vs -5%, P < 0.01. IL-6 fell significantly more with simvastatin than placebo (-30% vs -11%, P < 0.01) among participants who had more than a 20% drop in HVPG from the baseline value. Among all participants, percent change in IL-6 correlated with percent change in HVPG (r = 0.42, P = 0.004).
Overall rate of adverse events (including asthenia, bradycardia, hypotension, and greater than 2-fold change in creatine kinase) did not differ between the simvastatin group and the placebo group. Percent change from baseline in bilirubin was greater among people taking simvastatin than placebo (-7.63 vs -1.64 mmol/L).
The researchers concluded that adding simvastatin to carvedilol "potentiates the portal pressure-lowering effect observed with carvedilol and improves antiinflammatory efficacy." They suggested those changes may mean simvastatin can bolster clinical efficacy of carvedilol.
1. Alvarado-Taplas E, Brujats A, Pujol C, et al. Carvedilol plus simvastatin modulates systemic inflammation in cirrhosis with portal hypertension and non-response to beta-blockers: randomised double-blind study. EASL International Liver Congress 2022, London, June 22-26, 2022. Abstract OS128.
2. ClinicalTrials.gov. Hemodynamic effect of simvastatin with beta blockers in clinical portal hypertension (SIMBETA). ClinicalTrials.gov identifier NCT01282385. https://clinicaltrials.gov/ct2/show/NCT01282385.