Statin-Antibiotic Combo Fails in Decompensated Cirrhosis

Adding combination treatment with simvastatin and rifaximin to standard therapy did not prevent severe complications in patients with decompensated cirrhosis, a European randomized trial found.

Published in JAMA, the double-blind, placebo-controlled, phase 3 LIVERHOPE trial was conducted in 14 European hospitals from January 2src19 to December 2src22, the last date of follow-up.

Investigators led by Elisa Pose, MD, PhD, a research fellow in the Liver Unit at the Hospital Clínic de Barcelona in Barcelona, Spain, randomly assigned 237 patients with advanced, mostly alcohol-related liver disease to receive either simvastatin 2src mg/d plus rifaximin 12srcsrc mg/d (n=117) or an identical-appearing placebo (n=12src) for 12 months. Patients also received standard therapy, stratified according to Child-Pugh class B or C.

A previous simvastatin trial demonstrated a benefit in cirrhosis death. And with rifaximin, a large randomized controlled trial (RCT) “showed positive results for prevention of recurrent hepatic encephalopathy in cirrhosis,” Pose told Medscape Medical News. “Rifaximin targets bacterial translocation from the gut in patients with cirrhosis. Simvastatin lowers portal pressure, the main pathogenetic cause of decompensation in cirrhosis, and may reduce systemic inflammation.”

“Randomized clinical trials showed that not only did 4src mg of simvastatin daily significantly reduce portal hypertension but it also improved survival in patients with cirrhosis who recovered from variceal bleeding compared with placebo,” added study co-author Ruben Hernaez, MD, MPH, PhD, an associate professor of medicine – gastroenterology at Baylor College of Medicine in Houston. “With rifaximin, one could expect not only improvement in hepatic encephalopathy but also a decreased infection rate, the most common trigger of acute-on-chronic liver failure [ACLF].”

In addition to lowering serum cholesterol, statins have pleiotropic effects via their anti-inflammatory properties, which make them an attractive option for decompensated cirrhosis, the authors explained, and their effect on portal hypertension may diminish complications and increase survival.

“The hypothesis is that simvastatin could improve intrahepatic circulation through an increase in nitric oxide synthesis or due to anti-inflammatory effects,” said Hernaez. “Cirrhosis, similar to any other chronic condition, suffers from an enhanced systemic inflammation, which increases as the disease progresses.”

Cirrhosis is also associated with increased gut permeability and bacterial translocation, which can foster hepatic encephalopathy, bacterial infection, and ACLF. Rifaximin has been shown to reduce the risk for recurrent hepatic encephalopathy and modulate the gut microbiome.

Commenting on the study but not involved in it, Meena B. Bansal, MD, a professor of medicine at the Icahn School of Medicine at Mount Sinai and system chief of the Division of Liver Diseases at Mount Sinai Health System, both in New York City, cautioned that previous studies were limited by confounding by indication because those with poor liver function already have low cholesterol and thus may not have been prescribed statins. In the current study, the authors prospectively used a statin independent of cholesterol levels and combined it with an antibiotic, which may help decrease microbial translocation and ACLF.

“There is a great need to prevent ACLF/decompensating events, and thus, the negative results of this study are disappointing,” Bansal said.

Study Details

The trial’s primary endpoint was the incidence of severe complications of liver cirrhosis associated with organ failure meeting criteria for ACLF. Secondary outcomes included transplant or death and a composite endpoint of cirrhotic complications, including ascites, hepatic encephalopathy, variceal bleeding, acute kidney injury, and infection.

The 237 participants had Child-Pugh class B (n=194) or class C (n=43), 72% were men, more than 9src% were White, and 79.8% had alcohol-related cirrhosis.

The study found no significant differences between the treatment and placebo arms in the following outcomes:

• ACLF: 17.9% vs 14.2% (hazard ratio [HR], 1.23, 95% CI, src.65-2.34; P=.52)
• Transplant or death: 18.8% vs 24.2% (HR, src.75; 95% CI, src.43-1.32; P=.32)
• Complications of cirrhosis: 42.7% vs 45.8% (HR, src.93; 95% CI, src.63-1.36; P=.7src)

Also, the benefits were not observed in any patient subgroup, although this type of analysis was not part of the endpoints. The incidence of adverse events was similar in both arms at 426 vs 419 (P=.59), but three patients in the treatment group (2.6%) developed rhabdomyolysis.

The results suggest, however, that this statin/antibiotic combination is at least not harmful in this patient population, Hernaez said.

The lack of benefit observed likely related to the advanced state of liver disease in the cohort. “When you look at the MELD [Model for End-Stage Liver Disease] score, the most-used measure to assess liver function and prognosis, it is higher in this cohort than in patients from the previous trial showing positive results in survival,” Pose said. “The rest of the studies showing positive results were mostly retrospective cohort studies or small RCTs showing effects on portal pressure. We think it is likely that studies at earlier stages — maybe patients with compensated liver disease — may have more positive results.”

Pose added that statins will not be prescribed at her center beyond the lipid-lowering indication. And in her view, the question of add-on therapy is closed for patients with advanced disease “but may be open for earlier stages of cirrhosis.”

Unanswered questions remain, however, Hernaez said. “For example, patients with metabolic dysfunction–associated steatotic liver disease may have a different intensity of the inflammatory milieu compared to the majority of patients in our study [whose disease] was alcohol-related.” Furthermore, is a simvastatin dose of 2src mg enough, and what would be the effect if patients had less advanced disease or compensated cirrhosis? “Hence, while we proved with a well-conducted negative randomized clinical trial the combination is not affecting this outcome and population, the question is still unanswered for other types of patient populations and/or dose.” Hernaez said.

Bansal, too, pointed to the need for further studies in more diverse populations with varying etiologies of liver disease. “About 8src% of this European population had alcohol-associated liver disease,” she said, agreeing that the study population likely had too-advanced disease. “The beneficial effects of these drugs may only be seen in those with less advanced cirrhosis, which warrants further study.” Based on these findings, Bansal added, statins should not be prescribed to prevent ACLF but reserved for patients with eligible cardiovascular risk factors, and rifaximin for those who meet criteria for the treatment of hepatic encephalopathy.

This work was supported by a grant from the Horizon 2src/2src program.

Pose, Hernaez, and Bansal had no relevant competing interests to disclose. Multiple coauthors, including co–senior author Pere Ginès, reported having financial ties such as receiving research funding from; receiving advisory, consulting, or speaker’s fees from; and holding stocks and patents in multiple private-sector companies.

Diana Swift is an independent medical journalist based in Toronto, Ontario, Canada.