Rifaximin and Lactulose for HE

Published

Sharma BC, et al. "A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy". The American Journal of Gastroenterology. 2013. 108(9):1458-1463.
PubMed • Full text • PDF

Clinical Question

Does the addition of rifaximin to lactulose improve reversal of hepatic encephalopathy among hospitalized patients?

Bottom Line

In this small, single-center, randomized trial of hospitalized patients with acute hepatic encephalopathy, the addition of rifaximin to lactulose therapy increased the rate of reversal of encephalopathy and reduced mortality at 10 days.

Major Points

Hepatic encephalopathy (HE) is a major cause of morbidity for individuals with cirrhosis. Lactulose had been used as treatment for this condition long before it was demonstrated effective as secondary prevention in a 2009 trial by Sharma and colleagues. This medication lowers pH in the colon, which promotes development of insoluble ammonium over soluble ammonia. Furthermore, its laxative effects increase removal of ammonia from the GI tract. Rifaximin is a minimally-absorbed antibiotic that reduces urease-producing bacteria in the GI tract, which results in decreased ammonia production. Its efficacy in prevention of HE was shown in a 2010 publication by Bass and colleagues. The role of rifaximin as an add-on to lactulose therapy in acute HE was unknown.

This study, published in 2013 by Sharma and colleagues, randomized 120 hospitalized patients with HE at a single center in India to lactulose plus rifaximin or lactulose plus placebo. At ten days, rifaximin was associated with a significant increase in total reversal of HE (76% vs. 44%) as well as a significant reduction in mortality (23.8% vs. 49.1%), which was driven by a reduction in sepsis (11.1% vs. 36.2%). The generalizability of this trial is limited given that the patients were more ill than most hospitalized patients with HE. Also, the standard therapy group had a much higher mortality rate than US patients with HE.

Of note, a small 2014 trial found superiority of polyethylene glycol over lactulose for resolution of HE. This finding has yet to be reproduced in a larger clinical trial.

Guidelines

As of May 2014, no guidelines have been published that reflect the results of this trial.

Design

• Prospective, single-center, double-blind, randomized controlled trial
• N=120 (172 screened)
  • Lactulose + rifaximin (n=63)
  • Lactulose + placebo (n=57)
• Setting: One tertiary care center in New Delhi, India
• Enrollment: 2010-2012
• Follow-up: 10 days
• Analysis: Not specified
• Primary outcome: Total reversal of hepatic encephalopathy

Population

Inclusion Criteria

• Age 18-80 years
• Cirrhosis, defined by a combination of any of the following:
  • Laboratory findings
  • Endoscopic results
  • Ultrasound
  • Histology
• Overt hepatic encephalopathy

Exclusion Criteria

• Creatinine >1.5 mg/dl
• Alcohol use within prior 4 weeks
• Non-hepatic metabolic encephalopathy
• Hepatocellular carcinoma
• Degenerative CNS disease
• Any significant psychiatric illness or other medical comorbidity

Baseline Characteristics

From the lactulose + rifaximin group.

• Demographics: Age 40.4 years, male sex 75%
• Etiology of liver disease: Alcohol 63.4%, HBV 15.9%, HCV 4.8%, other 15.9%
• Baseline laboratory data: Hgb 8.1 g/dL, platelets 83,560, bilirubin 4.9 mg/dL, albumin 2.5 g/dL, AST 62.9 IU/L, ALT 68.1 IU/L, alk phos 101.2 U/L, INR 2.7, urea 27.8 mg/dL, creatinine 0.9 mg/dL, Na 132.4 mEq/L, K 3.6 mEq/L, arterial ammonia 132.6 umol/L
• Disease severity:
  • Child-Turcotte-Pugh score: 9.9 (24.1% B, 75.9% C)
  • MELD: 24.9
• HE-specific:
  • HE grade:
    • 1: 0%
    • 2: 16.7%
    • 3: 31.7%
    • 4: 52.4%
  • Prior HE: 47.6%
  • Triggers: SBP 19%, sepsis from UTI 9%, sepsis from pneumonia 3%, GI bleed 24%, constipation 19%, electrolyte imbalance 5%, unknown 21%

Interventions

• Randomized to a group:
  • Lactulose + rifaximin
  • Lactulose + placebo
• Rifaximin dosing: 400 mg capsules PO TID
• Lactulose dosing: 30-60 mL PO TID with goal 2-3 semisoft stools per day

Outcomes

Presented as lactulose + rifaximin vs. lactulose + placebo.

Primary Outcome

Total reversal of hepatic encephalopathy

76% vs. 44% (P=0.004; NNT 3)

Secondary Outcomes

All-cause mortality

23.8% vs. 49.1% (P<0.05; NNT 4)

Sepsis mortality: 11.1% vs. 36.2% (P<0.01; NNT 4)

GI bleed mortality: 6.3% vs. 8.5% (NS)

Hepatorenal syndrome mortality: 6.3% vs. 14.9% (NS)

Criticisms

• The mortality in the standard group in this trial was much higher than the average mortality in a similar population in the US (49% vs. ~15%)
• Participants had more severe illness than average patients with acute HE in the US, thereby limiting generalizability to other populations
• Unclear if the mortality reduction from sepsis is secondary to prevention of endotoxins in the gut bacteria or if there was a mortality benefit from the reversal of the HE alone

Funding

None identified by authors.