A new analysis indicates that rifaximin monotherapy is more effective than lactulose in preventing the recurrence of overt hepatic encephalopathy (OHE) in patients with cirrhosis. The findings, presented at the American College of Gastroenterology (ACG) annual meeting, suggest a potential shift in treatment strategies for managing this debilitating condition.
Reduced OHE Recurrence with Rifaximin
The post-hoc analysis of two randomized trials showed that only 23.2% of patients on rifaximin monotherapy experienced an OHE breakthrough episode over 6 months, compared to 49% of patients on lactulose monotherapy (P < 0.0001). This indicates a substantial reduction in OHE recurrence with rifaximin.
"This is an important and timely study given the significant morbidity associated with overt hepatic encephalopathy," said Yee Hui Yeo, MD, MSc, a clinical fellow at Cedars-Sinai Medical Center in Los Angeles.
Mortality Benefits
Beyond reducing OHE recurrence, rifaximin also demonstrated a significant impact on mortality. The mortality rate was significantly lower in the rifaximin group (1.6%) compared to the lactulose group (4.8%, P < 0.001). The time to all-cause mortality was also significantly longer in the rifaximin group (HR 0.048, 95% CI 0.01-0.29, P < 0.001). The number needed to treat to prevent mortality was 19.
Lactulose Intolerance
Many patients struggle with lactulose due to its side effects, including gastrointestinal adverse events, personalized dosing requirements, and unpleasant taste, leading to nonadherence. "For those who have actually dealt with patients dealing with lactulose, it has a plethora of side effects," Bajaj told attendees. "Many of them lead to patients not taking this, which includes GI adverse events, dosing and volume requirements -- which have to be incredibly personalized -- and there's an unpleasant taste."
Drug-related adverse effects occurred in 24.1% of lactulose patients and 6.4% of rifaximin patients, and 39.3% and 20% discontinued treatment due to an adverse effect. There was a statistically significantly higher rate of diarrhea in the lactulose group compared with the rifaximin group (14.5% vs 4.8%).
Study Details
The analysis combined data from a phase III double-blind trial and a phase IV open-label trial. The 270 participants were predominantly white (87-90%) and male (60-68%) with an average age of 56-58 and an average baseline Model for End-Stage Liver Disease (MELD) score of 12-13. Participants received either 550 mg of rifaximin twice daily or lactulose titrated to two to three soft stools per day for up to 6 months.
Cost Considerations
While rifaximin is more expensive (at least $2,000 a month) compared to lactulose ($5-15 for 16 oz), Bajaj noted that the cost of unnecessary hospitalizations for hepatic encephalopathy, which can sometimes result in an ICU stay, should also be considered. He added that lactulose requires a lot of human resources, including time spent on the phone explaining the medication to the patient and caregiver, and seeing them in the hospital because they could not tolerate the lactulose.
Limitations
The trial's biggest limitation was that it was a post-hoc analysis of two separate trials, rather than a head-to-head comparison, and it had a relatively small sample size that can inhibit generalizability. "Additionally, the design may not fully capture the heterogeneity in real-world patient populations with cirrhosis, including differences in adherence, access to medications, and comorbidities," Yeo said. "Given these limitations, these findings should be validated in larger, prospective, and diverse patient cohorts before making broad changes to current treatment guidelines."
