Rifaximin plus lactulose versus lactulose alone for reducing the risk of HE recurrence

Abstract

Background:

The aim was to examine rifaximin plus lactulose efficacy in patients with cirrhosis at a risk of developing overt HE who were stratified by important baseline characteristics such as comorbid ascites or diabetes.

Methods:

Pooled post hoc subgroup analysis of adults receiving rifaximin 550 mg twice daily plus lactulose or lactulose alone for 6 months in a phase 3 randomized, double-blind trial and a phase 4 open-label trial was conducted.

Results and Conclusion:

Rifaximin plus lactulose was more efficacious than lactulose alone for reducing the risk of overt HE recurrence and HE-related hospitalization in adults grouped by select baseline disease characteristics.

INTRODUCTION

Patients with cirrhosis have a worsening prognosis as they transition from the compensated to decompensated state, which is marked by the onset of complications, including ascites and HE.¹ Reducing the risk and severity of complications is a cornerstone of managing cirrhosis.² Overt hepatic encephalopathy (OHE) is a common complication of cirrhosis, with a widely varying clinical presentation (eg, personality/behavioral changes, time disorientation, and confusion).³ Risk factors for the development of OHE include ascites and diabetes mellitus.^4–6 Rifaximin 550 mg tablets are indicated for reducing the risk of OHE recurrence in adults.⁷ Guidelines from the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver state that rifaximin is effective as an add-on therapy to lactulose for OHE prevention.^3,8 The current aim was to examine the efficacy and safety of rifaximin plus lactulose versus lactulose alone, in patients with cirrhosis stratified by important baseline demographic and disease characteristics, to further explore the potential benefits of rifaximin add-on therapy.

METHODS

A pooled post hoc analysis of a phase 3 randomized, double-blind trial (ClinicalTrials.gov identifier NCT00298038)⁹ and a phase 4 open-label trial (NCT01842581) was conducted. Adults with cirrhosis and a history of OHE during the previous 6 months who were in OHE remission were stratified post hoc by baseline demographic and disease characteristics (age, ascites, Child-Pugh class, cirrhosis etiology, diabetes, duration of current HE remission, Model for End-Stage Liver Disease category, race, sex, time since first diagnosis of advanced liver disease, and time since first diagnosis of HE). In the phase 3 trial, rifaximin 550 mg or placebo was administered twice daily (bid) with optional lactulose (titrated to 2–3 soft stools/d) for 6 months. In the phase 4 trial arm, rifaximin 550 mg bid plus lactulose (titrated to 2–3 soft stools/d) was administered for 6 months. Only patients who received rifaximin plus lactulose or placebo plus lactulose (defined as lactulose alone herein) were included in the current analyses.

In the phase 3 trial, follow-up occurred on day 0 (±1), days (±2) 7, 14, 28, 42, 56, 70, 84, 98, 112, 126, 140, 154, 168, and during the follow-up visit (14±2 days after the end of treatment). In the phase 4 trial, follow-up occurred on day 1, days (±2) 28, 56, 84, 112, 140, 168, and during the follow-up visit (14±2 days after the end of treatment). Outcomes assessed included the time to onset of OHE episode (Conn score ≥2) and the time to first HE-related hospitalization (original endpoints in both trials). HR estimates were obtained using a Cox proportional hazards model with effect for treatment; p values were based on the score statistic.

RESULTS

Overall, 381 patients (62.5% male; mean [SD] MELD score, 12.6 [3.6]) were included in the current analyses (rifaximin plus lactulose [n=236]; lactulose alone [n=145]). Overall, at baseline, 135 patients had comorbid ascites and 135 had comorbid diabetes. Baseline disease characteristics were generally comparable between treatment groups (Supplemental Table S1, http://links.lww.com/HC9/A875). Significantly fewer patients treated with rifaximin plus lactulose had an OHE episode versus lactulose alone during 6 months in the total population (19.1% vs. 49.0%, respectively; p<0.0001) and in most demographic and baseline characteristic subgroups (Supplemental Table S2, http://links.lww.com/HC9/A875), including those with baseline ascites (27.4% vs. 58.8%; p<0.001), without baseline ascites (14.5% vs. 43.6%; p<0.0001), with diabetes (22.6% vs. 51.0%; p<0.001), and without diabetes (17.1% vs. 47.9%; p<0.0001). The reduction in the risk of OHE recurrence for patients receiving rifaximin plus lactulose versus lactulose alone during 6 months of treatment was 68% (HR, 0.32; 95% CI, 0.22–0.47) for the overall population, 63% (HR, 0.37; number needed to treat [NNT], 3) for patients with baseline ascites, 72% (HR, 0.28; NNT, 3) for patients without baseline ascites, 64% (HR, 0.36; NNT, 4) for patients with diabetes, and 70% (HR, 0.30; NNT, 3) for patients without diabetes (Figure 1).

FIGURE 1.

Time to first breakthrough OHE episode in (A) the overall population and patients, (B) with or without baseline ascites, and (C) with or without baseline diabetes, and time to first HE-related hospitalization in (D) the overall population and patients, (E) without or without baseline ascites, and (F) with or without baseline diabetes. Triangles indicate censored observation(s). Abbreviations: NNT, number needed to treat; OHE, overt hepatic encephalopathy.

Patients receiving rifaximin plus lactulose had a significantly lower incidence of a first HE-related hospitalization versus patients receiving lactulose alone in the overall population (11.9% vs. 23.4%; p<0.001) and in patients with baseline ascites (14.3% vs. 35.3%; p<0.001), patients with diabetes (14.3% vs. 29.4%; p=0.01), and patients without diabetes (10.5% vs. 20.2%; p<0.01). For the subgroup of patients without baseline ascites, there was a numeric difference favoring rifaximin plus lactulose versus lactulose alone, but it was not statistically significant, possibly due to the smaller number of patients in the lactulose-alone arm (10.5% vs. 17.0%; p=0.06). The reduction in the risk of first HE-related hospitalization for patients receiving rifaximin plus lactulose versus lactulose alone during 6 months of treatment was 59% (HR, 0.41; 95% CI, 0.25–0.67) for the overall population, 70% (HR, 0.30; NNT, 5) for patients with baseline ascites, 48% (HR, 0.52; NNT, 15) for patients without baseline ascites, 60% (HR, 0.40; NNT, 7) for patients with diabetes, and 59% (HR, 0.41; NNT, 10) for patients without diabetes (Figure 1).

DISCUSSION

These post hoc analyses demonstrate that rifaximin plus lactulose was more efficacious than lactulose alone for reducing the risk of OHE recurrence and HE-related hospitalization in adults, even when stratified by baseline demographic or disease characteristics. The presence of ascites is a risk factor for the development of OHE,^3,4 and rifaximin was shown to be effective in this high-risk population. Diabetes is a common condition in cirrhosis and can affect HE therapy efficacy.^5,10 However, the current results indicate that the efficacy of rifaximin plus lactulose for reducing the risk of OHE recurrence is not affected by comorbid diabetes; however, hemoglobin A1c levels were not collected during the trials. Rifaximin plus lactulose therapy should be considered for adults with cirrhosis and a history of OHE, including those with comorbid diabetes or ascites and those being discharged from an inpatient setting after a recurrent OHE episode.

Supplementary Material

hc9-8-e0436-s001.docx ^{(22.5KB, docx)}

FUNDING INFORMATION

The trials were funded by Salix Pharmaceuticals, Bridgewater, NJ. Salix Pharmaceuticals had a role in the design and conduct of the study; a role in the collection, management, analysis, and interpretation of the data; and a role in the review of the manuscript; however, the company had no decision in the submission of the final manuscript for publication.

CONFLICTS OF INTEREST

Arun J. Sanyal consults and received grants from Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Gilead, Intercept, Inventiva, Madrigal, Mallinckrodt, Merck, Novartis, Novo Nordisk, and Pfizer. He consults and owns stock in GENFIT and HemoShear. He consults for 89bio, Albireo, Alnylam, Amgen, AstraZeneca, Covance, Genentech, HistoIndex, Janssen, NGM Bio, PathAI, Poxel, ProSciento, Regeneron, Roche, Salix, Siemens, and Terns. He received grants from Fractyl. He owns stock in Durect, Exhalenz, Indalo, NorthSea, Rivus, and Tiziana. He receives royalties from Elsevier and UpToDate. Kris V. Kowdley consults, is on the speakers' bureau, and received grants from Gilead and Intercept. He consults and received grants from 89bio, CymaBay, GENFIT, Madrigal, Mirum, NGM, and Pfizer. He consults and owns stock in Inipharm. He consults for Enanta, HighTide, and Salix. He is on speakers' bureau for AbbVie. He received grants from Corcept, GlaxoSmithKline, Hanmi, Novo Nordisk, Pliant, Terns, and Viking. Nancy S. Reau consults for AbbVie, Gilead, Intercept, and Salix. She received grants from Eiger. Nikolaos T. Pyrsopoulos consults for Salix. Christopher Allen is employed by Salix. Zeev Heimanson is employed by Salix. Jasmohan S. Bajaj consults for Merz. He received grant from Cosmo, Grifols, Mallinckrodt, Salix, and Sequana Medical.