Rifaximin for Hepatic Encephalopathy
Rifaximin treatment in hepatic encephalopathy.
Bass NM, Mullen KD, Sanyal A, er al.
N Engl J Med. 2010 Mar 25;362(12):1071-81. [Full text]
Summary by Sara Kiparizoska
A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy.
Sharma BC, Sharma P, Lunia MK, et al.
Am J Gastroenterol. 2013 Sep;108(9):1458-63. [Full text]
Visual Abstract @ VIsualMed
Rifaximin is an expensive (GoodRx price for Rifaximin 550 mg is over $2,000 for 42 tablets), yet well tolerated antibiotic with minimal risk profile that is commonly used for hepatic encephalopathy (HE) cirrhotic patients. What is the evidence for this routine use and does that evidence justify its expense, especially considering that lactulose is significantly more affordable (GoodRx $14)? Here we review two of the foundational studies of rifaximin in HE.
Patients
The NEJM 2010 [1] study was an international, multi center, randomized, placebo-controlled trial with 229 patients in 70 sites throughout the US, Canada, and Russia. A total of 159 patients receive placebo and 140 patients received Rifaximin. The groups were followed for 6 months and they were all included in the intention to treat and safety populations.
Patients that used benzodiazepines, warfarin, other antibiotics, or narcotics were not included. Patients with GI bleed or TIPS within 3 months were excluded, as were those with creatinine >2.0 mg/dL, Na <125 mEq/L, intercurrent infection, or active spontaneous bacterial peritonitis.
The Am J Gastro 2013 [2] study was from a single-center in India with a prospective randomized design that included 120 hospitalized patients with acute hepatic encephalopathy. A total of 63 patients received lactulose + rifaximin while 57 recieved lactulose + placebo.
Patients with a creatinine >1.5 mg/dL, alcohol use within 4 weeks, and hepatocellular carcinoma were excluded.
Outcome Measures and Design
The primary end point of this study was the time to the first breakthrough episode of HE. The secondary end point was the time to the first hospitalization with HE.
Rifaximin was dosed at 550 mg PO BID for up to 6 months or held for a breakthrough episode of HE. Lactulose dosing was not prescribed but, 90% of all patients were receiving lactulose. Hence, though this was rifaximin vs. placebo design, effectively it was rifaximin + lactulose vs. lactulose alone.
The primary end point of the study was complete reversal of HE as per West Haven criteria. The secondary end points were mortality and hospital stay.
Rifaximin was dosed at 400 mg PO TID for up to 10 days. Lactulose was dosed at 30-60 mL PO TID with goal 2-3 semisoft stools per day.
Results
Most patients were male (~60%) and < 65 yo (~80%). 64% had a MELD of 11-18 with another ~28% with a MELD ≤10. All patients had a history of 2 or less HE episodes in the 6 month period before the study.
The mean duration of treatment was 130 days in the Rifaximin group and 105 days in the placebo group. The rate of compliance was > 80% in both study groups.
Breakthrough Episodes: 31 of 140 (22.1%) patients in the Rifaximin group vs 73 of 159 (45.9%) in the placebo group had an episode of breakthrough HE for a HR pf 0.42 (95% CI, 0.28 to 0.64; P< 0.001) and NNT of 4.
Hospitalizations: 13.6% patients in the Rifaximin group vs 22.6% in the placebo group were hospitalized with HE for a HR of 0.50 (95% CI, 0.29 to 0.87; P=0.01) and a NNT of 9.
Safety: The incidence of reported adverse events was similar in both groups. Important to note, of the reported adverse events related to infection, two patients in the Rifaximin group contracted C. Diff compared to zero in the placebo; however, both affected patients had multiple concurrent risk factors and continued Rifaximin together with the treatment for their C.Diff.
Most patients were male (~75%) had alcoholic cirrhosis (~63%) and most had a Child-Pugh score of C (~76%) with a MELD of ~25.
Many had a prior episode of HE (~48%) and many presented with HE grade 3 (31.7%) or 4 (52.4%). Triggers for HE included SBP (19%), sepsis (12%), GI bleed (24%) and constipation (19%).
More patients in the lactulose + rifaximin group had the primary outcome of total reversal of hepatic encephalopathy (76% vs. 44%; P=0.004; NNT 3).
In regards to secondary outcomes, lactulose + rifaximin was associated with a lower all-cause mortality (23.8% vs. 49.1%; P<0.05) with especially less sepsis mortality (11.1% vs. 36.2%; P<0.01).
Discussion
Overall, compared to other antibiotics (neomycin, paromomycin, vancomycin, and metronidazole) that have been used for HE, Rifaximin has desirable great safety profile. Plasma levels in patients receiving Rifaximin are negligible, and the risk of bacterial resistance and C. difficile is low. The major barrier, as noted, is cost.
What are the potential benefits of rifaximin when added to the more affordable lactulose? For outpatients with less severe liver disease (most pts MELD ≤ 18), rifaximin in addition to lactulose led to less breakthrough HE and fewer hospitalizations [1]. Additionally, if hospitalized with HE, more patients receiving rifaximin in addition to lactulose had more complete reversal of HE [2]. There is a suggestion of improved mortality in the inpatient study, though that mortality is extremely higher than would be expected (49%!), and most of that mortality was via sepsis mortality (36%). Perhaps improved sepsis management might negate this finding and would not be attributable to rifaximin.
The added expense of rifaximin is likely justified from a value added perspective. Whether patients can afford it is a separate issue. Practice guidelines, which are from 2014 but included these trials recommend lactulose as the first choice for treatment of HE (grade II-1, A) and notes that rifaximin is effective add-on therapy to lactulose for prevention of HE recurrence (grade 1, A), effectively endorsing it but not as first line therapy [3].
| F: Follow up | 6 months (Clinic visits d 7 + 14 + Q2 wks through d 168) |
| R: Randomization | Yes |
| I: Intention to treat | Yes |
| S: Similar at baseline | Yes |
| B: Blinding | Yes |
| E: Equal treatment | Not discussed |
| S: Source (funding) | Salix Pharmaceuticals |
| F: Follow up | Duration of hospital stay |
| R: Randomization | Yes, |
| I: Intention to treat | Yes |
| S: Similar at baseline | Yes |
| B: Blinding | Yes* of rifaximin, not lactulose |
| E: Equal treatment | Not discussed |
| S: Source (funding) | Not disclosed |
- Bass NM, Mullen KD, Sanyal A, er al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010 Mar 25;362(12):1071-81.
- Sharma BC, Sharma P, Lunia MK, et al. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol. 2013 Sep;108(9):1458-63.
- American Association for the Study of Liver Diseases; European Association for the Study of the Liver. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. J Hepatol. 2014 Sep;61(3):642-59.
