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Rifaximin Treatment in Hepatic Encephalopathy
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NEJM March 25 2020
Nathan M. Bass, M.B., Ch.B., Ph.D., Kevin D. Mullen, M.D., Arun Sanyal, M.D., Fred Poordad, M.D., Guy Neff, M.D., Carroll B. Leevy, M.D., Samuel Sigal, M.D., Muhammad Y. Sheikh, M.D., Kimberly Beavers, M.D., Todd Frederick, M.D., Lewis Teperman, M.D., Donald Hillebrand, M.D., Shirley Huang, M.S., Kunal Merchant, Ph.D., Audrey Shaw, Ph.D., Enoch Bortey, Ph.D., and William P. Forbes, Pharm.D.
"For patients in remission from hepatic encephalopathy, the minimally absorbed antibiotic rifaximin (Xifaxan) reduces the risk of recurrence by nearly 60%, researchers said.....Rifaximin is a minimally absorbed oral antimicrobial agent that is concentrated in the gastrointestinal tract, has broad-spectrum in vitro activity against gram-positive and gram-negative aerobic and anaerobic enteric bacteria, and has a low risk of inducing bacterial resistance"
ABSTRACT
Background - Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established.
Methods - In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy.
Results - Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P<0.001). A breakthrough episode of hepatic encephalopathy occurred in 22.1% of patients in the rifaximin group, as compared with 45.9% of patients in the placebo group. A total of 13.6% of the patients in the rifaximin group had a hospitalization involving hepatic encephalopathy, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29 to 0.87; P=0.01). More than 90% of patients received concomitant lactulose therapy. The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events.
Conclusions - Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038 [ClinicalTrials.gov] .)
Approximately 5.5 million persons in the United States have hepatic cirrhosis, a major cause of complications and death.1,2,3 Hepatic encephalopathy, a complication of hepatic cirrhosis, imposes a formidable burden on patients, their families, and the health care system.1,4 Overt episodes of hepatic encephalopathy are debilitating, can occur without warning, render the patient incapable of self-care, and frequently result in hospitalization.1,4 In 2003, more than 40,000 patients were hospitalized with hepatic encephalopathy, a number that increased to over 50,000 in 2004.4 Although the occurrence of episodes of hepatic encephalopathy appears to be unrelated to the cause of cirrhosis,5 increases in the frequency and severity of such episodes predict an increased risk of death.6,7
Hepatic encephalopathy is a neuropsychiatric syndrome for which symptoms, manifested on a continuum, are deterioration in mental status, with psychomotor dysfunction, impaired memory, increased reaction time, sensory abnormalities, poor concentration, disorientation, and - in severe forms - coma.1,7,8 The clinical diagnosis of overt hepatic encephalopathy is based on two concurrent types of symptoms: impaired mental status, as defined by the Conn score (also called West Haven criteria) (on a scale from 0 to 4, with higher scores indicating more severe impairment),9 and impaired neuromotor function.1,10 The Conn score is recommended by the Working Party on Hepatic Encephalopathy8 for assessment of overt hepatic encephalopathy in clinical trials. Signs of neuromotor impairment include hyperreflexia, rigidity, myoclonus, and asterixis (a coarse, myoclonic, "flapping" muscle tremor), which is measured with the use of an asterixis severity scale.10,11,12
Most therapies for hepatic encephalopathy focus on treating episodes as they occur and are directed at reducing the nitrogenous load in the gut, an approach that is consistent with the hypothesis that this disorder results from the systemic accumulation of gut-derived neurotoxins, especially ammonia, in patients with impaired liver function and portosystemic shunting.2,3,13 The current standard of care for patients with hepatic encephalopathy, treatment with nonabsorbable disaccharides lactitol or lactulose, decreases the absorption of ammonia through cathartic effects and by altering colonic pH.14
In an open-label, single-site study, Sharma et al. reported that lactulose, as compared with placebo, was effective in the prevention of overt hepatic encephalopathy.15 In that study, 125 patients who had recovered from a recent episode of hepatic encephalopathy were randomly assigned, in a 1:1 ratio, to receive either lactulose or placebo for up to 20 months. During a median study period of 14 months, the proportion of patients with episodes was smaller in the lactulose group than in the placebo group (19.6% vs. 46.8%, P=0.001). However, side effects of lactulose therapy - including an excessively sweet taste and gastrointestinal side effects such as bloating, flatulence, and severe and unpredictable diarrhea possibly leading to dehydration - result in frequent noncompliance.16,17,18
In general, the oral antibiotics neomycin, paromomycin, vancomycin, and metronidazole have been effectively used, with or without lactulose, to reduce ammonia-producing enteric bacteria in patients with hepatic encephalopathy.14,16,17 However, some oral antibiotics are not recommended for long-term use because of nephrotoxicity, ototoxicity, and peripheral neuropathy19,20 and are specifically contraindicated in patients with liver disease.19,21,22
Rifaximin is a minimally absorbed oral antimicrobial agent that is concentrated in the gastrointestinal tract, has broad-spectrum in vitro activity against gram-positive and gram-negative aerobic and anaerobic enteric bacteria, and has a low risk of inducing bacterial resistance.23,24,25 In randomized studies, rifaximin was more effective than nonabsorbable disaccharides and had efficacy that was equivalent to or greater than that of other antibiotics used in the treatment of acute hepatic encephalopathy.26,27,28,29,30,31,32,33,34,35,36,37,38,39 Furthermore, with minimal systemic bioavailability, rifaximin may be more conducive to long-term use than other, more bioavailable antibiotics with detrimental side effects.
In this phase 3, multicenter, randomized, double-blind, placebo-controlled study conducted over a 6-month period, we evaluated the efficacy and safety of rifaximin, used concomitantly with lactulose, for the maintenance of remission from episodes of hepatic encephalopathy in outpatients with a recent history of recurrent, overt hepatic encephalopathy.
Discussion
The prevention of episodes of hepatic encephalopathy is an important goal in the treatment of patients with liver disease,1,2,4,6,7 especially since symptoms of overt encephalopathy are debilitating and decrease the ability for self-care, leading to improper nutrition and nonadherence to a therapeutic regimen, which in turn leads to severe symptoms, frequent hospitalizations, and a poor quality of life. Our study showed that the use of rifaximin reduced the risk of a breakthrough episode of hepatic encephalopathy during a 6-month period among patients in remission who had a recent history of recurrent overt hepatic encephalopathy (≥2 episodes within the previous 6 months) before enrollment. The reduced risk was seen across subgroups, further showing the consistency of the results, which expand previously reported findings of the efficacy of rifaximin in the treatment of overt hepatic encephalopathy.26,27,28,29,30,31,32,33,34,39
The current study differs from previous randomized studies in that it examined the protective effect of rifaximin against breakthrough episodes of hepatic encephalopathy rather than its effect in the treatment of acute, overt symptoms; the study also involved a larger group of patients and a longer study period. In previous randomized studies, rifaximin was administered for 21 days or less26,27,28,29,30,32,33 or intermittently, for 14 or 15 days per month for 3 or 6 months.33,34,39
Our study shows the superiority of rifaximin therapy over treatment with lactulose alone. More than 90% of patients received concomitant lactulose during the study period, and a significant treatment effect was noted within 28 days after randomization. In contrast, a recent single-center, open-label study of 120 patients showed that although lactulose therapy was more effective than no active treatment in the prevention of overt hepatic encephalopathy,15 the treatment effects favoring lactulose were apparent only after approximately 4 months.
In the current, prospective study, rifaximin therapy reduced the risk of hospitalization involving hepatic encephalopathy, reflecting the clinical significance of our efficacy findings. Also, the reduced risk of hospitalization supports the results of retrospective chart reviews,4,43 which have shown that rifaximin, as compared with lactulose, is associated with a significantly lower frequency and duration of hospitalization and lower hospital costs.
The incidences of adverse events in general and adverse events consisting of infection in particular were similar in the rifaximin group and the placebo group. The safety profile of rifaximin appears to be superior to that of systemic antibiotics, particularly for patients with liver disease.31 The occurrence of nephrotoxicity and ototoxicity with the use of aminoglycosides (e.g., neomycin and paromomycin) and of nausea and peripheral neuropathy with prolonged use of metronidazole restricts their use in patients with hepatic encephalopathy.19,21,22
The risk of bacterial resistance appears to be lower with rifaximin than with systemic antibiotics. Plasma levels of rifaximin are negligible; therefore, bacteria outside the gastrointestinal tract are not exposed to appreciable selective pressure. In addition, whereas resistance to other antimicrobial agents is plasma-mediated, resistance to rifaximin is mediated through reversible genomic change. For chromosomally mediated mutation and selection to result in clinically relevant resistance, the mutation cannot be lethal and cannot significantly decrease virulence; otherwise, the resistant trait will not be transmitted. Both in vitro and in vivo studies of the effects of rifaximin on commensal flora suggest that rifaximin-resistant organisms have low viability.25,44,45
In summary, this study shows a robust protective effect of rifaximin against episodes of hepatic encephalopathy. Rifaximin also reduces the risk of hospitalization involving hepatic encephalopathy.1,31
Results
Study Patients
A total of 299 patients in the United States (205 patients), Canada (14 patients), and Russia (80 patients) were randomly assigned to receive a study drug at 70 investigative sites. The study began on December 5, 2005, and was completed on August 15, 2008. All patients received at least one dose of study medication and underwent at least one safety assessment after enrollment. Therefore, all patients were included in both the intention-to-treat population and the safety population (Figure 1). As specified by the study protocol, the study drug was discontinued at the time of the first breakthrough episode of hepatic encephalopathy. The incidence of early withdrawal for any reason other than a breakthrough episode was similar in the rifaximin group and the placebo group.
Baseline characteristics were similar in the two groups (Table 1). Patients were predominantly white, male, and younger than 65 years of age. All patients had a history of overt episodic hepatic encephalopathy associated with advanced liver disease, diagnosed on the basis of two or more episodes of overt hepatic encephalopathy (Conn score, ≥2) within 6 months before the screening visit.
Similar percentages of patients in the placebo group (91.2%) and rifaximin group (91.4%) were receiving lactulose at baseline, and the mean daily doses of lactulose during the study period were stable (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Commonly used concomitant medications were those that would be expected for patients with chronic liver disease (Table 1).
The mean (± SD) duration of treatment was 130.3± 56.5 days in the rifaximin group and 105.7± 62.7 days in the placebo group. The rate of compliance, defined as use of at least 80% of the dispensed tablets, was high in both study groups (84.3% in the rifaximin group and 84.9% in the placebo group).
Breakthrough Episodes
Breakthrough episodes of hepatic encephalopathy were reported in 31 of 140 patients in the rifaximin group (22.1%) and 73 of 159 patients in the placebo group (45.9%). Figure 2A shows the time to a breakthrough episode (the primary end point). The hazard ratio for the risk of a breakthrough episode in the rifaximin group, as compared with the placebo group, was 0.42 (95% confidence interval [CI], 0.28 to 0.64; P<0.001), reflecting a relative reduction in the risk of a breakthrough episode by 58% with rifaximin as compared with placebo during the 6-month study period. These data suggest that four patients would need to be treated with rifaximin for 6 months to prevent one episode of overt hepatic encephalopathy. The degree to which rifaximin reduced the risk of a breakthrough episode was consistent across subgroups (Figure 3).
Hospitalizations
Hospitalization involving hepatic encephalopathy was reported for 19 of 140 patients in the rifaximin group (13.6%) and 36 of 159 patients in the placebo group (22.6%). The hazard ratio for the risk of such hospitalization in the rifaximin group, as compared with the placebo group, was 0.50 (95% CI, 0.29 to 0.87; P=0.01), reflecting a reduction in the risk by 50% with rifaximin as compared with placebo (Figure 2B). Thus, nine patients would need to be treated with rifaximin for 6 months to prevent one hospitalization involving hepatic encephalopathy.
Safety
The incidence of adverse events reported during the study was similar in the rifaximin group (80.0%) and the placebo group (79.9%), as was the incidence of the more common serious adverse events (Table 2). Among the adverse events related to infection, Clostridium difficile infection was reported in two patients in the rifaximin group and none in the placebo group; both affected patients had several concurrent risk factors for C. difficile infection, such as advanced age, numerous recent hospitalizations involving multiple courses of antibiotic therapy, and use of the proton-pump inhibitor pantoprazole. In both patients, rifaximin therapy was continued concomitantly with treatment for the infection, from which they fully recovered.
A total of 20 patients died during the study (9 in the rifaximin group and 11 in the placebo group). Most of the deaths were attributed to conditions associated with disease progression: five patients in each of the two groups had hepatic cirrhosis, decompensated cirrhosis, hepatic failure, alcoholic cirrhosis, or end-stage liver failure, and two patients in each of the two groups had esophageal varices or hemorrhage from esophageal varices. Nearly all the patients who died had had evidence at baseline, apart from hepatic encephalopathy, of decompensated liver cirrhosis (i.e., portal hypertension, ascites or edema, or jaundice), which is associated with a reduced probability of survival.41,42
Methods
Study Patients
Eligibility criteria were an age of at least 18 years, at least two episodes of overt hepatic encephalopathy (Conn score, ≥2)9,12 associated with hepatic cirrhosis during the previous 6 months, remission (Conn score, 0 or 1) at enrollment, and a score of 25 or less on the Model for End-Stage Liver Disease (MELD) scale40 (on which scores can range from 6 to 40, with higher scores indicating more severe disease). Episodes of hepatic encephalopathy that were precipitated by gastrointestinal hemorrhage requiring transfusion of at least 2 units of blood, by medication use, by renal failure requiring dialysis, or by injury to the central nervous system were not counted as previous episodes.
Exclusion criteria included the expectation of liver transplantation within 1 month after the screening visit and the presence of conditions that are known precipitants of hepatic encephalopathy (including gastrointestinal hemorrhage and the placement of a portosystemic shunt or a transjugular intrahepatic portosystemic shunt) within 3 months before the screening visit, chronic renal insufficiency (creatinine level, >2.0 mg per deciliter [177 µmol per liter]) or respiratory insufficiency, anemia (hemoglobin level, <8 g per deciliter), an electrolyte abnormality (serum sodium level, <125 mmol per liter; serum calcium level, >10 mg per deciliter [2.5 mmol per liter]; or potassium level, <2.5 mmol per liter), intercurrent infection, or active spontaneous bacterial peritonitis. All patients or their legally authorized representatives provided written informed consent.
Study Design and Procedures
The protocol was approved by the institutional review board or ethics committee at each center and was conducted in accordance with International Conference on Harmonisation guidelines and other applicable laws and regulations. The study included a screening visit, an observation period between the screening visit and enrollment, and a 6-month treatment phase. On day 0, eligible patients were randomly assigned, in a 1:1 ratio, to receive either 550 mg of rifaximin or placebo, twice daily, for 6 months or until they discontinued the study drug because of a breakthrough episode of hepatic encephalopathy or another reason. Concomitant administration of lactulose was permitted during the study.
The study protocol was designed by representatives of Salix Pharmaceuticals and the academic authors. Data were collected by the principal investigators at each center (see the Appendix) and were monitored by Omnicare Clinical Research, Clinical Trial Management Services (now Chiltern International), and ClinStar Europe under the supervision of Salix representatives, who also analyzed the data. All authors participated in the interpretation of the data and the writing of the manuscript. An editorial consultant was paid by Salix to assist in the revision of subsequent drafts before submission. All authors vouch for the completeness and veracity of the data and data analyses.
Efficacy and Safety Assessments
Clinic visits occurred on days 7 and 14 and every 2 weeks thereafter through day 168 (end of the treatment period), with optional visits on days 42, 70, 98, 126, and 154. Patients were monitored by telephone during the weeks without clinic visits. Assessments included the Conn score and asterixis grade. Conn scores are defined as follows: 0, no personality or behavioral abnormality detected; 1, trivial lack of awareness, euphoria or anxiety, shortened attention span, or impairment of ability to add or subtract; 2, lethargy, disorientation with respect to time, obvious personality change, or inappropriate behavior; 3, somnolence or semistupor, responsiveness to stimuli, confusion, gross disorientation, or bizarre behavior; and 4, coma.9 Asterixis was assessed according to standard practice, by asking patients to extend their arms with wrists flexed backward and fingers open for 30 seconds or more.11,39 Asterixis was then graded as follows: 0, no tremors; 1, few flapping motions; 2, occasional flapping motions; 3, frequent flapping motions; and 4, almost continuous flapping motions.11 Investigators and site personnel who performed assessments were trained in order to ensure consistency across sites.
Statistical Analysis
Efficacy data were analyzed for the intention-to-treat population, which included patients who received at least one dose of the study medication. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy, defined as the time from the first dose of the study drug to an increase from a baseline Conn score of 0 or 1 to a score of 2 or more or from a baseline Conn score of 0 to a Conn score of 1 plus a 1-unit increase in the asterixis grade. The key secondary efficacy end point was the time to the first hospitalization involving hepatic encephalopathy (defined as hospitalization because of the disorder or hospitalization during which an episode of hepatic encephalopathy occurred).
The Cox proportional-hazards model was used, with a 2-sided test and a significance level of 0.05, to compare the time to a breakthrough episode between the rifaximin group and the placebo group (after adjustment for geographic region). Kaplan-Meier methods were used to estimate the proportions of patients having a breakthrough episode at successive time points during the study. Patients who withdrew from the study early for reasons other than the development of hepatic encephalopathy (e.g., another adverse event or the subject's request) were contacted 6 months after randomization to determine whether a breakthrough episode of hepatic encephalopathy had occurred since withdrawal. Data for patients who did not have breakthrough hepatic encephalopathy before day 168 were censored at the time of last contact or on day 168, whichever was earlier. Data for patients who did not have a hospitalization involving hepatic encephalopathy before day 168 were censored at the time of study termination or on day 168, whichever was earlier. The same statistical methods were used to analyze the key secondary end point: time to the first hospitalization involving hepatic encephalopathy.
The primary efficacy end point was evaluated in subgroups of patients according to the following characteristics: geographic region, sex, age, race or ethnic group, baseline MELD score, baseline Conn score, diabetes at baseline, duration of current verified remission, number of episodes of hepatic encephalopathy within the 6-month period before randomization, lactulose use at baseline, and previous placement of a transjugular intrahepatic portosystemic shunt.
Sample-size calculations were based on an assumption of breakthrough episodes of hepatic encephalopathy occurring in 50% and 70% of patients receiving rifaximin and placebo, respectively. These calculations indicated that to show the superiority of rifaximin over placebo with a statistical power of more than 80%, we would need to evaluate 100 patients per group. Safety data were summarized with the use of descriptive statistics. Safety assessments included adverse events, serious adverse events, and adverse events specifically consisting of infection, including respiratory and gastrointestinal infections and their symptoms. Infections are of special interest because of known potential side effects of systemic antibiotics, as a drug class, and known effects of rifaximin.
Supported by Salix Pharmaceuticals (study RFHE3001).
Dr. Bass reports receiving consulting or advisory fees from Salix and Hyperion and lecture fees from Salix; Dr. Mullen, steering committee and lecture fees from Salix; Dr. Sanyal, consulting fees or advisory fees from Salix, Takeda, Sanofi-Aventis, Ikaria, Astellas, Pfizer, Gilead, Vertex, Exhalenz, Bayer-Onyx, Amylin, and Norgine and grant support from Salix, Sanofi-Aventis, Gilead, Intercept, and Roche; Dr. Poordad, advisory fees from Salix; Dr. Neff, lecture fees from Roche, Three Rivers, and Bristol-Myers Squibb; Dr. Sigal, consulting fees or advisory fees from Salix, Otsuka, Ikaria, and Roche, lecture fees from Otsuka, and grant support from Salix and Gilead; Dr. Sheikh, grant support from Salix; Dr. Frederick, consulting fees or advisory fees from Salix and Hyperion and lecture fees from Salix; Ms. Huang, Dr. Merchant, Dr. Shaw, and Dr. Bortey report being employees of and holding stock in Salix; and Dr. Forbes reports being an officer and employee of Salix and holding stock in the company. No other potential conflict of interest relevant to this article was reported.
We thank Jane Saiers, Ph.D., of WriteMedicine and David Sorscher, Ph.D., of Salix Pharmaceuticals for their assistance in the preparation of a previous draft of the manuscript.
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