Journal clubApril 2010Dr AucampDr Buchel

Rifaximin treatment in hepatic encephalopathy

BACKGROUND

HEPATIC ENCEPHALOPATHY Neuropsychiatric syndrome Deterioration in mental status Psychomotor dysfunction Impaired memory Increased reaction time Sensory abnormalities Poor concentration Disorientation Severe cases: Coma

Complication of cirrhosis

Burden on family, patient, system

Overt episodes Debilitating Without warning Incapable of self care Frequently result in hospitalization

Occurrence unrelated to cause of cirrhosis

Increase in frequency, increase in death

WHY THIS STUDY?

CURRENT CURRENT Most therapies focus on treating

episodes Directed at reducing the nitrogenous

load Hypothesis: Systemic accumulation Gut derived neurotoxins e.g.

Ammonia In patients with impaired liver

function and porto-systemic shunting

Nonabsorbable disaccharides Decreases ammonia absorption Sharma et al reported it to be

effective in prevention Side effects: GIT, taste Frequent non compliance

Oral antibiotics Neomycin, Vancomycin, Metronidazole With or without lactulose Reduce ammonia producing enteric

bacteria Side effects: ototoxicity, nephrotoxicity

peripheral neuropathy

Rifaximin Minimally absorbed, concentrate in GIT Broad spectrum activity against Gr + &

- Low risk of inducing resistance More conducive to long term use More effective than lactulose At least equal to other antibiotics

METHODS

INCLUSION EXCLUSION At least 18y

At least 2 episodes of overt encephalopathy

Conn >2 Associated with hepatic cirrhosis In previous 6 months

Remission at enrolment Conn 0 or 1

MELD scale 25 or less

Expectation of transplant within 1 month

Presence of known precipitants GIT haemorrhage Placement of portosystemic shunt Trans jugular intrahepatic

portosystemic shunt Chronic renal insufficiency (Cr > 177) Respiratory insufficiency Anemia (Hb < 8 ) Electrolyte abnormality ( Na <125, Ca

> 2.5) Potassium <2.5 Infection Active spontaneous bacterial

peritonitis

METHODSSTUDY DESIGN AND PROCEDURES Multicenter, randomized, double-blind, placebo-controlled study

Conducted over a 6 month period

Screening visit, observation period, enrolment and 6-month treatment phase

On day 0, eligible patients were randomly assigned, in a 1:1 ratio, to receive either 550mg

Rifaximin or placebo, twice daily, for 6 months or until they discontinued the study drug because of a breakthrough episode of encephalopathy or another reason

Concomitant use of lactulose was permitted

Study designed by representatives of Salix pharmaceuticals and the academic authors

METHODSEFFICACY AND SAFETY ASSESSMENTS Clinic visits every two weeks through day 168 (end of study period)

Optional visits days 42, 70, 98, 126, 154

Patients were monitored by telephone in between clinic visits

Assessments included Conn score and asterixis grade

Investigators and site personnel who performed assessments were trained in order to ensure consistency across sites

METHODSSTATISTICAL ANALYSIS Efficacy data were analyzed for the intention-to-treat population, which included

patients who received at least 1 dose of the study medication Primary efficacy end point was the time to the first breakthrough episode of

hepatic encephalopathy Defined as: Time to increase from baseline Conn 0 or 1 to a score of 2 or

more

Time to increase from Conn 0 to 1 plus 1 unit increase in asterixis grade Secondary end point was the time to first hospitalization Cox potential-hazards model was used, with a 2 sided test and a significance level

of 0.05 to compare the time to breakthrough between the groups Kaplan-Meier methods were used to estimate the proportions of patients having

breakthrough episodes at successive time points during the study Same methods to study secondary end point At least 100 patients per group were needed to show superiority of Rifaximin vs

placebo Safety assessments included adverse events, serious adverse events and adverse

events consisting of infection

RESULTSSTUDY PATIENTS 299 patients at 70 sites, were randomly assigned

All patients included in safety population and intention-to-treat population

Baseline characteristics similar in the two groups

Similar percentages of patients received lactulose at baseline (91.2% vs 91.%) and doses remained stable

Mean duration of treatment was 130.3 days in Rifaximin group vs 105.7 days in placebo group

Compliance 84.3% in Rifaximin group vs 84.9% in placebo group

RESULTSBREAKTHROUGH EPISODESRifaximin group: 31 of 140 (22.1%)Placebo group: 73 of 159 (45.9%)Relative risk: 0.48 ----> risk in exposed is less than in

unexposed

NNTT: 4 patients need to be treated for 6 months, to prevent one episode of overt hepatic encephalopathy

The degree to which Rifaximin reduced the risk was consistent across subgroups

HOSPITALIZATIONSRifaximin group: 19 of 140 (13.6%)Placebo group: 36 of 159 (22.6%)Relative risk: 0.60 ----> risk in exposed is less than in

unexposed

NNTT: 9 patients need to be treated for 6 months to prevent one hospitalization involving hepatic encephalopathy.

RESULTSSAFETY Incidence of adverse events reported during the study was similarRifaximin group: 80%Placebo group: 79.9%

Clostridium difficile was reported in two patients, both had other risk factors Advanced age Numerous recent hospitalizations Multiple courses of antibiotics Use of pantoprazole (Pantoloc®)

In both patients, Rifaximin was continued concomitantly with treatment for the infection , from which they fully recovered.

20 patients died during the study, 9 in Rifaximin group, 11 in placebo groupMost of the deaths attributed to disease progression

DISCUSSIONThe study showed that the use of Rifaximin: Reduced the risk of hepatic encephalopathy During a 6 month period Among patients in remission Recent history of recurrent overt hepatic encephalopathy

The reduced risk was seen across all subgroups Which expands previously reported findings of efficacy of Rifaximin in

the treatment of overt hepatic encephalopathy

The current study differs from previous studies in that it: Examined the protective effect of Rifaximin rather than the treatment

effect Larger study group Longer study period

DISCUSSIONThis study showed the superiority of Rifaximin over treatment with Lactulose

alone >90% of patients received concomitant lactulose during the study period Significant treatment effect after 28 days Lactulose treatment effects only after approximately 4 months

Rifaximin therapy reduced the hospitalizations involving hepatic encephalopathy Shows clinical significance of the findings Supports the findings of previous retrospective chart reviews

The safety profile of Rifaximin appears to be superior to that of systemic antibiotics, particularly for patients with liver disease

The risk of bacterial resistance appears to be lower with Rifaximin than with systemic antibiotics

Plasma levels of Rifaximin negligible, thus bacteria outside GIT not exposed to selective pressure

STUDY REVIEWARE THE RESULTS VALID

Did the study address a clear question?

Yes

Was the assignment of pts randomised?

Yes

Were all patients who entered the trial properly accounted for?

Yes

Were pts analysed in the groups to which they were randomised?

Yes

Were pts, health workers and study personnel “blind” to treatment?

Yes

Were the groups similar at the start?

Yes

Aside from the experimental interventions, were the groups treated equally?

Yes

STUDY REVIEWHow large was the treatment effect?

Encephalopathy - RR reduction 58%Hospitalization - RR reduction 50%

How precise was the treatment effect?

Encephalopathy - 95% CI p = <0.001Hospitalization - 95% CI p = 0.01

Can the results be applied to my patients care?

No, at present Rifaximin not available in RSA

What are the likely benefits? Prevent overt hepatic encephalopathyPrevent hospitalizationSave money