Encephalopathy Update Stuart Gordon, MD

Transcription

1 Encephalopathy Update Stuart Gordon, MD Henry Ford Hospital Detroit, MI

2 Rifaximin Improves Driving Simulator Performance in Minimal Hepatic Encephalopathy: A Double-Blind, Placebo-Controlled, Prospective Randomized Trial Bajaj JS, Heuman DM, Saeian K, Hafeezullah M, Bell DE, Sterling RK, Stravitz R, Wegelin JA, White M, and Sanyal AJ AASLD Abstract 22, Oral Presentation 10/31/10

3 Rifaximin Improved Driving Simulator Performance in Patients With MHE Randomized, double-blind, placebo-controlled trial of the effect of rifaximin on driving performance in patients with MHE* and no history of overt HE (N=42) Patients received rifaximin 550 mg (n=21) or placebo (n=21) twice daily for 8 weeks Assessments at baseline and week 8 Driving simulator Cognitive battery QOL (using SIP) Serum markers of inflammation, endothelial function, and neuro-glial function *MHE defined by Z score < -2 in 2 of the following tests: NCT-A, NCT-B, DST, BDT, and ICT lures. 3 parts: training simulation, drive testing task, and navigation task. Included NCT-A, NCT-B, DST, ICT lures, and BDT. BDT = block design test; DST = digit symbol test; HE = hepatic encephalopathy; ICT = inhibitory control test; MHE = minimal hepatic encephalopathy; NCT = number connection test; QOL = quality of life; SIP = sickness impact profile. Bajaj et al. Gastroenterology [Epub ahead of print].

4 Demographics and Baseline Characteristics* Characteristic Rifaximin 550 mg b.i.d. (n=21) Placebo (n=21) Mean age ± SD, y 55 ± 5 57 ± 5 Alcoholic cirrhosis, n (%) 5 (24) 3 (14) Median MELD score 9 9 Child score, n (%) A B 19 (90) 2 (10) 17 (81) 4 (19) Venous ammonia ± SD, μg/dl 49 ± ± 20 AST ± SD, U/L 67 ± ± 48 ALT ± SD, U/L 60 ± ± 57 Duration of driving ± SD, y 34 ± ± 12 *No significant differences between groups. ALT = alanine aminotransferase; AST = aspartate aminotransferase; b.i.d. = twice daily; MELD = model for end-stage liver disease; SD = standard deviation. Bajaj et al. Gastroenterology [Epub ahead of print].

5 Rifaximin Improved Driving Simulator Results Driving Performance* P= Baseline Week 8 P=0.006 P=0.03 Placebo (n=21) Rifaximin 550 b.i.d. (n=21) *Error bars indicated standard deviation. Sum of speeding tickets, illegal turns, and collisions. b.i.d. = twice daily. Bajaj et al. Gastroenterology [Epub ahead of print].

6 Rifaximin Improved Driving Simulator Performance Outcomes by Group P=0.01 P=0.005 Patients with reduction in driving errors, % P=0.01 *Sum of speeding tickets, illegal turns, and collisions. b.i.d. = twice daily. Bajaj et al. Gastroenterology [Epub ahead of print].

7 Rifaximin Improved Cognitive Test Results * * *,, *Significant difference between groups. Scores significantly improved from baseline with rifaximin. Scores significantly improved from baseline with placebo. BDT = block design test; b.i.d. = twice daily; DST = digit symbol test; ICT = inhibitory control test; NCT = number connection test. Bajaj et al. Gastroenterology [Epub ahead of print].

8 Driving Outcomes Correlated With Improvement in Cognitive Function Significantly correlate Significantly correlate Significantly correlate ICT = inhibitory control test; NCT = number connection test. Bajaj et al. Gastroenterology [Epub ahead of print].

9 Rifaximin Effects on QOL and Serum Cytokines Rifaximin 550 mg b.i.d. or placebo for 8 weeks did not improve overall SIP scores However, the psychosocial dimension was significantly improved with rifaximin at week 8 compared with baseline (P=0.04) Rifaximin 550 mg b.i.d. significantly increased levels of IL-10 at week 8 compared with baseline (P=0.01) Levels of IL-10 were not significantly altered in patients who received placebo Levels of other cytokines were not significantly altered with either treatment Rifaximin 550 mg b.i.d. did not affect MELD scores or levels of venous ammonia or liver enzymes (ie, ALT, AST) compared with baseline ALT = alanine aminotransferase; AST = aspartate aminotransferase; b.i.d. = twice daily; IL = interleukin; MELD = model for end-stage liver disease; QOL = quality of life; SIP = sickness impact profile. Bajaj et al. Gastroenterology [Epub ahead of print].

10 Adverse Events Adverse event Patients, n (%) Rifaximin 550 mg b.i.d. (n=21) Placebo (n=21) Flatulence 4(19) 9(43) Headache 4 (19) 7 (33) Abdominal pain 5 (24) 5 (24) Nausea 3 (14) 3 (14) Diarrhea* 1 (5) 1 (5) Vomiting 1 (5) 1 (5) Constipation 1 (5) 0 (0) Flu-like symptoms 1 (5) 0 (0) Anorexia 0 (0) 1 (5) Dry mouth 0 (0) 1 (5) Itching 0 (0) 1 (5) *1 patient was tested and was negative for Clostridium difficile and fecal leukocytes. Diarrhea resolved within 3 days without antibiotic treatment. b.i.d. = twice daily. Bajaj et al. Gastroenterology [Epub ahead of print].

11 Rifaximin Improved Driving Simulator Performance in Patients With MHE Conclusions Rifaximin 550 mg b.i.d. for 8 weeks significantly improved overall driving simulator performance with specific reductions in speeding tickets and illegal turns compared with baseline and with placebo in patients with MHE Rifaximin 550 mg b.i.d. also significantly improved cognitive function and the psychosocial dimension of QOL b.i.d. = twice daily; MHE = minimal hepatic encephalopathy; QOL = quality of life. Bajaj et al. Gastroenterology [Epub ahead of print].

12 Long-Term Administration of Rifaximin Improves the Prognosis of Patients with Alcohol-Related Decompensated Cirrhosis: A Case-Control Study Vlachogiannakos J, Viazis N, Vasianopoulou P, Vafiadis-Zouboulis I, Karamanolis DG, and Ladas SD AASLD Abstract 19, Oral Presentation 10/31/10

13 Long-term Rifaximin Improved Prognosis for Patients With Alcohol-Related Decompensated Cirrhosis Prospective study of long-term rifaximin 1200 mg/d in patients with alcohol-related decompensated cirrhosis 1 Continuation of previous study demonstrating rifaximin 1200 mg/d for 4 weeks significantly improved HVPG with a correlative reduction in plasma endotoxin levels 2 Patients with improvement in HPVG in previous study continued to receive rifaximin 1200 mg/d (n=23) compared with age- (± 5 years), sex-, and Child-Pugh score matched controls with alcohol-related decompensated cirrhosis who did not receive treatment (n=46) 1 Patients were assessed every 3 months for survival and risk of developing portal hypertension related complications for up to 5 years or until variceal bleeding, liver transplant, or death 1 HVPG = hepatic venous pressure gradient. 1. Vlachogiannakos et al. Presented at: The Liver Meeting: The 61st Annual Meeting of the American Association for the Study of Liver Diseases; October 31, 2010; Boston, MA. 2. Vlachogiannakos et al. Aliment Pharmacol Ther. 2009;29:

14 Rifaximin Significantly Reduced the Risk of Complications of Cirrhosis Complication Patients, % Rifaximin 1200 mg/d (n=23) Control (n=46) P value Variceal bleeding HE SBP HRS In multivariate analysis, rifaximin was independently associated with lower risk of developing variceal bleeding, HE, SBP, and HRS HE = hepatic encephalopathy; HRS = hepatorenal syndrome; SBP = spontaneous bacterial peritonitis. Vlachogiannakos et al. Presented at: The Liver Meeting: The 61st Annual Meeting of the American Association for the Study of Liver Diseases; October 31, 2010; Boston, MA.

15 Rifaximin Significantly Improved Survival After 5 years, rifaximin 1200 mg/d significantly improved the cumulative probability of survival compared with controls (61% vs 14%; P=0.01) In multivariate analysis, rifaximin and Child-Pugh score were independent variables associated with greater survival Controls (n=46) Rifaximin 1200 mg/d (n=23) HE = hepatic encephalopathy; HRS = hepatorenal syndrome; SBP = spontaneous bacterial peritonitis. Vlachogiannakos et al. Presented at: The Liver Meeting: The 61st Annual Meeting of the American Association for the Study of Liver Diseases; October 31, 2010; Boston, MA.

16 Rifaximin Was Well Tolerated 1 patient who received rifaximin discontinued after 22 months because of diarrhea Of patients who received rifaximin, 2 had nausea,1 had rash, and 2 were lost to follow-up 5 patients discontinued from the control group

17 Long-term Rifaximin Improved Prognosis for Patients With Alcohol-Related Decompensated Cirrhosis Conclusions Rifaximin 1200 mg/d for up to 5 years reduced the risk of complications associated with portal hypertension Rifaximin 1200 mg/d for up to 5 years also improved survival Rifaximin was well tolerated Vlachogiannakos et al. Presented at: The Liver Meeting: The 61st Annual Meeting of the American Association for the Study of Liver Diseases; October 31, 2010; Boston, MA.

18 Impact of Rifaximin Treatment on Survival in Patients with End-Stage Liver Disease Leise MD, Pedersen R, Kamath PS, Themeau TM, and Kim W AASLD Abstract 24, Oral Presentation 10/31/10

19 Impact of Rifaximin on Survival of Patients With ESLD Aim: To compare survival of patients receiving rifaximin for HE with that of patients with comparable ESLD on the liver transplant waiting list Data set 1: Patients with history of overt HE who participated in open-label study of rifaximin 550 mg b.i.d. for maintenance of HE remission (n=315) Data set 2: Registrant data from adult primary liver transplant waiting list from OPTN in 2005 (n=6539) Multivariable models developed to determine if HE predicts survival independent of MELDNa Patients divided into 3 tiers of increasing mortality risk Expected survival compared with actual survival ESLD = end-stage liver disease; HE = hepatic encephalopathy; MELDNa = model for end-stage liver disease with incorporation of serum sodium; OPTN = Organ Procurement and Transplant Network. Leise et al. Presented at: The Liver Meeting: The 61st Annual Meeting of the American Association for the Study of Liver Diseases; October 31, 2010; Boston, MA.

20 HE as a Predictor of Survival in ESLD OPTN Population In first model (did not account for HE), age, MELDNa, and ascites predicted survival In second model, HE was associated with 1.2-fold (18%) increase in mortality Grade 3-4 HE associated with 2-fold increase in mortality ESLD = end-stage liver disease; HE = hepatic encephalopathy; MELDNa = model for end-stage liver disease with incorporation of serum sodium; OPTN = Organ Procurement and Transplant Network. Leise et al. Presented at: The Liver Meeting: The 61st Annual Meeting of the American Association for the Study of Liver Diseases; October 31, 2010; Boston, MA.

21 Rifaximin Significantly Improved Survival of Patients With Grade 1 or 2 HE and High Mortality Risk Patients with HE grade 1 or 2 and high mortality risk There was no significant effect of rifaximin on survival in patients with low or intermediate mortality risk or in any risk group of patients with HE grade 0 b.i.d. = twice daily; HE = hepatic encephalopathy; OPTN = Organ Procurement and Transplant Network. Leise et al. Presented at: The Liver Meeting: The 61st Annual Meeting of the American Association for the Study of Liver Diseases; October 31, 2010; Boston, MA.

22 Impact of Rifaximin on Survival of Patients With ESLD Conclusions HE was an independent predictor of mortality after adjusting for MELDNa Severity of HE increased mortality risk Rifaximin 550 mg b.i.d. significantly improved 2- year survival in patients with history of overt HE (grades 1 or 2) and high mortality risk b.i.d. = twice daily; HE = hepatic encephalopathy; MELDNa = model for end-stage liver disease with incorporation of serum sodium. Leise et al. Presented at: The Liver Meeting: The 61st Annual Meeting of the American Association for the Study of Liver Diseases; October 31, 2010; Boston, MA.