Is Cognitive Impairment Following Overt Hepatic … · Is Cognitive Impairment Following Overt...
Transcript of Is Cognitive Impairment Following Overt Hepatic … · Is Cognitive Impairment Following Overt...
• This activity has been planned and implemented in
accordance with the Essential Areas and Policies of the
Accreditation Council for Continuing Medical Education
(ACCME) through the sponsorship of Purdue University
College of Pharmacy and the Chronic Liver Disease
Foundation. Purdue University School of Pharmacy is
accredited by the ACCME to provide continuing medical
education for physicians.
• This program is supported by an educational grant from
Salix Pharmaceuticals.
Program Disclosure
Educational Objectives
• Evaluate data suggesting cognitive impairment
may persist following apparent recovery from an
overt hepatic encephalopathy episode
• Discuss the importance of primary and
secondary prophylactic therapy for preventing
hepatic encephalopathy
• Primary complications include:
– Ascites
– Jaundice
– Variceal hemorrhage
– Hepatic encephalopathy
• Other complications that can occur include:
– Spontaneous bacterial peritonitis
– Hepatic hydrothorax
– Hepatorenal syndrome
– Portopulmonary hypertension
– Hepatocellular carcinoma
– Portal vein thrombosis
Lefton HB et al. Med Clin N Am 2009;93:787-799.
Hepatic Encephalopathy is One of the
Primary Complications of Cirrhosis
TIPS = transjugular intrahepatic portosystemic shunt.
Poordad FF. Aliment Pharmacol Ther. 2006;25(Suppl 1):3-9.
Two Forms of HE are Recognized
• Covert hepatic encephalopathy (CHE) affects approximately 20% to 60% of patients with liver disease – Has been called subclinical encephalopathy or
minimal encephalopathy (MHE) in the past
– International Society for Hepatic Encephalopathy and Nitrogen Metabolism has recently endorsed using the term covert encephalopathy
• Overt hepatic encephalopathy (OHE) occurs in: – 30% to 45% of cirrhotic patients
– 10% to 50% of patients with TIPS
Hospital Discharges Due to
Cirrhosis Increased by 6% in 2010
6% growth
Year
*ICD-9-CM diagnosis codes 571.2. 571.5, 571.6; all listed diagnoses.
HCUPnet, Healthcare Cost and Utilization Project. Agency for Healthcare Research and Quality, Rockville, MD.
http://hcupnet.ahrq.gov. Accessed September 2012
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HE = hepatic encephalopathy; ICD = International Classification of Diseases.
*Data calculated using ICD-9-CM codes 291.2 (alcoholic dementia, not elsewhere classified), 348.30 (encephalopathy,
not otherwise specified), and 572.2 (hepatic coma). †Includes all listed discharge diagnoses.
HCUPnet, Healthcare Cost and Utilization Project. Agency for Healthcare Research and Quality, Rockville, MD.
http://hcupnet.ahrq.gov. Accessed September 2012.
Hospital Discharges Associated with HE
Increased by 21% in 2010
21% growth
Frederick RT. Clin Liver Dis 2012;16:147-158.
Cognitive Impairment Associated with OHE
May Not Be Reversible
• Traditional concept: Most OHE events are potentially
reversible
– Patients who regain consciousness and survive a severe HE
event typically seem to return to their baseline level of cognitive
functioning with supportive care, or with disaccharides, or with
rifaximin
– A subset of patients with OHE continue to suffer with symptoms
and are classified as chronic persistent HE that may not be
reversible with medical therapy
• Neuropathologic characteristics found in brains of
patients with HE at autopsy suggest that the concept of
complete reversibility requires more in-depth analysis
Prior overt HE*
(n=54)
‘Normal’ cirrhotic patients
(n=52)
P value
MELD score (median) 10 8 0.10
Number connection test-A (sec) 4532 278 0.001
Number connection test-B (sec) 13172 7541 0.0001
Digit symbol test (raw score) 4618 7213 0.0001
Block design test (raw score) 2611 3712 0.0001
ICT lures (# responded to out of 40) 139 54 0.0001
ICT targets (% correct response) 9110 983 0.0001
*Patients had first experienced OHE a mean of 12 5 months prior to study. Patients with neither covert HE nor prior OHE.
Bajaj JS et al. Gastroenterology 2010;138:2332-2340.
Psychometric Test Results In ‘Normal’
Cirrhotic Patients* vs. Prior OHE Patients
*Median 2 episodes, all on lactulose
Bajaj JS et al. J Hepatol 2012;56(Suppl 2):S242.
Prior OHE* (n=32) No OHE (n=131)
P value
NCT-A 65 44 0.02
NCT-B 146 102 0.01
DST 32 45 <0.0001
LTT time 130 100 0.02
LTT errors 49 31 0.1
SDT 86 74 0.2
BDT 13 34 <0.0001
Lures 16 15 0.6
Weighted lures 31 18 0.01
Targets 77% 92% 0.001
Persistence of Cognitive Impairment
after OHE
Patient Status First PHES
Evaluation*
Second PHES
Evaluation* P value
Normal cirrhotic patients (No previous
episode of OHE; no MHE; n=45) -0.751.6 -0.351.8 0.04
Cirrhotic patients without previous
episode of OHE but with MHE; n=34 -6.7 2 -5.73.2 0.016
Cirrhotic patients with at least 1
previous episode of OHE; n=27 -53.2 -4.33.2 NS
*PHES was considered altered if its value was -4. Second evaluation within 3 days after the first one.
Riggio O et al. Clin Gastroenterol Hepatol 2011;9:181-183.
Persistent Cognitive Impairment of Learning
Capacity After Resolution of OHE
(N=50)
Number of
hospitalizations for
OHE
Number of
episodes of
OHE
Duration from first
episode to testing
R P value R P value R P value
NCT-A (sec) 0.264 0.144 0.218 0.238 0.166 0.373
NCT-B (sec) 0.353 0.047 0.354 0.05 0.158 0.396
DST (raw score) -0.387 0.02 -0.461 0.009 -0.364 0.04
BDT (raw score) -0.108 0.631 -0.203 0.378 -0.282 0.292
ICT Lures (number) 0.502 0.002 0.591 0.001 0.483 0.007
ICT Targets (% correct) -0.433 0.009 -0.442 0.015 -0.2 0.135
Correlations Between OHE Episodes and Psychometric Tests
Bajaj JS et al. Gastroenterology 2010;138:2332-2340.
Cognitive Impairment May be Cumulative
Domains
PHES Results
OHE-PreLT
(n=25)
No OHE-PreLT
(n=14)
Controls
(n=20)
NCT-A (seconds) 34.08.3* 23.38.4 19.63.9
NCT-B (seconds) 98.430.5* 76.035.1 54.517.0
Digit symbol (points) 41.28.9*ǂ 50.49.8 54.68.4
Serial dotting (seconds) 61.325.2 59.320.1 54.818.1
Line tracing (seconds) 77.022.7 78.118.2 70.726.2
Line tracing (errors) 11.011.9 10.415.0 5.44.9
*p<0.001 vs. controls; p<0.01 vs. No HE-PreLT; ǂp<0.05 vs. No HE-PreLT.
Sotil EU et al. Liver Transpl 2009;15:184-192.
Impact of Preoperative OHE on Neurocognitive
Function after Liver Transplantation
• Neurocognitive abnormalities were more severe in liver transplant
recipients that had suffered from OHE prior to OLT
Drug Name Drug Class Indication
Lactulose Poorly absorbed disaccharide
• Decrease blood ammonia concentration
• Prevention and treatment of portal-
systemic encephalopathy
Rifaximin Non-aminoglycoside semi-
synthetic, nonsystemic antibiotic
Reduction in risk of OHE recurrence in
patients ≥ 18 years of age
Neomycin Aminoglycoside antibiotic Adjuvant therapy in hepatic coma
Metronidazole Synthetic antiprotozoal and
antibacterial agent Not approved for HE
Adapted from:
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugsAdvisoryCommitt
ee/UCM201081.pdf.
Accessed 10/22/12, and http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022554lbl.pdf. Accessed 10/22/12.
Current Treatment Options for HE
Sharma BC et al. Gastroenterology. 2009;137:885-891.
Proposed Terminology for Prophylactic
Treatment of HE
• Treating patients with covert HE to prevent
development of a first episode is referred to as
primary prophylaxis of HE
• Preventing recurrence of HE in patients who had
a previous episode of HE is referred to as
secondary prophylaxis of HE
Hartmann IJ, et al. Am J Gastroenterol. 2000;95(8):2029-2034.
Consequences of Covert HE
• Those diagnosed with CHE are at increased risk
for progression to OHE: >50% develop overt HE
within 30 months
Sharma BC et al. J Hepatol 2012;56(Suppl 2):S238.
MHE at Baseline Develop OHE Died
32/60 36/60 6/55 15/50 5/55 10/50
Median follow-up 12 months
P=0.29
P=0.02
P=0.16
Primary Prophylaxis of Overt HE with
Lactulose in Cirrhotic Patients
Duration of Treatment
n=45 n=45 n=49 n=49
P<.0001
P<.0001
Sidhu S, et al. Am J Gastroenterol. 2011;106:307-316.
Rifaximin vs Placebo: Reversal of CHE
*Values in parentheses indicate the cumulative number of subjects who developed HE.
Patients at risk*
Lactulose 61 60(1) 59(2) 58(3) 51(8) 45(9) 38(11) 28(12) 10(12) 7(12) 1(12)
Placebo 64 62(1) 59(4) 50(13) 37(24) 33(27) 28(27) 19(29) 13(30) 8(30) 4(30)
Sharma BC, et al. Gastroenterology. 2009:137:885-891.
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P=.001
Placebo (n=70)
Lactulose (n=70)
Probability of Developing HE in Patients Receiving
Prophylactic Lactulose vs Placebo
Bass NM, et al. N Engl J Med. 2010; 362(12):1071-1081.
Rifaximin Treatment in HE: Time to First
Breakthrough Episode (Primary End Point)
Pati
en
ts (
%)
Days since randomization
Hazard ratio with rifaximin, 0.42(95% CI, 0.28-0.64)
P<.001
(77.9%)
Rifaximin
Placebo
(54.1%)
100
80
60
40
20
0
0 28 56 84 112 140 168
2009 2010 2011
Eligible Patients Identified (n) 13,623 15,529 16,328
Patients with Inpatient Claims (%) 89.2% 87.8% 86.4%
Patients Receiving Ongoing Treatment (%) 39.7% 37.7% 36.1%
Neff GW, Frederick, RT. Abstract 1612. Poster presentation at The Liver Meeting 2012, Boston, MA,
November 12, 2012.
Most Patients are Not Receiving
Prophylactic Therapy to Prevent Recurrence
Is Cognitive Impairment Following Overt Hepatic
Encephalopathy Completely Reversible? Conclusions
• OHE occurs in 30% to 45% of cirrhotic patients
• Cognitive impairment after an OHE episode may be
persistent
• Impairment from recurrent OHE episodes may be
cumulative
• Treating patients with covert HE (primary prophylaxis)
can prevent development of a first episode of overt HE
• Treating patients following an overt HE episode
(secondary prophylaxis) can prevent recurrence
• Most patients, however, are not receiving prophylactic
therapy