Program Disclosure

• 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.

• To ensure compliance with the Physician Payment Sunshine Act

requirements, the CLDF will report to all industry supporters any

transfers of value to any meeting participants.

2

Educational Objectives

• Assess the benefits of primary prophylactic therapy for

cirrhotic patients with covert hepatic encephalopathy and of

secondary prophylactic therapy for patients who have

recovered from an overt hepatic encephalopathy episode

• Evaluate data that suggest cognitive impairment following an

episode of overt hepatic encephalopathy may not be

completely reversible and that impairment from recurrent

episodes of hepatic encephalopathy may be cumulative

3

Prevalence of Cirrhosis

• The prevalence of cirrhosis, both worldwide and in the

US, is unknown1

– Cirrhosis is an outcome of a variety of causes, and the

underlying cause is commonly used for surveillance

purposes2

– Compensated cirrhosis often goes undetected for

prolonged periods of time1

• Experts estimate that 5.5 million people in the United

States have cirrhosis3

4

1. Schuppan D, Afdhal NH. Lancet 2008;371(9615):838-851.

2. Available at http://pubs.niaaa.nih.gov/publications/surveillance83/Cirr05.htm. Accessed 01/15/12.

3. Khungar V, Poordad F. Clin Liver Dis 2012;16:73-89.

Hospital Discharges Due to

Cirrhosis Increased by 6% in 2010

5

*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 January 2013

Nu

mb

er

of

dis

ch

arg

es

for

pati

en

ts w

ith

cir

rho

sis

*

6% growth

Year

Hepatic Encephalopathy is One of the

Primary Complications of Cirrhosis

• Primary complications of cirrhosis include:

– Ascites

– Jaundice

– Variceal hemorrhage

– Hepatic encephalopathy

• Other complications that can occur include:

– Hepatocellular carcinoma

– Spontaneous bacterial peritonitis

– Hepatic hydrothorax

– Hepatorenal syndrome

– Portopulmonary hypertension

– Portal vein thrombosis

– Hepatopulmonary syndrome

6 Lefton HB et al. Med Clin N Am 2009;93:787-799.

Hepatic Encephalopathy

7 Consensus recommendation of Working Party on Hepatic Encephalopathy, World Congress of Gastroenterology

Ferenci P et al. Hepatology 2002;35:716-721.

“Hepatic encephalopathy reflects

a spectrum of neuropsychiatric

abnormalities seen in patients with

liver dysfunction after exclusion

of other known brain disease.”

Hospital Discharges Associated with HE*

Increased by 21% in 2010

8

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 January 2013.

To

tal N

um

ber

of

Dis

ch

arg

es

21% growth

Year

Hepatic Encephalopathy: Pathophysiology

9

Inflammation

ICP

NH3

Proinflammatory Cytokines

Nitric Oxide & Oxidative Stress

Glutamate

& NH3

Glutamine

Increased brain water, deterioration in

neuropsychological function & hepatic

encephalopathy

Cerebral Blood Flow Astrocyte

Swelling

Adapted from Mullen KD et al. Semin Liver Dis. 2007;27(Suppl 2):32-47.

Astrocyte

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

10

TIPS = transjugular intrahepatic portosystemic shunt.

Mullen KD, et al. Semin Liver Dis. 2007;27(Suppl 2):32-47.

Mullen KD, Prakash RK. Clin Liver Dis 2012;16:91-93,

Poordad FF. Aliment Pharmacol Ther. 2006;25(Suppl 1):3-9.

Characterization of HE Stages

11

Normal Covert HE I II III IV

Overt HE Stages

Categorization is often arbitrary and

varies between raters

Simple Clinical

Diagnosis

Worsening cognitive dysfunction

coma

Bajaj JS, et al. Hepatology. 2009;50:2014-2021.

Overt HE is Associated with a

Poor Prognosis

• <50% survival at 1 year after diagnosis of HE; <25%

survival at 3 years

12

100

80

60

40

20

0

Su

rviv

al, %

0 12 24 36 48

Months

42% survival at 1

year 23% survival at

3 years

Bustamante et al. J Hepatol. 1999;30:890-895.

Comparative Outcome Probabilities for

Various Complications of Cirrhosis

• Projected survival rates 1 year after diagnosis of overt HE are comparable

to survival rates of cirrhotic patients with bleeding varices

13

Complication Survival at

1 year Survival at 3

years

Varices (non-bleeding) w/o ascites1 97% NA

Ascites ± varices1,2 80% 50%

Bleeding Varices ± Ascites1 43% NA

Hepatic Encephalopathy3 42% 23%

NA=Not Available

1. Adapted from D’Amico G et al. J Hepatol 2006;44:217-231.

2. Arroyo V, Colmenero J. J Hepatol. 2003;38:S69-S89.

3. Adapted from Bustamante et al. J Hepatol. 1999;30:890-895.

Acute Overt Hepatic Encephalopathy

14

Diagnosis of OHE

• Clinical recognition of the distinctive neurologic features of HE

• Knowledge that underlying cirrhosis is present

• Exclusion of all other etiologies of neurologic and/or metabolic abnormalities

• Identification of precipitating factors

• Grading systems to evaluate mental status

• Portal-systemic encephalopathy score (PSE score; Conn score) to evaluate overall severity

15

Adapted from:

Mullen KD. Semin Liver Dis. 2007;27(suppl 2):3-9.

Lawrence KR, Klee JA. Pharmacotherapy. 2008;28(8):1019-1032.

Neurologic Manifestations of OHE

16

Common Less Common

• Confusion or coma

• Asterixis

• Loss of fine motor skills

• Hyper-reflexia

• Cognitive deficits detected

by special testing

• Babinski sign

• Slow, monotonous speech

• Extrapyramidal-type

movement disorders

• Clonus

• Decerebrate posturing

• Decorticate posturing

• Hyperventilation

• Seizures*

*Seizures seen primarily in type A HE.

Mullen KD. Semin Liver Dis. 2007;27(suppl 2):3-9.

Other Causes of Altered Mental Status*

17

• Intracranial hematomas

• Thyroid dysfunction

• Hypoglycemia

• Hypoxia

• Hypercapnia

• Drug intoxication

• Hypoglycemia

• Hyperglycemia

• Acidosis

• Encephalitis

• Severe sepsis

• Uremia

*Most entities can be diagnosed by brain imaging or laboratory tests. Severe sepsis can cause encephalopathy or precipitate HE.

Mullen KD. Semin Liver Dis. 2007;27(Suppl 2):3-9.

West Haven Criteria for Grading

Mental State in Patients With Cirrhosis

18

Grade Features

0 No abnormalities detected

I Trivial lack of awareness

Euphoria or anxiety

Shortened attention span

Impairment of addition or subtraction

II Lethargy or apathy

Disorientation for time

Obvious personality change

Inappropriate behavior

III Somnolence to semi-stupor

Responsive to stimuli

Confused

Gross disorientation

Bizarre behavior

IV Coma, unable to test mental state

Bajaj JS, et al. Aliment Pharmacol Ther. 2011;33:739-747.

Proposed Algorithm for In-Patient

OHE Management

19

Patient with possible OHE

Confirm that it is HE: Yes

No HE: Other causes of

altered mental status

Search for precipitating factor

Precipitating factors

found

Precipitating factors

not found

Treatment directed to

the precipitating factor

• Admit to ICU for grade 3 HE

• Specific HE therapy with

lactulose or rifaximin

Adapted from Bajaj JS. Aliment Pharmacol Ther 2010;31:537-547.

Treatment Approach for Acute

Overt Hepatic Encephalopathy

20

Treating precipitating events

GI bleeding Octreotide, IV proton pump inhibitors, endoscopic or

angiographic therapy

Blood transfusions, correction of coagulopathy

Nasogastric lavage to remove blood from stomach

Infection Antibiotic therapy

Sedating medications Discontinue benzodiazepines, narcotics; consider

flumazenil or naloxone

Electrolyte abnormalities Discontinue diuretics; perform serial paracentesis if

needed

Correct hypokalemia or hyperkalemia, hyponatremia

Constipation Provide laxatives and enemas

Renal failure Discontinue diuretics

Albumin administration

Discontinue nephrotoxic medications

Khungar V, Poordad F. Clin Liver Dis 2012;16:73-89.

Treatment Approach for Acute

Overt Hepatic Encephalopathy

21 Khungar V, Poordad F. Clin Liver Dis 2012;16:73-89.

Lowering serum ammonia

Ammonia

excretion Lactulose enemas

Ammonia

production Minimally absorbed antibiotics--rifaximin

Nonabsorbable disaccharide--lactulose

Probiotics--lactobacillus, bifidobacterium

Closure of spontaneous portal systemic shunt

Liver transplantation

Artificial liver support

Treatment Approach for Acute

Overt Hepatic Encephalopathy

22 Khungar V, Poordad F. Clin Liver Dis 2012;16:73-89.

General supportive and nutritional interventions

General

supportive care Fall precautions in disoriented patients

Prevention of infections--changing IV lines, prevent aspiration

pneumonia, isolation

Monitor fluid status

Maintain normoglycemia and electrolytes

Correct alkalosis

Nutritional support Energy intake of 35-40 kcal/kg body weight/day and protein

intake of 1.2-1.5 g/kg body weight/day

Consider addition of branched-chain amino acids, zinc; consider

eliminating wheat and milk proteins

Out-Patient Management after

an Episode of OHE

• Treatment goals

– Prevention of recurrent episodes of HE

– Improvement of daily functioning

– Evaluation for liver transplant

23 Bajaj JS. Aliment Pharmacol Ther. 2010;31:537-547.

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

24 Sharma BC et al. Gastroenterology. 2009;137:885-891.

Secondary prophylaxis of HE:

Preventing recurrence of HE in patients

who had a previous episode of HE

25

Secondary Prophylactic Therapy Following

Overt Episode(s) of HE

• After an episode of overt HE has resolved,

patients with cirrhosis should remain on therapy

for an indefinite period of time or until they

undergo liver transplantation

• Goals of therapy: To prevent recurrent episodes

of HE and to ensure a reasonable quality of life

26 Prakash R, Mullen KD. Nat Rev Gastroenterol Hepatol. 2010;7:515-525.

Bajaj, JS et al. Gastroenterology 2010;138:2332–2340

Current Treatment Options for HE

27

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; is not currently used

Metronidazole Synthetic antiprotozoal

and antibacterial agent Not approved for HE

Adapted from:

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugsAdvi

soryCommittee/UCM201081.pdf.

Accessed January 2013, and http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022554lbl.pdf.

Accessed January 2013.

Secondary Prophylaxis of OHE:

Lactulose vs. Placebo

• Open-label randomized controlled trial

• Consecutive cirrhotic patients who recovered

from HE randomized to receive lactulose (n=70)

or placebo (n=70)

• Primary end point was development of OHE

• Median follow-up of 14 months (range 1-20

months)

28 Sharma BC et al. Gastroenterology 2009:137:885-891.

Probability of Developing HE in Patients

Receiving Prophylactic Lactulose vs. Placebo

29

*Values in parentheses indicate the cumulative number of subjects who developed HE.

1.0 0.8 0.6 0.4 0.2 0.0

Pro

ba

bilit

y o

f h

ep

ati

c e

nce

ph

alo

path

y

Follow-up in months

0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00

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)

P=.001

Sharma BC, et al. Gastroenterology. 2009:137:885-891.

Placebo (n=70)

Lactulose (n=70)

Side Effects in Patients Receiving

Prophylactic Lactulose vs. Placebo

30

Lactulose

(n=61)

Placebo

(n=64)

Diarrhea 14 (23%) ---

Abdominal bloating 6 (10%) ---

Distaste to lactulose 8 (13% ---

Constipation --- 10 (16%)

• In this study from New Delhi, India, all patients could tolerate and

remained compliant to lactulose therapy

Sharma BC et al. Gastroenterology 2009:137:885-891.

Compliance with Lactulose Therapy is a

Concern in the United States

• Compliance with lactulose therapy is a concern in

the US because many patients find the side effects

difficult to tolerate

• Most common side effects include:

– Severe diarrhea leading to dehydration, hypokalemia,

hypernatremia, and other electrolyte disturbances

– Bloating

– Flatulence

– Nausea and vomiting

– Unpleasant sweet taste

31 Khungar V, Poordad F. Clin Liver Dis 2012;16:73-89.

Lactulose Side Effects and Noncompliance are

the Most Common Precipitating Factors for OHE

32 Pantham G et al. Gastroenterology 2012;142(Suppl 1):S-950.

Precipitating Factor, 109 patients, 200 hospital admissions, 2005-2010

Frequency per 200 admissions

Percentage

Lactulose noncompliance 78 39

Constipation 44 22

Opioids and benzodiazepines 34 17

Dehydration 32 16

Infections 30 15

Acute renal failure 17 8.5

Hypokalemia (potassium <3.5) 14 7

Gastrointestinal bleeding 12 6

Large volume paracentesis 4 2

TIPS 4 2

Hyponatremia (sodium <130) 4 2

High protein diet 2 1

Unknown precipitants 18 9

Secondary Prophylaxis of HE:

Rifaximin vs. Placebo

33

Rifaximin 550 mg BID

for 6 mo (n=140) Placebo

for 6 mo (n=159)

Discontinued n=52 (37%)

Breakthrough HE: n=28

Adverse event: n=8

Death: n=6

Patient request: n=6

Exclusion criteria: n=1

Other: n=3

Discontinued n=93 (58%)

Breakthrough HE: n=69

Patient request: n=9

Adverse event: n=7

Death: n=3

Exclusion criteria: n=3

Other: n=2

Completed Study

n=88

Completed

Study

n=66

Randomization 1:1

N=299

(Randomized

Controlled Trial)

Bass NM et al. N Engl J Med 2010;362:1071-1081

Rifaximin Treatment in HE: Lactulose Use at

Baseline and During Study

34

Rifaximin

(n=140)

Placebo

(n=159)

Lactulose use at baseline—no (%)* 128 (91.4%) 145 (91.2%)

Lactulose use during study—no (%)* 128 (91.4%) 145 (91.2%)

*During the study, 3 patients who had been receiving lactulose discontinued

the therapy and another three patients started lactulose (1 in the rifaximin

group and 2 in the placebo group)

Bass NM et al. N Engl J Med 2010;362:1071-1081.

Rifaximin Treatment in HE: Time to First

Breakthrough Episode (Primary End Point)

35 Bass NM, et al. N Engl J Med . 2010; 362(12):1071-1081.

100

80

60

40

20

0

Pati

en

ts (

%)

Days since randomization

0 28 56 84 112 140 168

Hazard ratio with rifaximin, 0.42(95% CI, 0.28-0.64)

P<.001

(77.9%)

Rifaximin

Placebo

(54.1%)

Rifaximin Treatment in HE: Time to First

HE-Related Hospitalization (Secondary End Point)

36 Bass NM et al. N Engl J Med 2010; 362(12):1071-1081.

100

80

60

40

20

0

Days since randomization

0 28 56 84 112 140 168

Hazard ratio with rifaximin, 0.50(95% CI, 0.29-0.87)

P=0.01

(86.4%)

Rifaximin

Placebo

(77.4%)

Pati

en

ts (

%)

Rifaximin and HE:

Side Effects Similar to Placebo

37

Adverse Events Reported in ≥10% of Patients in Either Study Group

Event Rifaximin (n=140)

Placebo (n=159)

Any event, n (%) 112 (80.0) 127 (79.9%)

Nausea 20 (14.3) 21 (13.2)

Diarrhea 15 (10.7) 21 (13.2)

Fatigue 17 (12.1) 18 (11.3)

Peripheral edema 21 (15.0) 13 (8.2)

Ascites 16 (11.4) 15 (9.4)

Dizziness 18 (12.9) 13 (8.2)

Headache 14 (10.0) 17 (10.7)

Bass NM et al. N Engl J Med 2010;362:1071-1081.

• The incidences of adverse events did not differ significantly between

the two study groups (p>0.05 for all comparisons)

Long-Term Administration of Rifaximin: Effect on

Complications of Cirrhosis and Survival

• Patients were followed for up to 5 years, death, or liver transplantation

38

Rifaximin

(n=23)

Controls

(n=46) P value

Variceal bleeding (%) 35.0% 59.5% P=0.011

Hepatic encephalopathy (%) 31.5% 47.0% P=0.034

Spontaneous bacterial

peritonitis (%) 5.5% 46.0% P=0.027

Hepatorenal syndrome 4.5% 51.0% P=0.037

Death 7 / 23 (30.4%) 24 / 46 (52.2%) --

5-year cumulative probability

of survival (%) 61% 13.5% P=0.012

Vlachogiannakos J et al. Hepatology 2010:52(Suppl S1):328A-329A.

Long-Term Administration of Rifaximin:

Effect on Breakthrough OHE

39 Bajaj J et al. Hepatology 2012;56(Suppl S1):925A-926A

Time to first breakthrough OHE event

0 84 168 84 168 252 336 420 840

Days Post-study Drug Initiation

Pro

po

rtio

n M

ain

tain

ing

Rem

issio

n

n=82

Placebo events

39/82

Placebo

Crossover to

RFX events

14/82

6 mths OL

Treatment

Placebo

Crossover to

RFX events

37/82

Event rate † P-Value

PBO RCT 1.50 <0.0001

PBO Crossover 0.42

RCT Open-Label Maintenance

Long-Term Administration of Rifaximin:

Adverse Events

40 Bajaj J et al. Hepatology 2012;56(Suppl S1):925A-926A

Adverse events

n (rate)

Six-month trial Long-term

Placebo

PYE=26.2ǂ (n=82)

Crossover to rifaximin

PYE=134.2ǂ (n=82)

Peripheral edema 9 (0.36) 18 (0.16)

Nausea 11 (0.47) 17 (0.14)

Dizziness 8 (0.33) 7 (0.06)

Fatigue 8 (0.32) 8 (0.06)

*Treatment emergent adverse events occurring in 10% of patients in

placebo arm of six-month trial Rate is calculated as number of patients with particular adverse event +

total person years of exposure ǂPYE, total person years of exposure

Incidence and rate of treatment emergent adverse events*

Long-Term Administration of Rifaximin:

Incidence and Rate of Infections

41 Bajaj J et al. Hepatology 2012;56(Suppl S1):925A-926A

Adverse events n (rate)

Six-month trial Long-term

Placebo PYE=26.2ǂ (n=82)

Crossover to rifaximin PYE=134.2ǂ (n=82)

Cellulitis 2 (0.08) 11 (0.09)

Intestinal infections 0 (0) 1 (0.007)

Peritonitis 3 (0.11) 5 (0.04)

Pneumonia 0 (0) 10 (0.08)

Sepsis/septic shock 2 (0.08) 10 (0.08)

Urinary tract/kidney infection

7 (0.29)

14 (0.12)

Rate is calculated as number of patients with particular adverse event + total person years of exposure ǂPYE, total person years of exposure

Incidence and rate of infections

42

Choice of Secondary Prophylactic Therapy

Affects Survival

Neff GW et al. Am J Gastroenterol 2012;107(Suppl 1S):S606.

Su

rviv

al

(%)

Months

RFX (n=28)

Lac/RFX (n=55)

Lac (n=58)

None (n=44)

Lac vs. Lac/RFX, P=0.057; Lac vs. RFX, P=0.049

Treatment Paradigm for OHE is Changing

• Subset of national claims for medical and hospital activity between

2009 and 2011 was examined

• Patient selection was based on claims with an ICD-9 code 572.2

(Hepatic Encephalopathy)

• Claims from eligible patients were examined for any filled prescription

in (Lac), or RFX + Lac as an indicator of ongoing treatment

43 Neff GW, Frederick RT. Hepatology 2012;56(Suppl S1):954A

2009 2011

Received rifaximin alone (%) 3.9% 13.2%

Received rifaximin + lactulose (%) 8.1% 8.8%

Received lactulose alone (%) 27.9% 14.1%

Most Patients are Not Receiving

Prophylactic Therapy to Prevent Recurrence

• Subset of national claims for medical and hospital activity, Jan 2009

to Dec 20011, ICD-9 code 572.2 and filled prescriptions for rifaximin,

lactulose, or rifaximin + lactulose

44

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 et al. Hepatology 2012;56(Suppl S1):945A.

Covert Hepatic Encephalopathy

45

Covert Hepatic Encephalopathy

• Significantly diminishes quality of life1

• Significantly diminishes working and earning capacity in blue-

collar workers1

• Impairs driving on structured driving tests2,3

• Increases risk of traffic accidents and violations4

• Increases risk for progression to OHE: >50% develop overt

HE within 30 months5

46

1. Groeneweg M et al. Hepatology. 1998;28(1):45-49.

2. Wein C et al. Hepatology. 2004;39(3):739-745.

3. Watanabe A et al. Metab Brain Dis. 1995;10(3):239-248.

4. Bajaj JS et al. Am J Gastroenterol. 2007;102(9):1903-1909.

5. Hartmann IJ, et al. Am J Gastroenterol. 2000;95(8):2029-2034.

Diagnosis of Covert HE

• Patients with covert HE have no clinical signs

and symptoms of HE

– The diagnosis of covert HE is only possible through

specialized psychometric or neurological measures

• No consensus on diagnostic criteria or

diagnostic tests has been established

47 Bajaj JS et al. Hepatology 2009;50:2014-2021.

Mullen KD. Aliment Pharmacol Ther 2006;25(suppl 1):11-16.

Diagnostic Methods for Detecting CHE

48

Methods Advantages Limitations

Formal neuropsychological assessment

• Established and well-recognized clinical significance

• Expensive • Time consuming

Short neuropsychological batteries

• Easy to administer in office setting • Inexpensive • Rapid results • High sensitivity for discerning covert HE from other encephalopathies

• Test often copyrighted • Limited access

Computerized tests (CFF, ICT, reaction times, etc.)

• Easy to apply • Limited data on diagnostic significance • Require standardization

Neurophysiologic tests (EEG, spectral EEG, P300)

• Allows for objective repeat testing

• Equipment • Limited data on diagnostic significance

CFF, critical flicker frequency; ICT, inhibitory control test; P300, auditory event-related evoked potential

Adapted from Mullen KD et al. Semin Liver Dis. 2007;27(Suppl 2):32-47.

Primary prophylaxis of HE:

Preventing a first occurrence of OHE in

patients with advanced liver disease

49 Sharma BC et al. Gastroenterology. 2009;137:885-891.

Data Suggesting Therapy Should Be

Directed at Patients Diagnosed with CHE

50

CHE positive

CHE negative

Develo

pm

en

t o

f o

vert

HE

100

90

80

70

60

50

40

30

20

10

0

0 10 20 30 40

Months

P < 0.001

(21) (25)

(20)

(11)

(91) (88)

(84)

Adapted from: Hartmann IJ et al. Am J Gastroenterol. 2000;95(8):2029-2034.

Primary Prophylactic Therapy:

CHE Treatment Goals

• Goals of primary prophylactic therapy

– Delay progression to overt HE

– Improve quality of life

– Maintain employment status

– Preserve driving privilege

51 Prakash R, Mullen KD. Nat Rev Gastroenterol Hepatol. 2010;7:515-525.

Lactulose for Primary Prophylaxis of

Overt HE in Cirrhotic Patients

52 Sharma BC et al. J Hepatol 2012;56(Suppl 2):S238.

CHE at

Baseline

Developed

OHE

Died

% o

f P

ati

en

ts

32/

60

36/

60

6/

55

15/

50 5/55

10/

50

Lactulose

No Lactulose

Median follow-up 12 months

P=0.29

P=0.02

P=0.16

Lactulose Improves Cognitive Functions

in Patients With CHE

• Patients randomly assigned to receive lactulose in a dose of 30-60 ml

in 2 or 3 divided doses so that patients passed 2-3 semisoft stools/day

or no treatment in a nonblinded design

53

No Treatment Lactulose

Baseline (n=30)

3 Months (n=20)

Baseline (n=31)

3 Months (n=25)

Mean number of abnormal NP test results*

2.47 2.55 2.74 0.75

Number of patients with CHE

30 18 31 5

Development of overt HE

-- 2 -- 1

*Patients were administered 6 tests: NCT A, NCT B, FCT A, FCT B, picture completion, and block design tests.

Prasad S et al. Hepatology 2007;45:549-559.

Lactulose Improves Health-Related QoL

in Patients With CHE

54

Mean

Sic

kn

ess I

mp

act

Pro

file

(S

IP)

Sco

re

3 months 0 months

Prasad S, et al. Hepatology. 2007;45:549-559.

Rifaximin Improves Cognitive Functions in

Patients With CHE

55

*1200 mg/day for 8 weeks. P<0.0001, rifaximin compared to placebo. ‡5 NP tests (2 number and figure connection, picture completion, digit symbol,

block design).

Sidhu S et al. Gastroenterology. 2010;139:e18-e19.

Rifaximin* (n=49) Placebo (n=45)

Improvement

-at 2 weeks

-at 8 weeks

28/49 (57.1%)

37/49 (75.5%)

8/45 (17.8%)

9/45 (20%)

Mean number of

abnormal NP

tests‡

-baseline

-at 2 weeks

-at 8 weeks

2.35 (2.17-2.53)

1.29 (1.02-1.56) P=0.002

0.81 (0.61-1.02) P=0.000

2.31 (2.03-2.59)

2.03 (1.74-2.31)

1.97 (1.69-2.25) P>0.05

Rifaximin Improves Health-related QoL

in Patients With CHE

• Patients randomized to receive placebo or rifaximin 1200 mg/day for 8 weeks

56

Mean

Sic

kn

ess I

mp

act

Pro

file

(S

IP)

Sco

re

8 Weeks

(n=37)

Baseline

(n=42)

P=.007 P=.050

P=.002

P=.000

P=.000

Sidhu S, et al. Am J Gastroenterol. 2011;106:307-316.

Rifaximin Improves Driving

Simulator Performance

• Trial involved driving and navigation simulation at baseline

• Patients were randomized to rifaximin 550 mg or placebo BID

• Driving simulation tests repeated on the 8-week visit

57

Rifaximin

(n=21)

Placebo

(n=21) P value

Improved cognitive tests 91% 61% .02

Reduced total driving errors 76% 33% .013

Reduced speeding tickets 81% 33% .005

Reduced illegal turns 62% 19% .012

Reduced collisions 43% 33% .751

Bajaj JS, et al. Gastroenterology 2011;140:478-487.

Is cognitive impairment following

overt hepatic encephalopathy

completely reversible?

58

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

59 Frederick RT. Clin Liver Dis 2012;16:147-158.

Psychometric Test Results In ‘Normal’

Cirrhotic Patients vs. Prior OHE Patients

60

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.

Persistence of Cognitive

Impairment after OHE

61

*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

Persistent Impairment of Learning Capacity

After Resolution of OHE

62

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.

Cognitive Impairment May be Cumulative

63

(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.

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

64

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.

Hepatic Encephalopathy:

Update 2013 Summary

• Hepatic encephalopathy (HE) is a complication of

cirrhosis for which effective prophylactic therapy is

available

• Secondary prophylactic treatment following an overt HE

episode can prevent recurrent episodes of HE and

improve quality of life

• Primary prophylactic treatment of covert HE can delay

progression to overt HE, improve quality of life, and

possible preserve driving privilege

• Prevention of overt HE is important because cognitive

impairment may be irreversible and cumulative

65