This program is supported by educational grants from · 1 million 0 million 10% Reduction 65%...
Transcript of This program is supported by educational grants from · 1 million 0 million 10% Reduction 65%...
This program is supported
by educational grants from
Dova Pharmaceuticals, Inc.,
Mallinckrodt Pharmaceuticals,
and Salix Pharmaceuticals
Disclosures
All faculty and staff involved in the planning or presentation of continuing education activities
provided by the Annenberg Center for Health Sciences at Eisenhower (ACHS) are required
to disclose to the audience any real or apparent commercial financial affiliations related to
the content of the presentation or enduring material. Full disclosure of all commercial
relationships must be made in writing to the audience prior to the activity. Staff at the
Annenberg Center for Health Sciences at Eisenhower and the Chronic Liver Disease
Foundation (CLDF) have no relationships to disclose.
Planning Committee Member
Lisa D. Pedicone, PhD – Nothing to disclose.
Faculty
All faculty disclosures can be found in your meeting guide.
4
Breaking News in Chronic Liver Disease
Kimberly Brown, MD, FAST,
FAASLD, AGAF
Acute Hepatitis C on the Rise
CDC (2013-2016): Estimated HCV Prevalence Among Adults in the United States
• HCV antibody positive (including past
and current infection)
– Number: 4.1 million (95% CI 3.4-4.9)
– Prevalence: 1.7% (95% CI 1.4-2.0)
• HCV RNA positive
(including current infection)
– Number: 2.4 million (95% CI 2.0-2.8)
– Prevalence: 1.0% (95% CI 0.8-1.1) 0
1
2
3
4
5
Nu
mb
er
(in
mil
lio
ns)
73%
3.5
Number (in millions) With HCV Infection
NHANES NHANES adjusted
HCV Ab Positive
HCV RNA Positive
HCV Ab Positive
HCV RNA Positive
2003-2010 2013-2016
2.7
57%
2.4
2.1
Estimated adult US population in 12/2016: 245 million.
Datasets analyzed: National Health and Nutrition Examination Survey (noninstitutionalized civilian population).
Combination of literature reviews and population size estimation approaches (incarcerated people, unsheltered homeless people, active-duty
military personnel, and nursing home residents).
Hofmeister MG, et al. Hepatology. 2019 Mar;69(3):1020-1031. doi: 10.1002/hep.30297. Epub 2018 Nov 6. 7
Changing Trends in Acute HCV in the US (2001-2016)
• New acute HCV infection in 2016
– Reported cases (n=2967)
– Estimated (n=41,200, adjusted for under-
ascertainment and under-reporting)
• 3.5-fold increase in new cases since 2010
– Reflects new infections associated with
rising rates of injection-drug use
• Most newly acquired acute HCV infections
occurred among young, white, PWIDs,
who live in non-urban areas (i.e.,
Appalachian, Midwestern, and New
England states)
Acute HCV Rate in US 2001-2016
CDC. Surveillance for viral hepatitis - United States, 2016. https://www.cdc.gov/hepatitis/statistics/2016surveillance/index.htm
0
0.5
1
1.5
2
2.5
3
2001 2004 2007 2010 2013 2016
Rate
(p
er
100,0
00 p
op
ula
tio
n)
Year
0-19 yrs
20-29 yrs
30-39 yrs
40-49 yrs
50-59 yrs
> 60 yrs
8
Populations at Risk
1960s Up to 300,000 cases
of acute HCV per year; risk of
exposure via blood
transfusion up to 33%
30-70% prevalence
Baby Boomers (born 1945-1965) People Who Inject
Drugs (PWID)
1992 Widespread
introduction
of HCV antibody
testing
1970s Volunteer donor system
reduces risk of exposure
via blood transfusion
1989 HCV
discovered
Alter HJ. Nat Med. 2000;6:1082-1086. 9
CDC report identified >220
counties vulnerable to outbreaks of
HIV and HCV among people who
inject drugs
Risk Factors – Unemployment rates
– Overdose deaths
– Prescription opioid sales
Counties Vulnerable to Outbreaks of HIV and Hepatitis C
Geographic Areas Most at Risk for HCV
Van Handel MM. J Acquir Immune Defic Syndr. 2016;73:323. 10
WHO Goal:
Global Elimination of Viral Hepatitis
Global Health Sector Strategy:
Eliminate Viral Hepatitis as a Major Public Health Threat by 2030
30%
Reduction
90%
Reduction
NEW INFECTIONS
DEATHSHEPATITIS B + C HEPATITIS B + C
2015 2020 2025 2030 2015 2020 2025 2030
10 million
9 million
8 million
7 million
6 million
5 million
4 million
3 million
2 million
1 million
0 million
10%
Reduction 65%
Reduction
2 million
1,8 million
1,6 million
1,4 million
1,2 million
1 million
0,8 million
0,6 million
0,4 million
0,2 million
0 million
Reduction in new infections by 90% Reduction in deaths by 65%
Programmatic Targets
90% of people
infected are
diagnosed
80% of people
diagnosed are
treated
90% coverage of BD
and B3 doses
(PAHO: 95%)
100% of blood
products are safe
90% of injections in
health facilities
are safe
Impact Targets
12
HCV No Longer a Disease Limited to Baby Boomers H
CV
Cases (
nu
mb
er)
2005
0
50
100
150
200
250
300
350
400Male
Female
20 30 0 10 60 70 40 50 80 90
Age (years)
2012
0
50
100
150
200Male
Female
20 30 0 10 60 70 40 50 80 90
Age (years)
2015
0
50
100
150
200Male
Female
20 30 0 10 60 70 40 50 80 90
Age (years)
Data for New York State (excluding NYC).
https://www.health.ny.gov/statistics/diseases/communicable/index.htm. 13
Claims data for HCV Ab screening from a single large commercial payer (CPT and ICD-9 codes):
Screened (n=1,056,583); not screened (n=1,243,581).
Factors that increased the odds of getting screened: female gender, Medicare, presence of comorbidities.
Mehta D, et al. J Hepatol. 2018;68(suppl S1):S177. Abstract THU-113.
Effectiveness of HCV Screening in the US (2010-2016)
• In the US, to meet the 2030 diagnosis
targets, this means diagnosing at least
– 110,000 cases/year until 2020
– 89,000 cases/year between 2020-2024
– >70,000 cases/year between 2025-
2030
• At the current screening rate, 92% of
US states are not on target to meet
WHO screening goals of HCV
elimination by 2030
14
Timeline to Achieve WHO Screening Target for HCV Elimination
Reach WHO Target by: 2030 2040 2050 Beyond 2050
Negative
Positive
Test for
Quantitative HCV RNA
Refer to specialist for Disease
Staging and Management Plan
Positive
Negative Retest in
6 months
STOP
Genotyping testing
also recommended
Screening Test for Anti-HCV
HCV Screening Is Straightforward: Algorithm for Screening/Diagnosis
Modified from http://www.cdc.gov/hepatitis/HCV/PDFs/hcv_flow.pdf.
Ghany MG, et al. Hepatology. 2011;54(4):1433-1444. 15
HCV Continuum of Care Among PWIDs: Philadelphia Department of Health
• Random sample of newly reported
HCV antibody positive persons
(n=29,820; 2013-2017)
– Interviewed and disclosed being a
PWID (n=2390)
• Measurable gaps exist in the HCV
continuum of care for PWIDs,
especially those ≤35 years of age
– Among those HCV RNA positive
• Only 25% and 8% of PWIDs >35
and ≤35 years of age, respectively,
were treated
• Need for enhanced navigation
to services
0
20
40
60
80
100
Pati
en
ts (
%)
81% 85%
90%
75%
HCV Continuum of Care Among
HCV Ab-Positive PWIDs
Years of age
>35 (n=1151)
≤35 (n=1239)
Ever Tested for HCV RNA
HCV RNA Positive
Initiated HCV Care
Treated
66%
25%
41%
8%
Addish E, et al. Hepatology. 2018;68:929A-930A. Abstract 1632. 16
Important New Treatment for
Primary Biliary Cholangitis
PBC is characterized by destruction of the interlobular and septal bile ducts
that may lead to cirrhosis
Immune
response
Bile duct
damage
Environment
Genetics
Primary Biliary Cholangitis (PBC) Is a Chronic, Progressive Autoimmune Disease
• Factors possibly associated with onset
and perpetuation of bile-duct injury in PBC
Poupon R. J Hepatol. 2010;52(5):745-758; Selmi C, et al. Lancet. 2011;377(9777):1600-1609;
Carey EJ, et al. Lancet. 2015;386(10003):1565-1575. 18
Farnesoid X Receptor Signaling
Bile Acids
(Primary ligands
for FXR)
↓ Bile Acid
Synthesis
and
Uptake
↑ Gene
Expression (BSEP, MDR3, MRP
2/3/4, OST α/β)
↓ Gene
Expression (CYP7A1, NTCP,
OATP)
FXR
(Hepatocytes, biliary
epithelium, small
bowel enterocytes,
renal tubular cells,
adrenal cells,
adipocytes, beta
cells)
Binding
Direct
Effects
Indirect
Effects
↑ Bile Acid
Efflux
Abbreviations: BSEP, bile salt export pump; FXR, farnesoid X receptor; MRP 2/3/4, multidrug resistant protein 2/3/4;
NTCP, sodium/taurocholate cotransporting polypeptide; OATP, organic anion transporting polypeptide; OST α/β, organic soluble transporter α/β.
Neuschwander-Tetri BA. Curr Gastroenterol Rep. 2012;14:55-62. 19
Obeticholic Acid (OCA): Approved FXR Agonist for PBC
• PBC: OCA is associated with statistically significant, clinically
meaningful improvements
– Biochemical criteria correlated with clinical benefit (alkaline
phosphatase and bilirubin)
– Markers of inflammation (C-reactive protein) and apoptosis (CK18)
• Nonalcoholic steatohepatitis (NASH): Phase 3 topline results
released February 19th
– OCA showed statistically significant improvement in liver fibrosis without
worsening of NASH at 18 months
– Very active research area; however, OCA is expected to be the first FDA
approved drug for NASH 20
Long Term Side Effects Reduced with
New Treatment for Hepatitis B
*Nonresponders included pts with HBV rebound or genotypic resistance, primary nonresponse, NE due to early event (death, LT, LTFU).
Jang JW, et al. Hepatology. 2015;61:1809-1820.
HBV Therapy Reduces Risk of Disease Progression
• Patients with HBV and first-onset complications of decompensated cirrhosis treated
predominantly with lamivudine or entecavir
• Antiviral therapy improved transplant-free survival over mean follow-up of 49 mos
(P = .0098 vs untreated)
Treated, responder (n = 245)
Treated, nonresponder* (n = 178)
Untreated (n = 284)
Bonferroni-adjusted P < .0003 LT-F
ree
Su
rviv
al (%
)
Mos 0 84 12 24 36 48 60 72
100
80
60
40
20
0
22
The Evolution of HBV Therapy
1998 2002 2005 2006
1992 2008 2016
Lamivudine Entecavir Telbivudine Tenofovir
Alafenamide
IFN-α Adefovir PegIFN-α Tenofovir Disoproxil Fumarate
23
Guidelines: What to Start as Initial HBV Therapy
Treatment Preferred Notes
Entecavir Yes High potency, high genetic barrier to resistance
TAF Yes High potency, high genetic barrier to resistance
TDF Yes High potency, high genetic barrier to resistance
PegIFN
Should only be considered as initial therapy
for pts with mild/moderate CHB or
selected pts with compensated cirrhosis
(no portal hypertension)
Less safe in pts with cirrhosis, contraindicated in
pts with decompensated cirrhosis
Adefovir No Low genetic barrier to resistance
Lamivudine No Low genetic barrier to resistance
Telbivudine No Low genetic barrier to resistance
ETV, TDF, TAF have very favorable safety and resistance profiles
TAF= Tenofovir alafenamide
TDF= Tenofovir disoproxil fumarate
Terrault NA, et al. Hepatology. 2018 Apr;67(4):1560-1599. doi: 10.1002/hep.29800. 24
Chronic Hepatitis B: Newest Therapy (Tenofovir AF)
• Higher levels of TFV-diphosphate
in target cells at lower doses than
tenofovir DF
• Tenofovir AF has a lesser effect on
the proximal
renal tubule
• 90% lower TFV levels in plasma
minimizes renal
and bone effects while maintaining
high potency for suppressing HBV
HBV TARGET CELL PLASMA
TAF 25 mg TFV HBV
TDF 300 mg
TFV
TFV
TFV
GI Tract
25 TFV= Tenofovir
TAF TDF
HBeAg loss, n/N (%) 135/565 (24) 39/175 (22)
HBeAg seroconversion, n/N (%) 105/565 (19) 23/175 (13)
HBsAg loss, n/N (%) 9/857 (1) 3/251 (1)
HBsAg seroconversion, n/N (%) 7/857 (1) 1/251 (<1)
No resistance to TAF and TDF was detected through Week 144
p =0.71 87 85
20
40
60
80
100
TAF TDF
74 71
0
20
40
60
80
100
TAF TDF
p=0.59
Study 108 and 110 Pooled Analysis: TAF vs TDF at 144 Weeks
HBeAg-Negative HBeAg-Positive
HB
V D
NA
<29 IU
/mL
, %
248/285 63/74 428/581 127/178
Chan. AASLD 2018. Abstracts 0381 and 0386. 26
HBeAg-Negative
71
59
0
20
40
60
80
100
188/
264
Pati
en
ts,
%
43/
73
TDF TAF
P=0.052
64
53
0
20
40
60
80
100
362/
567
Pati
en
ts,
%
91/
172
TDF TAF
P=0.01
There were higher rates of ALT normalization by AASLD 2018 criteria in
patients on TAF compared to TDF
HBeAg-Positive
ALT Normalization at Week 144
AASLD 2018 criteria ULN: males ≤ 35 U/L, females ≤ 25 U/L.
Chan. AASLD 2018. Abstract 0381.
Study 108 and 110 Pooled Analysis: TAF vs TDF at 144 Weeks
27
Change in Renal Parameters Over 144 Weeks
There were significantly smaller decreases in eGFRCG and smaller changes in proximal
tubular markers with TAF compared to TDF at Week 144
Med
ian
Ch
an
ge F
rom
Baseli
ne,
mL
/min
(Q
1, Q
3)
TAF TDF
−1.2
−6.0
p<0.001
Week
144 120 96 72 48 24 0 -20
-10
0
10
-5
0
50
100
150
200
250
β2-Microglobulin:Cr
54.2
102.7
23.1
120.7
Med
ian
% C
han
ge F
rom
Baseli
ne (
Q1, Q
3)
p<0.001* p<0.001*
Change in eGFRCG
388.5
Retinol-Binding
Protein:Cr
*From 2-sided Wilcoxon rank-sum test.
Chan. AASLD 2018. Abstract 0381. 28
There were significantly less declines in hip BMD in patients on TAF compared to TDF
Changes in Bone Mineral Density (BMD) in Patients Over 144 Weeks
Hip TAF TDF
Week
-0.41
-2.49
144 120 96 72 48 24 0 -8
-6
-4
-2
0
2
4 M
ea
n c
han
ge f
rom
baseli
ne,
% (
SD
)
p<0.001*
*From analysis of variance model including treatment as fixed effect. †From Cochran-Mantel-Haenszel test for ordinal data (row mean scores differ statistic was used).
Chan. AASLD 2018. Abstract 0381. 29
> 3%
≤ 3%
≤ 3%
≤ 3%
≤ 3%
> 3%
P<0.001†
0
20
40
60
80
100
TAF TDF
Pati
en
ts,
%
Improvement Decline
> 3%
> 3%
E/C/F/TAF vs E/C/F/TDF in HIV Infection: Wk 144 Renal and Bone Outcomes
• Randomized phase III trials conducted
in treatment-naive HIV-infected pts
with eGFR ≥ 50 mL/min
Renal Events Leading to
Discontinuation, n
E/C/F/TAF (n = 866)
E/C/F/TDF (n = 867)
Proximal renal tubulopathy 0 4
Cr elevation or
eGFR decrease 0 3
Renal failure 0 2
Nephropathy 0 1
Proteinuria 0 1
Bladder spasm 0 1
Total 0 12
Change in Spine and Hip BMD Through Wk 144*
2
0
-2
-4 Mean
% C
han
ge
(95
% C
I)
-1.3 -1.0 -0.9
-2.8 -3.0
∆ 2.0
E/C/F/TAF E/C/F/TDF
P < .001 for all
Spine
0 48 96 144 Wk n =
n = 845 850
797 816
795 790
744 745
702 686
2
0
-2
-4 Mean
% C
han
ge
(95
% C
I)
-0.7 -0.6 -0.8
-2.9 -3.3 -3.4
∆ 2.6 Hip
0 48 96 144 Wk n =
n = 836 848
789 815
791 784
735 742
690 683
E, elvitegravir; C, cobicistat; F, emtricitabine; TAF, tenofovir alafenamide.
*P values calculated using analysis of variance model including treatment as a fixed effect.
Arribas JR, et al. CROI 2017. Abstract 453. 30
Clinical Case Forum I: Current and
Emerging Management Approaches for the
Cirrhotic Patient with Thrombocytopenia
Sammy Saab, MD, MPH, AGAF,
FACG, FAASLD
History of Present Illness – June 2018
MEDICATIONS LABS PROGRESS
NOTES
OTHER HISTORY
& PE
47 year old male with
decompensated alcohol-
related cirrhosis
• 47 year old gentleman with decompensated alcohol-
related cirrhosis returns to clinic after being recently
admitted and banded for bleeding esophageal varices.
– Pertinent admission labs:
• HB 5.2, PLT 32, INR 1.4, TB 1.2
– Required 6 bands.
– Transfused PRBCs and Platelets
• Follow up outpatient endoscopy with additional
banding recommended.
32
47 year old male with
decompensated alcohol-
related cirrhosis
Patient Case
MEDICATIONS LABS PROGRESS
NOTES
OTHER HISTORY
& PE
• Family History
– No family history of liver disease.
• Social History:
– No history of injectable drugs. Stopped
drinking alcohol about 3 years ago. Not
currently working.
33
47 year old male with
decompensated alcohol-
related cirrhosis
Past Medical History
MEDICATIONS LABS PROGRESS
NOTES
OTHER HISTORY
& PE
• PMH:
– Alcohol related cirrhosis
– Diabetes
– No hypercoagulable state
• PSH:
– Noncontributory
34
HISTORY
& PE
47 year old male with
decompensated alcohol-
related cirrhosis
Past Medical History
LABS PROGRESS
NOTES
OTHER
• Medications:
– Propranolol
– Diabetes
• Allergies:
– None
35
MEDICATIONS
47 year old male with
decompensated alcohol-
related cirrhosis
Physical Examination
MEDICATIONS LABS PROGRESS
NOTES
OTHER HISTORY
& PE
• 98.7 temp; 65 heart rate, 110/65.
• General: Overweight.
• Neurology: A&O x 4. No asterixis.
• Neck: Supple. Oral cavity not examined.
• Heart: Regular rate and rhythm. No murmurs, rubs, or gallops.
• Lungs: Clear to auscultation. No wheezes, rhonchi, or rales.
• Skin: Spider angiomas and palmar erythema. No caput medusa. No
fluid wave.
• Abdomen: Overweight. Splenomegaly. Normoactive bowel sounds.
• Extremity: No edema.
36
47 year old male with
decompensated alcohol-
related cirrhosis
HISTORY
& PE
Outpatient Labs
MEDICATIONS PROGRESS
NOTES
OTHER
WBC 2.7 INR 1.2
HB 10.9 Na 137
PLT 37 CR 1.1
ALB 3.8 MELD 11
TB 1.4
AST 52
ALT 48
AP 119
STUDIES
37
Laboratory
Thrombocytopenia in CLD
• Thrombocytopenia is a common problem in patients with
cirrhosis (platelets <100,000)
– Estimated to affect up to 70% of CLD patients
– Extent worsens with severity of portal hypertension and disease
– Patients may be ineligible for elective surgical or diagnostic
procedures due to risk of bleeding
– Increases risk of mortality
– Increases risk of poor clinical outcomes
Mitchell O, et al. Hepatic Medicine: Evidence and Research. 2016;8:39-50; Maan, et al. Drugs. 2015;75(17):1981-92;
Giannini EG. Aliment Pharmacol Ther. 2006;23:1055-65. 38
Etiologies of Thrombocytopenia in Chronic Liver Disease
• Splenic sequestration secondary to
portal hypertension
• Direct bone marrow suppression secondary
to viruses, alcohol, iron, or drugs
• Increased destruction secondary
to anti-platelet antibodies, shear stress,
infection, or increased fibrinolysis
• Decreased production of thrombopoietin
(TPO) by the liver
Mitchell O, et al. Hepatic Medicine: Evidence and Research. 2016;8:39-50; Maan, et al. Drugs. 2015;75(17):1981-92;
Afdhal N et al. Journal of Hepatology. 2008;48:1000-1007. 39
47 year old male with
decompensated alcohol-
related cirrhosis
HISTORY
& PE
Radiology
MEDICATIONS PROGRESS
NOTES
OTHER
STUDIES
40
• Abdominal ultrasound
– Nodular liver
– No hepatocellular carcinoma
– No ascites
– Portal vein patent
HISTORY
& PE
47 year old male with
decompensated alcohol-
related cirrhosis
History of Present Illness – July 2018
MEDICATIONS LABS OTHER
• Patient referred to outpatient
EGD with banding.
• Because of thrombocytopenia,
platelet transfusion also ordered.
41
PROGRESS
NOTES
Platelet Transfusions: Benefits and Considerations
Benefits:
• Prevent the risk of bleeding:
– Thrombocytopenic patients
– Patients with
platelet dysfunction
• Control bleeding in patients with
active bleed
Considerations:
• Risk of infections
• Hemolytic/Febrile
non-hemolytic/Allergic/
Anaphylactic Reactions
• Refractoriness
(immune vs nonimmune)
• Storage logistics
• Patient scheduling logistics
• Limited shelf life
• Cost
• Supply vs demand
42
HISTORY
& PE
47 year old male with
decompensated alcohol-
related cirrhosis
History of Present Illness – July 2018
MEDICATIONS LABS OTHER
• Patient returns for follow up
• Said he will never undergo endoscopy again
– Developed platelet transfusion reaction with fever
and rigor
• Discussed risks of recurrent esophageal
variceal bleeding
43
PROGRESS
NOTES
Current Landscape in Patients with Thrombocytopenia and CLD
• Patients require 1-3 procedures annually
• Different procedures are associated with different risks of bleeding
– Procedures are required to clinically manage patients with CLD
– Thrombocytopenia can lead to serious uncontrolled bleeding in these
patients negatively impacting clinical care
• Prolonged hospitalizations
• Serious complications
• Poor clinical outcomes
• Historically, the only treatment option was platelet transfusion
Szczepiorkowski ZM and Dunbar NM. Hematology Am Soc Hematol Educ Program. 2013;2013:638-44;
Lin Y and Foltz LM. BCMJ. 2005;47(5):245-248. 44
Thrombopoietin Receptor Agonists
• Mimics effects of
thrombopoietin (TPO) to
increase platelet production
• Binds to a different region of
the TPO receptor and does not
block native TPO
• Predictable PK/PD profile
45
TPO agonist
PRE-RANDOMIZATION FOLLOW-UPRANDOMIZATION(2:1 avatrombopag:placebo)
mean Baseline PC<40 x 109/L
mean Baseline PC40 to <50 x 109/L
Screening PeriodDay -14 to -1
BASELINE
DAY 1
TREATMENT
DAY 2-5
PROCEDURE*
DAY 10-13
7 DAYS POST
PROCEDUREDAY 35
6 TISIV5 TISIV4 TISIV3 TISIV2 TISIV1 TISIV
Low BaselinePlatelet Count Cohort
High BaselinePlatelet Count Cohort
5-8 days afterlast dose ofstudy drug
30 days afterlast dose ofstudy drug
60 mg AVATROMBOPAGqd x 5 Days
40 mg AVATROMBOPAGqd x 5 Days
PLACEBO
PLACEBO
R2:1
R2:1
Avatrombopag Phase 3 Study Design ADAPT-1 & ADAPT-2 (N=435)
*Platelet transfusions were not mandatory
AASLD 2017 46
Study Endpoints
• Primary Endpoint:
– Proportion of patients who do not require a platelet transfusion or any
rescue procedure for bleeding after randomization and up to 7 days
following a scheduled procedure
• Secondary Endpoints:
– Proportion of patients achieving target platelet count of ≥ 50 × 109/L on
Procedure Day
– Change in platelet count from Baseline to Procedure Day
– Safety
47
22.9%
65.6%
38.2%
88.1%
0%
20%
40%
60%
80%
100%
p<0.0001 p<0.0001
RESULTS: Patients Who Did Not Require Platelet
Transfusion or Rescue Procedure for Bleeding
48
Pati
en
ts (
%)
Low Baseline Platelet
Count Cohort
<40 x 109/L
High Baseline Platelet
Count Cohort
40 to <50 x 109/L
4.2%
68.9%
20.6%
88.1%
0%
20%
40%
60%
80%
100%
p<0.0001 p<0.0001
Low Baseline Platelet
Count Cohort
<40 x 109/L
High Baseline Platelet
Count Cohort
40 to <50 x 109/L
Adapt 1 (231 patients) Adapt 2 (204 patients)
Terrault N et al. Abstract 217. AASLD 2017.
Mean Platelet Counts by Treatment Group and Visit Day
Low Baseline Platelet Count Cohort:
HighBaseline Platelet Count Cohort:
60 mg AvatrombopagPlacebo
40 mg AvatrombopagPlacebo
0 5 10 15 20 25 30 35
90
80
70
60
50
40
30
Me
an
Pla
tele
t C
ou
nt
x 1
09/L
DaysDosing
Visit 2
Day 1
Visit 3
Day 4
Visit 4
Day 10
Visit 5
Day 17
Visit 6
Day 35
Baseline Procedure Day49
Combined ADAPT-1 & ADAPT-2 Safety
Combined Safety Data
Low Baseline Platelet Count Cohort
<40 x 109/L
High Baseline Platelet Count Cohort
40 to <50 x 109/L
Placebo
(n=91)
%
Avatrombopag
60 mg
(n=159)
%
Placebo
(n=65)
%
Avatrombopag
40 mg
(n=115)
%
TEAEs, n (%) 53 (58.2) 89 (56.0) 33 (50.8) 59 (51.3)
Pyrexia (fever) 8 (8.8) 18 (11.3) 6 (9.2) 9 (7.8)
Abdominal pain 6 (6.6) 10 (6.3) 4 (6.2) 8 (7.0)
Nausea 7 (7.7) 10 (6.3) 4 (6.2) 8 (7.0)
Headache 7 (7.7) 7 (4.4) 3 (4.6) 8 (7.0)
Diarrhea 4 (4.4) 7 (4.4) 2 (3.1) 3 (2.6)
Fatigue 4 (4.4) 7 (4.4) 1 (1.5) 3 (2.6)
Portal vein thrombosis 0 1 (0.6) 0 0
50 Terrault, Norah et al. Gastroenterology. Volume 155, Issue 3, 705 – 718.
Lusutrombopag Study Design
• Phase 3, multinational, randomized, double-blind, placebo-controlled study
– Conducted at 138 study sites in 22 countries
• Platelet transfusion was required by the protocol if a patient’s post treatment pre-procedural
platelet count was below 50 x 109/L
US/CT/MRI on portal vein US/CT/MRI on portal vein
ICF
108
pts LUSU (3 mg/day)
Invasive
Procedure Follow-up
107
pts PBO Day 9 to 14 Day 35
Screening (0 - 4 weeks) Treatment period* (up to 7 days) Post-treatment period (28 days)
Rando
miz
atio
n
*If a patient met the stopping criterion on Day 5, 6 and 7 (platelet count ≥ 50 x 109/L with an increase of ≥ 20 x 109/L from baseline),
no additional dose of study drug was administered.
CT, computed tomography; ICF, informed consent form; LUSU, lusutrombopag; MRI, magnetic resonance imaging; PBO, placebo; US, ultrasonography.
Peck-Radosavljevic, M et al. Hepatology. Feb 2019. https://doi.org/10.1002/hep.30561. 51
Endpoints
• Primary endpoint:
– Proportion of patients who required no platelet transfusion prior to the primary
invasive procedure and no rescue therapy for bleeding from randomization
through 7 days after the primary elective procedure
• Key secondary endpoints (prespecified in the SAP):
– Proportion of patients who required no platelet transfusion during
the study
– Proportion of responders: patients who achieved a platelet count ≥50 x 109/L with
an increase of ≥20 x 109/L from baseline at any time during the study
– Number of days during which the platelet count was ≥50 x 109/L
SAP, statistical analysis plan.
Peck-Radosavljevic, M et al. Hepatology. Feb 2019. https://doi.org/10.1002/hep.30561. 52
Lusutrombopag
29
64.8
0
10
20
30
40
50
60
70
No platelet transfusions or rescue therapy (%)
Placebo Lusu
13
64.8
0
10
20
30
40
50
60
70
Platelet > 50K and increased > 20K (%)
Placebo Lusu
Peck-Radosavljevic, M et al. Hepatology. Feb 2019. https://doi.org/10.1002/hep.30561.
Pa
tie
nt
%
53
0
20
40
60
80
100
120
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35
LUSU (n=74)
PBO (n=73)
Mean
Pla
tele
t C
ou
nt
(x 1
09/L
) ±S
D
Study Drug
Administration
Invasive
Procedure
Platelet Response (ITT Population)
LUSU: platelet count in patients who did not receive platelet transfusion.
PBO: platelet count in patients who received platelet transfusion.
Peck-Radosavljevic, M et al. Hepatology. Feb 2019. https://doi.org/10.1002/hep.30561.
Day
54
Lusutrombopag
Lusutrombopag Placebo
TEAE 47.7 % 48.6%
SAE 6.5% 6.5%
Bleeding related
TEAE 3 6
PVT 1 2
TEAE: Treatment Emergent Adverse Events
SAE: Serious Adverse Events
Peck-Radosavljevic, M et al. Hepatology. Feb 2019. https://doi.org/10.1002/hep.30561. 55
HISTORY
& PE
47 year old male with
decompensated alcohol-
related cirrhosis
History of Present Illness – July 2018 (cont.)
MEDICATIONS LABS OTHER
• Discussed TPO receptor agonists as an alternative to
platelet transfusion.
• Searched Package Insert for drug interactions and signature
adverse events.
• Undergoes repeat EGD with banding. Platelet count doubles
measured immediately prior to procedure.
– 34 to 67
• Patient tolerated TPO receptor agonist and endoscopy.
• Additional EGD with banding recommended.
56
PROGRESS
NOTES
HISTORY
& PE
47 year old male with
decompensated alcohol-
related cirrhosis
History of Present Illness – August 2018
MEDICATIONS LABS OTHER
• Undergoes 3rd repeat EGD with banding.
Platelet count doubles again.
– Platelet increases from 31 to 59
• Additional EGD recommended in 3 months.
57
PROGRESS
NOTES
Conclusions
• Patients with cirrhosis often need multiple invasive procedures
• Thrombocytopenia is common in patients with cirrhosis
• Severe thrombocytopenia places patients at risk of bleeding with
invasive procedures
• Use of platelet transfusion to mitigate the risk is cumbersome and
can be associated with adverse events
• The use of TPO agonists significantly increases platelet counts and
can avoid the need for platelet transfusion
58
Clinical Case Forum II: Current and Emerging
Management Approaches for the Patient with
Hepatorenal Syndrome
R. Todd Frederick, MD
Acute Kidney Injury (AKI) in Cirrhosis
• Traditional criteria (IAC criteria)1
– 50% increase in SCr
over baseline
– Cut-off value of SCr: 1.5 mg/dL
• New definition of AKI2
– in SCr ≥0.3 mg/dL within 48
hours or SCr ≥50% from
baseline that is known or
presumed to have occurred
within the prior 7 days
1. Angeli P, et al. J Hepatol. 2015;62:968-974; 2. J Hepatol. 2018;69:406-460.
Stage AKI1 Criteria
Stage 1 Increase in SCr ≥0.3 mg/dL or an increase
in SCr ≥1.5-fold to 2-fold from baseline
Stage 2 Increase in SCr >2- to 3-fold from baseline
Stage 3
Increase of SCr >3-fold from baseline or
SCr ≥4.0 mg/dL with an acute increase ≥0.3
mg/dL or initiation of renal replacement
therapy
60
HRS-1 AKI-HRS
HRS-2 CKD-HRS
AKI in Cirrhosis: Differential Diagnosis
• Prerenal
– Hypovolemia: diuretics, GI bleeding, diarrhea
– Hepatorenal syndrome
• Acute tubular necrosis: shock, nephrotoxic drugs, other
• Nephrotoxicity: NSAIDs, Iodinated contrast, other
• Intrinsic renal disease (glomerulonephritis, interstitial nephritis)
• Obstructive
• Miscellaneous, unknown
61 Graupera I, et al. Clin Liver Dis. 2013;2:128-131.
AKI and Cirrhosis
• AKI diagnosed with AKIN criteria associated with increased mortality
in patients with cirrhosis1
• Progression through stages strongly correlates with
increased mortality2
• However, serum creatinine cutoff of 1.5 mg/dL is still prognostic3
– Identifies patients at increased risk of mortality
• New AKI-HRS criteria enable earlier treatment (by 4 days) at lower
creatinine (1 mg/dL lower)4
– Baseline serum creatinine is a predictor of response to therapy
1. Piano S, et al. Hepatology. 2013;57:753-762; 2. Belcher JM, et al. Hepatology. 2013;57:753-762;
3. Fagundes C, et al. J Hepatol. 2013;59:474-481; 4. Wong F. et al. Journal Hepatology 2019;70(1)Supp. 62
Prospective Studies in Nonselected Hospitalized Patients
Fagundes C et al. J Hepatol. 59(3), 474-481; Piano S et al. J Hepatol. 59(3), 482-489.
Pro
ba
bil
ty o
f s
urv
iva
l (%
)
100
75
50
25
00 30 60 90
p <0.0001
88% No-AKI
84% AKI-1#
68% AKI-1*
42% AKI-2
31% AKI-3
Days
No AKIN Stage 1 Stage 2 Stage 3
AKIN
Mo
rta
lity
(%
)
100
80
60
40
20
0
p <0.0001
p <0.0001
n.s.
n.s.
p <0.001
p <0.01
sCR <1.5 mg/dlsCR ≥1.5 mg/dl
No AKI (n = 198 191 182 172
AKI-1 (n = 44) 41 39 37
AKI-1 (n = 66) 57 48 40
AKI-2 (n = 30) 18 11 11
AKI-3 (n = 37) 18 12 10
63
HISTORY
& PE
Patient Case
MEDICATIONS LABS PROGRESS
NOTES
60-Year Old Woman
with Decompensated Cirrhosis
• Alcoholic liver disease
• Listed for liver transplant
• History of ascites, HE, esophageal varices with
prior bleeding
• Labs 12 weeks ago in clinic: Na 136, Cr 1.1, bilirubin
1.8, INR 1.3, MELD 13
• Admitted to the hospital with worsening confusion
64
MEDICATIONS LABS PROGRESS
NOTES HISTORY
& PE
Patient Case (cont.)
• Worsening ascites over the past 3 months despite
sodium restriction and alcohol abstinence
• Diuretics recently increased to furosemide 80 mg daily,
spironolactone 200 mg daily
• Now requiring therapeutic paracentesis every 2 weeks
(last 5 days ago)
• Takes lactulose and rifaximin for HE
• Takes propranolol for prophylaxis of EVH
60-Year Old Woman
with Decompensated Cirrhosis
65
60-Year Old Woman
with Decompensated Cirrhosis
MEDICATIONS LABS PROGRESS
NOTES HISTORY
& PE
Patient Case (cont.)
• On admission she is awake but disoriented with + asterixis
• Initial BP 102/54, HR 78, T 100.2, RR 18, SpO2 95% on
ambient air
• Exam shows a distended abdomen with erythema, warmth,
and severe tenderness at previous paracentesis site
• Labs now: Cr 1.7, INR 2, Bili 4.5, Na 131, Ascites WBC 345
(46% PMNs, ANC 159), Blood Cx pending; MELD-Na 28
• Oliguric and UA shows: Na <10, no protein or RBC, Cx pend
66
60-Year Old Woman
with Decompensated Cirrhosis
MEDICATIONS LABS PROGRESS
NOTES HISTORY
& PE
Patient Case (cont.)
• On admission she is awake but disoriented with + asterixis
• Initial BP 102/54, HR 78, T 100.2, RR 18, SpO2 95% on
ambient air
• Exam shows a distended abdomen with erythema, warmth,
and severe tenderness at previous paracentesis site
• Labs now: Cr 1.7, INR 2, Bili 4.5, Na 131, Ascites WBC 345
(46% PMNs, ANC 159), Blood Cx pending; MELD-Na 28
• Oliguric and UA shows: Na <10, no protein or RBC, Cx pend
• AKI (AKIN Grade 1)
• HE (Grade 2)
• Abdominal wall cellulitis
• Acute decompensation of cirrhosis
67
MEDICATIONS LABS PROGRESS
NOTES HISTORY
& PE
Patient Case (cont.)
• Doppler US of abdomen shows moderate ascites, no liver
masses, no hydronephrosis, no flow in portal vein visible
• Repeat BP is 88/52, HR 108
• Started on IV vancomycin and piperacillin/tazobactam
• IV albumin infused (1 gm/kg)
• Furosemide, spironolactone, and propranolol are discontinued
• Lactulose and rifaximin are continued 60-Year Old Woman
with Decompensated Cirrhosis
68
Patient Case (cont.): Urine Output
69
-2000
-1500
-1000
-500
0
500
1000
1500
2000
Volume Intake/Output
output intake
1 2 3 4 5
Vo
lum
e m
L
Time, Days
IV Albumin
Hepatorenal Syndrome International Ascites Club – Diagnostic Criteria
• Diagnosis of cirrhosis and ascites (portal hypertension)
• Meet AKI criteria
• No response after 2 days with withdrawal of diuretics and volume
expansion with albumin (0.5-1 g/kg/day with max of 100 g/day)
• Absence of shock and recent use of nephrotoxic drugs
• No parenchymal kidney disease
– No proteinuria > 500 mg/day, no microhematuria (> 50 RBC) and/or
abnormal renal ultrasound (“medical renal disease”)
70 EASL website. Hepatorenal Syndrome.
Pathophysiology AKI-HRS
• Portal Hypertension
• Decreased effective arterial
volume (splanchnic)
• Endogenous vasoconstrictors
• Superimposed inflammatory
response (infection, other)
• Reduced cardiac reserve
(cirrhotic cardiomyopathy)
• Overwhelmed renal
compensatory mechanisms
• Abrupt decline in GFR
71 Ginès P, et al. Nat Rev Dis Primers. 2018;4:23.
Initial Management
• Early identification
• Assess and treat bacterial infection
– Blood, urine, ascitic fluid culture
• Avoid large-volume paracentesis
• Stop β-blockers
• Stop nephrotoxic medications: NSAIDs, diuretics
• Volume expansion
Tapper EB, et al. Am J Med. 2016;129:461-467. 72
Patient Case (cont.): Renal Function
0
0.5
1
1.5
2
2.5
3
3.5
1 2 3 4 5
Octreotide/Midodrine S
eru
m C
rea
tin
ine m
g/d
l
Time, Days
Albumin
AKI-HRS Confirmed
73
Albumin
Patient Case (cont.): Renal Function
0
0.5
1
1.5
2
2.5
3
3.5
1 2 3 4 5
Octreotide/Midodrine S
eru
m C
rea
tin
ine m
g/d
l
Time, Days
Albumin
74
Albumin
Patient Case (cont.)
• Progressive renal failure despite albumin, midodrine and
octreotide; creatinine rises to 4.3mg/dL
• Oliguria worsens and anasarca and hypoxemia develop
• Hypotension worsens
• Moved to the ICU and started on norepinephrine infusion
• Urgent activation for liver transplantation
• Discussions regarding renal replacement therapy
75
Patient Case (cont.): Renal Function
0
1
2
3
4
5
6
1 2 3 4 5 6 7 8 9
Octreotide/Midodrine
Norepinephrine
Se
rum
Cre
ati
nin
e m
g/d
l
Time, Days 76
Pharmacologic Therapy for HRS
IV Albumin
• 0.5-1gm/kg (max 100gm/d) for resuscitation; then
• 25 to 50 g/day
Plus
Vasoconstrictors
• Midodrine (+/- octreotide)
• Norepinephrine
• Terlipressin
77 Ginès P, et al. Nat Rev Dis Primers. 2018;4:23
**Midodrine Plus Octreotide: Dosing
Midodrine: initially 7.5 mg oral 3 times daily
• Titrate to maximum of 12.5 mg 3 times daily
Octreotide: 100 µg SC 3 times daily
• Maximum dose 200 µg SC 3 times daily
• Titrate to achieve increase of MAP by 15 mmHg
78 Runyon BA. Hepatology. 2013;57:1651-1653.
**Note this is off-label treatment for HRS but
recommended by AASLD Practice Guidelines
Comparative Efficacy of Midodrine and Norepinephrine:
Systematic Review and Network Meta-Analysis
Short-Term Mortality Reversal of HRS
OR (95% CI) Quality of Evidence OR (95% CI) Quality of Evidence
Efficacy vs Placebo
Midodrine + octreotide 0.61 (0.19, 1.93) Low (network) 0.44 (0.06, 3.23) Low (network)
Noradrenaline 0.75 (0.32, 1.76) Low (network) 4.17 (1.37, 12.50) Low (network)
Efficacy vs Midodrine + Octreotide
Noradrenaline 1.50 (0.60, 3.78) Low (network) 10.00 (1.49, 50.00) Low (network)
79 Facciorusso A, et al. Lancet Gastroenterol Hepatol. 2017;2:94-102.
Terlipressin and Albumin
• Vasopressin analogue
• Prodrug with longer
half-life
• Selective V1a > V1b or
V2 activity
• Splanchnic and portal
vasoconstriction
• Requires IV Albumin
for HRS treatment
Solà E, et al. Curr Opin Organ Transplant. 2013;18:265-270.
Diagnosis of HRS
Terlipressin bolus IV 1 mg every 4-6 hours or
continuous IV infusion (2 to 12 mg/day)
0 3 6 9 12 15 Days
Albumin IV
1 g/kg Albumin 20 to 40 g/day
Increase terlipressin dose if creatinine
does not decrease by 25% on day 3
80
Improvement in Renal Function: TERLI vs MID/OCT
Cavallin M, et al. Hepatology. 2015;62:567-574.
70.4
28.6
55.6
4.8
0
10
20
30
40
50
60
70
80
90
100
Terlipressin Midodrine + Octreotide
Resp
on
se t
o T
reatm
en
t, %
Complete/partial response Complete response
P=0.01
P <0.001
81
Su
rviv
al
Time (days)
P< 0.0011,0
0,8
0,6
0,4
0,2
0,0
0 30 60 90
Group TERLI
Su
rviv
al
Time (days)
P = N.S.1,0
0,8
0,6
0,4
0,2
0,0
0 30 60 90
Group MID/OCT
TERLI vs MID/OCT: 90-Day Survival
Fig. 4. Cumulative 3-month survival in patients who were randomized to terlipressin plus albumin (TERLI group) or to midodrine and
octreotide plus albumin (MID/OCT group) according to the response: solid line represents responders; dotted line represents nonresponders.
Abbreviation: N.S., nonsignificant.
Cavallin M, et al. Hepatology. 2015;62:567-574.
Probability of 90-Day, Transplant-Free Survival
According to Response to Treatment
82
Systematic Review with Meta-Analysis: Vasoactive Drugs for the Reversal of HRS Type 1
Gifford FJ, et al. Aliment Pharmaceutical Ther. 2017;45:593-603. 83
Safety: Terlipressin and Albumin
Adverse Cardiovascular Effects Terli+Alb
n (%)
Albumin
n (%)
Arrhythmias 2 (9) 0
Circulatory overload 7 (30) 4 (17)
Suspected intestinal ischemia 3 (13) 0
Arterial hypertension 1 (4) 0
Myocardial infarction 1 (4) 0
Martin-Liahi, et al. Gastroenterology. 2008;134:1352-1359.
EASL website. Hepatorenal Syndrome.
Not statistically significantly different
84
Survival: Terlipressin and Albumin – ACLF
• Cumulative mortality at 90-
days according to ACLF grade
in responders and
nonresponders to terlipressin
and albumin
– Baseline SCr and ACLF
grade independently
associated with response
– Patient age, WBC, ACLF
grade, and no response
to treatment associated
with mortality
85 Piano S, et al. Clin Gastroenterol Hepatol. 16(11), 1792-1800.
A
Cu
mu
lati
ve i
ncid
en
ce o
f d
ea
th
Days
0 30 60 90
1.0
0.8
0.6
0.4
0.2
0.0
P = .001
Responders
ACLF III
ACLF II
ACLF I
B
Cu
mu
lati
ve i
ncid
en
ce o
f d
ea
th
Days
0 30 60 90
1.0
0.8
0.6
0.4
0.2
0.0
P < .001
Nonresponders
ACLF III
ACLF II
ACLF I
Patients at risk
ACLF I
ACLF II
ACLF III
106
43
7
90
36
5
81
27
3
70
21
2
68
47
20
44
24
4
33
19
3
18
14
3
RCT (Open Label): Terlipressin vs Norepinephrine in Patients with ACLF and HRS-AKI
• Continuous IV infusion of terlipressin (2 to 12 mg/day) vs. norepinephrine (0.5 to 3 mg/hour)
• Terlipressin reduced need for RRT
• Terlipressin improved survival
Response Rate, n/N (%)
Norepinephrine Terlipressin P Value
Day 4 7/60 (11.7%) 16/60 (26.7%) 0.03
Day 7 12/60 (20%) 25/60 (41.7%) 0.01
Reversal of
HRS-AKI
(Day 14)
10/60 (16.7%) 24/60 (40%) 0.004
p=0.001 at Day 28
Time in Days
Intention to Treat Analysis
0
0.0
0.2
0.4
0.6
0.8
1.0
5 10 15 20 25 30
GroupsTerlipression
Noradrenaline
1-censored
2-censored
86 Arora V, et al. Hepatology. 2019; 0:1-11.
Renal Function Predicts Post-LT Outcomes
Survival in Days
00.4
0.5
0.6
0.7
0.8
0.9
1.0
1000 2000 3000 4000 5000
1
2
3
4
1=CCr>70
3=CCr20-39.9
2=CCr40-69.9
4=CCr<20
• UNOS Database
• GFR < 40 predicted
worse graft and
patient survival post
liver transplant
87 Nair, et al. Hepatology. 2002.
Treatment of HRS Pre-LT
p=0.15
0
0
0.2
0.4
0.6
0.8
1.0
1 2 3 Years
Patients at risk
HRS-treated
No-HRS 27
9 9 9 9
27 24 23
• Successful reversal of
HRS may improve post-
LT outcomes
88 Restuccia, et al. J Hepatology. 2004;40:140-146.
Hepatorenal Syndrome
• Devastating complication of cirrhosis and ACLF
• Early recognition essential to improve outcomes; new diagnostic
criteria offer promise
• Currently available treatment in the US has limited efficacy
• Terlipressin may be superior to other vasoconstrictors in reversing HRS
• In suitable patients, liver transplantation is the best treatment option
• Improving renal function reduces short-term mortality and need for RRT and
may improve post-liver transplant outcomes
89
Clinical Case Forum III:
Current Management Approaches for the
Patient with Hepatic Encephalopathy
Steven L. Flamm, MD, FAASLD
MEDICATIONS LABS PROGRESS
NOTES
OTHER
Patient Case
56-yr-old woman
admitted for OHE for the
first time
HPI
• History of NASH and noted
cirrhosis based on abdominal US
about 4 years ago
• Noted melena one day prior to and
hematemesis on the day of
admission
• Her husband noted that she
became confused on the way to
the Emergency Unit and became
unresponsive at the hospital
Social History
• Used to drink heavily as an
bartender when she
was young
• Quit drinking and smoking for
the last 12 years
• Lives with husband
91
HISTORY
& PE
56-yr-old woman
admitted for OHE for the
first time
MEDICATIONS LABS PROGRESS
NOTES
OTHER
Patient Case (cont.)
PE
• Confused, disoriented
• Anemic, but not icteric
• Positive flapping, tremor
• No ascites, not tender
• Trace edema
• Stool tarry and hemoccult (+)
BP 108/54 mm Hg
PR 116/min
RR 16/min
BMI 35 kg/m2
92
HISTORY
& PE
56-yr-old woman
admitted for OHE for the
first time
HISTORY
& PE LABS PROGRESS
NOTES
OTHER
Patient Case (cont.)
• Lisinopril
• Metformin
• Simvastatin
• Baby aspirin
93
MEDICATIONS
56-yr-old woman
admitted for OHE for the
first time
MEDICATIONS HISTORY
Patient Case (cont.)
PROGRESS
NOTES
OTHER
H/H 8.9/28
Platelets 79,000
INR 1.5
Ammonia
level 108
BUN 30
Creatinine 1.4
Na 132
K 3.2
Albumin 3.1
AST/ALT 45/32
Bilirubin 1.2
Alk phos 122
MELD 19
94
LABS
Patient Case
How do you classify this
patient’s HE?
What is the role of
ammonia testing?
95
Normal “Covert” HE I II III IV
“Overt” HE Stages
Categorization is often arbitrary and
varies between raters
Clinical
Diagnosis
Worsening cognitive dysfunction
coma
Characterization of HE Stages
Bajaj JS, et al. Hepatology. 2009;50:2014-2021. 96
Role of Ammonia Testing in HE
• “Increased blood ammonia alone does not add any
diagnostic, staging, or prognostic value for HE in patients
with CLD. A normal value calls for diagnostic
reevaluation (GRADE II-3, A, 1)”
97 Vilstrup H, et al. Hepatology. 2014;60:715-35.
US Hospital Discharges Due to Cirrhosis Are Increasing
403,665 411,029 436,901 444,883 459,496 498,181
526,096 576,573
0
100000
200000
300000
400000
500000
600000
700000
2004 2005 2006 2007 2008 2009 2010 2011
10% increase
*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 2014. 98
Resource Utilization for Patients Hospitalized with Hepatic Encephalopathy, 2005-2009
0
10000
20000
30000
40000
50000
60000
70000
2005 2006 2007 2008 2009
Health Care Resource Utilization in Patients Discharged
with HE Diagnosis
Avera
ge c
harg
e,
2009 U
SD
P<0.001
0
0.4
0.8
1.2
1.6
2
2.4
2005 2006 2007 2008 2009
Number of procedures
P<0.001
Average hospitalization charges
Nu
mb
er
of
pro
ced
ure
s
Stepanova M, et al. Clin Gastroenterol Hepatol. 2012;10(9):1034-1041. 99
Patient Case
How do you manage
this patient?
100
Specific Approach to Overt HE Treatment
• Four-pronged approach to management of HE
(GRADE II-2, A, 1):
– Initiation of care for patients with altered consciousness
– Alternative causes of AMS should be sought and treated
• e.g. diabetic ketoacidosis, drugs (benzodiazepines, neuroleptics, opioids),
neuroinfections, electrolyte disorders, intracranial bleeding and stroke1
– Identification of precipitating factors and their correction
– Commencement of empirical HE treatment
Vilstrup H, et al. Hepatology. 2014;60:715-35. 101
Current Therapy Options for HE
Agent Drug Class Indication
Lactulose1 Poorly absorbed disaccharide
• Decrease blood ammonia concentration
• Prevention and treatment of
portal-systemic encephalopathy
Rifaximin2 Non-aminoglycoside semi-
synthetic, nonsystemic antibiotic
Reduction in risk of OHE recurrence in
patients ≥18 years of age
Neomycin3 Aminoglycoside antibiotic Not to be used, renal and ototoxic risk
Metronidazole1 Synthetic antiprotozoal and
antibacterial agent Not approved for HE
Vancomycin1 Aminoglycoside antibiotic Not approved for HE
1. USNLM. DailyMed. Available at https://dailymed.nlm.nih.gov/dailymed. Accessed March 22, 2018; 2. Xifaxan (rifaximin) [prescribing information].
Valeant Pharmaceuticals North America LLC; Bridgewater, NJ; 2018; 3. Mullen KD, et al. Semin Liver Dis. 2007;27(Suppl 2):32-47. 102
Rifaximin Randomized, Controlled Trial:
Time to First Breakthrough HE Episode Primary Endpoint
0
100
80
60
40
20
028 56 84 112 140 168
Pro
po
rtio
n o
f P
ati
en
ts W
ith
ou
t
Bre
akth
rou
gh
HE
(%
) Rifaximin*
(77.9%)
Placebo*
(54.1%)
Hazard ratio with rifaximin, 0.42 (95% Cl, 0.28–0.64) P<0.001
Days Since Randomization
*Rifaximin 550 mg or placebo twice daily. 91% of patients in both arms received concomitant lactulose.
Bass NM, et al. N Engl J Med. 2010;362:1071-1081. 103
58% relative reduction in the risk of a breakthrough episode
0
0
20
40
60
80
100
28 56 84 112 140 168
Hazard ratio with rifaximin, 0.50 (95% Cl, 0.29-0.87)
P=.01
Placebo
(77.4%)
(86.4%)
Rifaximin
Days Since Randomization
0
Hazard ratio with rifaximin, 0.50 (95% Cl, 0.29-0.87)
P=.01
Placebo
(77.4%)
(86.4%)
Rifaximin
Rifaximin Randomized, Controlled Trial:
Time to First HE-Related Hospitalization (Secondary Endpoint)
Bass NM, et al. N Engl J Med. 2010;362(12):1071-81. 104
50% relative reduction in the risk of HE-related hospitalization
56-yr-old woman
admitted for OHE for the
first time
LABS MEDICATIONS HISTORY
Patient Case (cont.)
OTHER
Hospital Course
• She has an EGD with variceal banding and bleeding stopped
• Mental status improved with lactulose but dosage has to be
reduced due to significant diarrhea and rifaximin was added
3 days before discharge
– Her husband was instructed to follow up in one week
after discharge
105
PROGRESS
NOTES
Prevention of Overt HE (OHE)
• Lactulose is recommended for prevention of recurrent episodes of HE after
the initial episode (GRADE II-1, A, 1)
• Rifaximin as an add-on to lactulose is recommended for prevention of
recurrent episodes of HE after the second episode (GRADE I, A, 1)
• Routine prophylactic therapy (lactulose or rifaximin) is not recommended for
the prevention of post-TIPS HE (GRADE III, B, 1)
• Under circumstances where the precipitating factors have been well
controlled (i.e., infections and VB) or liver function or nutritional status
improved, prophylactic therapy may be discontinued (GRADE III, C, 2)
106 AASLD Practice Guideline. 2014.
Patient Case (cont.)
What is the social burden
of HE?
107
56 46
16 15 11 10 7 5
0
20
40
60
80
100
Stoppedsaving
In debt Noeducation
Late on bills No food Moved out Bankrupt Evicted
HE Impacts Family Daily Functioning
Impact of Cirrhosis-Related Expenses on Daily Activities
of Affected Families Within Past 3 Years
Pati
en
ts r
esp
on
din
g y
es,
%
Bajaj JS, et al. Am J Gastroenterol. 2011;106(9):1646-1653. 108
Caregiver Burden Increases with HE Severity
Mean (±SE) Caregiver Scores in the Objective Burden
Domain of the Caregiver Burden Inventory
10
8
6
4
2
0
-2
-4Unimpaired (n=7) Minimal HE (n=6) Overt HE (n=18)
CB
I O
bje
cti
ve
Bu
rde
n
*
1.8(1.3)
Montagnese S, et al. Metab Brain Dis. 2012;27(4):567-572. 109
56-yr-old woman
admitted for OHE for the
first time
LABS MEDICATIONS HISTORY
Patient Case (cont.)
OTHER
Hospital Course
• She was re-admitted 9 days later due to recurrent grade III
encephalopathy without melena
• She is taking lactulose only since unable to obtain rifaximin
after discharge due to high co-pay
– She has not seen her PCP yet
110
PROGRESS
NOTES
Hospital Readmissions Among Patients with Decompensated Cirrhosis Are Common
• Retrospective study of 402 patients from an
academic transplant center
– Follow-up time censored at death, elective
admissions such as transplant or post-
procedure observation, or the date of last clinic
note; median follow-up was 203 days
– Included cirrhotic patients hospitalized for
ascites, SBP, renal failure, hepatic
encephalopathy, or variceal hemorrhage
• Median time to readmission was 67 days
• Median number of readmissions was
2 (range 0-40); overall rate was 3
hospitalizations/person-year
111
14%
37%
69%
0
10
20
30
40
50
60
70
80
Within 1 wk Within 1 mo Overall
Pati
en
ts,
%
Hospital Readmissions
Volk ML, et al. Am J Gastroenterol. 2012;107(2):247-252.
All-Cause and HE-Related Re-Hospitalization for Patients with Hepatic Encephalopathy
N=8,125 alive
at discharge
27.4
49.7
56.4
17.6
33.7 39.5
0
10
20
30
40
50
60
30 days 180 days 1 year
Pati
en
ts (
%)
All-cause HE-related
Neff GW, et al. Poster presented at AASLD Annual Liver Meeting 2013. November 2, 2013. Abstract No. 374. 112
Unadjusted and Adjusted Odds Ratios for 30-Day Readmissions
by Condition for Complications of Liver Disease
Unadjusted OR
(95% Cl)
Model 1 OR
(95% Cl)
Model 2 OR
(95% Cl)
Ascites 1.28 (1.20-1.37) 1.47 (1.37-1.58) 1.78 (1.66-1.90)
Variceal hemorrhage 1.85 (1.71-2.00) 1.69 (1.56-1.83) 1.55 (1.43-1.69)
Hepatic
encephalopathy 2.62 (2.41-2.83) 2.67 (2.46-2.89) 3.23 (2.97-3.52)
Hepatorenal syndrome 2.33 (1.90-2.85) 2.46 (2.00-3.02) 1.41 (1.13-1.77)
Hepatocellular
carcinoma 1.79 (1.61-2.00) 1.64 (1.45-1.84) 1.70 (1.51-1.91)
30-Day Hepatology Readmission
Tapper EB, et al. Clin Gastro Hepatol. 2016;14:1181-1188. 113
Unadjusted and Adjusted Odds Ratios for 90-Day Readmissions
by Condition for Complications of Liver Disease
Unadjusted OR
(95% Cl)
Model 1 OR
(95% Cl)
Model 2 OR
(95% Cl)
Ascites 1.11 (1.05-1.18) 1.31 (1.23-1.39) 1.60 (1.52-1.69)
Variceal hemorrhage 2.03 (1.90-2.16) 1.83 (1.71-1.95) 1.70 (1.60-1.82)
Hepatic
encephalopathy 2.44 (2.28-2.60) 2.53 (2.37-2.70) 3.07 (2.86-3.30)
Hepatorenal syndrome 2.06 (1.75-2.43) 2.31 (1.96-2.73) 1.43 (1.20-1.71)
Hepatocellular
carcinoma 1.98 (1.82-2.15) 1.79 (1.63-1.96) 1.83 (1.67-2.01)
Tapper EB, et al. Clin Gastro Hepatol. 2016;14:1181-1188.
90-Day Hepatology Readmission
114
Reasons for Readmission
Polypharmacy
Psychological
Comorbidities
Frailty
Malnutrition
Home situation
Communication issues
Transplant candidacy
Inpatient care
Goals of care
Discharge instructions
Outpatient care
Multidisciplinary management
Patient Factors
System Factors
Medical Factors
Tapper EB, et al. Clin Gastroenterol Hepatol. 2016;14:1181-1188. 115
The Majority of Overt HE Patients Do Not Receive Proper Management Therapy After Discharge
• Analysis of medical and
hospital claims
– Outpatients who had ≥1 OHE
episodes from 2009 to 2011
during a 3-year period
• >60% of patients did not
receive ongoing prophylactic
therapy to reduce risk of HE
recurrence after discharge
Neff GW, Frederick RT. Hepatology. 2012;56(suppl 1):945A. 116
Reducing 30 Day Readmission by Intervention Phase
• Electronic phase
– Checklist items incorporated
into electronic provider
order system
• Check list phase
– QI checklist prompted
medication review and dosing
Reasons for 30-day Readmission
By Intervention Phase
Electronic n=146
Checklist n=139
Control n=194
Percentage
Study phase
0 100
HE
Infection
GI bleeding
Symptomatic
ascites
Other
Tapper EB, et al. Clin Gastro Hepatol. 2016;14:753-759. 117
56-yr-old woman
admitted for OHE for the
first time
LABS MEDICATIONS HISTORY
Patient Case (cont.)
OTHER
Discharge
• Follow up visit scheduled with gastroenterologist in 6 days
• 14 days of rifaximin obtained
118
PROGRESS
NOTES
Conclusions
• Hepatic encephalopathy is an economic and social burden
– Increased burden is realized not only by patients but also experienced
by caregivers
• Hepatic encephalopathy is an important cause of hospital
readmission
– To avoid the “revolving door”, treat after discharge
• Lactulose and rifaximin are important for secondary prophylaxis
119
Panel Discussion / Q&A
120