Battle of the Bands: Can You Deny the PPI? · 1. Compensatory mechanism to overcome portal...
Transcript of Battle of the Bands: Can You Deny the PPI? · 1. Compensatory mechanism to overcome portal...
Battle of the Bands: Can You Deny the PPI?
Andrea Whitaker, PharmD.
PGY1 Pharmacy Practice Resident
University Health System, San Antonio, TX
Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy
Pharmacotherapy Education and Research Center
University of Texas Health Science Center at San Antonio
January 6, 2017
Learning Objectives
1. Describe cirrhosis pathophysiology and esophageal varices development
2. Explain treatment options available for esophageal varices
3. Review current treatment evidence for proton pump inhibitors (PPI) in esophageal varicesafter endoscopic variceal band ligation (banding)
4. Identify treatment recommendation for PPIs in patients with esophageal varices post-banding based on available literature
A. Whitaker | 2 of 20
Battle of the Bands: Can You Deny the PPI
Andrea Whitaker, PharmD. PGY1 Pharmacy Practice Resident
University Health System, San Antonio, TX Division of Pharmacotherapy, University of Texas at Austin College of Pharmacy
Pharmacotherapy Education and Research Center University of Texas Health Science Center at San Antonio
January 6, 2017
Learning Objectives: At the completion of this activity, the participant will be able to:
1. Describe cirrhosis pathophysiology and esophageal varices development 2. Explain treatment options available for esophageal varices 3. Review current treatment evidence for proton pump inhibitors (PPI) in esophageal varices
after endoscopic variceal band ligation (banding) 4. Identify treatment recommendation for PPIs in patients with esophageal varices based on
available literature Assessment Questions:
1. T F Varices are a complication of cirrhosis that develop as a mechanism to overcome the portal hypertension
2. What are the safety concerns associated with using PPI in cirrhotic patients? A. Risk for pneumonia in 30 days B. Risk for SBP within 90 days C. Risk for Clostridium difficile infection in 90 days D. All of the above
3. T F If a PPI is going to be used post-banding the maximum duration should be 10 days. ***To obtain CE credit for attending this program please sign in. Attendees will be emailed a link to an electronic CE Evaluation Form. CE credit will be awarded upon completion of the electronic form. If you do not receive an email within 72 hours, please contact the CE Administrator at [email protected] *** Faculty (Speaker) Disclosure: Andrea Whitaker has indicated she has no relevant financial relationships to disclose relative to the content of her presentation.
A. Whitaker | 3 of 20
GASTROINTESTINAL BLEEDS
I. Upper and Lower Gastrointestinal (GI) Bleeds
A. Lower1
1. Bleeding originating from distal portion of duodenum (ligament of Treitz) to rectum
2. Classifications
a. Vascular
b. Inflammatory
c. Tumors
d. Traumatic
e. Iatrogenic
B. Upper1
1. Bleeding from esophagus to ligament of Treitz
2. Classifications
a. Non-variceal
(1) Ulcerative
(2) Vascular
(3) Traumatic
(4) Iatrogenic
(5) Tumors
b. Variceal/portal hypertension
CIRRHOSIS
I. Definition
A. Irreversible liver fibrosis due to chronic inflammation and damage2
B. End-stage chronic liver disease diagnosis3,4
II. Etiology 3-5
A. Developed countries
1. Hepatitis C
2. Alcohol abuse
3. Non-alcoholic liver disease
B. Underdeveloped countries
1. Hepatitis B
C. Prevalence is underreported due to early stages being asymptomatic
III. Epidemiology
A. United States prevalence: 0.27% equating to ~ 600,000 adults4,5
B. 8th leading cause of death in United States2
A. Whitaker | 4 of 20
IV. Classifications
A. Compensated cirrhosis4
1. Asymptomatic
a. ± gastroesophageal varices
b. No cirrhosis complications
2. Child-Pugh score A – See Appendix A
3. Life expectancy: 10-13 years2
B. Decompensated cirrhosis4
1. Symptomatic cirrhosis
a. Cirrhotic complications develop
2. Child-Pugh score B or C - See Appendix A
3. Life expectancy: 2 years2
V. Cirrhosis Complications2-4
A. Portal hypertension
1. First cirrhosis consequence
2. Underlying cause for all other complications
B. Hepatic encephalopathy
C. Ascites
D. Spontaneous bacterial peritonitis (SBP)
E. Hepatorenal syndrome
F. Varices and variceal bleed/hemorrhage
VARICES AND VARICEAL BLEEDS
I. Epidemiology
A. Approximately 50% of cirrhotic patients have varices and development correlates with disease severity4
1. Child-Pugh A ~ 40% have varices
2. Child-Pugh C ~ 85% have varices
B. Risk of developing varices is 7-8% each year3,4
C. Risk of bleeding from varices is 12% each year3.4
II. Pathophysiology4
A. Portal hypertension
Figure 1: Portal Hypertension Development
Chronic inflammation
↑ Resistance of portal blood
flow
Blood pools in portal vein
Increasee pressure in portal vein
Chronic portal hypertension
A. Whitaker | 5 of 20
1. Compensatory mechanism to overcome portal hypertension
a. Increase in nitric oxide vasodilation of intrahepatic blood flow
b. Increase in splanchnic vasculature vasoconstriction decrease blood flow to portal vein
Figure 2: Portal Venous System Figure 3: Esophageal Varices
B. Variceal formatio6,7
1. Compensatory mechanism insufficient to overcome increased portal pressure
2. New or reopening embryotic vasculature allowing blood to by bass liver
a. Structurally, variceal vasculature is fragile and has low elasticity
C. Variceal rupture4,6,7
Figure 4: Variceal Rupture Development
1. Predictors for variceal bleed
a. Hepatic venous pressure gradient (HVPG): > 12 mmHg4,6,7
(1) Difference in pressure between portal vein and intra-abdominal vena cava pressure8
(2) Appendix B describes HVPG interpretations
Increased portal
pressure
Increased variceal
wall tension
Variceal enlargement
Decreased stability of
vessels
Vessel rupture
A. Whitaker | 6 of 20
b. Endoscopic findings: red signs and variceal size of medium or large4,6,7
(1) Red wale sign: longitudinal veins on varices surface that looks like a whip mark and often red in color
(2) Refer to Appendix C for details about variceal size
c. Decompensated cirrhosis: Child-Pugh score B or C 4,6,7
III. Diagnosis
A. Portal hypertension
1. HVPG > 5 mmHg – Appendix B4
B. Varices
1. Gold Standard– esophagogastroduodenoscopy (EGD)4
a. Classified by size – Appendix C
b. EGD done at cirrhosis diagnosis to screen for varices
IV. Treatment Overview4
A. Primary prophylaxis4
Table 1: Primary prophylaxis treatment for variceal bleeds
Variceal Classification Treatment EGD Screening
No Varices none CC: every 2-3 years
Small varices without risk factors
± non-selective β–blocker
CC: every 1-2 years, if no β-blocker DC: yearly
Small varices with risk factors
non-selective β–blocker
None
Medium/large varices without risk factors
non-selective β-blocker
None
Medium/large varices with risk factors1
non-selective β-blocker or banding
None
1Risk Factors: Child-Pugh B/C, red wale marks or spots on EGD; CC: compensated cirrhosis; DC: decompensated cirrhosis; banding: endoscopic variceal band ligation
B. Acute variceal bleeding (AVB)
1. Hemodynamic stability3,4,9
a. Blood volume resuscitation
(1) Goal hemoglobin: ~ 7-8 g/dL
(2) Higher goals increase re-bleeding and mortality
b. Use normal saline cautiously
(1) Increase risk for ascites and fluid accumulation
c. Fresh frozen plasma and platelets
(1) For coagulopathies or thrombocytopenia present
2. SBP prophylaxis
a. Increased SBP risk during variceal bleeding4,10
(1) Invasive procedures increase bacteremia risk
A. Whitaker | 7 of 20
(2) Infection causes inflammatory cascade and release of vasoactive peptides increasing variceal pressure
(a) Increased risk for rupture and re-bleeding
(3) Decompensated cirrhosis > compensated cirrhosis
b. Decreased rates of SBP and mortality 4,11
c. Treatment: ceftriaxone 1 g IV daily for 5-7 days 4
(1) Alternative: ciprofloxacin 400 mg IV twice daily
3. Management of bleeding
a. Pharmacologic therapy + EGD therapy4
(1) EGD therapy plus pharmacologic therapy shown to be most efficacious4,12
Table 2: Meta-analysis on efficacy of combination therapy12 EGD therapy +
pharmacologic therapy*
EGD therapy alone
Relative Risk (95% confidence interval)
Initial hemostasis** 88% 76% 1.10 (1.04-1.17)
Control of bleeding at day 5
77% 58% 1.28 (1.18-1.39)
5 day mortality 7% 9% 0.73 (0.45-1.18)
*Pharmacologic therapy varied between trials - octreotide, somatostatin, vapreotide, or terlipressin for 2-5 days **Hemostasis defined as the clinical absence of continued bleeding within 6 to 48 hours of treatment;
b. Pharmacologic therapy
(1) Somatostatin analogues4,13
Table 3: Drug information on octreotide
Drug Mechanism of action Dose Side Effects Clinical Pearls
Octreotide Selective splanchnic vasoconstriction via direct vasoconstriction and inhibition of glucagon, serotonin, gastrin, VIP, and insulin
50 µg IV bolus, then 50 µg/ hours studied up to 5 days
Sinus bradycardia
Hyper/o-glycemia
Abdominal pain
Fatigue
Headache
Tachyphlaxis
(2) Alternative Treatments4,13
(a) Vasopressin ± nitroglycerin
1. Potent splanchnic vasoconstrictor
2. Use limited by adverse effects of peripheral ischemia, arrhythmias, hypertension, and bowel ischemia
3. Maximum duration for 24 hours due to side effect development
A. Whitaker | 8 of 20
C. Secondary prophylaxis for variceal bleed4
1. Combination therapy of non-selective β -blocker and banding
2. Repeat banding every 7-14 days until varices have eradicated
3. Repeat EGD every 3-6 months to evaluate for variceal recurrence
ENDOSCOPIC THERAPY
Table 4: Comparison of EGD therapies for variceal treatment
EGD therapy Sclerotherapy14 Banding14-16
Technique Injection of sclerosant causing thrombosis in vessel and inflammation in surrounding tissue
EGD places rubber bands around bleeding varices
Duration ~5 sessions every 14 days until eradicated
~4 sessions every 14 days until eradicated
Benefits Cheap Easy to perform
Fewer complications
Complications Esophageal ulcers Bleeding ulcers Fever Retrosternal chest pain Dysphagia Esophageal strictures Bacteremia and infections ↑ portal pressure
Shallow ulcers Bleeding ulcer Transient dysphagia, chest discomfort Esophageal laceration and perforation Retrosternal chest pain Esophageal strictures
Pearls Complications are unpredictable Experience by endoscopist can affect the outcome
I. Banding is preferred treatment14
A. Ulcers developed are more shallow compared to sclerotherapy
1. Average post-banding ulcer size (± standard deviation): 10.4 ± 5.1 mm17
B. Greater initial control of bleeding and reduced re-bleeding20
1. Risk factors for re-bleeding16,18,19
a. Emergent banding
b. Child-Pugh score ≥ 9
c. MELD ≥18
d. Alcoholic cirrhosis
C. Re-bleeding risk after banding 1-3% compared to 20% with sclerotherapy16,18,19
II. PPI have been used to reduce gastric ulcers and re-bleeding
A. Increased 6% mortality for every 1 mm increase in gastric or duodenal ulcer >10 mm21
B. Inconsistent results on whether they provide benefit and/or prevent re-bleeding post banding16,18,19
A. Whitaker | 9 of 20
CLINICAL CONTROVERSY
I. Are PPIs harmful in cirrhotic patients after endoscopic therapy for varices?
II. How effective are PPIs in preventing re-bleeding after banding?
III. How long should PPIs be used after banding?
IV. What dose of PPI should be used?
PROTON PUMP INHIBITORS
I. Mechanism of action
A. Inhibits the parietal cell H+/K+ ATP pump decreasing HCl secretion13,22-23
B. Increases the gastric pH to ≥ 424-25
1. Improves clot formation, platelet aggregation and decreases fibrinoloysis25-26
II. Adverse effects13,22
A. Minimal short term adverse effects
1. Headache, nausea, vomiting, abdominal pain
III. Warnings and precautions
Table 5: Warning and precautions for PPI in general population Warning and Precautions Hypothesized mechanism Duration of PPI use Pneumonia27 Decreased acidic environment alters
leukocyte function
Development of colonization in the upper
gastrointestinal tract
Within first 30 days
Clostridium difficile infection (CDI)28
Decreased acidic environment promotes
germination of spores
Altered leukocyte and other immunological
functions with pH changes
Altered toxin production by organism
90 days to 2 years
Hypomagnesemia13,22
Unspecified ≥3 months
Vitamin B12 deficiency13,22 Decreased acidity, decreases absorption 1-2 years
Osteoporosis related bone fractures29
Decrease calcium absorption leading to
decreased bone density
Inhibits osteoclast activity
1-4 year
A. Whitaker | 10 of 20
IV. Current Place in Therapy
A. Non-variceal ulcers/bleeding
1. Active gastric or duodenal ulcer bleed25
a. PPI used after EGD therapy stops bleeding
(1) Shown to reduce re-bleeding and surgery
b. Dose: pantoprazole or omeprazole 80 mg IV bolus followed by continue infusion of 8 mg/hour for 72 hours, then 40 mg by mouth daily thereafter
2. Gastric or duodenal ulcer healing
a. Pantoprazole or omeprazole 40 mg once daily for 2-8 weeks or indefinitely depending on precipitating cause30
3. Other conditions13,22
a. GERD
b. Erosive esophagitis
c. Hypersecretory conditions EVALUATION OF PPI USE IN CIRRHOSIS
I. Prescribing Habits
A. PPI use without indication in cirrhotic patients: 33.7-63%31-34
1. Risk factors associated with inappropriate use32
a. Esophageal varices
(1) Continued use for 2-6 months observed 32-33
b. Prescribed PPI during hospital stay
II. Safety
A. Increased risk for SBP associated with PPI use31,35
1. PPIs decrease acidic environment lowering defense mechanism against bacteria and increased bacterial overgrowth
a. Increases risk for SBP by 4.3 times3
b. Increased risk observed within 90 days 31,34,36
2. SBP increases risk for mortality37
a. In-hospital mortality with first event: 10-50%
b. 1-year mortality after first event: 31-93%
B. Development of CDI increases in-hospital mortality and length of stay in cirrhotic patients compared to non-cirrhotic patients38
III. Efficacy
A. Esophageal Varices16,18,19
1. Inconsistent results on use of PPI providing protection from re-bleeding after banding
A. Whitaker | 11 of 20
Table 6: Guideline Recommendations
Source Year Recommendations AASLD Guidelines4 2007 Studies favor use post-banding
Lo and colleagues – Systematic review39 2015 Post-banding: 10 days of therapy is reasonable Acute variceal bleed: should be stopped as soon as variceal bleed is the cause
UK Guidelines on variceal hemorrhage9 2016 No, unless peptic ulcer disease
Table 7: Univariate analysis of PPI for reducing risk of re-bleeding post-banding
Study Design n p-value
Sinclair et al Retrospective cohort 728 NS
Vanbievliet et al Case-control 101 NS
Kang et al Retrospective cohort 491 0.001
LITERATURE REVIEW
Alaniz C, Mohammad RA, Welage LS. Pharmacotherapy. 2009;29(3):248-54. Objective Evaluate the use of PPI in acute variceal hemorrhage Design/Method Single center, retrospective cohort study Patient Population Variceal hemorrhage diagnosed by EGD Intervention Treatment group (PPI group)
Octreotide + pantoprazole >24 hours Control group: Octreotide alone
Octreotide + pantoprazole <24 hours
Octreotide + intermittent acid suppression Endpoints Primary Endpoint
Units of packed red blood (PRBC) cells transfused during
hospitalization
Secondary Endpoints Number of FFP, platelets, and cryoprecipitate transfused
Endoscopic intervention
Re-bleeding
Mortality rate
Baseline Characteristics
Average age was 52 and majority of participants were male
Control (n=77) PPI (n=53) p-value
Child Pugh Score, n ±SD 9.4 ± 2.1 9.9±2.4 NS
Prior variceal bleed, n (%) 44 (57) 23 (43) NS
β-blocker at entry, n (%) 35 (45) 16 (30) NS
Hemoglobin level (g/dL) 9.1 ± 2.5 9.1 ± 2.2 NS
Duration of infusion (hours)
Octreotide 48.4 ± 31.9 70.9 ± 31.9 0.0001
Pantoprazole 3.5 ± 6.8 63.3 ± 48.9 <0.001
A. Whitaker | 12 of 20
Results Control (n=77) PPI (n=53) p-value
PRB transfused throughout hospitalization, mean ± SD
5.8 ± 6.6 6.4 ± 6.5 NS
FFP transfused throughout hospitalization, mean ± SD
2.9 ± 6.2 6.1 ± 10.6 0.05
Recurrent variceal bleed1, n (%)
4 (5) 7 (13) NS
Mortality, n (%) 13 (17) 7 (13) NS
Endoscopic intervention, n (%)
Banding 31 (40) 22 (42) NS
Sclerotherapy 23 (30) 19 (36) NS
TIPS 24 (31) 18 (34) NS
Authors Conclusion No benefit in prolonged continuous infusion (>24 hours) of pantoprazole compared to short term (<24 hours)
Strengths Only study to evaluate immediate use of a PPI in variceal bleeds
Methods allow for high external validity
Limitation/Critique Retrospective study
o Did not specific the duration of follow up for endpoints which are
important for re-bleeding and mortality
o Time to EGD therapy not reported; within 12 hours is standard of
care
Questionable severity of patients
o Initial Hgb > 8 g/dL which is above goal transfusion
o Control might have lower severity of patients compared to PPI
group based on octreotide
o ICU LOS was not reported even though it was a stated endpoint
Now powered for detecting re-bleeding
Primary endpoint inappropriate for determining PPI benefit as its place
in therapy reduced re-bleeding
Take away
In the first 24 hours there is no harm and no benefit in using PPI for acute variceal bleed
1Determined by use of blood transfusion after initial stabilization, repeated endoscopy, or repeated transjugular intrahepatic portosystemic shunting; NS: Not statistically significant; SE: standard error; FFP: fresh frozen plasma; ICU: intensive care unit; LOS: length of stay
A. Whitaker | 13 of 20
Shaheen NJ, Stuart E, Schmitz SM, et al. Pantoprazole reduces the size of post-banding ulcers after variceal band ligation: a randomized, controlled trial. Hepatology. 2005; 41:588–594. Objective Evaluate the use of proton pump inhibitors with elective variceal band ligation Design/Method Randomized, double-blind, placebo-controlled Patient Population Inclusion:
Portal hypertension with
varices
History of variceal
hemorrhage
Having elective banding
Exclusion: Pre-existing esophageal ulcers
Currently on any anti-acid agent
Prior surgical anti-reflux procedure,
including Nissen, Belsey, or Toupet
Barrett’s esophagus
Liver transplantation Pregnancy Allergy or adverse reaction to PPI
Intervention PPI group: pantoprazole 40 mg IV x 1 day after banding, then 40 mg orally for 9 days
Control group: NS IV bolus following banding, then placebo tablet for 9 days
All patients were on a β-blocker if tolerated Endpoints Primary endpoint:
Size of esophageal ulcers at 10-14 day follow-up endoscopy after original
banding
Secondary Endpoints: Occurrence of bleeding complications post-banding
Number of esophageal ulcers (adjusted for number of bands placed)
Dysphagia and chest pain ratings at follow-up endoscopy after banding
Assess safety for second banding procedure, if indicated
Global SF-36 score
Baseline Characteristics
The average age of participants was 50 years.
Control (n=20) PPI (n=22) p-value
Sex, male, n (%) 14 (64) 10 (45) NS
Child Pugh Score A/B/C, n 9/10/3 10/8/4 NS
β-blocker at entry, n (%) 12 (55) 15 (68) NS
Variceal Grade 1/2/3/4 0/14/8/0 0/16/6/0 NS
Results A total of 44 patients were enrolled and 42 completed the study
Control(n=20) PPI (n=22) p-value
Bands placed, mean (range) 2.8 (1-5) 3.2 (1-6) -
# ulcers at day 10, mean (SE) 2.25 (±0.31) 2.18 (±0.20) NS
Ulcer size (mm2) at day 10, mean (SE)
82 (±22) 37 (±9) 0.01
Child-Pugh A/B, mean 74 30 -
Child-Pugh C, mean 143 65 -
SF-36 between control and PPI: NS
A. Whitaker | 14 of 20
Safety: Bleeding events: control 2/20; PPI 0/22; NS
o Post-banding ulcer bleeding
Dysphagia: control 1/20 (5%); PPI 3/22 (14%)
Chest pain: control 0/20 (0%); PPI 1 /22 (5%)
Authors Conclusion Use of PPI reduces the size of the post-banding ulcer by 50% at follow-up endoscopy and should be implemented due to benign profile of intervention
Strengths Evaluated use of PPI after elective banding for varices Randomized, placebo controlled trial
Limitation/Critique Primary endpoint was a surrogate marker Not powered to detect difference in bleeding events Lower incidence of β-blocker therapy in control group, increasing risk for
variceal bleed Take away Showed reduced ulcer size with 10 days of PPI use
No evaluation on clinical outcomes of increased bleeding risk with PPI use Unequal use of β-blocker therapy could impact bleeding events observed
NS: Not statistically significant; SE: standard error Lo G, Perng D, Chang C, et al. Controlled trial of ligation plus vasoconstrictor versus proton pump inhibitors in the control of acute esophageal variceal bleeding. J Gastroenterol Hepatol. 2013;28(4):684-9. Objective Compare use of vasoconstrictors and PPI use in cirrhotic patients after arrest
of acute variceal bleeding by banding Design/Method Randomized, single-blinded, non-inferiority controlled trial Patient Population Inclusion:
Acute variceal
bleeding
Cirrhosis
Age 18-75
Emergency banding
stopped bleeding
Exclusion: Severe systemic illness - sepsis, COPD, uremia Gastric variceal bleeding Failure to control bleed with banding Died within 12 hours of enrollment Banding or scleroptherapy within 1 month of
enrollment Child-Pugh’s score > 13 Hepatocellular carcinoma
Intervention PPI group: pantoprazole or omeprazole 40 mg IV x 5 days, then pantoprazole 40 mg PO x 14 days
Vasoconstrictor group: somatostatin CI250 µg/hr or terlipressin 1 mg q 6 hours x 5 days
Standard therapy: FFP, fluids and electrolytes replacement, cefazolin 1 g every 6 hours for 5 days, and lactulose as clinically indicated
Endpoints Primary endpoints: Failure to control of acute bleeding1
Secondary endpoint: Very early re-bleeding2, treatment failure3, esophageal ulcer bleeding, adverse events, blood requirements, and 42-day mortality and re-bleeding
A. Whitaker | 15 of 20
Definitions Failure to control acute bleeding: at least one of the criteria happened in the first 48 hours: 1)hematemesis after enrollment 2) SBP drop of ≥ 20 mmHg ± HR ≥ 20 bpm with 2 g hemoglobin drop 3) transfusion of 4 units of blood to keep hematocrit > 27% or hemoglobin > 9 g/dL 4) death
Very early re-bleeding: developed one of the above criteria within 48-120 hours
Treatment failure: failure to control acute bleed, very early re-bleeding, or death within 5 days
Baseline Characteristics
Average age was 53 and majority of participants were male
Vasoconstrictor (n=60) PPI (n=58) p-value
MELD score 12.4 ± 3.7 13.3 ± 4.2 NS
Child Pugh Score A/B/C, n
18/32/10 15/24/19 NS
Active variceal bleeding 12 13 NS
EV size F1/F2/F3* 5/31/24 5/33/20 NS *See Appendix D for definition
Results A total of 186 screened → 118 randomized
Vasoconstrictor(n=60) PPI(n=58) p-value
Bands placed, mean (range) 3.5 (2-5) 3.2 (3-5) NS
Failure to control acute bleeding
1 0 NS
Very early re-bleeding 1 1 NS
Treatment failure 2 1 NS
Total re-bleeding at 6-42 days
5 5 NS
Esophageal ulcer 1 0 NS
Esophageal varice 3 4 NS
Gastric varices 1 1 NS
42-day mortality 4 3 NS
Source of very early re-bleeding - esophageal ulcer
Observations at follow up endoscopy at 2 weeks Vasoconstrictor (n=21) PPI(n=22) p-value
# esophageal ulcers, n (%)
18 (86) 14 (64) NS
Esophageal ulcer > 1.5 cm, n (%)
6 (29) 1 (5) <0.04
Vasoconstrictor (n=60) PPI (n=58) p-value
Adverse Effect 33 3 <0.001
Chest pain 9 0 <0.01
Abdominal pain 13 0 <0.01
Esophageal ulcer bleeding
2 1 NS
A. Whitaker | 16 of 20
Authors Conclusion Once bleeding is stopped by banding, PPI’s were just as effective as vasoconstrictors at maintaining homeostasis and preventing very early re-bleeding. PPI’s price, adverse effect profile and ability to heal ulcers have advantages over the vasoconstrictors.
Strengths Provided a study with direct comparison of vasoconstrictor (current standard of therapy) to PPI therapy
Randomized controlled trial Excluded gastric varices which is a confounding variable for use of PPI
Limitation/Critique Inappropriate use of statistical analysis
o Non-inferiority with no delta or hazard ratio or 95% confidence
interval were given for interpretation
Somatostatin and terlipressin were used in the vasoconstrictor group.
o Not standard of care in US o Terlipressin has more side effects o Somatostatin is less potent than octreotide which could lead to less
effectiveness Non-guideline directed SBP prophylaxis increasing risk for SBP and re-
bleeding Take away
No difference in re-bleeding after banding Smaller size in the ulcer around the banded varices Increased adverse effects due to vasoconstrictors of choice, non-standard
of care in the US NS: Not statistically significant; CI: Continuous infusion
SUMMARY
I. PPI Efficacy post-banding 40-42
A. Decreased ulcer size after banding
B. Reduction in bleeding events has not been correlated with PPI use after banding
C. Other causes have consistently shown to be risk factors for risk of re-bleeding
1. Emergent banding
2. Child-Pugh score ≥ 9
3. MELD ≥18
4. Alcoholic cirrhosis
II. Safety in cirrhotic patients
A. Duration
1. Appears to be safe when used within first 24 hours of an acute bleed with EGD therapy
2. Greater than 90 days:
a. Increase risk for severe SBP, CDI, pneumonia, and other complications
3. Intermediate (24 hours to 90 days): no clear evidence for harm
B. Prescribing habits
1. PPI continued for at least 2-6 months post hospitalization and after diagnosis of varices
A. Whitaker | 17 of 20
III. Dosing
A. Studies have used pantoprazole 40 mg IV once daily for 1-5 days, followed by pantoprazole 40 mg by mouth for 9-14 days
RECOMMENDATIONS
Figure 4: Recommendation for use of PPI post-banding
I. Consider using PPI after variceal bleeds when there is data supported co-morbid indications
A. Data supported indications:
1. GERD
2. Erosive esophagitis
3. Gastric ulcers
4. Duodenal ulcers
5. Hypersecretory conditions
II. Areas for further studies
A. Portal hypertension gastropathy
B. Gastric varices
A. Whitaker | 18 of 20
References
1. Bong Sik MK, Li BT, Engel A, et al. Diagnosis of gastrointestinal bleeding: A practical guide for
clinicians. World J Gastrointest Pathophysiol. 2014 Nov 15; 5(4): 467–478.
2. Ge PS and Bunyon B. Treatment of patients with Cirrhosis. N Engl J Med. 2016;375:767-77.
3. Tsochatzis EA, Bosch J, Burroughs AK. Liver Cirrhosis. Lancet. 2014;383:1749-61.
4. Garcia-Tsao G, Sanyal AJ, Grace N, et al. Prevention and management of gastroesophageal varices and
variceal hemorrhage in cirrhosis. Hepatology. 2007;46(3):922-38.
5. Scaglione S, Kliethermes S, Cao G. The Epidemiology of Cirrhosis in the United States: A Population-
based Study. J Clin Gastroenterol. 2015 Sep;49(8):690-6.
6. Berzigotti, Escorsell A, Bosch J. Pathophysiology of variceal bleeding in cirrhotics. Ann Gastroenterol.
2001;14(3):150-157.
7. Maruyama H, Yokosuka O. Pathophysiology of portal hypertension and esophageal varices. Int J
Hepatol. 2012;2012:895787.
8. Kumar A. Sharma P, and Sarin SK. Hepatic venous pressure gradient measurement: Time to learn!
Indian J Gastroenterol. 2008 Mar-Apr; 27:74-80.
9. Tripathi D, Stanley A, Hayes P, et al. UK guidelines on the management of variceal hemorrhage in
cirrhotic patients. GUT. 2015;0:1-25.
10. Soares-Weiser K, Brezis M, Tur-Kaspa R, Leibovici L. Antibiotic prophylaxis for cirrhotic patients with
gastrointestinal bleeding. Cochrane Database Syst Rev. 2002;(2):CD002907.
11. Hou MC, Lin HC, Liu TT, et al. Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in
acute variceal hemorrhage: a randomized trial. Hepatology. 2004;39:746–53.
12. Banares R, Albillos A, Rincon D, et al. Endoscopic treatment versus endoscopic plus pharmacologic
treatment for acute variceal bleeding: A meta-analysis. Hepatology. 2002;305:609-15.
13. Lexicomp Online ®. Lexi-Drugs ®, Hudson, Ohio: Lexi-Comp, Inc.; October 23, 2016
14. Cordon JP, Torres CF, Garcia AB, et al. Endoscopic management of esophageal varices. World J
Gastrointest Endosc. 2012 July; 4(7):312-22.
15. Garcia-Paga´n JC, Bosch J. Endoscopic band ligation in the treatment of portal hypertension. Nat Clin
Pract Gastroenterol Hepatol. 2005;2:526–35.
16. Kang SH, Yiim HJ, Kim SY, et al. Proton pump inhibitor therapy is associated with reduction of early
rebleeding risk after prophylactic endoscopic variceal band ligation: a retrospective cohort study.
Medicine. Feb 2016; 95 (8). e2903-e2911.
17. Young MF, Sanowski RA, Rasche R. Comparison and characterization of ulceration induced by
endoscopic ligation of esophageal varices versus endoscopic sclerotherapy. Gastrointest. Endosc.
1993; 39: 119–22.
18. Vanbiervliet G, Giudicelli-Comard S, Riche T, et al. Predictive factors of bleeding related to post-
banding ulcer following endoscopic variceal ligation in cirrhotic patients: a case-control study.
Aliment Pharmacol Ther. 2010;32:225–32.
19. Sinclair M, Vaughan R, Angus PW et al. Risk factors for band-induced ulcer bleeding after
prophylactic an therapeutic endoscopic variceal band ligation. Eur J Gastroenterol Hepatol. 2015;
Aug;27(8):928-32.
20. Laine L and Cook D. Endoscopic ligation compared with sclerotherapy for treatment of esophageal
variceal bleeding. Ann Intern Med. 1995;123:280-87.
21. Camus M. Jensen DM. Kovasc TO, et al. Independent risk factors of 30-day outcomes in 1264 patients
with peptic ulcer bleeding in the USA: large ulcers do worse. Aliment Pharmacol Ther. 2016 May;
43(10):1080-9.
A. Whitaker | 19 of 20
22. DRUGDEX® System (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA.
Available at: http://www.micromedexsolutions.com.libproxy.uthscsa.edu. Accessed October 23,
2016.
23. Lodato F, Azzaroli F, Di Girolamo M, et al. Proton pump inhibitors in cirrhosis: tradition or evidence
based practice? World J Gastroenterol. 2008; 14 (19): 2980-2985.
24. Shin JM and Kim N. Pharmacokinetic and pharmacodynamics of the proton pump inhibitors. J
Neuroastroenterol Motil. 2013;19(1):25-35.
25. Gralnek IM, Barkun AN, and Bardou M. Management of acute bleeding from a peptic ulcer. N Engl J
Med. 2008 Aug 28;359(9):928-37.
26. Barkun AN, Cockeram AW, Plourde V, Fedorak RN. Review article: acid suppression in non-variceal
acute upper gastrointestinal bleeding. Aliment Pharmacol Ther 1999;13:1565-84.
27. Laheij RJ, Sturkenboom MC, Hassing RJ, et al. Risk of community-acquired pneumonia and use of
gastric acid-suppressive drugs. JAMA. 2004 Oct 27;292(16):1955-60.
28. McDonald EG, Milligan J, Frenette C, and Lee TC. Continuous proton pump inhibitor therapy and the
associated risk of recurrent Clostridium difficile infection. JAMA Intern Med. 2015 May;175(5):784-
91.
29. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip
fracture. JAMA. 2006;296:2947–53.
30. Laine and Jensen. Management of patients with ulcer bleeding. Am J Gastroenterol 2012;107:345–60.
31. Goel GA, Deshpande A, Lopez R, Hall GS, Van Duin D, Carey WD. Increased rate of spontaneous
bacterial peritonitis among cirrhotic patients receiving pharmacologic acid suppression. Clin
Gastroenterol Hepatol. 2012;10:422-7.
32. Chavez-Tapia NC, Tellez-Avila FI, Garcia-Leiva J, Valdovinos MA. Use and overuse of proton pump
inhibitors in cirrhotic patients. Med Sci Monit. 2008;14:CR468-72.
33. Kalaitzakis E and Bjomsson E. Inadequate use of proton-pump inhibitors in patients with liver
cirrhosis. Eur J Gastroenterol Hepatol. 2008; 20:512–18.
34. Bajaj J, Zadvornova Y, Heuman D, et al. Association of proton pump inhibitor therapy with
spontaneous bacterial peritonitis in cirrhotic patients with ascites. Am J Gastroenterol.
2009;104:1130- 4.
35. Siple JF, Morey JM, Gutman TE, et al. Proton pump inhibitor use and association with spontaneous
bacterial peritonitis in patients with cirrhosis and ascites. Ann Pharmacother. 2012; 46(10):1413-18.
36. Trikudanathan G, Israel J, Cappa J, O’Sullivan DM. Association between proton pump inhibitors and
spontaneous bacterial peritonitis in cirrhotic patients—a systematic review and meta-analysis. Int J
Clin Pract. 2011;66:674-8.
37. Wiest R, Krag A, and Gerbes A. Spontaneous bacterial peritonitis: recent guidelines and beyond. Gut.
2012 Feb;61(2):297-310.
38. Bajaj JS. Anathakrishnan AN. Hafeezullah M, et al. Clostridium difficile is associated withpoor
outcomes in patients with cirrhosis: a national and teriary center perspective. Am J Gastroenterol
2010;105:106–13.
39. Lo EAG, Wilby KJ, and Ensom MHH. Use of proton pump inhibitors in the management of
gastroesophageal varices: a systematic review. Ann Pharmacother. 2015; 49(2):207-19.
40. Alaniz C, Mohammad RA, Welage LS. Pharmacotherapy. 2009; 29 (3): 248-54.
41. Shaheen NJ, Stuart E, Schmitz SM, et al. Pantoprazole reduces the size of postbanding ulcers after
variceal band ligation: a randomized, controlled trial. Hepatology. 2005;41:588–94.
42. Lo G, Perng D, Chang C, et al. Controlled trial of ligation plus vasoconstrictor versus proton pump
inhibitors in the control of acute esophageal variceal bleeding. J Gastroenterol Hepatol.
2013;28(4):684-9.
A. Whitaker | 20 of 20
Appendix A: Child – Pugh Classification for Cirrhosis Severity 4
Points
1 2 3
Encephalopathy None Grade 1-2
(precipitant-induced) Grade 3-4 (Chronic)
Ascites None Mild/Moderate
(diuretic-responsive) Tense
(diuretic-refractory)
Bilirubin (mg/dL) <2 2-3 >3
Albumin (g/dL) >3.5 2.3-3.5 <2.8
Prolong PT or INR <4 or <1.7 4-6 or 1.7-2.3 >2.3
1. Interpretation a. Child-Pugh score A: 5-6 points b. Child-Pugh score B: 7-9 points c. Child-Pugh score C: 10-15 points
Appendix B: Portal Hypertension HVPG measurements 4
HVPG measurements Interpretation
3-5 mmHg Normal
> 10-12 mmHg Predictive for esophageal varices
>20 mmHg In the presence of bleeding; predictive of early re-bleeding
Appendix C – Variceal Size classification4
Size Semi-quantitative morphological Assessment Quantitative size
Small minimally elevated veins above the esophageal mucosal surface
≤ 5 mm in diameter
Medium tortuous veins occupying less than one-third of the esophageal lumen > 5 mm in diameter
Large occupying more than one-third of the esophageal lumen
Appendix D – Variceal Grading on shape and size
Grade Semi-quantitative morphological Assessment
F0 No esophageal varices
F1 Small straight esophageal varices
F2 Slightly enlarged tortuous esophageal varices < 1/3 size of the lumen
F3 Large coil-shaped EV that occupied > 1/3 of the esophageal lumen