Latest Pharmacological Development in Peptic Ulcer Bleeding Management

Initial management of peptic ulcer bleeding

Treatment of peptic ulcer bleeding aims to stabilize the circulation, stop ongoing bleeding and prevent re-bleeding and includes: fluid replacement (with blood transfusion if needed) prompt endoscopy, with endoscopic haemostasis if necessary

surgery, if bleeding cannot be controlled by the above measures

Leontiadis GI, et al. Health Technol Assess 2007;11:1164

Endoscopic haemostasis

Epinephrine injection

Heater probe

Haemoclip

Monotherapy with either epinephrine injection or thermal treatment (e.g. with a heater probe)
or A combination of epinephrine injection plus thermal treatment and/or haemoclips

Laine L. Peterson WL. NEJM. 1994;331:717-27

Latest Endoscopic management

Early endoscopy Endoscopic therapy in patient with adherent clot

Best endoscopic therapy

Position of second look endoscopy

Barkun AN, et al. Ann Intern Med. 2010;152:101-113

Latest pharmacologic management

The role of prokinetic pre-endoscopy Position of high dose of PPI iv

The need of maintenance of PPI oral in PUB management

Barkun AN, et al. Ann Intern Med. 2010;152:101-113

The role of prokinetic pre-endoscopy

Blood in the stomach or duodenum may obscure the view or expose the patient to potential bronchoaspiration Blood in the stomach delays a definitive surgical treatment and explains why repeat endoscopy is performed in 5%-12% of cases The role of prokinetics : clearing the stomach before emergency endoscopy The objective of prokinetics usage: improve diagnostic yield for patients with suspected bleeding Prokinetics widely used : erythromycin, metoclopramide
Frossard JL et al. Gastroenterology 2002;123:1723 Barkun AN, et al. Ann Intern Med. 2010;152:101-113

Erythromycin infusion before endoscopy in patients with recent hematemesis makes endoscopy shorter and easier, - reducing the need for a repeat procedure
No of patients Erithromycin infusion Placebo 82% 16.4 7.8 n = 105 p < 0,001 33% 13.7 4.5

Endoscopic duration (minutes)

Length of hospital stay and blood units transfused did not significantly differ between the 2 groups.
Frossard JL et al. Gastroenterology 2002;123:1723

 Because of adequate visualization allows proper

treatment, prokinetics agents should not be used routinely before endoscopy to increase the diagnostic yield
Somatostatin and octreotide are not recommended

in the routine management of patients with acute ulcer bleeding (I C) *

* Recommendation unchanged from 2003 guidelines.

Barkun AN, et al. Ann Intern Med. 2010;152:101-113

PPI therapy with or without endoscopy reduced re-bleeding

Leontiadis GI, Sharma VK, Howden CW. Cochrane Database Syst Rev. 2006

Cost effective analysis of PPI therapy in acute peptic ulcer bleeding

Scenario to compare :
1. Diagnostic endoscopy with oral PPI therapy;

2. Diagnostic and therapeutic endoscopy with high-dose

intravenous PPI therapy;

3. Diagnostic and therapeutic endoscopy available with

oral PPI therapy;

4. Diagnostic and therapeutic endoscopy (no PPI) Cost analysis based on : episodes of bleeding and

quality-adjusted life years

Erstad BL. Crit Care Med 2004;32:1277-1283

High-dose intravenous PPI therapy in conjunction with therapeutic endoscopy is the most cost-effective approach for the management of hospitalized patients with acute peptic ulcer bleeding.
Cost in $ (+000)
14 10.2 12.5 8.8 Scenario 1

8.5 7

5.5

4.8

4.9

5.9

Scenario 2

Scenario 3
Scenario 4

0 Bleeding episodes Quality-adjusted life years

Erstad BL. Crit Care Med. 2004;32:1277-83

Percentage of time pH>6 during first 3 hours with esomeprazole iv (healthy volunteers)
Mean fraction of first 3 hours (%) 100

80 60

*p<0.05 versus 80 mg + 8 mg/hour

46.7% 40 23.3%* 20 2% 0
Baseline n=25 40 mg + 8 mg/hour n=23 80 mg + 4 mg/hour n=24 80 mg + 8 mg/hour n=24

46.7%

43.3%

36.7%*

120 mg 120 mg (2hours) +8 mg/hour + 8 mg/hour n=22 n=20

Rhss K, et al. Intl J Clin Pharm Ther 2007;45:34554

Gastric acid inhibits haemostasis in bleeding peptic ulcers

A pH>6 is needed to maintain platelet aggregation

Aggregation (%) 0 20 40 60 80 100

ADP

pH=6.0 Disaggregation=77%

Buffer

pH=6.4 Disaggregation=16% pH=7.3 Disaggregation=0%

5 Time (minutes)

ADP: adenosine diphosphate

Green FW, et al. Gastroenterology 1978;74:3843

H2-receptor antagonists do not reliably increase gastric pH to 6

There are no convincing data to support the use of H2-receptor antagonists [in non-variceal bleeding], and these drugs do not reliably or consistently increase gastric pH to 6.
Non-variceal upper gastrointestinal haemorrhage: guidelines British Society of Gastroenterology

British Society of Gastroenterology Endoscopy Committee. Gut 2002;51(Suppl IV):iv1iv6

H2RA develop tolerance within 72 hours

Omeprazole iv Gastric pH

Ranitidine iv

Netzer P et al. Am J Gastroenterol 1999;94:351 357 Netzer, 1999

Guidelines recommend high-dose iv PPI therapy for the treatment of bleeding peptic ulcers

An intravenous bolus followed by continuous infusion proton pump inhibitor is effective in decreasing re-bleeding in patients who have undergone successful endoscopic therapy.
Evidence-based management guidelines developed by the multidisciplinary Non-variceal Upper GI Bleeding Consensus Conference Group

Barkun AN, et al. Ann Intern Med. 2010;152:101-113

Comparison of acid control between PPIs

Intragastric pH with high-dose iv PPI therapy

Clinical pharmacology studies
H. pylori-negative healthy volunteers 24 hour iv infusion n Median/mean 24-hour pH 5.8 5.0 Time pH>6 (024 hours) 12.6 5.56.7

Esomeprazole 80 mg + 8 mg/hour1
Pantoprazole 80 mg + 8 mg/hour2
* This is not a head to head study

25 36

1Rhss

K, et al. Intl J Clin Pharm Ther 2007;45:34554; 2Metz DC, et al. Aliment Pharmacol Ther 2006;23:98595

Comparison of PPI oral efficacy at pH > 4

Day 5 data, 5-way crossover study in patients with GERD
esomeprazole, 40 mg once daily rabeprazole, 20 mg once daily omeprazole, 20 mg once daily lansoprazole, 30 mg once daily

***

n=34 ***p<0.001 versus rabeprazole p<0.0001 versus lansoprazole, omeprazole and pantoprazole 0 5 10 15 Time intragastric pH>4 (hours) 20

pantoprazole, 40 mg once daily

Miner P, et al Am J Gastroenterol 2003;98:261620; Am J Gastroenterol 2006;101:404 - 406

Oral esomeprazole provides more effective acid control than pantoprazole iv

10.4

***

Day 1
6.0

esomeprazole oral, 40 mg once daily pantoprazole iv, 40 mg once daily

n=29 14.2

***

***p<0.001

Day 5
8.1

6 12 18 Time intragastric pH>4 (hours)

24

Armstrong D, et al. Aliment Pharmacol Ther 2003;18:70511

Study in Peptic Ulcer Bleeding (PUB)

Study PPI in peptic ulcer bleeding (PUB)

Author PPI Comparison Result Lin et al, 1998 Omeprazole Cimetidine, 300 mg Significant (n=50) iv, followed by 1200 mg continuous infusion for 3 d (n=50) Comment Gastric pH > 6.0 for 84% of time in those receiving omeprazole and 54% of time in those receiving cimetidine (P < 0.001)

Lau et al, 2000

Omeprazole Placebo (n =120) (n =120)

Significant

Included a significant proportion of patients with shock at presentation; trial stopped prematurely at 3rd interim analysis because of magnitude of therapeutic difference between the groups

Lin HJ . Etal, Arch Intern Med 1998;158:54-58; Lau JYW. Et al. NEJM 2000;343(5): 310-316

Study PPI in peptic ulcer bleeding (PUB)

Author
Van Rensburg et al, 2009

PPI

Comparison Result
Significant only in patients with arterial spurting and gastric ulcers. Not significant difference in ulcer rebleeding rates

Comment
Nonstandardized endoscopic inclusion criteria; performance of routine second-look endoscopy

Pantoprazole iv Ranitidine iv (n = 618) (n = 626)

Jensen et al, 2006

Pantoprazole iv Ranitidine iv (n = 72) (n = 77)

Trial stopped prematurely because of poor enrollment

Van Rensburg C. et al. Aliment Pharmacol Ther 2009;29:497-507; Jensen DM. Et al. Am J Gastroenterology 2006;101:1991-1999

2006

Efficacy of PPI iv in Peptic Ulcer Bleeding

No of patients with re-bleeding

16% 14%

12%
10% 8% 6% 4% 2% 0%
NS NS

14%

Pantoprazole iv pantoprazole iv80 mg + 8 80mg + mg/hour 8mg/jam n = 72 ranitidine iv ranitidine iv 50 mg + 6.25 mg/hour 50mg + 6.25mg/jam n = 77

8%
NS

7% 3%

7%

4%

72 hours

4-7 days

Total

Jensen study failed to demonstrate convincing beneficial effects with high dose pantoprazole iv vs ranitidine iv in PUB study because the study stopped prematurely due to slow enrollment
Jensen DM, et al. Am J Gastroenterol 2006;101:19911999

2009
No of patients (%)
40

35
30 25 20 15 18
NS

NS

38

33

pantoprazole iv 80 mg + 8 mg/hour n = 618

ranitidine iv 50mg + 13 mg/hour n = 626

20 12

NS

10
5 0 Clinically suspected rebleeding

13

Surgery due to rebleeding

Total haemostatic retreatment

Subject of study is patients with low risk re-bleeding Re-bleeding definition between group is not clear Ranitidine iv not a standard therapy of peptic ulcer bleeding
Rensburg CV, et al. Aliment Pharmacol Ther 2009;29:497 - 507

Limitations of Previous PUB Studies

Patients:
Low risk patients without ulcer bleeding Potential variation in interpretation of endoscopy sign Single-center and limited to specific ethnic
The rate of PPI metabolism (genotype CYP2C19) Prevalence of H.pylori infection Gastric parietal cell mass

Therapy used in study:

No standard for endoscopic therapy Selection of PPI preparation iv or oral Use H2RA as a control

Analysis of study result:

Re-bleeding definition is not clear

No independent analyst
Choice of composite endpoint No ITT population

The need to investigate the efficacy of PPI in heterogenous population of patients with PUB with an appropriately designed, multicentre, controlled study

Peptic Ulcer Bleeding Study with esomeprazole iv

iv treatment (72 hours)
Esomeprazole iv, 80 mg for 30 minutes followed by esomeprazole iv, 8 mg/hour for 71.5 hours

oral treatment (27 days)

Esomeprazole oral, 40 mg once daily

Enrollment phase: Endoscopic therapy (0max 24 hours)

Placebo iv for 30 minutes followed by placebo iv for 71.5 hours

Esomeprazole oral, 40 mg once daily

Conduct in 91 centers in 16 countries multicenter Including 3 ethnic (Asian, African and Caucasian) - heterogeneous Used placebo as control controlled study

Sung JJ, et al. Ann Intern Med 2009;150:455-464

Re-bleeding rates with esomeprazole iv (within 72 hours)

Patients with re-bleeding (within 72 hours) (%) 15 12 9 6
* 5.9 10.3

esomeprazole iv, 80 mg + 8 mg/hour placebo

*p<0.05

3
0

Sung JJ, et al. Ann Intern Med 2009;150:455-464

Esomeprazole iv + oral regimen: re-bleeding rates (within 7 and 30 days)

Patients with re-bleeding (%) 15 12 9
**
12.9 13.6 esomeprazole iv, 80 mg + 8 mg/hour for 3 days then esomeprazole oral, 40 mg once daily, for 27 days placebo iv for 3 days then esomeprazole oral, 40 mg once daily, for 27 days

** 7.7

6 3

7.2

**p<0.01

Within 7 days

Within 30 days

Sung JJ, et al. Ann Intern Med 2009;150:455-464

Esomeprazole iv + oral regimen: endoscopic re-treatment rates (within 30 days)

Patients requiring endoscopic re-treatment (%) 15 12
11.6 esomeprazole iv, 80 mg + 8 mg/hour for 3 days then esomeprazole oral, 40 mg once daily, for 27 days placebo iv for 3 days then esomeprazole oral, 40 mg once daily, for 27 days

9 6 3
* 6.4

*p<0.05

Sung JJ, et al. Ann Intern Med 2009;150:455-464

Esomeprazole iv + oral regimen: blood transfusion required (within 30 days)

Total units of blood transfused (within 30 days) 1000 800 600 400
* 589 935 esomeprazole iv, 80 mg + 8 mg/hour for 3 days then esomeprazole oral, 40 mg once daily, for 27 days placebo iv for 3 days then esomeprazole oral, 40 mg once daily, for 27 days

200
*p<0.05

Sung JJ, et al. Ann Intern Med 2009;150:455-464

Esomeprazole iv + oral regimen: additional time in hospital due to re-bleeds (within 30 days)
Total number of additional days in hospital for re-bleeding (within 30 days) 600 500
500 esomeprazole iv, 80 mg + 8 mg/hour for 3 days then esomeprazole oral, 40 mg once daily, for 27 days placebo iv for 3 days then esomeprazole oral, 40 mg once daily, for 27 days

400
300 200
**

284

100
0

**p<0.01

Sung JJ, et al. Ann Intern Med 2009;150:455-464

Esomeprazole iv + oral regimen: surgery and mortality rates (within 30 days)

Result : Numerical, but not statistically significant, differences in favour of the esomeprazole peptic ulcer bleeding therapy regimen were obtained for surgery and mortality

30-day overall surgery rate with esomeprazole iv followed by esomeprazole oral was 2.7% of patients compared with 5.4% with placebo (not significant) 30-day mortality rate with esomeprazole iv followed by esomeprazole oral was 0.8% of patients compared with 2.1% with placebo (not significant)

Sung JJ, et al. Ann Intern Med 2009;150:455-464

Safety and tolerability

Esomeprazole was similarly well tolerated to placebo
Infusion site reactions occurred in <5% of esomeprazoletreated patients

No safety concerns were raised regarding the use of esomeprazole in this population

Sung JJ, et al. Ann Intern Med 2009;150:455-464

What about therapy upon discharge?

Discharge PPI dosing

Patients should be discharged on a single daily dose oral PPI for a duration as dictated by the underlying etiology If bleeding esophagitis, consider double-dose Length of treatment varies according to location of the ulcer, or presence of ASA, clopidogrel

Barkun AN, et al. Ann Intern Med. 2010;152:101-113

Summary
Latest pharmacological in PUB Management Normal hemostatic mechanism are impaired in an acidic environment, need to increase pH > 6 Compared to pantoprazole iv, esomeprazole is more effective in acid control at pH > 6 Intravenous bolus followed by continuous infusion PPI therapy is recommended for patients with high risk stigmata Patients should be discharged with single dose oral PPI New study on PUB with esomeprazole with multicenter, controlled study reduced recurrent rebleeding at 72 hours and has sustained clinical benefits for up to 30 days

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