Latest Pharmacological in PUB Management (RTD Dokter)1

7/30/2019 Latest Pharmacological in PUB Management (RTD Dokter)1

1/40

Latest Pharmacological Development

in Peptic Ulcer Bleeding Management


2/40

Initial management of peptic ulcer bleeding

Treatment of peptic ulcer bleeding aims to stabilizethe circulation, stop ongoing bleeding and preventre-bleeding and includes:

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

fluid replacement (with blood transfusion if needed)

prompt endoscopy, with endoscopic haemostasisif necessary

surgery, if bleeding cannot be controlledby the above measures


3/40

Endoscopic haemostasis

Monotherapy with either epinephrine injection or thermal

treatment (e.g. with a heater probe)orA combination of epinephrine injection plus thermaltreatment and/or haemoclips

Epinephrine injection HaemoclipHeater probe

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


4/40

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


5/40

Latest pharmacologic management

The role of prokinetic pre-endoscopy

Position of high dose of PPI iv

The need of maintenance of PPI oral in PUBmanagement



6/40

The role of prokinetic pre-endoscopy

Blood in the stomach or duodenum may obscure theview or expose the patient to potential broncho-aspiration

Blood in the stomach delays a definitive surgicaltreatment and explains why repeat endoscopy is

performed in 5%-12% of casesThe role of prokinetics : clearing the stomach beforeemergency 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;123:1723Barkun AN, et al. Ann Intern Med. 2010;152:101-113


7/40

Erythromycin infusion before endoscopy in patients withrecent hematemesis makes endoscopy shorter and easier,

- reducing the need for a repeat procedure

No of p at ients

n = 105p < 0,001

Endoscopic duration (minutes)

PlaceboErithromycin infusion

Length of hospital stay and blood units transfused did not

significantly differ between the 2 groups.

Frossard JL et al. Gastroenterology 2002;123:1723

82%

33%

16.4 7.8

13.7 4.5


8/40

Because of adequate visualization allows propertreatment, prokinetics agents should not be used

routinelybefore endoscopy to increase thediagnostic yield

Somatostatin and octreotide are not recommended

in the routine management of patients with acute

ulcer bleeding (I C) *


* Recommendation unchanged from 2003 guidelines.


9/40

PPI therapy with or without endoscopyreduced re-bleeding

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


10/40

Cost effective analysis of PPI therapy in acutepeptic ulcer bleeding

Scenario to compare :

1. Diagnostic endoscopy with oral PPI therapy;

2. Diagnostic and therapeutic endoscopy with high-doseintravenous PPI therapy;

3. Diagnostic and therapeutic endoscopy available withoral PPI therapy;

4. Diagnostic and therapeutic endoscopy (no PPI)

Cost analysis based on : episodes of bleeding andquality-adjusted life years

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


11/40

High-dose intravenous PPI therapy in conjunction withtherapeutic endoscopy is the most cost-effective approach for

the management of hospitalized patients with acute pepticulcer bleeding.

Cost in $ (+000)

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

10.2

5.5

8.5

4.8

8.8

4.9

12.5

5.9

0

7

14

Bleeding episodes Quality-adjusted life years

Scenario 1

Scenario 2

Scenario 3

Scenario 4


12/40

Percentage of time pH>6 during first 3 hourswith esomeprazole iv (healthy volunteers)

0

20

40

60

80

100Mean fraction of first 3 hours (%)

*p


13/40

Gastric acid inhibits haemostasis in

bleeding peptic ulcers


14/40

A pH>6 is needed to maintain plateletaggregation

Time (minutes)0

80

60

40

20

0

ADP

Buffer

1001 2 3 4 5

Aggregation (%)

pH=6.0Disaggregation=77%



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


15/40

H2-receptor antagonists do not reliablyincrease 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 orconsistently increase gastric pH to 6.

Non-var iceal upper gastro intest inal haemorrhage: guid el ines

Bri t ish Society of Gastroenterology

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


16/40

H2RA develop tolerance within 72 hours

Netzer, 1999

Omeprazole iv

Ranitidine iv

Gastric pH

Netzer P et al. Am J Gastroenterol 1999;94:351357


17/40

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

An intravenous bolus followed by continuous

infusion proton pump inhibitor is effective in

decreasing re-bleeding in patients who haveundergone successful endoscopic therapy.

Evidence-based management guidel ines developed by the m ult id iscip l inary

Non-var iceal Upper GI Bleeding Consensus Conference Group



18/40

Comparison of acid control

between PPIs


19/40

Intragastric pH with high-dose iv PPI therapy

Clinical pharmacology studies H. pylori-negative healthy volunteers

24 hour iv infusion

1Rhss K, et al. Intl J Clin Pharm Ther 2007;45:34554; 2Metz DC, et al. Aliment Pharmacol Ther 2006;23:98595

n Median/mean Time pH>624-hour pH (024 hours)

Esomeprazole80 mg + 8 mg/hour1 25 5.8 12.6

Pantoprazole

80 mg + 8 mg/hour2 36 5.0 5.56.7

* This is not a head to head study


20/40

p4 (hours)

15

***

***


21/40

Oral esomeprazole provides more effectiveacid control than pantoprazole iv

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

esomeprazole

oral,40 mg once daily

pantoprazole iv,

40 mg once daily

n=29

***p4 (hours)

0 6 12 18

***

***

10.4

14.2

6.0

8.1


22/40

Study in Peptic Ulcer Bleeding (PUB)


23/40

Study PPI in peptic ulcer bleeding (PUB)

Author PPI Comparison Result Comment

Lin et al, 1998 Omeprazole

(n=50)

Cimetidine, 300 mg

iv, followed by 1200

mg continuous

infusion for 3 d

(n=50)

Significant 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, Omeprazole Placebo Significant Included a significant

2000 (n =120) (n =120) proportion of patients

with shock at

presentation; trial

stopped prematurely at 3rdinterim 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


24/40

Study PPI in peptic ulcer bleeding (PUB)

Author PPI Comparison Result Comment

Van Rensburget al, 2009

Pantoprazole iv(n = 618)

Ranitidine iv(n = 626)

Significantonly in

patients with

arterial

spurting

and gastric

ulcers.

Nonstandardizedendoscopic inclusion

criteria; performance

of routine

second-look

endoscopy

Jensen et al,

2006

Pantoprazole iv

(n = 72)

Ranitidine iv

(n = 77)

Not

significant

difference in

ulcer

rebleeding

rates

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


25/40

4%3%

7%8%

7%

14%

0%

2%

4%

6%

8%

10%

12%

14%

16%

72 hours 4-7 days Total

pantoprazole iv

80mg + 8mg/jam

ranitidine iv50mg +

6.25mg/jam

Efficacy of PPI iv in Peptic Ulcer Bleeding

No of patients with re-bleeding

Jensen study failed to demonstrate convincing beneficial effects with highdose pantoprazole iv vs ranitidine iv in PUB study because the study stoppedprematurely due to slow enrollment

NS

NS

NS

Jensen DM, et al. Am J Gastroenterol 2006;101:19911999

n = 72

2006

Pantoprazole iv 80mg + 8 mg/hour

ranitidine iv 50 mg+ 6.25 mg/hour

n = 77


26/40

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

18

12

33

20

13

38

0

5

10

15

20

25

30

35

40

Clinically suspected rebleeding Surgery due to rebleeding Total haemostatic retreatment

No of patients (%)

NS

NS

NS

Rensburg CV, et al. Aliment Pharmacol Ther 2009;29:497 - 507

2009

pantoprazole iv 80mg + 8 mg/hourn = 618

ranitidine iv 50mg +13 mg/hourn = 626


27/40

Limitations of Previous PUB Studies

Patients:

Low risk patients without ulcer bleeding

Potential variation in interpretation of endoscopy sign

Single-centerand limited to specific ethnic

The rate of PPI metabolism (genotype CYP2C19)

Prevalence ofH.pyloriinfection

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


28/40

The need to investigate the efficacyof PPI in heterogenous population

of patients with PUB with an

appropriately designed,multicentre, controlled study


29/40

Peptic Ulcer Bleeding Study withesomeprazole iv

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

oral treatment(27 days)iv treatment(72 hours)

(0max 24 hours)

Esomeprazole iv,80 mg for 30 minutes

followed by

esomeprazole iv, 8mg/hour for 71.5 hours

Placebo iv for30 minutes followed

by placebo iv for71.5 hours

Esomeprazole oral,40 mg once daily

R

Esomeprazole oral,40 mg once daily

Enrollment phase:

Endoscopic therapy

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


30/40

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

Patients with re-bleeding (within 72 hours)(%)

5.9

10.3

0

3

6

9

12

15

*p


31/40

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

Within 7 days

Patients with re-bleeding (%)

Within 30 days

7.27.7

12.913.6

0

3

6

9

12

15esomeprazole iv,80 mg + 8 mg/hourfor 3 days thenesomeprazole oral,40 mg once daily,

for 27 days

placebo iv for3 days thenesomeprazole oral,40 mg once daily,for 27 days

**p


32/40

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

Patients requiring endoscopicre-treatment (%)

0

3

6

9

12

15

6.4

11.6

*

esomeprazole iv,80 mg + 8 mg/hourfor 3 days thenesomeprazole oral,40 mg once daily,

for 27 days


*p


33/40

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

Total units of blood transfused(within 30 days)

589

935

0

200

400

600

800

1000

*


for 27 days


*p


34/40

Esomeprazole iv + oral regimen: additionaltime in hospital due to re-bleeds (within 30days)

Total number of additional days in hospitalfor re-bleeding (within 30 days)

284

500

0

100

200

300

400

500

600

**


for 27 days


**p


35/40

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

30-day overall surgery rate with esomeprazole iv

followed by esomeprazole oral was 2.7% of patientscompared with 5.4% with placebo (not significant)

30-day mortality rate with esomeprazole iv followedby esomeprazole oral was 0.8% of patients

compared with 2.1% with placebo (not significant)

Result : Numerical, but not statistically significant, differences in favour of theesomeprazole peptic ulcer bleeding therapy regimen were obtained forsurgery and mortality

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


36/40

Safety and tolerability

Esomeprazole was similarly well toleratedto placebo

Infusion site reactions occurred in


37/40

What about therapy upon discharge?


38/40

Discharge PPI dosing

Patients should be discharged on a single daily doseoral PPI for a duration as dictated by the underlyingetiology

If bleeding esophagitis, consider double-dose

Length of treatment varies according to location ofthe ulcer, or presence of ASA, clopidogrel



39/40

Summary

Latest pharmacological in PUB Management

Normal hemostatic mechanism are impaired in anacidic environment, need to increase pH > 6

Compared to pantoprazole iv, esomeprazole is moreeffective in acid control at pH > 6

Intravenous bolus followed by continuous infusionPPI therapy is recommended for patients with highrisk stigmata

Patients should be discharged with single dose oral

PPINew study on PUB with esomeprazole withmulticenter, controlled study reduced recurrent re-bleeding at 72 hours and has sustained clinical

benefits for up to 30 days


40/40

THANK YOU

Documents

Latest Pharmacological in PUB Management (RTD Dokter)1