Pumping the Brakes on Continuous Infusion: Prevention …sites.utexas.edu/pharmacotherapy-rounds/files/2015/10/wong10-23... · Pumping the Brakes on Continuous Infusion: Prevention

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Pumping the Brakes on Continuous Infusion:

Prevention of Peptic Ulcer Rebleeding

Dana Wong, Pharm.D.

PGY2 Internal Medicine Pharmacy Resident

South Texas Veterans Health Care 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

October 23, 2015

Learning Objectives

1. Describe the etiology, risk factors, and classification of peptic ulcers

2. Evaluate current literature comparing continuous infusion and intermittent dosing of proton pump

inhibitors (PPIs) for prevention of peptic ulcer rebleeding

3. Recommend appropriate dosing strategies for PPIs for prevention of peptic ulcer rebleeding

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I. Upper Gastrointestinal (GI) Bleeding and Peptic Ulcers

A. Upper GI bleeding1-3

1. Diagnosed in 50-150 per 100,000 individuals per year

2. 300,000 hospitalizations per year

3. Mortality rate of 6-10% annually

4. Hospitalization costs >$2.5 billion per year

B. Causes of acute upper GI bleeding4

1. Peptic ulcer disease (PUD)— 40-79%

2. Gastritis/duodenitis—5-30%

3. Esophageal varices—6-21%

4. Mallory-Weiss tear—3-15%

5. Esophagitis—2-8%

6. Gastric cancer—2-3%

C. Symptoms of bleed4

1. Anemia, hemodynamic instability

2. Vomiting fresh blood, “coffee ground” emesis, melena, hematochezia, abdominal pain

D. Peptic ulcer disease

1. Three common forms5

a. Nonsteroidal anti-inflammatory drug (NSAID)-induced (~30%)

b. Helicobacter pylori (H. pylori) positive (~20%)

c. Stress-related mucosal damage (75-100%)

2. Risk factors for peptic ulcers1: smoking, alcohol, corticosteroids, oral anticoagulants

3. Pathophysiology6:

Figure 1. http://www.hopkinsmedicine.org

4. Forrest classification7-8

Stigmata of

hemorrhage

Forrest

classification

Prevalence Rebleeding

rate

Mortality

Active spurting

bleeding

IA

12% 55% 11%

Active oozing

bleeding

IB

Non-bleeding visible

vessel

IIA 8% 43% 11%

Adherent clot IIB 8% 22% 7%

Flat spot IIC 16% 10% 3%

Clean base III 55% 5% 2%

Table 1.

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5. Rockall score9-10

a. Predicts the risk of rebleeding and mortality based on the patient’s age, signs of shock on

presentation, comorbidities, and endoscopic criteria

b. Scoring

Figure 2.

6. Treatment options

a. Octreotide, somatostatin

i. Inhibits acid and pepsin secretion

ii. Data has shown no benefit11-12

b. Sucralfate

i. Binds to the gastric mucosa creating a physical barrier that prevents both the

diffusion of acid into the GI tract and prevents acid’s degradation of mucus

ii. Shown to have equal efficacy to ranitidine13

c. H2 receptor antagonists (H2RAs)

i. Prevents acid secretion by inhibiting the action of histamine at the histamine H2-

receptors of the parietal cells

ii. Studies showed more effective acid suppression with a PPI14-15

d. Surgery and interventional radiology18

i. Surgery is utilized when endoscopic therapy is unavailable or has failed

ii. Interventional radiology is typically reserved when endoscopic therapy has

failed, especially in high-risk surgical candidates

e. Endoscopic hemostasis

i. Primary hemostasis achieved in >90% of cases16

ii. Significant reduction in further bleeding, surgical intervention, and mortality

iii. Methods17

1. Mechanical method (i.e. hemoclip, ligation)

2. Injection method (i.e. epinephrine)

3. Thermo-coagulation (i.e. heater probe, argon plasma coagulation)

ii. Unimodal (one method) vs. multimodal (>1 method) endoscopic therapy

f. Proton pump inhibitors (PPIs)

i. Inhibit acid secretion by direct covalent and irreversible binding to the H+/K

+

ATP present in the canaliculi of parietal cells19

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ii. Following endoscopic therapy, rebleeding within 72 hours is still prevalent (up

to 20%) and is associated with high mortality rate9

iii. PPI availability20-21

1. United States formulations

PPI Formulations

Dexlansoprazole (Dexilant) Oral (capsule)

Esomeprazole (Nexium®) Intravenous, oral (capsule, oral packet)

Lansoprazole (Prevacid®) Oral (capsule, tablet, oral suspension)

Omeprazole (Prilosec®) Oral (capsule, tablet, oral packet)

Pantoprazole (Protonix®) Intravenous, oral (tablet, oral packet)

Rabeprazole (Aciphex®) Oral (capsule, tablet)

Table 2.

2. Cost comparisons

40 mg vial Continuous TDD cost Intermittent TDD cost

Pantoprazole $6.00 $36.00 $12.00

Esomeprazole $41.88 $251.28 $83.76

Table 3. TDD cost: total daily dose cost based on Average Wholesale Price

II. Dosing of PPIs

A. pH studies

1. Rationale for the need for profound gastric acid suppression (target a pH >6.0) is extrapolated

from in vitro data showing clot stabilization22-23

2. Platelet aggregation and plasma coagulation totally inhibited at a pH of 5.4

B. Initial continuous PPI infusion study showed reduced risk of bleeding compared to placebo (6.7% vs.

22.5%; HR 3.9; 95% CI, 1.7 – 9.0)24

C. British Society of Gastroenterology 2002 guidelines25

1. Initial guidelines recommending the use of continuous infusion intravenous (IV) PPI therapy

2. 80 mg IV bolus omeprazole, then 8 mg/hr continuous infusion for 72 hours

D. American College of Gastroenterology 2012 Practice Guidelines26

Strength of

recommendation

Recommendation

Strong

recommendation

After successful endoscopic hemostasis, intravenous (IV) PPI therapy with

80 mg bolus followed by 8mg/h continuous infusion for 72 h should be

given to patients who have an ulcer with active bleeding, a non-bleeding

visible vessel, or adherent clot

Strong

recommendation

Patients with ulcers that have flat pigmented spots or clean bases can

receive standard PPI therapy (e.g., oral PPI once-daily)

Table 4.

1. Meta-analysis of continuous infusion PPI therapy vs placebo trials confirms significant reduction

in further rebleeding, surgery, and mortality27

2. Guidelines state “intermittent PPI therapy may be sufficient for high-risk stigmata” based on

outcomes from several small trials comparing continuous infusion versus intermittent16,19,28-30

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E. Do pH outcomes translate to clinical outcomes?

1. Evidence for continuous infusion therapy based off of in vitro data and placebo comparison

2. Hung et al. 2007.16

Figure 3.

F. Clinical controversy

Can intermittent PPI therapy be used in place of continuous infusion therapy for prevention of

peptic ulcer rebleeding following endoscopic hemostasis?

III. Clinical Studies

A. Review of primary literature

1. Andruilli, et al.—200828

2. Chen, et al.—201231

3. Liu, et al.—201232

4. Sachar, et al.—201433

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B. Andruilli, et al. 2008.30

Objective Compare two strategies for IV PPI administration in the prevention of rebleeding,

surgery, and death in patients with high-risk bleeding peptic ulcers

Design Prospective, randomized, double-blind superiority study conducted in 11 Italian

centers from October 2004 to March 2007

Interventions:

o Endoscopic hemostasis (modality at the discretion of the endoscopist)

o Continuous infusion regimen (80 mg loading dose, followed by continuous

infusion of 8 mg/hr x 72 hr)

o Intermittent regimen (40 mg bolus of PPI once daily x 72 hr)

o After 72 hr, switched to oral PPI (20 mg twice daily) until discharge

Inclusion/

exclusion

criteria

Inclusion Exclusion

- Overt GI bleeding or recent history

(<24 hr before presentation) of

hematemesis and/or melena, or ulcer

hemorrhage started after hospitalization

- Ulcer with active bleeding (spurting

arterial or persistent oozing) or a

nonbleeding lesion (nonbleeding

visible vessel or adherent clot)

- Malignant-appearing ulcers

- Severe comorbid conditions

- Ulcers with a flat spot or clean base

- Severe coagulopathy (platelet count

<100,000; INR >1.5)

- Need for continuous anticoagulation

- PPI therapy prior to index endoscopy

- Unsuccessful endoscopic hemostasis

Outcomes Primary: in-hospital occurrence of rebleeding (confirmed by repeat endoscopy)

o Rebleeding: blood pressure (< 100 mmHg), pulse rate (> 100 beats per

minute), Hgb (>20 g/L), no change in Hgb levels with red blood cell

transfusions, or reappearance of overt bleeding (new hematemesis or melena)

Secondary: surgery, transfusion requirement, length of hospital stay, mortality

Statistical

analyses Expected rebleeding rate: 15% with intermittent and 7% with continuous infusion

235 patients needed per arm; α=0.05, power= 0.80

Two-sided χ2 Pearson’s test for primary endpoint

Two-sample t-test for continuous variables; Fisher exact test for discrete variables

Results

Demographics 482 patients randomized

Continuous

(n=238)

Intermittent

(n=236)

Mean age (years) 66.3 + 15.6 66.8 + 16.7

Previous bleeding (%) 10.5 5.9

Previous ulcer disease (%) 13.4 15.3

Mean Hgb (g/dL) 9.1 + 2.4 9.5 + 2.2

Forrest classification (%)

Ia

Ib

IIa

IIb

10.5

34.5

34.0

21

10.6

30.9

36.0

22.5

Shock at presentation (%) 8.4 14.8

Rockall Score > 6 points (%) 26.9 34.3

Severe comorbidity (%) 8.0 12.7

Endoscopic hemostasis modality (%)

Unimodal

Multimodal

50.0

50.0

57.6

42.4

Time from bleeding to endoscopy

< 24 hr

>24 hr

86.6

13.4

85.1

13.9

PPI administered (%)

Omeprazole

Pantoprazole

70.2

29.8

69.1

30.9

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Outcomes Continuous

(n=238)

Intermittent

(n=236)

p-value

Rebleeding (%) 11.8 8.1 0.18

Rebleeding according to endoscopic

hemostasis (%)

Unimodal

Multimodal

5.5

6.3

5.5

2.5

0.14

Rebleeding according to Rockall

score > 6 (%)

4.6 4.7 0.21

Rebleeding according to PPI

administered (%)

Omeprazole

Pantoprazole

7.1

4.6

4.7

3.4

0.84

Death because of rebleeding (%) 1.3 1.3 1.00

Hospital stay

Mean—days

<5 days (%)

7.3 + 4.4

37.0

6.6 + 3.7

47.0

0.36

0.03

Surgery (%) 1.3 0.4 0.62

No. of units of blood transfused 1.7 + 2.1 1.5 + 2.1 0.75

More patients with the intensive regimen had a hospital stay >5 days (p=0.03)

Independent predictive factors for rebleeding:

o Rockall score > 6 at presentation (HR 2.14; p=0.017)

o Active index bleeding (HR 1.88; p=0.043)

Author’s

conclusion

Following endoscopic hemostasis of bleeding ulcers, intermittent PPI regimen was as

effective as a continuous infusion regimen in reducing the risk of recurrent bleeding

Strengths Study design (multicentered, larger population compared to prior studies)

Assessed for independent predictive factors for rebleeding

Limitations Differences in baseline characteristics

Differing endoscopic interventions

Only in-hospital bleed events were reported

Appraisal Outcomes support continuous infusion is not superior to intermittent bolus regimens of

PPIs (despite higher percentage of patients with hemodynamic instability, Rockall

score > 6, severe comorbidities, and unimodal endoscopic hemostasis in the standard

regimen group)

o Significantly higher percentage of patients in the intensive regimen group

with prolonged hospital stay

o No difference in mortality due to bleeding

Table 5.

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C. Chen, et al. 2012.31

Objective Compare rebleeding rate of continuous infusion vs. intermittent PPI after endoscopic

hemostasis

Design Prospective, randomized, superiority trial conducted in a single hospital in Taiwan

from January 2008 to August 2010

Interventions:

o Endoscopic hemostasis within 24 hr

o Continuous infusion pantoprazole regimen (80 mg loading dose, followed

by continuous infusion of 8 mg/hr x 72 hr)

o Intermittent pantoprazole regimen (40 mg bolus once daily x 72 hr)

o After 72 hr, switched to oral pantoprazole (40 mg once daily) x 27 days

Inclusion/

exclusion

criteria

Inclusion Exclusion

- > 16 years of age

- Overt gastrointestinal bleeding

- Endoscopy within 24 hr

- Forrest Ia, Ib, IIa ulcers

- Acute myocardial infarction or cerebral

infarction within 7 days

- Bleeding tendency (platelet count

<50,000; INR >1.5, or taking

anticoagulants)

- Failed initial hemostasis

- Received >40 mg of PPI IV within 24 hr

of enrollment

Outcomes Primary: recurrent bleeding within 30 days (confirmed at repeat endoscopy)

o Rebleeding: blood pressure (< 90mmHg) or in pulse rate (> 110 beats

per minute) with melena; Hgb (>2 g/dL) within 24 hr after stabilization;

reappearance of over bleeding (new hematemesis or melena)

Secondary: need for transcatheter arterial embolization (TAE) or surgery, transfusion

requirement, length of hospital stay, and mortality

Statistical

analyses Estimated rebleeding rate: 5% with continuous infusion PPI and 13.2% with

intermittent PPI

201 patients per treatment arm needed (α=0.05; power= 0.80)

Intention-to-treat (ITT) and per-protocol (PP) analyses

Planned interim analysis when n=201

Baseline characteristics and outcome measures: Student’s t-test for parametric data,

Pearson’s chi-squared test or Fisher’s exact test for proportions

Kaplan-Meier method to compare differences of cumulative proportions

Stepwise Cox regression model to detect independent risk factors for rebleeding

Results

Demographics 201 patients randomized; study terminated after interim analysis

Continuous

(n=100)

Intermittent

(n=101)

p-value

Mean age (years) 65.5 + 15.1 64.9 + 12.2 0.76

H. pylori infection (%) 62.0 67.3 0.43

Hemodynamic shock (%) 28.0 34.7 0.31

Previous ulcer disease (%) 54.0 48.5 0.44

Previous ulcer bleeding (%) 35.0 32.7 0.73

Mean Hgb (g/dL) 9.7 + 2.5 10.0 + 2.3 0.41

Rockall score > 6 41.0 45.5 0.52

Forrest classification (%)

Ia

Ib

IIa

9.0

32.9

59.0

3.0

38.6

59.0

0.07

0.33

0.93

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Outcomes Continuous

(n=100)

Intermittent

(n=101)

p-value

Rebleeding within 30 days (%)

ITT analysis

PP analysis

7.0

6.2

6.9

5.2

0.98

0.77

Total hospital stay within 5 days (%) 56.7 59.3 0.70

Mean units of blood transfused

within 30 days

2.9 + 6.2 1.6 + 2.2 0.05

Bleeding-related mortality within 30

days (%)

1.0 1.0 0.99

Surgery within 30 days 0 0 1

TAE within 30 days 1.0 0 0.32

Independently associated with rebleeding: ESRD (HR 37.15; p<0.001), hematemesis

(HR 10.07; p=0.004); COPD (HR 9.12; p=0.011), H. pylori (HR 0.20; p=0.042)

Author’s

conclusion

Following combined endoscopic hemostasis, co-morbidities, hematemesis, and H. pylori

status, but not PPI dosage, are associated with rebleeding. Continuous infusion

pantoprazole had no advantage with respect to recurrent bleeding within 30 days,

transfusion amount, need for surgery or TAE, length of hospital stay, or death.

Strengths Uniform method for endoscopic therapy

Examined effects of comorbidities, H. pylori status, and CYP2C19 genotypes

Followed outcomes for 30 days

Limitations Single center study in Taiwan

Appraisal Interim analyses showed similar rates of rebleeding in both groups, suggesting that

continuous infusion is not superior to bolus dosing of PPIs

o Interim analysis indicated >8400 patients in each arm would be needed

based on the narrow difference of rebleeding rate

o No difference in length of hospital stay, bleeding-related mortality, or

intervention requirement

Table 6.

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D. Liu, et al. 2012.32

Objective Determine the most efficient PPI regimen and optimal timing of endoscopy

Design Prospective, randomized, double blind study conducted in a single hospital in China

from May 2005 to May 2010

Endoscopy groups:

o Early endoscopy group (within 24 hr of presentation)

o Late endoscopy group (24 – 72 hr after presentation)

Interventions (omeprazole or esomeprazole):

o Continuous infusion: 80 mg PPI loading dose, followed by a continuous

infusion of 8 mg/h x 72 hr

o Intermittent: 40 mg IV bolus PPI twice daily x 72 hr

o After 72 hr, switched to oral PPI therapy (20 mg twice daily) until

discharge

Inclusion/

exclusion

criteria

Inclusion Exclusion

- Age > 18 years

- Peptic ulcer at index endoscopy

- Malignant-appearing ulcers

- Bleeding from alternate sources

- Severe comorbid conditions (including

advanced cardiac and pulmonary disease,

chronic renal insufficiency)

- Coagulopathy (platelets <100K; INR >1.5)

- Need for continuous anticoagulation

- Hemodynamic shock (SBP <90 mmHg)

Outcomes Primary: rebleeding (confirmed at repeat endoscopy)

o Rebleeding: blood pressure (< 100 mmHg), pulse rate (> 100 bpm),

Hgb (>2.0 g/dL), no change in Hgb levels with RBC transfusions, and

reappearance of overt bleeding (new hematemesis or melena)

Secondary: need for endoscopic therapy at the first endoscopic examination, number

of instances of endoscopic therapy, transfusion requirements, duration of hospital

stay, need for surgery, mortality

Statistical

analyses Two-sided χ

2 Pearson’s test for the primary endpoint

Two-sample t-test for continuous variables

Fisher’s exact test for discrete variables

Results

Demographics 875 patients included for analysis

Continuous

(n=419)

Intermittent

(n=456)

p-value

Mean age (years) 53.8 + 19.9 55.3 + 17.8 0.24

Timing of endoscopy (%)

Early (< 24 hr)

Late (> 24 hr)

45.2

54.8

39.9

60.1

0.26

Type of PPI administered (%)

Omeprazole

Esomeprazole

59.7

40.3

57.7

42.3

0.55

Previous ulcer disease (%) 12.9 10.7 0.33

Forrest classification (%)

Ia

IIa

IIb

IIc

III

9.5

9.1

6.9

36.3

37.9

9.0

11.0

9.9

32.0

36.0

0.78

0.35

0.12

0.59

0.54

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Outcomes Continuous

(n=419)

Intermittent

(n=456)

p-value

Endoscopic therapy (%)

Early therapy

Late therapy

25.5

15.9

10.0

29.8

16.7

13.2

0.20

0.64

0.50

Rebleeding (%)

Early endoscopy

Late endoscopy

6.4

2.4

4.0

11.0

3.5

7.5

0.02

0.32

0.03

Rebleeding after endoscopic

therapy (%)

Early therapy

Late therapy

7.5

4.7

2.8

16.2

8.8

7.4

0.04

0.31

0.20

Number of endoscopic

therapies (%)

1

> 2

23.6

1.9

25.0

4.8

0.64

0.02

No. of units of blood transfused

Early endoscopy

Late endoscopy

1.23 + 2.13

0.65 + 1.64

1.81 + 2.62

1.93 + 2.12

1.15 + 1.89

2.71 + 2.35

<0.001

0.007

<0.001

Hospital stay (days)

Early endoscopy

Late endoscopy

6.2 + 4.6

5.2 + 4.0

7.2 + 5.2

9.4 + 5.7

8.5 + 5.1

10.3 + 6.3

<0.001

<0.001

<0.001

Surgery (%) 3.1 4.2 0.40

Death within 180 days (%) 0.2 1.3 0.16

Blood transfusion (0.90 + 1.76 units vs. 2.26 + 2.48 units; p<0.001) was significantly

lower and hospital stay (6.8 + 4.6 days vs. 8.8 + 5.8 days; p<0.001) was significantly

shorter in the early endoscopy group vs. late endoscopy group

Author’s

conclusion

Continuous infusion PPI is more efficacious in reducing rebleeding rate, blood

transfusion requirements, and hospital stay. The difference in rebleeding was restricted to

patients in the late endoscopy group, suggesting the special role of continuous infusion

when endoscopy is delayed >24 hours. Early endoscopy is safe and more effective than

late endoscopy.

Strengths Large sample size

Patients followed for 180 days after randomization

Limitations Single center

Excluded patients with severe comorbidities or hemodynamic shock

Method of endoscopic therapy was at the discretion of the treating endoscopist

Difficulty separating effects of timing of endoscopy from effects of PPI regimen

Unclear statistics

Appraisal Results show increased rebleeding with intermittent therapy; however, study may be

limited by several confounding factors and methodological limitations (i.e.,

exclusion criteria, and unclear statistics)

Table 7.

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E. Sachar, et al. 2014.33

Objective Compare intermittent with continuous-infusion PPI therapy for reduction of rebleeding

Design Searches of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled

Trials through December 2013; US and European gastroenterology meeting abstracts

from 2009 to 2013; and bibliographies of systematic reviews

Interventions:

o Intermittent therapy: PPIs administered in intermittent boluses (no restriction on

frequency or dose of boluses or the route of administration)

o Continuous therapy: 80 mg IV loading dose, followed by continuous 8mg/hr IV

infusion x 72 hr

Inclusion/

exclusion

criteria

Inclusion Exclusion

- Patients with upper GI bleeding

- Class I, IIa, or IIb gastric or duodenal

ulcer

- Received successful endoscopic

hemostatic therapy, with

randomization to intermittent or

continuous PPI treatment

- Patients with class IIc or III ulcers

with flat spots and clean bases

Outcomes Primary: rebleeding within 7 days

Secondary: rebleeding within 3 days and 30 days, mortality, need for surgery and

radiologic intervention, need for urgent intervention, RBC transfusions, and length

of hospitalization

Data analysis Cochrane Collaboration’s risk-of-bias tool and criteria used for assessing risk of bias

Mantel-Haenszel statistical method used to calculate risk ratios (RRs) for

dichotomous pooled outcomes

Primary analysis: noninferiority analysis (noninferiority margin: absolute risk

difference of 3%), 1-sided 95% CI

χ2 test and the Ι

2 statistic to assess heterogeneity (significant heterogeneity: p<0.05)

Results

Demographics 13 studies included for analysis

Outcomes Primary outcome (rebleeding for intermittent vs. continuous within 7 days):

o Per-protocol: RR 0.72; upper boundary of the 1-sided 95% CI of the absolute

risk difference was -0.28%

o Intention-to-treat: RR 0.74; upper boundary of the 1-sided 95% CI of absolute

risk difference was 0%

Secondary outcomes (intermittent vs. continuous):

Outcome # of

studies

# of

patients

Risk ratio (95%

CI, upper

boundary)

Absolute risk

difference, %

(95% CI, upper

boundary)

Recurrent bleeding

Within 7 d

Within 3 d

Within 30 d

10

9

13

1346

1146

1691

0.72 (0.97)

0.73 (1.02)

0.89 (1.17)

-2.64 (-0.28)

-2.36 (0.17)

-0.97 (1.49)

Mortality 11 1453 0.64 (1.21) -0.74 (0.43)

Surgery/Interven Rad 12 1491 0.87 (1.49) -0.30 (1.12)

Urgent interventions 9 1283 0.95 (1.27) -0.45 (2.43)

Hospital stay, d 8 1204 -0.26 -

Blood transfusion, U 9 1242 -0.22 -

No significant interaction effect seen in the predefined subgroup analyses

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Author’s

conclusion

Intermittent PPI therapy is comparable to continuous infusion of PPIs in patients with

endoscopically treated high-risk bleeding ulcers.

Strengths Included several studies to assess a larger population

Only included high-risk ulcers

Assessed for heterogeneity of studies

Assessed for potential influencing factors on rebleeding rate

Limitations Differences in endoscopic treatment

Variation in PPI dosing between studies

Appraisal Outcomes show noninferiority of intermittent dosing of PPI vs. continuous infusion

Table 8.

IV. Summary/Recommendations

A. Majority of data show comparable outcomes for prevention of rebleeding with intermittent dosing of

PPIs compared to continuous infusion

B. For most patients with peptic ulcers with high risk stigmata, it would be appropriate to administer PPI

as intermittent boluses rather than as a continuous infusion for prevention of recurrent peptic ulcer

bleeding after endoscopic therapy

C. Evaluate patients individually

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