Alan N. Barkun

ADVANCES IN THE MANAGEMENT OF NON

VARICEAL GASTROINTESTINAL HEMORRHAGE – a 2004 update

Division of GastroenterologyMcGill University and the McGill

University Health CentreMontréal, Canada

INTRODUCTION Significant evolution in the management of

patients with non variceal upper GI bleeding (supportive care, pharmacological treatment and endoscopic hemostasis)

The last Consensus guidelines published: Gut 2002 – incomplete Before that: NIH Consensus Conference, almost

15 years ago

AIMS

To review major advances in the management of patients with gastrointestinal hemorrhage

To highlight the contribution of 2 major Canadian initiatives that have helped set the international standards of care: RUGBE The Banff Consensus Conference

Ann Int Med., 2003 – Banff Consensus group on Non Variceal Upper GI Bleeding

NON VARICEAL UPPER GASTROINTESTINAL BLEEDING

ALL GI BLEEDERS

Identify thehigh risk Pt

80% stop bleeding 20% bleed on,on their own or re-bleed

20% RE-BLEEDING RATE TARGET GROUP ANY Rx

RUGBE: Endoscopic Findings

PUD56%

Other30%

Esophagitis

8%

M-W tear

4%

Dieulafoy

2%oozing22%

visiblevessel14%

clean base46%

other

Spurting

3%

clot

7%

spot

4%

2484 procedures in 1869 patients

Endoscopy performed within 24 hrs in 76%

Barkun et al., Am J Gastroenterol. 2004

Main Outcomes

Continued bleeding/rebleeding 14.1%

Surgery 6.5%

Mortality 5.4%

Mean hospitalization 5.6±6.1 d

Barkun et al., Am J Gastroenterol. 2004

Hospitals should develop institution specific protocols for multidisciplinary

management, which should include access to an endoscopist with training

in endoscopic hemostasis (III C)

A: 100%

STATEMENT 1

80% of RUGBE sites did not have aspecific protocol

Support staff trained to assist in endoscopy should be available for

urgent endoscopy (III C)

A: 92%, B: 8%

STATEMENT 2

Only 40% of all RUGBE sites had anurse taking availability call

Immediate evaluation and appropriate resuscitation is

critical to proper management (III C)

A: 96%, B: 4%

STATEMENT 3

Recent level II data suggest that is true, but only historical controlgroup (Baradarian Am J Gastro 2004)

Clinical (non-endoscopic) stratification of patients into low- and high-risk categories for rebleeding and mortality is important for proper management. Available prognostic scales may be used to assist in decision making. (II-2 B)

A: 76%, B: 24%

STATEMENT 5

Blatchford criteria (BMJ, 1997)

Risk factor for mortality

N=1334

Multifactorial analysis

Age >75 vs 45-59 yrs 304 4.5 (2-10)

Urea 8-24.9 vs 6.5 mmol/L >25 vs <6.5 mmol/L

67863

5.5 (2-15)18 (5.3-59)

Blood Pressure (diast.) 60- 69 vs >70 mmHg <60 vs >70 mmHg

261116

3.8 (1.8-7.7)3.1 (1.7-5.6)

Co-morbidity Cardiac failure Hepatic failure Disseminated cancer Other major diseases

253371

304

9.4 (3.2-28)43 (14-133)3.8 (1.8-8.1)1.8 (1-3.1)Adapted from BMJ 1997

Independent Predictors of Mortality Clinical Scenarios (all patients who were not transferred)

• Age = 65• Nb of comorbidities > 1• ASA > score 1• Bright blood per NGT = No• Systolic blood pressure

at initial assessment = 120 mm Hg

Inpatientsstatus at time

of bleeding

yes

no

Bright blood

per rectal exam

yes

no

Bright blood

per rectal exam

Rebleeding

Rebleeding

yes

no

yes

no

yes

no

Rebleeding

Rebleeding

yes

no

yes

no

Probability of Mortality

1.3 %

6.6 %

3.8 %

17.3 %

3.6 %

9.9 %

36.7 %

16.4 %

In selected patients, the placement of a naso-gastric tube can be

considered because the findings may have prognostic value (II-3 B)

A: 42%, B: 33%, C: 25%

STATEMENT 4

ROLE of NGA

Diagnostic criteria Bloody Bloody or coffee grounds

Any NGA result other than clear/bile

Sensitivity (%) 48.4 (CI: 40.3-56.5) 80.4 (CI: 73.3-86.4) 93.5 (CI: 88.3-96.8)

Specificity (%) 75.8 (CI: 70.0-80.0) 31 (CI: 26.4-36.0) 15.8 (CI: 12.3-20.0)

PPV (%) 45.4 (CI: 37.6-53.3) 32.7 (CI: 28.0-37.8) 31.6 (CI: 27.4-36.2)

NPV (%) 77.9 (CI: 73.2-82.0) 79.2 (CI: 71.6-85.5) 85.3 (CI: 74.6-92.7)

Positive likelihood ratio

2.00 (CI: 1.6-2.6) 1.20 (CI: 1.1-1.3) 1.1 (CI: 1.0-1.2)

Diagnostic accuracy (%)

67.7 (CI: 63.7-71.7) 45.6 (CI: 41.3-49.9) 38.7 (CI: 34.5-42.8)

Aljebreen AM et al., 2003

Early stratification of patients into low- and high-risk categories for rebleeding and mortality, based on clinical AND endoscopic criteria, is important for proper management. Available prognostic scales may be used to assist in decision making. (I A)

A: 96%, B: 0, C: 4%

STATEMENT 6

Rockall Score – Risk assessment of Death/Rebleeding (N=4185)

Variable 0

Score 1

2

3

Age (yrs) < 60 60-79 ≥ 80

Shock No shockP < 100Syst BP ≥ 100

P ≥ 100 plusSys BP ≥ 100

Hypotension

Diagnosis MW tear, normal endoscopy with no blood seen

All other diagnosis Malignancy of UGI tract

Major SRH None or dark spot Blood in UGI tractAdherant clot, visible or spurting vessel

Comorbidity No or mild coexisting Moderate coexisting (e.g., hypertension)

Severe coexisting (e.g., CHF)

Life threatening (e.g., RF)

Rockall, Lancet 1996

RUGBE validation of the Rockall scoring has been submitted for

publication (Enns et al.)

Early endoscopy (within the first 24 hours)

Allows for safe and prompt discharge of patients classified as low-risk* (I A)– A: 92%, B: 8%

Improves patient outcomes for patients classified as high-risk* (II-2 C)– A: 64%, B: 36%

Reduces resource utilization for patients classified as either low- or high-risk* (IA)– A: 88%, B: 12%*by clinical and endoscopic criteria

STATEMENT 7

Increasing risk of negative outcome

Early endoscopy

23.41%

14.41%

9.53% 9.21%

10.61%

5.09%

1.39%0.75%

1.29% 1.55%

3.48%

10.28%9.00%

0

5

10

15

20

25

</= 4 4-8 8-12 12-16 16-20 20-24 24-28 28-23 32-36 36-40 40-44 40-48 >/=48

Time (hours)

Pat

ient

s (%

)

FIGURE 1

23.41%

14.41%

9.53% 9.21%

10.61%

5.09%

1.39%0.75%

1.29% 1.55%

3.48%

10.28%9.00%

0

5

10

15

20

25

</= 4 4-8 8-12 12-16 16-20 20-24 24-28 28-23 32-36 36-40 40-44 40-48 >/=48

Time (hours)

Pat

ient

s (%

)

FIGURE 1

75%

Prognostic Factors: Endoscopic

Laine, Peterson, N Engl J Med 1994.

5%10%

22%

43%

55%

0%

20%

40%

60%

80%

% o

f p

ati

en

ts r

eb

lee

din

g

Clean base Flat spot Adherentclot

Nonbleedingvisiblevessel

Activebleeding

Ia = spurterIa = spurterIb = oozerIb = oozer

IIaIIaIIbIIb

ForrestForrest

Incidence of Re-bleeding by Appearance of Ulcer at EndoscopyIncidence of Re-bleeding by Appearance of Ulcer at Endoscopy

The clean base ulcerThe clean base ulcer

The clean base ulcer / The pigmented dotThe clean base ulcer / The pigmented dot

A finding of low-risk endoscopic stigmata (a clean based ulcer, or a

non-protuberant pigmented dot in an ulcer bed) is not an indication for

endoscopic hemostatic therapy (I A)

A: 100%

STATEMENT 8

The outcome of adherent clots

A finding of clot in an ulcer bed warrants targeted irrigation in an attempt at

dislodgment. Endoscopic therapy for persistently adherent clots is controversial

(III C -- Ia)

A: 32%, B: 56%, C: 4%, D: 8% -- more unanimity

STATEMENT 9

Visible vessel

Active bleeding: “Spurter” (= trouble!)

Trouble – in slow motion

A finding of high-risk endoscopic stigmata (active bleeding or a visible

vessel in an ulcer bed) is an indication for immediate endoscopic hemostatic

therapy (I A)

A: 100%

STATEMENT 10

Endoscopic Therapy

Meta-analysis (Cook, et al.Gastroenterol,1992)

30 trials (n=2,412)

Similar results in an earlier meta-analysis of 25 trials (Sacks, et al. JAMA,1990)

Treatments studied:thermal (laser), few injection, no combination or clips

0.40-0.760.55Mortality

0.28-0.450.36Surgery

0.32-0.450.38Further

Bleeding

95% CIOR

OR=odds ratio for treatment vs. controls. Statistical heterogeneity was observed for bleeding and surgery.

OR CI

Recently confirmed by Bardou et al, 2003(71 studies, 9000 patients)

Injection therapy

Injection therapy

Inj Only (n=261), 38%

Thermal Only (n=161), 23%

Comb Them. and Inj. (n=232), 34%

Clips (alone or comb) (n=24), 3%

Other (n=10), 2%

Endoscopic Therapy

Monotherapy, with injection or thermal coagulation, is an effective endoscopic

hemostatic technique for high-risk stigmata; however, the combination is superior to either treatment alone (I B)

A: 36%, B: 48%, C: 16%

STATEMENT 13

The placement of clips is a promising

endoscopic hemostatic therapy for

high-risk stigmata (I B)

A: 44%, B: 52%, C: 4%

STATEMENT 14

Clipping a visible vessel / oozer

Clipping a visible vessel / oozer

Routine second look endoscopy is not recommended (I E)

STATEMENT 15

A: 92%, B: 8%

In cases of rebleeding, a second attempt at endoscopic therapy is

generally recommended (I A)

A: 100%

STATEMENT 16

Somatostatin and octreotide are not recommended in the routine management of patients (I C) **

A: 96%, B: 4%

STATEMENT 19

Most re-bleeding occurs withinthe first 72 hours

Lau et al, 1998

Early Risk of Re-bleedingNatural History of the Visible Vessel

25

613 95 9 8 8

00

20

40

80

100

Day 1 Day 2 Day 3

Pre

sen

ce f

ollo

win

g

end

osc

op

ic t

reat

men

t o

n D

ay 0

Visible Vesselsn = 25-52

60Adherent clot

Visible vessel

Active bleeding

%

Effect of acid suppression

• Acid is associated withDecreased platelet aggregation, and

platelet disaggregation (in vivo, and animal models) – ideal pH approximately 6.5

Increased clot lysis due to pepsin activation by acid (in vitro)

Increased fibrinolytic activity, that is impaired by acid suppression (in vitro, cell culture assays)

H2 receptor antagonists are not recommended in the management

of patients (I D)

A: 92%, B: 8%

STATEMENT 18

Effect of IV H2RA on Upper GI Bleeding:meta analysis of 1062 patients, 24 RCT’s

•NONO differences in outcomes attributable to IV differences in outcomes attributable to IV H2RA’s for ALL patientsH2RA’s for ALL patients•OnlyOnly significant differences amongst patients with significant differences amongst patients with bleeding gastric bleeding gastric ulcersulcers

-50

-30

-10

10

30

50

Levine JA et al., APT, 2002

Absolute change

(%)IV H2RA vsplacebo -7.2%

NNT =14

-3.2%

NNT =15

-6.7%

* *

NNT =32

Re-bleeding Surgery Mortality

o

Tolerance of H2RA

Netzer, 1999

Omeprazole IV

Ranitidine IV

Gastric pH

Role of PPI for UGI Bleeding:Continuous Infusion

6.7%

22.5%

2.5%7.5% 4.2%

10%

0%

20%

40%

60%

80%

100%

% P

ati

en

ts

Rebleeding Surgery Mortality

Outcomes in 240 patients treated with IV omeprazole or placebo post-endo Rx (Ia-IIa)

OME IV B 80 mg + 8mg /hrs x 3d (n=120) Placebo (n=120)

HR = 3.9 (1.7-9.0)*

P = 0.14 P = 0.13

Lau, et al. NEJM 2000.

3 RCT’s concur1RCT “negative”*

An IV bolus followed by continuous infusion intravenous proton pump inhibitor is effective in decreasing rebleeding in patients who have

undergone successful endoscopic therapy (I A)

A: 100%

STATEMENT 20

ci IV PPIvs placebo

ci IV PPIvs H2RA

Continuous Infusion IV PPI vs H2RA and placebo: meta-analysis

Bardou et al., submitted, 2004

0

5

10

15

20

25

30

20%

15.6%

2.8%

Absoluteriskreduction in % in themodel

Meta-analysisof 71 studies andover 9000 patientsincluded 16 H2RA and 4 CI IVPPIstudies since 1990

**

*

0

0.2

0.6

0.8

0.4

1

PPI use Endo Rx

Rebleeding

(all patients) (high-risk)

Worse effect

Protective effect

Od

ds

rati

o

0.53

*

0.39

*

n=1,677 n=601

Predictors of Outcome: Therapies

Barkun et al., Am J Gastroenterol. 2004

0

0.2

0.6

0.8

0.4

1

Mortality

(out-patients and high-risk)

PPI use Endo Rx

Worse effect

Protective effect

Od

ds

rati

o

0.18

*

0.31

*

n=432 n=432

Predictors of Outcome: Therapies

Barkun et al., Am J Gastroenterol. 2004

Role of PPI for UGI Bleeding – Oral - Following Endoscopic Therapy

Khuroo et a., 1997, Javid et al, 2001, Kaviani et al., 2002

As follow-up and in response to criticisms of the study by Khuroo et al, 1997

7

21

0

5

10

15

20

25

30

Rebleed

8.3

24

Surgery

1.22.4

Mortality

OME PO 40 mg q12h x 5d (n=82)

Placebo PO q12h x 5d (n=84)

P<0.022 P=NS

P=NS

Outcomes in 166 patients treated with

oral PPI or placebo after injection (Ia to IIb) OME PO 20 mg q6 h x 5d

(n=82)Placebo PO q12h x 5d (n=84)

17

33

GENERALIZABILITY OF RESULTS?Re: choice of endoscopic therapy

andeffect of pharmacotherapy

In patients awaiting endoscopy,

empiric therapy with high dose

proton pump inhibitor should be

considered (III C)

A: 40%, B: 32%, C: 16%, D: 12%

STATEMENT 21

Patients with ulcer bleeding should be tested for Helicobacter

pylori and receive eradication therapy if infection is present (I A)

A: 96%, B: 4%

STATEMENT 23

Cost-effectiveness of IV PPI therapy in 2004

Oral PPI’s?

Effectiveness

Costincreased decreased

increased

decreased

PRE- ENDOSCOPY

POST- ENDOSCOPY

US – Barkun, abs 2002Canada – Barkun, abs 2002

US – Gagnon, 2003Canada – Enns, 2003

HK – Lee, 2002US – Spiegel, 2003US – Barkun, 2004Canada – Gregor, abs 2001 Barkun, 2004

• Hospitalization - rebleed: CDN $5,220 – US $11,802

- no rebleed: CDN $2696 – US $7,993

• Yet over-utilization noted … (Cornish et al, 2002, Romagnuolo et al. x2 2004)

Why are IVPPI so cost-effective?

Medication costs$240

Cost of 1 re-bleeding$11,802

NNT – approx 5-6

Barkun et al., CJG, 2004

Future directions ABC’s and triaging remain the cornerstone of

optimal management More data are needed regarding

– Hemostatic clips and how they compare to other endoscopic hemostatic therapies

– Combination endoscopic therapies– Optimal IV PPI dosing, utilization patterns– Role of oral PPIs– Role of PPIs prior to endoscopy

An effort must be made to improve utilization