Do PPIs Reduce Bleeding in ICU?

Revisiting Stress Ulcer Prophylaxis

Deborah Cook

ICU-Acquired Upper GI Bleeding

Case series of 300

ICU patients describing ‘stress-

related erosive syndrome’

Frequent

Fatal

Endoscopically proven

Lucas et al, Arch Surg 1971

All About Risk

• Etiologic risk - pathophysiology

• Temporal risk - trends over time

• Baseline risk – incidence of upper GI bleeding

• Attributable risk – associated morbidity & mortality

• Risk factors - clinical

• Risk minimization – stress ulcer prophylaxis

• Risk : benefit ratio of stress ulcer prophylaxis

• Risk of withdrawing ‘standard practice’

Past Present Future

Clinically Important

Bleeding

common uncommon rare?

Prophylaxis universal targeted highly

selected?

# Prophylactic

Drugs

2 1 none?

Which Prophylactic

Drugs

Antacids,

Sucralfate

H2RAs

PPIs

H2RAs

PPIs, if any?

Etiologic Risk

Temporal Risk

Impression of Upper GI Bleeding Rates

> 3.5%

< 1 %

1999 2017

Inci

den

ce

Years

…..Is SUP still needed?

0

50

100

150

200

1 2 3 4 5 6

Baseline Risk

Number Needed to Prophylax

Baseline Risk

NNP

Baseline Risk

Bleeding Definitions Are Key

• Endoscopic: erosions or ulcerations only

• Microscopic: occult, non-visualized

bleeding

• Macroscopic: nasogastric blood,

hematemesis, melena, hematochezia

• Clinically important bleeding: overt

bleeding with hypotension, tachycardia,

need for blood transfusions in the

absence of other causes

• >75%

• >50%

• >20%

• ~2-4%

• Objective: to describe the prevalence, risk factors, and attributable mortality of upper GI bleeding

• Design: 7 day observational study• Population: 1034 patients (without GI bleeding on

admission) • Setting: 97 ICUs in 11 countries (UK, Denmark, Sweden,

Finland, Canada, New Zealand, Australia, Norway, Iceland, Netherlands, Italy)

• Overt GI bleeding: 4.7% (3.4-6.0%)• Clinically important GI bleeding: 2.6% (1.6%-3.6%)

ICM 2015

Attributable Risk

Attributable Mortality & Length of ICU Stay

of Clinically Important Upper GI Bleeding

Mortality

Relative Risk Increase

LOS

Mean Difference

Crude comparison 2.2 (1.6 - 2.9) 17.2 (13.2 - 21.3)

Matched cohort 2.9 (1.6 - 5.5) 3.8 (-0.01 - 7.6)

Model-based

matched cohort

1.8 (1.1 - 2.9) 6.7 (2.7 - 10.7)

Regression 4.1 (2.6 - 6.5) 7.9 (1.4 - 14.4)

Adjusted regression 1.0 (0.6 - 1.7) 6.2 (1.0 - 11.4)

Cook et al & the CCCTG, Crit Care 2001

ICM 2015

Risk Factors

• Multicenter observational study of withholding stress ulcer prophylaxis from 2,252 patients

• Multiple logistic regression revealed only 2 independent risk factors with 4% bleeding risk:

– mechanical ventilation >48 h (OR 16)

– coagulopathy (OR 4)

• Other patients have a very low risk <0.01%CCCTG, NEJM 1994

Risk Factors for Clinically Important GI bleeding

• Independent risk factors

– >3 co-existing diseases (OR 8.9, 2.7-28.8)

– chronic liver disease (OR 7.6, 3.3-17.6)

– renal replacement therapy (OR 6.9, 2.7-17.5)

– acute coagulopathy (OR 5.2, 2.3-11.8)

– chronic coagulopathy (OR 4.2, 1.7-10.2)

– acid suppressing agents (OR 3.6, 1.3-10.2)

– higher organ failure score (OR 1.4, 1.2-1.5)

ICM 2015

Risk Minimization

• H2RA decreased risk of CIB

• RR 0.44; 95% CI, 0.21 to 0.92; P 0.02

57 RCTs enrolling 7293 patients

High risk of bias in 30 trials

Low risk of bias in 16 trials

Unclear risk of bias in 11 trials

ICM 2018

SUP Network Meta-analysis57 RCTs enrolling 7293 patients

H2RA

Placebo

PPI

Sucralfate

Design: Blinded pilot RCT

Inclusion: 4 months – 18 years

>48 h expected MV

Intervention: Pantoprazole 1

mg/kg or placebo q24h

The PIC-UP Pilot RCT

85 of 120 children randomized

7 centers

Outcomes: 1. Effective screening

2. Satisfactory enrolment

3. Protocol timeliness

4. Protocol adherence

Funding: CIHR, Hamilton Health

Sciences, IWK Health Centre

Risk: Benefit of Prophylaxis

Do the risks outweigh the benefits?

Upper GI Bleeding

PneumoniaClostridium

Difficile

Meta-analysis of PPIs vs Placebo: 6 RCTs enrolling 713 Patients as of October 2018

Outcomes All outcomes: low quality evidence; I2=0%

Upper GI Bleeding

OR 0.96; 95% CI 0.24, 3.82; p=0.95

Clostridium Difficile

OR 2.10; 95% CI 0.31, 14.07; p=0.44

VAP OR 1.45; 95% CI 0.84, 2.50; p=0.18

Mortality OR 1.11; 95% CI 0.76, 1.61; p=0.58

Risk of

Withdrawing Standard Practice

Why Is the Intervention Placebo?

• Article 6

“Even the ‘best proven interventions’

must be evaluated continually

through research for their safety,

effectiveness, efficiency, accessibility

and quality”

Declaration of Helsinki

SUP-ICU Trial

Aim

• To evaluate the effects of pantoprazole vs placebo

Hypotheses• Pantoprazole will decrease bleeding

• Pantoprazole will increase infections

Sample Size • 3350 patients would give 90% power for PPIs to detect a

decrease in the 90d mortality rate of 25% by 20%, to 20%

Design • Randomized concealed blinded superiority trial

Setting • 33 ICUs in Denmark, Finland, Netherlands, Norway,

Switzerland, UK

ResultsOutcomes PPI Placebo Relative Risk

(95%CI)

Primary:

90d mortality

510

(31.1%)

499

(30.4%)

1.02 (0.91-1.13)

Secondary:

>1 Clin impt event

(Clinically important bleed,

Pneumonia, Clostridium

difficile, Myocardial ischemia)

Days alive without

advanced life support

360

(21.9%)

92

(60,97)

372

(22.6%)

92

(65,97)

0.96 (0.83-1.11)

--

Do PPIs Increase Risk of Death?

Subgroup PPI Placebo Relative Risk

(95%CI)

SAPS II >53

(37.5% sample)

272/579

(47.0%)

229/558

(41.0%)

1.13 (0.99-1.30)

SAPS<53

(p=0.05)

205/929

(22.1%)

231/967

(23.9%)

0.92 (0.78-1.09)

Pantoprazole

N~1642

Placebo

N~1640

Relative Risk

(95%CI)

Clinically

important

bleeding

41

(2.5%)

69

(4.2%)

0.58 (0.40-0.86)

Pneumonia 266

(16.2%)

266

(16.2%)

1.00 (0.84-1.19)

Clostridium

Difficile

19

(1.2%)

25

(1.5%)

0.76 (0.42-1.39)

Myocardial

ischemia

77

(4.7%)

66

(4.0%)

1.17 (0.84-1.65)

Secondary Composite

Bleeding Characteristics

PPI Placebo

Decrease in SBP, DBP or MAP by > 20mmHg

25/41 46/69

Vasopressor started or increased by > 20%

22/41 35/69

> 2g/dl hemoglobin drop 23/41 41/69

> 2U PRBC transfusion 29/41 39/69

Pts transfused overall 535/1644 (32.5%) 488/1647 (29.6%)

Transfused RBCs/patient 0 (0,1) 0 (0,1)

Bleeding Characteristics

PPI

N=41

Placebo

N=69

Endoscopy 16 28

Surgery 3 5

Coiling 2 4

Ulcer 10 17

Gastritis 4 4

Other 6 14

NEJM 2018

Bye Bye,

PPI!

This raises concern about high risk

patients!

This will

change my

practice!

In the twittersphere

Editorialists’ Take Home Messages:

“Though no mortality difference, bleeding reduction may still support PPIs, based on admittedly small 1.7% ARR”

“Additional data needed to determine effects of PPIs in the ICU, especially in patients at very high risk for this complication & to quantify any protective or harmful effects attributable to coadministration of enteral nutrition”

NEJM 2018

Decrease in

Clinically Important

Bleeding

No effect on:

Mortality

LOS

Life support

Clinically important events

Pneumonia

Clostridium difficile

Myocardial ischemia

Transfusions

Concern about harm in most severely ill

Questionable cost-effectiveness

Uncertain utility with enteral feeding

Crit Care 2018

GI bleeding

C. difficile

Mechanisms for Enteral Nutrition Prophylaxis

Buffering acid

InducingProstaglandins

Enhancing blood flow

Sparse RCT data For this Daily Intervention

Mortality

6 RCTs, 1124 events

3884 patients

Pneumonia

5 RCTs, 565 events

3863 patients

Clinically Important

GI Bleeding

6 RCTs, 118 events

3893 patients

Clostridium Difficile

Infection

3 RCTs, 48 events

3596 patients

J Clin Epi 2013

J Clin Epi 2013

Special ConsiderationsAs of November 2018

• 6 RCTs of 3800 patients

• Frailty for some outcomes

• Variable practice

• Unclear approach to pre-ICU PPI use

• Prophylactic potential of enteral nutrition

• Remaining concern about harm

• Not enough data to continue adoption

• Not enough data to continue de-adoption

• Not enough data to inform cost-effectivenes

• Unclear policy implications

INCLUSION

• > 18 years old in ICU• Invasive mechanical ventilation • Enteral nutrition

Pantoprazole indicated or contraindicated Active or high risk for GI bleed Mechanical ventilation > 72hrs Received > 24 h PPI or H2RA in ICU Dual anti-platelet therapy Limitation of life support Pregnancy

EXCLUSION

Placebo Pantoprazole

Clinically impt upper GI bleed, pneumonia, C Difficile,

AKI, mortality

Randomize

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