Do PPIs Reduce Bleeding in ICU? Revisiting Stress Ulcer Prophylaxis. Deborah Cook

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1 Do PPIs Reduce Bleeding in ICU? Revisiting Stress Ulcer Prophylaxis Deborah Cook

2 ICU-Acquired Upper GI Bleeding Case series of 300 ICU patients describing stressrelated erosive syndrome Frequent Fatal Endoscopically proven Lucas et al, Arch Surg 1971

3 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

4 Past Present Future Clinically Important Bleeding common uncommon rare? Prophylaxis universal targeted highly selected? # Prophylactic Drugs 2 1 none? Which Prophylactic Drugs Antacids, Sucralfate PPIs H2RAs PPIs, if any? H2RAs

5 Etiologic Risk

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7 Temporal Risk

8 Incidence Impression of Upper GI Bleeding Rates > 3.5% < 1 % 1999 Years Is SUP still needed?

9 200 Number Needed to Prophylax NNP Baseline Risk Baseline Risk

10 Baseline Risk

11 Bleeding Definitions Are Key Endoscopic: erosions or ulcerations only >75% Microscopic: occult, non-visualized bleeding Macroscopic: nasogastric blood, hematemesis, melena, hematochezia >50% >20% Clinically important bleeding: overt bleeding with hypotension, tachycardia, need for blood transfusions in the absence of other causes ~2-4%

12 ICM 2015 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% ( %) Clinically important GI bleeding: 2.6% (1.6%-3.6%)

13 Attributable Risk

14 Attributable Mortality & Length of ICU Stay of Clinically Important Upper GI Bleeding Mortality Relative Risk Increase LOS Mean Difference Crude comparison 2.2 ( ) 17.2 ( ) Matched cohort 2.9 ( ) 3.8 ( ) Model-based matched cohort 1.8 ( ) 6.7 ( ) Regression 4.1 ( ) 7.9 ( ) Adjusted regression 1.0 ( ) 6.2 ( ) Cook et al & the CCCTG, Crit Care 2001

15 ICM 2015

16 Risk Factors

17 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

18 ICM 2015 Risk Factors for Clinically Important GI bleeding Independent risk factors >3 co-existing diseases (OR 8.9, ) chronic liver disease (OR 7.6, ) renal replacement therapy (OR 6.9, ) acute coagulopathy (OR 5.2, ) chronic coagulopathy (OR 4.2, ) acid suppressing agents (OR 3.6, ) higher organ failure score (OR 1.4, )

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20 Risk Minimization

21 H2RA decreased risk of CIB RR 0.44; 95% CI, 0.21 to 0.92; P 0.02

22 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

23 SUP Network Meta-analysis 57 RCTs enrolling 7293 patients Placebo PPI H2RA Sucralfate

24 Design: Blinded pilot RCT Inclusion: 4 months 18 years >48 h expected MV The PIC-UP Pilot RCT Intervention: Pantoprazole 1 mg/kg or placebo q24h Outcomes: 1. Effective screening 2. Satisfactory enrolment 3. Protocol timeliness 4. Protocol adherence Funding: CIHR, Hamilton Health Sciences, IWK Health Centre 7 centers 85 of 120 children randomized

25 Risk: Benefit of Prophylaxis

26 Do the risks outweigh the benefits? Upper GI Bleeding Pneumonia Clostridium Difficile

27 Meta-analysis of PPIs vs Placebo: 6 RCTs enrolling 713 Patients as of October 2018 Outcomes All outcomes: low quality evidence; I 2 =0% Upper GI Bleeding Clostridium Difficile VAP Mortality OR 0.96; 95% CI 0.24, 3.82; p=0.95 OR 2.10; 95% CI 0.31, 14.07; p=0.44 OR 1.45; 95% CI 0.84, 2.50; p=0.18 OR 1.11; 95% CI 0.76, 1.61; p=0.58

28 Risk of Withdrawing Standard Practice

29 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

30 Aim SUP-ICU Trial 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

31 Primary: 90d mortality Secondary: Results Outcomes PPI Placebo Relative Risk (95%CI) >1 Clin impt event (Clinically important bleed, Pneumonia, Clostridium difficile, Myocardial ischemia) Days alive without advanced life support 510 (31.1%) 360 (21.9%) 92 (60,97) 499 (30.4%) 372 (22.6%) 92 (65,97) 1.02 ( ) 0.96 ( ) --

32 Do PPIs Increase Risk of Death? Subgroup PPI Placebo Relative Risk (95%CI) SAPS II >53 272/ / ( ) (37.5% sample) (47.0%) (41.0%) SAPS<53 205/ / ( ) (p=0.05) (22.1%) (23.9%)

33 Secondary Composite Clinically important bleeding Pantoprazole N~ (2.5%) Pneumonia 266 Clostridium Difficile (16.2%) 19 (1.2%) Placebo N~ (4.2%) 266 (16.2%) 25 (1.5%) Relative Risk (95%CI) 0.58 ( ) 1.00 ( ) 0.76 ( ) Myocardial ischemia 77 (4.7%) 66 (4.0%) 1.17 ( )

34 Decrease in SBP, DBP or MAP by > 20mmHg Vasopressor started or increased by > 20% Bleeding Characteristics PPI Placebo 25/41 46/69 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)

35 Bleeding Characteristics PPI Placebo N=41 N=69 Endoscopy Surgery 3 5 Coiling 2 4 Ulcer Gastritis 4 4 Other 6 14

36 NEJM 2018

37 In the twittersphere This will change my practice! Bye Bye, PPI! This raises concern about high risk patients!

38 Editorialists Take Home Messages: NEJM 2018 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

39 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

40 GI bleeding Crit Care 2018 C. difficile

41 Mechanisms for Enteral Nutrition Prophylaxis Buffering acid Inducing Prostaglandins Enhancing blood flow

42 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

43 J Clin Epi 2013

44 J Clin Epi 2013

45 Special Considerations As of November 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

46 INCLUSION > 18 years old in ICU Invasive mechanical ventilation Enteral nutrition Randomize EXCLUSION 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 Placebo Pantoprazole Clinically impt upper GI bleed, pneumonia, C Difficile, AKI, mortality

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