Do PPIs Reduce Bleeding in ICU? Revisiting Stress Ulcer Prophylaxis Deborah Cook
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
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 PPIs H2RAs PPIs, if any? H2RAs
Etiologic Risk
Temporal Risk
Incidence Impression of Upper GI Bleeding Rates > 3.5% < 1 % 1999 Years 2017..Is SUP still needed?
200 Number Needed to Prophylax NNP 150 100 50 0 1 2 3 4 5 6 Baseline Risk Baseline Risk
Baseline Risk
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%
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% (3.4-6.0%) Clinically important GI bleeding: 2.6% (1.6%-3.6%)
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
ICM 2015 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)
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-analysis 57 RCTs enrolling 7293 patients Placebo PPI H2RA Sucralfate
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
Risk: Benefit of Prophylaxis
Do the risks outweigh the benefits? Upper GI Bleeding Pneumonia Clostridium Difficile
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
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
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
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 (0.91-1.13) 0.96 (0.83-1.11) --
Do PPIs Increase Risk of Death? Subgroup PPI Placebo Relative Risk (95%CI) SAPS II >53 272/579 229/558 1.13 (0.99-1.30) (37.5% sample) (47.0%) (41.0%) SAPS<53 205/929 231/967 0.92 (0.78-1.09) (p=0.05) (22.1%) (23.9%)
Secondary Composite Clinically important bleeding Pantoprazole N~1642 41 (2.5%) Pneumonia 266 Clostridium Difficile (16.2%) 19 (1.2%) Placebo N~1640 69 (4.2%) 266 (16.2%) 25 (1.5%) Relative Risk (95%CI) 0.58 (0.40-0.86) 1.00 (0.84-1.19) 0.76 (0.42-1.39) Myocardial ischemia 77 (4.7%) 66 (4.0%) 1.17 (0.84-1.65)
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)
Bleeding Characteristics PPI Placebo N=41 N=69 Endoscopy 16 28 Surgery 3 5 Coiling 2 4 Ulcer 10 17 Gastritis 4 4 Other 6 14
NEJM 2018
In the twittersphere This will change my practice! Bye Bye, PPI! This raises concern about high risk patients!
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
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
GI bleeding Crit Care 2018 C. difficile
Mechanisms for Enteral Nutrition Prophylaxis Buffering acid Inducing Prostaglandins 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 Considerations As 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 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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