Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICUOCTOBER 24, 2018, NEJM

OutlineØBackground

ØMethods

ØResults

ØDiscussion & Conclusion

Background

Adverse OutcomeGI bleeding(Stress Ulcer)

Critically Ill Patients

Cook, et al. Crit Care 2001

Stress Ulcer Prophylaxis (SUP)

Indications:lMechanical ventilation

lCoagulopathy

lPrevious GI bleeding

lProlonged duration of ICU stay

lSteroid therapy

l……

Krag, et al. Acta Anaesthesiol Scand 2015

Guidelines

Proton-pump inhibitors(PPI) are the most common choice for SUP

Krag, et al. Acta Anaesthesiol Scand 2015

Proton-pump inhibitors(PPI) are the most common choice for SUP

Barletta, et al. J Intensive Care Med 2015

Pantoprazole was the most frequently used PPI

Maclaren, et al. JAMA Intern Med 2014

Quality of evidence supporting the prophylactic use of PPI is limited

Cook, et al. N Engl J Med 2018

Adverse outcome associated with PPIlClostridium difficile infection

lPneumonia

lMyocardial ischemia

l……

Krag, et al. Curr Opin Crit Care 2016

Aim

To evaluate the effects of and adverse events associated with the prophylactic use of the PPI pantoprazole in adult patients in the ICU who were at risk for GI bleeding

Methods

Study DesignüMulticenterüStratifiedüParallel-groupüPlacebo-controlledüBlinded From January 4, 2016 to October 22, 2017, in 33 ICUs in Denmark, Finland, the Netherlands, Norway, Switzerland, and the United Kingdom

Inclusion Criteriaü Acute admission to the ICU

ü Aged ≥ 18 years

ü One or more of risk factors for clinically important gastrointestinal bleeding

Risk factorsüShock (continuous infusion with vasopressors or inotropes, systolic blood pressure < 90 mmHg, mean arterial blood pressure < 70 mmHg or lactate > 4mmol/l)

üOngoing treatment with anticoagulant drugs

üAcute or chronic intermittent or continuous renal-replacement therapy

üInvasive mechanical ventilation (expected to last >24 hours)

üHistory of liver disease(portal hypertension, cirrhosis proven by biopsy, computed tomography (CT) scan or ultrasound, history of variceal bleeding or hepatic encephalopathy in the past medical history)

üOngoing or history of coagulopathy (platelets < 50 x 109 /l or INR > 1.5 or PT > 20 seconds within 6 months prior to hospital admission)

Exclusion criteriaü Contraindications to PPI

ü Ongoing treatment with PPI and/or H2RA on a daily basis

ü GI bleeding of any origin during current hospital admission

ü Diagnosed with peptic ulcer during current hospital admission

ü Organ transplant during current hospital admission

ü Withdrawal from active therapy or brain death

ü Fertile woman with positive urine human chorionic gonadotropin (hCG) or plasma-hCG

ü Consent according to national regulations not obtainable

Randomization Patients who were included, were randomly assigned in a 1:1 ratio with the use of permuted blocks of varying sizes to receive pantoprazole or placebo.

Interventions Enrolled patients received an intravenous injection of pantoprazole (40 mg suspended in 10 ml of 0.9% sodium chloride) or matching placebo (suspended in 10 ml of 0.9% sodium chloride) as a single bolus once daily from randomization until ICU discharge or death, for a maximum of 90 days.

Outcomes Primary outcome: 90-day mortality post-randomization

Secondary outcome:

üClinically important events in the ICU

üInfectious adverse events in the ICU (new-onset pneumonia or C. difficile infection)

üSerious adverse reactions in the ICU （ any adverse reaction that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, or results in persistent or significant disability or incapacity）

üPercentage of days alive without the use of life support (mechanical ventilation, circulatory support, or renal-replacement therapy)

Clinically important events Including:

ü Clinically important GI bleeding*

ü New onset pneumonia

ü C. difficile infection

ü Acute myocardial ischemia

Clinically important GI bleeding *overt gastrointestinal bleeding and at least one of the following four features within 24 hours of gastrointestinal bleeding, in the absence of other causes, in the ICUü Spontaneous decrease in systolic blood pressure, mean arterial pressure, or diastolic blood pressure of 20 mm Hg or more

ü Initiation of treatment with a vasopressor or a 20% increase in vasopressor dose

ü Decrease in hemoglobin of at least 2 g per deciliter

ü Transfusion of two or more units of packed red cells

Statistical analysis•The primary analysis of all dichotomous outcomes will compare the outcome at 90 days after randomization in the two groups by binary logistic regression analysis with adjustment for stratification variables

•The secondary analysis will be performed adjusting for stratification variables together with other known major prognostic co-variates

•A two-sided P value of less than 0.05 will be considered statistically significant

Results

Trial populationØ3298 patients were enrolled in the trial

Ø1645 were assigned to receive pantoprazole

Ø1653 were assigned to receive placebo

Baseline characteristicsThe characteristics of the patients at baseline were similar in the two groups besides:ØChronic lung disease(P=0.05)

ØCoagulopathy(P=0.02)

ØEmergency surgery(P=0.01)

OutcomesØAt 90 days after randomization, 510 of 1642 patients (31.1%) in the pantoprazole group and 499 of 1640 (30.4%) in the placebo group had died. The results were similar in the analysis with adjustment for baseline risk factors and in the per-protocol population

ØIn predefined subgroup analyses, there was no heterogeneity in the effect of pantoprazole as compared with placebo on mortality at 90 days between patients with and patients without a history of liver disease, a history of or ongoing coagulopathy, shock, or mechanical ventilation, or between patients with different types of ICU admission

OutcomesØThe proportions of patients in each group with the other secondary outcomes and with single components of the composite outcome were similar in the two groups

OutcomesØ In the pantoprazole group, 41 patients (2.5%) had clinically important gastrointestinal bleeding, as compared with 69 (4.2%) in the placebo group.

Discussion &Conclusion

Discussionl 90-day mortality, percentages of days alive without the use of life support, and numbers of patients with clinically important events, infectious adverse events, or serious adverse reactions were similar between those treated with pantoprazole and those who received placebo

l Fewer patients in the pantoprazole group than in the placebo group had clinically important gastrointestinal bleeding in the ICU

Similar to previous studies

StrengthslLarge sample size

lVariety of ICUs and countries involved

Limitationsl Lack of assessment of other medical interventions

l Absence of reported serious adverse reactions to pantoprazole

l Absence of diagnostic endoscopy to assess the cause of GI bleeding

l Lack of determine whether patients had used acid suppressants before ICU admission or were receiving enteral nutrition at baseline

ConclusionlAdult patients who were admitted to the ICU for an acute condition and were at risk for gastrointestinal bleeding, no significant differences were found between pantoprazole and placebo with regard to either 90-day mortality or the number of patients with a composite outcome of clinically important events.

Thank you