SUP-ICU

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Krag M, et al. "Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU". The New England Journal of Medicine. 2018. 379:2199-2208.
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Clinical Question

Among adult patients emergently admitted to an ICU with an increased risk for GI bleed, does administration of acid-suppressive therapy with the PPI pantoprazole alter mortality at 90 days when compared to placebo?

Bottom Line

Among adults admitted to a medical or surgical ICU with increased risk for GI bleed, PPI acid-suppressive therapy with pantoprazole does not affect 90-day mortality in an adult critical care population when compared to placebo.

Major Points

Critical illness is associated with upper GI bleeding, which may be exacerbated by gut dysmotility, inability to tolerate enteral feedings, and development of stress ulcers. Historically these issues have been addressed by routinely delaying enteral nutrition and by routinely using prophylactic acid suppression in critically ill patients. Routine stress ulcer prophylaxis may be associated with infectious complications including C. difficile-associated diarrhea, pneumonia, and death.[1][2] Strong evidence supporting the routine use of PPIs was lacking.

Published in 2018, the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial randomized 3298 patients in 33 European ICUs to PPI (pantoprazole 40 mg IV daily) or placebo. There was no difference between the groups for 90 day mortality (31.1% PPI vs. 30.4% placebo; P=0.76). There were no differences in secondary outcomes including rates of pneumonia, C. difficile infection, clinically important gastrointestinal bleed, or severe adverse events. The median percentage of days alive without the use of life support was similar, both at 92%. Interestingly, numerically more patients in the treatment group received blood products.

There are several limitations in this trial. The authors also did not assess the the feeding status of patients and other critical care medical interventions. Gastrointestinal bleeding was not assessed for source of bleeding (ie, endoscopically) so it is impossible to definitively describe the cause of bleeding. No serious adverse events being reported suggests under-reporting may have occurred.

This study provides additional evidence against the universal use of PPIs among ICU patients. PPI use may still be appropriate among ICU patients at very high risk for GI bleeding.[3]

Guidelines

As of November 2018, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, stratified, parallel-group, placebo-controlled, blinded clinical trial
  • N=3298
    • Pantoprazole (n=1645)
    • Placebo (n=1653)
  • Setting: 33 ICUs in Europe
  • Enrollment: 2016-2017
  • Follow-up: 90 Days
  • Analysis: Intention-to-treat
  • Primary Outcome: Mortality at 90 days

Population

Inclusion Criteria

  • ≥18 years old
  • Admitted to medical or surgical ICU for an acute condition (i.e., not elective)
    • Some individuals with elective surgeries in the prior week were included if they were acutely admitted to the ICU
  • ≥1 risk factor for clinically important GI bleeding:
    • Shock, use of anticoagulant agents, renal-replacement therapy, mechanical ventilation (expected to last >24 hours), any history of liver disease, or any history of or ongoing coagulopathy
      • Acute coagulopathy defined as platelets <50x109/L, INR >1.5, PT >20 seconds. Chronic coagulopathy defined as prior diagnosis of any coagulopathy.

Exclusion Criteria

  • Contraindication to proton pump inhibitor therapy (intolerance or receiving atazanavir)
  • Receiving acid-altering therapy prior to enrollments (PPI or H2 blocker)
  • Diagnosis of peptic ulcer disease during current hospital admission
  • Pregnant
  • Organ transplant
  • Withdrawal of active therapy

Baseline Characteristics

Pantoprazole group displayed

  • Demographics: Age 67 years, 63% male
  • Comorbidities: Chronic lung disease 21%, prior myocardial infarction 9%, heart failure 6%, use of glucocorticoids 2%, hematologic malignancy 4%, metastatic cancer 3%, AIDS <1%, coagulopathy 21%
  • Timeline: median time from ICU admission to randomization 15h, median time from hispital admission to randomization 1day
  • ICU Admission Type: Medical 61%, emergency surgery 30%, elective surgery 9%
  • Critical Care interventions: invasive mechanical ventilation 77%, vasopressors/inotropes 67%, renal replacement therapy 7%
  • Scoring: median SAPS II 49, median SOFA 9

Interventions

  • Pantoprazole 40 mg IV daily
    • Continued from randomization to 90 days or ICU discharge/death
  • Matched placebo

Outcomes

Comparisons are pantoprazole vs. placebo.

Primary Outcomes

Mortality at 90 days
31.1% vs. 30.4% (RR 1.02; 95% CI 0.91-1.13; P=0.76)

Secondary Outcomes

Any clinically important events
Including GI bleeding, pneumonia, C. difficile infection, and myocardial ischemia.
21.9% vs. 22.6% (RR 0.96; 95% CI 0.83-1.11)
GI bleeding: 2.5% vs. 4.2% (RR 0.58; 95% CI 0.40-0.86)
Pneumonia or C. difficile infection: 16.8% vs. 16.9% (RR 0.99; 95% CI 0.84-1.16)
Clinically important GI bleeding
2.5% vs. 4.2% (P not specified)
Severe adverse reaction
Including anaphylactic reactions, agranulocytosis, pancytopenia, acute hepatic failure, Stevens–Johnson syndrome, toxic epidermal necrolysis, interstitial nephritis, and angioedema
0% vs. 0%
Median percentage of days alive without the use of life support
92% vs. 92% of days

Subgroup Analysis

For the primary outcome.

SAPS II score
≤53: RR 1.13 (95% CI 0.99-1.30)
>53: RR 0.92 (95% CI 0.78-1.09)
P value for heterogeneity = 0.05

There were no other significant interactions by subgroups defined by status at randomization, including shock, mechanical ventilation, coagulopathy, liver disease, or medical vs. surgical admissions.

Criticisms

  • Due to drop-outs and exclusions did not meet their target enrollment
    • The higher event rate than anticipated increased power so unlikely to be underpowered with achieved enrollment
  • Did not assess feeding status of patients
  • No assessment of other medical interventions
  • No serious adverse events reported suggests under-reporting
  • Clinical diagnosis of bleeds could not differentiate between stress-ulcers versus other sources of bleeds
  • Did not assess prior acid-suppression therapy

Funding

  • Multiple public institutions, including Innovation Fund Denmark

Further Reading

  1. Marik PE et al. Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis. Crit. Care Med. 2010. 38:2222-8.
  2. Alhazzani W et al. Efficacy and safety of stress ulcer prophylaxis in critically ill patients: a network meta-analysis of randomized trials. Intensive Care Med 2018. 44:1-11.
  3. Barkun A & Bardou M Proton-Pump Inhibitor Prophylaxis in the ICU - Benefits Worth the Risks?. N. Engl. J. Med. 2018. :.