REVISE – Stress Ulcer Prophylaxis during Invasive Mechanical Ventilation

Stress Ulcer Prophylaxis during Invasive Mechanical Ventilation (REVISE)

D. Cook. NEJM 2024. DOI: 10.1056/NEJMoa2404245

Clinical Question

  • In mechanically ventilated adults, does stress ulcer prophylaxis with intravenous pantoprazole (40 mg daily), compared with placebo (0.9% saline), reduce the occurrence of clinically important upper gastrointestinal bleeding at 90 days?

Background

  • Critical illness is associated with an increased risk of gastrointestinal (GI) stress ulceration and consequent upper GI bleeding
  • Prophylactic proton-pump inhibitors (PPI) have been shown to reduce the risk of clinically significant bleeding in critical illness [SUP-ICU]
  • Increased mortality in a subgroup of the most severely ill patients in SUP-ICU (vs. placebo), as well as a trend towards increased mortality with PPI (vs. H2RA) in the PEPTIC trial, however, suggest that PPI use in critically ill patients may be associated with harm despite a reduction in UGI bleeding
  • A meta-analysis (Wang, et al. 2020) demonstrated that PPI use may be associated with an increased risk of ventilator associated pneumonia (low certainty) and that harm from increased risk of C. Difficile infection cannot be excluded

Design

  • Re-EValuating the Inhibition of Stress Erosions (REVISE trial)
  • International, multi-centre randomised controlled trial
  • Web-based randomisation in 1:1 ratio
    • Permuted blocks of undisclosed, variable size
    • Stratification by trial centre and prehospital receipt of acid suppression
  • Blinding: treating clinicians, patients, research staff members, outcome adjudicators and biostatisticians blinded until completion of data analysis
  • Sample size calculation:
    • 4800 patients for 85% power to detect 1.5% difference in primary outcome
    • Assuming baseline risk of 3% and α = 0.05
  • Intention to treat analysis
  • Pre-specified sensitivity and subgroup analyses
  • Secondary and tertiary outcomes adjusted for multiple comparisons

Setting

  • 68 hospitals in Australia, Brazil, Canada, England, Kuwait, Pakistan, Saudi Arabia, and the United States
  • Enrolment between July 2019 and October 2023

Population

  • Inclusion:
    • Adults (≥18 years old)
    • Receiving mechanical ventilation in ICU
    • Expected to remain ventilated beyond the calendar day after randomisation
  • Exclusion:
    • Duration of mechanical ventilation ≥72 hours
    • Acid suppression for active or high-risk of GI bleeding (e.g. current bleeding, peptic ulcer bleeding within 8 weeks, recent severe oesophagitis)
    • Prior acid suppression in ICU (>1 daily dose equivalent of PPI or H2RA)
    • Dual anti-platelet therapy or antiplatelet agent and therapeutic anticoagulation
    • Contraindication to pantoprazole
  • 6221 patients eligible at time of screening → 4900 randomised → 4821 in final analysis
    • 79 excluded post-randomisation (consent withdrawn for 73 subjects)
  • Baseline characteristics well balanced between groups
    • Comparing pantoprazole vs placebo groups:
      • Age: 58 vs 58
      • APACHE II: 21.8 vs 21.7
      • Male: 63.5% vs 63.8%
      • Patient status
        • Medical: 72.5% vs 73.5%
        • Trauma: 15.3% vs 13%
        • Surgical: 12.2% vs 13.5%
      • Admitting diagnostic category
        • Respiratory: 31.1% vs 31.9%
        • Neurologic: 21.8% vs 23%
        • Trauma: 15.3% vs 13%
        • Cardiovascular: 9.6% vs 10.5%
        • Sepsis: 8.3% vs 8.3%
        • Gastrointestinal: 4.5% vs 4.5%
        • Metabolic: 4.2% vs 3.7%
        • Renal: 1.4% vs 1.3%
        • Other medical: 1.6% vs 1.3%
        • Other surgical: 2.4% vs 2.4%
      • Acid suppression prior to hospitalisation:
        • None: 76.4% vs 77.1%
        • PPI: 22.7% vs 22.3%
        • H2RA: 0.6% vs 0.4%
      • Glucocorticoid ≥1 week before randomisation: 35.4% vs 34.9%
      • Organ support
        • Inotrope or vasopressor infusion 69.5% vs 71.1%
        • Renal-replacement therapy 6.3% vs 6.4%

Intervention

  • Intravenous pantoprazole 40mg daily (reconstituted with 0.9% sodium chloride)
    • Median 5 days of drug receipt

Control

  • Matched placebo (0.9% sodium chloride) with similar appearance
    • Median 5 days of drug receipt

Management common to both groups

  • Pantoprazole or placebo administered for 90 days or until the discontinuation of mechanical ventilation
  • Could also be discontinued in the event of pre-specified clinical indication (e.g. upper GI bleed) or contra-indication to PPI
  • Other care and interventions at discretion of treating clinicians

Outcome

  • Primary outcome: clinically important upper GI bleeding in ICU (or requiring ICU readmission) at 90 days
    • Defined as overt GI bleeding PLUS ≥1 of following within 24hrs:
      • haemodynamic change (decrease SBP/DBP/MAP ≥20 mmHg)
      • orthostatic hypotension/tachycardia
      • commencement of vasopressor
      • haemoglobin decrement ≥20g/L over 24hrs
      • transfusion of ≥2 units packed RBC over 24hrs
      • requirement for therapeutic intervention
    • Significantly reduced risk in pantoprazole group:
      • Pantoprazole 25/2385 (1%) vs Placebo 84/2377 (3.5%)
        • Absolute difference: 2.5% (95% CI, 1.6 to 3.3)
        • NNT 40
        • HR: 0.3 (0.19 to 0.47; P < 0.001)
        • Table S6 provides breakdown of components
  • Primary safety outcome: comparing pantoprazole vs placebo groups:
    • No significant difference in all-cause mortality at day 90: 29.1% vs 30.9% (HR 0.94, 0.85 – 1.04)
  • Secondary outcomes: comparing pantoprazole vs. placebo groups:
    • Significantly reduced patient-important upper GI bleeding in ICU: 1.5% vs 4.2%
    • No significant difference in:
      • Ventilator associated pneumonia in ICU (23.2% vs 23.8%)
      • Clostridioides difficile infection in hospital (1.2% vs 0.7%)
      • New renal-replacement therapy in ICU (6.1% vs 6%)
      • ICU mortality (20.3% vs 21.5%)
      • Hospital mortality (26.3% vs 28.4%)
  • Tertiary outcomes: comparing pantoprazole vs. placebo groups:
    • No significant difference in
      • Median number red-cell units transfused in first 14 days in ICU (0 vs 0)
      • Median peak serum creatinine level in ICU (99 vs 99µmol)
      • Median duration mechanical ventilation (6 vs 6 days)
      • Median ICU length of stay (10 vs 10 days)
      • Median hospital length of stay (20 vs 21 days)
  • Subgroups: no significant effect modification of primary outcome in any prespecified subgroup:
    • Pre-hospital acid suppression vs none (p=0.91)
    • Low APACHE II score (<25) vs high (≥25) (p=0.12)
    • Surgical vs medical ICU admission (p=0.75)
    • SARS-CoV-2 active infection vs no active infection (p=0.98)
    • Male vs female (p=0.55)

Authors’ Conclusions

  • In critically ill patients receiving mechanical ventilation, use of IV pantoprazole resulted in a lower risk of clinically important upper GI bleeding than placebo, with no overall effect on mortality

Strengths

  • Large, well-powered RCT with good separation between groups
  • Excellent internal validity
    • Minimal loss to follow-up
    • Allocation concealment
    • Intention-to-treat analysis
    • Good adherence to protocol (Table S5)
  • Blinding of clinicians protects against performance bias (for example, decision to proceed to endoscopy)
  • Good external validity: multi-national, pragmatic trial with broad inclusion criteria
  • Corroboration of primary outcome with patient-important secondary outcome
  • Secondary outcomes are clinically relevant and informative for practice
  • ~90% of subjects received enteral feeding (Table S4) – provides evidence of GI protective effect even in presence of enteral nutrition
  • Multiple sensitivity analyses, including competing risk assessment for death, render results unchanged (Table S8)

Weaknesses

  • Primary outcome – effect of PPI on clinically important upper GI bleeding – is not especially contentious following SUP-ICU and PEPTIC
    • Powering the trial for specific adverse effects/harms may have been more informative
  • ~50% subjects exposed to corticosteroids within first 14 days of ICU (Supp. Table 4)
    • Given corticosteroid use is a risk-factor for stress-ulceration, it would have been interesting to see sensitivity analysis for those without exposure
    • Detracts from external validity
  • Unclear how many patients were screened but deemed not eligible
  • Does not inform prophylactic PPI use in non-ventilated patients
  • Does not inform if oral PPI use is equivalent to the IV formulation

The Bottom Line

  • Robust study which demonstrates clinical and patient-important benefits of stress-ulcer prophylaxis with PPI in ventilated patients
  • Provides strong evidence for the safety of prophylactic PPI use in ventilated patients, with no significant increase in the risk of mortality or infectious complications
  • I will now prescribe IV pantoprazole for all ventilated patients (unless specifically contraindicated), even when enterally fed, for the duration of mechanical ventilation

External Links

Metadata

Summary primary author: Jim Soares

Co-author: Celia Bradford @celiabradford
Summary date: July 6 2024
Peer-review editor: George Walker

Picture by: Marcelo Leal / Unsplash

 

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