# APBA Kısa Özet

This study is a substudy of the multi-center randomized controlled REVISE (Re‑evaluating the Inhibition of Stress Erosions) trial. It investigated the effect of pantoprazole on upper gastrointestinal (GI) bleeding in mechanically ventilated ICU patients and compared clinical outcomes between SARS-CoV-2 positive and negative patients. Propensity score matching was used to balance demographics and baseline characteristics. The findings indicate that while SARS-CoV-2 infection significantly increases mortality and length of stay, pantoprazole effectively reduces clinically important upper GI bleeding without worsening mortality, and this protective effect is consistent across SARS-CoV-2 positive and negative patients.

# Çalışma neyi araştırdı?

The primary objectives of this embedded substudy were:

  1. To describe the clinical characteristics of critically ill patients with SARS-CoV-2 receiving mechanical ventilation.
  2. To compare clinical outcomes between SARS-CoV-2 infected patients and a propensity-matched non-infected cohort.
  3. To assess whether the treatment effect of pantoprazole on upper GI bleeding and mortality differed by SARS-CoV-2 infection status.

The REVISE trial, conducted from July 2019 to October 2023, enrolled 4,821 eligible participants across 68 ICUs in eight countries. Of these, 11.9% (540/4,550) had documented SARS-CoV-2 infection. For the substudy analysis, 532 SARS-CoV-2 positive patients were identified and matched 1:1 with 532 SARS-CoV-2 negative controls based on age, sex, APACHE II score, and other relevant covariates.

# Yöntem

  • Deneme Tasarımı: The REVISE trial was a double-blind, randomized controlled trial comparing intravenous pantoprazole (40 mg once daily) versus placebo in mechanically ventilated patients. It was conducted across 68 ICUs in eight countries.
  • Katılımcılar: A total of 4,821 patients were enrolled. The substudy analysis included 532 SARS-CoV-2 positive patients and 532 propensity-matched SARS-CoV-2 negative controls.
  • Müdahale: Patients received either intravenous pantoprazole 40 mg once daily or a matching placebo for the duration of their ICU stay, up to a maximum of 28 days.
  • Ana Sonuç Ölçütleri: The primary outcomes were clinically important upper GI bleeding (defined as requiring transfusion or meeting other clinical criteria) and 90-day mortality. Secondary outcomes included duration of mechanical ventilation, ICU length of stay, and hospital length of stay.
  • İstatistiksel Analiz: Propensity score matching was performed to create comparable groups. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated for time-to-event outcomes. Subgroup analyses were conducted to evaluate the consistency of pantoprazole's effect across SARS-CoV-2 status.

# Temel bulgular

  • SARS‑CoV‑2 Enfeksiyonu ve Mortalite: After propensity matching, SARS-CoV-2 infection was associated with significantly higher ICU mortality, hospital mortality, and 90-day mortality. The adjusted hazard ratios indicated a marked increase in risk for infected patients compared to matched controls. Additionally, the duration of mechanical ventilation and both ICU and hospital length of stay were significantly longer in the SARS-CoV-2 positive group.
  • Pantoprazol ÜGG Kanaması: Pantoprazole significantly reduced the risk of clinically important upper GI bleeding. The treatment effect was consistent regardless of SARS-CoV-2 status, meaning the benefit of pantoprazole in reducing bleeding was observed in both infected and non-infected patients. Importantly, pantoprazole did not adversely affect mortality, ventilation duration, or length of stay.
  • COVID‑19 Tedavileri ve Komplikasyonlar: Of the 532 SARS-CoV-2 positive patients, 87.8% received COVID-19-directed treatments, with dexamethasone used in 75.2% of cases. Pulmonary embolism developed in 11.7% and deep-vein thrombosis in 9.2% of the SARS-CoV-2 positive cohort.

# Bulgular ne anlama geliyor?

The results demonstrate that SARS-CoV-2 infection in invasively ventilated patients is a significant risk factor for increased mortality and prolonged ICU/hospital stays, but it is not associated with an increased risk of clinically important upper GI bleeding. Furthermore, pantoprazole, a proton pump inhibitor commonly used to stress-related mucosal protection, effectively reduces the incidence of upper GI bleeding in this population without compromising survival or extending ICU stays. The consistency of pantoprazole's effect across SARS-CoV-2 status supports its routine use for GI prophylaxis in mechanically ventilated patients, regardless of COVID-19 status.

# Klinik önem

  • Üst GI Kanama Önleme: Pantoprazole remains an effective agent for preventing clinically important upper GI bleeding in mechanically ventilated patients. Its use does not increase the risk of mortality and is safe in the context of SARS-CoV-2 infection.
  • Mortalite Risk Yönetimi: The finding that SARS-CoV-2 infection independently increases mortality underscores the need for vigilant monitoring and potentially aggressive management of COVID-19 in the ICU, separate from GI prophylaxis considerations.
  • Protokol Uyarlaması: ICU protocols for stress ulcer prophylaxis can continue to include pantoprazole for ventilated patients without concern for worsening COVID-19 outcomes. The drug's benefit-risk profile remains favorable.

# Sınırlılıklar

  • Propensity Eşleştirme Karşıtı Karıştırma: While propensity score matching balanced observed covariates, unmeasured or unrecorded confounders may still influence the results. The observational components of the analysis carry inherent risk of residual confounding.
  • Blinding ve Yönetim: Blinding status was not fully specified for all trial components, which could introduce performance or detection bias.
  • SARS‑CoV‑2 Alt Grubu Boyutu: The subset of SARS-CoV-2 positive patients (n≈532) was relatively limited. This may reduce the statistical power to detect rare bleeding events or subtle differences in mortality effects.
  • Imprecise Mortality Estimates: The hazard ratios for mortality were described as imprecise, indicating that the true effect size could lie within a wider interval, and the confidence in these estimates is lower.
  • Genelleme: Although the trial spanned eight countries and 68 ICUs, variations in healthcare systems, concomitant medication practices, and local COVID-19 protocols may limit the generalizability of the findings to other settings or populations.