Effect of hydrocortisone on mortality in patients with severe community-acquired pneumonia : The REMAP-CAP Corticosteroid Domain Randomized Clinical Trial

Abstract

Purpose: To determine whether hydrocortisone improves mortality in severe community-acquired pneumonia (CAP).

Methods: In an international adaptive randomized controlled platform trial testing multiple interventions, adults admitted to the intensive care unit (ICU) with severe CAP were randomized to a 7-day course of intravenous hydrocortisone (50 mg every 6 h) or control (no corticosteroid). The primary end point was 90-day all-cause mortality, analyzed iteratively by a Bayesian hierarchical model estimating distinct treatment effects for patients presenting with influenza (Y/N) and shock (Y/N).

Results: Fixed 7-day course hydrocortisone enrollment was stopped for futility (< 5% probability of > 20% relative improvement). Of 658 patients enrolled, 536 were randomized to hydrocortisone and 122 to control. Vital status at day 90 was missing for 15 patients. Day 90 mortality was 15% (78/521) and 9.8% (12/122) for the hydrocortisone and control groups. The adjusted odds ratio ranged from 1.52 to 1.63 (with all 95% CrI crossing 1), while the probability of > 20% relative reduction of day 90 mortality ranged from 7.1 to 3.3% across influenza and shock strata. Results were consistent in sensitivity and pre-specified secondary outcomes. In exploratory analyses, the duration of shock appeared lower in the hydrocortisone group compared with control (median (IQR) of 2 (2-5) days compared to control 3 (2-6.75) days, p value = 0.05).

Conclusions: Among patients with severe CAP, treatment with a 7-day course of hydrocortisone, compared with no hydrocortisone, appears unlikely to yield a large reduction in mortality. Smaller benefits and possible harm are not excluded.

Trial registration: Clinicaltrials.gov identifier: NCT02735707 (registration date: November 4th, 2016).

Keywords: Adaptive platform trial; Corticosteroid; Hydrocortisone; Intensive care; Pneumonia; Shock.

Fig. 1

Screening, randomization, and follow-up of participants in the REMAP-CAP Corticosteroid Domain Randomized Clinical Trial. #Patients could meet more than one ineligibility criterion. Full details are provided in the supplement. *Currently, there are two primary statistical models for the REMAP-CAP platform: the pandemic model (including participants with suspected or proven COVID-19 infection) and the interpandemic model (including participants with non-pandemic CAP and with COVID-19 infection who were randomized in domains eligible to both pandemic and non-pandemic CAP). +The primary model estimates treatment effects directly from those patients randomized within the corticosteroid domain, comparing the outcomes of those randomized in one arm to the outcomes of those who could have been randomized to that arm, but were in fact randomized to another. However, the model also adjusts for other patient and site characteristics and other intervention effects within other domains that affect outcome. To provide the most reliable and stable estimation of these patient, site, and intervention factors, the model uses data from all patients with non-pandemic CAP or with pandemic CAP in domains eligible to both pandemic and non-pandemic CAP. ^Contraindications include known hypersensitivity, current treatment with a medicine that cannot be co-administered with a corticosteroid, and pregnancy

Fig. 2

Primary outcome. Kaplan–Meier curves for day 90 survival according to intervention group. Of the 536 patients randomized to hydrocortisone, 535 (99.8%) are included because one was lost to follow-up with no known date of last contact, precluding an ability to provide a censoring date