REMAP-CAP Corticosteroid Domain — Hydrocortisone in Severe CAP

1. Publication

• Title: Effect of hydrocortisone on mortality in patients with severe community-acquired pneumonia: The REMAP-CAP Corticosteroid Domain Randomized Clinical Trial
• Acronym: REMAP-CAP Corticosteroid Domain
• Year & Journal: Intensive Care Medicine, published April 22, 2025 (2025;51(4):665-680; erratum July 2025)
• Citation: Angus DC, Shankar-Hari M, REMAP-CAP Investigators. Intensive Care Med. 2025;51(4):665-680. doi:10.1007/s00134-025-07861-w

2. Context & Rationale

Background: Corticosteroids may reduce mortality in severe CAP via anti-inflammatory and renin-angiotensin-aldosterone effects. The CAPE-COD trial (NEJM 2023) had reported a significant 28-day mortality reduction (absolute 5.6%) with hydrocortisone, prompting guideline updates recommending corticosteroids in severe CAP (moderate-certainty evidence) — REMAP-CAP's corticosteroid domain tested this in its own large, international platform.

Research Question/Hypothesis: In adults with severe CAP requiring ICU admission, does a 7-day fixed course of IV hydrocortisone reduce 90-day all-cause mortality compared with no corticosteroid?

3. Design & Methods

• Study Type: International, adaptive platform, randomized, controlled, open-label trial (REMAP-CAP corticosteroid domain)
• Population: Adults admitted to ICU with severe CAP
• Intervention: Fixed 7-day course IV hydrocortisone, 50mg every 6h (n=536)
• Comparator: No corticosteroid (control) (n=122)
• Randomization: Bayesian hierarchical model estimating distinct treatment effects by influenza status (Y/N) and shock status (Y/N)
• Blinding: Open-label
• Statistical Power & Follow-Up: Primary: 90-day all-cause mortality. Enrollment stopped for futility (DSMB recommendation, Dec 6, 2023) when <5% probability of >20% relative mortality improvement was reached.

4. Key Results

658 patients enrolled (536 hydrocortisone, 122 control); vital status missing for 15.

5. Internal Validity Assessment

Bayesian adaptive design with prespecified stratified analysis; stopped appropriately for futility per DSMB recommendation. Overall: Moderate-to-strong — clean, if numerically unfavorable, result; however, a published correspondence flagged that 23% of control-group patients nevertheless received corticosteroids off-protocol (median 4 days) due to the open-label design — authors themselves stated this contamination was unlikely to have alone reversed the result, but it remains a real limitation given the trial's much smaller control arm (122 vs 536).

6. External Validity Assessment

International REMAP-CAP platform population with severe CAP requiring ICU admission — broadly representative, though the wide credible interval (0.80-3.31) reflects real residual uncertainty given the modest control-arm size.

7. Strengths & Limitations

Strengths: International adaptive platform; prespecified subgroup (influenza×shock) analysis; appropriately stopped for futility.

Limitations: Open-label design with meaningful control-arm contamination (23% received off-protocol corticosteroids); small, asymmetric control arm (122 vs 536) limiting precision; wide credible interval compatible with both harm and modest benefit.

8. Interpretation & Practice Impact

Does not support routine hydrocortisone for unselected severe CAP — contrasts notably with the earlier, positive CAPE-COD trial. Per the trial's own conclusion, hydrocortisone "appears unlikely to yield a large reduction in mortality" in severe CAP, though smaller benefits or possible harm are not excluded given the wide credible interval.

9. Controversies & Subsequent Evidence

An accompanying editorial ("REMAP-CAP corticosteroids: yet, another swing of the pendulum?", Pirracchio & Sprung) directly frames the tension between this null/unfavorable result and CAPE-COD's positive finding, and a 2025 updated meta-analysis (Lee et al., J Gen Intern Med) concluded systemic corticosteroids "continue to reduce mortality" in severe CAP when pooling across the broader evidence base — illustrating genuine, ongoing controversy rather than a settled question. Published correspondence specifically raised concerns about control-arm corticosteroid contamination and a possible "enrollment sequence effect" (early-enrolled patients at each site having higher mortality and more protocol violations), issues the original authors acknowledged but did not consider sufficient to reverse their conclusions.

10. Summary & Executive Takeaway

Summary: The REMAP-CAP corticosteroid domain, stopped early for futility, randomized 658 severe CAP ICU patients to 7-day fixed-dose hydrocortisone or control. 90-day mortality was numerically higher with hydrocortisone (15% vs 9.8%; adjusted OR 1.56, 95% CrI 0.80-3.31), with no benefit across any of 4 predefined influenza/shock strata.

Overall Takeaway: This large international trial found no mortality benefit from routine 7-day hydrocortisone in severe CAP — directly contrasting with the earlier positive CAPE-COD trial and creating genuine, unresolved tension in the corticosteroid-for-severe-CAP evidence base, compounded by real methodological limitations (control-arm contamination, small control arm) that neither fully explain away the unfavorable point estimate nor allow confident practice guidance in either direction.

11. Bibliography

• Dequin PF, Meziani F, Quenot JP, et al; CRICS-TriGGERSep Network. Hydrocortisone in Severe Community-Acquired Pneumonia (CAPE-COD). N Engl J Med. 2023;388:1931-1941.
• Pirracchio R, Sprung CL. REMAP-CAP corticosteroids: yet, another swing of the pendulum? [editorial]. Intensive Care Med. 2025;51:1135-1138.
• Lee TC, Albuquerque AM, Lawandi A, et al. Systemic corticosteroids continue to reduce mortality in severe CAP: an updated meta-analysis. J Gen Intern Med. 2025.