REMAP-CAP: IL-6 Antagonists in Critically Ill Patients with Covid-19 (2021)

“In critically ill patients with Covid-19 receiving organ support in intensive care, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival.”

  • The REMAP-CAP Investigators

1. Publication Details

  • Trial Title: Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19
  • Citation: The REMAP-CAP Investigators. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med. 2021;384(16):1491-1502. DOI: 10.1056/NEJMoa2100433
  • Published: April 29, 2021, in The New England Journal of Medicine
  • Author: The REMAP-CAP Investigators
  • Funding: The European Union; National Institute for Health Research (UK); and others.

2. Keywords

  • COVID-19, Critical Care, Interleukin-6 (IL-6), Tocilizumab, Sarilumab, Platform Trial, Randomized Controlled Trial

3. The Clinical Question

  • In critically ill adult patients with COVID-19 requiring respiratory or cardiovascular organ support (Population), does treatment with an interleukin-6 (IL-6) receptor antagonist (tocilizumab or sarilumab) (Intervention) compared to standard care (Comparison) increase the number of organ support-free days at 21 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Severe COVID-19 was known to be associated with a hyper-inflammatory state, often called a “cytokine storm,” in which the immune system overreacts and causes organ damage. Interleukin-6 (IL-6) is a key pro-inflammatory cytokine in this process.
  • Knowledge Gap: It was hypothesized that blocking the IL-6 pathway with specific receptor antagonists (like tocilizumab and sarilumab) could dampen this harmful inflammation and improve outcomes. However, evidence from earlier, smaller trials was conflicting, and a large, definitive trial was needed.
  • Proposed Hypothesis: The authors hypothesized that treatment with an IL-6 receptor antagonist would be superior to standard care in increasing the number of organ support-free days.

5. Study Design and Methods

  • Design: A large, international, multicenter, prospective, randomized, embedded, multifactorial, adaptive platform trial (REMAP). (This advanced design allows for the simultaneous evaluation of multiple interventions within a single trial infrastructure. The trial adapts over time, for example by stopping recruitment to interventions that are found to be futile or harmful, and by adjusting randomization probabilities to favor interventions that appear to be beneficial).
  • Setting: 113 intensive care units (ICUs) in 10 countries.
  • Trial Period: Enrollment for this domain ran from March 2020 to January 2021.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to an ICU with suspected or confirmed COVID-19 who were receiving respiratory or cardiovascular organ support.
    • Exclusion Criteria: Included imminent death and contraindications to the study drugs.
  • Intervention: Patients were randomized to receive either tocilizumab (8 mg/kg IV) or sarilumab (400 mg IV).
  • Control: Patients were randomized to receive standard care without an IL-6 antagonist.
  • Management Common to Both Groups: All patients received standard of care for COVID-19, which included corticosteroids (dexamethasone) for the majority of patients.
  • Power and Sample Size: The adaptive design of the trial does not use a fixed sample size. The trial was designed to continue until a high probability of superiority or futility was reached for one of the interventions.
  • Outcomes:
    • Primary Outcome: The number of organ support-free days up to day 21 (a composite of in-hospital mortality and days free of respiratory or cardiovascular support).
    • Secondary Outcomes: Included 90-day survival, hospital survival, and duration of organ support.

6. Key Results

  • Enrollment and Baseline: 903 patients were randomized in this domain (353 to tocilizumab, 48 to sarilumab, and 402 to control). The groups were well-matched at baseline.
  • Trial Status: The trial was ongoing, but this domain was concluded after the prespecified statistical trigger for efficacy was met for the IL-6 antagonists.
  • Primary Outcome: Patients in the IL-6 antagonist group had a significantly higher median number of organ support-free days: 10 days in the pooled IL-6 antagonist group, compared with 0 days in the control group.
  • Secondary Outcomes: Hospital mortality was significantly lower in the IL-6 antagonist group: 103 of 395 patients (27%) died, compared with 142 of 397 patients (36%) in the control group. This survival benefit was sustained at 90 days.
  • Adverse Events: The incidence of serious adverse events was similar between the groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using a Bayesian statistical model.
  • Statistical Tests Used: The primary outcome was analyzed using a Bayesian hierarchical ordinal model.
  • Primary Outcome Analysis: The primary outcome was a comparison of the distribution of organ support-free days between the groups.
  • Key Statistic(s) Reported: Adjusted Odds Ratio (OR) for a better outcome on the organ support-free days scale. For tocilizumab vs. control, the OR was 1.64 (95% Credible Interval, 1.25 to 2.14).
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR):
      • Calculation: The paper reports the adjusted median OR as 1.64 for tocilizumab.
      • Clinical Meaning: An OR of 1.64 means that the odds of having a better outcome (more organ support-free days) were 64% higher for patients treated with tocilizumab compared to control.
    • Bayesian Probability: The analysis concluded that there was a >99.9% probability that tocilizumab was superior to standard care for the primary outcome.
  • Clinical Impact Measures (for hospital mortality):
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 36% – 27% = 9%.
      • Clinical Meaning: For every 100 critically ill patients with COVID-19 treated with an IL-6 antagonist, about 9 additional deaths were prevented.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.09 = 11.
      • Clinical Meaning: You would need to treat 11 patients with an IL-6 antagonist to prevent one additional death.
  • Subgroup Analyses: The benefit was consistent across pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, international, adaptive platform RCT design is a major strength, allowing for efficient and rapid evaluation of multiple therapies during a pandemic.
  • Generalizability: The pragmatic design and inclusion of a large, diverse population of critically ill COVID-19 patients make the findings highly generalizable.
  • Statistical Power: The adaptive design and Bayesian analysis provide a high degree of statistical certainty in the findings.
  • Patient-Centered Outcomes: The primary outcome of organ support-free days is a robust and patient-centered composite endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label, which introduces a risk of performance bias.
  • External Validity (Generalizability): The findings are specific to critically ill patients with COVID-19 requiring organ support.
  • Other: The trial was conducted at a time when the standard of care (including corticosteroid use) was rapidly evolving.

10. Conclusion of the Authors

  • The authors concluded that in critically ill patients with COVID-19 receiving organ support, treatment with the IL-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. It provided definitive evidence, along with the RECOVERY trial’s IL-6 domain, that targeted immunomodulation with IL-6 antagonists is a life-saving therapy in a select group of the sickest COVID-19 patients.
  • Specific Recommendations:
    • Patient Selection: For adult patients in the ICU with COVID-19 who require respiratory or cardiovascular organ support and have evidence of systemic inflammation.
    • Actionable Intervention: Administer an IL-6 receptor antagonist (tocilizumab or sarilumab) in addition to standard care with corticosteroids.
    • Expected Benefit: This intervention can be expected to prevent approximately one death for every 11 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that all patients with COVID-19 should receive an IL-6 antagonist. The benefit is limited to the critically ill population with evidence of hyper-inflammation.
  • Implementation Caveats: The key is to use this therapy in conjunction with, not as a replacement for, corticosteroids like dexamethasone.

12. Context and Related Studies

  • Building on Previous Evidence: The REMAP-CAP trial (2021) was designed to provide a definitive answer to the question of IL-6 blockade, which had been suggested by smaller, conflicting studies.
  • Influence on Subsequent Research: The definitive positive result of this trial, along with the consistent findings from the RECOVERY trial’s IL-6 domain, led to the rapid incorporation of tocilizumab and sarilumab into international COVID-19 treatment guidelines for critically ill patients.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal timing of administration and the identification of which patients are most likely to benefit (e.g., based on inflammatory biomarkers) remain areas of investigation.
  • Future Directions: The success of this platform trial has spurred the use of similar adaptive trial designs for other infectious diseases and critical illnesses.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was of the highest relevance, testing a targeted immunomodulatory therapy for a novel and devastating disease.
  • Methods: The large, multicenter, adaptive platform RCT design was a major strength and a triumph of international collaboration, allowing for a rapid and efficient answer during a public health crisis. The main methodological weakness is the open-label design, but the primary outcome was a composite of objective endpoints.
  • Results: The study reported a statistically significant and clinically profound benefit for the intervention, with a high Bayesian probability of superiority and a low NNT of 11 to save a life.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The trial is a landmark in the management of COVID-19 and a powerful demonstration of the utility of adaptive platform trials in a pandemic. Its findings are highly applicable to the care of critically ill COVID-19 patients worldwide.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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