HYPERION: Hypothermia for Non-shockable Cardiac Arrest (2019)

“In patients with coma after cardiac arrest with a nonshockable rhythm, therapeutic hypothermia at 33°C did not significantly reduce 90-day mortality as compared with targeted normothermia.”

  • The HYPERION Investigators

1. Publication Details

  • Trial Title: Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm
  • Citation: Lascarrou JB, Merdji H, Le Gouge A, et al. Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm. N Engl J Med. 2019;381(24):2327-2337. DOI: 10.1056/NEJMoa1906661
  • Published: December 12, 2019, in The New England Journal of Medicine
  • Author: Jean-Baptiste Lascarrou, M.D.
  • Funding: French Ministry of Health

2. Keywords

  • Cardiac Arrest, Nonshockable Rhythm, Asystole, PEA, Therapeutic Hypothermia, Targeted Temperature Management, Randomized Controlled Trial

3. The Clinical Question

  • In comatose adult patients after cardiac arrest with a nonshockable initial rhythm (Population), does moderate therapeutic hypothermia (33°C) (Intervention) compared to targeted normothermia (37°C) (Comparison) improve functional outcome at 90 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Therapeutic hypothermia was an established standard of care for comatose survivors of cardiac arrest with an initial shockable rhythm (ventricular fibrillation), based on the landmark HACA (2002) and Bernard (2002) trials.
  • Knowledge Gap: The majority of cardiac arrests are due to nonshockable rhythms (asystole and pulseless electrical activity [PEA]), and these patients have a much worse prognosis. It was completely unknown if the neuroprotective benefits of hypothermia would extend to this larger and sicker patient population.
  • Proposed Hypothesis: The authors hypothesized that therapeutic hypothermia at 33°C would be superior to targeted normothermia in improving the 90-day functional outcome in patients with nonshockable cardiac arrest.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, open-label, controlled trial with blinded outcome assessment (used to test the effectiveness of interventions).
  • Setting: 25 intensive care units (ICUs) in France.
  • Trial Period: Enrollment ran from January 2014 to January 2018.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) who were comatose after resuscitation from an in-hospital or out-of-hospital cardiac arrest with a nonshockable initial rhythm.
    • Exclusion Criteria: Included a no-flow time >10 minutes, a low-flow time >60 minutes, and terminal illness.
  • Intervention: Patients were cooled to a target temperature of 33°C for 24 hours, followed by gradual rewarming.
  • Control: Patients were managed with targeted normothermia, with a goal temperature of 37°C, using a cooling device to prevent fever for 48 hours.
  • Management Common to Both Groups: All patients received standard post-cardiac arrest care according to international guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 584 patients would provide 80% power to detect a 10% absolute difference in the primary outcome. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: Survival with a favorable functional outcome (Cerebral Performance Category [CPC] score of 1 or 2) at day 90.
    • Secondary Outcomes: Included 90-day mortality, organ dysfunction scores, and adverse events.

6. Key Results

  • Enrollment and Baseline: 584 patients were randomized (284 to hypothermia and 300 to normothermia). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: A significantly higher proportion of patients in the hypothermia group had a favorable neurologic outcome at 90 days. A CPC score of 1 or 2 occurred in 31 of 284 patients (10.2%) in the hypothermia group, compared with 17 of 300 patients (5.7%) in the normothermia group (p=0.04).
  • Secondary Outcomes: There was no significant difference in 90-day mortality between the groups (82% in the hypothermia group vs. 84% in the normothermia group).
  • Adverse Events: The incidence of adverse events was similar between the two groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of patients with a favorable outcome between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute rates of the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.04 for the primary outcome is below the 0.05 threshold, indicating that the observed difference in favorable neurologic outcome is statistically significant and unlikely to be due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR) (for the adverse outcome of poor neurologic recovery):
      • Formula: ARR = (Risk of Poor Outcome in Control Group) – (Risk of Poor Outcome in Intervention Group)
      • Calculation: ARR = (100% – 5.7%) – (100% – 10.2%) = 94.3% – 89.8% = 4.5%.
      • Clinical Meaning: For every 100 patients treated with hypothermia, about 4-5 additional patients were saved from a poor neurologic outcome.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.045 = 22.
      • Clinical Meaning: You would need to treat 22 patients with therapeutic hypothermia to achieve one additional favorable neurologic outcome.
  • Subgroup Analyses: The benefit appeared to be more pronounced in patients who had an out-of-hospital cardiac arrest.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design with blinded outcome assessment provided high-quality evidence on an important clinical question.
  • Generalizability: The inclusion of 25 diverse ICUs increases the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The primary outcome of 90-day functional status is a robust and highly relevant patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label, which introduces a risk of performance bias, particularly in decisions related to withdrawal of life-sustaining therapy.
  • External Validity (Generalizability): The overall rate of good outcomes was very low in both groups, reflecting the poor prognosis of this patient population.
  • Other: The trial was stopped after the publication of the TTM2 trial, which found no benefit of hypothermia in a mixed population of cardiac arrest patients. The fragility of the p-value (0.04) is a point for discussion.

10. Conclusion of the Authors

  • The authors concluded that in patients with coma after a nonshockable cardiac arrest, therapeutic hypothermia at 33°C resulted in a higher percentage of patients with a favorable 90-day neurologic outcome than targeted normothermia.

11. To Summarize

  • Impact on Current Practice: This trial is highly controversial. It is the only major RCT to show a neurologic benefit for hypothermia in nonshockable cardiac arrest, a finding that directly contradicts the larger and more definitive TTM2 trial. This has created significant clinical uncertainty.
  • Specific Recommendations:
    • Patient Selection: For comatose adult patients after a nonshockable cardiac arrest.
    • Actionable Intervention: The results suggest a potential benefit for therapeutic hypothermia at 33°C, but this is not a universal recommendation given the conflicting evidence.
  • What This Trial Does NOT Mean: This trial does NOT definitively prove that hypothermia is beneficial in this population. Its results must be interpreted in the context of the larger, neutral TTM2 trial.
  • Implementation Caveats: The decision to use therapeutic hypothermia in nonshockable cardiac arrest remains a complex one, and clinicians should be aware of the conflicting evidence. Aggressive fever prevention is a reasonable goal for all post-arrest patients.

12. Context and Related Studies

  • Building on Previous Evidence: The HYPERION trial (2019) was designed to answer the question of hypothermia’s efficacy in the nonshockable population, which was a major gap left by the original HACA (2002) and Bernard (2002) trials.
  • Influence on Subsequent Research: The positive findings of this trial are in direct conflict with the neutral findings of the much larger TTM2 trial (2021), which included a large subgroup of patients with nonshockable rhythms. This discrepancy is a major source of ongoing debate and research.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is why the results of HYPERION and TTM2 were different. Potential explanations include differences in the patient populations, the control group interventions (active fever prevention vs. standard care), and statistical chance.
  • Future Directions: Future research, including individual patient data meta-analyses of all the major temperature management trials, is needed to clarify the role of hypothermia in specific subgroups of cardiac arrest patients.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a large and high-mortality patient population for which there were no proven neuroprotective therapies.
  • Methods: The multicenter RCT design with blinded outcome assessment was of high quality. The main methodological weakness is the open-label design, which introduces a significant risk of bias in prognostication and decisions to withdraw life-sustaining therapy.
  • Results: The study reported a statistically significant but modest benefit in its primary outcome (NNT of 22). The fragility of the p-value (0.04) and the lack of a mortality benefit are important considerations.
  • Conclusions and Applicability: The authors’ conclusion is a fair reflection of their primary outcome data. However, the applicability of these findings is highly controversial in light of the conflicting results from the larger TTM2 trial. Most international guidelines have not adopted a strong recommendation for hypothermia in this population based on this trial alone, instead emphasizing the importance of active fever prevention.

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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