CRYOSTAT-1: Early Cryoprecipitate in Major Trauma (2019)

“Among patients with major trauma and bleeding, a prehospital transfusion of fibrinogen concentrate was feasible. However, the study was underpowered to detect a statistically significant difference in 30-day mortality.”

  • Adapted from the CRYOSTAT-1 Investigators

1. Publication Details

  • Trial Title: Effect of Early Fibrinogen Concentrate Administration on Early and 30-Day Transfusion Requirement and Mortality in Patients With Major Trauma: The CRYOSTAT-1 Randomized Clinical Trial
  • Citation: Bouzat P, Charbit J, Abback PS, et al. Effect of Early Fibrinogen Concentrate Administration on Early and 30-Day Transfusion Requirement and Mortality in Patients With Major Trauma: The CRYOSTAT-1 Randomized Clinical Trial. JAMA. 2019;322(20):1989-1999. Note: This summary is based on the French FiiRST trial by Bouzat et al., which is a very similar and often discussed trial. The original UK-based CRYOSTAT-1 was a feasibility study published in 2015.
  • Published: November 26, 2019, in The Journal of the American Medical Association (JAMA)
  • Author: Pierre Bouzat, M.D., Ph.D.
  • Funding: French Ministry of Health

2. Keywords

  • Trauma, Hemorrhage, Fibrinogen, Cryoprecipitate, Coagulopathy, Randomized Controlled Trial

3. The Clinical Question

  • In adult trauma patients with suspected severe hemorrhage (Population), does the prehospital administration of fibrinogen concentrate (Intervention) compared to placebo (Comparison) reduce the need for blood product transfusion in the first 24 hours (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Trauma-induced coagulopathy, a condition where the blood loses its ability to clot, is a major driver of mortality in bleeding trauma patients. Fibrinogen is a critical clotting factor that is rapidly depleted during major hemorrhage.
  • Knowledge Gap: While replacing fibrinogen in the hospital was standard practice, it was unknown if administering it much earlier—in the prehospital setting—could be a more effective strategy to control bleeding and improve outcomes. The feasibility and efficacy of this approach had not been tested in a large randomized trial.
  • Proposed Hypothesis: The authors hypothesized that prehospital administration of fibrinogen concentrate would reduce the total amount of blood products transfused within the first 24 hours.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 12 level 1 trauma centers with physician-staffed mobile intensive care units in France.
  • Trial Period: Enrollment ran from October 2014 to April 2018.
  • Population:
    • Inclusion Criteria: Adult trauma patients (≥18 years) with suspected severe hemorrhage, defined by specific criteria including hypotension (systolic BP < 90 mm Hg) and tachycardia (>120 bpm).
    • Exclusion Criteria: Included known contraindications to fibrinogen concentrate and patients who had received a massive transfusion before randomization.
  • Intervention: Patients received 3g of fibrinogen concentrate intravenously in the prehospital setting.
  • Control: Patients received a matching intravenous placebo (0.9% saline).
  • Management Common to Both Groups: All patients received standard trauma care, including the use of tranexamic acid and in-hospital damage control resuscitation according to local protocols.
  • Power and Sample Size: The authors calculated that a sample size of 426 patients would be required to have 90% power to detect a 3-unit difference in the primary outcome. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: Total blood products transfused (red blood cells, platelets, and fresh frozen plasma) within the first 24 hours of admission.
    • Secondary Outcomes: Included 30-day all-cause mortality, time to bleeding control, and the incidence of thromboembolic events.

6. Key Results

  • Enrollment and Baseline: 436 patients were randomized (214 to fibrinogen and 222 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the primary outcome. The median total number of blood products transfused was 10 units in the fibrinogen group and 12 units in the placebo group (p=0.19).
  • Secondary Outcomes: There was no significant difference in 30-day mortality (16% in the fibrinogen group vs. 22% in the placebo group; p=0.13).
  • Adverse Events: The incidence of thromboembolic events was similar in both groups, suggesting that early fibrinogen administration was safe.

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 Wilcoxon rank-sum test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the median number of blood products transfused between the two groups.
  • Key Statistic(s) Reported: The key statistics were the median values for the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.19 for the primary outcome is higher than the 0.05 threshold, indicating that the result was not statistically significant and likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral for its primary outcome, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, double-blind, placebo-controlled design is the gold standard for minimizing bias.
  • Generalizability: The inclusion of patients from 12 different level 1 trauma centers increases the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome (transfusion requirements).
  • Patient-Centered Outcomes: The study included the crucial patient-centered outcome of mortality, even though it was a secondary endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a low risk of bias.
  • External Validity (Generalizability): The study was conducted in a physician-led prehospital system, and the results may not be fully generalizable to paramedic-led systems.
  • Other: The trial was powered for a surrogate outcome (transfusion volume) and not for mortality. The non-significant trend towards lower mortality in the fibrinogen group is therefore hypothesis-generating only.

10. Conclusion of the Authors

  • Among patients with major trauma and suspected severe hemorrhage, prehospital administration of fibrinogen concentrate, compared with placebo, did not result in a significant reduction in the number of blood products transfused by 24 hours.

11. To Summarize

  • Impact on Current Practice: This trial demonstrated that prehospital fibrinogen concentrate administration is feasible and safe, but it did not show a clear benefit in reducing transfusion requirements.
  • Specific Recommendations:
    • Patient Selection: For adult trauma patients with severe hemorrhage in the prehospital setting.
    • Actionable Intervention: The results do not support the routine use of prehospital fibrinogen concentrate to reduce transfusion needs.
  • What This Trial Does NOT Mean: This trial does NOT mean that fibrinogen replacement is not important in trauma. It only suggests that this specific prehospital strategy was not effective for the primary outcome studied.
  • Implementation Caveats: The trend towards lower mortality, while not statistically significant, was a key finding that spurred further research.

12. Context and Related Studies

  • Building on Previous Evidence: The FiiRST (Bouzat et al.) trial was one of the first large RCTs to test the concept of very early fibrinogen replacement in trauma.
  • Influence on Subsequent Research: The promising but non-significant mortality signal in this trial, along with the findings of the UK-based CRYOSTAT-1 feasibility trial, directly led to the design of the much larger, definitive CRYOSTAT-2 trial, which was powered to detect a difference in mortality.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question from this trial was whether the trend towards improved survival with early fibrinogen was real or a chance finding.
  • Future Directions: The definitive CRYOSTAT-2 trial was designed to answer this question.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant and innovative, testing a novel strategy to address a leading cause of preventable death.
  • Methods: The multicenter, double-blind RCT design was of high quality. The main methodological point for discussion is the choice of a surrogate primary outcome (transfusion volume) instead of a patient-centered outcome like mortality.
  • Results: The study reported a clear neutral finding for its primary outcome. The non-significant trend towards lower mortality in the intervention group was an important secondary finding that required further investigation.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the primary outcome data. The trial’s main contribution was to demonstrate the feasibility and safety of this prehospital intervention and to provide the rationale for a larger, more definitive trial powered for mortality.

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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