CRYOSTAT-2: Early Cryoprecipitate for Major Haemorrhage in Trauma (2023)

“Among adults with trauma and bleeding who were receiving a blood transfusion, the early administration of cryoprecipitate, as compared with standard care, did not significantly reduce 28-day all-cause mortality.”

— The CRYOSTAT-2 Trial Investigators

1. Publication Details

  • Trial Title: Cryoprecipitate for Acute Traumatic Coagulopathy in Patients With Major Haemorrhage (CRYOSTAT-2): A Multicentre, Randomised, Controlled, Open-Label, Phase 3 Trial.
  • Citation: Davenport R, Curry N, Fox EE, et al; for the CRYOSTAT-2 Trial Investigators. Early and Empirical High-Dose Cryoprecipitate for Haemorrhage in Trauma (CRYOSTAT-2): A Randomised, Controlled, Open-Label, Phase 3 Trial. Lancet Haematol. 2023;10(9):e701-e711. doi:10.1016/S2352-3026(23)00182-4.
  • Published: September 1, 2023, in The Lancet Haematology.
  • Author: Ross Davenport, Ph.D.
  • Funding: UK National Institute for Health Research and Barts Charity.

2. Keywords

Trauma, Major Hemorrhage, Bleeding, Cryoprecipitate, Fibrinogen, Coagulopathy, Transfusion.

3. The Clinical Question

In adult trauma patients with active major hemorrhage (Population), does the early empirical administration of high-dose cryoprecipitate (Intervention) compared to standard care (Comparison) reduce 28-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Uncontrolled bleeding is a leading cause of preventable death after severe injury. A key component of trauma-induced coagulopathy is the rapid depletion of fibrinogen, a critical clotting protein. Cryoprecipitate is a blood product rich in fibrinogen.
  • Knowledge Gap: While major hemorrhage protocols often include cryoprecipitate, it is typically given late, guided by laboratory results which can take time. It was unknown if giving a large, empirical dose of cryoprecipitate very early to all bleeding trauma patients, before lab results are available, would improve survival.
  • Proposed Hypothesis: The authors hypothesized that early and empirical high-dose cryoprecipitate would improve survival by rapidly correcting fibrinogen deficiency and reducing bleeding.

5. Study Design and Methods

  • Design: A multicenter, randomized, controlled, open-label, phase 3 trial.
  • Setting: 26 major trauma centers in the United Kingdom.
  • Trial Period: Enrollment from July 2017 to November 2021.
  • Population:
    • Inclusion Criteria: Adult trauma patients (≥16 years) with active hemorrhage requiring activation of the major hemorrhage protocol, who were within 3 hours of injury.
    • Exclusion Criteria: Patients who had received cryoprecipitate before randomization or had known religious objections to blood products.
  • Intervention: Early cryoprecipitate group received three pools of cryoprecipitate (approximately 6g of fibrinogen) as soon as possible after randomization, in addition to standard major hemorrhage care.
  • Control: Standard care group received blood products according to the local major hemorrhage protocol, with cryoprecipitate administered later based on clinical judgment and laboratory results.
  • Management Common to Both Groups: Both groups received red blood cells, plasma, and tranexamic acid as part of standard care.

6. Key Results

  • Enrollment and Baseline: 1573 patients were randomized (779 to early cryoprecipitate, 794 to standard care). The groups were well-matched at baseline for age, injury severity, and physiological parameters.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 28-day all-cause mortality between the two groups (25.3% in the early cryoprecipitate group vs. 26.1% in the standard care group; P=0.74).
  • Secondary Outcomes: A key secondary outcome, death from bleeding within 24 hours, was significantly lower in the early cryoprecipitate group (4.9% vs. 7.4%; P=0.03). Patients in the intervention group also received significantly less red blood cells and platelets.
  • Adverse Events: There was no significant difference in the rates of thrombotic events between the two groups.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using logistic regression, adjusted for key baseline variables.
  • Key Statistic(s) Reported:
    • Primary Outcome (28-day mortality): Adjusted Odds Ratio (OR) 0.96 (95% CI, 0.75 to 1.23; P=0.74).
    • Secondary Outcome (Death from bleeding at 24h): Adjusted Odds Ratio (OR) 0.65 (95% CI, 0.43 to 0.97; P=0.03).
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR) for Primary Outcome: An OR of 0.96 means the odds of dying at 28 days were 4% lower in the early cryo group, but this was not statistically significant.
    • Confidence Interval (CI) for Primary Outcome: The 95% CI ranged from a 25% benefit to a 23% harm and broadly crossed 1.0, indicating that the result is consistent with chance and no definitive conclusion about a mortality benefit can be made.
    • P-value for Primary Outcome: The p-value of 0.74 is far above the 0.05 threshold, confirming the lack of a statistically significant difference.
  • Clinical Impact Measures (for Death from Bleeding at 24h):
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group).
      • Calculation: ARR = 7.4% – 4.9% = 2.5%.
      • Clinical Meaning: For every 100 severe trauma patients treated with early cryoprecipitate, approximately 2 to 3 fewer will die from bleeding within the first 24 hours.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR.
      • Calculation: NNT = 1 / 0.025 = 40.
      • Clinical Meaning: Approximately 40 patients with major traumatic hemorrhage need to be treated with early, empirical cryoprecipitate to prevent one additional death from bleeding in the first 24 hours.

8. Strengths of the Study

  • Pragmatic Design: The trial was embedded within existing major trauma systems, making the results highly generalizable to real-world practice.
  • Large Sample Size: It is the largest randomized trial to date investigating the role of cryoprecipitate in trauma.
  • Patient-Centered Outcomes: The trial focused on mortality and other important clinical outcomes like blood product consumption.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label, which could have introduced performance bias, although the primary outcome of mortality is objective.
  • External Validity (Generalizability): The trial was conducted in a single, well-developed trauma system (UK), and results may differ in systems with different logistics or patient populations.
  • Other: A significant portion of the control group (77%) received cryoprecipitate later in their resuscitation, which may have diluted the difference between the groups.

10. Conclusion of the Authors

“Early empirical high-dose cryoprecipitate transfusion in patients with traumatic major haemorrhage did not reduce all-cause 28-day mortality. However, it was associated with a significant reduction in death from bleeding in the first 24 h.”

11. To Summarize

  • Impact on Current Practice: This is a landmark trial in trauma resuscitation. While it did not show an overall 28-day survival benefit, the significant reduction in early death from bleeding provides strong evidence to support a change in the process of care. It reinforces the importance of rapid fibrinogen replacement and supports moving cryoprecipitate administration earlier in major hemorrhage protocols.
  • Specific Recommendations:
    • Patient Selection: For adult trauma patients with active, major bleeding requiring activation of a major hemorrhage protocol.
    • Actionable Intervention: Administer high-dose cryoprecipitate (or an equivalent fibrinogen concentrate) empirically, as part of the initial resuscitation package, rather than waiting for laboratory results.
    • Expected Benefit: A reduction in death from bleeding within the first 24 hours (NNT ~40).
  • What This Trial Does NOT Mean: This trial does not mean that early cryoprecipitate is a “magic bullet” that saves all trauma patients. Many trauma deaths are due to non-bleeding causes (like head injury), which this intervention would not affect. It is one component of a comprehensive resuscitation strategy.

12. Context and Related Studies

  • Building on Previous Evidence: CRYOSTAT-2 was designed to provide a definitive answer to a question raised by smaller trials and observational studies that suggested a benefit to early fibrinogen replacement. It provides the high-quality evidence that was previously lacking.
  • Influence on Subsequent Research: This trial’s findings will likely lead to updates in international trauma and transfusion guidelines. It shifts the focus from if fibrinogen should be replaced to how early it should be done.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: What is the optimal dose and timing of cryoprecipitate? Is fibrinogen concentrate a better alternative to cryoprecipitate? Are there specific subgroups of trauma patients who benefit more from this strategy?
  • Future Directions: Research will likely focus on comparing different fibrinogen sources, optimizing dosing strategies, and developing point-of-care tests to better guide early coagulopathy management.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was of fundamental importance to trauma care, addressing a key component of resuscitation for a leading cause of preventable death.
  • Methods: The large, multicenter, pragmatic randomized trial design was of high quality and appropriate for the question.
  • Results: This is a classic example of a trial with a “negative” primary outcome but a clinically important, statistically significant “positive” secondary outcome. The lack of 28-day mortality benefit is likely due to the high number of deaths from other causes (e.g., severe brain injury) in this population, but the reduction in early bleeding deaths is a crucial finding.
  • Conclusions and Applicability: The authors’ conclusion is a precise and fair interpretation of the data. The results are highly applicable to all major trauma centers and provide strong evidence to support the incorporation of early, empirical cryoprecipitate into major hemorrhage protocols.

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.

Scroll to Top