CRYOSTAT-2: Early Empiric Cryoprecipitate in Major Trauma

Background: Hemorrhage is the leading cause of trauma related mortality. The initial injury is often complicated by multifactorial coagulopathy that can exacerbate bleeding.  Fibrinogen is the precursor to fibrin and a major component of stable clot formation. Fibrinogen and fibrin are often depleted during major trauma as a result of consumption, breakdown, and dilution. Most major hemorrhage protocols give a balanced transfusion of PRBCs, FFP, and platelets in ratios approaching concentrations found in whole blood. Fibrinogen products may also be needed to stabilize clots and stem bleeding. The optimal approach to fibrinogen administration in massive hemorrhage protocols is unknown.

Paper: Davenport R et al. Early and Empirical High-Dose Cryoprecipitate for Hemorrhage After Traumatic Injury: The CRYOSTAT-2 Randomized Clinical Trial. JAMA 2023. PMID: 37824155

 Clinical Question: Does transfusion of early and empiric high-dose cryoprecipitate in addition to standard care improve survival in bleeding patients with trauma who require activation of a major hemorrhage protocol?

What They Did:

• Interventional, randomized, open-label, parallel-group, controlled, international, phase 3, multicenter study
• Patients enrolled at 26 UK and US major trauma centers
• Injured adults requiring activation of major hemorrhage protocol with evidence of active hemorrhage, SBP < 90mmHg at any time, and receiving at least 1U of any blood component
• Patients within 90 minutes of randomization and 3 hours of injury were randomized to:
  • Standard Care: Local major hemorrhage protocol
    • 1:1:1 ratio of PRBCs, FFP, and Platelets
  • Cryoprecipitate: Local major hemorrhage protocol + 3 pools of cryoprecipitate (6g fibrinogen equivalent)

Outcomes:

• Primary: All-cause mortality at 28d (intention to treat population)
• Secondary: 25 Prespecified outcomes
• Safety: Thrombotic events at 28d 

Inclusion:

• Adult trauma patient (≥16 years of age)
• Severe injury with evidence of active hemorrhage requiring activation of local massive hemorrhage protocol
• Started or received at least 1U of any blood component
• SBP<90mmHg at any point

 Exclusion:

• Patient being transferred from another hospital
• Injuries incompatible with life as assessed by the trauma team leader
• >3hrs elapsing from the time of injury 

Results:

• 1604 eligible patients (1531 (95%) of patients were included in the primary analysis population)
  • Most patients recruited from UK (1555 patients); US recruited 49 patients
  • Median Age: 39 years (26 to 55years)
  • Median ISS: 29 (18 to 43)
  • Penetrating Injury: 36%
  • Blunt Injury: 64%
  • SBP <90mmHg at Hospital Arrival: 33%
• Timing/Interventions
  • Prior to hospital arrival 43% of patients received a blood component and 79% received TXA (96% of patients received TXA either before or in the hospital)
  • Median time from injury to ED arrival: 76 minutes
  • Median time from admission to randomization: 15 minutes
  • 85% of patients in cryoprecipitate group received cryoprecipitate vs 32% in the standard care group
  • Median time from admission to first administration of cryoprecipitate: 68 minutes (cryoprecipitate group) vs 120min (standard care group)
• All-Cause 28d Mortality:
  • Standard Care Group: 26.1%
  • Cryoprecipitate Group: 25.3%
  • OR 0.96; 95% CI 0.75 to 1.23; p = 0.74
• Mortality at 6 hours ad 24 hours was similar between groups
  • The proportion of deaths from bleeding in the 1^st 6 and 24 hours was not different between groups
  • Median time to death from hemorrhage: 191min in cryoprecipitate group vs 86min in the standard care group
• Penetrating trauma 28-day mortality: significantly higher in the cryoprecipitate group than the standard care group (16.2% vs 10%; OR 1.74; 95% CI 1.20 to 2.51)
• No difference in safety outcomes, incidence of thrombotic events, or transfusion requirements between groups

Strengths:

• Asks a clinically important question with limited prior data
• Randomized, international trial
• Independent data monitoring committee reviewed interim data analysis and monitored patient safety
• Used an intention-to-treat plan which does a better job of estimating real world practice (as opposed to per protocol)
• Both groups were well-matched in baseline clinical characteristics
• Included patients who were severely injured, hypotensive, and received substantial blood component transfusions (i.e. very sick cohort)
• Minimal loss to follow up for primary analysis

Limitations:

• Convenience sample of patients which could cause selection bias (888 patients not randomized due to unavailability of research team)
• Due to a lack of a placebo group it is difficult to examine the effect of timing of cryoprecipitate administration on outcomes
• Some cross-over between groups: 15% of patients in the cryoprecipitate group did not receive cryoprecipitate and 9% of patients in the standard care group got cryoprecipitate within 90 minutes (32% within 24 hours). This could dilute any beneficial effects seen
• Lack of blinding may bias results (Although mortality is a solid objective primary outcome, bias may still creep in terms of management)

Discussion:

• Authors were looking for an absolute mortality difference of 7% from baseline mortality of 26% with a 90% power. The 26% mortality rate was based on the 28% mortality rate in the feasibility study (CRYOSTAT-1)
• Giving early, empiric cryoprecipitate most likely results in a substantial proportion of patients receiving fibrinogen who do not develop hypofibrinogenemia (i.e. a negative trial). This trial would advocate for a precision-guided coagulation therapy
  • A blood sample to determine fibrinogen level prior to cryoprecipitate administration was not required (some patients may have received cryoprecipitate without having low fibrinogen levels)
• Cryoprecipitate was given to 85% of the intervention group and 32% of the standard card group. This would normally make me worry about dilution of results and biasing the results to the null hypothesis, but in the per protocol analysis (170 patients excluded from the full cohort, due to no longer requiring blood transfusion, dying within 90 minutes of arrival or being randomized in error) didn’t seem to affect this result either.
• Interestingly the use of early, empiric cryoprecipitate did impact 28 mortality in the prespecified subgroup of patients with penetrating trauma (16.2% vs 10%; OR 1.74; 95% CI 1.20 to 2.51). As this is a secondary outcome this is hypothesis generating but does require further research to see if blunt vs penetrating trauma are phenotypically different

Author Conclusion: “Among patients with trauma and bleeding who required activation of a major hemorrhage protocol, the addition of early and empirical high-dose cryoprecipitate to standard care did not improve all cause 28-day mortality.”

Clinical Take Home Point: Among adult patients with trauma and bleeding who required activation of a major hemorrhage protocol, the addition of early and empiric cryoprecipitate to standard care did not improve all cause 28-day mortality. Until better evidence is presented this trial would advocate for a precision-guided coagulation therapy (i.e. based on fibrinogen levels).

References:

1. Davenport R et al. Early and Empirical High-Dose Cryoprecipitate for Hemorrhage After Traumatic Injury: The CRYOSTAT-2 Randomized Clinical Trial. JAMA 2023. PMID: 37824155

For More Thoughts on This Topic Checkout:

• First10EM: CRYOSTAT-2 – Empiric Cryoprecipitate in Traumatic Massive Hemorrhage
• Emlyn’s: CRYOSTAT-2
• The Bottom Line: Early and Empirical High-Dose Cryoprecipitate for Hemorrhage After Traumatic Injury

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter/X: @EMSwami)