Cryoprecipitate Fails to Improve Survival in Trauma Patients Requiring MHP Activation

Early, empirical, high-dose cryoprecipitate does not appear to improve survival of bleeding trauma patients who trigger a massive hemorrhage protocol (MHP), compared with standard care. The findings come from the 1,531-patient CRYOSTAT-2 trial published last week in JAMA. 

At 28 days, all-cause mortality, the primary outcome, was 25.3% for patients randomized to receive cryoprecipitate compared with 26.1% for patients who received standard care. Likewise, mortality was similar between the two groups at 6 and 24 hours and at 6 and 12 months. 

Despite the biologic rationale for fibrinogen supplementation and positive results from smaller trials, “the addition of early and empirical high-dose cryoprecipitate to standard care did not improve clinical outcomes in patients who were severely injured and bleeding,” the researchers wrote.  “There were no differences in mortality at any time or in secondary or safety outcomes.”  

The phase III randomized trial involved 25 major trauma centers in the United Kingdom and one in the United States. Patients were included if they had evidence of active hemorrhage that required activation of the local MHP, to have started or received at least one unit of any blood component and no more than 3 hours had elapsed since the time of injury. MHPs were reviewed, and activation criteria at all centers included systolic blood pressure less than 90 mm Hg at any point. 

All patients received standard treatment according to the local MHP, with a balanced, empirical ratio of red blood cells (RBCs) and fresh frozen plasma (FFP). Standard practice is generally to transfuse RBCs and FFP in 4 + 4-unit packs; platelet pools are transfused with the second and subsequent packs in a 1:1:1 ratio. Two pools of cryoprecipitate (4-g fibrinogen equivalent) are also generally added to the second and subsequent packs. For patients randomized to the intervention, an additional three pools of cryoprecipitate (6-g fibrinogen equivalent) were given as early as possible, preferably within 90 minutes of admission. 

Overall, 36% of patients sustained a penetrating injury and 26% had a severe head injury. Thirty-three percent had systolic blood pressure less than 90 mm Hg at the time of admission; 43% of patients received a blood component transfusion and 79% received tranexamic acid prior to hospital arrival. A total of 96% of patients received tranexamic acid either before or in the hospital.  

Cryoprecipitate was not always given in the first 24 hours (85% of patients in the intervention group and 32% of those in the control group). Reasons for not administering cryoprecipitate included no evidence of active bleeding (56 patients), hemostasis achieved (21 patients) or patient mortality (18 patients). Sixty-eight percent of patients in the cryoprecipitate group received their first dose of cryoprecipitate within the study goal of 90 minutes post-admission compared with 9% in the standard care group. 

In terms of secondary outcomes, there were no observed differences between the study groups for 24-hour non-cryoprecipitate transfusion requirements, critical care and hospital stays, or Glasgow Outcome Scale score. The cumulative incidence of thrombotic events was similar for the two groups — 12.7% for cryoprecipitate and 12.9% for standard care.  

Mortality at 28 days was better with earlier cryoprecipitate administration based on a prespecified analysis; the odds ratio for 28-day mortality in the intervention group was 1.45 with cryoprecipitate transfusion within 45 minutes of arrival, 0.57 within 61-90 minutes, and 1.00 for more than 90 minutes. Notably, 28-day mortality was significantly greater for the 36% of patients with penetrating trauma in the cryoprecipitate group compared with the standard care group — 16.2% versus 10%.