CRYOSTAT-2
Major haemorrhage is the most common preventable cause of death in the trauma population. We have shown that low fibrinogen levels on admission to hospital are independent predictors of early mortality in trauma patients, and in pilot studies (CRYOSTAT-1) early replacement of fibrinogen using cryoprecipitate found a signal for improved survival.
More information about the CRYOSTAT-1 trial can be found in this article and also here.
Importantly, there are two sources of fibrinogen for use in major blood loss; cryoprecipitate and fibrinogen concentrate. Despite being a fifth of the cost (per gram of fibrinogen) compared with fibrinogen concentrate, cryoprecipitate is a pooled blood component with high but variable fibrinogen concentration and contains other plasma proteins which may confer additional clotting benefit. However, a larger more definitive study was required to evaluate the use of fibrinogen replacement in major trauma haemorrhage.
Thus began the CRYOSTAT-2 study. In 2017, C4TS and NHS Blood & Transplant were awarded £2.4m from the National Institute for Health Research Health and Bart’s Charity to carry out a large multi-centre Randomised Controlled Trial (RCT) to evaluate early cryoprecipitate in major traumatic haemorrhage (CRYOSTAT-2) (ISRCTN14998314 and ClinicalTrials.gov NCT04704869).
In November 2022, recruitment for CRYOSTAT-2 was completed, having commenced in 2017, with results being published in October 2023. The trial protocol is available here .
The trial published in JAMA in October 2023 and available here tested the effect of early cryoprecipitate (within 90 minutes of admission) compared to standard blood transfusion therapy, on 1604 severely bleeding trauma patients from 26 Major Trauma Centre (MTC) across England, Wales and North Ireland, as well as 1 trauma centre in the US (Houston). There is a very interesting blog article here about the study accessible here. Further, the results were presented at the Critical Care Reviews meeting in Belfast in June 2023 and a recording of the presentations and slides are available here.
To our surprise, overall, there was no difference in mortality between those patients who got high dose cryoprecipitate and those who received standard of care. Indeed, there were signals that patients may do worse with the extra fibrinogen treatment.
*For an interesting video of the panelist discussion held in 2023, watch here.
Further, the results fit with our current thinking that one-size fits all does not work for trauma patients, and we need to bring early diagnostic tests close to the patient in the emergency room (or into prehospital care at the scene) to allow more precision approaches to treating severe bleeding and abnormal clotting.
In other words, give fibrinogen emergently to people who need it, but not to those who don't. Interestingly, it may also explain why similar trials in post-partum haemorrhage and cardiac surgery have also been negative that have tested empiric use of fibrinogen.
The trial has only answered one question and that is giving a large dose of fibrinogen to all bleeding trauma patients does not improve survival overall. However, there remain many unanswered questions and opportunities for future research. For example:
Is the effect the same for all trauma patients? Do patients with blunt injury e.g. car accident respond in the same way to fibrinogen treatment as a patient who has sustained penetrating trauma e.g. stab wound.
Why might fibrinogen treatment not work? Is it because the fibrinogen levels are not low overall or only become low later during bleeding for some patients and therefore giving the treatment later may still be beneficial? Or does something happen to the fibrinogen that stops it from working as a result of the molecules released into the blood stream following major injury?
We thank the patients and their relatives who supported the trial, principal investigators and other research staff at the study sites, participating blood banks, NHS Blood & Transplant Clinical Trials Unit and Sponsors office, the Trial Steering Committee and the Data Monitoring Committee.
For any queries, please contact Principal Investigator: Dr Ross Davenport
