Two newer approaches to management of major hemorrhage missed the mark in randomized clinical trials published in a special transfusion-related issue of JAMA.
In the CRYOSTAT-2 trial, adding early, high-dose cryoprecipitate to standard major hemorrhage protocols as a fibrinogen replacement didn’t improve all-cause mortality at 28 days compared with standard care alone.
In the UK-REBOA trial, resuscitative endovascular balloon occlusion of the aorta (REBOA) didn’t improve on standard hemorrhagic care in the emergency department and may actually have increased 90 day-mortality.
Both trials were the first randomized clinical trial look at the intervention tested, noted an accompanying editorial by Samuel A. Tisherman, MD, of the University of Maryland Shock Trauma Center in Baltimore, and Megan L. Brenner, MD, of the University of California Los Angeles.
“Although neither intervention improved outcomes, the studies have provided important information pertinent to trauma care and lessons for future studies,” they noted.
Early, High-Dose Cryoprecipitate
Cryoprecipitate — a whole-blood derived, concentrated fibrinogen replacement treatment — is often given to correct the complex derangement of coagulation, including acute fibrinogen deficiency, that occurs in major hemorrhage.
“A key question in contemporary trauma resuscitation is whether fibrinogen treatment should be given empirically and in high doses to rapidly correct levels or later in the course of bleeding as is current practice,” noted Ross Davenport, PhD, of the University of London Centre for Trauma Sciences, and colleagues.
Their trial included 799 injured patients at 26 U.K. and U.S. major trauma centers, who were actively hemorrhaging, hypotensive (systolic <90 mm Hg at any time), and being transfused with at least 1 U of a blood component under the hospital’s major hemorrhage protocol. They were randomized to standard of care following that protocol adhering to guidelines either alone or with addition of three pools of cryoprecipitate (6-g fibrinogen equivalent) within 90 minutes of randomization and 3 hours of injury.
For the primary endpoint, cryoprecipitate didn’t improve all-cause 28-day mortality in the intention-to-treat population compared with standard care (25.3% vs 26.1%; OR 0.96, 95% CI 0.75-1.23, P=0.74).
Cause of death, 24-hour transfusion requirements of other blood products, and all other secondary endpoints likewise did not differ between groups. Safety outcomes and incidence of thrombotic events were similar between cryoprecipitate and standard of care groups as well (12.7% vs 12.9%).
“The findings of the CRYOSTAT-2 study are not consistent with the biological rationale for fibrinogen supplementation in trauma hemorrhage, the results of observational studies, or previous pilot or feasibility randomized controlled trials,” the researchers wrote.
Potential problems included median time to first transfusion of 68 minutes after arrival, “reflecting the logistical challenge of preparing and administering a frozen blood component stored in a blood laboratory remote from the patient,” as well as 15% of the cryoprecipitate group not getting cryoprecipitate within 24 hours of hospital admission, most often for no evidence of active bleeding (56 cases), achievement of hemostasis (21 cases), or death (18 cases).
“Any potential benefit of early supplementation may only be seen in those who are bleeding quickly and the most coagulopathic,” Davenport’s group concluded.
For exsanguinating torso hemorrhage from trauma, the novel REBOA approach to stop bleeding via a percutaneous balloon inflated in the aorta actually appeared to increase risk of death in the UK-REBOA trial.
REBOA increased 90-day all-cause mortality compared with standard care (54% vs 42%; OR 1.58, 95% credible interval 0.72-3.52); the posterior probability of increased odds of death with REBOA was 86.9% by bayesian analysis.
Although military protocols and surgical and emergency physician position statements support its use, the trial suggested that the procedure delayed or prevented definitive control of the hemorrhage as a result of or during REBOA insertion attempts, noted researchers led by Jan O. Jansen, PhD, of the University of Alabama at Birmingham Center for Injury Science.
“It is also noteworthy that the ORs and posterior probabilities for increased mortality increased with earlier time points, which are more specific for deaths due to hemorrhage,” they wrote.
Among the 10 secondary outcomes, the odds of increased mortality were also increased with the procedure for 6-month, in-hospital, and 24-, 6-, or 3-hour mortality. There were twice as many deaths due to bleeding in the REBOA group (32% vs 17%), and most occurred within 24 hours.
The variety of treatment pathways experienced in the study patients, the researchers said, “reflect the challenges in obtaining arterial access in patients with severe shock and in distinguishing between patients who are experiencing continuing hemorrhage from those in whom bleeding has stopped. These experiences reflect real life and highlight the complexity of trauma care, and the challenges inherent in evaluating it.”
The trial was stopped early due to risk of harm after enrolling 90 patients at 16 major trauma centers in the U.K. The pragmatic design included patients believed to be at least age 16 years who presented with confirmed or suspected life-threatening torso hemorrhage that was deemed amenable to adjunctive REBOA. Any brand of REBOA device was allowed.
“Although both trials found no benefit, it is time to conduct more rigorous studies of cryoprecipitate and REBOA,” the editorialists argued.
The lessons for further studies, they said, were: “First, participant selection is critical. Judgment by a clinician that a patient has uncontrolled bleeding is very subjective. Both studies enrolled many patients who actually were not actively bleeding. More detailed selection criteria are needed.”
“[T]he interventions must be implemented as soon as possible,” they added. “Delay in cryoprecipitate administration or REBOA placement likely decreased potential benefit.”
CRYOSTAT-2 was funded by Barts Charity and the U.K. National Institute for Health and Care Research: Health Technology Assessment.
Davenport reported receiving grants from both trial funders, plus relationships with Octapharma, Werfen, and HemoSonics.
UK-REBOA was funded by the National Institute for Health and Care Research Health Technology Assessment Programme.
Jansen reported receiving personal fees from CSL Behring, Cellphire, and InfraScan, and grants from CSL Behring, InfraScan, and RevMedX.
Editorialists Tisherman reported having a patent issued for an emergency preservation and resuscitation method, and Brenner reported a relationship with Prytime Medical that ended in May 2023.
Source Reference: Davenport R, et al “Early and empirical high-dose cryoprecipitate for hemorrhage after traumatic injury: the CRYOSTAT-2 randomized clinical trial” JAMA 2023; DOI: 10.1001/jama.2023.21019.
Source Reference: Jansen JO, et al “Emergency department resuscitative endovascular balloon occlusion of the aorta in trauma patients with exsanguinating hemorrhage: the UK-REBOA randomized clinical trial” JAMA 2023; DOI: 10.1001/jama.2023.20850.
Source Reference: Tisherman SA, Brenner ML “Contemporary adjuncts to hemorrhage control” JAMA 2023; DOI: 10.1001/jama.2023.16135.