Earlier Endpoints are Required for Hemorrhagic Shock Trials Among Severely Injured Patients

Abstract

Background Choosing the appropriate endpoint for a trauma hemorrhage control trial can determine the likelihood of its success. Recent Phase 3 trials and observational studies have used 24-hour and/or 30-day all-cause mortality as the primary endpoint and some have not used exception from informed consent (EFIC), resulting in multiple failed trials. Five recent high-quality prospective studies among 4,064 hemorrhaging trauma patients provide new evidence to support earlier primary endpoints. Methods The goal of this project was to determine the optimal endpoint for hemorrhage control trials using existing literature and new analyses of previously published data. Results Recent studies among bleeding trauma patients show that hemorrhagic deaths occur rapidly, at a high rate, and in a consistent pattern. Early preventable deaths among trauma patients are largely due to hemorrhage and the median time to hemorrhagic death from admission is 2.0-2.6 hours. Approximately 85% of hemorrhagic deaths occur within 6 hours. The hourly mortality rate due to traumatic injury decreases rapidly after enrollment from 4.6% per hour at 1 hour post-enrollment to 1% per hour at 6 hours to <0.1% per hour by 9 hours and thereafter. Early primary endpoints (within 6 hours) have critically important benefits for hemorrhage control trials, including being congruent with the median time to hemorrhagic death, biologic plausibility, and enabling the use of all-cause mortality, which is definitive and objective. Conclusions Primary endpoints should be congruent with the timing of the disease process. Therefore, if a resuscitation/hemorrhage control intervention is under study, a primary endpoint of all-cause mortality evaluated within the first 6 hours is appropriate. Before choosing the timing of the primary endpoint for a large multicenter trial, we recommend performing a Phase 2 trial under EFIC to better understand the effects of the hemorrhage control intervention and distribution of time to death. When early primary endpoints are used, patients should be monitored for multiple subsequent secondary safety endpoints, including 24 hour and 30 day all-cause mortality as well as the customary safety endpoints.

Response to: “Misunderstanding the PROPPR trial”

“…After publication of the PROPPR (Pragmatic Randomized Optimal Platelet and Plasma Ratios) trial, we initiated a discussion of the data with the US Food and Drug Administration, which resulted in a report that was just published in the journal Shock. 2 That article reports on the median time to hemorrhagic death from multiple randomized studies (2-3 hours), the issue of combined TBI and hemorrhagic shock, and the significant difference in all-cause mortality 3 hours after admission. We conclude that earlier (3-6 hours after admission) all-cause mortality should be the primary endpoint of future studies evaluating resuscitation protocols after hemorrhagic shock.…”

Outcomes of traumatic hemorrhagic shock and the epidemiology of preventable death from injury

“…36,37 While the concept of damage control resuscitation evolved across the battlefields of Iraq and Afghanistan, research to substantiate the observed successes of fresh whole blood and balanced ratio transfusion practices drew additional attention to the timing of hemorrhagic deaths. 38 Consistently, studies supported the fact that for patients who arrive at a trauma center, death from hemorrhage occurs within approximately 2 hours of hospital arrival. [39][40][41] Prospective trauma resuscitation studies in hemorrhaging patients showed that the median time to hemorrhagic death was 2.0 to 2.6 hours, with at least 50% of all deaths occurring within 3 hours of hospital arrival.…”

“…[39][40][41] Prospective trauma resuscitation studies in hemorrhaging patients showed that the median time to hemorrhagic death was 2.0 to 2.6 hours, with at least 50% of all deaths occurring within 3 hours of hospital arrival. 38 In contrast to the well-characterized outcome of injury mortality after reaching the hospital, there is a paucity of evidence that substantively defines injury-associated death in the civilian prehospital environment or across the continuum of care. One important analysis that included both prehospital and in-hospital traffic injury mortality demonstrated an overall 35% decrease in motor vehicle crash-related deaths over a period of 36 years.…”

Barriers to clinical research in trauma

“…The PROPPR study demonstrated how using 30‐day all‐cause mortality as the primary end point resulted in a failure to show a significant difference between treatment arms. In PROPPR, 86 patients died of hemorrhagic shock between both treatment arms, and of those 86 patients 72 (84%) died in the first 6 hours, contrasting this to TBI which had 62 deaths in the first 30 days, of which 10 (16%) died in the first 6 hours . The majority of deaths from hemorrhage occurred in the first 6 hours while the majority of deaths from TBI occurred later.…”