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-h 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 to 2.6 h. Approximately 85% of hemorrhagic deaths occur within 6 h. The hourly mortality rate due to traumatic injury decreases rapidly after enrollment from 4.6% per hour at 1 hour postenrollment to 1% per hour at 6 h to <0.1% per hour by 9 h and thereafter. Early primary endpoints (within 6 h) 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 h 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 h and 30-day all-cause mortality as well as the customary safety endpoints.
*Center for Translational Injury Research, Division of Acute Care Surgery, Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas
†Division of Trauma and Critical Care, Department of Surgery, School of Medicine, University of Washington, Seattle, Washington
‡Division of Biostatistics, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas
Address reprint requests to Erin E. Fox, PhD, 6410 Fannin Street, Suite 1100, University of Texas Health Science Center at Houston, Houston, TX, 77030. E-mail: firstname.lastname@example.org
Received 26 August, 2016
Revised 9 September, 2016
Accepted 27 October, 2016
The content is the sole responsibility of the authors and is not to be construed as official or as reflecting the views of any sponsor.
This work was sponsored by the US National Heart, Lung, and Blood Institute (U01HL077863) and the US Department of Defense, as well as Defence Research and Development Canada in partnership with the Canadian Institutes of Health Research (CIHR)—Institute of Circulatory and Respiratory Health (CRR-120612). NHLBI and the DoD were consulted regarding study design only. No sponsors were involved in the collection, management, or analysis of the data; preparation of the manuscript; or the decision to submit the manuscript for publication.
Trial Registration: Clinicaltrials.gov, NCT01545232.
The authors report no conflicts of interest.