Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial: Design, rationale and implementation☆
Introduction
Injury is the leading cause of death between the ages of 1 and 44 years. Nearly 50% of injury-related deaths occur before the individual reaches the hospital, and much of this mortality is currently difficult to prevent [1], [2], [3], [4]. However, approximately 40% of the in-hospital deaths among injured patients involve massive truncal haemorrhage that is considered potentially salvageable with rapid haemorrhage control and improved resuscitation techniques [5], [6], [7], [8], [9], [10], [11].
One method to improve the outcome of rapidly bleeding patients is to deliver predetermined ratios of platelets, plasma, and red blood cells (RBCs). However, the optimal ratio of these products is unclear. The current United States (US) Department of Defense (DoD) guideline specifies the use of 1:1:1 [12]. In civilian observational studies, investigators have reported good outcomes across a range of different blood product ratios [13], [14], [15], [16], [17], [18], [19]; the largest observational transfusion study of bleeding trauma patients, the PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study, was conducted in 10 Level I trauma centres in the US. In PROMMTT, clinicians generally delivered transfusion ratios that cumulated in the range of 1:1 or 1:2 [20], showing clinical equipoise for these two ratios.
The DoD and the National Heart, Lung and Blood Institute (NHLBI) recognized the need to address optimal blood product ratios and to characterize the natural history of coagulopathy and inflammation in bleeding patients [21], [22]. They recommended a large trial comparing blood product ratios and collecting serial blood samples and subsequently funded the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial through the Resuscitation Outcomes Consortium (ROC) in 2010, with additional funds from Defence Research and Development Canada and the Canadian Institutes of Health Research. PROPPR worked within a complex structure of review and oversight for the design and conduct of the trial (Fig. 1).
Section snippets
Study design and hypotheses
PROPPR was a randomized, two-group, Phase III trial conducted in subjects requiring the highest level of trauma activation and predicted to receive a massive transfusion as defined by ABC score or physician gestalt [23]. Subjects were randomized into transfusion ratio interventions: 1:1:1 or 1:1:2 (Table 1). Based upon the timing of haemorrhagic death the Food and Drug Administration (FDA) approved two co-primary endpoints [24]. The clinical hypotheses are below:
Ha1: A greater proportion of
Enrollment
Fig. 3 shows enrollment over the course of the trial. Throughout the trial, recruitment was higher than projected. Four sites began enrolling within 19 days of the first subject (3 Aug 2012), and all 12 sites were enrolling within a 6 month span A total of 35 patients withdrew consent; however, these patients were followed for mortality under EFIC guidelines and are included in mortality analyses. No subjects were lost-to-follow-up at 24 h, and four were lost-to-follow-up at 30 days.
Process time measures
Fig. 4
Discussion
Previous Phase III studies of hemostasis or resuscitation in acutely injured trauma patients have largely failed to show mortality differences between groups [36], [37], [38], [39], [40]. Reasons for the negative findings have included enrolling either moribund or minimally injured patients, delays in enrollment due to not utilizing EFIC, lack of blinding, high protocol deviation rates after unblinding, lack of blood product availability and limited biological effect of the study agent [36],
Conflicts of interest statement
No conflicts of interest have been declared by any author in regards to this manuscript.
Acknowledgements
We would like to thank the members of the DSMB, including Lance Becker, Charles Cairns, Ralph D’Agostino, Karl Jern, Nigel Key, Laurence McCullough, Jeremy Perkins, Herbert Wiedemann, Janet Wittes, and Jay Mason. The members of the PROPPR External Advisory Committee, including Kenneth G. Mann, Kathleen Brummel, Beth Hartwell, Charles Esmon, Morris Blajchman, Andrew P. Cap, Andrei Kindzelski, and Anthony E. Pusateri, also contributed to the design of PROPPR and we thank them for their time and
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Clinicaltrials.gov number: NCT01545232.
- 1
See Appendix A for the PROPPR Study Group.