Objective: To address the clinical and regulatory challenges of optimal primary endpoints for bleeding patients by developing consensus-based recommendations for primary clinical outcomes for pivotal trials in patients within 6 categories of significant bleeding, (1) traumatic injury, (2) intracranial hemorrhage, (3) cardiac surgery, (4) gastrointestinal hemorrhage, (5) inherited bleeding disorders, and (6) hypoproliferative thrombocytopenia. Background: A standardized primary outcome in clinical trials evaluating hemostatic products and strategies for the treatment of clinically significant bleeding will facilitate the conduct, interpretation, and translation into clinical practice of hemostasis research and support alignment among funders, investigators, clinicians, and regulators. Methods: An international panel of experts was convened by the National Heart Lung and Blood Institute and the United States Department of Defense on September 23 and 24, 2019. For patients suffering hemorrhagic shock, the 26 trauma working-group members met for almost a year, utilizing biweekly phone conferences and then an in-person meeting, evaluating the strengths and weaknesses of previous high quality studies. The selection of the recommended primary outcome was guided by goals of patient-centeredness, expected or demonstrated sensitivity to beneficial treatment effects, biologic plausibility, clinical and logistical feasibility, and broad applicability. Conclusions: For patients suffering hemorrhagic shock, and especially from truncal hemorrhage, the recommended primary outcome was 3 to 6-hour all-cause mortality, chosen to coincide with the physiology of hemorrhagic death and to avoid bias from competing risks. Particular attention was recommended to injury and treatment time, as well as robust assessments of multiple safety related outcomes.

Background Emerging evidence suggests aspirin may be an effective venous thromboembolism (VTE) prophylaxis for orthopaedic trauma patients, with fewer bleeding complications. We used a patient-centered weighted composite outcome to globally evaluate aspirin versus low-molecular-weight heparin (LMWH) for VTE prevention in fracture patients. Methods We conducted an open-label randomized clinical trial of adult patients admitted to an academic trauma center with an operative extremity fracture, or a pelvis or acetabular fracture. Patients were randomized to receive LMWH (enoxaparin 30-mg) twice daily (n = 164) or aspirin 81-mg twice daily (n = 165). The primary outcome was a composite endpoint of bleeding complications, deep surgical site infection, deep vein thrombosis, pulmonary embolism, and death within 90 days of injury. A Global Rank test and weighted time to event analysis were used to determine the probability of treatment superiority for LMWH, given a 9% patient preference margin for oral administration over skin injections. Results Overall, 18 different combinations of outcomes were experienced by patients in the study. Ninety-nine patients in the aspirin group (59.9%) and 98 patients in the LMWH group (59.4%) were event-free within 90 days of injury. Using a Global Rank test, the LMWH had a 50.4% (95% CI, 47.7–53.2%, p = 0.73) probability of treatment superiority over aspirin. In the time to event analysis, LMWH had a 60.5% probability of treatment superiority over aspirin with considerable uncertainty (95% CI, 24.3–88.0%, p = 0.59). Conclusion The findings of the Global Rank test suggest no evidence of superiority between LMWH or aspirin for VTE prevention in fracture patients. LMWH demonstrated a 60.5% VTE prevention benefit in the weighted time to event analysis. However, this difference did not reach statistical significance and was similar to the elicited patient preferences for aspirin.

Therapeutic study, level V.

Prognostic/Epidemiologic, level III.