Recombinant Factor VIIa as Adjunctive Therapy for Bleeding Control in Severely Injured Trauma Patients: Two Parallel Randomized, Placebo-Controlled, Double- Blind Clinical Trials Bofford KD, Riou B, Warren B, et al. J Trauma 2005;59:8-18.

Background Coagulopathy is a major contributing factor to bleeding related mortality in trauma. Coagulopathy in association with metabolic acidosis and hypothermia referred to as the “Lethal Triad”. Boffard KD et al. J Trauma 2005;59:8-18.

Purpose Evaluate the efficacy and safety of rFVIIa as adjunctive therapy for control of bleeding in patients with severe blunt or penetrating trauma. Boffard KD et al. J Trauma 2005;59:8-18.

Methods Blunt or penetrating trauma, 32 centers Inclusion Severely traumatized 6 units PRBC within 4 hours of admission ≥ 16 to < 65 years Exclusion Cardiac arrest, GSW head, GCS 15, pH < 7, 8 or more units PRBC prior to arrival to trauma center, injury ≥12 hours prior to randomization Boffard KD et al. J Trauma 2005;59:8-18.

Two parallel trials –Blunt trauma and penetrating trauma Intervention –Randomization to rFVIIa or PL Dose 200mcg, 100mcg, 100mcg at 0,1,3 hours, respectively, administered after the 8 th unit PRBC Monitoring –Transfusion and infusion requirements 48 h after rFVIIa –Blood samples to evaluate changes in coagulation and blood biochemistry parameters Boffard KD et al. J Trauma 2005;59:8-18. Methods

Primary end point –RBC units 48 hours after first rFVIIa dose. Secondary end points –Other transfusion products, mortality, days on ventilator, ICU LOS. –Adverse events, coagulation-related lab variables –Composite of death and critical complications –MOF and ARDS Boffard KD et al. J Trauma 2005;59:8-18. End Points

Estimated PL rFVIIa RBC reduction p N Median N Median [90% CI] Blunt (# of Units)(# of Units) (# of Units) Alive 48 h (0-35) 527.0(0-29) 2.6[0.7;4.6] 0.02 All patients (0-35) 647.8(0-48) 2.0[0.0;4.6] 0.07 Penetrating Alive 48 h (0-41) (0-30) 1.0[0.0;2.6] 0.10 All patients (0-41) 694.0(0-37) 0.2[-0.9;2.4] 0.24 Boffard KD et al. J Trauma 2005;59:8-18. Results- RBC Transfusions

P=0.03 P=0.08 Boffard KD et al. J Trauma 2005;59:8-18. Results- Need for Massive Transfusion

Blunt Trauma Penetrating Trauma PL (n=74) rFVIIa (n=69) p PL (n=64) rFVIIa (n=70) p Mortality 48 h M 13(18%) 13(19%) (16%) 12(17%) d M 22(30%) 17(25%) (28%) 17(24%) 0.69 Boffard KD et al. J Trauma 2005;59:8-18. Results- Mortality

Blunt Trauma Penetrating Trauma PL (n=74) rFVIIa (n=69) p PL (n=64) rFVIIa (n=70) p 30 day complication ARDS 12(16%) 3(4%) (8%) 4(6%) 0.74 MOF 9(12%) 5(7%) (11%) 2(3%) 0.09 Mortality, ARDS, or MOF 31(42%) 20(29%) (34%) 20(29%) 0.57 Vent free(d) 13 (0-29) 17(0-29) (0-29) 25(0-29) 0.21 ICU free(d) 8 (0-29) 12(0-29) (0-29) 23(0-29) 0.34 Boffard KD et al. J Trauma 2005;59:8-18. Results- Clinical Outcomes

Blunt Trauma Penetrating Trauma PL (n=74) rFVIIa (n=69) PL (n=64) rFVIIa (n=70) Serious adverse events Patients 49(66%) 44(64%) 36(56%) 36(51%) No. events Thrombotic adverse events Patients 3(4%) 2(3%) 3(5%) 4(6%) No. events Boffard KD et al. J Trauma 2005;59:8-18. Results- Adverse Events

Conclusions rFVIIa significantly improved bleeding control in blunt trauma –Decrease RBC transfusions –Decrease in number of patients requiring massive transfusion Similar trend in patients with penetrating trauma Adverse events were not increased with rFVIIa Boffard KD et al. J Trauma 2005;59:8-18.