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.

MethodsBlunt 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 < 8 unless NL CT, BD > 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 8th 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 59 7.5 (0-35) 52 7.0(0-29) 2.6[0.7;4.6] 0.02All patients 72 7.2 (0-35) 64 7.8(0-48) 2.0[0.0;4.6] 0.07

PenetratingAlive 48 h 52 4.2 (0-41) 57 3.9(0-30) 1.0[0.0;2.6] 0.10All patients 61 4.8 (0-41) 69 4.0(0-37) 0.2[-0.9;2.4] 0.24

Boffard KD et al. J Trauma 2005;59:8-18.

Results- RBC Transfusions

33%

14%19%

7%

0%

5%

10%

15%

20%

25%

30%

35%

mas

sive

tran

sfus

ion

(% p

atie

nts)

Blunt Penetrating

% alive at 48 hours and > 12 units within 48 hours of first dose

Placebo rFVIIa

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%) 1.00 10(16%) 12(17%) 1.00

30 d M 22(30%) 17(25%) 0.58 18(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%) 0.03 5(8%) 4(6%) 0.74

MOF 9(12%) 5(7%) 0.41 7(11%) 2(3%) 0.09

Mortality, ARDS,

or MOF 31(42%) 20(29%) 0.16 22(34%) 20(29%) 0.57

Vent free(d) 13 (0-29) 17(0-29) 0.43 20(0-29) 25(0-29) 0.21

ICU free(d) 8 (0-29) 12(0-29) 0.31 18(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 109 91 76 57

Thrombotic adverse events

Patients 3(4%) 2(3%) 3(5%) 4(6%)

No. events 3 2 3 4

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.