Results of the control trial: Efficacy and safety of recombinant activated factor VII in the management of refractory traumatic hemorrhage

Carl J. Hauser, Kenneth Boffard, Richard Dutton, Gordon R. Bernard, Martin Croce, John B. Holcomb, Ari Leppaniemi, Michael Parr, Jean Louis Vincent, Bartholomew J. Tortella, Jeannett Dimsits, Bertil Bouillon

Research output: Contribution to journalArticle

168 Citations (Scopus)

Abstract

Background: Traumatic coagulopathy contributes to early death by exsanguination and late death in multiple organ failure. Recombinant Factor VIIa (rFVIIa, NovoSeven) is a procoagulant that might limit bleeding and improve trauma outcomes. Methods: We performed a phase 3 randomized clinical trial evaluating efficacy and safety of rFVIIa as an adjunct to direct hemostasis in major trauma. We studied 573 patients (481 blunt and 92 penetrating) who bled 4 to 8 red blood cell (RBC) units within 12 hours of injury and were still bleeding despite strict damage control resuscitation and operative management. Patients were assigned to rFVIIa (200 μg/kg initially; 100 μg/kg at 1 hour and 3 hours) or placebo. Intensive care unit management was standardized using evidence-based trauma "bundles" with formal oversight of compliance. Primary outcome was 30-day mortality. Predefined secondary outcomes included blood products used. Safety was assessed through 90 days. Study powering was based on prior randomized controlled trials and large trauma center databases. Results: Enrollment was terminated at 573 of 1502 planned patients because of unexpected low mortality prompted by futility analysis (10.8% vs. 27.5% planned/predicted) and difficulties consenting and enrolling sicker patients. Mortality was 11.0% (rFVIIa) versus 10.7% (placebo) (p = 0.93, blunt) and 18.2% (rFVIIa) versus 13.2% (placebo) (p = 0.40, penetrating). Blunt trauma rFVIIa patients received (mean ± SD) 7.8 ± 10.6 RBC units and 19.0 ± 27.1 total allogeneic units through 48 hours, and placebo patients received 9.1 ± 11.3 RBC units (p = 0.04) and 23.5 ± 28.0 total allogeneic units (p = 0.04). Thrombotic adverse events were similar across study cohorts. Conclusions: rFVIIa reduced blood product use but did not affect mortality compared with placebo. Modern evidence-based trauma lowers mortality, paradoxically making outcomes studies increasingly difficult.

Original languageEnglish (US)
Pages (from-to)489-500
Number of pages12
JournalJournal of Trauma - Injury, Infection and Critical Care
Volume69
Issue number3
DOIs
StatePublished - Sep 1 2010

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Factor VIIa
Hemorrhage
Safety
Placebos
Wounds and Injuries
Mortality
Erythrocytes
Randomized Controlled Trials
Medical Futility
Exsanguination
recombinant FVIIa
Phase III Clinical Trials
Multiple Organ Failure
Trauma Centers
Hemostasis
Resuscitation
Compliance
Intensive Care Units
Cohort Studies
Outcome Assessment (Health Care)

All Science Journal Classification (ASJC) codes

  • Surgery
  • Critical Care and Intensive Care Medicine

Cite this

Results of the control trial : Efficacy and safety of recombinant activated factor VII in the management of refractory traumatic hemorrhage. / Hauser, Carl J.; Boffard, Kenneth; Dutton, Richard; Bernard, Gordon R.; Croce, Martin; Holcomb, John B.; Leppaniemi, Ari; Parr, Michael; Vincent, Jean Louis; Tortella, Bartholomew J.; Dimsits, Jeannett; Bouillon, Bertil.

In: Journal of Trauma - Injury, Infection and Critical Care, Vol. 69, No. 3, 01.09.2010, p. 489-500.

Research output: Contribution to journalArticle

Hauser, CJ, Boffard, K, Dutton, R, Bernard, GR, Croce, M, Holcomb, JB, Leppaniemi, A, Parr, M, Vincent, JL, Tortella, BJ, Dimsits, J & Bouillon, B 2010, 'Results of the control trial: Efficacy and safety of recombinant activated factor VII in the management of refractory traumatic hemorrhage', Journal of Trauma - Injury, Infection and Critical Care, vol. 69, no. 3, pp. 489-500. https://doi.org/10.1097/TA.0b013e3181edf36e
Hauser, Carl J. ; Boffard, Kenneth ; Dutton, Richard ; Bernard, Gordon R. ; Croce, Martin ; Holcomb, John B. ; Leppaniemi, Ari ; Parr, Michael ; Vincent, Jean Louis ; Tortella, Bartholomew J. ; Dimsits, Jeannett ; Bouillon, Bertil. / Results of the control trial : Efficacy and safety of recombinant activated factor VII in the management of refractory traumatic hemorrhage. In: Journal of Trauma - Injury, Infection and Critical Care. 2010 ; Vol. 69, No. 3. pp. 489-500.
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AU - Croce, Martin

AU - Holcomb, John B.

AU - Leppaniemi, Ari

AU - Parr, Michael

AU - Vincent, Jean Louis

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N2 - Background: Traumatic coagulopathy contributes to early death by exsanguination and late death in multiple organ failure. Recombinant Factor VIIa (rFVIIa, NovoSeven) is a procoagulant that might limit bleeding and improve trauma outcomes. Methods: We performed a phase 3 randomized clinical trial evaluating efficacy and safety of rFVIIa as an adjunct to direct hemostasis in major trauma. We studied 573 patients (481 blunt and 92 penetrating) who bled 4 to 8 red blood cell (RBC) units within 12 hours of injury and were still bleeding despite strict damage control resuscitation and operative management. Patients were assigned to rFVIIa (200 μg/kg initially; 100 μg/kg at 1 hour and 3 hours) or placebo. Intensive care unit management was standardized using evidence-based trauma "bundles" with formal oversight of compliance. Primary outcome was 30-day mortality. Predefined secondary outcomes included blood products used. Safety was assessed through 90 days. Study powering was based on prior randomized controlled trials and large trauma center databases. Results: Enrollment was terminated at 573 of 1502 planned patients because of unexpected low mortality prompted by futility analysis (10.8% vs. 27.5% planned/predicted) and difficulties consenting and enrolling sicker patients. Mortality was 11.0% (rFVIIa) versus 10.7% (placebo) (p = 0.93, blunt) and 18.2% (rFVIIa) versus 13.2% (placebo) (p = 0.40, penetrating). Blunt trauma rFVIIa patients received (mean ± SD) 7.8 ± 10.6 RBC units and 19.0 ± 27.1 total allogeneic units through 48 hours, and placebo patients received 9.1 ± 11.3 RBC units (p = 0.04) and 23.5 ± 28.0 total allogeneic units (p = 0.04). Thrombotic adverse events were similar across study cohorts. Conclusions: rFVIIa reduced blood product use but did not affect mortality compared with placebo. Modern evidence-based trauma lowers mortality, paradoxically making outcomes studies increasingly difficult.

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