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 A. Croce; John B. Holcomb; Ari Leppaniemi; Michael Parr; Jean-Louis Vincent; Bartholomew J. Tortella; Jeannett Dimsits; Bertil Bouillon

doi:10.1097/TA.0b013e3181edf36e

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 A. Croce, John B. Holcomb, Ari Leppaniemi, Michael Parr, Jean-Louis Vincent, Bartholomew J. Tortella, Jeannett Dimsits, Bertil Bouillon

Research output: Contribution to journal › Article › peer-review

262 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 language	English
Pages (from-to)	489-500
Number of pages	12
Journal	Journal of Trauma - Injury, Infection and Critical Care
Volume	69
Issue number	3
DOIs	https://doi.org/10.1097/TA.0b013e3181edf36e
Publication status	Published - 1 Sep 2010
Externally published	Yes

Keywords

Hemorrhage
Outcome
Randomized clinical trial
Recombinant Factor VIIa
Trauma

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10.1097/TA.0b013e3181edf36e

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Hauser, C. J., Boffard, K., Dutton, R., Bernard, G. R., Croce, M. A., Holcomb, J. B., Leppaniemi, A., Parr, M., Vincent, J-L., Tortella, B. J., 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, 69(3), 489-500. https://doi.org/10.1097/TA.0b013e3181edf36e

Hauser, Carl J. ; Boffard, Kenneth ; Dutton, Richard ; Bernard, Gordon R. ; Croce, Martin A. ; 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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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.",

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author = "Hauser, {Carl J.} and Kenneth Boffard and Richard Dutton and Bernard, {Gordon R.} and Croce, {Martin A.} and Holcomb, {John B.} and Ari Leppaniemi and Michael Parr and Jean-Louis Vincent and Tortella, {Bartholomew J.} and Jeannett Dimsits and Bertil Bouillon",

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Hauser, CJ, Boffard, K, Dutton, R, Bernard, GR, Croce, MA, Holcomb, JB, Leppaniemi, A, Parr, M, Vincent, J-L, 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

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 A.; 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 journal › Article › peer-review

TY - JOUR

T1 - Results of the CONTROL trial

T2 - Efficacy and safety of recombinant activated factor VII in the management of refractory traumatic hemorrhage

AU - Hauser, Carl J.

AU - Boffard, Kenneth

AU - Dutton, Richard

AU - Bernard, Gordon R.

AU - Croce, Martin A.

AU - Holcomb, John B.

AU - Leppaniemi, Ari

AU - Parr, Michael

AU - Vincent, Jean-Louis

AU - Tortella, Bartholomew J.

AU - Dimsits, Jeannett

AU - Bouillon, Bertil

PY - 2010/9/1

Y1 - 2010/9/1

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.

AB - 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.

KW - Hemorrhage

KW - Outcome

KW - Randomized clinical trial

KW - Recombinant Factor VIIa

KW - Trauma

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AN - SCOPUS:77957577047

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SN - 1079-6061

IS - 3

ER -

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

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