rFVIIa and Civilian and Combat Trauma: Primum Non Nocere

1
rFVIIa and Civilian and Combat Trauma Primum Non
Nocere?

• Meagan Jacoby
• Grand Rounds
• May 23, 2008

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Recombinant FVIIa

• Developed for use in severe hemophilia
  complicated by development of inhibitors
• rFVIIa approved for use in hemophilia with
  inhibitors and acquired hemophilia
• As of 2006 16 thrombotic events/700,000 standard
  doses (90 mcg/kg) in congenital or acquired
  hemophiliacs

Reviewed in Hedner, U. J of Biotech. 2006.
124747-757.
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Mechanism of Action
From Novoseven website Reviewed in Hedner, U. J
of Biotech. 2006.124747-757.
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Death From Combat Trauma

• Autopsy review shows 80-85 combat deaths are
  nonsurvivable1
• 15-20 potentially survivable of these 66-80
  die of hemorrhage1

1Holcomb,J. Ann Surg. 2007.245986-991.
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Damage Control Resuscitation

• Vicious cycle Bleeding?resuscitation?hemodilution
  hypothermia?coagulopathy?bleeding
• Relies on FWB or 11.4 ratio plasma to PRBCs,
  minimal crystalloid, aggressive use of plt,
  cryoprecipitate, /- use of rFVIIa
• Trauma exsanguination protocol using 10 U PRBC, 4
  U FFP, 2 U plts decreased mortality1

1Cotton et al.J Trauma. 20086411771183
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First Reported Case rFVIIa in Trauma

• 19 yo Israeli soldier with rifle injury to IVC at
  L5 resulting in shock, DIC, hypothermia
• Bleeding cont despite surgery, 5 L PRBC,3 L FFP
  20 U plts, 10 U cryo. Bleeding at 300 ml/min
• Desperate attempt used 60 mcg/kg rFVIIa.
  Bleeding slowed 15 ml/min
• Pt survived

Kenet, et al. 1999. Lancet. 3541879.
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Preclinical Trauma Studies

• Pig models clamp to create grade V liver injury,
  cooled, given 60 isovolumetic exchange with
  fluid
• Pigs receiving rFVIIa had significantly less
  blood loss (527 mL vs 976 mL)
• Follow up study showed rFVIIa resulted less blood
  loss, higher nadir pressures, but no difference
  in mortality

Reviewed in Schreiber, et al. Critical Care.
2005, 9S25-28)
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Development of GuidelinesIsraeli
Multidisciplinary rFVIIa Task Force

• Consecutive cases 57 of trauma pt treated with
  rFVIIa (excluded TBI and non-salvageable pt) were
  examined in Israel
• 37 cases analyzed
• Median age 19.5 years
• Had penetrating (44), blunt (42), blast (14)
  injuries
• All critically ill with life threatening bleeds

Martinowitz and Michaelson. 2005. J Thromb Haem.
3640-648.
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Development of Guidelines

• Median requirement of 21 U PRBC over 5.4/-4 h
• Pt were hypothermic (34.1/-2.5oC
• Pt were acidotic (pH 7.2/-0.15)
• Pt were coagulopathic (median plt 89.5, median
  fibrinogen 149, mean PT 20.6, PTT 75

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Development of Guidelines

• Pt received replacement Tx (FFP median 15U
  Cryo median 17.5 U plts median 20 U)
• If bleeding continued and exsanguination seemed
  inevitable, 90-120 mcg/kg rFVIIa given with
  additional doses prn

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Development of Guidelines

• 26/36 responders
• 9/10 nonresponders exsanguinated lt24 hrs
• Decrease in transfusion requirements
• 22/36 pt survived to day 90
• Favorable compared to historical controls (30-57)

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Development of Guidelines
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A Randomized, Placebo Controlled Trial in Trauma

• Multicenter, randomized, placebo controlled
  double blind study conducted on severe trauma
  (blunt and penetrating arms)
• Severe trauma 6 U/4 hours
• Excluded Cardiac arrest, pHlt7,GSW to head
• Randomized to rFVII (200, 100, 100mcg/kg) or
  placebo
• 143 blunt trauma and 134 penetrating pt

Boffard et al. J of Trauma. 2005 59 8-18.
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Primary Endpoint Transfusion Requirements
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Primary Endpoint Transfusion Requirements
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Secondary Endpoints
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Post-hoc Subgroup Analysis

• Post hoc analysis of effect of rFVIIa on subgroup
  of coagulopathic pt from trial
• Coagulopathy retrospectively defined requiring
  FFP, plts, or cryo
• 60 rFVIIa and 76 placebo identified

Rizoli et al. Critical Care. 200610
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Transfusion Requirements
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Secondary Endpoints
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Use in Military and Attention in the Popular Press

• Baltimore Sun reported Nov 2006 that 1000 wounded
  US troops in Iraq and 300 Israelis received
  rFVIIa
• After successful case study, Martinowitz put
  siren on bicycle and race to scenes of suicide
  bombings, etc with rFVIIa
• Holcomb introduced rFVIIa in 2004 based on early
  review of Boffard et al

Little. Baltimore Sun. Nov 19-21, 2006.
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Use in Military and Attention in the Popular Press

• Reported that Army administering liberally, life
  threatening hemorrhage not established
• 2004-2006 Army spent 11.2 million on rFVIIa
• Reported Walter Reed and Landsthul observing more
  TE complications than expected
• Reported Army not tracking cases no database
  existed at that time

Little. Baltimore Sun. Nov 19-21, 2006.
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Questions About Adverse Events

• FDA examined Adverse Events Reporting System
  Database from 1999-2004
• 185 TE events in 168 pt 17 events in
  hemophiliacs

OConnell et al. JAMA. 2006. 295 293-298.
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Retrospective Study of TE Complications From a
Shock Trauma Center

• R. Adams Cowley Shock Trauma Center has largest
  single center experience with rFVIIa in trauma
• Retrospective review of all pt receiving rFVIIa
  from 6/01-6/06
• 285 pt identified

Rhys Thomas, et al. 2007. J of Trauma. 62564-569.
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Cowley Shock Trauma Center

• 27/285 pt had TE event
• 9/27 highly related to rFVIIa (2 died)
• 14/27 pt died
• 10/14 deaths at least partially related
• 18/27 TE events occurred in region of trauma
• Changed this centers practice
• Avoiding in certain arterial injury
• More surveillance for TE events

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Effect of rFVIIa on Severe Combat Trauma Mortality

• Retrospective study of Joint Theater Trauma
  Register queried for all trauma pt admitted to
  combat support hospital in Iraq from 12/03-9/05
• Compared 24 hour, 30 day mortality and severe
  thrombotic events between received rVIIa and
  those who did not
• 5293 pt traumatic injury ?246 received massive
  transfusion?157 ISSgt15 ?124 had day 30 data

Spinella et al. J Trauma. 2008. 64286-294.
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Combat Trauma Data

• Massive transfusion 10 U within 24 hrs
• Clinical practice guidelines for transfusion and
  administration of rFVIIa were established during
  the time period of this study

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Combat Trauma Data

• 49/124 (40) received rVIIa

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Combat Trauma Data
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Discussion

• Are there pt who got rFVIIa that did not require
  massive transfusion? Outcomes? Adverse events?
• Does rFVII make nonsalvageable pt salvageable?
• Does it result in unacceptable of TE events?
• How should it be tracked/who should approve it?

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Clinical Trials

• Official Title  A Multi-Center, Randomized,
  Double-Blind, Parallel Group, Placebo Controlled
  Trial to Evaluate the Efficacy and Safety of
  Activated Recombinant Factor VII
  (rFVIIa/NovoSeven/ NiaStase) in the Treatment
  of Refractory Bleeding in Severely Injured Trauma
  PatientsFurther study details as provided by
  Novo Nordisk
• Primary Outcome Measures
• Mortality and Morbidity  Time Frame Through day
  30 
• Secondary Outcome Measures
• All cause mortality
• Hospital-free days
• Number of transfusion units
• Days free of renal replacement therapy
• ICU-free days
• Days free of ventilator support
• Estimated Enrollment  1502 Study Start Date
   May 2006