Recombinant Factor VIIa in obstetric anaesthesia

1
Recombinant Factor VIIa in obstetric anaesthesia

• Dr Steve Thomas, Anaesthesia Fellow, BC Womens
  hospital, 27th November 2009

2
Learning objectives

• By the end of this lecture you will have learnt
• How rFVIIa is hypothesised to work
• Potential benefits and hazards of rFVIIa
• Evidence for the use of rFVIIa in massive
  haemorrhage
• Evidence for the use of rFVIIa within massive
  obstetric haemorrhage
• Existing guidelines
• Considerations of using rFVIIa at BCWH

3
The clotting cascade

• Exposed Tissue Factor (TF) on endothelial wall
  injury binds to endogenous FVII
• This complex generates FXa and subsequently small
  amounts of thrombin
• Thrombin activates FV, FVIII, FIX and platelets
• FVIII/FIX complex activates FX on platelets and
  binds to FVa
• Full thrombin burst mediated by FVa and FXa
  complex
• Thrombin burst converts fibrinogen into fibrin
  to form stable clot

4
rFVIIa
The thrombin burst leads to the formation of a
stable clot
5
rFVIIa

• NiaStase (Canada) or Novoseven
• Genetically engineered
• Perceived benefits
• Does not contain human protein, therefore no risk
  of viral transmission
• May halt/reduce bleeding
• May reduce transfusion requirements
• But..increased risk of thrombotic events

6
Current licensing (FDA)

• Haemophilia A and B with
• Inhibitors to factors VIII or IX
• Bleeding episodes during after surgery
• On label dosing
• 70-90mck/kg Association of Haemophilia Clinic
  Directors of Canada (1999)
• 90 mcg/kg UK Haemophilia Centre Doctors
  Organisation (2006)
• But has been used off label in
• life threatening haemorrhage including PPH
• factor VII deficiency or platelet defects
• Reversal of anticoagulation e.g. warfarin

7
Off-licence use of rFVIIa in non-obstetric
haemorrhage

• Reduces blood product requirement in liver and
  cardiac surgery, vascular surgery, neurosurgery
  and trauma.
• Cardiac PRC, platelets, FFP and cryoprecipitate
  fell from 4, 15, 8 10 to 1, 0, 0, 0 respectively
  after administration of FVIIa. (McCall P et al,
  CJA, 2006)
• Trauma significant blood sparing effect,
  although no affect on mortality. (Boffard K et
  al, J Trauma, 2005)

8
The evidence for the use of rFVIIa in massive
bleeding development of a transfusion policy
framework (Moltzan CJ et al, Transfusion
Medicine, 2008)

• Canadian National Advisory Committee
• Review of evidence on unlicenced use up to Nov
  2006
• Recommend
• Attempt to correct coagulapthy and correct
  acidosis before requesting rFVIIa
• Transfusedgt/ 8U in 24hrs orgt 4U in 1hr with
  ongoing uncontrolled bleeding
• 20-50mcg/kg rounded to nearest vial
• Repeat at 30 mins if still bleeding
• 3rd dose up to 2hrs later
• Give as slow bolus unmixed over 2-5 mins
• Reconstituted solution lasts 3hrs
• Cannot recommend it for routine use based on
  current evidence

9
Thromboembolic adverse events after use of rFVIIa
(OConnell KA et al, JAMA, 2006)

• FDAs Adverse Event Reporting System
• March 1999-December 2004
• Non-obstetric population
• US and non-US data, including off-licence use
• Clinician reporting is voluntary, therefore under
  reported
• 185 thromboembolic reports, 151 were off label
• CVA (39)
• MI (34)
• other arterial thromboembolism (26)
• DVT (42)
• PTE (32)
• clotting of indwelling devices (10)
• other venous thromboembolism (42)
• A further 61 thromboembolic reports were made in
  the following 10 months!

10
A Review Recombinant factor VIIa for the
prevention and treatment of bleeding in patients
without haemophilia (Cochrane Collaboration, Lin
Y et al, 2009)

• 25 RCTs, 24 double-blinded, 3500 patients
• Haemophiliacs excluded
• In 14 trials of prophylactic use
• No evidence of mortality benefit
• Decreased blood loss
• Decreased need for RBC transfusion (lt1U PRC!)
• Increased thromboembolic adverse events (not
  statistically significant)
• In 11 trials of therapeutic use
• No difference in transfusion requirements
• Reduction in mortality (not statistically
  significant)
• Increased thromboembolic adverse effects (not
  statistically significant)

11
Cochrane Collaboration

• The effectiveness of rFVIIa remains unproven.
  The use of rFVIIa outside its current licensed
  indications should be restricted to clinical
  trials (2007)
• rFVIIa is not effective in patients without
  haemophilia A (2009)

12
Last ditch use of recombinant factor VIIa in
patients with massive haemorrhage is ineffective
(Clark AD et al, Vox Sanguinis, 2004)

• 50 patients, retrospective over 1 year, gt10 unit
  transfusions
• rFVIIa used at 90mcg/kg in 10 patients with
  retractable bleeding, despite pharmacological and
  blood product support and no foreseeable surgical
  correction of bleeding
• Transient reduction/cessation blood loss in 60
  of treated patients. Not sustained.
• Mortality rates higher in the treated group 70
  died by day 7
• rFVIIa did not rescue these patients.

13
Timely intervention

• A randomized trial of early vs late use of FVIIA
  in PPH in Nimes, France is not yet published
  (http//clinicaltrials.gov/ct2/show/NCT00370877)
• The main objectives of the study are
• to evaluate the reduction of the absolute risk of
  arterial embolization/surgery/hysterectomy in
  patients receiving a unique early infusion of
  rFVIIa (60 µg/kg body weight)
• to evaluate the number of women necessary to
  treat to avoid one arterial embolization/surgery/h
  ysterectomy.

14
rFVIIa in PPH

• First described in 2001 (Moscardo et al)
• Largely case reports.
• rFVIIa for life threatening PPH (Ahonen J et al,
  BJA, 2005)
• 90-120 mcg/kg
• 11/12 patients treated with FVIIa showed a
  response .
• Reduced PRC, FFP and platelets from 16, 5, 9 to
  3, 1, 8 after FVIIa.
• Timing optimal when patient has lost 1.5 blood
  volume.
• Consider before hysterectomy
• Better if diffuse bleeding, embolisation if
  localised.

15
Review Article Recombinant factor VIIa in
massive post partum haemorrhage (Karalapillai D
et al, IJOA, 2007)

• Dose of 90-100mcg/kg following conventional
  therapy although optimal dose unclear.
• Dose repeat after 2 hrs.
• May reduce blood product use ( Ahonen J et al,
  BJA, 2005)
• rFVIIa requires other clotting factors and
  platelets to work therefore maintain plateletsgt
  50 x 109/L, fibrinogengt 1g/L (British and Israeli
  guidelines)
• Hypothermia and acidosis reduce factor VIIa
  activity significantly
• If localised, correct surgical bleeding
  (embolisation)
• FVIIa more effective in diffuse bleeding or as
  bridge to embolisation if off-site
• Administration should be considered before
  hysterectomy
• Resistance exists (up to 7)
• Timing unclear
• Of use in Jehovahs Witnesses as synthetic
• No data on thrombotic complication in obstetric
  haemorrhage

16
A Critical Review on the Use of Recombinant
Factor VIIa in Life-Threatening Obstetric
Postpartum Hemorrhage (Franchini M et al, Semin
Thromb Hemost, 2008)

• 2001 onwards
• Unlicensed use
• 31 studies. 118 cases.
• No RCTs or prospective clinical studies to date.
  All studies uncontrolled.
• Median dose 71.6 mcg/kg
• Effective in stopping or reducing bleeding in 90
  cases
• But..successful cases more likely to be reported
• Recommended use of 60-90mcg/kg repeated at 30
  minutes
• Not as last ditch but to be given before
  hysterectomy.
• It should not delay surgery or embolisation.
• Used with caution in sepsis, disseminated
  malignancy or after other coagulation bypassing
  agents due to thrombotic potential.
• More data needed!

17
The value of protocols for management of post
partum haemorrhage(American Society of
Anesthesiologists, 2009)

• The use of recombinant factor VII in primary post
  partum haemorrhage The Northern European
  Registry 2000-2004. (Alfirevic et al, Obstet
  Gynecol, 2007)
• 9 European countries
• 113 reports
• Exponential increase in use
• Most common doselt/ 90 mcg/kg
• Improvements noted in over 80 women after 1
  dose
• 4 cases of thromboembolism

18
The value of protocols for management of post
partum haemorrhage(American Society of
Anesthesiologists, 2009)

• US vs. European Practice
• American Congress of Obstetricians and
  Gynaecologists (2006) Practice Bulletin
  Postpartum haemorrhage.
• No mention of rFVIIa.
• World Health Organisation (2009)Guidelines for
  the management of PPH and retained placenta.
• No mention of rFVIIa.

19
Guidelines for the use of recombinant factor VII
in massive obstetric haemorrhage (Welsh A,
McLintock C, Gatt S et al, 2008)

• Only following blood component therapy and
  medical and surgical intervention, consider
  rFVIIa. This includes
• uterotonics, uterine massage
• B-lynch suture, arterial ligation, balloon
  catheters
• radiological embolisation
• Transfusion targets plateletsgt50, aPTT
  ratiogt1.5, Hbgt7, fibronogengt1
• 90mcg/kg as single bolus over 3-5 mins
• After 20 mins if no response
• Optimise temperature, acidaemia, serum calcium,
  platelets, fibrinogen, then... 2nd dose of
  90mcg/kg
• Consider hysterectomy if bleeding persists
• 24hrs after bleeding stops
• Calf compression/stockings
• LMWH

20
BCW Haematology

• 90mcg/kg for Haemophilia
• 30-90mcg/kg in cardiac
• For obstetrics 30-45mcg/kg, wait 30 mins, then
  2nd dose.
• However10-15 minutes wait from requesting and
  authorisation, plus 15 mins to make up, plus
  transport 30 mins at best!
• Cost 1000/mggt over 6000 for 70kg patient
• Conditions of use Any surgical correction of
  bleeding has already been done and other clotting
  factors have already been given.

21
In summary

• It is associated with thrombotic events in a
  non-obstetric population.
• Its use has been successful outwith obstetrics
• Little strong evidence supports its use in
  obstetrics.Is a RCT ever going to be possible
  anyway?
• It is being used widely across Europe and in
  Australia/New Zealand.
• Guidelines are beginning to emerge.
• If given, there may be benefit in using it early
  rather than as last ditch.
• Acidosis and hypothermia should be corrected
  first
• Surgical correction and clotting factors should
  be given first
• Its use should be considered prior to
  hysterectomy
• Although available at BCW it takes a long time to
  become available

22
Questions