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Recombinant Factor Recombinant Factor VIIa in obstetric VIIa in obstetric anaesthesia anaesthesia Dr Steve Thomas, Anaesthesia Fellow, BC Dr Steve Thomas, Anaesthesia Fellow, BC Women’s hospital, 27 Women’s hospital, 27 th th November 2009 November 2009

Recombinant Factor VIIa in obstetric anaesthesia

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Recombinant Factor VIIa in obstetric anaesthesia. Dr Steve Thomas, Anaesthesia Fellow, BC Women’s hospital, 27 th November 2009. Learning objectives. By the end of this lecture you will have learnt: How rFVIIa is hypothesised to work Potential benefits and hazards of rFVIIa - PowerPoint PPT Presentation

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Page 1: Recombinant Factor VIIa in obstetric anaesthesia

Recombinant Factor VIIa in Recombinant Factor VIIa in obstetric anaesthesiaobstetric anaesthesia

Dr Steve Thomas, Anaesthesia Fellow, BC Dr Steve Thomas, Anaesthesia Fellow, BC Women’s hospital, 27Women’s hospital, 27thth November 2009 November 2009

Page 2: Recombinant Factor VIIa in obstetric anaesthesia

Learning objectivesLearning objectives

By the end of this lecture you will have By the end of this lecture you will have learnt: learnt: – How rFVIIa is hypothesised to workHow rFVIIa is hypothesised to work– Potential benefits and hazards of rFVIIaPotential benefits and hazards of rFVIIa– Evidence for the use of rFVIIa in massive Evidence for the use of rFVIIa in massive

haemorrhagehaemorrhage– Evidence for the use of rFVIIa within massive Evidence for the use of rFVIIa within massive

obstetric haemorrhageobstetric haemorrhage– Existing guidelinesExisting guidelines– Considerations of using rFVIIa at BCWHConsiderations of using rFVIIa at BCWH

Page 3: Recombinant Factor VIIa in obstetric anaesthesia

The clotting cascadeThe clotting cascade Exposed Tissue Factor (TF) on endothelial Exposed Tissue Factor (TF) on endothelial

wall injury binds to endogenous FVIIwall injury binds to endogenous FVII This complex generates FXa and This complex generates FXa and

subsequently small amounts of thrombinsubsequently small amounts of thrombin Thrombin activates FV, FVIII, FIX and Thrombin activates FV, FVIII, FIX and

platelets platelets FVIII/FIX complex activates FX on platelets FVIII/FIX complex activates FX on platelets

and binds to FVaand binds to FVa Full thrombin burst mediated by FVa and Full thrombin burst mediated by FVa and

FXa complexFXa complex ‘‘Thrombin burst’ converts fibrinogen into Thrombin burst’ converts fibrinogen into

fibrin to form stable clotfibrin to form stable clot

Page 4: Recombinant Factor VIIa in obstetric anaesthesia

Tissue factor (TF)/FVIIa,or TF/rFVIIa interaction,is necessary to initiatiate haemostasis

At pharmacological concentrations rFVIIa directly activates FX on the surface of locally activated platelets.This activation will initiatethe ”thrombin burst”independently of FVIII and FIX. This step is independent of TF.

The thrombin burst leads to the formation of a stable clot

rFVIIarFVIIa

Page 5: Recombinant Factor VIIa in obstetric anaesthesia

rFVIIarFVIIa

NiaStaseNiaStase (Canada) or (Canada) or NovosevenNovoseven Genetically engineeredGenetically engineered Perceived benefits:Perceived benefits:

– Does not contain human protein, Does not contain human protein, therefore no risk of viral transmissiontherefore no risk of viral transmission

– May halt/reduce bleedingMay halt/reduce bleeding– May reduce transfusion requirementsMay reduce transfusion requirements

But…..increased risk of thrombotic But…..increased risk of thrombotic eventsevents

Page 6: Recombinant Factor VIIa in obstetric anaesthesia

Current licensing Current licensing (FDA)(FDA)

Haemophilia A and B with:Haemophilia A and B with:– Inhibitors to factors VIII or IXInhibitors to factors VIII or IX– Bleeding episodes during after surgeryBleeding episodes during after surgery

‘‘On label’ dosing:On label’ dosing:– 70-90mck/kg: Association of Haemophilia Clinic 70-90mck/kg: Association of Haemophilia Clinic

Directors of Canada (1999)Directors of Canada (1999)– 90 mcg/kg: UK Haemophilia Centre Doctors Organisation 90 mcg/kg: UK Haemophilia Centre Doctors Organisation

(2006)(2006)

But has been used ‘off label’ in:But has been used ‘off label’ in:– life threatening haemorrhage life threatening haemorrhage including PPHincluding PPH– factor VII deficiency or platelet defectsfactor VII deficiency or platelet defects– Reversal of anticoagulation e.g. warfarinReversal of anticoagulation e.g. warfarin

Page 7: Recombinant Factor VIIa in obstetric anaesthesia

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

Reduces blood product requirement in Reduces blood product requirement in liver and cardiac surgery, vascular liver and cardiac surgery, vascular surgery, neurosurgery and trauma.surgery, neurosurgery and trauma.

Cardiac: PRC, platelets, FFP and Cardiac: PRC, platelets, FFP and cryoprecipitate fell from 4, 15, 8 10 to 1, 0, cryoprecipitate fell from 4, 15, 8 10 to 1, 0, 0, 0 respectively after administration of 0, 0 respectively after administration of FVIIa. FVIIa. ((McCall PMcCall P et al, CJA, 2006) et al, CJA, 2006)

Trauma: significant blood sparing effect, Trauma: significant blood sparing effect, although no affect on mortality.although no affect on mortality. ( (Boffard KBoffard K et et al, J Trauma, 2005)al, J Trauma, 2005)

Page 8: Recombinant Factor VIIa in obstetric anaesthesia

The evidence for the use of rFVIIa in massive The evidence for the use of rFVIIa in massive bleeding: development of a transfusion policy bleeding: development of a transfusion policy

frameworkframework ( (Moltzan CJMoltzan CJ et al, Transfusion Medicine, 2008) et al, Transfusion Medicine, 2008)

Canadian National Advisory CommitteeCanadian National Advisory Committee Review of evidence on unlicenced use up to Nov 2006 Review of evidence on unlicenced use up to Nov 2006 Recommend:Recommend:

Attempt to correct coagulapthy and correct acidosis before Attempt to correct coagulapthy and correct acidosis before requesting rFVIIarequesting rFVIIa

Transfused>/= 8U in 24hrs or> 4U in 1hr with ongoing Transfused>/= 8U in 24hrs or> 4U in 1hr with ongoing uncontrolled bleedinguncontrolled bleeding

20-50mcg/kg rounded to nearest vial20-50mcg/kg rounded to nearest vial Repeat at 30 mins if still bleedingRepeat at 30 mins if still bleeding 33rdrd dose up to 2hrs later dose up to 2hrs later Give as slow bolus unmixed over 2-5 minsGive as slow bolus unmixed over 2-5 mins Reconstituted solution lasts 3hrsReconstituted solution lasts 3hrs

Cannot recommend it for routine use based on current Cannot recommend it for routine use based on current evidenceevidence

Page 9: Recombinant Factor VIIa in obstetric anaesthesia

Thromboembolic adverse events after Thromboembolic adverse events after use of rFVIIa use of rFVIIa

((O’Connell KAO’Connell KA et al, JAMA, 2006) et al, JAMA, 2006) FDA’s Adverse Event Reporting SystemFDA’s Adverse Event Reporting System March 1999-December 2004March 1999-December 2004 Non-obstetric populationNon-obstetric population US and non-US data, including off-licence useUS and non-US data, including off-licence use Clinician reporting is voluntary, therefore under reportedClinician reporting is voluntary, therefore under reported 185 thromboembolic reports, 151 were ‘off label’185 thromboembolic reports, 151 were ‘off label’

– CVA (39) CVA (39) – MI (34) MI (34) – other arterial thromboembolism (26)other arterial thromboembolism (26)– DVT (42) DVT (42) – PTE (32)PTE (32)– clotting of indwelling devices (10)clotting of indwelling devices (10)– other venous thromboembolism (42)other venous thromboembolism (42)

A further 61 thromboembolic reports were made in the A further 61 thromboembolic reports were made in the following 10 months!following 10 months!

Page 10: Recombinant Factor VIIa in obstetric anaesthesia

A Review: Recombinant factor VIIa for the A Review: Recombinant factor VIIa for the prevention and treatment of bleeding in patients prevention and treatment of bleeding in patients

without haemophilia (without haemophilia (Cochrane CollaborationCochrane Collaboration, , Lin YLin Y et al, 2009)et al, 2009)

25 RCTs, 24 double-blinded, 3500 patients25 RCTs, 24 double-blinded, 3500 patients Haemophiliacs Haemophiliacs excludedexcluded In 14 trials of prophylactic use:In 14 trials of prophylactic use:

– No evidence of mortality benefitNo evidence of mortality benefit– Decreased blood lossDecreased blood loss– Decreased need for RBC transfusionDecreased need for RBC transfusion (<1U PRC!) (<1U PRC!)– Increased thromboembolic adverse events (not Increased thromboembolic adverse events (not

statistically significant)statistically significant) In 11 trials of therapeutic use:In 11 trials of therapeutic use:

– No difference in transfusion requirementsNo difference in transfusion requirements– Reduction in mortality (not statistically significant)Reduction in mortality (not statistically significant)– Increased thromboembolic adverse effects (not Increased thromboembolic adverse effects (not

statistically significant)statistically significant)

Page 11: Recombinant Factor VIIa in obstetric anaesthesia

Cochrane CollaborationCochrane Collaboration

“ “The effectiveness of rFVIIa The effectiveness of rFVIIa remains unproven. The use of remains unproven. The use of rFVIIa outside its current rFVIIa outside its current licensed indications licensed indications should be should be restricted to clinical trialsrestricted to clinical trials” ” (2007)(2007)

“ “rFVIIa is rFVIIa is not effectivenot effective in in patients without haemophilia patients without haemophilia AA” (2009)” (2009)

Page 12: Recombinant Factor VIIa in obstetric anaesthesia

‘‘Last ditch’ use of recombinant factor VIIa in Last ditch’ use of recombinant factor VIIa in patients with massive haemorrhage is ineffective patients with massive haemorrhage is ineffective

((Clark ADClark AD et al, Vox Sanguinis, 2004) et al, Vox Sanguinis, 2004)

50 patients, retrospective over 1 year, >10 unit 50 patients, retrospective over 1 year, >10 unit transfusionstransfusions

rFVIIa used at 90mcg/kg in 10 patients with rFVIIa used at 90mcg/kg in 10 patients with retractable bleeding, despite pharmacological retractable bleeding, despite pharmacological and blood product support and no foreseeable and blood product support and no foreseeable surgical correction of bleedingsurgical correction of bleeding

Transient reduction/cessation blood loss in 60% of Transient reduction/cessation blood loss in 60% of treated patients. Not sustained.treated patients. Not sustained.

Mortality rates higher in the treated group: 70% Mortality rates higher in the treated group: 70% died by day 7 died by day 7

rFVIIa did not rescue these patients.rFVIIa did not rescue these patients.

Page 13: Recombinant Factor VIIa in obstetric anaesthesia

Timely intervention Timely intervention

A randomized trial of early vs late use of A randomized trial of early vs late use of FVIIA in PPH in Nimes, France is not yet FVIIA in PPH in Nimes, France is not yet published (published (http://clinicaltrials.gov/ct2/show/NCT00370877http://clinicaltrials.gov/ct2/show/NCT00370877))

The main objectives of the study are:The main objectives of the study are:– to evaluate the reduction of the absolute risk of arterial to evaluate the reduction of the absolute risk of arterial

embolization/surgery/hysterectomy in patients receiving embolization/surgery/hysterectomy in patients receiving a unique early infusion of rFVIIa (60 µg/kg body weight); a unique early infusion of rFVIIa (60 µg/kg body weight);

– to evaluate the number of women necessary to treat to to evaluate the number of women necessary to treat to avoid one arterial embolization/surgery/hysterectomy.avoid one arterial embolization/surgery/hysterectomy.

Page 14: Recombinant Factor VIIa in obstetric anaesthesia

rFVIIa in PPHrFVIIa in PPH

First described in 2001 (First described in 2001 (MoscardoMoscardo et et al)al)

Largely case reports.Largely case reports.– rFVIIa for life threatening PPH (rFVIIa for life threatening PPH (Ahonen JAhonen J

et al, BJA, 2005):et al, BJA, 2005): 90-120 mcg/kg90-120 mcg/kg 11/12 patients treated with FVIIa showed a response .11/12 patients treated with FVIIa showed a response . Reduced PRC, FFP and platelets from 16, 5, 9 to 3, 1, 8 Reduced PRC, FFP and platelets from 16, 5, 9 to 3, 1, 8

after FVIIa.after FVIIa. Timing optimal when patient has lost 1.5 blood volume.Timing optimal when patient has lost 1.5 blood volume. Consider before hysterectomyConsider before hysterectomy Better if diffuse bleeding, embolisation if localised.Better if diffuse bleeding, embolisation if localised.

Page 15: Recombinant Factor VIIa in obstetric anaesthesia

Review Article: Recombinant factor VIIa in Review Article: Recombinant factor VIIa in massive post partum haemorrhage massive post partum haemorrhage

((Karalapillai DKaralapillai D et al, IJOA, 2007) et al, IJOA, 2007) Dose of 90-100mcg/kg following conventional therapy Dose of 90-100mcg/kg following conventional therapy

although optimal dose unclear.although optimal dose unclear. Dose repeat after 2 hrs.Dose repeat after 2 hrs. May reduce blood product use May reduce blood product use ( ( Ahonen JAhonen J et al, BJA, 2005) et al, BJA, 2005) rFVIIa requires other clotting factors and platelets to work rFVIIa requires other clotting factors and platelets to work

therefore maintain platelets> 50 x 10therefore maintain platelets> 50 x 1099/L, fibrinogen> 1g/L /L, fibrinogen> 1g/L (British and Israeli guidelines)(British and Israeli guidelines)

Hypothermia and acidosis reduce factor VIIa activity Hypothermia and acidosis reduce factor VIIa activity significantlysignificantly

If localised, correct surgical bleeding (embolisation)If localised, correct surgical bleeding (embolisation) FVIIa more effective in diffuse bleeding or as bridge to FVIIa more effective in diffuse bleeding or as bridge to

embolisation if off-siteembolisation if off-site Administration should be considered before hysterectomyAdministration should be considered before hysterectomy Resistance exists (up to 7%)Resistance exists (up to 7%) Timing unclearTiming unclear Of use in Jehovah’s Witnesses as syntheticOf use in Jehovah’s Witnesses as synthetic No data on thrombotic complication in obstetric haemorrhageNo data on thrombotic complication in obstetric haemorrhage

Page 16: Recombinant Factor VIIa in obstetric anaesthesia

A Critical Review on the Use of Recombinant Factor A Critical Review on the Use of Recombinant Factor VIIa in Life-Threatening Obstetric Postpartum VIIa in Life-Threatening Obstetric Postpartum

HemorrhageHemorrhage ((Franchini MFranchini M et al, Semin Thromb Hemost, 2008) et al, Semin Thromb Hemost, 2008)

2001 onwards2001 onwards Unlicensed useUnlicensed use 31 studies. 118 cases. 31 studies. 118 cases. No RCTs or prospective clinical studies to date. All studies No RCTs or prospective clinical studies to date. All studies

uncontrolled.uncontrolled. Median dose 71.6 mcg/kgMedian dose 71.6 mcg/kg Effective in stopping or reducing bleeding in 90% casesEffective in stopping or reducing bleeding in 90% cases But…..successful cases more likely to be reportedBut…..successful cases more likely to be reported Recommended use of 60-90mcg/kg repeated at 30 minutesRecommended use of 60-90mcg/kg repeated at 30 minutes Not as ‘last ditch’ but to be given before hysterectomy.Not as ‘last ditch’ but to be given before hysterectomy. It should not delay surgery or embolisation.It should not delay surgery or embolisation. Used with caution in sepsis, disseminated malignancy or Used with caution in sepsis, disseminated malignancy or

after other coagulation bypassing agents due to thrombotic after other coagulation bypassing agents due to thrombotic potential.potential.

More data needed!More data needed!

Page 17: Recombinant Factor VIIa in obstetric anaesthesia

The value of protocols for management of post The value of protocols for management of post partum haemorrhagepartum haemorrhage

(American Society of Anesthesiologists, 2009)(American Society of Anesthesiologists, 2009)

The use of recombinant factor VII in The use of recombinant factor VII in primary post partum haemorrhage: The primary post partum haemorrhage: The Northern European Registry: 2000-2004. Northern European Registry: 2000-2004. (Alfirevic et al, Obstet Gynecol, 2007)(Alfirevic et al, Obstet Gynecol, 2007)– 9 European countries9 European countries– 113 reports113 reports– Exponential increase in useExponential increase in use– Most common dose</= 90 mcg/kgMost common dose</= 90 mcg/kg– ‘‘Improvements noted’ in over 80% women Improvements noted’ in over 80% women

after 1 doseafter 1 dose– 4 cases of thromboembolism4 cases of thromboembolism

Page 18: Recombinant Factor VIIa in obstetric anaesthesia

The value of protocols for management of post The value of protocols for management of post partum haemorrhagepartum haemorrhage

(American Society of Anesthesiologists, 2009)(American Society of Anesthesiologists, 2009)

US vs. European Practice:US vs. European Practice:– American Congress of Obstetricians and American Congress of Obstetricians and

Gynaecologists (2006): Practice Bulletin; Gynaecologists (2006): Practice Bulletin; Postpartum haemorrhage. Postpartum haemorrhage. No mention of rFVIIaNo mention of rFVIIa..

– World Health Organisation World Health Organisation (2009):’Guidelines for the management (2009):’Guidelines for the management of PPH and retained placenta.’of PPH and retained placenta.’ No mention of rFVIIaNo mention of rFVIIa..

Page 19: Recombinant Factor VIIa in obstetric anaesthesia

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

Only following blood component therapy and medical and surgical Only following blood component therapy and medical and surgical intervention, consider rFVIIa. This includes:intervention, consider rFVIIa. This includes:

– uterotonics, uterine massageuterotonics, uterine massage

– B-lynch suture, arterial ligation, balloon cathetersB-lynch suture, arterial ligation, balloon catheters

– radiological embolisationradiological embolisation Transfusion targets: platelets>50, aPTT ratio>1.5, Hb>7, Transfusion targets: platelets>50, aPTT ratio>1.5, Hb>7,

fibronogen>1fibronogen>1 90mcg/kg as single bolus over 3-5 mins90mcg/kg as single bolus over 3-5 mins After 20 mins if no response:After 20 mins if no response: Optimise temperature, acidaemia, serum calcium, platelets, Optimise temperature, acidaemia, serum calcium, platelets,

fibrinogen, then... 2nd dose of 90mcg/kgfibrinogen, then... 2nd dose of 90mcg/kg Consider hysterectomy if bleeding persistsConsider hysterectomy if bleeding persists 24hrs after bleeding stops:24hrs after bleeding stops:

– Calf compression/stockingsCalf compression/stockings

– LMWHLMWH

Page 20: Recombinant Factor VIIa in obstetric anaesthesia

BCW HaematologyBCW Haematology 90mcg/kg for Haemophilia90mcg/kg for Haemophilia 30-90mcg/kg in cardiac30-90mcg/kg in cardiac For obstetrics: 30-45mcg/kg, wait 30 mins, then For obstetrics: 30-45mcg/kg, wait 30 mins, then

22ndnd dose. dose. However……10-15 minutes wait from requesting However……10-15 minutes wait from requesting

and authorisation, plus 15 mins to make up, plus and authorisation, plus 15 mins to make up, plus transport = transport = 30 mins at best!30 mins at best!

Cost: $1000/mg> over $6000 for 70kg patientCost: $1000/mg> over $6000 for 70kg patient

Conditions of use: Any surgical correction of Conditions of use: Any surgical correction of bleeding has already been done and other bleeding has already been done and other clotting factors have already been given.clotting factors have already been given.

Page 21: Recombinant Factor VIIa in obstetric anaesthesia

In summaryIn summary It is associated with thrombotic events in a non-obstetric It is associated with thrombotic events in a non-obstetric

population. population. It’s use has been successful outwith obstetricsIt’s use has been successful outwith obstetrics Little strong evidence supports it’s use in obstetrics……….Is a RCT Little strong evidence supports it’s use in obstetrics……….Is a RCT

ever going to be possible anyway?ever going to be possible anyway? It is being used widely across Europe and in Australia/New It is being used widely across Europe and in Australia/New

Zealand. Zealand. Guidelines are beginning to emerge.Guidelines are beginning to emerge. If given, there may be benefit in using it early rather than as last If given, there may be benefit in using it early rather than as last

ditch.ditch. Acidosis and hypothermia should be corrected firstAcidosis and hypothermia should be corrected first Surgical correction and clotting factors should be given firstSurgical correction and clotting factors should be given first It’s use should be considered prior to hysterectomyIt’s use should be considered prior to hysterectomy Although available at BCW it takes a long time to become Although available at BCW it takes a long time to become

availableavailable

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QuestionsQuestions