Transcript Willebrand in Nederland 22 november 2008 Eva de Wee

Indicaties voor recombinant factor VIIa (Novoseven)
Frank W.G. Leebeek, MD PhD
Dept of Hematology
Erasmus MC Rotterdam, The Netherlands
5 juli 2012
Regionaal Bloedtransfusieoverleg Zuidwest: Kliniek van Bloedtransfusie
coagulation
NEJM 2001,344:1527
Recombinant Factor VIIa
 Activated eptacog alpha, Novoseven®
 Developed for use in haemophilia patients with inhibitors against FVIII
or IX
 First clinical use in 1983
 Dose: 90 microgram/kg i.v. every 2-3 hours, or continuous infusion
 Half-life 2 -3 hours
 Excellent efficacy in haemophilia patients with inhibitors
 Rarely thrombo-embolic events in these patients
Recombinant Factor VIIa
 Tissue factor dependent mechanism of action
 Activates FX on activated platelets
 Inhibits fibrinolysis by upregulating TAFI by generation of thrombin
Mannucci, PM .NEJM 2007;356:2301
Current indications of rFVIIa
 Bleeding (spontaneous and surgical) in patients with congenital and
acquired haemophilia A or B with inhibitors against FVIII or FIX
 Glanzmann thrombasthenia
 Factor VII deficiency
rFVIIa in Haemophilia
Other possible indications for rFVIIa
 Without pre-existing coagulopathy
 Excessive, uncontrollable bleeding post-surgery, trauma
 Major surgery (prostatectomy, cardiac surgery)
 Acute intracerebral hemorrhage
 With coagulopathy
 Liver surgery, transplantation
 Thrombocytopenia
 Gastro-intestinal bleeding
 Bleeding associated with anticoagulant treatment
 Extensive study program has been done
Randomized-controlled trials rFVIIa: Efficacy
 Trauma: reduction in RBC transfusion in severe blunt trauma
 Liver transplantation: no reduction in blood loss, number of patients
requiring RBC transfusion was lower
 Hepatectomy: no reduction in blood loss
 Upper gastrointestinal bleeding: rVIIa showed no advantage over
standard treatment
Boffard J Trauma 2005;59:8 Planinsic Liver transpl 2005;11:895
Shao Am J Surg 2006;191:245; Lodge Anestesiology 2005;102:269Lodge
Liver transpl 2005;11:973, Bosch Gastroenterology 2004;127:1123
Recombinant Factor VIIa use in the US
O’Connell et al. JAMA 2006;295:293-298
Recombinant Factor VIIa for excessive bleeding
 Several case series on succesful use of rVIIa in excessive bleeding
 rFVIIa not registered for this indication
 >90 % of rVIIa use in the US is off-label
What is excessive blood loss
 Several definitions of massive blood loss
 Replacement of total blood volume with RBC in<24 hrs
 Blood loss of > 50% within 3 hrs
 Blood loss of > 150 ml/min
rVIIa in treatment of excessive bleeding
 Retrospective, uncontrolled chart audit
 196 non-hemophilic individuals in 21 US academic centers
 Surgical bleeding
37%
 Gastro-intestinal
31%
 Intra-cranial
13 %
 Pulmonary
11 %
 Others
8%
 75 % of patients was treated once
MacLaren et al Transfusion 2005;45:1434-1442
Outcome after rVIIa
 52.6 % of patients bleeding stopped
 26 % of these rebled
 37 % of patient died from bleeding < 48 hrs
 Dependent upon acidosis (pH<7.20 neg. predictor, OR 0.2; 0.1-0.51)
MacLaren et al Transfusion 2005;45:1434-1442
Effectiveness of rFVIIa and acidosis
Laffan, NM et al Blood Coagul Fibrinolysis 2003:14(suppl 1): S35-S38
Adverse events off-label vs trial patients:
O’Connell et al. JAMA 2006;295:293-298
Considerations regarding adverse events rFVIIa
 Thrombo-embolic events hardly occur in haemophilia patients
 Thromboembolic events in studies are low, comparable to controls
 rFVIIa might be more thrombogenic in patients predisposing to
thrombosis, as is seen in ICU patients
 FDA adverse event reporting system does not mention the total number
of patients treated. Not all SAE may have been reported
 Most patients will also have been treated with other prohaemostatic
drugs
Deaths due to trauma
Pharmacological measures to reduce blood loss
Desmopressin
Fibrinolysis inhibitors
 Plasminogen inhibitors
Tranexamic acid
Epsilon-amino-caproic acid
 Serine protease inhibitors
Aprotinin
Recombinant factor VIIa
Topical agents (thrombin//collagen/fibrin sealants)
Coagulation factor concentrates
Desmopressin (DDAVP)
 Increases VWF and FVIII in plasma
 Improves platelet function
 Improvement of primary hemostasis
 Hardly any randomized trials available
 Effect in cardiac surgery (+ aspirin) (several studies)
 No effect in scoliosis surgery
(Spine 1999)
 No effect in hepatectomy
(Can J Anaesthesia, 2003)
 No effect in variceal bleeding
(Hepatology 1993)
Antifibrinolytics in excessive bleeding
 Tranexamic acid
 Epsilon amino caproic acid (EACA)
 Aprotinin
Tranexamic acid and Epsilon-Amino caproic acid
Inhibits binding of plasmin to fibrin by interfering with the lysine binding
sites of the proenzyme plasminogen
Tranexamic acid is 10 times more active than EACA
Dose:
4 times daily 1 gram
In cardiac surgery: total dose 3-10 g; loading dose of 3-7 g, followed by
continuous infusion of 20-250 mg/hr
Mannucci, PM .NEJM 2007;356:2301
Fibrinolyis inhibitors and clinical events
Significant lower transfusion need for aprotinin and tranexamic acid
Mannucci, PM .NEJM 2007;356:2301
Fibrinolysis inhibitors do not increase the risk of thrombosis
Transfusie protocol massaal bloedverlies
Transfusie protocol massaal bloedverlies
Transfusie protocol massaal bloedverlies
Transfusie protocol massaal bloedverlies
Transfusie protocol massaal bloedverlies
Transfusiegids
New therapeutic indications for Novoseven
Recommendations concerning rFVIIa
 Strict transfusion guidelines for each individual hospital (RBC, FFP and
platelet concentrates)
 Based on laboratory control of APTT, PT, Fbg and platelets
 Limit the use of rVIIa to indications and off-label use only in very
selected cases (diffuse oozing patient)
 No rFVIIa in patients with severe hypothermia or acidosis
 Last-ditch use is ineffective