Prise en charge du risque hémorragique lors d une chirurgie chez les hémophiles avec inhibiteurs

Transcription

1 Prise en charge du risque hémorragique lors d une chirurgie chez les hémophiles avec inhibiteurs Pr Claude Negrier Hôpital cardiologique Louis Pradel Université Claude Bernard Lyon 1 claude.negrier@chu-lyon.fr

2 Joint Limitation in Patients with Severe Hemophilia 6 Joint Limitation (%) P< With Inhibitors (7.8%) Without Inhibitors (92.2%) Soucie JM, et al. Blood. 2004;103:

3 Advanced haemophilic arthropathy Personal data

4 Risks associated with surgery in inhibitor-developing hemophiliacs Excessive/uncontrolled bleeding Death Thromboembolism/DIC Wound healing and subsequent infectious risk Anamnestic response Cost issue

5 Points to consider for surgery in inhibitor patients Age of patient Inhibitor titre and anamnestic response Relevant co-morbidities Indication for surgery Urgency of the surgical procedure Type of surgical procedure Experience of surgeon Availability of multidisciplinary team of experts experienced in perioperative management of haemophilia (haemophilia treatment centre) Risk factors for thrombosis (age, type of procedure, thrombophilic genotypes) Patient and family preferences Sufficiency of supply of replacement and bypassing products Cost of replacement and bypassing products to national blood system, patient, or third-part insurer Teitel J et al., Haemophilia 2008

6 Which option to choose? Human FVIII / FIX or porcine FVIII if titer < 5 BU/mL because of the predictibility of the clinical/biological response, but... Risk of surgical procedure itself Previous history of the patient to discriminate «good responders» and «bad responders» to a particular product Other medical conditions affecting PK parameters National guidelines and national specifications for use No universal hemostatic agent

7 BLEEDING Hemophilia A no inhibitor FVIII concentrate Hemophilia B no inhibitor FIX concentrate inhibitor titer known inhibitor titer unknown < 5 BU > 5 BU Human FVIII (FIX) Porcine FVIII apcc rfviia porcine FVIII plasmapheresis apcc rfviia Negrier C, Textbook on Haemophilia, 2014

8 Use of Factor VIII for bleeding prevention during surgery in patients with inhibitors

9 Characteristics of study population (retrospective evaluation ) No. of patients 60 No. of high responders 54/54 No. of low-responders 0/54 No. of anti-fviii alloantibodies 52 No. of anti-fviii autoantibodies 6 No. of anti-fix alloantibodies 2 No. of evaluable bleeding episodes 433

10 Surgical procedures performed with human or porcine FVIII as a first-line therapy No. of episodes Initial therapy Dose U/kg/d Introduction of FEIBA Duration (days). Retroperitoneal hematoma 2 Human FVIII. Pyelotomy 1 Human FVIII. Synoviorthesis 1 Human FVIII. Forearm 1 Human amputation FVIII. Osteotomy 1 Porcine FVIII. Splenectomy 1 Porcine FVIII Day 4 Day Day Day Day Day Day 7 6

11 Use of rfviia for bleeding prevention during surgery in patients with inhibitors

12 First report on rfviia use 31 year-old haemophilia A patient Inhibitor 53 new Oxford units Synovectomy and joint debridement of the left knee rfviia 54 µg/kg before, 2h, 4-hourly for 2 days, and 6-hourly for 10 days Additional treatment : fibrin glue, tranexamic acid (Hedner et al. Lancet, 1988)

13 rfviia - Dose finding study in surgery (1) Prospective, randomized, double-blind, multicentre FVIII, n = 26 FIX, n = 3 rfviia prior to incision, intraoperatively as needed, every 2h for 48h, every 2-6h for the following 3 days Haemostasis evaluation on the first 5 days 23 patients (13/14 high dose) successfully completed the study (Shapiro et al., Thromb Haemost 1998)

14 rfviia - Dose finding study in surgery No. (%) patients in each dose group Minor surgery Major surgery p-value 35 mcg/kg (n=10) 90 mcg/kg (n=8) 35 mcg/kg (n=5) 90 mcg/kg (n=6) 35 mcg/kg vs 90 mcg/kg Intraoperative 10 (100) 7 (88) 5 (100) 6 (100) NS Hour (90) 10 (100) 9 (90) 8 (100) 8 (100) 8 (100) 5 (100) 4 (80) 3 (60) 6 (100) 6 (100) 6 (100) NS NS NS Day (80) 7 (70) 7 (70) 8 (100) 8 (100) 8 (100) 2 (40) 2 (40) 2 (40) 6 (100) 6 (100) 5 (83) (Shapiro et al., Thromb Haemost 1998)

15 rfviia - Surgical setting (1) 13 major surgeries (including 3 knee arthroplasties) reported in 1996 (Ingerslev et al., Haemostasis 1996) -----> haemostasis achieved in all patients (initial dose µg/kg, duration 5 to 43 days) 11 major and 14 minor surgical procedures reported in a prospective, open, multicentre study in Italy. Bolus doses of 90 to 150 g/kg (median: 100) followed by CI ( median rates 20 µg/kg/h for major surgery and of 17 µg/kg/h for minor surgery. Haemostasis achieved in 88% of cases (Santagostino et al, TH 2001) Over 100 procedures (Lusher et al., BCF 1998) major minor dental Haemostasis achieved 81% 86% 92%

16 rfviia - Surgical setting (2) Injections every 2-3h usually the first 2 days after which dosage intervals are prolonged Continuous infusion of rfviia was proposed as an alternative to bolus injections Feasibility demonstrated by Schulman at al. (Thromb Haemost 1996) who evaluated stability during 3 days, microbiological safety, clinical efficacy and tolerance in 2 patients (4 treatment episodes) including a total knee arthroplasty Possible reduction of the total dose by 50-75% No clear correlation with plasma levels of FVII (Santagostino et al, TH 2001)

17 Bleeding/surgical intervention and dosing regimen during continuous infusion of rviia Bleeding/surgical intervention Start bolus (mcg/kg) Dose (mcg/kg/h) Duration (days) Efficacy dental extraction dental extraction joint/muscle bleed tongue bleed psoas bleed lymph node surgery GI bleed hip arthroplasty hip arthroplasty Effective Partially effective Effective Effective Effective Effective Effective Effective Effective (Mauser-Bunschoten et al., Neth J Med 1998)

18 Conclusion Hundreds of patients with antibodies to FVIII/FIX have received rfviia for treating bleeding episodes or preventing surgical haemorrhages Haemostasis achieved in 75 to 90 % of cases Safety profile Rare thrombotic complications No anamnestic response to FVIII/FIX No documented viral seroconversion Need for surrogate markers of haemostasis Cost issue

19 Use of FEIBA for bleeding prevention during surgery in patients with inhibitors

20 Main characteristics of 15 minor surgical procedures No. Procedure No of infusions Duration (days) Total dose (U) Dose (U/kg/d) 1 Trephine biopsy Insertion of Hickman-line Tooth extraction Cataract & intraocular lens implantation Cataract & intraocular lens implantation Circumcision (phimosis) Teleangiectasia (tongue)/laser coagulation Cataract & intraocular lens implantation Tooth extraction Cystoscopy/pyelography Endoscopic Tx of eroded vessel in oesophageal ulcer Excision of prepatellar bursa Tooth extraction Tooth extraction Paronychia/toenail excision

21 Main characteristics of 7 major surgical procedures No Procedure No of infusion s Duration (days) Total dose (10 3 U) Dose U/kg/day Complications Hemostatic outcome 5 Arthroplasty (knee) 5 Arthroplasty (hip) 6 Nephrectomy/ Splenectomy Drainage 750 ml HGB 45 gl HGB dropped to 68 gl -1 2 PRC Yes, splenic hemorrhage Good Good Good 6 Wound rupture Revision 17 5 a No Excellent 7 Sigmoidect Yes; MI Excellent 8 Arthroplasty (knee) HGB 62 gl -1 2 PRC Good 10 Arthroplasty (knee) No Excellent a due to shortness of supplies, FEIBA was followed by rviia (NovoSeven ) for an additional three days; a total dose of 57.6 mg rfviia was administered

22 SURF project - Objectives Efficacy of FEIBA in surgery - intra-operative haemostasis - post-operative haemostasis - duration of treatment - dosage Safety - immediate tolerance - recommended maximum daily dose - anamnestic response Explore correlation of clinical efficacy and safety with laboratory markers (e.g. TGA, or others?) Identify best practices in haemostatic management of haemophiliacs with inhibitors undergoing surgery

23 Patient demographic and surgery characteristics Negrier C et al, Haemophilia 2012

24 FEIBA dosing regimens for severe risk surgical procedures Negrier C et al, Haemophilia 2012

25

26 Conclusion Favorable efficacy/tolerance profile of FEIBA Very few AEs Can be used for surgeries (over 100 in the last 20 years) More precise definition of the mode of action Need for a biological test to assess haemostatic efficacy World-wide PMS to increase the knowledge on the use of FEIBA for surgeries

27 Do anti-fibrinolytics increase efficacy? Patients treated with rfviia Without anti-fibrinolytics: 66% efficacy With anti-fibrinolytics: 96% efficacy (Schulman S., Haemophilia 4 (1998) ) Patients treated with FEIBA Not in label as systematic use not documented However, safe application reported (of 2g/day for 5 days) (Menart C et al, Haemophilia 5 (1999) )

28 EU Consensus on FEIBA dosage in surgery Rodriguez-Merchan et al: Haemophilia 10, Suppl 2, 50-52, 2004

29 Usual Doses of NovoSeven For Surgeries NovoSeven SmPC 1 Teitel et al. Obergfell et al. Mathew et al. Giangrande et al. (2008) 2 (2008) 3 (2007) 4 (in press) 5 Dose Preoperatoire 90 µg/kg, à répéter après 2 h 90 µg/kg immediately Minimum initial bolus of 120 µg/kg µg/kg µg/kg immediately followed by 90 µg/kg every 2 h Immediate post-operative dosing 90 µg/kg every 2-3 h for 1 2 days 90 µg/kg every 2 h for at least 48 h µg/kg every 2 h by bolus injection Continuous infusion*: 50 µg/kg per hour µg/kg every 2 h for at least 48 h 90 µg/kg every 2 h for 48 h Days/weeks after surgery 90 µg/kg every 2-4 h for 6-7 days Dose interval may be increased to 6-8 h for another 2 weeks Dosage interval may be increased thereafter based on clinical outcome (grade 1A) Higher doses have been used safely (grade 1B) Decreasing the dose to every 4 h on the 3-4 post operative days and then to every 6 h for another week 90 µg/kg every 3 h if haemostasis good at 48 h 90 µg/kg every 4 h on days µg/kg every 6 h on day 8+ until discharge Administration mode Bolus Continuous infusion* after initial bolus therapy appears to be a promising modality (grade 2B) but it is premature to recommend this mode of administration for routine use Bolus or continuous Infusion* Use of bolus injections predominantly, with continuous Infusion* used only as a part of clinical trial Bolus * Continuous infusion not included in NovoSeven SmPC Novo Nordisk Health Care AG ;Teitel et al. Haemophilia 2008.;Obergfell et al. Haemophilia 2008; 14: Mathew et al. Transfusion 2007; 47: 8-14; Giangrande et al. Haemophilia; in press.

30 Use of new monitoring tools/surrogate markers for the choice of the most adequate therapeutic strategy

31 FEIBA: Sites of Action FXII Intrinsic Pathway FVIII FXI FXIIa FIX, FIXa FXIa FIX Ca ++ -PL FVIIIa Blood coagulatio FEIBA n PL=Phospholipid Feedback FII s mechanism s TF=Tissue Factor FEIBA FIXa FII FVa FEIBA FX, FXa FX FXa FXa FEIBA FXa/FII FV Fibrinogen FVIIa FEIBA FVII, FVIIa TF FIIa FIIa (Thrombin) FXIII FXIIIa Fibrin FEIBA FVII Extrinsic Pathway Common Pathway Leading to Clot Fibrin Polymer Adapted from: Turecek et al. Vox Sang 1999;77(suppl 1): CLOT

32 FXa/FII and FEIBA: Reduction of Bleeding Times Rate of Blood Flow (µl/min) Normal rabbits Untreated Buffer FXa Prothrombin (FII) * p<0.05 **p ** ** FXa/FII FEIBA (75 U/kg) FXa/FII and FEIBA produce nearly identical clotting times in a rabbit model. * ** Turecek et al. Vox Sang 1999;77 (suppl. 1):

33 TF-bearing cells

34

35 «Base your judgement only on the evidence» - Sherlock Holmes The Sign of Four

36 Risk/Safety/Efficacy Assessments of Treatment Options Human and porcine FVIII/FIX Anamnestic response Allergic reactions Bypassing therapy apcc rfviia Infection risk 1 plasma-derived recombinant Thrombotic risk low 1-3 low 1,2,4 Anti-FVIII immune response yes 5 no Duration of infusion Volume Cost Efficacy 64%-90% 1,2,5 80%-95% 1,2,6 1. Tjønnfjord and Holme. Vasc Health Risk Manag. 2007;3(4): Freydin. J Young Investig [serial online]. 2009;19(13) Ehrlich et al. Haemophilia. 2002;8(2): O Connell et al. JAMA. 2006;295(3): Negrier et al. Thromb Haemost. 1997;77(6): Key et al. Thromb Haemost. 1998;80(6):

37 In hemophilia, there is a failure of platelet-surface factor X activation, leading to a decrease in plateletsurface thrombin generation and ineffective clot formation Roberts et al, Blood 2004

38 Thrombin generation curve

39 TGA and Bypassing Agents Varadi K et al J Thromb Haemost 2003;1:

40 A three-step Protocol for Individually Tailoring Bypassing Agents In vitro spiking experiment to determine both the bypassing agent and the effective dose to achieve correction of TG Ex vivo assessment of the dose chosen in the in vitro assay Monitoring of the bypassing therapy in bleeding or surgical situations to adapt the dose and/or intervals between infusions Dargaud Y et al., Blood 2010

41 Individually Tailoring and Monitoring of Bypassing Agents in Surgical Situations Up to now, this 3 step-protocol has been prospectively used in 10 surgical procedures performed in 7 patients with hemophilia and inhibitors using TGA as: a laboratory tool to determine the «individual treatment protocol» a surrogate marker in the perioperative period Patient # Elective surgery and other invasive procedures Lower limb amputation Bilateral total knee arthroplasty Total knee arthroplasty Ankle arthroplasty Total knee arthroplasty Elbow synovectomy Laser cataract surgery Partial colectomy Elbow (radioactive) synovectomy Total knee arthroplasty Dargaud Y et al., Blood 2010

42 Patient characteristics and in vitro spiking data Dargaud Y et al., Blood 2010

43 Ex vivo TGT data Dargaud Y et al., Blood 2010

44 thrombin (nm) thrombin (nm) time (min) In vitro FVIII < 1 IU/dl Ab= 7 BU/ml Total Knee Arthroplasty PRP N7 45µg/kg N7 90µg/kg N7 120µg/kg N7 160 µg/kg N7 200µg/kg N7 240µg/kg N7 270µg/kg time (min) PPP Feiba 0.5U/ml Feiba 1U/ml Feiba 2U/ml ETP (nm.min) ETP (nm.min) In vitro Ex vivo Feiba (U/kg) time (h) TF 1pM PL 4µM CTI 1.45µM CAT method apcc 75 U/kg

45 Perioperative Monitoring of FEIBA (75 U/kg q.8h) 1600 F F F F D0 D1 D ETP (nm.min) thrombin (nm) time (hour) time (min) T0 T30min T 6H 2ème inj Feiba T 8h (residuel) Hb (g/dl) TIME (H) TF 1pM PL 4µM CTI 1.45µM CAT method

46 Lower Limb Amputation with rfviia ETP (nm.min) In vitro TF 1pM PL 4µM CTI 1.45µM CAT method rfviia (µg/kg) PRP PPP ETP (nm.min) FVIII < 1 IU/dl Ab titre = 21 BU/ml Ex vivo rfviia 200µg/kg PRP PPP time (minutes)

47 Perioperative Monitoring of rfviia Therapy rfviia 200µg/kg rfviia 200µg/kg rfviia 90µg/kg rfviia 90µg/kg Surgery ETP (nm.min) PRP PPP Control time (min) TF 1pM PL 4µM CTI 1.45µM CAT method

48 ETP (nm.min) /2h /3h /4h rfviia 20 µg/kg/h TF 1 pm PL 4 µm CTI 1.45 µm CAT method Hb (g/dl) Time (d) PRP PPP Control Time (d) FVII:C (IU/dL) Time (d) Dargaud. Haemophilia. 2008;14(suppl 4):20-27.

49 Bilateral total knee arthroplasty with FVIII and further switch to FEIBA In vitro ETP (nm.min) rfviia FEIBA Ex vivo ETP (nm.min) rfviia (µg/kg) Feiba (U/ml) Feiba Thrombin (nm) Time (min) T0 T30min T 1h T 3h T 6h T 8h T 12h Control FVIII< 1 IU/dl Ab titre = 75 BU/ml Dargaud Y. et al. Haemophilia, 2005;11:552-8

50 Perioperative monitoring of FVIII/FEIBA FVIII inhibitor levels (BU) , ,7 20 9,6 6 5,2 3,5 3,7 0d-12 d- 11 d-8 d-6 d-3 d-1 d0 preoperative period from day-12 to day 0 (days) 11,8 1,8 Surgery FVIII concentrate Dargaud Y. et al. Haemophilia, 2005;11:552-8

51 Dargaud Y et al, Haemophilia 2011

52 Synergistic effect of rfviia + FEIBA (PPP in vitro-thrombin peak) Livnat T et al, Haemophilia 2008; Martinowitz et al, Haemophilia

53 Conclusion Until recently, surgery in haemophilia patients with inhibitors was strongly contraindicated and was therefore often not even contemplated The availability of bypassing therapy has made it possible to safely and effectively perform minor, major, and dental surgical procedures on patients with haemophilia and inhibitors The choice of treatment for bleeding in inhibitor patients is dictated by a combination of several parameters: severity of the bleeding risk (major/moderate/minor), current inhibitor titre, previous anamnestic response to FVIII/IX, previous clinical response and side-effect profile of the agents available Need to develop laboratory assays to monitor therapeutic efficacy, together with a better understanding of the causes of treatment resistance. These surrogate parameters might serve to evaluate FEIBA/rFVIIa pharmacokinetic before and/or during surgery and should correlate with clinical efficacy and follow-up, as well as with early detection of an abnormal activation of the coagulation system

54 Conclusion (cont d) FVII:C levels attained in plasma do not always predict efficacy because similarly high levels are attained during successful treatments and in those that failed Additional options: Temporary inhibitor removal using extracorporeal immunoadsorption (column system including either protein A or antihuman IgG) prior to surgery, thus rendering the patient more responsive to ordinary replacement therapy with factor VIII or factor IX. Desmopressin can be especially recommended in mild haemophilia complicated by an inhibitor Antifibrinolytics are often administered as an adjunct therapy to the treatment protocol Topical fibrin glue An organized team approach is critical to success

55 The potential impact of environmental factors