Reversal of Old and New Antithrombotic Drugs. Mike Makris

Transcription

1 Reversal of Old and New Antithrombotic Drugs Mike Makris

2 BCSH guidelines Guidelines on oral anticoagulation with warfarin fourth edition 1 Guideline on the urgent or emergency reversal of antithrombotic agents 2 Effects on routine coagulation screens and assessment of anticoagulant intensity in patients taking oral dabigatran or rivaroxaban 3 1. Keeling et al BJ Haem, 2011;154: Makris et al, BJ Haem 2013;160: Baglin et al, BJ Haem 2012,159:

3 Antithrombotic Drug Reversal General non-pharmacological measures Non-specific pharmacological agents Specific pharmacological agents

4 General non-pharmacological measures Stop the antithrombotic drug Document the timing and amount of the last drug dose Half-life/length of functional defect induced by the drug Assess the source of bleeding Request FBC, PT, APTT, TT, fibrinogen, U&E, LFT If available: laboratory test to measure the antithrombotic effect Correct haemodynamic compromise: iv fluids and transfusion Apply mechanical pressure, if possible Use endoscopic, radiological or surgical measures

5 Non-specific pharmacological agents DDAVP Tranexamic acid rfviia In unlicensed indication, arterial thrombosis of 5.5% vs 3.2% in placebo overall and 10.8% vs 4.1% in placebo at age over 75 years (Levi et al N Engl J Med 2010;363: ) PCC APCC (FEIBA)

6 Vitamin K antagonists Life or limb threatening bleeding

7 Vitamin K Correction within 6-8 hours 24 hours Subcutaneous 0 + Oral * 0/+ +++ Intravenous ** * Use the intravenous preparation orally ** Use the new micelle preparation

8 Factor activity vs INR (Vit K-dependent Coagulation factors VII, IX, X, II) Factor activity INR Modified after: Yuan S et al Thrombos Res 2007

9 Prothrombin complex concentrate (PCC) Contain factors II, VII, IX, and X Lyophilised concentrate Can be administered in 5-10 min (despite manufacturer recommendations) Corrects the INR within 5 minutes

10 Emergency reversal of oral anticoagulation: FFP vs PCC FFP (800 ml) PCC (25-50u FIX / kg) % FII FVII FIX FX FII FVII FIX FX Makris M et al. Thromb Haemost 1997

11 Comparison of FFP and Concentrate FFP PCC Volume Large Small Availability Widespread Limited Administration speed Slow Fast Viral inactivation Pooled product Only for SD-FFP and MB-FFP Yes for SD-FFP No for standard FFP Yes Yes Blood group specific Yes No Thrombogenicity No Yes Cost 300 per litre 900 for 70kg person

12 BCSH guideline Br J Haematol 2011; 154: All hospitals managing patients on warfarin should stock a 4-factor PCC In emergency reversal use 25-50u/kg PCC and 5mg iv vitamin K rfviia is not recommended FFP produces suboptimal correction and should only be used if PCC is not available

13 Reversal of Unfractionated Heparin Stopping the UFH infusion is usually sufficient to stop or prevent bleeding Protamine sulphate (1mg per u UFH) will fully reverse UFH Give protamine at <5mg/min to minimise adverse reaction risk Maximum dose of 50mg protamine will reverse UFH in most settings

14 LMWH reversal Protamine reversed 60% of LMWH in animal studies Largest series in patients using protamine 1 3 emergency surgery: no complications 14 patients with active bleeding, 12 evaluable: appeared successful in 8 Anti Xa levels after protamine did not correlate with bleeding rfviia: Contradictory animal studies Registry study including 6 patients successful 2 1. van Veen et al Blood Coagul Fibrinolysis. 2011;22: Ingerslev et al J Postgrad Med 2007; 53:17 22

15 BCSH guidelines: LMWH reversal Makris et al, BJ Haem 2013;160:34-46 LMWH administration < 8 hours of the time of requirement for correction of anticoagulation: give protamine sulphate (1 mg per 100 anti-xa units of LMWH) If ineffective, consider further protamine sulphate 0.5 mg per 100 anti Xa units LMWH administration >8 hours from the time of requirement for correction of anticoagulation: consider smaller doses of protamine Consider rfviia if there is continued life threatening bleeding despite protamine sulphate and the time frame suggests there is residual effect from the LMWH contributing to bleeding

16 Danaparoid Reversal No antidote Long half life (25hours) Protamine no effect Plasmapheresis for critical bleeding

17 Fondaparinux Synthetic pentasaccharide Indirect anti Xa activity Renal clearance T1/ hours up to 72 hours if CrCl, 30ml/min Levels by anti Xa activity No specific antidote rfviia partially effective on spiked samples

18 BCSH guidelines: fondaparinux reversal Makris et al, BJ Haem 2013;160:34-46 There is no specific antidote for fondaparinux. Management of bleeding should be through cessation of treatment and general haemostatic measures Recombinant FVIIa should be considered for critical bleeding

19 Anti-platelet Drug Reversal Anti-platelet effect longer than drug half life Careful decision to reverse due to underlying thrombotic risk General haemostatic measures first Platelet transfusion (2-3 pools) for critical bleeding Platelet transfusion in severe thrombocytopenia (<10x10 9 /l) caused by abciximab

20 Fibrinolytic Drug Reversal Stop the infusion Administer 12ml/kg FFP Administer iv tranexamic acid 1g tds If there is fibrinogen depletion, administer fibrinogen concentrate or cryoprecipitate Further management depending on coagulation tests

21 New Oral Anticoagulants Orthopaedic thromboprophylaxis General thromboprophylaxis Dabigatran (IIa inhibitor) Rivaroxaban (Xa inhibitor) Apixaban (Xa inhibitor) AF DVT PE Other FXa inhibitors in development: Edoxaban (Daiitchi Sankyo) licensed in Japan for thromboprophylaxis Otamixaban (Sanofi Aventis) Betrixaban (Portola)

22 Dabigatran Direct oral thrombin inhibitor Licensed for Thromboprophylaxis after THR/TKR (150/220mg OD) SPAF (110/150mg BD) T½ 13 18hrs depending on renal function 27hrs if CrCl<30ml/min Peak plasma concentration 2 3 hours. Renal excretion Levels by specific Hemoclot assay

23 Dabigatran reversal 35% bound to plasma proteins and dialysis reduces levels in patients with ESRF: dialysis 1,2 Activated charcoal binds dabigatran in water 3 : charcoal within 2 hours of ingestion Charcoal haemoperfusion removes 85% dabigatran in vitro 4 rfviia, (a)pcc: preliminary, inconclusive and contradictory. In vitro data and animal experiments rfviia failed to correct thrombin generation in healthy volunteers who were given melagatran 5 PCC failed to correct thrombin generation in healthy volunteers who were given dabigatran 6 1. Stangier et al Clin.Pharmacokinet 2010., 49, Woltz et al Thrombosis and Haemostasis, , Van Ryn et al Thromb.Haemost 2010., 103, Eerenberg et al Circulation. 2011;124: Van Ryn et al ASH Annual Meeting Abstracts,2009, 114, Van Ryn, Haematologica,2010, 95, 293

24 BCSH guidelines: dabigatran reversal Makris et al, BJ Haem 2013;160:34-46 There is no specific antidote for dabigatran. Management of bleeding should be through cessation of treatment and general haemostatic measures (2C) In bleeding patients who have taken a dose of dabigatran in the last 2 hours consider oral activated charcoal to prevent further absorption (2C) If rapidly deployable, haemodialysis, haemofiltration and charcoal haemoperfusion offer the possibility of enhanced clearance of the active drug (2C) In situations with ongoing life-threatening bleeding PCC, APCC and rfviia should be considered (2C)

25 Specific Dabigatran antidote Developed by Boehringer Ingelheim Humanised monoclonal antibody fragment Fab: Rapid high affinity binding to dabigatran Dose dependent reversal of bleeding in dabigatran treated rats. Dabigatran treated Rhesus monkeys: Non-bleeding state given Fab Biphasic half life, initial 0.4h followed by terminal t½ of 4.3h No human data Abstracts 22 & 3418; ASH 2012

26 Direct oral Xa inhibitor Licensed for Rivaroxaban Thromboprophylaxis after THR/TKR (10mg OD) Treatment of DVT (15mg BD for 21days then 20mg OD or 15 mg OD for CrCl ml/min) SPAF (20mg OD or 15mg OD for CrCl ml/min) T1/ hours, renal and hepatic clearance. Peak plasma concentration at 2 3 hrs High plasma protein binding: not dialysable PT prolonged > APTT Sensitivity dependent on reagents used. Levels by specific anti Xa assay

27 Rivaroxaban reversal No specific antidote Partial effects by in vitro and animal studies with rfviia, PCC and FEIBA Controlled trial in healthy volunteers 1 : PCC corrected PT and thrombin generation No clinical data 1. Eerenberg et al Circulation 2011;124:

28 BCSH guidelines: rivaroxaban reversal Makris et al, BJ Haem 2013;160:34-46 There is no specific antidote for rivaroxaban. Management of bleeding should be through cessation of treatment and general haemostatic measures (2C) In situations with ongoing life-threatening bleeding PCC, APCC and rfviia should be considered (2C)

29 Specific FXa inhibitor antidote Being developed by Portola Has its own Xa inhibitor Betrixaban Formal collaborations to develop antidote with: Bayer (Rivaroxaban) Pfizer / Bristol-Myers Squibb (Apixaban) r-antidote

30 r-antidote Lu G et al. Nature Medicine 2013; 19: Recombinant FX expressed in CHO cells with 3 changes 1. Deletion of the GLA domain 2. Deletion of the activation peptide 3. Mutation (S419A) in catalytic domain r-antidote is truncated inactive Xa that avidly binds Xa inhibitors

31 r-antidote effect on Xa activity Lu G et al. Nature Medicine 2013; 19:

32 r-antidote effect on PT in Rivaroxaban containing human plasma Lu G et al. Nature Medicine 2013; 19:

33 r-antidote reduces rivaroxaban induced bleeding (rat liver laceration model) Lu G et al. Nature Medicine 2013; 19:

34 Universal NOAC antidote? PER977 from Perosphere Inc Synthetic small molecule (~500Da) Binds all approved NOACs Dabigatran, Rivaroxaban, Apixaban, Edoxaban Stable for >1 year at room temperature Reverses dabigatran and rivaroxaban in human blood ex vivo Reduces blood loss after NOAC use in rat tail transection model No publications in peer review journals No human studies

35 AHA 2012 meeting presentation

36 Summary Anticoagulant related bleeding is common For warfarin the antidotes are vitamin K and PCC, not FFP Protamine sulphate is valuable in LMWH reversal The NOACs do not have antidotes at present. Management is with supportive care, waiting and possibly (a)pcc/viia Specific NOAC antidotes are likely to be available within the next 3 years.

37 Acknowledgement Writing committee Makris M, Van Veen J, Tait C, Mumford A, Laffan M BCSH Haemostasis and Thrombosis Task Force Keeling D, Watson H, Laffan M, Chalmers E, Mumford A, Jennings I, Walker I, Gray E, Tait C, Makris M