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Wat betekent de komst van NOAC antidota voor de klinische praktijk? Professor Saskia Middeldorp | Department of Vascular Medicine | MiddeldorpS Nationale antistollingsdag 6 november 2018 Disclosures Research Support, Advisory Boards


  1. Wat betekent de komst van NOAC antidota voor de klinische praktijk? Professor Saskia Middeldorp | Department of Vascular Medicine | MiddeldorpS Nationale antistollingsdag 6 november 2018

  2. Disclosures Research Support, Advisory Boards and Lecture Fees Aspen Bayer BMS/Pfizer Boehringer Ingelheim Daiichi Sankyo GSK Portola Sanquin Sanofi

  3. Evidence for antidotes Surrogate Clinical endpoint endpoint To c orrect INR To improve outcome What we have What we need…

  4. Hemostatic efficacy – The New Benchmark Effective/Good Ineffective/ Poor

  5. VKA 30 d Thromboembolism 8%

  6. Vitamin K antagonist related bleeding and PCC • Retrospective cohort study in 5 Dutch hospitals • 41% ICH; 36% GI • Hemostatic efficacy: 68% • Thromboembolic rate 5% • Death 22%, 60% bleeding-related Brekelmans, RPTH 2017

  7. DOAC antidota Dabigatran: Idarucizumab (Praxbind) • Humanized antibody • 300x binding to dabigatran than dabigatran with thrombin • single bolus of 2 x 2.5 gram i.v. • Registered in 2015, available in most hospitals now SPC Praxbind; www.ema.europe.eu

  8. RE-VERSE-AD Diluted thrombin time N= 90 130 Mortality 20% 120 110 100 Acute bleeding n=51 90 Idarucizumab 11.4 u until cessation of dTT (s) 2x 2.5 g 80 bleeding 70 60 Acute surgery n=39 50 Assay upper 92% normalization of 40 limit of normal 30 coagulation 20 10 – 30 Baseline Between 1h 2h 4h 12h 24h vials min Time post idarucizumab Pollack, N Eng J Med 2015/ Full cohort analysis NEJM 2017

  9. DOAC antidota Factor Xa inhibitors: Andexanet alfa Catalytic domain Gla domein Siegal, N Eng J Med 2015

  10. Andexanet alfa – not yet on the market Anti-Xa activity decrease: 89% (58 – 94%) Connolly NEJM 2017

  11. Hemostatic Efficacy with Andexanet • Excellent or good in 79% (95%CI 64-89) Connolly NEJM 2017

  12. Andexanet alfa – almost on the market in NL? Siegal NEJM 2015

  13. PCC in rivaroxaban treated healthy volunteers 50 IU/kg 50 IU/kg Surrogate Clinical endpoint endpoint???? To c orrect INR

  14. Factor Xa inhibitor and Prothrombin complex concentrate (PCC) apixaban Eerenberg, Circulation 2011 Cheung, J Thromb Haemost 2015

  15. Recent Regulatory Trials of Reversal Agents Thrombotic Hemostatic Efficacy Mortality Number Event Rate (95CI) (95CI) Pivotal Reversal agent (95 CI) Study Anti-coagulant Total % ICH Total ICH Total ICH Total ICH Andexanet 85% 83% 11% 10% 11% 10% ANNEXA-4 227 61 FXa Inhibitors (77-90) (72-91) (7-16) (5-18) (7-16) (5-18) REVERSE- Idarucizumab 5% 6% 5% 6% 301 33 68% a NR b AD Dabigatran (3-8) (2-13) (3-8) (2-13) Sarode 4F-PCC 72% 42% 8% 8% 98 12 NR NR 2013 Warfarin (64-81) (15-72) (3-15) (3-15) Sarode Plasma 65% 58% 6% 6% 4F-PCC = Four factor prothrombin complex concentrate; ICH = Intracranial hemorrhage; NR = Not reported 104 12 NR NR 2013 Warfarin (56-75) (28-85) (3-13) (3-13) a 68% had investigator-determined, non-adjudicated time to hemostasis within 24 hours b Time to hemostasis not calculated in ICH patients

  16. EHRA 2013 practice guidelines idarucizumab Heidbuchel, Europace 2013

  17. Reversal for DOAC in urgent surgery How important is this? Peri-procedural bleeds in RE-LY (dabigatran) No difference with warfarin despite the absence of a specific antidote Urgent surgery VKA Dabigatran 110 mg Dabigatran 150 mg N=111 bid bid N=107 N=141 % Major bleeds 21.6 17.8 17.7 RR (95%CI) vs VKA 1 0.82 (0.48-1.41) 0.82 (0.50-1.35) Healey, Circulation 2012

  18. Clinical scenario’s The bleeding patient The patient undergoing urgent surgery The patient on DOAC with ischemic stroke Does having an antidote influence the choice of anticoagulant drug?

  19. • AMC • MUMC+ • Erasmus MC • Albert Schweitzer Ziekenhuis • UMCG.

  20. Use of idarucizumab January – August 2016 Kermer, Int J Stroke 2017

  21. Retrospective cohort study 19 patients with ischemic stroke • 18 < 4,5 hrs after onset • 1 wake up stroke R/ idarucizumab + r-tPA 79% benefit of thrombolysis Kermer, Int J Stroke 2017

  22. Retrospective cohort study 12 patients with intracranial bleeding • 2 patients with hematoma growth R/ idarucizumab 67% favourable outcome TE events: 1 fatal pulmonary embolism after 5 days Kermer, Int J Stroke 2017

  23. Dutch experience First 2 years after release in January 2016 12 centers 86 patients • 51 severe bleeding (20 GI, 18 intracranial) • 34 urgent surgery • Mortality in 90 days 20% • ? Effective hemostasis in 16 (31%) bleeding patients • ? Large proportion of inappropriate use Van der Wall, Eur Heart J abstract 2018

  24. What about andexanet? • Full cohort results expected early 2019 • Phase 4 RCT with standard of care comparison in patients with intracranial hemorrhage required by FDA • Surgery intervention not studied • Very high costs … Andexa FDA approval Letter May 3, 2018

  25. In a bleeding patient, ask the right questions 1. What anticoagulant is prescribed? 2. Is anticoagulant present at high quantity? • When was last dose taken? • Half-life and renal function, (age, weight)? 3. Site and severity of bleed? • Local measures? • Is reversal necessary?

  26. Antidotes … . • First, they were not there • Controversy regarding the need • Now that we have them, we need them …

  27. Take home messages • The choice of an antidote may drive the choice for an anticoagulant, particularly in patients at high risk of bleeding • Idarucizumab is easy to administer and widely available • Andexanet is complicated and not yet available • Guidance for stringent use needed

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