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Future Challenges

Alexander G G Turpie Professor Emeritus of Medicine McMaster University Hamilton ON Canada. Future Challenges. Disclosures for Dr A.G.G. Turpie. New anticoagulants. Direct Thrombin Inhibitors - Dabigatran Factor Xa Inhibitors - Rivaroxaban - Apixaban - Edoxaban.

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Future Challenges

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  1. Alexander G GTurpie Professor Emeritus of Medicine McMaster University Hamilton ON Canada Future Challenges

  2. Disclosures for Dr A.G.G. Turpie

  3. New anticoagulants Direct Thrombin Inhibitors - Dabigatran Factor Xa Inhibitors - Rivaroxaban - Apixaban - Edoxaban

  4. Future challenges • Management of bleeding - Prevention - Treatment • Measurement • Antidotes

  5. All anticoagulants can cause bleeding

  6. Bleeding in VKA anticoagulated patients • Is common • Major bleeding 1-5% per year in AF • Intracranial bleeding 0.5-1.2% per year in AF • Associated with adverse outcomes • 3 to 5-fold increase in thrombotic events and death • Rapid and timely control of bleeding is likely to improve clinical outcomes but the efficacy of anticoagulant reversal is unproven

  7. Management of bleeding • Prevention • Treatment

  8. Prevention of bleeding • Anticoagulant selection • Patient and dose selection • Appropriate management of interruption

  9. Perioperative Management of NOAC-treated Patients

  10. Management of interruption of treatment

  11. Last intake of drug before elective surgical intervention *Many of these patients may be on lower dose of NOAC Low risk = surgery with low risk of bleeding, high risk = surgery with high risk of bleeding Heidbuchelet al, 2013

  12. Resumption of NOAC Heidbuchelet al, 2013

  13. Monitoring vs measuring • Monitoring implies dose adjustment according to test result • Measuring the drug or drug effect may be useful in: • Bleeding • Overdosage • Questions of compliance • Urgent surgery, interventions, thrombolysis • Extreme body weights • Children • Renal insufficiency

  14. Measurement of anticoagulant effects of NOACs

  15. Point of care testing Future

  16. Management of VKA bleeding • Hold drug(s) • Vitamin K • Resuscitation (i.v. access, fluid administration, blood product transfusion) • Maintain diuresis to clear drug • Mechanical compression and surgical methods to stop bleeding

  17. Replace clotting factors *Half life of factor VII is 6 hours Quinlan D, et al. Circulation 2013; 128:1179-81.

  18. Frozen plasma or PCC? Sarode R, et al. Circulation 2013; 128:1234-1243.

  19. Management of NOAC bleeding • Hold drug(s) • No Vit K • Resuscitation (i.v. access, fluid administration, blood product transfusion) • Maintain diuresis to clear drug • Mechanical compression and surgical methods to stop bleeding

  20. Reversal of NOACs • Activate coagulation to overcome the effect of the drug • Remove drug • Neutralize drug LauwMN, et al. Can J Cardiol. 2014;30:381-384.

  21. Activate coagulation • Recombinant factor VIIa (rVIIa) • Prothrombin complex concentrates (PCC) • II, VII, IX, X, C, S, • 25-50 units per kg • Activated prothrombin complex concentrates (aPCC) • Antifibrinolytic agents (e.g., tranexamic acid)

  22. Effect of NOACs on prothrombin time and endogenous thrombin potential with PCC

  23. Rivaroxaban: Effect on prothrombin time and endogenous thrombin potential with PCC Prothrombin time (PT) Endogenous thrombin potential (ETP) • PCC demonstrated the potential to reverse rivaroxabaneffects on PT and ETP in humans Eerenberg et al, 2011

  24. Antidotes to anticoagulants • Bleeding • Emergency Intervention • Elective Intervention • Overdose

  25. Specific antidotes to NOACs Lauw M, et al. Can J Cardiol 2014 (accepted).

  26. Andexanet Alpha - Phase 2 clinical study overviewDouble blind, randomized 2:1 (9 healthy subjects per cohort) Checkout Inpatient Unit Last Safety f/u Factor Xa Inhibitor PRT064445/ Placebo IV Days 1-6 (to steady state) Day 6 3h after last fXa inhibitor dose Day 13 Day 48 Study 1 - Apixaban Cohort 1: 90 mg IV x 1 Cohort 2: 210 mg IV x 1 Cohort 3: 420 mg IV x 1 Cohort 4: TBD Study 1: Apixaban 5 mg PO Q12 Study 2: Rivaroxaban 20 mg PO QD Study 3: Enoxaparin 1 mg/kg SQ Q12 Study 4: Betrixaban 80 mg PO QD Study 5: Edoxaban TBD

  27. Dose-dependent reversal of Apixaban-induced Anti-FactorXa activity correlates with reduction in Apixaban plasma free fraction Anti-fXa activity Apixaban free fraction Mean ± SEM

  28. Andexanet Alpha • FDA designated breakthrough therapy • Phase III Clinical Trials - ANNEXA-A: apixaban - ANNEXA-R: rivaroxaban

  29. Conclusions • NOACs provide opportunity to minimize growing burden of potentially preventable thromboembolism (especially AF) • Reductions in both stroke and bleeding translate into important benefits for patients • Most bleeding can be managed without specific antidotes • Specific antidotes in development will provide reassurance to physicians • Education to overcome the fear of bleeding as a barrier to appropriate anticoagulant use important

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