Antiplatelets anticoagulation and antodotes

Antiplatelet and hemoraghe

1. Anti- trombotik ilaçlar ve Kanama D r . İrfan ŞAHİN BAĞCILAR EĞİTİM VE ARAŞTIRMA HASTANESİ -Kardiyoloji 07.05.2024

2. Anticoagulation Reversal Strategies for Platelet Aggregation Inhibitors

3. Mechanism of action of desmopressin Vasopressin is a secretagogue of VWF. This hormone functions through two receptors, termed V1 and V2, which activate different intracellular second messengers. 7  Agonist activity at V2 receptors leads to a rise in intracellular concentrations of cyclic adenosine monophosphate , which in turn induces exocytosis of VWF from its storage sites ( ie , Weibel –Palade bodies of endothelial cells) into the circulation. Interestingly, tissue plasminogen activator, a molecule involved in fibrinolysis and therefore in opposition to the effects of VWF, is also released into circulation along with VWF. Desmopressin (1‐desamino‐8‐ d ‐arginine vasopressin, also abbreviated DDAVP) is a synthetic analogue of vasopressin, which activates only V2 receptors and thus lacks its vasoconstrictor and uterotonic properties. Intravenous or intranasal administration of desmopressin to healthy individuals is followed by a rise in levels of both VWF and its precious cargo, FVIII. 2  Individuals who lack V2 receptors—that is, patients with nephrogenic diabetes insipidus —expectedly do not show this increase in VWF and FVIII leve

4. Warfarin-Associated ICH and Major Hemorrhage

5. Warfarin-Associated Bleeding

6. Epidemiology of ICH

7. Overview

8. Direkt FIIa ( Trombin ) & FXa İnhibitörleri Temel Olarak Farklı Farmakolojik Özelliklere Sahiptir 1–12 FXa İnhibitörleri DTI Rivaroksaban Apiksaban Edoksaban Dabigatran Hedef Faktör Xa Trombin Ön ilaç Hayır Hayır Hayır Evet Oral biyoyararlanım %80-100* ~%66 % 62 %6,5 Emilime uğrayan aktif ilacın renal klirensi %33 %27 ~%5 >%80 T maks (sa) 2-4 1-3 1-2 2-6 # Yarılanma ömrü (sa) 5-13 8-13 9-11 12-14 Sabit Dozlama (SPAF endikasyonu) OD BID OD BID *Yemeklerle birlikte 15-20 mg; # Postoperatif dönem; 1. Eriksson BI et al. Annu Rev Med. 2011;62:41-57; 2. Frost et al. J Thromb Haemost. 2007;5(Suppl 2):P-M-664; 3. Kubitza D et al. Clin Pharmacol Ther. 2005;78(4):412-421; 4. Lopes RD et al. Am Heart J. 2010;159(3):331–339; 5. Ogata K et al. J Clin Pharmacol. 2010;50(7):743-753; 6. ROCKET AF Study Investigators. Am Heart J. 2010;159(3):340–347.e1; 7. Ruff CT et al. Am Heart J. 2010;160(4):635–641; 8. Stangier J et al. J Clin Pharmacol 2005;45(5):555–563; 9. Dabigatran KÜB; 10. Apiksaban KÜB; 11. Rivaroksaban KÜB; 12: Matsushima et al. Clin Pharmacol Drug OD: once a day (günde bir kez); BID: twice a day (günde iki kez)

9. Pharmacokinetics of DOACs

10. US Indications and Dosage

11. DOACs Bleeding Events Systematic Review and Meta-Analysis

12. Bleeding With DOACs

13. Decisions in the ED

14. Updated European Heart Rhythm Association Practical Guide: Management of NOAC-Associated Bleeding

15. Anticoagulation Reversal With Vitamin K

16. Management of Urgent Anticoagulation Reversal: 4F-PCC vs FFP

17. Bleeding events on vitamin K antagonists. The risk of bleeding events for patients on VKAs increases markedly when the nternational normalized ratio (INR) exceeds . Four RCTs have compared vitamin K1 with placebo in patients with an INR of 4.5–10 in the absence of ongoing bleeding, though they have only showed benefit on the surrogate outcome of reversing supratherapeutic INRs more rapidly, without evidence of benefit for hard clinical outcomes. Vitamin K1 administration can be used in the absence of ongoing haemorrhage in patients with an INR >10, as the risk of bleeds may be substantial. In the presence of a major or life-threatening bleed on a VKA, a combination of vitamin K1 with a rapid reversal agent (i.e. prothrombin complex concentrate, fresh frozen plasma, or recombinant activated Factor VII) should be considered.

18. FFP for Anticoagulation Reversal

19. 4F-PCC vs Plasma for Rapid VKA Reversal in Patients Needing Urgent Surgical or Invasive Interventions: Primary Endpoint Results

20. Bleeding events on non-vitamin K antagonist oral anticoagulants With patients treated with Factor Xa ( FXa ) inhibitors ( apixaban , edoxaban , rivaroxaban ), prothrombin complex concentrate should be the first-line treatment.299 A specific antidote for FXa inhibitors, andexanet alfa , has been tested in patients with acute major bleeding associated with FXa inhibitors. At a dose of 400 mg bolus, followed by 480 mg infusion over 2 h, andexanet alfa significantly reduced anti- FXa activity , with effective haemostasis occurring in 79% of patie nts .

21. Candidates for Reversal Agents

22. Prior to Reversal Factors to Consider

23. Reversal Agents

24. Reversal Agents

25. Idarucizumab

26. Andexanet Alfa

27. NOAC Anticoagulation Reversal Agents

28. Bleeding events on non-vitamin K antagonist oral anticoagulants After cessation of non-VKA oral anticoagulants (NOACs), improvement in haemostasis is to be expected within 12–24 h, unless patients have reduced renal function. Intracerebral haemorrhage or bleeding involving a critical organ, such as the eye, warrants immediate attempts to neutralize the anticoagulant effect of the NOAC . The first-line reversal agent to consider is the specific dabigatran antidote idarucizumab , which has been effectively tested in an uncontrolled phase III trial at a dose of 5 g i.v . in patients with uncontrollable overt bleeds or in patients requiring surgery. Prothrombin complex concentrates or activated prothrombin complex concentrates (i.e. with the addition of activated Factor VII) can be considered as second-line treatments when idarucizumab is not available. Based on studies with prothrombin complex concentrates in pre-clinical models and in healthy volunteers, an initial dose of 25 U/kg is suggested, with repeat dosing if clinically indicated. Activated prothrombin complex concentrates (50 IE/kg, with a maximum of 200 IE/kg/day) may be considered if available . Although product information for some of the NOACs mentions the use of fresh frozen plasma to help control bleeding, it seems unlikely that this would counteract drug effects. Thus , plasma should be administered only for major or life-threatening bleeds with additional dilutional coagulopathy. Neither vitamin K1 nor protamine have a role in the management of NOAC-associated bleeds.

29. Teşekkürler …