1. Bleeding with antiplatelet agents Giuseppe Biondi-Zoccai, MD Sapienza University of Rome, Italy giuseppe.biondizoccai@uniroma1.it

2. Learning goals Scope of the problem Definitions Pragmatic approach to bleeding Specific recommendations

3. Learning goals Scope of the problem Definitions Pragmatic approach to bleeding Specific recommendations

4. Coagulation

5. Platelets <- Aspirin <- PAR inhibitors <- P2Y12 inhibitors <- Anticoagulants IIb/IIIa inhibitors Jackson et al, Nat Rev Drug Discov 2003

6. Bleeding is commond and kills, irrespective of definition Mehran et al, Circulation 2011

7. Bleeding kills after PCI Chhatriwalla et al, JAMA 2013

8. GI bleeding kills in the ICU Cook et al, Crit Care 2001

9. Learning goals Scope of the problem Definitions Pragmatic approach to bleeding Specific recommendations

10. Historical definition: TIMI Mehran et al, Circulation 2011

11. New-entries: GUSTO, CURE, ACUITY, HORIZONS Mehran et al, Circulation 2011

12. Bleeding Academic Research Consortium Type 0: no bleeding Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a healthcare professional; may include episodes leading to self-discontinuation of medical therapy Type 2: any overt, actionable sign of hemorrhage (eg, more bleeding than would be expected for a clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria for type 3, 4, or 5, but does meet at least one of the following criteria: (1) requiring nonsurgical, medical intervention by a healthcare professional, (2) leading to hospitalization or increased level of care, or (3) prompting evaluation Mehran et al, Circulation 2011

13. Bleeding Academic Research Consortium Type 3a: Overt bleeding plus hemoglobin drop of 3 to 5 g/dL* (provided hemoglobin drop is related to bleed), or any transfusion with overt bleeding Type 3b: Overt bleeding plus hemoglobin drop 5 g/dL* (provided hemoglobin drop is related to bleed), cardiac tamponade, bleeding requiring surgery (excluding dental, nasal, skin, hemorrhoid), or bleeding requiring intravenous vasoactive agents Type 3c: Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation, does include intraspinal), subcategories confirmed by autopsy or imaging or lumbar puncture, or intraocular bleed compromising vision Mehran et al, Circulation 2011

14. Bleeding Academic Research Consortium Type 4 - CABG-related bleeding: Perioperative intracranial bleeding within 48 h, reoperation after closure of sternotomy for the purpose of controlling bleeding, transfusion of 5 U whole blood or packed red blood cells within a 48-h period, or chest tube output 2L within a 24-h period Type 5a - Probable fatal bleeding: no autopsy or imaging confirmation but clinically suspicious Type 5b - Definite fatal bleeding: overt bleeding or autopsy or imaging confirmation Mehran et al, Circulation 2011

15. Clinical impact Ndrepepa et al, Circulation 2012

16. Access site versus non-access site bleeding US CathPCI Registry (2004-2011): 57,246 bleeding events (1.7%) in 3,386,688 PCI procedures Chhatriwalla et al, JAMA 2013

17. Clarifying the mechanism Peddinghaus et al, Clin Lab Med 2009

18. Learning goals Scope of the problem Definitions Pragmatic approach to bleeding Specific recommendations

19. Comprehensive approach to bleeding Risk-stratification of patient/procedure Preventing bleeding Monitoring for bleeding Limiting bleeding Transfusion of RBC Discontinuation of antiplatelet agent Reversal of antiplatelet effect Makris et al, Br J Haematol 2012

20. Bleeding scores www.crusadebleedingscore.com

21. UK guidelines Makris et al, Br J Haematol 2012

22. UK guidelines Makris et al, Br J Haematol 2012

23. UK guidelines Makris et al, Br J Haematol 2012

24. Usefulness of thromboelastography- guided transfusions Schulman, Hematology 2012

25. Many platelet function tests are available Peddinghaus et al, Clin Lab Med 2009

26. But beware of variability in assays Santilli et al, J Am Coll Cardiol 2009

27. Also avoid overtreating: hazards of anti-fibrinolytics Hutton et al, BMJ 2012

28. Learning goals Scope of the problem Definitions Pragmatic approach to bleeding Specific recommendations

29. Activation and clearance Tan et al, Cardiovasc Ther 2012

30. Time to normal platelet function Makris et al, Br J Haematol 2012

31. Aspirin Oral drug Irreversibly inactivates cyclooxygenase Reversal possible with platelet transfusion, desmopressin, or rFVIIa Schulman, Hematology 2012; Makris et al, Br J Haematol 2012; Altman et al, J Thromb Haemost 2006

32. Clopidogrel Oral drug Irreversibly inactivates the P2Y12 platelet receptor for ADP Reversal possible with platelet transfusions, desmopressin, methyl prednisolone or rFVIIa Schulman, Hematology 2012; Levine et al, J Med Toxicol 2012; Makris et al, Br J Haematol 2012; Leithäuser et al, Clin Hemorheol Microcirc 2008

33. rFVIIa in healthy subjects receiving clopidogrel Skolnick et al, Anesth Analg 2011

34. Prasugrel Oral drug Irreversibly inactivates the P2Y12 platelet receptor for ADP Reversal possible with platelet transfusions, or desmopressin Zafar et al, J Thromb Haemost 2012

35. Effect of platelets on prasugrel Zafar et al, J Thromb Haemost 2012

36. Ticagrelor Oral drug Reversibly antagonizes the P2Y12 platelet receptor for ADP Renal clearance Reversal possible (only animal/in vitro data) with rFVIIa an FII and platelet transfusion Nylander et al, J Am Coll Cardiol 2013

37. Adjusted indirect comparison Biondi-Zoccai et al, Int J Cardiol 2011

38. What about intravenous glycoprotein IIb/IIIa inhibitors? Abciximab: IV monoclonal antibody Irreversibly inactivates glycoprotein IIb/IIIa receptors Plasma t 1/2 30 minutes, but platelets remain inhibited 12-24 h Reversal possible with platelet transfusions Eptifibatide and tirofiban: IV drugs Reversibly inactivate glycoprotein IIb/IIIa receptors Plasma t 1/2 2.5 hours for eptifibatide and 1.5 hours for tirofiban Renal clearance (thus t 1/2 longer if renal failure) Reversal may be achieved with dialysis

39. Pragmatic approach to platelet transfusion Campbell et al, World Neurosurg 2010

40. Possible thresholds for platelet Rx Peddinghaus et al, Clin Lab Med 2009

41. Take home messages A comprehensive approach to bleeding is recommended, from risk-stratification, to prediction, and management. When bleeding does occur, non-pharmacologic approaches should be envisioned first. If these are failing or unlikely to succeed, discontinuaton is possible, but it should be based on a multidisciplinary evaluation. In highly selected cases, reversal with platelet tranfusions, desmopressin, rFVIIa or other agents can be implemented, notwithstanding the major risk of iatrogenic thrombosis.

42. Many thanks for your attention For these slides and further ones on similar topics feel free to visit: www.metcardio.org/slides.html For additional details or queries feel free to contact me directly: giuseppe.biondizoccai@uniroma1.it