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Bleeding with antiplatelet agents
Giuseppe Biondi-Zoccai, MD
Sapienza University of Rome, [email protected]
Learning goals
• Scope of the problem• Definitions• Pragmatic approach to bleeding• Specific recommendations
Learning goals
• Scope of the problem• Definitions• Pragmatic approach to bleeding• Specific recommendations
Coagulation
Platelets<- Aspirin
<-
<-
PAR inhibitors
<-
P2Y12inhibitors
<-Anticoagulants
IIb/IIIainhibitors
Jackson et al, Nat Rev Drug Discov 2003
Bleeding is commond and kills, irrespective of definition
Mehran et al, Circulation 2011
Bleeding kills after PCI
Chhatriwalla et al, JAMA 2013
GI bleeding kills in the ICU
Cook et al, Crit Care 2001
Learning goals
• Scope of the problem• Definitions• Pragmatic approach to bleeding• Specific recommendations
Historical definition: TIMI
Mehran et al, Circulation 2011
New-entries: GUSTO, CURE, ACUITY, HORIZONS
Mehran et al, Circulation 2011
Bleeding Academic Research ConsortiumType 0: no bleedingType 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
Bleeding Academic Research ConsortiumType 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
Bleeding Academic Research ConsortiumType 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
Clinical impact
Ndrepepa et al, Circulation 2012
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
Clarifying the mechanism
Peddinghaus et al, Clin Lab Med 2009
Learning goals
• Scope of the problem• Definitions• Pragmatic approach to bleeding• Specific recommendations
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
Bleeding scores
www.crusadebleedingscore.com
UK guidelines
Makris et al, Br J Haematol 2012
UK guidelines
Makris et al, Br J Haematol 2012
UK guidelines
Makris et al, Br J Haematol 2012
Usefulness of thromboelastography-guided transfusions
Schulman, Hematology 2012
Many platelet function tests are available
Peddinghaus et al, Clin Lab Med 2009
But beware of variability in assays
Santilli et al, J Am Coll Cardiol 2009
Also avoid overtreating: hazards of anti-fibrinolytics
Hutton et al, BMJ 2012
Learning goals
• Scope of the problem• Definitions• Pragmatic approach to bleeding• Specific recommendations
Activation and clearance
Tan et al, Cardiovasc Ther 2012
Time to normal platelet function
Makris et al, Br J Haematol 2012
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
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
rFVIIa in healthy subjects receiving clopidogrel
Skolnick et al, Anesth Analg 2011
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
Effect of platelets on prasugrel
Zafar et al, J Thromb Haemost 2012
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
Adjusted indirect comparison
Biondi-Zoccai et al, Int J Cardiol 2011
What about intravenous glycoprotein IIb/IIIa inhibitors?
Abciximab:• IV monoclonal antibody• Irreversibly inactivates glycoprotein IIb/IIIa receptors• Plasma t1/2 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 t1/2 2.5 hours for eptifibatide and 1.5 hours for tirofiban
• Renal clearance (thus t1/2 longer if renal failure)• Reversal may be achieved with dialysis
Pragmatic approach to platelet transfusion
Campbell et al, World Neurosurg 2010
Possible thresholds for platelet Rx
Peddinghaus et al, Clin Lab Med 2009
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.
Many thanks for your attention
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