Dr Robert F. Storey Senior Lecturer and Honorary Consultant in Cardiology, University of Sheffield, Sheffield UK Managing bleeding post PCI

MY CONFLICTS OF INTEREST ARE Research grants: AstraZeneca, Eli Lilly, Daiichi Sankyo Consultancy/honoraria/travel: AstraZeneca, Eli Lilly, Daiichi Sankyo, The Medicines Company, Schering-Plough, Shire

Moscucci, M. et al. Eur Heart J : Major bleeding in ACS GRACE registry Adjusted OR for mortality associated with major bleeding = 1.64 (CI ) Adjusted OR associated with PCI = 1.63 (CI )

REPLACE-2 trial Increased mortality associated with major bleeding Feit F et al. Am J Cardiol. 2007; 100:1364-9

Sites of action of antithrombotic drugs Storey RF. Current Pharmaceutical Design 2006 Thrombin Thromboxane A 2 5HT P2Y 12 ADP 5HT PLATELET ACTIVATION P2Y 1 5HT 2A PAR1 PAR4 Dense granule Thrombin generation Shape change  IIb  3   3 Fibrinogen  IIb  3 Aggregation Amplification Alpha granule Coagulation factors Inflammatory mediators TP  Coagulation GPVI Collagen ATP P2X 1 ASPIRIN x CLOPIDOGREL PRASUGREL ACTIVE METABOLITE x AZD6140 CANGRELOR GPIIB/IIIA ANTAGONISTS x UFH LMWH BIVALIRUDIN FONDAPARINUX x SCH E5555 x

Antidotes for bleeding UFH and LMWH – protamine Warfarin – FFP, vitamin K Aspirin, clopidogrel – platelet transfusion Abciximab – platelet transfusion Eptifibatide, tirofiban - haemodialysis Unproven, nonselective agents with safety concerns in CAD patients: –Recombinant factor VIIa –Desmopressin –Norepinephrine/epinephrine

Risks of reversing antithrombotic drugs Stent occlusion and myocardial infarction/death Transfusion reaction to platelet transfusion e.g. acute lung injury Drug allergy Overdose of protamine has an anticoagulant effect

Bivalirudin Angioplasty Trial (BAT) Bittl J et al. N Engl J Med 1995;333:764-9 P < 0.001

Dumaine R et al. Arch Intern Med 2007; 167: LMWH vs UFH in PCI meta-analysis End pointHR for LMWH vs UFH (95% CI) P Major bleeding0.57 (0.40–0.82)0.002 Minor bleeding0.75 (0.47–1.20)ns Death/MI0.99 (0.79–1.24)ns

HR 0.81 ( ) P= Prasugrel Clopidogrel Days Endpoint (%) HR 1.32 ( ) P=0.03 Prasugrel Clopidogrel TRITON Efficacy and Safety Results CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 46 NNH = 167

Healthy volunteer crossover study of prasugrel and clopidogrel IPA (20  M ADP) at 24 hours Brandt JT et al. Am Heart J 2007

Effect of cangrelor on ADP-induced platelet aggregation in patients with NSTE ACS Whole blood impedance aggregometry Time after onset of infusion (h)Time after termination of infusion 0.05  g/kg/min 0.2  g/kg/min 0.5  g/kg/min 2  g/kg/min Infusion dose Storey RF et al. Thromb Haemost. 2001; 85:401-7.

Conclusions Major bleeding in PCI patients is associated with increased mortality risk Strategies that reduce the risk of major bleeding should be developed Safer alternatives to high doses of unfractionated heparin are currently available and should be adopted New agents with improved reversibility may allow safer management of bleeding associated with PCI