2. Evolution of pharmaceutical antithrombotic therapy in CVD Dr Rob Butler Dept of Cardiology University Hospital of North Staffordshire Drug It!

3. Summary Current standard of careCurrent standard of care –STEMI –NSTEMI –PCI adjuncts Medication on the HorizonMedication on the Horizon

5. STEMI ThrombolysisThrombolysis –Little change PHT ASAP and <30mins (ACC/AHA/DOH)PHT ASAP and <30mins (ACC/AHA/DOH) Door to needle time 20mins (ACC/AHA/NSF)Door to needle time 20mins (ACC/AHA/NSF) Call to needle time <60mins (NSF)Call to needle time <60mins (NSF) –Finding the balance PHT and pPCIPHT and pPCI STREAMSTREAM

6. STEMI Adjunctive IIb/IIIa to thrombolysisAdjunctive IIb/IIIa to thrombolysis –FINESSE : 2400 pt 1:1:1 Increased stroke/bleeding riskIncreased stroke/bleeding risk Adjunctive IIb/IIIa to pPCIAdjunctive IIb/IIIa to pPCI –ON-TIME-2: pre-hospital tirofiban STEMI with likely pPCISTEMI with likely pPCI –984 pts; aspirin and plavix 600mg 1 o : ST segment much better1 o : ST segment much better 2 o : less thrombotic bailout and abrupt vessel closure2 o : less thrombotic bailout and abrupt vessel closure Long transit times did bestLong transit times did best ON-TIME: Lancet 2008;372:537

7. STEMI Adjunctive IIb/IIIa to pPCIAdjunctive IIb/IIIa to pPCI –BRAVE-3 800 STEMI pts with planned pPCI800 STEMI pts with planned pPCI DtB time ~ 78-80minsDtB time ~ 78-80mins Adjunctivre ReoPro vs placeboAdjunctivre ReoPro vs placebo Loading strategy: clopidogrel 600mgLoading strategy: clopidogrel 600mg –MACE UnchangedUnchanged Trend to increased bleeding/thrombocytopeniaTrend to increased bleeding/thrombocytopenia

8. STEMI - ADP ClopidogrelClopidogrel –New recommendation of 28 day therapy (NICE/ACC and AHA) COMMIT-CCS-2 (75mg, 28d)COMMIT-CCS-2 (75mg, 28d) –45 852 patients within 24 hours of suspected MI –~10% RRR of MACE: 10.1% vs.9.2% –Benefit reperfused or not CLARITY: (300mg / 75mg)CLARITY: (300mg / 75mg) –3491 patients receiving fibrinolytic therapy within 12 hours of STEMI –~35% RRR in MACE 21.7% vs. 15.0% –No increase in SAER

9. STEMI - ADP Prasugrel: TRITON-TIMI 38Prasugrel: TRITON-TIMI 38 –Novel thienopyridine –~14k patients with ACS NSTEACS with planned C/C ? proceedNSTEACS with planned C/C ? proceed STEMI with planned PCISTEMI with planned PCI –Prasugrel 60/10mg vs clopidogrel 300/75mg –Hypothesis Quicker onset 30mins c/w 6 hoursQuicker onset 30mins c/w 6 hours More complete ADP inhibitionMore complete ADP inhibition More consistent ADP inhibitionMore consistent ADP inhibition

10. Days MACE Wiviott SD et al NEJM 357: 2001, 2007

11. Stent Thrombosis (Landmark Analysis - 3 days) 0 1 2 3 0123 306090180270360450 Stent Thrombosis (%) Stent Thrombosis (%) Prasugrel Clopidogrel Loading Dose HR 0.49 P=0.006 0.67 0.33 Prasugrel Clopidogrel HR 0.45 P<0.0001 1.74 0.80 Maintenance Dose Days Antman E et al JACC 51: 2028,2008

12. 0 5 10 15 0306090180270360450 HR 0.81 (0.73-0.90) P=0.0004 Prasugrel Clopidogrel Days Endpoint (%) 12.1 9.9 HR 1.32 (1.03-1.68) P=0.03 Prasugrel Clopidogrel 1.8 2.4 138 events 35 events Balance of Efficacy and Safety CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 46 NNH = 167 Wiviott SD et al NEJM 357: 2001, 2007

13. STEMI Fondaparinux - Xa inhibitor –OASIS-6 Marginally better that UFH post thrombolysis; superior outcome and less bleedingMarginally better that UFH post thrombolysis; superior outcome and less bleeding Not an alternative to UFH in pPCI or bail-out PCI (catheter thrombosis)Not an alternative to UFH in pPCI or bail-out PCI (catheter thrombosis) Enoxaparin – LMWtH –ExTRACT-TIMI 25 Better outcome post thrombolysisBetter outcome post thrombolysis Increased bleedingIncreased bleeding Suitable in place of UFH during PCISuitable in place of UFH during PCI

14. NSTEMI ADP inhibitionADP inhibition –Clopidogrel Loading strategiesLoading strategies Clopidogrel resistanceClopidogrel resistance –Prasugrel TRITON-TIMI 38TRITON-TIMI 38 –19% RRR or 2.2%ARR Increased harmIncreased harm –Bleeding in CABG –Weight <60kg –Age >75 –CVA

15. Xa in ACS-NSTEMI Apixaban – Xa inhibitorApixaban – Xa inhibitor –APPRAISE-1 Evaluation of 4 doses in ACS patients receiving current standard of careEvaluation of 4 doses in ACS patients receiving current standard of care 1700 patients1700 patients –Inclusion required one additional risk factor Age, DM, CVA/TIA etcAge, DM, CVA/TIA etc –Outcome Trend towards reduction in MACETrend towards reduction in MACE Trend towards increased bleeding with higher dosesTrend towards increased bleeding with higher doses

16. Adjunctive Rx to PCI ADP inhibitionADP inhibition –Clopidogrel loading strategies ARMYDA –2: MACE 12% vs 4%ARMYDA –2: MACE 12% vs 4% –255 patients, 30d follow up –300 vs 600mg clopidogrel –>6hrs pre PCI –Driven by procedural MI ARMYDA-RELOADARMYDA-RELOAD –568 patients with planned PCI –ACS and stable cases >10 days clopidogrel –RCT of reloading with 600mg or not –ACS patients: MACE reduced from 18% to 7% (p=0.035)

17. Adjunctive Rx to PCI ADP inhibitionADP inhibition –Clopidogrel maintenance strategies BASKET-LATEBASKET-LATE –746 patients post PCI DES 499 vs BMS 244DES 499 vs BMS 244 6 months clopidogrel, then followed for 1 year6 months clopidogrel, then followed for 1 year –MACE »4.9% vs. 1.3%; DES vs. BMS –LST »2.6% vs. 1.3%; DES vs. BMS

18. Adjunctive Rx to PCI ADP inhibitionADP inhibition –Prasugrel – –Demonstrably better platelet inhibition than clopidogrel 300mg: TRITON TIMI 38300mg: TRITON TIMI 38 600mg: PRINCIPLE TIMI 44600mg: PRINCIPLE TIMI 44 –201 patients –Prasugrel 60/10mg vs. Clopidogrel 600/150mg –Better inhibition by VASP/P2Y 12 bedside test

19. Adjunctive Rx to PCI BivalirudinBivalirudin –ISAR-REACT III Bivalirudin vs. UFHBivalirudin vs. UFH ~4500 patients; marker –ve, stable or unstable presentation~4500 patients; marker –ve, stable or unstable presentation 80%+ DES80%+ DES Pretreatment of 300-600/75-150 clopidogrelPretreatment of 300-600/75-150 clopidogrel –MACE unchanged –Bleeding reduced from 4.6% to 3.1% (RRR~33%) NEJM 2008;359:688

20. ADP inhibition in PCI CangrelorCangrelor –i.v. competitive P2Y 12 inhibitor T 1/2 : 5-9 mins, after 20mins – normal platelet fnT 1/2 : 5-9 mins, after 20mins – normal platelet fn –Phase II 199 patients undergoing PCI199 patients undergoing PCI MACE similar, Trend to less bleedingMACE similar, Trend to less bleeding –Phase III CHAMPION PCICHAMPION PCI –9000 patients: vs. plavix 600mg at start of PCI CHAMPION PLATFORMCHAMPION PLATFORM –6300 pts: vs. 600mg plavix at the end of the PCI

21. Platelet inhibition in stable CHD AZD 6149 – ADP inhibitorAZD 6149 – ADP inhibitor –DISPERSE 2 (Phase II) –platelet sub study by Rob Storey Better platelet inhibition than clopidogrelBetter platelet inhibition than clopidogrel Competitive non-thienopyridine inhibitorCompetitive non-thienopyridine inhibitor Increased SOB/hypotension/diarrhea/ventricular pausesIncreased SOB/hypotension/diarrhea/ventricular pauses Similar tolerability to clopidogrelSimilar tolerability to clopidogrel –Currently being investigated in the PLATO Study 18 000 stable patients; compared to clopidogrel 300/75mg18 000 stable patients; compared to clopidogrel 300/75mg

22. Platelet inhibition in stable CHD Thrombin receptor antagonismThrombin receptor antagonism –SCH 530348 TRANSCENDENCE-PCITRANSCENDENCE-PCI Non-urgent PCI, dose ranging studyNon-urgent PCI, dose ranging study Background of standard careBackground of standard care Drug given pre catheter and pre PCIDrug given pre catheter and pre PCI –Trends to reduced MACE –No difference in bleeding Phase III: TRA-2-P TIMI 50Phase III: TRA-2-P TIMI 50 –20k pts; secondary prevention study