Evolution of pharmaceutical Evolution of pharmaceutical antithrombotic therapy in CVDantithrombotic therapy in CVD

Dr Rob ButlerDr Rob Butler

Dept of CardiologyDept of Cardiology

University Hospital of North StaffordshireUniversity Hospital of North Staffordshire

Drug

Drug

It!It!

SummarySummary

• Current standard of careCurrent standard of care– STEMISTEMI– NSTEMINSTEMI– PCI adjunctsPCI adjuncts

• Medication on the HorizonMedication on the Horizon

STEMISTEMI• ThrombolysisThrombolysis

– Little changeLittle 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 Finding the balance • PHT and pPCIPHT and pPCI• STREAMSTREAM

STEMISTEMI• Adjunctive IIb/IIIa to thrombolysisAdjunctive IIb/IIIa to thrombolysis

– FINESSE : 2400 pt 1:1:1FINESSE : 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 tirofibanON-TIME-2: pre-hospital tirofiban

• STEMI with likely pPCISTEMI with likely pPCI– 984 pts; aspirin and plavix 600mg984 pts; aspirin and plavix 600mg

• 11oo: ST segment much better: ST segment much better• 22oo: less thrombotic bailout and abrupt vessel : less thrombotic bailout and abrupt vessel

closureclosure• Long transit times did bestLong transit times did best

ON-TIME: Lancet 2008;372:537

STEMISTEMI

• Adjunctive IIb/IIIa to pPCIAdjunctive IIb/IIIa to pPCI– BRAVE-3BRAVE-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

– MACEMACE• UnchangedUnchanged• Trend to increased Trend to increased

bleeding/thrombocytopeniableeding/thrombocytopenia

STEMI - ADPSTEMI - ADP

• ClopidogrelClopidogrel– New recommendation of 28 day therapy New recommendation of 28 day therapy

(NICE/ACC and AHA)(NICE/ACC and AHA)• COMMIT-CCS-2 (75mg, 28d)COMMIT-CCS-2 (75mg, 28d)

– 45 852 patients within 24 hours of suspected MI45 852 patients within 24 hours of suspected MI– ~10% RRR of MACE: 10.1% vs.9.2%~10% RRR of MACE: 10.1% vs.9.2%– Benefit reperfused or not Benefit reperfused or not

• CLARITY: (300mg / 75mg)CLARITY: (300mg / 75mg)– 3491 patients receiving fibrinolytic therapy within 12 3491 patients receiving fibrinolytic therapy within 12

hours of STEMI hours of STEMI – ~35% RRR in MACE 21.7% vs. 15.0%~35% RRR in MACE 21.7% vs. 15.0%– No increase in SAERNo increase in SAER

STEMI - ADPSTEMI - ADP

• Prasugrel: TRITON-TIMI 38Prasugrel: TRITON-TIMI 38– Novel thienopyridineNovel thienopyridine– ~14k patients with ACS~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 300/75mgPrasugrel 60/10mg vs clopidogrel 300/75mg– HypothesisHypothesis

• 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

Days

MACEMACE

Wiviott SD et al NEJM 357: 2001, 2007Wiviott SD et al NEJM 357: 2001, 2007

Stent ThrombosisStent Thrombosis(Landmark Analysis - 3 days)(Landmark Analysis - 3 days)

0

1

2

3

0 1 2 3

30 60 90 180 270 360 450

Ste

nt

Th

rom

bosi

s (%

)S

ten

t Th

rom

bosi

s (%

)

Prasugrel

Clopidogrel

Loading DoseLoading Dose

HR 0.49P=0.006

0.67

0.33

Prasugrel

Clopidogrel

HR 0.45P<0.0001

1.74

0.80

Maintenance DoseMaintenance DoseDaysDays

Antman E et al JACC 51: 2028,2008Antman E et al JACC 51: 2028,2008

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

Days

En

dp

oin

t (%

)

12.1

9.9

HR 1.32(1.03-1.68)

P=0.03

Prasugrel

Clopidogrel1.82.4

138138 events events

3535 events events

Balance of Balance of Efficacy and SafetyEfficacy and Safety

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 46

NNH = 167

Wiviott SD et al NEJM 357: 2001, 2007Wiviott SD et al NEJM 357: 2001, 2007

STEMISTEMI

Fondaparinux - Xa inhibitorFondaparinux - Xa inhibitor– OASIS-6OASIS-6

• Marginally better that UFH post thrombolysis; Marginally better that UFH post thrombolysis; superior outcome and less bleedingsuperior outcome and less bleeding

• Not an alternative to UFH in pPCI or bail-out PCI Not an alternative to UFH in pPCI or bail-out PCI (catheter thrombosis)(catheter thrombosis)

Enoxaparin – LMWtHEnoxaparin – LMWtH– ExTRACT-TIMI 25ExTRACT-TIMI 25

• Better outcome post thrombolysisBetter outcome post thrombolysis• Increased bleeding Increased bleeding • Suitable in place of UFH during PCISuitable in place of UFH during PCI

NSTEMINSTEMI

• ADP inhibitionADP inhibition– ClopidogrelClopidogrel

• Loading strategiesLoading strategies• Clopidogrel resistanceClopidogrel resistance

– PrasugrelPrasugrel• TRITON-TIMI 38TRITON-TIMI 38

– 19% RRR or 2.2%ARR19% RRR or 2.2%ARR

• Increased harmIncreased harm– Bleeding in CABGBleeding in CABG– Weight <60kgWeight <60kg– Age >75Age >75– CVACVA

Xa in ACS-NSTEMIXa in ACS-NSTEMI

• Apixaban – Xa inhibitorApixaban – Xa inhibitor– APPRAISE-1APPRAISE-1

• Evaluation of 4 doses in ACS patients receiving Evaluation of 4 doses in ACS patients receiving current standard of carecurrent standard of care

• 1700 patients1700 patients

– Inclusion required one additional risk factorInclusion required one additional risk factor• Age, DM, CVA/TIA etcAge, DM, CVA/TIA etc

– OutcomeOutcome• Trend towards reduction in MACETrend towards reduction in MACE• Trend towards increased bleeding with higher Trend towards increased bleeding with higher

dosesdoses

Adjunctive Rx to PCIAdjunctive Rx to PCI

• ADP inhibitionADP inhibition– Clopidogrel loading strategiesClopidogrel loading strategies

• ARMYDA –2: MACE 12% vs 4%ARMYDA –2: MACE 12% vs 4%– 255 patients, 30d follow up255 patients, 30d follow up– 300 vs 600mg clopidogrel 300 vs 600mg clopidogrel – >6hrs pre PCI>6hrs pre PCI– Driven by procedural MI Driven by procedural MI

• ARMYDA-RELOADARMYDA-RELOAD– 568 patients with planned PCI568 patients with planned PCI– ACS and stable cases >10 days clopidogrelACS and stable cases >10 days clopidogrel– RCT of reloading with 600mg or notRCT of reloading with 600mg or not– ACS patients: MACE reduced from 18% to 7% (p=0.035)ACS patients: MACE reduced from 18% to 7% (p=0.035)

Adjunctive Rx to PCIAdjunctive Rx to PCI

• ADP inhibitionADP inhibition– Clopidogrel maintenance strategiesClopidogrel maintenance strategies

• BASKET-LATEBASKET-LATE– 746 patients post PCI746 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

– MACEMACE» 4.9% vs. 1.3%; DES vs. BMS4.9% vs. 1.3%; DES vs. BMS

– LSTLST» 2.6% vs. 1.3%; DES vs. BMS2.6% vs. 1.3%; DES vs. BMS

Adjunctive Rx to PCIAdjunctive Rx to PCI

• ADP inhibitionADP inhibition– Prasugrel – Prasugrel – – Demonstrably better platelet inhibition Demonstrably better platelet inhibition

than clopidogrel than clopidogrel • 300mg: TRITON TIMI 38300mg: TRITON TIMI 38• 600mg: PRINCIPLE TIMI 44600mg: PRINCIPLE TIMI 44

– 201 patients201 patients– Prasugrel 60/10mg vs. Clopidogrel 600/150mgPrasugrel 60/10mg vs. Clopidogrel 600/150mg

– Better inhibition by VASP/P2YBetter inhibition by VASP/P2Y1212 bedside test bedside test

Adjunctive Rx to PCIAdjunctive Rx to PCI

• BivalirudinBivalirudin– ISAR-REACT IIIISAR-REACT III

• Bivalirudin vs. UFHBivalirudin vs. UFH• ~4500 patients; marker –ve, stable or ~4500 patients; marker –ve, stable or

unstable presentationunstable presentation• 80%+ DES80%+ DES• Pretreatment of 300-600/75-150 clopidogrelPretreatment of 300-600/75-150 clopidogrel

– MACE unchangedMACE unchanged– Bleeding reduced from 4.6% to 3.1% Bleeding reduced from 4.6% to 3.1%

(RRR~33%)(RRR~33%)

NEJM 2008;359:688NEJM 2008;359:688

ADP inhibition in PCIADP inhibition in PCI

• CangrelorCangrelor

– i.v. competitive P2Yi.v. competitive P2Y1212 inhibitor inhibitor

• TT1/21/2: 5-9 mins, after 20mins – normal platelet fn: 5-9 mins, after 20mins – normal platelet fn

– Phase IIPhase II• 199 patients undergoing PCI199 patients undergoing PCI• MACE similar, Trend to less bleedingMACE similar, Trend to less bleeding

– Phase IIIPhase III• CHAMPION PCI CHAMPION PCI

– 9000 patients: vs. plavix 600mg at start of PCI9000 patients: vs. plavix 600mg at start of PCI• CHAMPION PLATFORMCHAMPION PLATFORM

– 6300 pts: vs. 600mg plavix at the end of the PCI6300 pts: vs. 600mg plavix at the end of the PCI

Platelet inhibition in Platelet inhibition in stable CHDstable CHD

• AZD 6149 – ADP inhibitorAZD 6149 – ADP inhibitor– DISPERSE 2 (Phase II)DISPERSE 2 (Phase II)

– platelet sub study by Rob Storeyplatelet sub study by Rob Storey• Better platelet inhibition than clopidogrelBetter platelet inhibition than clopidogrel• Competitive non-thienopyridine inhibitorCompetitive non-thienopyridine inhibitor• Increased Increased

SOB/hypotension/diarrhea/ventricular pausesSOB/hypotension/diarrhea/ventricular pauses• Similar tolerability to clopidogrelSimilar tolerability to clopidogrel

– Currently being investigated in the PLATO StudyCurrently being investigated in the PLATO Study• 18 000 stable patients; compared to 18 000 stable patients; compared to

clopidogrel 300/75mgclopidogrel 300/75mg

Platelet inhibition in Platelet inhibition in stable CHDstable CHD

• Thrombin receptor antagonismThrombin receptor antagonism– SCH 530348SCH 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 MACETrends to reduced MACE– No difference in bleedingNo difference in bleeding

• Phase III: TRA-2-P TIMI 50Phase III: TRA-2-P TIMI 50– 20k pts; secondary prevention study20k pts; secondary prevention study