Tct Asia Pacific April 24 2008

PharmacoPharmaco--invasiveinvasive strategiesstrategies forfor acuteacute myocardialmyocardial infarction:infarction: thethe CARESSCARESS-- inin--AMIAMI TrialTrial

Carlo Di Mario, MD, PhD, FRCP, FACC, FSCAI, FESC Consultant Cardiologist Professor of Clinical Cardiology President Elect EAPCI-ESC Imperial College STEMISTEMI

AspirinAspirin Clopidogrel/Clopidogrel/ Prasugrel/Prasugrel/ AZD6140/AZD6140/ CangrelorCangrelor UFH/UFH/ LMWH/LMWH/ Fondaparinux/Fondaparinux/ BivalirudinBivalirudin Beta-Beta- blockers blockers

≥90min to PCI <90min<90min toto PCIPCI ≥90min to PCI

ContraindicationContraindication AcceleratedAccelerated AlteplaseAlteplase toto lytics/lytics/ latelate ReteplaseReteplase presenterspresenters TenecteplaseTenecteplase failed ComboCombo lytics+½IIb/IIIalytics+½IIb/IIIa PrimaryPrimary PCIPCI FacilitatedFacilitated PCIPCI RescueRescue PCIPCI IIb/IIIaIIb/IIIa +/-+/- ½dose ½dose lyticslytics PCIPCI postpost preadministeredpreadministered thrombolysisthrombolysis

ASSENT 4 PCI FINESSE IIb/IIIa IIb/IIIa DelayedDelayed PCIPCI ImmediateImmediate PCIPCI

BRAVE-3 1,345 Pts Consecutively Treated in the Regional PCI System for STEMI Minneapolis-Minnesota Network between 2003 and 2006 Patients (%)

<60 miles 60-120 miles 73% Pts Transported n=297 n=627 n=421 by Helicopter

Henry, T. D. et al. Circulation 2007;116:721-728 1,650 consecutive STEMI pts in the EUROTRANSFER Registry ; 7 european countries from 2005 to 2007 Diagnosis-to-Balloon Time (%)

Dudek, Siudak, Janzon et al. ESC 2007 ImmediateImmediate (within(within 24h)24h) oror DeferredDeferred PCIPCI afterafter LysisLysis

Lytics + angio within 24 hrs Lytics + angio when clinically mandated

GRACIA-1 499 Pts SIAM III 163 Pts CAPITAL AMI 170 Pts P<0.001 P<0.04 50.6

P<0.00008 21 25.6 24.4

9 11.6

12 m †, MI, TLR 6 m †, MI, RI,TLR 6 m †, MI, UAP, Stroke Fernandez-Aviles et al, Scheller et al, LeMay et al, Lancet 2004;364:1045-53 JACC 2003;42:634-41 JACC 2005;46:417-24 ST-elevation MI, High risk

Reteplase 5U+5U+Abciximab, UFH SPOKE Hospital Randomization 1:1 Immediate PCI Standard Care/ Rescue PCI Transfer to PCI Centre N=301 N=299

Assess chest pain, ST↑ resolution at 90 min

Failed Reperfusion* Successful Reperfusion 35.7% 64.3%

HUB PCI Centre Angio for symptoms/ischemia Angio+/- PCI Angio+Rescue PCI 30.5%

1ary EP: 30day Death/ ReMI/ Recurrent Ischemia

Di Mario et al. Lancet 2008;371:559-68 Pozzuoli, 22 November 2006, 14:33 • 60 Yr old man, type II DM treated with oral antidiabetic drugs; Heavy smoker (40 cigarettes); Hypertension; Dyslipidaemia; ECG evidence of previous (silent) inferior MI Pozzuoli 22 November 2006: 16:34, Bolus given • Aspirin 150 mg + Clopidogrel 300 • Reteplase 5 U • Heparin 40 mg/Kg • Abciximab 25 µg/Kg On the Road: 55 min transfer time, arrival 17:58

‘ Reteplase 5 U 2nd bolus after 30 m’ Heparin 7 U/Kg/hour Abciximab 0.125 mcg/Kg/min Chest pain disappears 18:11 First Angio Naples Before PTCA: TIMI 3 AFTER Taxus stent 3.5 x 16 mm ECG 90 minutes after PCI • AngioSeal 6 Fr: no haematoma • Uneventful hospital stay • Discharged after 4 days CARESSCARESS--inin--AMIAMI SymptomSymptom onsetOnset to thrombolysis to Reteplase ReteplaseThrombolysis to to Angiography angiography/PCI

Immediate PCI Standard/Rescue PCI Immediate PCI Standard/Rescue PCI 1440 298N=298 Pts 300 N=300 Pts 1440 1440 298N=289 Pts 107 N=107 Pts 1440 720 720 720 720

660 660 660 660

600 600 600 600

540 540 540 540

480 480 480 480

420 420 420 420

360 360 360 360 Time, minutes Time, minutes 300 300 300 300

240 240 240 240 171 m’ 212 m’ 180 169 180 180 136 180 120 120 120 120 Time (min, medians + IQR) Time (min, medians + IQR)

60 60 60 60

0 0 0 0

60483624120 1224364860 80 64 48 32 16 0 16 32 48 64 80 ImmediatePCI Standard/Rescue PCI

Di Mario et al. Lancet 2008;371:559-68 TIMITIMI flowflow prepre inin CARESSCARESS andand FINESSFINESS

Reteplase to Angio Reteplase to Angio 132 mins 72 min

Di Mario et al. Lancet 2008;371:559-68 Ellis et al. NEJM 2008 in press CARESSCARESS--inin--AMIAMI

Primary Endpoint Death, re-MI, refractory ischaemia 12 11.1% Standard Care/ Rescue PCI 10 OR 0.34 8 Logrank p=0.004 (95%CI 0.17-0.68) 6 4.1% Imme diate PCI P=0.001 4 Cumulative incidence Cumulative of 1ary endpoint (%) endpoint 1ary of 2

0 0 5 10 15 20 25 30 Time from randomization (days)

Standard/Rescue 300 283 275 273 269 268 268 Immediate PCI 298 292 287 285 285 284 284

Di Mario et al. Lancet 2008;371:559-68 CARESSCARESS--inin--AMIAMI p=0.005

11.1%

P=0.403

4.4% 4.1% (n13) p=0.003 3.1% (n=9) P=0.104

Di Mario et al. Lancet 2008;371:559-68 CARESSCARESS--inin--AMIAMI

*

* p=0.002

Di Mario et al. Lancet 2008;371:559-68 Criticisms & Comments F. Verheugt, commentator ESC 2007 ™ Neither clopidogrelclopidogrel nornor LMWHLMWH were used ™ Early PCI after lytics is clearly beneficial but when: 17 hours as in GRACIA-1 or immediate? N.Danchin, Editorial Comment, Lancet 2008; ™ The trial suggests a benefit but it was stopped before scheduled rectuitment was completed and numbers are too low to confirm it

Owen, Letter, Lancet 2008, in press ™ Combo therapy with 2b-3a inhibitors is not a recommended lytic regimen in Guidelines. An approved lytic type and dose should be tested ClopidogrelClopidogrel trialstrials inin comparisoncomparison

COMMIT/ CLARITY CCS-2 - 1ary EP: TIMI flow on angio -1ary EP: Mortality, Death/MI/CVA - n=3500 - n=46000! - MI < 12 hrs - MI < 24 hrs - ≤ 75 years - ≤ 100 years! - 100% Fibrinolytic - ~50% Fibrinolytic (also SK) - Loading dose 300mg - No loading dose - Angio 2-8 days - Non-invasive Strategy - Europe / North America - China CLARITYCLARITY COMMIT/CCSCOMMIT/CCS--22 n=3500 n=46000

Death ReMI Stroke OR 0.64, 95% CI 0.53-0.76, p<0.0001 before discharge

%

Bleeds ns

Sabatine et al. N Engl J Med 2005;352:1179-89. Lancet. 2005 Nov 5;366(9497):1607-21 LMWHLMWH inin AMI:AMI: EXTRACTEXTRACT TIMITIMI--2525 STEMI Fibrinolysis with SK/TNK/Atleplase/Reteplase Clopidogrel at operators discretion

ENOXAPARIN UFH Until discharge or <8days ≥48h n=10256 n=10223 Median treatment 7 days Median treatment 2 days

1ary EP=Death/ reMI 30days

Antman et al. N Engl J Med 2006;354:1477-88. ASSENTASSENT 4:4: FacilitatedFacilitated PCIPCI

STEMI≤6h PCI delay1-3h ASA, UFH bolus (no infusion)

PCI TNK+PCI N=833 N=829

1ary EP: 90day Death/ CHF/ Shock Planned 4000 pts: Stopped due to ↑in-hospital mortality

Lancet 2006; 367: 569–78 ProthromboticProthrombotic effecteffect ofof thrombolysisthrombolysis

ASSENT-4 PCI (TNK)

1h 44min. GRACIA-1 (rtPA) 16h 42min.

2h 25min (≥90min)

4 hours

2h 12min (≥40min) The Krakow Network (1/2 tPA + abciximab= combo lytic) ↑ F1,2 fragments== ↑ prothrombin activation 2h 31min. Merlini et al. Am J Cardiol 2004;93:195–198 GUSTOGUSTO VV

STEMI<12h No age limit

tPA (10+10U) in the ED Abciximab 12h+tPA (5+5U) Heparin 5000+1000U/h UFH 60 U/kg → 7 U/kg TIMI14 At discretion of investigator:Angiography+/-PCI

1ary EP: All-cause mortaltiy Safety EP: Severe Bleeding (hemodynamic compromise), moderate (transfusion), mild (other)

All-cause mortality at 30 days (5·9 vs5·6%) test for superiority, p=0·43; for non-inferiority, relative risk 0·95 [95% CI 0·84–1·08]).

GUSTO V. Lancet 2001; 357: 1905–14 GUSTOGUSTO V:V: BleedingBleeding

4 P<0.0001 rtPA 3.5 rtPA+Abcx 3

2.5 P=0.069

% 2 P<0.0001 1.5 1 P=0.79 P=0.27 0.5 0

H r ere erate IC Sev 5years 75yea < Mod H>7 IC ICH ‘High‘High Risk’Risk’ ST ST ElevationElevation MIMI withwithinin 1212 hourshours ofof symptomsymptom onsetonset

TNKTNK ++ ASAASA ++ HeparinHeparin // EnoxaparinEnoxaparin ++ ClopidogrelClopidogrel Community Hospital Randomization stratified by age (≤75 vs. > 75) and by enrolling site Emergency “Pharmacoinvasive“Pharmacoinvasive “Standard“Standard Treatment”Treatment” Strategy”Strategy” N=508N=508 Department UrgentUrgentTransferTransfer toto PCIPCI CentreCentre N=522N=522 Assess chest pain, ST↑ resolution at 60-90 minutes after randomization

FailedFailed Reperfusion*Reperfusion* Successful Reperfusion

CathCath // PCIPCI withinwithin 66 hrshrs regardlessregardless ofof reperfusionreperfusion CathCath andand RescueRescue PCIPCI ±± Elective Cath PCI Centre statusstatus GPGP IIb/IIIaIIb/IIIa InhibitorInhibitor ± PCI Cath Lab ¾24 hrs later PCI within 12h from RepatriationRepatriation ofof stablestable papatientstients withinwithin 2424 hrshrs ofof PCIPCI thrombolysis=47%

* ST segment resolution < 50% & persistent chest pain, or hemodynamic instability Cantor ACC 2008 CARESSCARESS--inin--AMIAMI vsvs TRANSFERTRANSFER--MIMI In TRANSFER-AMI endpoint included CHF + shock at 30 days

18 TRANSFER MI STANDARD 16

14

12 CARESS STANDARD/RESCUE

10 TRANSFER MI PHARMACOINVASIVE 8 Cumulative incidence of 1ary endpoint (%) endpoint 1ary of 6

4 CARESS IMMEDIATE PCI 2

0 0 5 10 15 20 25 30 Time from randomization (days) Cantor, ACC 2008. www.cardiosource.com Di Mario et al. Lancet 2008;371:559-68 CARESSCARESS--inin--AMIAMI && TRANSFERTRANSFER--AMIAMI

Cantor, ACC 2008. www.cardiosource.com Di Mario et al. Lancet 2008;371:559-68 CARESSCARESS--inin--AMIAMI && TRANSFERTRANSFER--AMIAMI BleedingBleeding

P=0.066

Cantor, ACC 2008. www.cardiosource.com Di Mario et al. Lancet 2008;371:559-68 PharmacologicPharmacologic strategiesstrategies inin AMIAMI Primary PCI possible Primary PCI NOT possible within 90 minutes within 90 minutes ANTIPLATELET - Aspirin - Clopidogrel - Prasugrel -Cangrelor -AZD6140 - GP IIb/IIIa Inhibitors Rescue

ANTITHROMBOTIC -UFH -LMWH - Bivalirudin

THROMBOLYTICS COMBINATION THERAPY (thrombolytics+GP IIb IIIa)

Recommended Under evaluation Discouraged IndividualIndividual 3030 dayday outcomesoutcomes Rescue/MedicalRescue/Medical TreatmentTreatment OnlyOnly DividedDivided 9.4% 10.6% (n=18) (n=11) P<0.002

6.7% (n=20) P=0.403

4.4% (n=13) 3.1% (n=9) 1.9% 1.0% 1.0% (n=2) (n=2) (n=3)

DEATH Re-MI/Refractory Ischaemia

Facilitated PCI (n=294) Med. Treatment/ Rescue (n=298) Rescue PCI (n=106) Med. Treatment Only (n=192)