landmark practice advances in st-elevation myocardial infarction (stemi) and acute coronary syndrome...

Landmark Practice Advances In ST-Elevation Myocardial Infarction (STEMI)

and Acute Coronary Syndrome (ACS)

Consistent and Unified Management Strategies for 2008 and Beyond—What Do New Trials Tell Us About Care

for High Risk ACS?

Landmark Practice Advances In ST-Elevation Myocardial Infarction (STEMI)

and Acute Coronary Syndrome (ACS)

Consistent and Unified Management Strategies for 2008 and Beyond—What Do New Trials Tell Us About Care

for High Risk ACS?

A Year 2008 UpdateA Year 2008 Update

Stefano Savonitto, MD, FESCStefano Savonitto, MD, FESCPrima Divisione di CardiologiaPrima Divisione di Cardiologia

Dipartimento Cardiologico “Angelo De Gasperis”Dipartimento Cardiologico “Angelo De Gasperis”Ospedale Niguarda Ca’ GrandaOspedale Niguarda Ca’ Granda

Milano, ItalyMilano, Italy

Carlo Di Mario, MD, PhD, FESC, Carlo Di Mario, MD, PhD, FESC, FACC, FRCPFACC, FRCPProfessor of Clinical CardiologyProfessor of Clinical CardiologyImperial College of Sciences, Medicine & Imperial College of Sciences, Medicine & Technology Technology Consultant in Interventional CardiologyConsultant in Interventional CardiologyRoyal Brompton HospitalRoyal Brompton HospitalLondon, UKLondon, UK

Program Co-ChairmenProgram Co-Chairmen

CME-accredited symposium jointly sponsored by the University of CME-accredited symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLCMassachusetts Medical School and CMEducation Resources, LLC

Commercial Support:Commercial Support: Sponsored by an independent educational grant Sponsored by an independent educational grant from The Medicines Companyfrom The Medicines Company

Mission statement:Mission statement: Improve patient care through evidence-based Improve patient care through evidence-based education, expert analysis, and case study-based managementeducation, expert analysis, and case study-based management

Processes:Processes: Strives for fair balance, clinical relevance, on-label Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and indications for agents discussed, and emerging evidence and information from recent studiesinformation from recent studies

COI:COI: Full faculty disclosures provided in syllabus and at the beginning Full faculty disclosures provided in syllabus and at the beginning of the programof the program

CME-accredited symposium jointly sponsored by the University of CME-accredited symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLCMassachusetts Medical School and CMEducation Resources, LLC

Commercial Support:Commercial Support: Sponsored by an independent educational grant Sponsored by an independent educational grant from The Medicines Companyfrom The Medicines Company

Mission statement:Mission statement: Improve patient care through evidence-based Improve patient care through evidence-based education, expert analysis, and case study-based managementeducation, expert analysis, and case study-based management

Processes:Processes: Strives for fair balance, clinical relevance, on-label Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and indications for agents discussed, and emerging evidence and information from recent studiesinformation from recent studies

COI:COI: Full faculty disclosures provided in syllabus and at the beginning Full faculty disclosures provided in syllabus and at the beginning of the programof the program

Welcome and Program OverviewWelcome and Program Overview Welcome and Program OverviewWelcome and Program Overview

Program Educational ObjectivesProgram Educational Objectives

As a result of this educational activity, physicians will:

► Learn how recently issued ESC and AHA/ACC guidelines for UA/Non ST-elevation myocardial infarction and STEMI are best applied to appropriately risk-stratified patients with high risk ACS and STEMI.

► Learn to understand the implications of recent clinical data, trials, and recommendations on upstream and catheterization laboratory-based management of STEMI and NSTEMI.

► Learn to apply guidelines and expert, consensus-based recommendations in order to optimize invasive vascular management of patients with high risk ACS.

As a result of this educational activity, physicians will:

► Learn how recently issued ESC and AHA/ACC guidelines for UA/Non ST-elevation myocardial infarction and STEMI are best applied to appropriately risk-stratified patients with high risk ACS and STEMI.

► Learn to understand the implications of recent clinical data, trials, and recommendations on upstream and catheterization laboratory-based management of STEMI and NSTEMI.

► Learn to apply guidelines and expert, consensus-based recommendations in order to optimize invasive vascular management of patients with high risk ACS.

Program FacultyProgram FacultyProgram FacultyProgram Faculty

Program Co-ChairmenProgram Co-Chairmen

Carlo Di Mario, MD, PhD, FESC, Carlo Di Mario, MD, PhD, FESC, FACC, FRCPFACC, FRCPProfessor of Clinical CardiologyProfessor of Clinical CardiologyImperial College of Sciences, Medicine & Imperial College of Sciences, Medicine & Technology Technology Consultant in Interventional CardiologyConsultant in Interventional CardiologyRoyal Brompton HospitalRoyal Brompton HospitalLondon, UKLondon, UK

Stefano Savonitto, MD, FESCStefano Savonitto, MD, FESCPrima Divisione di CardiologiaPrima Divisione di CardiologiaDipartimento Cardiologico “Angelo De Gasperis”Dipartimento Cardiologico “Angelo De Gasperis”Ospedale Niguarda Ca’ GrandaOspedale Niguarda Ca’ GrandaMilano, ItalyMilano, Italy

Distinguished Faculty PresentersDistinguished Faculty Presenters

Deepak L. Bhatt, MD, FACC, FSCAI, Deepak L. Bhatt, MD, FACC, FSCAI, FESC, FAHAFESC, FAHAChief of CardiologyChief of CardiologyVA Boston Healthcare SystemVA Boston Healthcare SystemDirector of the Integrated Cardiovascular Director of the Integrated Cardiovascular Intervention ProgramIntervention ProgramBrigham and Women’s Hospital and the Brigham and Women’s Hospital and the VA Boston Healthcare SystemVA Boston Healthcare SystemHarvard Medical SchoolHarvard Medical SchoolBoston, MassachusettsBoston, Massachusetts

Michael M. Hirschl, MDMichael M. Hirschl, MDAssociate ProfessorAssociate ProfessorHead of the Emergency RoomHead of the Emergency RoomMedical Department of Cardiology and Intensive Medical Department of Cardiology and Intensive Care MedicineCare MedicineLandesklinikum St. PöltenLandesklinikum St. PöltenA-3100 St. Pölten, AustriaA-3100 St. Pölten, Austria

Faculty COI DisclosuresFaculty COI DisclosuresFaculty COI DisclosuresFaculty COI Disclosures

Carlo Di Mario, MD, PhD, FESC, FACC, FRCPCarlo Di Mario, MD, PhD, FESC, FACC, FRCPResearch Grants:Research Grants: Eli Lilly, Cordis Johnson and Johnson, Biotronik, Biosensors, Medtronic Eli Lilly, Cordis Johnson and Johnson, Biotronik, Biosensors, MedtronicConsulting or Speaker’s Fees:Consulting or Speaker’s Fees: Boston Scientific, Abbott, The Medicines Company, Biosensors Boston Scientific, Abbott, The Medicines Company, Biosensors

Stefano Savonitto, MD, FESCStefano Savonitto, MD, FESCSpeaker’s Honoraria:Speaker’s Honoraria: sanofi-aventis, Eli Lilly, The Medicines Company sanofi-aventis, Eli Lilly, The Medicines CompanyConsultant Fees: Eli LillyConsultant Fees: Eli Lilly Deepak L. Bhatt, MD, FACC, FSCAI, FESC, FAHADeepak L. Bhatt, MD, FACC, FSCAI, FESC, FAHAConsultant Fees:Consultant Fees: Arena, Astra Zeneca, Bristol-Myers Squibb, Cardax, Cogentus, Daiichi Sankyo, Eli Arena, Astra Zeneca, Bristol-Myers Squibb, Cardax, Cogentus, Daiichi Sankyo, Eli Lilly, Eisai, Glaxo Smith Kline, Johnson & Johnson, Medtronic, Millennium, Otsuka, Paringenix, PDL, Lilly, Eisai, Glaxo Smith Kline, Johnson & Johnson, Medtronic, Millennium, Otsuka, Paringenix, PDL, Philips, Portola, sanofi-aventis, Schering Plough, The Medicines Company, tns Healthcare, Vertex. Philips, Portola, sanofi-aventis, Schering Plough, The Medicines Company, tns Healthcare, Vertex. Honoraria are donated to NPOs.Honoraria are donated to NPOs.PI and/or on steering committees of several potentially related trials.PI and/or on steering committees of several potentially related trials.This presentation discusses off-label and/or investigational uses of antithrombotic drugs and This presentation discusses off-label and/or investigational uses of antithrombotic drugs and interventional devices.interventional devices.

Michael M. Hirschl, MDMichael M. Hirschl, MDSpeakers Honoraria:Speakers Honoraria: Takeda-Austria, Merck Sharp&Dome, Actelion and Servier Austria. Takeda-Austria, Merck Sharp&Dome, Actelion and Servier Austria.Research grant:Research grant: Actelion-Austria Actelion-Austria

Issues and Challenges in Issues and Challenges in Acute Coronary SyndromesAcute Coronary Syndromes

A Review of Critical AdvancesA Review of Critical Advancesand Current Controversies in STEMI and and Current Controversies in STEMI and

High Risk ACSHigh Risk ACS

Landmark Practice Advances inLandmark Practice Advances inSTEMI and ACSSTEMI and ACS

Stefano Savonitto, MD, FESCStefano Savonitto, MD, FESCProgram Co-ChairmanProgram Co-Chairman

Prima Divisione di CardiologiaPrima Divisione di CardiologiaDipartimento Cardiologico “Angelo De Gasperis”Dipartimento Cardiologico “Angelo De Gasperis”

Ospedale Niguarda Ca’ GrandaOspedale Niguarda Ca’ GrandaMilano, ItalyMilano, Italy

NSTE-ACSNSTE-ACSNSTE-ACSNSTE-ACS

STEMISTEMISTEMISTEMI

TROPONINTROPONINTROPONINTROPONIN

SKSKSKSK

Landmark Practice Advances in Landmark Practice Advances in Acute Coronary SyndromesAcute Coronary Syndromes

SK+SK+ASPIRINASPIRIN

SK+SK+ASPIRINASPIRIN

r-tPAr-tPAr-tPAr-tPA TNKTNKTNKTNK

Pre-H lysisPre-H lysisMorrisonMorrison

Pre-H lysisPre-H lysisMorrisonMorrison

PRIMARY PCIPRIMARY PCIPRIMARY PCIPRIMARY PCI ABCIXIMABABCIXIMABABCIXIMABABCIXIMAB

CLOPIDOGRELCLOPIDOGRELCLOPIDOGRELCLOPIDOGREL

REACTREACTREACTREACT

BIVALIRUDINBIVALIRUDINBIVALIRUDINBIVALIRUDIN

VIENNA REGISTRYVIENNA REGISTRYVIENNA REGISTRYVIENNA REGISTRY

CARESSCARESSCARESSCARESS

ASPIRIN +ASPIRIN +HEPARINHEPARIN1983-’881983-’88

ASPIRIN +ASPIRIN +HEPARINHEPARIN1983-’881983-’88

CLOPIDOGRELCLOPIDOGRELCLOPIDOGRELCLOPIDOGREL

UPSTREAMUPSTREAMGP IIb/IIIaGP IIb/IIIa

UPSTREAMUPSTREAMGP IIb/IIIaGP IIb/IIIa

EARLY INVASIVEEARLY INVASIVEEARLY INVASIVEEARLY INVASIVE

ABCIXIMABABCIXIMABIN CATH LABIN CATH LABABCIXIMABABCIXIMAB

IN CATH LABIN CATH LAB

FONDAPARINUXFONDAPARINUXFONDAPARINUXFONDAPARINUX

BIVALIRUDINBIVALIRUDINBIVALIRUDINBIVALIRUDINENOXAPARINENOXAPARINENOXAPARINENOXAPARIN

1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008

ACC/AHAACC/AHAACC/AHAACC/AHA

ESCESCESCESC

19901990AMIAMI

R. GunnarR. Gunnar

19901990AMIAMI

R. GunnarR. Gunnar

19941994Unstable AnginaÛnstable Angina^

E. BraunwaldE. Braunwald

19941994Unstable AnginaÛnstable Angina^

E. BraunwaldE. Braunwald

20002000UA/NSTEMIUA/NSTEMI

RevisedRevisedE. BraunwaldE. Braunwald


RevisedRevisedE. BraunwaldE. Braunwald


UpdatedUpdatedE. BraunwaldE. Braunwald


UpdatedUpdatedE. BraunwaldE. Braunwald


RevisedRevisedJ. AndersonJ. Anderson


RevisedRevisedJ. AndersonJ. Anderson

20002000ACS w/o STEACS w/o STE

M. BertrandM. Bertrand


M. BertrandM. Bertrand


UpdatedUpdatedM. BertrandM. Bertrand


UpdatedUpdatedM. BertrandM. Bertrand

20072007NSTEACSNSTEACSJP. BassandJP. Bassand

20072007NSTEACSNSTEACSJP. BassandJP. Bassand

Development of ESC and ACC/AHA Development of ESC and ACC/AHA ACS Guidelines (modified from Ohman EM)ACS Guidelines (modified from Ohman EM)

ÂHCPR: Agency for Health Care Policy and Research.ÂHCPR: Agency for Health Care Policy and Research.

19991999AMI upd.AMI upd.T. RyanT. Ryan

19991999AMI upd.AMI upd.T. RyanT. Ryan

20042004STEMI RevisedSTEMI Revised

E. AntmanE. Antman

20042004STEMI RevisedSTEMI Revised

E. AntmanE. Antman

20072007STEMI STEMI

Focused upd.Focused upd.E. AntmanE. Antman

20072007STEMI STEMI

Focused upd.Focused upd.E. AntmanE. Antman

19961996AMIAMI

T. RyanT. Ryan

19961996AMIAMI

T. RyanT. Ryan

20032003STEMISTEMI

F. Van de WerfF. Van de Werf

20032003STEMISTEMI

F. Van de WerfF. Van de Werf

20082008STEMISTEMI

F. Van de F. Van de WerfWerf

20082008STEMISTEMI

F. Van de F. Van de WerfWerf

20052005PCIPCI

SC SmithSC Smith

20052005PCIPCI

SC SmithSC Smith

20052005PCI updPCI updSC SmithSC Smith

20052005PCI updPCI updSC SmithSC Smith

20052005PCIPCI

S. SilberS. Silber

20052005PCIPCI

S. SilberS. Silber

1990 1992 1994 1996 1998 2000 2002 2004 2006 2008

Reperfusion by TimeReperfusion by Time

Proportion %Proportion %

Uppsala Clinical Research Centre 2005Uppsala Clinical Research Centre 2005

1995 - 20041995 - 2004

0

10

20

30

40

50

60

70

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

Actilyse Rapilysin Acute CABG

Facilitated PCI Metalyse Streptokinase

Acute Angio Only Primary PCI

30-day AMI Mortality Over Time30-day AMI Mortality Over Time1995 - 20041995 - 2004

Mortality %

>= 75 yr

65 – 74 yr

< 65 yr

Women<65 Women 65-75

Women >75 Men<65 Men 65-75 Men >75

Uppsala Clinical Research Centre 2005Uppsala Clinical Research Centre 2005

Prehospital ECG and Time to ReperfusionPrehospital ECG and Time to ReperfusionBased on NRMI 4, 2000 to 2002Based on NRMI 4, 2000 to 2002

Lytic cohortLytic cohort

PCI cohortPCI cohort

% of pts with % of pts with door to needledoor to needle

<30’<30’N= 35,370N= 35,3704.5% with4.5% with

Pre-H ECGPre-H ECG

N= 21,277N= 21,2778.0% with8.0% with

Pre-H ECGPre-H ECG

Curtis JP , Curtis JP , JACCJACC 2006;47:1544 2006;47:1544

% of pts with % of pts with door to balloondoor to balloon

<90’<90’

40.860.6

28.3

22.0

30.917.4

0%

20%

40%

60%

80%

100%

Without phECG With phECG<30 30 to 45 > 45

33.155.2

30.3

24.6

36.620.2

0%

20%

40%

60%

80%

100%

Without phECG With phECG

<90 90 to 120 > 120

Impact of Direct Access to Cath Lab on Impact of Direct Access to Cath Lab on Hospital Mortality for STEMIHospital Mortality for STEMI

7.0

9.4

12.2

0

2

4

6

8

10

12

14

2002 (294) 2003 (449) 6m 2004 (272)

Ortolani P. Ortolani P. Eur Heart JEur Heart J 2006;27:1550 2006;27:1550

ThrombolysisThrombolysis

Primary PCIPrimary PCI Primary PCIPrimary PCIwith direct with direct

access via 118access via 118

Policlinico S.Orsola, Bologna - ItalyPoliclinico S.Orsola, Bologna - Italy

Mortality reduction over time = 43%Mortality reduction over time = 43%

%%

Pre-hospital Pre-hospital thrombolysisthrombolysisPre-hospital Pre-hospital thrombolysisthrombolysis

Rescue PCIRescue PCIRescue PCIRescue PCI

Facilitated Facilitated PPCI ?PPCI ?

Facilitated Facilitated PPCI ?PPCI ?

Primary Primary angioplastyangioplasty

Primary Primary angioplastyangioplasty

In-hospital In-hospital thrombolysisthrombolysisIn-hospital In-hospital

thrombolysisthrombolysis

GOALGOAL75% early75% early

reperfusionreperfusion

GOALGOAL75% early75% early

reperfusionreperfusion

Implementation of Reperfusion Therapy in STEMIImplementation of Reperfusion Therapy in STEMIESC Policy StatementESC Policy Statement

Bassand JP et al, Bassand JP et al, Eur Heart JEur Heart J 2005;26:2733 2005;26:2733

All forms of reperfusion, depending on local facilities,All forms of reperfusion, depending on local facilities,need to be available to patients with STEMIneed to be available to patients with STEMI

R-PCI: R-PCI: 93.8%93.8% ( CI 89.8%-97.7%) ( CI 89.8%-97.7%)

R-Lysis: R-Lysis: 87.3%87.3% (CI 81.9%-92.8%) (CI 81.9%-92.8%)

Conservative: Conservative: 87.2%87.2% (CI 81.7%-92.7%) (CI 81.7%-92.7%)

REACT: Survival at 6 months REACT: Survival at 6 months

Gershlick AH, Gershlick AH, N Engl J MedN Engl J Med 2005;353:2758 2005;353:2758

0 20 40 60 80 100 120 140 160 180 2000 20 40 60 80 100 120 140 160 180 200

Number of DaysNumber of Days

Sur

viva

l Dis

trib

utio

n F

unct

ion

Sur

viva

l Dis

trib

utio

n F

unct

ion

1.001.00

.90.90

.80.80

.70.70

.60.60

Time Trends of Primary and Rescue PCI for Time Trends of Primary and Rescue PCI for STEMI in Italy: The GISE RegistrySTEMI in Italy: The GISE Registry

Giornale Italiano di Cardiologia Invasiva 2008;(2) suppl 1

0

5000

10000

15000

20000

25000

1999 2000 2001 2002 2003 2004 2007

Primary Rescue

Primary EndpointPrimary Endpoint

Primary Composite Endpoint at Day 90

10.7% 10.5% 9.8%

0.0%

5.0%

10.0%

15.0%

20.0%

Pe

rce

nta

ge

Primary PCI with in-lab Abciximab (n=806)

Abciximab Facililated PCI (n=818)

Reteplase/Abciximab Facilitated PCI (n=828)

p=0.55p=0.55

Ellis S, Ellis S, NEJMNEJM 2008;358:2205 2008;358:2205

Primary Outcome at 30 DaysPrimary Outcome at 30 Days

4.1%4.1%

11.1%11.1%

Death, re-MI, refractory ischaemiaDeath, re-MI, refractory ischaemia

OR 0.34 (95%CI 0.17-0.68) P=0OR 0.34 (95%CI 0.17-0.68) P=0..001001

Di Mario C et al. Di Mario C et al. LancetLancet 2008; 371: 559 2008; 371: 559

600 STEMI pts with prior MI + >15 mm STE or new LBB, + Killip >2, ++ EF EF <<0.350.35

0 5 10 15 20 25 300 5 10 15 20 25 30

0.150.15

0.100.10

0.050.05

00Pro

port

ion

of P

atie

nts

Hav

ing

an E

vent

Pro

port

ion

of P

atie

nts

Hav

ing

an E

vent

Time Since Randomisation (Days)Time Since Randomisation (Days)

Medical Treatment/Rescue Group Facilitated PCI GroupMedical Treatment/Rescue Group Facilitated PCI Group

Kaplan-Meier Curves for SurvivalKaplan-Meier Curves for Survival

Krakow STEMI RegistryKrakow STEMI Registry1 Year Follow-Up1 Year Follow-Up

PRIMARYPRIMARY

Dudek D,Dudek D, EuroPCR 2005 EuroPCR 2005

Zone IZone I

Zone IIZone IIFACILITATEDFACILITATED

0 8 16 24 32 40 480 8 16 24 32 40 48

1,001,00

0,950,95

0,900,90

0,850,85

0,800,80

P=NS (log rank)P=NS (log rank)

Abciximab for Primary PCI in STEMI—Abciximab for Primary PCI in STEMI—Significant Mortality ReductionSignificant Mortality Reduction

-29%-29%

De Luca G, et al. De Luca G, et al. JAMAJAMA 2005;293:1759 2005;293:1759

Abciximab ControlAbciximab ControlControl Control (n-14,145)(n-14,145) Abciximab Abciximab (n=12,297)(n=12,297) Better Better P Value Better Better P Value

RAPPORTRAPPORT 11/242(4.5)11/242(4.5) 10/241(4.1)10/241(4.1) .83.83

ISAR-2ISAR-2 17/200(8.5)17/200(8.5) 12/201(6.0)12/201(6.0) .33.33

ADMIRALADMIRAL 11/151(7.3)11/151(7.3) 5/149(3.4)5/149(3.4) .13.13

CADILLACCADILLAC 45/103045/1030 44/1052(4.2)44/1052(4.2) .83.83

Petronio et alPetronio et al 6/45(13.3)6/45(13.3) 2/44(4.5)2/44(4.5) .15.15

Zorman et alZorman et al 7/51(13.7)7/51(13.7) 5/112(4.5)5/112(4.5) .04.04

ACEACE 21/197(10.5)21/197(10.5) 10/197(5.0)10/197(5.0) .04.04

Primary PCIPrimary PCI 118/1916(6.2)118/1916(6.2) 88/1996(4.4)88/1996(4.4) .01.01

No. of Deaths/Total (%)No. of Deaths/Total (%)

0.10.1 1.0 10.0 1.0 10.0

HORIZONS AMI—HORIZONS AMI—30 Day Mortality30 Day Mortality

Number at riskNumber at risk

BivalirudinBivalirudin 1800 1800 17581758 17511751 17461746 17421742 17291729 16661666

Heparin + GPIIb/IIIaHeparin + GPIIb/IIIa 1802 1802 17641764 17481748 17361736 17281728 17071707 16301630

Dea

th (

%)

Dea

th (

%)

Time in DaysTime in Days

3.1%3.1%

2.1%2.1%

HR [95%CI] =HR [95%CI] =0.66 [0.44, 1.00]0.66 [0.44, 1.00]

P=0.048P=0.048

Heparin + GPIIb/IIIa inhibitor (n=1802)Heparin + GPIIb/IIIa inhibitor (n=1802)

Bivalirudin monotherapy (n=1800)Bivalirudin monotherapy (n=1800)

Stone GW, et al. Stone GW, et al. N Engl J MedN Engl J Med. 2008 May 22;358(21):2218-30. 2008 May 22;358(21):2218-30

Adjudicated Cases of Myocardial Infarction Adjudicated Cases of Myocardial Infarction Ospedale Niguarda: Year 2003Ospedale Niguarda: Year 2003

1212

136136

216216

264264

MI ST MI ST

MI no ST MI no ST

CardiologyCardiology MedicineMedicine

228 (36%)228 (36%)

400 (64%)400 (64%)

148148480480 628628

Lagerqvist B, JACC 2002;40:1902-14Lagerqvist B, JACC 2002;40:1902-14

High risk (FRISC score 4-7) 30%High risk (FRISC score 4-7) 30%InvasiveInvasive Non-Inv. RR (95% CI) Non-Inv. RR (95% CI)32.7%32.7% 41.6% 0.79 (0.64-0.97) 41.6% 0.79 (0.64-0.97)

Medium risk (FRISC score 2-3) 53%Medium risk (FRISC score 2-3) 53%InvasiveInvasive Non-Inv. RR (95% CI) Non-Inv. RR (95% CI)14.6%14.6% 20.4% 0.72 (0.55-1.13) 20.4% 0.72 (0.55-1.13)

Death or MI During 5 Years and RiskDeath or MI During 5 Years and Risk

Low risk (FRISC score 0-1) 17%Low risk (FRISC score 0-1) 17%InvasiveInvasive Non-Inv. RR (95% CI) Non-Inv. RR (95% CI)10.3%10.3% 8.2% 1.26 (0.66-2.40) 8.2% 1.26 (0.66-2.40)

FRISC score (sum of):FRISC score (sum of):Age > 65 yearsAge > 65 yearsMale genderMale genderDiabetes mellitusDiabetes mellitusPrevious MIPrevious MIST-depressionST-depressionElevated troponinElevated troponinElevated II-6/CRPElevated II-6/CRP

0 1 2 3 4 50 1 2 3 4 5

Time since randomisation (years)Time since randomisation (years)

4040

3030

2020

1010

00

Dea

th o

r m

yoca

rdia

l inf

arct

ion

(%)

Dea

th o

r m

yoca

rdia

l inf

arct

ion

(%)

Impact of Abciximab on Top of ASA and Impact of Abciximab on Top of ASA and Clopidogrel Depends on Patients’ Baseline RiskClopidogrel Depends on Patients’ Baseline Risk

Death or MI at 30 daysDeath or MI at 30 days

Kastrati A, NEJM 2004, JAMA 2006Kastrati A, NEJM 2004, JAMA 2006

ISAR REACT 1ISAR REACT 1Stable patientsStable patients

ISAR REACT 2ISAR REACT 2NSTEACS TnT -NSTEACS TnT -

ISAR REACT 2ISAR REACT 2NSTEACS TnT +NSTEACS TnT +

P=0.98P=0.98P=0.91P=0.91

P=0.02P=0.02

4.0 4.6

18.3

4.0 4.6

13.1

0.02.04.06.08.0

10.012.014.016.018.020.0

Placebo Abciximab

Common Key Points of the Year Common Key Points of the Year 2007 ESC and ACC/AHA Editions2007 ESC and ACC/AHA Editions

Both guidelines indicate a grading for urgency at angiographyBoth guidelines indicate a grading for urgency at angiography

► Patients with refractory ischemia, haemodynamic or arrhythmic Patients with refractory ischemia, haemodynamic or arrhythmic instability must undergo urgent angiograhy with the intent of instability must undergo urgent angiograhy with the intent of revascularization (IC ESC, IB ACC/AHA) revascularization (IC ESC, IB ACC/AHA)

► Patients with intermediate and high risk characteristics, but Patients with intermediate and high risk characteristics, but without urgent characteristics, should undergo angiography, without urgent characteristics, should undergo angiography, within 72 hours according to ESC, without indication on timing within 72 hours according to ESC, without indication on timing according to ACC/AHA. (IA both)according to ACC/AHA. (IA both)

► Both guidelines recommend that, in conjunction with either Both guidelines recommend that, in conjunction with either management strategy, great care should be taken in management strategy, great care should be taken in considering the risk vs benefit ratio of antithrombotic therapyconsidering the risk vs benefit ratio of antithrombotic therapy

► Patients with refractory ischemia, haemodynamic or arrhythmic Patients with refractory ischemia, haemodynamic or arrhythmic instability must undergo urgent angiograhy with the intent of instability must undergo urgent angiograhy with the intent of revascularization (IC ESC, IB ACC/AHA) revascularization (IC ESC, IB ACC/AHA)

► Patients with intermediate and high risk characteristics, but Patients with intermediate and high risk characteristics, but without urgent characteristics, should undergo angiography, without urgent characteristics, should undergo angiography, within 72 hours according to ESC, without indication on timing within 72 hours according to ESC, without indication on timing according to ACC/AHA. (IA both)according to ACC/AHA. (IA both)

► Both guidelines recommend that, in conjunction with either Both guidelines recommend that, in conjunction with either management strategy, great care should be taken in management strategy, great care should be taken in considering the risk vs benefit ratio of antithrombotic therapyconsidering the risk vs benefit ratio of antithrombotic therapy

ACUITY: Primary Endpoint MeasuresACUITY: Primary Endpoint Measures

0 1 2

Bivalirudin alone betterBivalirudin alone betterBivalirudin alone betterBivalirudin alone better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa better

Risk ratioRisk ratio±95% CI±95% CI

Risk ratioRisk ratio±95% CI±95% CI

PrimaryPrimaryendpointendpoint

BivalBivalalonealone

UFH/EnoxUFH/Enox+ IIb/IIIa+ IIb/IIIa

RR (95% CI)RR (95% CI)

Net clinical Net clinical outcomeoutcome

Ischemic Ischemic compositecomposite

Major bleedingMajor bleeding

Upp

er b

oun

dary

non

-infe

riorit

y11.7%11.7%10.1%10.1% 0.86 (0.77-0.97)0.86 (0.77-0.97) <0.001<0.001

0.0150.015

7.3%7.3%7.8%7.8% 1.08 (0.93-1.24)1.08 (0.93-1.24)0.020.020.320.32

5.7%5.7%3.0%3.0% 0.53 (0.43-0.65)0.53 (0.43-0.65) <0.001<0.001<0.001<0.001

p valuep value(non-inferior)(non-inferior)

(superior)(superior)

UFH/Enoxaparin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin Alone UFH/Enoxaparin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin Alone

Stone GW et al. NEJM 2006;355:2203-16Stone GW et al. NEJM 2006;355:2203-16

ACUITY: Early and Late MortalityACUITY: Early and Late MortalityLandmark AnalysisLandmark Analysis

Stone GW. JAMA 2007;298:2497-506Stone GW. JAMA 2007;298:2497-506

0 30 60 90 120 150 180 210 240 270 300 330 360 3900

3

4

2

1

UFH/Enoxaparin + IIb/IIIaBivalirudin + IIb/IIIa

Bivalirudin alone

30 dayEstimate

P(log rank)

1.4%0.531.6%0.391.6%

—

EstimateP

(log rank)

3.1%0.542.7%0.212.3%

30d - 1 year

—

Mo

rtal

ity

(%)

Mo

rtal

ity

(%)

Days from RandomizationDays from Randomization

Mor

talit

y (%

)M

orta

lity

(%)


0 30 60 90 120 150 180 210 240 270 300 330 360 3900

5

15

30

10

25

20

1 yearEstimate

Major Bleed only (without MI) (N=551) 12.5%28.9%Both MI and Major Bleed (N=94)

3.4%No MI or Major Bleed (N=12,557)MI only (without Major Bleed) (N=611) 8.6%

ACUITY Trial: Impact of MI and Major Bleeding (non-ACUITY Trial: Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 YearCABG) in the First 30 Days on Risk of Death Over 1 Year

Stone GW, et al. Stone GW, et al. JAMAJAMA 2007; 298:2497-2506. 2007; 298:2497-2506.

Common Key Points of the Common Key Points of the 2007 ESC and ACC/AHA Editions2007 ESC and ACC/AHA Editions

► Risk stratification in relation to bleeding and the prevention of Risk stratification in relation to bleeding and the prevention of bleedingbleeding are considered of utmost importance in both GLs, are considered of utmost importance in both GLs, and particularly, in the ESC GLs. The validation and and particularly, in the ESC GLs. The validation and introduction in the GLs of newer antithrombotic agents introduction in the GLs of newer antithrombotic agents (particularly bivalirudin and fondaparinux), characterized by (particularly bivalirudin and fondaparinux), characterized by lower bleeding risk, based upon large scale RCTs, is one of lower bleeding risk, based upon large scale RCTs, is one of the most important new features of both ESC and ACC/AHA the most important new features of both ESC and ACC/AHA GLs.GLs.

► Recommendations about a restrictive approach to Recommendations about a restrictive approach to transfusionstransfusions and instructions for continuing antithrombotic and instructions for continuing antithrombotic therapies in the case of bleeding in order to avoid “rebound therapies in the case of bleeding in order to avoid “rebound phenomena” are similar and bear important clinical phenomena” are similar and bear important clinical implications. implications.

Bleeding and TransfusionsBleeding and Transfusions

Both GLs note special care required in frail/high risk populations Both GLs note special care required in frail/high risk populations

Common Key Points of the Common Key Points of the 2007 ESC and ACC/AHA Guidelines2007 ESC and ACC/AHA Guidelines

ELDERLYELDERLY30% of the30% of theNSTEACSNSTEACSPopulationPopulation

>75 y.o.>75 y.o.

WOMENWOMEN30% of the30% of thepopulationpopulation

in ACUITY Trial;in ACUITY Trial;40% in OASIS 540% in OASIS 5

DIABETICSDIABETICS25-30% of the25-30% of the

NSTE-ACSNSTE-ACSpopulationpopulation

CKDCKD10% of the10% of theNSTE-ACSNSTE-ACS

population withpopulation witheGFR<60mleGFR<60ml

Randomized Trials of Early Invasive TreatmentRandomized Trials of Early Invasive Treatmentin Elderly Patients with NSTE-ACSin Elderly Patients with NSTE-ACS

TrialTrial Average ageAverage age % pts % pts >>75y75y Outcome Outcome

TIMI IIIBTIMI IIIB 5959 33 Benefit only >65 yBenefit only >65 y

VANQWISHVANQWISH 6161 88 No differenceNo difference

FRISC IIFRISC II 6565 ExcludedExcluded Benefit only >65 yBenefit only >65 y

RITA 3RITA 3 6363 No age classes No age classes reportedreported Not reported by ageNot reported by age

TACTICSTACTICS 6262 12.512.539% RR >6539% RR >65

56% RR >7556% RR >75

ICTUSICTUS 6161 Not reportedNot reported Trend towards > Trend towards > benefit >65ybenefit >65y

Patients with CKD with CrCl < 60 ml/min are at high risk of further Patients with CKD with CrCl < 60 ml/min are at high risk of further ischaemic events, ischaemic events, and therefore, should be submitted to invasive and therefore, should be submitted to invasive evaluation and revascularisation whenever possibleevaluation and revascularisation whenever possible (IIa-B). (IIa-B).

Chronic Kidney DiseaseChronic Kidney DiseaseESC

Recommendations for Special PopulationsRecommendations for Special Populations

Chronic kidney disease carries a far worse prognosis, Chronic kidney disease carries a far worse prognosis, but but unlikeunlike in several other high-risk subsets, the value of in several other high-risk subsets, the value of aggressive therapeutic interventions is less certain and should aggressive therapeutic interventions is less certain and should be further studied.be further studied.

Chronic Kidney DiseaseChronic Kidney DiseaseACC/AHAACC/AHA

► CrCl and/or GFR should be calculated for every patient CrCl and/or GFR should be calculated for every patient hospitalised for NSTE-ACS (I-B). Elderly people, women and low hospitalised for NSTE-ACS (I-B). Elderly people, women and low body weight patients merit special attention as near normal serum body weight patients merit special attention as near normal serum creatinine levels may be associated with lower than expected creatinine levels may be associated with lower than expected CrCl and GFR levels (I-B).CrCl and GFR levels (I-B).

► Patients with CKD should receive the same first-line treatment as Patients with CKD should receive the same first-line treatment as any other patient, in the absence of contraindications (I-B).any other patient, in the absence of contraindications (I-B).

► Anticoagulants should be carefully dosed. In patients with CrCl < Anticoagulants should be carefully dosed. In patients with CrCl < 30ml/min or GFR <30ml/min/1.73m30ml/min or GFR <30ml/min/1.73m22 bivalirudin should be used at bivalirudin should be used at reduced doses, whereas fondaparinux, enoxaparin and other reduced doses, whereas fondaparinux, enoxaparin and other LMWHs are contraindicated (I-B).LMWHs are contraindicated (I-B).

Chronic Kidney DiseaseChronic Kidney DiseaseESCESC

Recommendations for Special PopulationsRecommendations for Special Populations

Reducing Residual Risk in Primary PCI Reducing Residual Risk in Primary PCI of STEMI Patientsof STEMI Patients

Approaches to Reducing Mortality in High Risk ACS—What Approaches to Reducing Mortality in High Risk ACS—What Do the Trials Teach Us?Do the Trials Teach Us?

Deepak L. Bhatt MD, FACC, FSCAI, FESC, FAHADeepak L. Bhatt MD, FACC, FSCAI, FESC, FAHAChief of Cardiology, VA Boston Healthcare SystemChief of Cardiology, VA Boston Healthcare System

Director, Integrated Interventional Cardiovascular Program at Brigham and Director, Integrated Interventional Cardiovascular Program at Brigham and Women’s Hospital and the VA Boston Healthcare SystemWomen’s Hospital and the VA Boston Healthcare System

Senior Investigator, TIMI GroupSenior Investigator, TIMI Group

Landmark Practice Advances inLandmark Practice Advances inSTEMI and ACS—Year 2008 UpdateSTEMI and ACS—Year 2008 Update

Bhatt DL et al. Bhatt DL et al. CirculationCirculation 2005; 112:906-923. 2005; 112:906-923.

ARTERIAL ARTERIAL INFLAMMATIONINFLAMMATION

Atheroma BurdenAtheroma Burden

Plaque VulnerabilityPlaque Vulnerability

StatinsStatins

ARTERIAL ARTERIAL INFLAMMATIONINFLAMMATION

Atheroma BurdenAtheroma Burden

Plaque VulnerabilityPlaque Vulnerability

StatinsStatins

ASPIRINASPIRINRESISTANCERESISTANCE

↓ ↓ AntihromboticsAntihrombotics ClopidogrelClopidogrel GP IIb/IIIaGP IIb/IIIa EnoxaparinEnoxaparin BivalirudinBivalirudin

ASPIRINASPIRINRESISTANCERESISTANCE

↓ ↓ AntihromboticsAntihrombotics ClopidogrelClopidogrel GP IIb/IIIaGP IIb/IIIa EnoxaparinEnoxaparin BivalirudinBivalirudin

INTERVENTIONAL INTERVENTIONAL DEVICEDEVICE

↑↑ AtherectomyAtherectomy

↓ ↓ EPD EPD

↓ ↓ Catheter aspirationCatheter aspiration

INTERVENTIONAL INTERVENTIONAL DEVICEDEVICE

↑↑ AtherectomyAtherectomy

↓ ↓ EPD EPD

↓ ↓ Catheter aspirationCatheter aspiration

Periprocedural MyonecrosisPeriprocedural MyonecrosisPeriprocedural MyonecrosisPeriprocedural Myonecrosis

Cardiovascular Morbidity and MortalityCardiovascular Morbidity and MortalityCardiovascular Morbidity and MortalityCardiovascular Morbidity and Mortality

Mechanisms Behind Periprocedural MIMechanisms Behind Periprocedural MI

Major BleedingMajor Bleeding

TransfusionTransfusionHypotensionHypotension Cessation of ASA/ClopCessation of ASA/Clop

MortalityMortality

IschemiaIschemia Stent ThrombosisStent Thrombosis InflammationInflammation

Bhatt DL et al. In Braunwald: Harrison’s Online 2005.Bhatt DL et al. In Braunwald: Harrison’s Online 2005.

Potential Relationship Between Potential Relationship Between Bleeding and MortalityBleeding and Mortality

Impact of Major Bleed and MI Impact of Major Bleed and MI after Elective and Urgent PCIafter Elective and Urgent PCI

Stone GW. Stone GW. J Inv CardiolJ Inv Cardiol 2004;16(suppl G):12–17. 2004;16(suppl G):12–17.

Time from Randomization in Days

Cu

mu

lativ

e %

Mor

talit

y

With MI 5.7%

Without major bleed 2.0%

Without MI 1.9%

With major bleed 8.8%

1-Year Mortality (N=6,012)1-Year Mortality (N=6,012)

VariableVariable GroupsGroups O.R.O.R. (95% CI)(95% CI) p-valuep-value

Creatinine clearanceCreatinine clearance

<30 mL/min<30 mL/min 7.217.21 (2.53–20.51)(2.53–20.51)

<0.0001<0.000130–60 mL/min30–60 mL/min 3.343.34 (1.92–5.78)(1.92–5.78)

60–90 mL/min60–90 mL/min 1.571.57 (0.96–2.57)(0.96–2.57)

CHFCHF YesYes 4.38 4.38 (2.83–6.78)(2.83–6.78) <0.0001<0.0001

Major BleedingMajor Bleeding YesYes 3.263.26 (1.78–5.96)(1.78–5.96) 0.00010.0001

MI @30dayMI @30day YesYes 2.772.77 (1.62–4.75)(1.62–4.75) 0.00020.0002

Urg Revasc @30dUrg Revasc @30d YesYes 2.772.77 (1.15–6.71)(1.15–6.71) .024.024

Hx anginaHx angina YesYes 2.182.18 (1.25–3.81)(1.25–3.81) 0.0060.006

Prior MIPrior MI YesYes 1.811.81 (1.09–3.03)(1.09–3.03) 0.0230.023

DiabetesDiabetes YesYes 1.641.64 (1.10–2.44)(1.10–2.44) 0.0150.015

Predictors of 1-year Mortality Predictors of 1-year Mortality after Elective and Urgent PCIafter Elective and Urgent PCI

Stone GW. Stone GW. J Inv CardiolJ Inv Cardiol 2004;16(suppl G):12–17. 2004;16(suppl G):12–17.

0.0

0.5

1.0

1.5

2.0

2.5

3.0

0 60 120 180 240 300 360

Heparin+GPllb/llla N=3008 Bivalirudin N=2994

1-year Mortality1-year MortalityAll 6,012 Patients (ITT)All 6,012 Patients (ITT)

P value = 0.16P value = 0.16

Cu

mu

lativ

e D

eat

hs

Cu

mu

lativ

e D

eat

hs

DaysDays

2.5%2.5%

1.9%1.9%

Lincoff AM et al. Lincoff AM et al. JAMAJAMA 2004;292:696–703 2004;292:696–703

Relation of Various MI and Bleeding Definitions Relation of Various MI and Bleeding Definitions Used in REPLACE-2Used in REPLACE-2

CK

-MB

ele

vatio

nC

K-M

B e

leva

tion 10x

1x

2x

3x

4x

5x

6x

7x

8x

9x

5g/dl

4g/dl

3g/dl

2g/dl

1g/dl

Intracranialhemorrhage(n=3)

Transfusion≥ 2 Units

Mls by CK-MB elevationoccurring ≤ 48 h

Mls occuring> 48 h (n=29)

Cha

nge

in h

aem

oglo

bin

Cha

nge

in h

aem

oglo

bin

CK > 1 ULN(n=940)

CK > 2 ULN(n=532)

CK > 3 ULN(n=388)

CK > 5 ULN(n=190)

CK > 10 ULN(n=47)

TIMImajorn=35

TIMImajor/minor

n=157Protocol

majorn=173

Protocolmajor/minor

n=1321

A B

Chew DP et al. Chew DP et al. HeartHeart 2006;92:945–50. 2006;92:945–50.

Bleeding definitionsBleeding definitionsMI threshold definitionsMI threshold definitions

Attributable Risk: Apportions Deaths at 12 Attributable Risk: Apportions Deaths at 12 Months Associated with 30-d EventsMonths Associated with 30-d Events

Stringent definition: Affects a small proportion of the population with high

overall relative risk of late mortality

Liberal definition: Affects a large proportion of the population with low overall relative risk of late mortality

Relative risk of late mortality associated with event

Absolute proportion of patients experiencing the event

Spectrum of possible clinical event definitionsEvent definitions with high sensitivity

Event definitions with high specificity


Effects of various endpoint definitionsEffects of various endpoint definitions

OR and Attributable Risk for Baseline Factors OR and Attributable Risk for Baseline Factors Associated with Death by 12 MonthsAssociated with Death by 12 Months

Pe

rce

nta

ge

att

ribu

tab

le f

ract

ion

20

Myocardial infarctionMyocardial infarctiondefinitions and late mortalitydefinitions and late mortality

> 1 x ULN

A

15

10

5

0

20

15

10

5

1

> 2 x ULN > 3 x ULN > 5 x ULN > 10 x ULN

Percentage attributable fraction

Odds Ratio

Od

ds

Ra

tio

2.0

2.83.5

5.3

7.6

11.6%

13.2%13.4%13.7%

4.6%

B

20

15

10

05

0

Pe

rce

nta

ge

att

ribu

tab

le f

ract

ion

20

15

10

5

1

Bleeding definitions and late mortalityBleeding definitions and late mortality

Od

ds

Ra

tio

Protocol major/minor bleed

Protocol majorbleed

TIMI major/minor bleed

TIMImajor bleed

1.6 2.2

4.0%3.9%

2.3

3.5%

6.1

12.0%


Odds ratio is represented by dotted lines; attributable risk by shaded areaOdds ratio is represented by dotted lines; attributable risk by shaded area

Mor

talit

y (%

)M

orta

lity

(%)


0 30 60 90 120 150 180 210 240 270 300 330 360 3900

5

15

30

10

25

20

1 yearEstimate

Major Bleed only (without MI) (N=551) 12.5%28.9%Both MI and Major Bleed (N=94)

3.4% No MI or Major Bleed (N=12,557) MI only (without Major Bleed) (N=611) 8.6%

Impact of MI and Major Bleeding (non-CABG) in Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Yearthe First 30 Days on Risk of Death Over 1 Year

28.9%

12.5%

8.6%

3.4%

Stone GW, et al. JAMA 2007; 298:2497-2506 Stone GW, et al. JAMA 2007; 298:2497-2506

HHarmonizing armonizing OOutcomes with utcomes with RRevascularevascularizizatiationon and and SStents in AMItents in AMI

≥≥3400* pts with STEMI with symptom onset ≤12 hours3400* pts with STEMI with symptom onset ≤12 hours

Emergent angiography, followed by triage to…Emergent angiography, followed by triage to…

Primary PCI StrategyPrimary PCI Strategy

UFH + GP IIb/IIIa inhibitorUFH + GP IIb/IIIa inhibitor(abciximab or eptifibatide)(abciximab or eptifibatide)

Bivalirudin monotherapyBivalirudin monotherapy(± provisional GP IIb/IIIa)(± provisional GP IIb/IIIa)

Aspirin, thienopyridineAspirin, thienopyridine R 1:1

3000 pts eligible for stent randomization3000 pts eligible for stent randomization R 1:3

Bare metal stentBare metal stent TAXUS paclitaxel-eluting stentTAXUS paclitaxel-eluting stent

*To rand 3000 stent pts*To rand 3000 stent pts

Clinical FU at 30 days, 1 year, and then yearly through 5 yearsClinical FU at 30 days, 1 year, and then yearly through 5 years

HORIZONS-AMI TrialHORIZONS-AMI Trial

Mehran R et al. Mehran R et al. Am Heart J.Am Heart J. 2008 Jul;156(1):44-56. 2008 Jul;156(1):44-56.

HHarmonizing armonizing OOutcomes with utcomes with RRevascularevascularizizatiationon and and SStents in AMItents in AMI

UFH +GP IIb/IIIaN=1802

BivalirudinMonotherapy

N=1800

R 1:1

RandomizedRandomized

30 day FU*30 day FU*

* Range ±7 days* Range ±7 days

ITT populationITT population

N=1778(98.7%)

N=1777(98.7%)

N=1802 N=1800

• • • • • • Withdrew • • •Withdrew • • •

• • • • • • Lost to FU • • •Lost to FU • • •99

15151010

1313

3602 pts with STEMI3602 pts with STEMI

HORIZONS-AMI TrialHORIZONS-AMI Trial


12.1

8.3

5.5

9.2

4.9 5.4

0

5

10

15

20

Net adverse clinicalevents

Major bleeding* MACE**

30 d

ay e

vent

rate

s (%

)

Heparin + GPIIb/IIIa inhibitor (N=1802) Bivalirudin monotherapy (N=1800)

RR = 0.99 [0.76, 1.30] RR = 0.99 [0.76, 1.30] PPsupsup = 0.95 = 0.95

Primary Outcome Measures Primary Outcome Measures (ITT)(ITT)

RR = 0.60 [0.46, 0.77]RR = 0.60 [0.46, 0.77]PPsupsup ≤ 0.0001 ≤ 0.0001

RR = 0.76 [0.63, 0.92] RR = 0.76 [0.63, 0.92] PPsupsup = 0.005 = 0.005

1 endpoint 1 endpoint

*Not related to CABG*Not related to CABG**MACE = All cause death, reinfarction,**MACE = All cause death, reinfarction,

ischemic TVR or strokeischemic TVR or strokeStone GW, et al. Stone GW, et al. N Engl J MedN Engl J Med. 2008 May 22;358(21):2218-30. 2008 May 22;358(21):2218-30

30-Day Bleeding Endpoints*30-Day Bleeding Endpoints*

*CEC adjudicated, except protocol minor; **Primary endpoint; ***Life threatening*CEC adjudicated, except protocol minor; **Primary endpoint; ***Life threatening

UFH + GP IIb/IIIaUFH + GP IIb/IIIa(N=1802)(N=1802)

BivalirudinBivalirudin(N=1800)(N=1800)

P ValueP Value

Protocol Major, non CABG**Protocol Major, non CABG** 8.3%8.3% 4.9%4.9% <0.0001<0.0001

Protocol Major, AllProtocol Major, All 10.8%10.8% 6.8%6.8% <0.0001<0.0001

Protocol MinorProtocol Minor 15.4%15.4% 8.6%8.6% <0.0001<0.0001

Blood transfusionBlood transfusion 3.5%3.5% 2.1%2.1% 0.0090.009

TIMI MajorTIMI Major 5.0%5.0% 3.1%3.1% 0.0020.002

TIMI MinorTIMI Minor 4.6%4.6% 2.8%2.8% 0.0060.006

TIMI Major or MinorTIMI Major or Minor 9.6%9.6% 5.9%5.9% <0.0001<0.0001

GUSTO LT*** or SevereGUSTO LT*** or Severe 0.6%0.6% 0.4%0.4% 0.490.49

GUSTO ModerateGUSTO Moderate 5.0%5.0% 3.1%3.1% 0.0020.002

GUSTO LT or Severe or GUSTO LT or Severe or ModerateModerate 5.6%5.6% 3.5%3.5% 0.0020.002


Thrombocytopenia in Thrombocytopenia in HORIZONS-AMIHORIZONS-AMI

3.9

1.1

0.5

1.8

0.50.1

0

1

2

3

4

5

Moderate Severe Profound

Thr

ombo

cyto

peni

a (%

)

Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800)

P = 0.02P = 0.02

P = 0.04P = 0.04

P = 0.002P = 0.002

<100,000 cells/mm3 <20,000 cells/mm3<50,000 cells/mm3


30-Day MACE Components*30-Day MACE Components*

*CEC adjudicated



P ValueP Value

DeathDeath 3.1%3.1% 2.1%2.1% 0.0470.047

- Cardiac- Cardiac 2.9%2.9% 1.8%1.8% 0.0280.028

- Non cardiac- Non cardiac 0.2%0.2% 0.3%0.3% 0.750.75

ReinfarctionReinfarction 1.8%1.8% 1.8%1.8% 0.900.90

- Q-wave- Q-wave 1.2%1.2% 1.4%1.4% 0.660.66

- Non Q-wave- Non Q-wave 0.7%0.7% 0.4%0.4% 0.370.37

Ischemic TVRIschemic TVR 1.9%1.9% 2.6%2.6% 0.180.18

- Ischemic TLR- Ischemic TLR 1.8%1.8% 2.5%2.5% 0.130.13

- Ischemic remote TVR- Ischemic remote TVR 0.3%0.3% 0.3%0.3% 1.01.0

StrokeStroke 0.6%0.6% 0.7%0.7% 0.680.68


30-Day Mortality30-Day Mortality




Dea

th (

%)

Dea

th (

%)


3.1%3.1%

2.1%2.1%

HR [95%CI] =0.66 [0.44, 1.00]

P=0.048

HR [95%CI] =0.66 [0.44, 1.00]

P=0.048




30-Day Mortality: 30-Day Mortality: Cardiac and Non CardiacCardiac and Non Cardiac




Dea

th (

%)

Dea

th (

%)


2.9%2.9%

1.8%1.8%



0.3%0.3%0.2%0.2%

CardiacCardiac

Non cardiacNon cardiac

HR [95%CI] =HR [95%CI] =0.62 [0.40, 0.96]0.62 [0.40, 0.96]

P=0.029P=0.029


30-Day Stent Thrombosis (N=3,124)30-Day Stent Thrombosis (N=3,124)

*Protocol definition of stent thrombosis, CEC adjudicated*Protocol definition of stent thrombosis, CEC adjudicated

UFH + GP UFH + GP IIb/IIIaIIb/IIIa

(N=1553)(N=1553)


PPValueValue

ARC 30d definite or ARC 30d definite or probable stent thrombosis*probable stent thrombosis* 1.9%1.9% 2.5%2.5% 0.300.30

- definitedefinite 1.4%1.4% 2.2%2.2% 0.090.09

- probableprobable 0.5%0.5% 0.3%0.3% 0.240.24

- acute (≤24 hrs)- acute (≤24 hrs) 0.3%0.3% 1.3%1.3% 0.00070.0007

- subacute (>24 hrs – 30d) - subacute (>24 hrs – 30d)

1.7%1.7% 1.2%1.2% 0.280.28

Time-updated Covariate Adjusted Cox Model Relating Time-updated Covariate Adjusted Cox Model Relating Single 30-Day Adverse Events to 30-Day MortalitySingle 30-Day Adverse Events to 30-Day Mortality

* Of 93 total deaths; ** in 3,124 successfully stented pts* Of 93 total deaths; ** in 3,124 successfully stented pts

***Only 2 pts with acute stent thrombosis died within 30 days, 1 in ***Only 2 pts with acute stent thrombosis died within 30 days, 1 in each randomized groupeach randomized group

Ischemic EventsIschemic Events HR (95% CI)HR (95% CI) PPAttributable Attributable

deaths*deaths* C-statC-stat

ReinfarctionReinfarction 11.09 [5.44,22.59] <0.001<0.001 9.1 [8.2,9.6] 0.830.83

Ischemic TVRIschemic TVR 6.91 [3.36,14.18] <0.001<0.001 7.7 [6.3,8.4] 0.830.83

Stent thrombosis, Stent thrombosis, definite**definite** - any- any - acute (<24 hours)- acute (<24 hours)

10.71 [3.93,29.18] 5.88 [0.78,44.30]

<0.001<0.0010.090.09

4.5 [3.7,4.8] 0.8 [-0.3,1]

0.830.830.820.82

StrokeStroke 5.44 [1.67,17.69] 0.0050.005 2.4 [1.2,2.8] 0.820.82

Time-updated Covariate Adjusted Cox Model Relating Time-updated Covariate Adjusted Cox Model Relating Single 30-Day Adverse Events to 30-Day MortalitySingle 30-Day Adverse Events to 30-Day Mortality

* Of 93 total deaths; ** * Of 93 total deaths; ** 88 deaths in 3550 patients* Of 93 total deaths; ** * Of 93 total deaths; ** 88 deaths in 3550 patients

Attributable deaths = N deaths among pts with the time updated Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HRevent (attribute) X (adj. HR – 1)/adj. HRAttributable deaths = N deaths among pts with the time updated Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HRevent (attribute) X (adj. HR – 1)/adj. HR

Bleeding EventsBleeding Events HR (95% CI)HR (95% CI) PP AttributableAttributable

deaths*deaths* C-statC-stat

Major bleed (non-CABG)Major bleed (non-CABG) 4.43 [2.67, 7.33] <0.001<0.001 20.1 [16.3,22.5] 0.850.85

Major bleed (all)Major bleed (all) 5.92 [3.73, 9.41] <0.001<0.001 29.1 [25.6,31.3] 0.860.86

TransfusionTransfusion 3.88 [2.09, 7.20] <0.001<0.001 11.9 [8.4,13.8] 0.830.83

Thrombocytopenia** Thrombocytopenia**

- <100,000 cells/mm- <100,000 cells/mm33

- <50,000 cells/mm- <50,000 cells/mm33

- <20,000 cells/mm- <20,000 cells/mm33

3.89 [2.22, 6.84]

6.44 [2.93,14.18]

4.98 [1.20,20.66]

<0.001<0.001

<0.001<0.001

0.030.03

11.1 [8.2,12.8]

5.9 [4.6,6.5]

1.6 [0.3,1.9]

0.780.78

0.780.78

0.770.77

HR [95% CI]HR [95% CI] P-valueP-valueRisk FactorRisk Factor

Time-updated Covariate Adjusted Cox Model Relating Time-updated Covariate Adjusted Cox Model Relating 30-Day Events to 30-Day Mortality30-Day Events to 30-Day Mortality

Hazard Ratio [95% CI]Hazard Ratio [95% CI]Hazard Ratio [95% CI]Hazard Ratio [95% CI]

0.010.01 0.10.1 11 1010 100100

C-statistic = 0.87. C-statistic = 0.87.

ReinfarctionReinfarction 9.75[2.72,34.91]

9.75[2.72,34.91]

<0.001 <0.001

Major bleeding (non CABG)Major bleeding (non CABG) 4.66[2.84, 7.63]

4.66[2.84, 7.63]

<0.001 <0.001

Ischemic TVRIschemic TVR 1.11[0.29, 4.21]

1.11[0.29, 4.21]

0.88 0.88

StrokeStroke 2.64[0.71, 9.75]

2.64[0.71, 9.75]

0.15 0.15

Complete model with MACE components and major bleedingComplete model with MACE components and major bleedingComplete model with MACE components and major bleedingComplete model with MACE components and major bleeding

Meadows TA, Bhatt DL. Meadows TA, Bhatt DL. Circ ResCirc Res. 2007;100:1261. 2007;100:1261

Bhatt DL. Bhatt DL. N Engl J MedN Engl J Med 2007;357:2078-81. 2007;357:2078-81.

Role of Platelet Activation and AggregationRole of Platelet Activation and Aggregation

Stent ThrombosisStent Thrombosis(ARC Definite + Probable)(ARC Definite + Probable)

0

1

2

3

00 3030 6060 9090 180180 270270 360360 450450

HR 0.48HR 0.48P <0.0001P <0.0001

Prasugrel Prasugrel

ClopidogrelClopidogrel2.42.4

(142)(142)

NNT= 77NNT= 77

1.1 1.1 (68)(68)

DaysDays

En

dpo

int (

%)

En

dpo

int (

%)

Any Stent at Index PCIAny Stent at Index PCI N= 12,844 N= 12,844

Wiviott SD et al Wiviott SD et al NEJMNEJM 2007;357: 2001. 2007;357: 2001. Slide courtesy of Dr. Elliott AntmanSlide courtesy of Dr. Elliott Antman

PLATOPLATOCan Can PLATPLATelet Inhibition be elet Inhibition be OOptimized to Prevent Vascular Eventsptimized to Prevent Vascular Events

At least 2 inclusion criteria:At least 2 inclusion criteria:1. ST segment changes 1. ST segment changes

biomarkersbiomarkers2. At least 1:2. At least 1:

- >60 yo- >60 yo- Previous MI/CABG- Previous MI/CABG- Known > 1 Vessel CAD- Known > 1 Vessel CAD- AODM- AODM- PVD- PVD -Renal dysfunction-Renal dysfunction

Double-blind, double-dummyDouble-blind, double-dummyMean f/u ~12.5 months. Range 6-24Mean f/u ~12.5 months. Range 6-24

AODM, adult-onset diabetes mellitus; PVD, peripheral vascular disease.AODM, adult-onset diabetes mellitus; PVD, peripheral vascular disease.Wallentin L, et al., for the PLATO study. Wallentin L, et al., for the PLATO study. A Comparison of AZD6140 and Clopidogrel in Patients With Acute A Comparison of AZD6140 and Clopidogrel in Patients With Acute Coronary Syndrome.Coronary Syndrome. Washington, DC. US Food and Drug Administration. Available at: http://clinicaltrials.gov. Washington, DC. US Food and Drug Administration. Available at: http://clinicaltrials.gov.

~18,000 patients within 24 hours of ~18,000 patients within 24 hours of an index ACS (STEMI or NSTEMI)an index ACS (STEMI or NSTEMI)

Primary Endpoint:Primary Endpoint: Time to first occurrence of the Time to first occurrence of the composite of death, MI or stroke.composite of death, MI or stroke.Primary Safety EndpointPrimary Safety Endpoint:: Major bleeding Major bleeding

ASA 75-100mg QD

AZD6140 90mg BID Clopidogrel 75mg QID

Cangrelor (AR-C69931MX)Cangrelor (AR-C69931MX)

Parenteral ADP-P2Y12 receptor antagonistParenteral ADP-P2Y12 receptor antagonist ATP analogue ATP analogue

Molecular weight 800 DaltonsMolecular weight 800 Daltons

Plasma half-life of 5-9 minutesPlasma half-life of 5-9 minutes

20 minutes for return to normal platelet function20 minutes for return to normal platelet function

NN

NN

NH

SCF

3

OHOH

OO

PO

O

PP

OO

OCl

Cl

OO

O

S

4Na+

CHAMPION ProgramCHAMPION Program

► Phase III program underwayPhase III program underway

11OO Endpoint – Superiority for ischemic events Endpoint – Superiority for ischemic events

vs. clopidogrel 600 vs. clopidogrel 600 mg at the start of PCImg at the start of PCI

vs. clopidogrel 600 vs. clopidogrel 600 mg at the end of PCImg at the end of PCI

N = 9,000 ptsN = 9,000 pts N = 6,300 ptsN = 6,300 pts

Filter Protection During Acute InfarctionFilter Protection During Acute Infarction

Bhatt DL et al. Bhatt DL et al. CirculationCirculation 2005; 112:906-923. 2005; 112:906-923.

TAPAS TrialTAPAS Trial

► Good myocardial blush: 46% with Good myocardial blush: 46% with aspiration and 32% with standard aspiration and 32% with standard PCI (p<0.001)PCI (p<0.001)

► ST-segment resolution: 57% and ST-segment resolution: 57% and 44%, respectively (p<0.001)44%, respectively (p<0.001)

► Death: 2.1% and 4.0%, Death: 2.1% and 4.0%, respectively (p=0.07)respectively (p=0.07)

Trial design: Patients with ST-elevation myocardial infarction were randomized to thrombus aspiration prior to PCI (n=535) or standard PCI without aspiration (n=536)

ResultsResults

ConclusionsConclusions

► In STEMI, thrombus aspiration prior to PCI In STEMI, thrombus aspiration prior to PCI is superior to standard PCI without is superior to standard PCI without aspirationaspiration

► Thrombus aspiration improves myocardial Thrombus aspiration improves myocardial blush and ST-segment resolutionblush and ST-segment resolution

► Thrombus aspiration may improve adverseThrombus aspiration may improve adverse events including survival

Svilaas T et al. Svilaas T et al. N Engl J MedN Engl J Med 2008;358:557-567 2008;358:557-567

Good myocardial blush

p < 0.001

Mortality

p = 0.07

%%

Thrombus Thrombus aspiration aspiration and PCIand PCIn = 535n = 535

PCI alonePCI alonen = 536n = 536

3246

2.1 4

www.cardiosource.comwww.cardiosource.com

Vlaar PJ, et al. Vlaar PJ, et al. LancetLancet. 2008 Jun 7;371(9628):1915-20.. 2008 Jun 7;371(9628):1915-20.

1071 STEMI patients randomized1071 STEMI patients randomized

530 complete follow-up at 1 year530 complete follow-up at 1 year 530 complete follow-up at 1 year530 complete follow-up at 1 year

TAPAS Trial DesignTAPAS Trial Design

33 did not undergo PCI33 did not undergo PCI502 underwent primary PCI502 underwent primary PCI

- - 295 underwent TA followed by 295 underwent TA followed by direct stentingdirect stenting

- - 153 underwent TA with additional 153 underwent TA with additional balloon dilationballoon dilation

- - 54 had crossover to conventional 54 had crossover to conventional PCIPCI

33 did not undergo PCI33 did not undergo PCI503 underwent primary PCI503 underwent primary PCI

- - 485 underwent balloon dilation 485 underwent balloon dilation followed by steningfollowed by stening

- - 12 underwent conventional PCI 12 underwent conventional PCI with additional TAwith additional TA

- - 6 had crossover to TA6 had crossover to TA

535 were assigned to535 were assigned tothrombus aspirationthrombus aspiration

536 were assigned to536 were assigned toconventional PCIconventional PCI

Mortality at 1 YearMortality at 1 Year

Log-Rank p = 0.040Log-Rank p = 0.040

Vlaar PJ, et al. Vlaar PJ, et al. LancetLancet. 2008 Jun 7;371(9628):1915-20.. 2008 Jun 7;371(9628):1915-20.

00 100 100 200200 300 300 400 400

1212

1010

88

66

44

22

00

Time (days)Time (days)

Mor

talit

y (%

)M

orta

lity

(%)

Conventional PCIConventional PCI

Thrombus-AspirationThrombus-Aspiration

Conclusions: Optimizing STEMI Care Conclusions: Optimizing STEMI Care

► Major bleeding is a powerful independent determinant of Major bleeding is a powerful independent determinant of mortality in PCI, ACS, STEMI, at least as important as MI mortality in PCI, ACS, STEMI, at least as important as MI and reinfarctionand reinfarction

► Bivalirudin versus heparin + GPI results in a significant Bivalirudin versus heparin + GPI results in a significant reduction in bleeding, thrombocytopenia, and transfusionsreduction in bleeding, thrombocytopenia, and transfusions

► In primary PCI for STEMI, a lower 30-day mortality rate is In primary PCI for STEMI, a lower 30-day mortality rate is observed with bivalirudin versus heparin + GPIobserved with bivalirudin versus heparin + GPI

► Novel antiplatelet agents may potentially further reduce Novel antiplatelet agents may potentially further reduce ischemic eventsischemic events

► Simple manual thrombus aspiration also appears to reduce Simple manual thrombus aspiration also appears to reduce mortalitymortality

Changing Anticoagulants Changing Anticoagulants in Midstreamin Midstream

Strategies for Optimizing OutcomesStrategies for Optimizing Outcomesin STEMI and High Risk ACS: Toin STEMI and High Risk ACS: ToSwitch or Not to Switch? Why?Switch or Not to Switch? Why?

When? How?When? How?


Carlo Di Mario, MD, PhD, FESC, FACC, FRCPCarlo Di Mario, MD, PhD, FESC, FACC, FRCPProfessor of Clinical CardiologyProfessor of Clinical Cardiology

Imperial College of Sciences, Medicine & Technology Imperial College of Sciences, Medicine & Technology Consultant in Interventional CardiologyConsultant in Interventional Cardiology

Royal Brompton HospitalRoyal Brompton HospitalLondon, UKLondon, UK

What is the Problem? We Always Mix What is the Problem? We Always Mix Antiplatelet AgentsAntiplatelet Agents

ThrombinThrombin

ThromboxaneThromboxaneAA22

5HT5HT

P2Y12

ADPADP ADPADPADPADP

5HT5HT

PLATELETPLATELETACTIVATIONACTIVATION

P2Y15HT2A

PAR1

PAR4

Densegranule

ThrombinThrombingenerationgeneration

ShapeShapechangechange

a IIbb3

a IIbb3

FibrinogenFibrinogena IIbb3

AggregationAggregation

AmplificationAmplificationAlpha

granule

Coagulation factorsCoagulation factorsInflammatory mediatorsInflammatory mediators

TPa

CoagulationCoagulation

GPVI

CollagenCollagen

ATPATPATPATP

P2X1

ASPIRINASPIRIN

xTICLOPIDINETICLOPIDINECLOPIDOGRELCLOPIDOGRELPRASUGRELPRASUGREL

ACTIVE ACTIVE METABOLITEMETABOLITE

x AZD6140 AZD6140 CANGRELORCANGRELOR

GP IIb/IIIa ANTAGONISTSGP IIb/IIIa ANTAGONISTS

x

Storey RF. Curr Pharm Des. 2006;12:1255-59.Storey RF. Curr Pharm Des. 2006;12:1255-59.

Yes, But: All Antithrombotic Drugs Act Yes, But: All Antithrombotic Drugs Act on Thrombin Activityon Thrombin Activity

► In ACS patientsIn ACS patients● 87% of patients receive either UFH or Enoxaparin within 24 87% of patients receive either UFH or Enoxaparin within 24

hours after admissionhours after admission11

● 72% of patients in SYNERGY and 50 % of patients in 72% of patients in SYNERGY and 50 % of patients in OASIS- 5OASIS- 5 received prior antithrombinreceived prior antithrombin2,32,3

11 CRUSADE( 1Q-2006 results); CRUSADE( 1Q-2006 results); 22 Synergy results; JAMA 2004; Synergy results; JAMA 2004; 33 OASIS -5; Yusuf et al, NEJM 2006; OASIS -5; Yusuf et al, NEJM 2006; 44 Cohen et al, JACC 2006; Cohen et al, JACC 2006;

► Anti-platelet Agents act on different mechanisms, with Anti-platelet Agents act on different mechanisms, with synergistic effects; some inhibit only the aggregation of synergistic effects; some inhibit only the aggregation of plateletsplatelets

► In most cases, we don’t need antithrombotic agents to In most cases, we don’t need antithrombotic agents to produce prolonged anticoagulation (unlike produce prolonged anticoagulation (unlike antiaggregation)antiaggregation)

Potential Risks of Combining Different Potential Risks of Combining Different Antithrombotic DrugsAntithrombotic Drugs

Unfractionated Unfractionated HeparinHeparin(UHF)(UHF)

Low Molecular Low Molecular Weight HeparinWeight Heparin(Enoxaparin sc)(Enoxaparin sc)

FondaparinuxFondaparinux BivalirudinBivalirudin

Half-LifeHalf-Life 3 Hrs3 Hrs 6 Hrs6 Hrs 4 Hrs4 Hrs 0.3 Hrs0.3 Hrs

Dose/KgDose/Kg 30-120 mg/Kg30-120 mg/Kg 1 mg/Kg1 mg/Kg 2.5 mg sc2.5 mg sc

STEMI: 0.75 mg/kg bolus STEMI: 0.75 mg/kg bolus followed by infusion 1.75 followed by infusion 1.75

mg/kg/hmg/kg/h

NSTE-ACS: 0.1 mg/kg NSTE-ACS: 0.1 mg/kg bolus followed by infusion bolus followed by infusion

0.25 mg/kg/h0.25 mg/kg/h(if PCI, additional 0.5 (if PCI, additional 0.5

mg/kg IV bolus followed mg/kg IV bolus followed by infusion 1.75 mg/kg/h)by infusion 1.75 mg/kg/h)

MonitoringMonitoring ACT/aPTTACT/aPTT Factor X (not Factor X (not required)required) Not requiredNot required ACT (not required)ACT (not required)

InactivationInactivation Protamine Protamine SulphateSulphate n.a.n.a. n.a.n.a. n.a.n.a.

RandomizeRandomize(n = 10,000)(n = 10,000)

60 U/kg 60 U/kg 12 U/kg/h 12 U/kg/h (aPTT 50 – 70 sec)(aPTT 50 – 70 sec)1 mg/kg SC Q12 h1 mg/kg SC Q12 h

SYNERGY Trial Investigators.SYNERGY Trial Investigators. JAMA JAMA 2004;292:45-54 2004;292:45-54SYNERGY Trial Investigators.SYNERGY Trial Investigators. JAMA JAMA 2004;292:45-54 2004;292:45-54

Primary Endpoint: Death or MI at 30 DaysPrimary Endpoint: Death or MI at 30 Days

Early Invasive StrategyEarly Invasive StrategyOther Therapy per ACC/AHA GuidelinesOther Therapy per ACC/AHA Guidelines

(ASA, (ASA, ßß-blocker, ACE, Clopidogrel, GP IIb/IIIa)-blocker, ACE, Clopidogrel, GP IIb/IIIa)

Enoxaparin IV UFHIV UFH

High-Risk ACS PatientsHigh-Risk ACS Patients

SYNERGY Study DesignSYNERGY Study Design

At Least 2 of 3 Required:At Least 2 of 3 Required: Age Age >> 60 60 ST ST (transient) or (transient) or (+) CK-MB or Troponin(+) CK-MB or Troponin

0.80.8 11 1.21.2

Hazard Ratio (95% CI)Hazard Ratio (95% CI)

EnoxaparinEnoxaparin UFHUFHBetterBetter BetterBetter

30-day Death/MI30-day Death/MI

HR 0.96 (0.86 – 1.06)HR 0.96 (0.86 – 1.06)

SYNERGY: Death and MI at 30 DaysSYNERGY: Death and MI at 30 Days

00 55 1010 1515 2020 2525 30300.80.8

0.90.9

0.950.95

1.01.0

Free

dom

from

Dea

th /

MI

Free

dom

from

Dea

th /

MI


0.850.85EnoxaparinEnoxaparinUFHUFH

SYNERGY Trial Investigators.SYNERGY Trial Investigators. JAMA JAMA 2004;292:45-54 2004;292:45-54

SYNERGY Bleeding EventsSYNERGY Bleeding Events

GUSTO severeGUSTO severe 2.7%2.7% 2.2%2.2% 0.080.08

TIMI major (clinical):TIMI major (clinical): 9.1%9.1% 7.6%7.6% 0.0080.008

CABG-relatedCABG-related 6.8%6.8% 5.9%5.9% 0.080.08

Non-CABG-relatedNon-CABG-related 2.4%2.4% 1.8%1.8% 0.030.03

Hb/HCT drop (algorithm)Hb/HCT drop (algorithm) 15.2%15.2% 12.5%12.5% < 0.001< 0.001

Any RBC transfusionAny RBC transfusion 17.0%17.0% 16.0%16.0% 0.160.16

ICHICH < 0.1%< 0.1% < 0.1%< 0.1% NSNS

EnoxaparinEnoxaparin UFHUFH P valueP value (n = 4,993)(n = 4,993) (n = 4,985)(n = 4,985)


SYNERGY: Relation of Heparin SYNERGY: Relation of Heparin Crossover to BleedingCrossover to Bleeding

0

2

4

6

8

10

Total No Crossover Crossover0

5

10

15

20

Total No Crossover Crossover

GUSTO Severe (%)GUSTO Severe (%) TIMI Major (%)TIMI Major (%)

n=9978 n=9180 n=798n=9978 n=9180 n=798 n=9978 n=9180 n=798n=9978 n=9180 n=798

Enoxaparin Unfractionated HeparinEnoxaparin Unfractionated Heparin


OASIS-6: FondaparinuxOASIS-6: FondaparinuxSynthetic Factor Xa InhibitorSynthetic Factor Xa Inhibitor

Yusuf S, et al. Yusuf S, et al. JAMAJAMA. 2006;295:1519-1530 . 2006;295:1519-1530

14%

Reduction in Death/MI at 30 days: Stratum 1 (No UFH indicated)

P<.05

12%

10%

8%

6%

4%

2%

0%

11.2%

14%

Fondaparinux Placebo

STEMISTEMI≤24h→≤12h≤24h→≤12hN=12092N=12092

STRATUM 1STRATUM 1: no indication for UFH: no indication for UFH STRATUM 2STRATUM 2: indication for UFH: indication for UFH

Fondaparinux 2.5 mg sc odFondaparinux 2.5 mg sc od≤≤8days or discharge8days or discharge PlaceboPlacebo Fondaparinux IVFondaparinux IV→ sc→ sc UFH bolus + infusion UFH bolus + infusion

24 to 48 hours24 to 48 hours

Reduction in Death/MI: Stratum 2(UFH Indicated)

P=NS

p=0.97p=0.97

14%

12%

10%

8%

6%

4%

2%

0%Fondaparinux UFH

8.3% 8.7%

31% 1ary PCI31% 1ary PCI

Do NOT use as sole anticoagulant DURING PCIDo NOT use as sole anticoagulant DURING PCI

2007 Focused Update of ACC/AHA STEMI Guidelines 20082007 Focused Update of ACC/AHA STEMI Guidelines 2008

15%

Primary End Point: Death/Reinfarction (%)

P=.008 P=.003 P=.008

Fre

quen

cy

12%

9%

6%

3%

0%

9.7%

11.2%

7.4%8.9%

13.4%14.8%

30 days 9 days 3- 6 months

Fondaparinux (n=6036) Control (n=6056)

ESC NSTE-ACS GuidelinesESC NSTE-ACS Guidelines

► At PCI procedures, the initial anticoagulant At PCI procedures, the initial anticoagulant should also be maintained during the procedure should also be maintained during the procedure regardless of whether this treatment is UFH (I-regardless of whether this treatment is UFH (I-C), enoxaparin (IIb-B), or bivalirudin (I-B)C), enoxaparin (IIb-B), or bivalirudin (I-B)

EHJ 2007;28:1598-60EHJ 2007;28:1598-60

Is It Safe Switching to Bivalirudin?Is It Safe Switching to Bivalirudin?

► Why should switching to bivalirudin monotherapy be Why should switching to bivalirudin monotherapy be reasonable?reasonable?

► Mechanistic rationale for switchingMechanistic rationale for switching● SWITCHSWITCH● REPLACE 2REPLACE 2● ACUITYACUITY

► Why should switching to bivalirudin monotherapy be Why should switching to bivalirudin monotherapy be reasonable?reasonable?

► Mechanistic rationale for switchingMechanistic rationale for switching● SWITCHSWITCH● REPLACE 2REPLACE 2● ACUITYACUITY

► SwitchSwitch: Protocol-mandated change in : Protocol-mandated change in antithrombotic therapy at randomizationantithrombotic therapy at randomization

► CrossoverCrossover: Post-randomization change : Post-randomization change in antithrombotic therapy due to in antithrombotic therapy due to physician choicephysician choice

SWITCHSWITCH

DefinitionsDefinitions

ACUITY — SWITCHACUITY — SWITCH

► HypothesisHypothesis● Bivalirudin improves bleeding outcomes while Bivalirudin improves bleeding outcomes while

preserving ischemic protection for ACS patients preserving ischemic protection for ACS patients even if the patients are switched from either even if the patients are switched from either UFH or enoxaparin to bivalirudin (monotherapy) UFH or enoxaparin to bivalirudin (monotherapy) at the time of presentationat the time of presentation

► Is it better to switch to bivalirudin or remain Is it better to switch to bivalirudin or remain on consistent therapy?on consistent therapy?

White HD, et al. J Am Coll Cardiol 2008;51:1734–41 White HD, et al. J Am Coll Cardiol 2008;51:1734–41

ACUITY – Primary ResultsACUITY – Primary Results

11.7%

7.3%5.7%

3.0%

10.1%

7.8%

Net clinical outcome Ischemic composite Major bleeding

30 d

ay e

vent

s (%

)

UFH/Enoxaparin+GPI (N=4603) Bivalirudin alone (N=4612)

UFH/Enoxaparin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin Alone

PPNINI <0.0001 <0.0001

PPSupSup = 0.015 = 0.015PPNINI = 0.011 = 0.011

PPSupSup = 0.32 = 0.32PPNINI <0.0001 <0.0001

PPSupSup <0.0001 <0.0001

Stone GW et al. Stone GW et al. NEJMNEJM 2006;355:2203-16 2006;355:2203-16

ACUITY — Switch AnalysisACUITY — Switch Analysis

► Study MethodsStudy Methods● Patients on prior antithrombin therapyPatients on prior antithrombin therapy

• Consistent:Consistent: No switchingNo switching from pre-randomization from pre-randomization antithrombin agent to randomized therapy:antithrombin agent to randomized therapy:

–Enoxaparin Enoxaparin →→Enoxaparin or UFH Enoxaparin or UFH →→ UFH UFH• Switch:Switch: Single switchSingle switch to bivalirudin determined by to bivalirudin determined by

randomization coderandomization code –From Enoxaparin From Enoxaparin →→ Bivalirudin or UFH Bivalirudin or UFH → →

BivalirudinBivalirudin

► Event rates at 30-daysEvent rates at 30-days• Net clinical outcome Net clinical outcome • Ischemic compositeIschemic composite• Major bleedingMajor bleeding

White HD, et al. J Am Coll Cardiol 2008;51:1734–41

ACUITY – Switch ConsortACUITY – Switch Consort

ACUITYACUITY1381913819

CONSISTENTCONSISTENTUFH/EnoxUFH/EnoxN = 2137N = 2137

SWITCHSWITCHBivalirudinBivalirudinN = 2078N = 2078

UFHUFH→UFH→UFHN = 1294N = 1294

EnoxEnox→Enox→EnoxN = 843N = 843

UFHUFH→Biv→BivN = 1313N = 1313

EnoxEnox→Biv→BivN = 765N = 765

Pts on Prior ATPts on Prior ATN = 4215 N = 4215 ╪╪

╪ ╪ excludes Arm B and pts. with multiple crossovers, missing dataexcludes Arm B and pts. with multiple crossovers, missing data

Consistent vs. SwitchConsistent vs. Switch

Comparing Consistent therapy on Enox + GPIIb/IIIa Inhibition vs. Switch to Bivalirudin Alone

P=0.15

0.80 [0.60 – 1.81]

P=0.430.86 [0.60 – 1.25]

P=0.030.58 [0.35 – 0.96]

11.0%

8.9%7.0%

6.1%5.0%

2.9%

0

5

10

15

20

Net clinical outcome Ischemic composite Major bleeding

30 d

ay

eve

nts

(%

)

Consistent Enox + GPIIb/IIIa Inhibition (N = 843)Consistent Enox + GPIIb/IIIa Inhibition (N = 843) Switch to Bivalirudin alone (N = 765)

White HD, et al. White HD, et al. J Am Coll CardiolJ Am Coll Cardiol 2008;51:1734–41 2008;51:1734–41

ACUITY – Switch ACUITY – Switch Consistent vs. Consistent vs. Switch High RiskSwitch High Risk

Comparing Comparing ConsistentConsistent UFH/Enox vs UFH/Enox vs SwitchSwitch Bivalirudin Bivalirudin Comparing Comparing ConsistentConsistent UFH/Enox vs UFH/Enox vs SwitchSwitch Bivalirudin BivalirudinHigh Risk PatientsHigh Risk Patients

ConsistentConsistentUFH/EnoxUFH/EnoxN = 1581N = 1581

SwitchSwitchBivalirudinBivalirudinN = 1496N = 1496

RRRR

Net Clinical OutcomeNet Clinical Outcome 13.0%13.0% 10.6%10.6% 0.82 [0.67-0.99]0.82 [0.67-0.99]

IschemiaIschemia 8.2%8.2% 7.7%7.7% 0.94 [0.74-1.20]0.94 [0.74-1.20]

Major BleedingMajor Bleeding 6.5%6.5% 3.5%3.5% 0.51 [0.39-0.75]0.51 [0.39-0.75]


ACUITY – SWITCH ACUITY – SWITCH Consistent vs. SwitchConsistent vs. Switch Patients Undergoing PCIPatients Undergoing PCI

Comparing Comparing ConsistentConsistent UFH/Enox vs UFH/Enox vs SwitchSwitch Bivalirudin Bivalirudin Comparing Comparing ConsistentConsistent UFH/Enox vs UFH/Enox vs SwitchSwitch Bivalirudin Bivalirudin

ConsistentConsistentUFH/EnoxUFH/Enox

N = 1236N = 1236

SwitchSwitchBivalirudinBivalirudin

N = 1292N = 1292RRRR

Net Clinical OutcomeNet Clinical Outcome 13.2%13.2% 11.8%11.8% 0.90 [0.73 -1.10]0.90 [0.73 -1.10]

IschemiaIschemia 8.2%8.2% 9.0%9.0% 1.10 [0.85 -1.42]1.10 [0.85 -1.42]

Major BleedingMajor Bleeding 6.7%6.7% 3.5%3.5% 0.52 [0.36-0.74]0.52 [0.36-0.74]

PCI PatientsPCI Patients


Relative Risk ± 95% CIRelative Risk ± 95% CI RR (95% CI)RR (95% CI)

Prior Antithrombin TherapyPrior Antithrombin Therapy

0.49 (0.36-0.66)0.49 (0.36-0.66)Major BleedingMajor Bleeding

0.77 (0.65-0.92)0.77 (0.65-0.92)Net Clinical OutcomeNet Clinical Outcome

0.93 (0.75-1.16)0.93 (0.75-1.16)Composite IschemiaComposite Ischemia

Switch to Bivalirudin Switch to Bivalirudin BetterBetter

Consistent UFH/Enox Consistent UFH/Enox + IIb/IIIa Better+ IIb/IIIa Better

ACUITY: SwitchACUITY: Switch

30 Days30 Days

00 11 22


ACUITY — SwitchACUITY — Switch

30 Days30 Days

Relative Risk Relative Risk ± ± 95% CI95% CI

0.52 (0.35-0.77)0.52 (0.35-0.77)Major BleedingMajor Bleeding

0.85 (0.67-1.07)0.85 (0.67-1.07)Net Clinical OutcomeNet Clinical Outcome

1.11 (0.83-1.49)1.11 (0.83-1.49)Composite IschemiaComposite Ischemia

Randomization to Randomization to Bivalirudin BetterBivalirudin Better

Randomization toRandomization toUFH/Enox + IIb/IIIa BetterUFH/Enox + IIb/IIIa Better

Naïve to Antithrombin TherapyNaïve to Antithrombin Therapy

RR (95% CI)RR (95% CI)

0 1 2


PCIPCI (n=2528)(n=2528)

Composite Composite ischemiaischemia 1.10 (0.85-1.42)1.10 (0.85-1.42)

Major bleedingMajor bleeding 0.52 (0.36-0.74)0.52 (0.36-0.74)

Switch to Switch to Bivalirudin Bivalirudin

betterbetter

Consistent UFH/EnoxConsistent UFH/Enox + IIb/IIIa better+ IIb/IIIa better

Switch to Switch to Bivalirudin Bivalirudin

betterbetter

Consistent UFH/EnoxConsistent UFH/Enox + IIb/IIIa better+ IIb/IIIa better

* High risk = * High risk = ↑Tn, CKMB or ECG ↑Tn, CKMB or ECG ΔΔ’s’s

Risk RatioRisk Ratio± 95% CI± 95% CI RR (95% CI)RR (95% CI)

Hazard RatioHazard Ratio± 95% CI± 95% CI HR (95% CI)HR (95% CI)

30-Day Results30-Day Results30-Day Results30-Day Results 1-Year Results1-Year Results1-Year Results1-Year Results

PCI HIGH RISK*PCI HIGH RISK*(n=1988)(n=1988)

Composite Composite ischemiaischemia 1.14 (0.86-1.52)1.14 (0.86-1.52)

Major bleedingMajor bleeding 0.56 (0.38-0.81)0.56 (0.38-0.81)

PCIPCI ((n=2528n=2528))

MortalityMortality 0.93 (0.58-1.48)0.93 (0.58-1.48)

PCI HIGH RISK*PCI HIGH RISK*((n=1988n=1988))

MortalityMortality 0.99 (0.60-1.63)0.99 (0.60-1.63)

ACUITY – SWITCH ACUITY – SWITCH ACUITY PCI: Switch from Prior AntithrombinACUITY PCI: Switch from Prior Antithrombin

0.10.1 11 10100.10.1 11 1010

White HD, et al. White HD, et al. J Am Coll CardiolJ Am Coll Cardiol 2008;51:1734–412008;51:1734–41

Naïve to Antithrombin TherapyNaïve to Antithrombin Therapy

9.5%9.5%

8.0%8.0%

5.8%5.8% 6.2%6.2%5.0%5.0%

2.5%2.5%

P=0.18P=0.180.83 [0.63 – 1.090.83 [0.63 – 1.09

P=0.74P=0.741.06 [0.76 – 1.49]1.06 [0.76 – 1.49]

P<0.01P<0.010.51 [0.33 – 0.78]0.51 [0.33 – 0.78]

00

55

1010

1515

2020

Net clinicalNet clinicaloutcomeoutcome

IschemicIschemiccomposite composite

MajorMajorbleedingbleeding

30 d

ay e

vent

s (%

)30

day

eve

nts

(%)

Randomized to Enox + GPIIb/IIIa Inhibition (N = 842)Randomized to Enox + GPIIb/IIIa Inhibition (N = 842)

Randomized to Bivalirudin (N = 1427)Randomized to Bivalirudin (N = 1427)


ACUITY – Switch LimitationsACUITY – Switch Limitations

► Post-hoc subgroup analysisPost-hoc subgroup analysis

► Pre-randomization use of antithrombin Pre-randomization use of antithrombin was not stratifiedwas not stratified

► Timing and dose of last UFH and Timing and dose of last UFH and enoxaparin was not collected in the enoxaparin was not collected in the CRFCRF

Randomize

Protocol major/minor bleeding, TIMI bleeding, transfusion, mortalityProtocol major/minor bleeding, TIMI bleeding, transfusion, mortalityProtocol major/minor bleeding, TIMI bleeding, transfusion, mortalityProtocol major/minor bleeding, TIMI bleeding, transfusion, mortality

Bivalirudin0.75 mg/kg bolus/1.75 mg/kg/h infusion with “provisional” GP IIb/IIIa (n=2,994)1

Prior UFH (n=287)2

Naïve – no prior AT

(n=2,345)2

Overall population: Urgent or elective PCI patientsOverall population: Urgent or elective PCI patients (N=6,002)(N=6,002)11

Overall population: Urgent or elective PCI patientsOverall population: Urgent or elective PCI patients (N=6,002)(N=6,002)11

UFH UFH 65 U/kg with planned GP IIb/IIIa 65 U/kg with planned GP IIb/IIIa

(n=3,008)(n=3,008)11

Prior LMWH

(n=258)2

Naïve – no Naïve – no prior ATprior AT

(n=2,325)(n=2,325)22

Prior UFH Prior UFH (n=349)(n=349)22

Prior Prior LMWHLMWH

(n=313)(n=313)22

REPLACE-2: SWITCH AnalysisREPLACE-2: SWITCH Analysis

1. Lincoff ML et al. JAMA. 2004;292:696-703.1. Lincoff ML et al. JAMA. 2004;292:696-703.2. Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.2. Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.

AT=antithrombin.AT=antithrombin.

†

Protocol Major/Minor Bleeding by Protocol Major/Minor Bleeding by SWITCH and Randomized TherapySWITCH and Randomized Therapy

► Regardless of prior heparin or not, patients administered bivalirudin had Regardless of prior heparin or not, patients administered bivalirudin had decreased bleedingdecreased bleeding

► There was a significant increase in major/minor protocol bleeding in There was a significant increase in major/minor protocol bleeding in patients administered UFH with prior heparin therapypatients administered UFH with prior heparin therapy

**PP=NS for all 3-way comparisons versus bivalirudin alone; =NS for all 3-way comparisons versus bivalirudin alone; ††PP<.05 vs prior treatment with UFH or enoxaparin; <.05 vs prior treatment with UFH or enoxaparin; ‡‡naïve=no prior AT therapy in preceding 48 hours.naïve=no prior AT therapy in preceding 48 hours.

Pro

toco

l maj

or/m

inor

ble

edP

roto

col m

ajor

/min

or b

leed

Naïve→Naïve→BivalirudinBivalirudin‡‡

(n=2,345)(n=2,345)

LMWH→LMWH→Bivalirudin Bivalirudin

(n=258)(n=258)

UFH→UFH→BivalirudinBivalirudin

(n=287)(n=287)

LMWH→UFH LMWH→UFH + GP IIb/IIIa+ GP IIb/IIIa

(n=313)(n=313)

Naïve→ Naïve→ UFH + UFH +

GP IIb/IIIaGP IIb/IIIa‡ ‡

(n=2,325)(n=2,325)

UFH→UFH UFH→UFH + GP IIb/IIIa + GP IIb/IIIa

(n=349)(n=349)

*

Gibson CM et al. Gibson CM et al. Am J Cardiol.Am J Cardiol. 2007;99:1687-1690. 2007;99:1687-1690.

15.6% 15.3% 16.7%

28.6%

33.8% 34.8%

0%0%

5%5%

10%

15%

20%

25%

30%

35%

TIMI Major/Minor Bleeding byTIMI Major/Minor Bleeding bySWITCH and Randomized TherapySWITCH and Randomized Therapy

► Patients switched from UFH or enoxaparin to bivalirudin had the lowest rates of TIMI bleeding Patients switched from UFH or enoxaparin to bivalirudin had the lowest rates of TIMI bleeding

► Patients administered UFH had higher rates of bleeding, with highest rates in patients switching Patients administered UFH had higher rates of bleeding, with highest rates in patients switching between heparinsbetween heparins

► Patients switched from UFH or enoxaparin to bivalirudin had the lowest rates of TIMI bleeding Patients switched from UFH or enoxaparin to bivalirudin had the lowest rates of TIMI bleeding

► Patients administered UFH had higher rates of bleeding, with highest rates in patients switching Patients administered UFH had higher rates of bleeding, with highest rates in patients switching between heparinsbetween heparins

TIM

I maj

or/m

inor

ble

edT

IMI m

ajor

/min

or b

leed

Naïve→Naïve→BivalirudinBivalirudin†† (n=2,345)(n=2,345)

LMWH → LMWH → Bivalirudin Bivalirudin

(n=258)(n=258)

UFH→UFH→BivalirudinBivalirudin

(n=287)(n=287)

LMWH→UFHLMWH→UFH+ GP IIb/IIIa+ GP IIb/IIIa

(n=313)(n=313)

Naïve→UFH + Naïve→UFH + GP IIb/IIIaGP IIb/IIIa†† (n=2,325)(n=2,325)

UFH→UFH UFH→UFH + GP IIb/IIIa + GP IIb/IIIa

(n=349)(n=349)

*

**PP=NS for all 3-way comparisons versus bivalirudin alone; =NS for all 3-way comparisons versus bivalirudin alone; ††naïve=no prior AT therapy in preceding 48 hours.naïve=no prior AT therapy in preceding 48 hours.

Gibson CM et al. Gibson CM et al. Am J Cardiol.Am J Cardiol. 2007;99:1687-1690. 2007;99:1687-1690.

1.9%1.4%

4.3%

5.4%

1.9%

3.5%

0%0%

1%1%

2%

3%

4%

5%

6%

SWITCHSWITCH

Waksman et al. Waksman et al. J Invasive CardiolJ Invasive Cardiol 2006;18:370 2006;18:370

p = 0.39p = 0.39

n = 30n = 30 n = 31n = 31n = 30n = 30

13%13%

3%3%

7%7%

0%0%

5%5%

10%10%

15%15%

GPI (0 - 4 hr)GPI (0 - 4 hr) GPII (4 - 8 hr)GPII (4 - 8 hr) GPIII (8 - 12 hr)GPIII (8 - 12 hr)

Time from last enoxaparin doseTime from last enoxaparin dose

Maj

or

Ble

edin

g %

Maj

or

Ble

edin

g %

4.8% 5.2%

8.5%7.5%

0%

2%

4%

6%

8%

10%

UFH pretreatmentUFH pretreatment(n=2,553)(n=2,553)

No UFHNo UFHpretreatmentpretreatment

(n=1,042)(n=1,042)

30-D

ay M

ajo

r B

leed

ing

4.6%

7.2%

5.2%5.6%

0%

2%

4%

6%

8%

10%

UFH pretreatmentUFH pretreatment(n=2,553)(n=2,553)

No UFHNo UFHpretreatmentpretreatment

(n=1,042)(n=1,042)

30-D

ay M

AC

E

Bivalirudin with "provisional" GP IIb/IIIa Bivalirudin with "provisional" GP IIb/IIIa Heparin + GP IIb/IIIaHeparin + GP IIb/IIIa

PPintint=0.08=0.08PPintint=0.47=0.47

HORIZONS AMI Trial Switching DataHORIZONS AMI Trial Switching Data

UFH pre-procedure was administered to 65.8% of UFH pre-procedure was administered to 65.8% of bivalirudin pts and 76.3% of heparin + GPIIb/IIIa ptsbivalirudin pts and 76.3% of heparin + GPIIb/IIIa pts

RR [95%CI]=RR [95%CI]=0.81 [0.58,1.14]0.81 [0.58,1.14]

RR [95%CI]=RR [95%CI]=1.39 [0.85,2.28]1.39 [0.85,2.28]

RR [95%CI]=RR [95%CI]=0.57 [0.42,0.77]0.57 [0.42,0.77]

RR [95%CI]=RR [95%CI]=0.69 [0.43,1.12]0.69 [0.43,1.12]

Which Protocol Should We Follow?Which Protocol Should We Follow?

From UFH to BivalirudinFrom UFH to Bivalirudin

• • Discontinue LMWH for 8 hours before Discontinue LMWH for 8 hours before starting bivalirudinstarting bivalirudin

• Discontinue UFH for 30 minutes before Discontinue UFH for 30 minutes before starting bivalirudinstarting bivalirudin

From LMWH to BivalirudinFrom LMWH to Bivalirudin

ConclusionsConclusions► Switching to bivalirudin is safeSwitching to bivalirudin is safe

● Switching from any heparin to Switching from any heparin to bivalirudin monotherapy is not bivalirudin monotherapy is not associated with an increased risk for associated with an increased risk for ischemic eventsischemic events

► FurthermoreFurthermore● Switch to bivalirudin provides patients Switch to bivalirudin provides patients

the 50% bleeding advantage of the 50% bleeding advantage of bivalirudinbivalirudin

Risks of Combining Risks of Combining Different Antithrombotic DrugsDifferent Antithrombotic Drugs

Guidelines and the Role of Bleeding Reduction Guidelines and the Role of Bleeding Reduction to Optimize Outcomes and Upstream to Optimize Outcomes and Upstream

Antithrombotic Care for STEMI and NSTEMIAntithrombotic Care for STEMI and NSTEMI

Stefano Savonitto, MD, FESCStefano Savonitto, MD, FESCPrima Divisione di CardiologiaPrima Divisione di Cardiologia

Dipartimento Cardiologico “Angelo De Gasperis”Dipartimento Cardiologico “Angelo De Gasperis”Ospedale Niguarda Ca’ GrandaOspedale Niguarda Ca’ Granda

Milano, ItalyMilano, Italy


Minimizing infarct sizeMinimizing infarct sizeClinical StabilizationClinical Stabilization

Prevention of early (re)infarctionPrevention of early (re)infarctionProtection of microcirculationProtection of microcirculation

Procedural MIProcedural MIBleeding Bleeding

Renal damageRenal damage

BenefitBenefit Risk Risk

Impact of Pharmacoinvasive Therapy Impact of Pharmacoinvasive Therapy in PCI and ACSin PCI and ACS

Reduction of death+MIReduction of death+MIin high-risk patientsin high-risk patients

Increased mortality?Increased mortality?

Emphasis on Bleeding Prevention in the Emphasis on Bleeding Prevention in the 2007 ESC and ACC/AHA NSTE-ACS Guidelines2007 ESC and ACC/AHA NSTE-ACS Guidelines

► Risk stratification in relation to bleeding and the prevention of Risk stratification in relation to bleeding and the prevention of bleedingbleeding are considered of utmost importance in both GLs, are considered of utmost importance in both GLs, and particularly in the ESC guidelines.and particularly in the ESC guidelines.

► The validation and introduction in the GLs of newer The validation and introduction in the GLs of newer antithrombotic agents characterised by lower bleeding risk is antithrombotic agents characterised by lower bleeding risk is one of the most important novelties of both guidelines.one of the most important novelties of both guidelines.

► Recommendations about a restrictive approach to Recommendations about a restrictive approach to transfusionstransfusions and instructions for continuing antithrombotic and instructions for continuing antithrombotic therapies in the case of bleeding in order to avoid “rebound therapies in the case of bleeding in order to avoid “rebound phenomena” bear important clinical implications. phenomena” bear important clinical implications.

Incidence of BleedingIncidence of Bleedingin ACSin ACS

Landmark Practice Advances inSTEMI and ACSLandmark Practice Advances inSTEMI and ACS

30-Day Bleeding Endpoints*30-Day Bleeding Endpoints* UFH + GP IIb/IIIaUFH + GP IIb/IIIa(N=1802)(N=1802)

BivalirudinBivalirudin(N=1800)(N=1800) P ValueP Value

Protocol Major, non CABG**Protocol Major, non CABG** 8.3%8.3% 4.9%4.9% <0.0001<0.0001

Protocol Major, AllProtocol Major, All 10.8%10.8% 6.8%6.8% <0.0001<0.0001

Protocol MinorProtocol Minor 15.4%15.4% 8.6%8.6% <0.0001<0.0001

Blood transfusionBlood transfusion 3.5%3.5% 2.1%2.1% 0.0090.009

TIMI MajorTIMI Major 5.0%5.0% 3.1%3.1% 0.0020.002

TIMI MinorTIMI Minor 4.6%4.6% 2.8%2.8% 0.0060.006

TIMI Major or MinorTIMI Major or Minor 9.6%9.6% 5.9%5.9% <0.0001<0.0001

GUSTO LT*** or SevereGUSTO LT*** or Severe 0.6%0.6% 0.4%0.4% 0.490.49

GUSTO ModerateGUSTO Moderate 5.0%5.0% 3.1%3.1% 0.0020.002

GUSTO LT or Severe or ModerateGUSTO LT or Severe or Moderate 5.6%5.6% 3.5%3.5% 0.0020.002

*CEC adjudicated, except protocol minor; **Primary endpoint; ***Life threatening*CEC adjudicated, except protocol minor; **Primary endpoint; ***Life threatening

HORIZONS-AMI TrialHORIZONS-AMI TrialBleeding Incidence Depends on DefinitionBleeding Incidence Depends on Definition

Major Bleeding in Italian RegistriesMajor Bleeding in Italian RegistriesMajor Bleeding in Italian RegistriesMajor Bleeding in Italian Registries

Same definition: Same definition: life threatening, Hb -5 mg/dL or Ht -15%, transfusion.life threatening, Hb -5 mg/dL or Ht -15%, transfusion.

Registry Registry refref YY

N° N° centers centers

N° patientsN° patients(% con ACS)(% con ACS)

Inclusion Inclusion CriteriaCriteria

Major Major BleedingBleeding

BLITZ-1 BLITZ-1 Eur Heart J Eur Heart J

2003200320012001 296296 1959 (100)1959 (100) Consecutive pts Consecutive pts

with MIwith MI 2.0%2.0%

BLITZ-2BLITZ-2Eur Heart J Eur Heart J

2006200620032003 275275 1888 (100)1888 (100)

Consecutive Consecutive patients with patients with NSTEACSNSTEACS

1.3%1.3%

IDEAIDEAItal Heart J Ital Heart J

2005200520032003 7979 1517 (50)1517 (50) Consecutive Consecutive

patients with PCIpatients with PCI

Stable 0.5%Stable 0.5%

ACS 1.3%ACS 1.3%

STEMI 4.3%STEMI 4.3%

ISAR-REACT 2 Trial (N=2020) ISAR-REACT 2 Trial (N=2020) Clopidogrel 600 mg and Abciximab in ACSClopidogrel 600 mg and Abciximab in ACS

Kastrati A. Kastrati A. JAMAJAMA 2006 2006

1.4%

4.2%

2.5%

1.4%

3.3%

2.0%

0%

1%

2%

3%

4%

5%

Major Bleeding Minor Bleeding Transfusion

Abciximab Placebo

In-hospital Major and Minor Bleeding (%)In-hospital Major and Minor Bleeding (%)

p=NSp=NS

30-Day Death According to Bleeding30-Day Death According to BleedingOASIS Registry, OASIS-2, CUREOASIS Registry, OASIS-2, CURE

J Eikelboom et al J Eikelboom et al CirculationCirculation 2006 2006

0022

4466

881

010

1212

1414

00 55 1010 1515 2020 2525 3030

BleedingBleeding

No BleedingNo Bleeding

No. at RiskNo. at RiskNo BleedingNo BleedingBleedingBleeding

3367633676 3341933419 3315733157 3299032990 3287932879 3276932769 3271032710

470 470

(1.4%)

459459 440440 430430 420420 410410 408408

Cum

ulat

ive

Eve

nts,

%C

umul

ativ

e E

vent

s, %

DaysDays

Association Between Bleeding and Outcome Association Between Bleeding and Outcome in ACS and PCIin ACS and PCI


Major Bleeding is Associated with an Increased Major Bleeding is Associated with an Increased Risk of Hospital Death in ACS PatientsRisk of Hospital Death in ACS Patients

Moscucci et al. Moscucci et al. Eur Heart JEur Heart J 2003;24:1815-23 2003;24:1815-23

GRACE Registry in 24,045 ACS patientsGRACE Registry in 24,045 ACS patients

*After adjustment for comorbidities, clinical presentation and hospital therapies*After adjustment for comorbidities, clinical presentation and hospital therapies**p<0.001 for differences in unadjusted death rates**p<0.001 for differences in unadjusted death rates

OR (95% CI) OR (95% CI) 1.64 (1.18 to 2.28*)1.64 (1.18 to 2.28*)

00

Overall ACSOverall ACS UAUA NSTEMI NSTEMI STEMISTEMI

1010

2020

3030

4040

****

**** ****

****

5.15.1

18.618.6

3.03.0

16.116.1

5.35.3

15.315.3

7.07.0

22.822.8

Inh

osp

ital d

ea

th (

%)

Inh

osp

ital d

ea

th (

%)

In hospital major bleedingIn hospital major bleeding YesYes

NoNo

30 -Death According to Bleeding30 -Death According to BleedingOASIS Registry, OASIS-2, CUREOASIS Registry, OASIS-2, CURE

J Eikelboom et al Circulation 2006 J Eikelboom et al Circulation 2006

0022

4466

881

010

1212

1414

00 55 1010 1515 2020 2525 3030

BleedingBleeding

No BleedingNo Bleeding

No. at RiskNo. at RiskNo BleedingNo BleedingBleedingBleeding

3367633676 3341933419 3315733157 3299032990 3287932879 3276932769 3271032710

470 470

(1.4%)

459459 440440 430430 420420 410410 408408

Cum

ulat

ive

Eve

nts,

%C

umul

ativ

e E

vent

s, %

DaysDays

Bleeding is Associated with an Increased Bleeding is Associated with an Increased 30-Day Mortality in NSTEMI Patients30-Day Mortality in NSTEMI Patients

Rao et al. Am J Cardiol 2005;96:1200-1206Rao et al. Am J Cardiol 2005;96:1200-1206

N=26,452 ACS patients from N=26,452 ACS patients from GUSTO IIb, PURSUIT and PARAGON A & BGUSTO IIb, PURSUIT and PARAGON A & B

Log-rank p values are 0.0001 for all 4 categories, 0.20 for no bleeding vs. mild bleeding, 0.0001 for Log-rank p values are 0.0001 for all 4 categories, 0.20 for no bleeding vs. mild bleeding, 0.0001 for mild vs. moderate bleeding, and 0.001 for moderate vs. severe bleeding.mild vs. moderate bleeding, and 0.001 for moderate vs. severe bleeding.

Adjusted HR Adjusted HR (95% CI)(95% CI)

% Death% Death

2.9%2.9% 1.01.03.5%3.5% 1.6 (1.3-1.9)1.6 (1.3-1.9)5.9%5.9% 2.7 (2.3-3.4)2.7 (2.3-3.4)

25.7%25.7% 10.6 (8.3-13.6)10.6 (8.3-13.6)

GUSTO bleedingGUSTO bleeding NoneNone MildMild ModerateModerate SevereSevere

00 55 1010 1515 2020 2525 3030

0.700.70

0.750.75

0.800.80

0.850.85

0.900.90

0.950.95

1.001.00

Days to DeathDays to Death

Cum

ula

tive

sur

viva

lC

umu

lativ

e s

urvi

val

Procedure- and Non-Procedure-Related Bleeds are Procedure- and Non-Procedure-Related Bleeds are Associated with an higher 30-Day Mortality in NSTEMIAssociated with an higher 30-Day Mortality in NSTEMI

Procedure-related Procedure-related GUSTO bleedsGUSTO bleeds

Non-procedure-related Non-procedure-related GUSTO bleeds GUSTO bleeds

Ris

k of

dea

th (

haza

rd R

atio

)R

isk

of d

eath

(ha

zard

Rat

io)

NoneNone

1.01.0

MildMild

1.31.3

SevereSevere

16.516.5

00

55

2020

1010

1515

NoneNone

1.01.0

MildMild

2.12.1

ModerateModerate

2.52.5

SevereSevere

10.910.9

ModerateModerate

3.73.7

Rao et al. Am J Cardiol 2005;96:1200-1206Rao et al. Am J Cardiol 2005;96:1200-1206

N=26,452 ACS patients from N=26,452 ACS patients from GUSTO IIb, PURSUIT and PARAGON A & BGUSTO IIb, PURSUIT and PARAGON A & B

Bleeding Within 30 Days is a Powerful and Bleeding Within 30 Days is a Powerful and Independent Predictor of 1-year Death After PCIIndependent Predictor of 1-year Death After PCI

Ndrepepa G. JACC 2008;51:690-7 * Calculated for a 10-year increase in age.Ndrepepa G. JACC 2008;51:690-7 * Calculated for a 10-year increase in age.

5,384 patients from 4 RCT on the value of abciximab after pretreatment with5,384 patients from 4 RCT on the value of abciximab after pretreatment with600 mg of clopidogrel: ISAR-REACT, SWEET, SMART-2 and REACT-2600 mg of clopidogrel: ISAR-REACT, SWEET, SMART-2 and REACT-2

““Our study demonstrates a strong relationship between the 30-day frequency of bleeding Our study demonstrates a strong relationship between the 30-day frequency of bleeding and 1-year mortality after PCI and supports the inclusion of periprocedural bleeding in a and 1-year mortality after PCI and supports the inclusion of periprocedural bleeding in a 30-day quadruple endpoint for the assessment of outcome after PCI.”30-day quadruple endpoint for the assessment of outcome after PCI.”

VariableVariable Hazard Ratio Hazard Ratio (95% CI)(95% CI) P ValueP Value

Bleeding within 30 daysBleeding within 30 days 2.96(1.96-4.48)2.96(1.96-4.48) <0.001<0.001

Myocardial infarction within 30 daysMyocardial infarction within 30 days 2.29(1.52-3.46)2.29(1.52-3.46) <0.001<0.001

Urgent revascularization within 30 daysUrgent revascularization within 30 days 2.49(1.16-5.35)2.49(1.16-5.35) 0.0190.019

Age (years)*Age (years)* 2.27(1.78-2.89)2.27(1.78-2.89) <0.001<0.001

DiabetesDiabetes 1.47(1.11-1.96)1.47(1.11-1.96) 0.0080.008

Multivessel coronary diseaseMultivessel coronary disease 2.72(1.56-4.67)2.72(1.56-4.67) <0.001<0.001

Elevated troponinElevated troponin 1.77(1.27-2.47)1.77(1.27-2.47) <0.001<0.001

Left ventricular ejection fractionLeft ventricular ejection fraction 0.71(0.60-0.85)0.71(0.60-0.85) <0.001<0.001

Creatinine levelCreatinine level 1.10(1.06-1.14)1.10(1.06-1.14) <0.001<0.001

Potential Mechanisms for the Higher Potential Mechanisms for the Higher Morbidity/Mortality Associated with BleedingMorbidity/Mortality Associated with Bleeding

1.1. Cessation of antithrombotic therapies after bleeding may Cessation of antithrombotic therapies after bleeding may increase subsequent ischemic eventsincrease subsequent ischemic events

2.2. Patients who bleed may have an heightened inflammatory Patients who bleed may have an heightened inflammatory statestate

3.3. Adverse effects of hypotension Adverse effects of hypotension

4.4. Adverse effects of transfusionAdverse effects of transfusion

5.5. Common risk factors for bleeding and adverse outcome Common risk factors for bleeding and adverse outcome

1. Gibbons & Fuster. N Engl J Med 2006;354:1524-7 1. Gibbons & Fuster. N Engl J Med 2006;354:1524-7 2. Califf. JAMA 2006;295:1579-802. Califf. JAMA 2006;295:1579-803. Jozic J. AJC 2006;98:36M3. Jozic J. AJC 2006;98:36M

Blood Transfusion is Associated with Blood Transfusion is Associated with an Increased 30-Day Mortality in NSTEMIan Increased 30-Day Mortality in NSTEMI

Rao et al. Rao et al. JAMAJAMA 2004;292:1555-62 2004;292:1555-62

N=24,112 ACS patients from GUSTO IIb, PURSUIT and PARAGONN=24,112 ACS patients from GUSTO IIb, PURSUIT and PARAGON

*Adjusted for baseline characteristics, bleeding and transfusion propensity and nadir hematocrit*Adjusted for baseline characteristics, bleeding and transfusion propensity and nadir hematocrit

HR=3.94*; HR=3.94*; 95%CI: 3.26 to 4.7595%CI: 3.26 to 4.75

30-day 30-day death ratedeath rate

TransfusionTransfusion

No TransfusionNo Transfusion

Cum

ula

tive

mor

talit

yC

umu

lativ

e m

orta

lity

Log-rank Log-rank p<0.001p<0.001

00

0.020.02

0.040.04

0.060.06

0.080.08

0.100.10

55 1010 1515 2020 2525 3030DayDay

8.00%8.00%

3.08%3.08%

Transfusion and 30-day MortalityTransfusion and 30-day Mortality

1.01.0 10100.10.1

Cox model, transfusion = time-dependent covariateCox model, transfusion = time-dependent covariate

Adjusted for transfusion Adjusted for transfusion propensitypropensity

Adjusted for baselineAdjusted for baselinecharacteristicscharacteristics

Adjusted for baseline Adjusted for baseline characteristics, bleedingcharacteristics, bleedingpropensity, transfusion propensity, transfusion propensity, and nadir HCTpropensity, and nadir HCT

3.83.8

3.53.5

3.93.9

Odds RatioOdds Ratio

Rao SV, et. al., JAMA 2004Rao SV, et. al., JAMA 2004

Bleeding is an independent predictor of outcomeBleeding is an independent predictor of outcome

Reducing bleeding improves outcomeReducing bleeding improves outcome

The Therapeutic TheoremThe Therapeutic Theorem

OASIS-5—Major Bleeding: 9 DaysOASIS-5—Major Bleeding: 9 Days

OASIS 5 Investigators. NEJM 2006;354:1464-76OASIS 5 Investigators. NEJM 2006;354:1464-76

0.000.00

0.010.01

0.020.02

0.030.03

0.040.04

Cu

mu

lativ

e H

aza

rdC

um

ula

tive

Ha

zard

DaysDays

Hazard ratio 0.53 Hazard ratio 0.53 (95% CI, 0.45-0.62)(95% CI, 0.45-0.62)

BleedingBleedingBleedingBleeding

00 11 22 33 44 55 66 77 88 99

FondaparinuxFondaparinuxEnoxaparinEnoxaparin

OASIS 5 Investigators. NEJM 2006;354:1464-76OASIS 5 Investigators. NEJM 2006;354:1464-76

OASIS-5—Efficacy Outcomes at Day 9OASIS-5—Efficacy Outcomes at Day 9

5.9%5.9%5.8%5.8%Death/MI/RIDeath/MI/RI

2.05%2.05%1.9%1.9%Refract Refract IschemiaIschemia

2.7%2.7%2.7%2.7%MIMI

1.8%1.8%1.9%1.9%DeathDeath

4.1%4.1%4.1%4.1%Death/MIDeath/MI

FondaFondaEnoxEnox

0.80.8 11 1.21.2

NonNon-- inferiorityinferiorityMargin=1.185Margin=1.185

Hazard RatioHazard RatioFonda BetterFonda Better EnoxEnox BetterBetter

Death/Reinfarction/Stroke/Severe BleedingDeath/Reinfarction/Stroke/Severe Bleeding

HRHR 95%CI95%CI

No reperfusion therapyNo reperfusion therapy

Thrombolytic therapyThrombolytic therapy

PCIPCI

OverallOverall

0.810.81 0.69-0.960.69-0.96 0.0160.016

0.830.83 0.73-0.950.73-0.95 0.0070.007

1.121.12 0.90-1.390.90-1.39 0.290.29

0.880.88 0.80-0.970.80-0.97 0.0070.007

1.0 100.1

Fondaparinux betterFondaparinux better Placebo/UFH betterPlacebo/UFH better

Hazard Ratio Hazard Ratio (log scale)(log scale)

p valuep value

The OASIS-6 Trial Group. The OASIS-6 Trial Group. JAMAJAMA 2006;295:1519-30 2006;295:1519-30

OASIS-6—Effect on PCI Patients:OASIS-6—Effect on PCI Patients:The Achilles Heel of FondaparinuxThe Achilles Heel of Fondaparinux

OASIS 5 Investigators. OASIS 5 Investigators. NEJMNEJM 2006;354:1464-76 2006;354:1464-76

OASIS-5: Mortality at 6 MonthsOASIS-5: Mortality at 6 Months

DaysDays

Cum

ulat

ive

Haz

ard

Cum

ulat

ive

Haz

ard

0.0

0.02

0.04

0.06

0 20 40 60 80 100 120 140 160 180

HR 0.89HR 0.89HR 0.89HR 0.89

95% CI 0.7995% CI 0.7995% CI 0.7995% CI 0.79 ---- 0.99 0.99 0.99 0.99

P=0.037P=0.037P=0.037P=0.037

Enoxaparin

Fondaparinux

OASIS-6: Fondaparinux Reduced Mortality OASIS-6: Fondaparinux Reduced Mortality up to Day 180up to Day 180

DaysDays

UFH or placeboUFH or placebo

FondaparinuxFondaparinux

HR: 0.88HR: 0.88

95% CI: 0.79-0.9995% CI: 0.79-0.99

p=0.03p=0.03

00

0.020.02

0.040.04

0.060.06

0.080.08

0.100.10

0.120.12

0.140.14

0.160.16

00

Cum

ulat

ive

Haz

ard

Cum

ulat

ive

Haz

ard

3030 6060 9090 120120 150150 180180

The OASIS-6 Trial Group. The OASIS-6 Trial Group. JAMAJAMA 2006;295:1519-30 2006;295:1519-30

10.0%

0.4%

6.2%

1.4%

4.1%

9.2%

0.2%

7.0%

1.2%

2.4%

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

Combined Death MI Revasc. Major Bleeding

Heparin + GPI (n=3,008) Bivalirudin (n=2,994)

Principal Endpoint Principal Endpoint

p = 0.324p = 0.324

p = 0.255p = 0.255

p = 0.430p = 0.430

p = 0.435p = 0.435

p < 0.001p < 0.001

Lincoff AM et al. Lincoff AM et al. JAMAJAMA. 2003; 289:853-863.. 2003; 289:853-863.

ACUITY: Primary Endpoint Measures (ITT)ACUITY: Primary Endpoint Measures (ITT)

UFH/Enoxaparin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin Alone

PNI <0.0001PNI <0.0001PSup = 0.015PSup = 0.015

PPNINI = 0.011 = 0.011

PPSupSup = 0.32 = 0.32PNI <0.0001PNI <0.0001

PSup <0.0001PSup <0.0001

11.7%11.7%

7.3%7.3%5.7%5.7%

3.0%3.0%

10.1%10.1%

7.8%7.8%

Net clinical outcomeNet clinical outcome Ischemic compositeIschemic composite Major bleedingMajor bleeding

30 d

ay e

vent

s (%

)30

day

eve

nts

(%)

UFH/Enoxaparin+GPI (N=4603)UFH/Enoxaparin+GPI (N=4603) Bivalirudin alone (N=4612)Bivalirudin alone (N=4612)

Stone GW et al. Stone GW et al. NEJMNEJM 2006;355:2203-16 2006;355:2203-16

Prim

ary

End

poin

tP

rimar

y E

ndpo

int

Maj

or B

leed

ing

(%)

Maj

or B

leed

ing

(%)


8.4%8.4%

5.0%5.0%

HR [95%CI] =HR [95%CI] =0.59 [0.45, 0.76]0.59 [0.45, 0.76]

P<0.0001P<0.0001



HORIZONS AMI—30-Day Major HORIZONS AMI—30-Day Major Bleeding (non-CABG)Bleeding (non-CABG)


HORIZONS AMI—30-Day HORIZONS AMI—30-Day Stent Thrombosis Stent Thrombosis (N=3,124)(N=3,124)



PPValueValue

ARC definite or ARC definite or probable*probable* 1.9%1.9% 2.5%2.5% 0.330.33

DefiniteDefinite 1.4%1.4% 2.2%2.2% 0.110.11

ProbableProbable 0.5%0.5% 0.3%0.3% 0.260.26

Acute Acute (≤24 hrs)(≤24 hrs) 0.3%0.3% 1.3%1.3% 0.00090.0009

Subacute Subacute (>24 hrs – 30d)(>24 hrs – 30d) 1.7%1.7% 1.2%1.2% 0.300.30


REPLACE-2REPLACE-2N=6,002N=6,002

Lincoff AM, JAMA 2005Lincoff AM, JAMA 2005

ACUITYACUITYN=13,819N=13,819

Stone GW, AHA 2007Stone GW, AHA 2007

HORIZONS AMIHORIZONS AMIN=3,602N=3,602

Stone GW, JAMA 2008Stone GW, JAMA 2008

1-year mortality1-year mortality-24%-24%p=0.16p=0.16

1-year mortality1-year mortality-14%-14%p=0.90p=0.90 30-day mortality30-day mortality

-32%-32%p=0.048p=0.048

Consistent Reduction in MortalityConsistent Reduction in MortalityAcross the Bivalirudin TrialsAcross the Bivalirudin Trials

2.5

4.4

3.1

1.9

3.8

2.1

0

1

2

3

4

5

6

7

8

Net Clinical BenefitNet Clinical BenefitDeath, MI, Stroke, Major Bleed (non CABG)Death, MI, Stroke, Major Bleed (non CABG)

00

55

1010

1515

00 3030 6060 9090 180180 270270 360360 450450DaysDays

En

dpo

int (

%)

En

dpo

int (

%)

HR 0.87HR 0.87P=0.004P=0.004

13.913.9

12.2 12.2

Prasugrel Prasugrel

ClopidogrelClopidogrelITT= 13,608ITT= 13,608

-23

6

-25

-20

-15

-10

-5

0

5

10

Events per 1000 ptsEvents per 1000 pts

MIMI Major BleedMajor Bleed(non CABG)(non CABG)

++All CauseAll CauseMortalityMortality

Clop 3.2%Clop 3.2%Pras 3.0 %Pras 3.0 %

-6%-6%P=0.64P=0.64

Antiplatelet Therapy in ACSAntiplatelet Therapy in ACS

0

1 08

Placebo APTC CURE TRITON-TIMI 38

Single Single Antiplatelet RxAntiplatelet Rx

Dual Dual Antiplatelet RxAntiplatelet Rx

Higher Higher IPAIPA

ASAASA

ASA +ASA + ClopidogrelClopidogrel ASA +ASA + PrasugrelPrasugrel

- 22%

- 20%

- 19%

+ 60% + 38% + 32%

Reduction in

IschemicEvents

Increase in

Major Bleeds

Better Outcomes Observed with Better Outcomes Observed with Newer Anticoagulants vs Antiplatelet DrugsNewer Anticoagulants vs Antiplatelet Drugs

• • Recent improvements in Recent improvements in anticoagulant therapyanticoagulant therapy have have

dramatically reduced acute bleeding at the expense of a dramatically reduced acute bleeding at the expense of a

slightly lower, but insignificant, anti-ischemic efficacy, slightly lower, but insignificant, anti-ischemic efficacy,

particularly in PCI patients. particularly in PCI patients. This shift in the efficacy vs This shift in the efficacy vs

safety ratio translated into a mortality reduction at follow upsafety ratio translated into a mortality reduction at follow up. .

• • Recent improvements in Recent improvements in anticoagulant therapyanticoagulant therapy have have

dramatically reduced acute bleeding at the expense of a dramatically reduced acute bleeding at the expense of a

slightly lower, but insignificant, anti-ischemic efficacy, slightly lower, but insignificant, anti-ischemic efficacy,

particularly in PCI patients. particularly in PCI patients. This shift in the efficacy vs This shift in the efficacy vs

safety ratio translated into a mortality reduction at follow upsafety ratio translated into a mortality reduction at follow up. .

• • Recent improvements in Recent improvements in antiplatelet therapyantiplatelet therapy have have

improved anti-ischemic protection, particularly in PCI improved anti-ischemic protection, particularly in PCI

patients, at the expense of a higher bleeding risk. This shift patients, at the expense of a higher bleeding risk. This shift

in the efficacy vs safety ratio translated into a prevention of in the efficacy vs safety ratio translated into a prevention of

acute and subsequent MI, however without a mortality acute and subsequent MI, however without a mortality

reduction at follow up. reduction at follow up.

• • Recent improvements in Recent improvements in antiplatelet therapyantiplatelet therapy have have

improved anti-ischemic protection, particularly in PCI improved anti-ischemic protection, particularly in PCI

patients, at the expense of a higher bleeding risk. This shift patients, at the expense of a higher bleeding risk. This shift

in the efficacy vs safety ratio translated into a prevention of in the efficacy vs safety ratio translated into a prevention of

acute and subsequent MI, however without a mortality acute and subsequent MI, however without a mortality

reduction at follow up. reduction at follow up.

Ischemic RiskIschemic Risk

Bleeding riskBleeding risk

0 25 50 75 100%0 25 50 75 100%

100-100-

80-80-

60-60-

40-40-

20-20-

0-0-

Anti-

isch

emic

effe

ct

Anti-

isch

emic

effe

ct

Net clinical benefit

Net clinical benefit

Tre

atm

ent

effe

ctT

reat

men

t ef

fect

The Relationships Among Baseline Risk, Bleeding Risk The Relationships Among Baseline Risk, Bleeding Risk and Net Clinical Benefit for an Effective Treatmentand Net Clinical Benefit for an Effective Treatment

NSTE-ACSNSTE-ACS• ST depressionST depression

• Tn elevationTn elevation

• Refractory ischemiaRefractory ischemia

• LV dysfunctionLV dysfunction

• DiabetesDiabetes

• ElderlyElderly

• Chronic Kidney Dysf.Chronic Kidney Dysf.

STEMISTEMI• ElderlyElderly

• High KillipHigh Killip

• Prior MIPrior MI

• Large MILarge MI

• Failed lysis Failed lysis

• DiabetesDiabetes

• CKDCKD

Independent Predictors of Independent Predictors of Ischemic and Bleeding EventsIschemic and Bleeding Events

PCI PATIENTSPCI PATIENTS• Female Female

• ElderlyElderly


• Prior PCIPrior PCI

• Cardiogenic shockCardiogenic shock

• NYHA >2NYHA >2

• Prior valve surgeryPrior valve surgery

PCI PATIENTSPCI PATIENTS• Female Female

• ElderlyElderly


• Prior PCIPrior PCI

• Cardiogenic shockCardiogenic shock

• NYHA >2NYHA >2

• Prior valve surgeryPrior valve surgery

ISCHEMIC EVENTSISCHEMIC EVENTS BLEEDINGBLEEDING

Mehta S, AHA 2007Mehta S, AHA 2007Risk model from 302,152 ptsRisk model from 302,152 ptsIn the NCDR databaseIn the NCDR database

2007 ESC and ACC/AHA2007 ESC and ACC/AHANSTEACS GuidelinesNSTEACS Guidelines

2004 ACC/AHA 2004 ACC/AHA STEMI GuidelinesSTEMI Guidelines

NSTE-ACSNSTE-ACS STEMISTEMI PCI PATIENTSPCI PATIENTS

19971997 2008 and Beyond2008 and Beyond

UrgentUrgentTVRTVR

Symptomatic Symptomatic MIMICKMBCKMB

GPIGPI

UrgentUrgentTVRTVR

Symptomatic Symptomatic MIMICKMBCKMB


MajorMajorbleedingbleeding

Net Clinical Benefit of Pharmacological Intervention in Net Clinical Benefit of Pharmacological Intervention in PCI: Should We Move From a Triangle to a Square?PCI: Should We Move From a Triangle to a Square?

Dauerman HL. JACC 2008;51:698Dauerman HL. JACC 2008;51:698

30-Day and 1-year30-Day and 1-yearMortality RatesMortality Rates30-Day30-Day

MortalityMortality


Translating Advances In STEMI And Translating Advances In STEMI And NSTEMI Into Real World PracticeNSTEMI Into Real World Practice

The Austrian Experience—EarlyThe Austrian Experience—EarlyFindings and ObservationsFindings and Observations


Michael M. Hirschl, MDMichael M. Hirschl, MDAssociate ProfessorAssociate Professor

Head of the Emergency RoomHead of the Emergency RoomMedical Department of Cardiology and Intensive Care MedicineMedical Department of Cardiology and Intensive Care Medicine

Landesklinikum St. PöltenLandesklinikum St. PöltenA-3100 St. Pölten, AustriaA-3100 St. Pölten, Austria

STEMISTEMI

Advances in STEMI ManagementAdvances in STEMI Management

LogisticLogistic PharmacologicalPharmacological

► Implementation of networks among Implementation of networks among cardiac catheterization centers cardiac catheterization centers (especially in urban areas) using a (especially in urban areas) using a rotation principle rotation principle

► Establishment of integrated systems of Establishment of integrated systems of care among primary care hospitals care among primary care hospitals without cardiac catheterization capability without cardiac catheterization capability and a high-volume tertiary cardiac care and a high-volume tertiary cardiac care centercenter

Logistical Advances in STEMI CareLogistical Advances in STEMI Care

► Concept of upstream treatment of Concept of upstream treatment of STEMI patientsSTEMI patients

► (Facilitated PCI) – A (Facilitated PCI) – A Pharmacoinvasive ConceptPharmacoinvasive Concept

Pharmacological AdvancesPharmacological Advances

Upstream Treatment: PrinciplesUpstream Treatment: Principles

► Early administration of antithrombotic Early administration of antithrombotic and/or anticoagulation therapy seems to and/or anticoagulation therapy seems to improve survival of STEMI patients.improve survival of STEMI patients.

► The optimal timing is still a matter of The optimal timing is still a matter of discussion:discussion:● In the cath lab (data available)In the cath lab (data available)● In the emergency department (data available)In the emergency department (data available)● In the EMS (NO DATA)In the EMS (NO DATA)

How can we establish these advances in How can we establish these advances in daily clinical practice?daily clinical practice?


LAMI: The NetworkLAMI: The Network

► 6 primary care hospitals – STEMI 6 primary care hospitals – STEMI referralreferral

► 1 STEMI-accepting hospital: 24 hours 1 STEMI-accepting hospital: 24 hours a day, 7 days a weeka day, 7 days a week

► Affiliated Emergency Medical Services Affiliated Emergency Medical Services (EMS) – Ground transport(EMS) – Ground transport

► Affiliated rescue helicopters (2): Day-Affiliated rescue helicopters (2): Day-time operation time operation

Two-Step ProgramTwo-Step Program

► 2006:2006: Assessment of the current logistic Assessment of the current logistic and treatment modalities in our networkand treatment modalities in our network

► January 2007:January 2007: Conference with the Conference with the heads of the hospitals, the EMS, and air heads of the hospitals, the EMS, and air rescue service to implement uniform rescue service to implement uniform logistic and treatment guidelines.logistic and treatment guidelines.

► February 2007:February 2007: Start of the uniform Start of the uniform protocolprotocol

Aim of the LAMI StudyAim of the LAMI Study

► Evaluation of the uniform Evaluation of the uniform protocol with regard to:protocol with regard to:

● Interhospital transfer intervalInterhospital transfer interval● Intrahospital transfer timeIntrahospital transfer time● Total ischemic timeTotal ischemic time● Adherence to treatment guidelinesAdherence to treatment guidelines● MORTALITYMORTALITY

The LAMI ProtocolThe LAMI Protocol

► Application of treatment as early as possible, i.e. Application of treatment as early as possible, i.e. at the time of first medical contact – normally at the time of first medical contact – normally administered by the EMS-staff!administered by the EMS-staff!

● Aspirin 300 mg i.v.Aspirin 300 mg i.v.● Clopidogrel 600 mg orallyClopidogrel 600 mg orally● Heparin (UFH or LMWH)Heparin (UFH or LMWH)● Thrombolysis if onset of symptoms < 2 hours Thrombolysis if onset of symptoms < 2 hours ● Primary PCI if onset of symptoms > 2 hoursPrimary PCI if onset of symptoms > 2 hours

• Until March 2008: Abciximab given in the EMSUntil March 2008: Abciximab given in the EMS• Since April 2008: Bivalirudin (bolus and continuous Since April 2008: Bivalirudin (bolus and continuous

infusioninfusion))

Transfer Intervals: Early FindingsTransfer Intervals: Early Findings

00

100100

200200

300300

400400

1.ECG-ED1.ECG-ED ED-PCIED-PCI TOTAL TIMETOTAL TIME

Min

utes

Min

utes

20062006

20072007

p=0.038p=0.038

p=0.042p=0.042

n.sn.s

Decrease from 235 to 180 minutesDecrease from 235 to 180 minutes

Reperfusion StrategiesReperfusion Strategies

20062006 20072007 OverallOverall

NN 113113 130130 243243

Primary PCIPrimary PCI 69%69% 69%69% 69%69%

Thrombolysis Thrombolysis 18%18% 16%16% 16%16%

No Acute No Acute InterventionIntervention 13%13% 15%15% 15%15%

Adherence to Treatment GuidelinesAdherence to Treatment Guidelines

20062006 20072007 OverallOverall

NumberNumber 113113 130130 243243

AspirinAspirin 90%90% 89%89% 89%89%

ClopidogrelClopidogrel 90% 90% 94%94% 92%92%

HeparinHeparin(UFH/LMWH)(UFH/LMWH) 87%87% 95%95% 92%92%

GPIIb/IIIa AntagonistGPIIb/IIIa Antagonist 82%82% 88%88% 85%85%

30-Day Mortality: LAMI30-Day Mortality: LAMI

10.6

16.6

14.7

7.5

13.3

9.3

0

2

4

6

8

10

12

14

16

18

PPCI TT TOTAL

2006

2007

Relative RR: 36%

Change From Abciximab to BivalirudinChange From Abciximab to Bivalirudin

► Percentage of bleeding Percentage of bleeding complicationscomplications

► Easier Handling: One drug from Easier Handling: One drug from initial ECG until 12 hours after initial ECG until 12 hours after interventionintervention

Bleeding Complications: LAMI ProtocolBleeding Complications: LAMI Protocol

AbciximabAbciximabN=243N=243

BivalirudinBivalirudinN=54N=54

Major ComplicationsMajor Complications 4.3%4.3% 2.1%2.1%

OverallOverall 9.2%9.2% 5.8%5.8%

Bivalirudin in the Real World IBivalirudin in the Real World I

► Start of bivalirudin treatment after Start of bivalirudin treatment after the 1st ECG:the 1st ECG:

● EMS (out-of-hospital)EMS (out-of-hospital)● Emergency department of the primary Emergency department of the primary

care hospitalcare hospital● Intravenous bolus: 0.1 mg/kg Intravenous bolus: 0.1 mg/kg ● Followed by continuous infusion with Followed by continuous infusion with

0.25 mg/kg i.v.0.25 mg/kg i.v.

Bivalirudin in the Real World IIBivalirudin in the Real World II

► Increase bivalirudin dose to 1.75 mg/kg Increase bivalirudin dose to 1.75 mg/kg i.v. in the cath lab in case of interventioni.v. in the cath lab in case of intervention

► Reduction of dose at the end of the Reduction of dose at the end of the intervention to 0.25 mg/kg i.v.intervention to 0.25 mg/kg i.v.

► End of continuous infusion 12 hours after End of continuous infusion 12 hours after intervention and switch to LMWHintervention and switch to LMWH

Adherence to Treatment GuidelinesAdherence to Treatment GuidelinesLAMI Protocol: 2008LAMI Protocol: 2008

20062006 20072007 March to June 2008March to June 2008

NN 113113 130130 5454

AspirinAspirin 90%90% 89%89% 92%92%

ClopidogrelClopidogrel 90% 90% 94%94% 94%94%

Heparin Heparin (UFH/LMWH)(UFH/LMWH) 87%87% 95%95%

GPIIb/IIIa-Antag.GPIIb/IIIa-Antag. 82%82% 88%88% Bivalirudin: 94%Bivalirudin: 94%

Summary ISummary I

► Logistical guidelines contribute substantially to Logistical guidelines contribute substantially to an improved survival of STEMI patients. an improved survival of STEMI patients. However, the total ischemic time was However, the total ischemic time was significantly prolonged compared to current significantly prolonged compared to current guidelines even after implementation (mean: guidelines even after implementation (mean: 180 min. vs. 90 minutes recommended) in real 180 min. vs. 90 minutes recommended) in real world.world.

► Reasons for these delays are enviromental Reasons for these delays are enviromental and infrastructural circumstances in rural and infrastructural circumstances in rural areas such as those served by our (LAMI) areas such as those served by our (LAMI) network.network.

Summary IISummary II

► Optimal adherence to guidelines and a high Optimal adherence to guidelines and a high percentage of PPCI are important factors to percentage of PPCI are important factors to offset the negative impact of extended offset the negative impact of extended transfer intervals.transfer intervals.

► The start of treatment as early as possible, i.e. The start of treatment as early as possible, i.e. in the EMS, plays a key role in the in the EMS, plays a key role in the establishment of a successful upstream establishment of a successful upstream strategy. strategy.

ConclusionsConclusions

► Transfer of scientific advances into real world is a time-Transfer of scientific advances into real world is a time-consuming and never-ending process.consuming and never-ending process.

► This process may reduce the gap between advances in This process may reduce the gap between advances in the ideal scientific world and daily clinical practice.the ideal scientific world and daily clinical practice.

► In the LAMI system, initial data suggests use of In the LAMI system, initial data suggests use of bivalirudin appears to decrease bleeding and is bivalirudin appears to decrease bleeding and is associated with high adherence to treatment associated with high adherence to treatment guidelines.guidelines.

Take Home Messages Take Home Messages


Landmark Advances and Novel Perspectives onLandmark Advances and Novel Perspectives onManagement of STEMI and High Risk ACSManagement of STEMI and High Risk ACS

Challenging the Conventional Wisdom—Applying Challenging the Conventional Wisdom—Applying

Clinical Trials and GLs to the FrontClinical Trials and GLs to the FrontLines of Interventional Cardiovascular PracticeLines of Interventional Cardiovascular Practice

Take Home MessagesTake Home Messages

► Major bleeding is a powerful independent determinant of Major bleeding is a powerful independent determinant of mortality in PCI, ACS, STEMI and is at least as important as mortality in PCI, ACS, STEMI and is at least as important as MI and myocardial reinfarctionMI and myocardial reinfarction

► In STEMI, bivalirudin versus heparin + GPI results in a In STEMI, bivalirudin versus heparin + GPI results in a significant reduction in bleeding, thrombocytopenia, and significant reduction in bleeding, thrombocytopenia, and transfusionstransfusions

► In primary PCI for STEMI, bivalirudin is associated with a In primary PCI for STEMI, bivalirudin is associated with a lower 30-day mortality as compared to heparin plus GPIlower 30-day mortality as compared to heparin plus GPI

► Novel antiplatelet agents may potentially further reduce Novel antiplatelet agents may potentially further reduce ischemic eventsischemic events


► Simple manual thrombus aspiration also appears to reduce Simple manual thrombus aspiration also appears to reduce mortality in STEMImortality in STEMI

► There are compelling studies to suggest that when assessing There are compelling studies to suggest that when assessing pharmacoinvasive strategies, net clinical benefit may be pharmacoinvasive strategies, net clinical benefit may be better assessed by a quadruple end point that includes better assessed by a quadruple end point that includes bleeding, MI, urgent TVR, and ischemic biomarkers.bleeding, MI, urgent TVR, and ischemic biomarkers.

► Risk stratification in relation to bleeding and the prevention of Risk stratification in relation to bleeding and the prevention of bleeding are considered of utmost importance in both GLs, bleeding are considered of utmost importance in both GLs, especially those published by the ESC.especially those published by the ESC.


► The validation and introduction in the ESC and AHA The validation and introduction in the ESC and AHA guidelines of newer antithrombotic agents (particularly guidelines of newer antithrombotic agents (particularly fondaparinux and bivalirudin) is characterized by lower fondaparinux and bivalirudin) is characterized by lower bleeding risk, based upon large scale RCTs, and is one of bleeding risk, based upon large scale RCTs, and is one of the most important new features of both GLs.the most important new features of both GLs.

► Therapeutic choices, especially as they relate to bleeding Therapeutic choices, especially as they relate to bleeding minimization, should be individualized for high risk subgroups minimization, should be individualized for high risk subgroups including the elderly, patients with diabetes, and those with including the elderly, patients with diabetes, and those with renal disease.renal disease.

► Switching from any heparin to bivalirudin monotherapy is not Switching from any heparin to bivalirudin monotherapy is not associated with an increased risk for ischemic events. associated with an increased risk for ischemic events. Furthermore, a switch to bivalirudin is associated with a 50% Furthermore, a switch to bivalirudin is associated with a 50% reduction in bleeding.reduction in bleeding.


► In one regional network for STEMI, the LAMI system, initial In one regional network for STEMI, the LAMI system, initial data suggests use of bivalirudin appears to decrease data suggests use of bivalirudin appears to decrease bleeding and is associated with high adherence to treatment bleeding and is associated with high adherence to treatment guidelines for STEMI.guidelines for STEMI.

► Initiation of treatment as early as possible, i.e. in the EMS, Initiation of treatment as early as possible, i.e. in the EMS, plays a key role in the establishment of a successful plays a key role in the establishment of a successful upstream strategy. upstream strategy.

► Mechanical thrombectomy in the select patients with STEMI Mechanical thrombectomy in the select patients with STEMI appears to improve mortality outcomeappears to improve mortality outcome

landmark practice advances in st-elevation myocardial infarction (stemi) and acute coronary syndrome...

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