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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 Angina^Unstable Angina^
E. BraunwaldE. Braunwald
19941994Unstable Angina^Unstable Angina^
E. BraunwaldE. Braunwald
20002000UA/NSTEMIUA/NSTEMI
RevisedRevisedE. BraunwaldE. Braunwald
20002000UA/NSTEMIUA/NSTEMI
RevisedRevisedE. BraunwaldE. Braunwald
20022002UA/NSTEMIUA/NSTEMI
UpdatedUpdatedE. BraunwaldE. Braunwald
20022002UA/NSTEMIUA/NSTEMI
UpdatedUpdatedE. BraunwaldE. Braunwald
20072007UA/NSTEMIUA/NSTEMI
RevisedRevisedJ. AndersonJ. Anderson
20072007UA/NSTEMIUA/NSTEMI
RevisedRevisedJ. AndersonJ. Anderson
20002000ACS w/o STEACS w/o STE
M. BertrandM. Bertrand
20002000ACS w/o STEACS w/o STE
M. BertrandM. Bertrand
20022002ACS w/o STEACS w/o STE
UpdatedUpdatedM. BertrandM. Bertrand
20022002ACS w/o STEACS w/o STE
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)
^AHCPR: Agency for Health Care Policy and Research.^AHCPR: 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
(%)
Days from RandomizationDays from Randomization
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
Chew DP et al. Chew DP et al. HeartHeart 2006;92:945–50. 2006;92:945–50.
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%
Chew DP et al. Chew DP et al. HeartHeart 2006;92:945–50. 2006;92:945–50.
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
(%)
Days from RandomizationDays from Randomization
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
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
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
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
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
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
30-Day MACE Components*30-Day MACE Components*
*CEC adjudicated
UFH + GP IIb/IIIaUFH + GP IIb/IIIa(N=1802)(N=1802)
BivalirudinBivalirudin(N=1800)(N=1800)
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
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
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] =0.66 [0.44, 1.00]
P=0.048
HR [95%CI] =0.66 [0.44, 1.00]
P=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
30-Day Mortality: 30-Day Mortality: Cardiac and Non CardiacCardiac and Non Cardiac
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
2.9%2.9%
1.8%1.8%
Heparin + GPIIb/IIIa inhibitor (n=1802)Heparin + GPIIb/IIIa inhibitor (n=1802)
Bivalirudin monotherapy (n=1800)Bivalirudin monotherapy (n=1800)
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
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
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)
BivalirudinBivalirudin(N=1571)(N=1571)
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
- definite- definite 1.4%1.4% 2.2%2.2% 0.090.09
- probable- probable 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?
Landmark Practice Advances inLandmark Practice Advances inSTEMI and ACSSTEMI and ACS
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
Days from RandomizationDays from Randomization
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 Trial Investigators.SYNERGY Trial Investigators. JAMA JAMA 2004;292:45-54 2004;292:45-54
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
SYNERGY Trial Investigators.SYNERGY Trial Investigators. JAMA JAMA 2004;292:45-54 2004;292:45-54
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]
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. 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
White HD, et al. White HD, et al. J Am Coll CardiolJ Am Coll Cardiol 2008;51:1734–41 2008;51:1734–41
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
White HD, et al. White HD, et al. J Am Coll CardiolJ Am Coll Cardiol 2008;51:1734–41 2008;51:1734–41
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
White HD, et al. White HD, et al. J Am Coll CardiolJ Am Coll Cardiol 2008;51:1734–41 2008;51:1734–41
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)
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 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
Landmark Practice Advances inLandmark Practice Advances inSTEMI and ACSSTEMI and ACS
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
Landmark Practice Advances inLandmark Practice Advances inSTEMI and ACSSTEMI and ACS
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
(%)
Time in DaysTime in Days
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
Heparin + GPIIb/IIIa inhibitor (n=1802)Heparin + GPIIb/IIIa inhibitor (n=1802)
Bivalirudin monotherapy (n=1800)Bivalirudin monotherapy (n=1800)
HORIZONS AMI—30-Day Major HORIZONS AMI—30-Day Major Bleeding (non-CABG)Bleeding (non-CABG)
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
HORIZONS AMI—30-Day HORIZONS AMI—30-Day Stent Thrombosis Stent Thrombosis (N=3,124)(N=3,124)
UFH + GP IIb/IIIaUFH + GP IIb/IIIa(N=1553)(N=1553)
BivalirudinBivalirudin(N=1571)(N=1571)
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
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
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
• Chronic Kidney Dysf.Chronic Kidney Dysf.
• Prior PCIPrior PCI
• Cardiogenic shockCardiogenic shock
• NYHA >2NYHA >2
• Prior valve surgeryPrior valve surgery
PCI PATIENTSPCI PATIENTS• Female Female
• ElderlyElderly
• Chronic Kidney Dysf.Chronic Kidney Dysf.
• 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
BivalirudinBivalirudin
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
BivalirudinBivalirudin
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
Landmark Practice Advances inLandmark Practice Advances inSTEMI and ACSSTEMI and ACS
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?
Landmark Practice Advances inLandmark Practice Advances inSTEMI and ACSSTEMI and ACS
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 Practice Advances inLandmark Practice Advances inSTEMI and ACSSTEMI and ACS
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
Take Home MessagesTake Home Messages
► 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.
Take Home MessagesTake Home Messages
► 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.
Take Home MessagesTake Home Messages
► 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
Recommended