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![Page 1: Introduction and Objectives Issues and challenges in ACS Philippe Gabriel Steg INSERM U-698 Hôpital Bichat – Claude Bernard Universit é Paris VII – Denis.](https://reader038.fdocuments.net/reader038/viewer/2022102809/56649e2a5503460f94b18936/html5/thumbnails/1.jpg)
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Introduction and ObjectivesIntroduction and ObjectivesIssues and challenges in ACSIssues and challenges in ACS
Philippe Gabriel StegPhilippe Gabriel Steg INSERM U-698INSERM U-698
Hôpital Bichat – Claude BernardHôpital Bichat – Claude Bernard
Université Paris VII – Denis DiderotUniversité Paris VII – Denis Diderot
High Risk Patients with ACS — High Risk Patients with ACS — EuroPCR 2008, Barcelona, SpainEuroPCR 2008, Barcelona, Spain
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DisclosuresDisclosures
Speaker’s name: Philippe Gabriel Steg
I have the following potential conflicts of interest to report: Consulting/Advisory Board: AstraZeneca, Boehringer-Ingelheim, BMS, GSK, MSD, Nycomed, sanofi-aventis, Servier, Takeda, The Medicines Company Research Grant: sanofi-aventis Speaker’s Bureau: Boehringer-Ingelheim, BMS, GSK, Nycomed,
sanofi-aventis, Servier, ZLB-Behring
I do not have any potential conflict of interest
Speaker’s name: Philippe Gabriel Steg
I have the following potential conflicts of interest to report: Consulting/Advisory Board: AstraZeneca, Boehringer-Ingelheim, BMS, GSK, MSD, Nycomed, sanofi-aventis, Servier, Takeda, The Medicines Company Research Grant: sanofi-aventis Speaker’s Bureau: Boehringer-Ingelheim, BMS, GSK, Nycomed,
sanofi-aventis, Servier, ZLB-Behring
I do not have any potential conflict of interest
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The LandscapeThe Landscape
• A changing pattern of care for all A changing pattern of care for all high-risk ACShigh-risk ACS
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Trends in Management of STEMI in the Trends in Management of STEMI in the GRACE RegistryGRACE Registry
Fox KAA et al. JAMA 2007;297:1892-1900Fox KAA et al. JAMA 2007;297:1892-1900
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The LandscapeThe Landscape
• A changing pattern of care for all A changing pattern of care for all high-risk ACShigh-risk ACS
• ……and outcomes which are and outcomes which are improvingimproving
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Fox KAA et al. JAMA 2007;297:1892-1900.Fox KAA et al. JAMA 2007;297:1892-1900.
In-Hospital and 6-Month Outcomes in In-Hospital and 6-Month Outcomes in Patients With STEMI or LBBBPatients With STEMI or LBBB
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CRUSADE In-Hospital Outcomes: CRUSADE In-Hospital Outcomes: Data from 2006Data from 2006
Death Death 3.6% 3.6%
(Re)-Infarction (Re)-Infarction 1.8% 1.8%
CHF CHF 6.6% 6.6%
Cardiogenic Shock Cardiogenic Shock 2.2% 2.2%
Stroke Stroke 0.7% 0.7%
RBC Transfusion* RBC Transfusion* 9.1% 9.1%
*Excluding CABG-related transfusionsCRUSADE DATA: January 1, 2006 – December 31, 2006 (n= 29,825)
*Excluding CABG-related transfusionsCRUSADE DATA: January 1, 2006 – December 31, 2006 (n= 29,825)
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The LandscapeThe Landscape
• A changing pattern of care for all A changing pattern of care for all high-risk ACShigh-risk ACS
• ……and outcomes which are and outcomes which are improvingimproving
• A growing level of complexityA growing level of complexity
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Antithrombotics for ACSAntithrombotics for ACSMore and More Choices (and Combinations)More and More Choices (and Combinations)
Aspirin
Heparin
LMWH
GP IIb/IIIa inhibitors
Clopidogrel
Lytics
Direct TIs
Fonda
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Anticoagulants: UFH LMWH Fonda Bival
Antiplatelets: ASA (dose) Clopidogrel (time/dose)
IV antiplatelets: None Abcix Ept/Tiro (timing)
Cath strategy: Early DelayedNever
Anticoagulants: UFH LMWH Fonda Bival
Antiplatelets: ASA (dose) Clopidogrel (time/dose)
IV antiplatelets: None Abcix Ept/Tiro (timing)
Cath strategy: Early DelayedNever
Choices Impacting Antithrombotic TherapyChoices Impacting Antithrombotic Therapy
72 Different Combinations!72 Different Combinations!
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Treatment of ACS is a JungleTreatment of ACS is a Jungle ! !
Antiplatelet RxAntiplatelet RxASAASAClopidogrelClopidogrel? Prasugrel? Prasugrel? AZD 6140? AZD 6140GpIIb/IIIA IV GpIIb/IIIA IV blockersblockers? Cangrelor? Cangrelor? TRA? TRA
Anticoagulant RxAnticoagulant RxUFHUFHEnoxaparinEnoxaparinBivalirudinBivalirudinFondaparinuxFondaparinuxWarfarinWarfarin? Anti X? Anti X? Anti II? Anti II
RevascularizationRevascularizationPCIPCIBMSBMSDESDESCABGCABG
Bleeding riskBleeding riskComorbiditiesComorbidities
Risk of thrombotic eventRisk of thrombotic event
Patient
Timing
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The LandscapeThe Landscape
• A changing pattern of care for all A changing pattern of care for all high-risk ACShigh-risk ACS
• ……and outcomes which are and outcomes which are improvingimproving
• A growing level of complexityA growing level of complexity• Use and timing of interventions Use and timing of interventions
impact therapeutic choicesimpact therapeutic choices
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The LandscapeThe Landscape
• A changing pattern of care for all A changing pattern of care for all high-risk ACShigh-risk ACS
• ……and outcomes which are improvingand outcomes which are improving• A growing level of complexityA growing level of complexity• Use and timing of interventions Use and timing of interventions
impact therapeutic choicesimpact therapeutic choices• Fortunately, we have guidelines to Fortunately, we have guidelines to
assist us !assist us !
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ObjectivesObjectives
• Know the current guidelines for the Know the current guidelines for the management of STEMI and NSTE management of STEMI and NSTE ACSACS
• Understand their implications for Understand their implications for patient managementpatient management
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New Horizons for Patients New Horizons for Patients
with ST-Elevation Myocardial with ST-Elevation Myocardial
InfarctionInfarction
Gregg W. Stone MDGregg W. Stone MD
Columbia University Medical Center Columbia University Medical Center Cardiovascular Research FoundationCardiovascular Research Foundation
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Potential Conflicts of InterestPotential Conflicts of Interest
Speaker’s name: Gregg W. Stone, MDSpeaker’s name: Gregg W. Stone, MD
I have the following potential conflicts of interest to report:I have the following potential conflicts of interest to report:
ConsultingConsulting
Employment in industryEmployment in industry
Stockholder of a healthcare companyStockholder of a healthcare company
Owner of a healthcare companyOwner of a healthcare company
Grant/Research Support: The Medicines Company and Grant/Research Support: The Medicines Company and Boston ScientificBoston Scientific
I do not have any potential conflict of interestI do not have any potential conflict of interest
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Major bleedingMajor bleeding (with or without (with or without blood product transfusions) blood product transfusions)
has emerged as a has emerged as a powerful powerful independent predictor of early independent predictor of early and late mortality and late mortality in pts with in pts with NSTEMI, STEMI and in those NSTEMI, STEMI and in those
undergoing PCIundergoing PCI
Major bleedingMajor bleeding (with or without (with or without blood product transfusions) blood product transfusions)
has emerged as a has emerged as a powerful powerful independent predictor of early independent predictor of early and late mortality and late mortality in pts with in pts with NSTEMI, STEMI and in those NSTEMI, STEMI and in those
undergoing PCIundergoing PCI
FACT
Ndrepepa et al. JACC 2008;51:690–7
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Time from Randomization in DaysTime from Randomization in Days
Cu
mu
lati
ve %
Mo
rta
lity
Cu
mu
lati
ve %
Mo
rta
lity
With MIWith MI 5.7%5.7%
Without major bleedWithout major bleed 2.0%2.0%
Impact of Major Bleed and MI Impact of Major Bleed and MI after Elective and Urgent PCIafter Elective and Urgent PCI
1-Year Mortality (N=6,012)1-Year Mortality (N=6,012)
Without MIWithout MI 1.9%1.9%
With major bleedWith major bleed 8.8%8.8%
Stone GW. J Inv Cardiol 2004;16(suppl G):12–17.Stone GW. J Inv Cardiol 2004;16(suppl G):12–17.
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VariableVariable GroupsGroups O.R.O.R. (95% CI)(95% CI) p-valuep-value
Creatinine clear.Creatinine clear. <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 MortalityPredictors of 1-year Mortality after Elective and Urgent PCIafter Elective and Urgent PCI
Stone GW. J Inv Cardiol 2004;16(suppl G):12–17.Stone GW. J Inv Cardiol 2004;16(suppl G):12–17.
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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
lati
ve D
eat
hs
Cu
mu
lati
ve D
eat
hs
DaysDays
2.5%2.5%
1.9%1.9%
Lincoff AM et al. JAMA 2004;292:696–703Lincoff AM et al. JAMA 2004;292:696–703
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Mo
rtal
ity
(%)
Days 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 the First 30 Days on Risk of Death Over 1 Year
Stone GW. ACC 2007
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Cox model adjusted for baseline predictors, with MI and major bleeding (non-CABG) as time-updated covariates
Cox model adjusted for baseline predictors, with MI and major bleeding (non-CABG) as time-updated covariates
Influence of Major Bleeding and MI in the First 30 Days on the Risk of Death within 30
Days
Myocardial infarction 5.25 (3.72-7.43) <0.0001
Major bleeding without or before transfusion 3.04 (1.66-5.55) <0.0001
Major bleeding after transfusion 5.45 (3.54-8.38) <0.0001
HR ± 95% CI P-valueHR (95% CI)
Stone GW. ACC 2008
Of 13,819 enrolled pts, 704 (5.1%) had a MI, 644 (4.7%) had a major bleed (non CABG), and 206 (1.5%) died within 30 days
Attributabledeaths
42.0*
38.2**
*20.4% of all deaths**18.5% of all deaths
Attributable deaths = N deathsAttributable deaths = N deathsamong pts with the time updatedamong pts with the time updatedevent (attribute) X (adj. HR – 1)/adj. HRevent (attribute) X (adj. HR – 1)/adj. HR
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Attributable deaths = N deathsAttributable deaths = N deathsamong pts with the time updatedamong pts with the time updatedevent (attribute) X (adj. HR – 1)/adj. HRevent (attribute) X (adj. HR – 1)/adj. HR Mehran RM et al. Submitted
Influence of Major Bleeding and MI in the First 30 Days on Risk of Death Over 1 Year
Cox model adjusted for baseline predictors, with MI and major bleeding (non-CABG) as time-updated covariates
Cox model adjusted for baseline predictors, with MI and major bleeding (non-CABG) as time-updated covariates
Of 13,819 enrolled pts, 524 (3.8%) died within 1 year
Myocardial infarction 2.51 (1.95-3.25) <0.0001
Major bleeding without or before transfusion 2.00 (1.30-3.06) <0.0001
Major bleeding after transfusion 3.93 (2.95-5.24) <0.0001
HR ± 95% CI P-valueHR (95% CI)Attributable
deaths
51.5*
66.5**
*9.8% of all deaths**12.7% of all deaths
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ACUITY: Early and Late MortalityLandmark analysis
ACUITY: Early and Late MortalityLandmark analysis
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
(%)
Days from Randomization
Stone GW. JAMA 2007;298:2497-506
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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 PCIPrimary PCICABGCABG –– Medical RxMedical Rx––
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, 6 months,1 year, and then yearly through 5 years
Clinical FU at 30 days, 6 months,1 year, and then yearly through 5 years
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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
Stone GW et al. In press.Stone GW et al. In press.
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Diff = Diff = 0.0% [-1.6, 1.5] RR = 0.99RR = 0.99 [0.76, 1.30]
PPsupsup = 0.95 = 0.95
Primary Outcome Measures (ITT)
Diff = Diff = -3.3% [-5.0, -1.6] RR = RR = 0.60 [0.46, 0.77]
PPNINI ≤ 0.0001 ≤ 0.0001
PPsupsup ≤ 0.0001 ≤ 0.0001
Diff = Diff = -2.9% [-4.9, -0.8]RR = RR = 0.76 [0.63, 0.92]
PPNINI ≤ 0.0001 ≤ 0.0001
PPsupsup = 0.005 = 0.005
1 endpoint 1 endpoint
*Not related to CABG*Not related to CABG**MACE = All cause death, reinfarction, ischemic TVR or stroke**MACE = All cause death, reinfarction, ischemic TVR or stroke
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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 Sev or ModGUSTO LT or Sev or Mod 5.6%5.6% 3.5%3.5% 0.0020.002
*CEC adjudicated, except protocol minor; *CEC adjudicated, except protocol minor; **Primary endpoint; ***Life threatening**Primary endpoint; ***Life threatening
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Thrombocytopenia
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. In press.Stone GW et al. In press.
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30 Day MACE Components*30 Day MACE Components*
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
*CEC adjudicated*CEC adjudicatedStone GW et al. In press.Stone GW et al. In press.
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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%
2.1%
HR [95%CI] =0.66 [0.44, 1.00]
P=0.048
Heparin + GPIIb/IIIa inhibitor (n=1802)Bivalirudin monotherapy (n=1800)
Stone GW et al. In press.Stone GW et al. In press.
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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%
1.8%
Heparin + GPIIb/IIIa inhibitor (n=1802)Bivalirudin monotherapy (n=1800)
0.3%0.2%
Cardiac
Non cardiac
HR [95%CI] =0.62 [0.40, 0.96]
P=0.029
Stone GW et al. In press.Stone GW et al. In press.
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30 Day Stent Thrombosis (N=3,124)30 Day Stent Thrombosis (N=3,124)
UFH + UFH + GP IIb/IIIaGP IIb/IIIa(N=1553)(N=1553)
BivalirudinBivalirudin(N=1571)(N=1571)
PPValueValue
ARC 30d definite or probable stent thrombosis* 1.9%1.9% 2.5%2.5% 0.300.30
- definite 1.4%1.4% 2.2%2.2% 0.090.09
- probable 0.5%0.5% 0.3%0.3% 0.240.24
- acute (≤24 hrs) 0.3%0.3% 1.3%1.3% 0.00070.0007
- subacute (>24 hrs – 30d) 1.7%1.7% 1.2%1.2% 0.280.28
*Protocol definition of stent thrombosis, CEC adjudicated*Protocol definition of stent thrombosis, CEC adjudicated
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Number at riskNumber at risk
Bivalirudin Bivalirudin 16781678 16471647 16401640 16351635 16321632 16201620 1563 1563
Heparin + GPIIb/IIIa Heparin + GPIIb/IIIa 16621662 16311631 16151615 16041604 15981598 15831583 1512 1512
Dea
th (
%)
Dea
th (
%)
Time in daysTime in days
1.8%
Heparin + GPIIb/IIIa inhibitor (n=1662)Bivalirudin monotherapy (n=1678)
0.2%0.1%
Cardiac
Non cardiac
30 Day Mortality: 30 Day Mortality: PCI CohortPCI Cohort
0
1
2
3
4
5
0 5 10 15 20 25 30
2.8%
HR [95%CI] =0.63 [0.40, 0.99]
P=0.049
Stone GW et al. In press.Stone GW et al. In press.
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Predictors of 30 Day MortalityPredictors of 30 Day Mortality32 Candidate Baseline Variables*32 Candidate Baseline Variables*
Demographic:Demographic: Age; sex; race; US vs. OUS; HTN, hyperlipidemia, Age; sex; race; US vs. OUS; HTN, hyperlipidemia, smoking, diabetes, diabetes on insulin, MI, PCI, CABG, CAD, smoking, diabetes, diabetes on insulin, MI, PCI, CABG, CAD, angina, CHF, major cardiac rhythm/rate disturbances, PVDangina, CHF, major cardiac rhythm/rate disturbances, PVD
Medication use at home previous 5 days:Medication use at home previous 5 days: aspirin, beta blocker, aspirin, beta blocker, thienopyridines, calcium channel blocker, ACE/ARB, diureticthienopyridines, calcium channel blocker, ACE/ARB, diuretic
Time from symptom onset to hospital ERTime from symptom onset to hospital ER
Physical exam:Physical exam: BMI; KILLIP classBMI; KILLIP class
Baseline labsBaseline labs: : Estimated CrCl, anemia, platelet count Estimated CrCl, anemia, platelet count
Medications in hospital prior to angiography:Medications in hospital prior to angiography: Randomized Randomized treatment (bivalirudin vs. heparin + GPI; pre-procedure heparin; treatment (bivalirudin vs. heparin + GPI; pre-procedure heparin; clopidogrel loadclopidogrel load
* Angiographic variables not yet available;* Angiographic variables not yet available; - treatment related variables not used- treatment related variables not used
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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
Ischemic EventsIschemic Events HR (95% CI)HR (95% CI) PP 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, definite**Stent thrombosis, definite**
- any- any 10.71 [3.93,29.18] <0.001<0.001 4.5 [3.7,4.8] 0.830.83
- acute (<24 hours)- acute (<24 hours) 5.88 [0.78,44.30] 0.090.09 0.8 [-0.3,1] 0.820.82
StrokeStroke 5.44 [1.67,17.69] 0.0050.005 2.4 [1.2,2.8] 0.820.82
AttributableAttributable
* 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 ***Only 2 pts with acute stent thrombosis died within 30 days, 1 in each randomized groupdays, 1 in each randomized group
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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
Bleeding EventsBleeding Events HR (95% CI)HR (95% CI) PP deaths* deaths* C-statC-stat
Major bleed Major bleed (non-CABG)(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 3.89 [2.22, 6.84] <0.001<0.001 11.1 [8.2,12.8] 0.780.78
- <50,000 cells/mm- <50,000 cells/mm33 6.44 [2.93,14.18] <0.001<0.001 5.9 [4.6,6.5] 0.780.78
- <20,000 cells/mm- <20,000 cells/mm33 4.98 [1.20,20.66] 0.030.03 1.6 [0.3,1.9] 0.770.77
AttributableAttributable
* Of 93 total deaths; ** * Of 93 total deaths; ** 88 deaths in 3550 patientsAttributable deaths = N deaths among pts with the time Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HRupdated event (attribute) X (adj. HR – 1)/adj. HR
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HR [95% CI] P-valueRisk Factor
Time-updated covariate adjusted Cox model Time-updated covariate adjusted Cox model relating 30-day events to 30-day mortalityrelating 30-day events to 30-day mortality
- Complete model with MACE components and major bleeding -- Complete model with MACE components and major bleeding -
Hazard Ratio [95% CI]Hazard Ratio [95% CI]
0.01 0.1 1 10 100
C-statistic = 0.87. C-statistic = 0.87.
Reinfarction 9.75[2.72,34.91]
<0.001
Major bleeding (non CABG) 4.66[2.84, 7.63]
<0.001
Ischemic TVR 1.11[0.29, 4.21]
0.88
Stroke 2.64[0.71, 9.75]
0.15
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HR [95% CI] P-valueAttributable
DeathsRisk Factor
Time-updated covariate adjusted Cox model Time-updated covariate adjusted Cox model relating 30-day events to 30-day mortalityrelating 30-day events to 30-day mortality
- - CompleteComplete model with MACE components and major bleeding - model with MACE components and major bleeding -
Hazard Ratio [95% CI]Hazard Ratio [95% CI]
0.01 0.1 1 10 100
C-statistic = 0.87. C-statistic = 0.87. Attributable deaths = N deaths among pts Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HRwith the time updated event (attribute) X (adj. HR – 1)/adj. HR
*9.7% of 93 total deaths*9.7% of 93 total deaths**21.9% of 93 total deaths**21.9% of 93 total deaths
Major bleeding(Non CABG)Incidence 238 (6.8%)26 deaths with event
4.66[2.84, 7.63]
<0.001 20.4**[16.8, 22.6]
ReinfarctionIncidence 69 (2.2%)10 deaths with event
9.75[2.72,34.91]
<0.001 9.0*[6.3, 9.7]
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HR [95% CI] P-valueAttributable
DeathsRisk Factor
Time-updated covariate adjusted Cox model Time-updated covariate adjusted Cox model relating 30-day events to 30-day mortalityrelating 30-day events to 30-day mortality
- - CompleteComplete model in 3,124 pts with successfully implanted stents - model in 3,124 pts with successfully implanted stents -
Hazard Ratio [95% CI]Hazard Ratio [95% CI]
0.01 0.1 1 10 100
C-statistic = 0.87. C-statistic = 0.87. Attributable deaths = N deaths among pts Attributable deaths = N deaths among pts with the time updated event (attribute) X (adj. HR – 1)/adj. HRwith the time updated event (attribute) X (adj. HR – 1)/adj. HR
*8.3% of 54 total deaths*8.3% of 54 total deaths**28.0% of 54 total deaths**28.0% of 54 total deaths
Major bleeding(non CABG)Incidence 195 (6.2%)18 deaths with event
6.22[3.33, 11.60]
<0.001 15.1** 15.1** [12.6, 16.4][12.6, 16.4]
Stent thrombosis(definite)Incidence 57 (1.8%)5 deaths with event
10.62[3.96, 28.48]
<0.001 4.5* 4.5*
[3.7, 4.8][3.7, 4.8]
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1. 1. Major bleeding is a powerful independent determinant Major bleeding is a powerful independent determinant of mortality in ACS, STEMI, and in pts undergoing PCI, of mortality in ACS, STEMI, and in pts undergoing PCI, at least as important as MI/reinfarction.at least as important as MI/reinfarction.
1. 1. Major bleeding is a powerful independent determinant Major bleeding is a powerful independent determinant of mortality in ACS, STEMI, and in pts undergoing PCI, of mortality in ACS, STEMI, and in pts undergoing PCI, at least as important as MI/reinfarction.at least as important as MI/reinfarction.
Conclusions
2. In high risk pts with STEMI undergoing primary PCI, treatment with bivalirudin compared to heparin + GPI results in a significant reduction in bleeding, thrombocytopenia and transfusions, with similar rates of reinfarction, stent thrombosis, iTVR and stroke.
3. This favorable balance of adverse events results in lower 30-day mortality in primary PCI pts treated with bivalirudin rather than heparin + GPI, representing a new standard of care for pts with STEMI.
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Changing Anticoagulants in Midstream — What Are the Benefits
and Risks?
Changing Anticoagulants in Midstream — What Are the Benefits
and Risks?
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
Harvey WhiteGreen Lane Cardiovascular Service and
Cardiovascular Research UnitAuckland City Hospital; Auckland, New Zealand
Harvey WhiteGreen Lane Cardiovascular Service and
Cardiovascular Research UnitAuckland City Hospital; Auckland, New Zealand
SWITCHSWITCH
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Potential conflicts of interestPotential conflicts of interestPotential conflicts of interestPotential conflicts of interest
Speaker’s name: Harvey D. White
I have the following potential conflicts of interest to report: Research Grants: Sanofi Aventis, The Medicines company,
Eli Lilly, Roche,Schering Plough, Pfizer, Johnson and Johnson, Astra Zenica, Merck Sharpe and Dohme and
NIH Consulting Fees: The Medicines Company Employment in industry Stockholder of a healthcare company Owner of a healthcare company
I do not have any potential conflict of interest
Speaker’s name: Harvey D. White
I have the following potential conflicts of interest to report: Research Grants: Sanofi Aventis, The Medicines company,
Eli Lilly, Roche,Schering Plough, Pfizer, Johnson and Johnson, Astra Zenica, Merck Sharpe and Dohme and
NIH Consulting Fees: The Medicines Company Employment in industry Stockholder of a healthcare company Owner of a healthcare company
I do not have any potential conflict of interest
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BackgroundBackground
► ACS patients 87% of patients receive either UFH or Enox within 24
hours after admission1
72% of patients in SYNERGY and 50 % of patients in OASIS- 5 received prior antithrombin2,3
► Published studies and perceptions Patients in SYNERGY who crossed over between UFH
and Enox had an increase in bleeding complications2
This activity occurred at various times through the study period: At times in response to clinical or clinician perception
Consistent therapy is better4
► ACS patients 87% of patients receive either UFH or Enox within 24
hours after admission1
72% of patients in SYNERGY and 50 % of patients in OASIS- 5 received prior antithrombin2,3
► Published studies and perceptions Patients in SYNERGY who crossed over between UFH
and Enox had an increase in bleeding complications2
This activity occurred at various times through the study period: At times in response to clinical or clinician perception
Consistent therapy is better4
1 CRUSADE( 1Q-2006 results); 2 Synergy results; JAMA 2004; 3 OASIS -5; Yusuf et al, NEJM 2006; 4 Cohen et al, JACC 2006; Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
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SwitchingSwitching
► Concern about switching antithrombins in Concern about switching antithrombins in patients with ACS (lessons from SYNERGY)patients with ACS (lessons from SYNERGY)
► European guidelinesEuropean guidelines► Why should switching to bivalirudin Why should switching to bivalirudin
monotherapy be reasonable?monotherapy be reasonable?► Mechanistic rationale for switchingMechanistic rationale for switching
SWITCHSWITCH REPLACE 2REPLACE 2 ACUITYACUITY
► Concern about switching antithrombins in Concern about switching antithrombins in patients with ACS (lessons from SYNERGY)patients with ACS (lessons from SYNERGY)
► European guidelinesEuropean guidelines► Why should switching to bivalirudin Why should switching to bivalirudin
monotherapy be reasonable?monotherapy be reasonable?► Mechanistic rationale for switchingMechanistic rationale for switching
SWITCHSWITCH REPLACE 2REPLACE 2 ACUITYACUITY
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
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ESC Non-STEACS GuidelinesESC Non-STEACS Guidelines
► At PCI procedures, the initial anticoagulant should also be maintained during the procedure regardless of whether this treatment is UFH (I-C), enoxaparin (IIb-B), or bivalirudin (I-B)
► At PCI procedures, the initial anticoagulant should also be maintained during the procedure regardless of whether this treatment is UFH (I-C), enoxaparin (IIb-B), or bivalirudin (I-B)
EHJ 2007;28:1598-60Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
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► Switch: Protocol mandated change in Switch: Protocol mandated change in antithrombotic therapy at randomizationantithrombotic therapy at randomization
► Crossover : Post randomization change in Crossover : Post randomization change in antithrombotic therapy due to physician antithrombotic therapy due to physician choicechoice
► Switch: Protocol mandated change in Switch: Protocol mandated change in antithrombotic therapy at randomizationantithrombotic therapy at randomization
► Crossover : Post randomization change in Crossover : Post randomization change in antithrombotic therapy due to physician antithrombotic therapy due to physician choicechoice
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
SWITCHSWITCH
DefinitionsDefinitions
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ACUITY — SWITCHACUITY — SWITCH
►Hypothesis Bivalirudin improves bleeding outcomes
while preserving ischemic protection for ACS patients even if the patients are switched from either UFH or enoxaparin to bivalirudin (monotherapy) at the time of presentation
►Is it better to switch to bivalirudin or remain on consistent therapy?
►Hypothesis Bivalirudin improves bleeding outcomes
while preserving ischemic protection for ACS patients even if the patients are switched from either UFH or enoxaparin to bivalirudin (monotherapy) at the time of presentation
►Is it better to switch to bivalirudin or remain on consistent therapy?
White HD. In Press JACC White HD. In Press JACCGreen Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
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ACUITY – Primary ResultsACUITY – Primary Results
UFH/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%
7.3%5.7%
3.0%
10.1%
7.8%
Net clinical outcome Ischemic composite Major bleeding
30 d
ay e
ven
ts (
%)
UFH/Enoxaparin+GPI (N=4603) Bivalirudin alone (N=4612)
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ACUITY — Switch AnalysisACUITY — Switch AnalysisACUITY — 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
► 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
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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 data
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
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Comparing Consistent therapy on Enox + GPIIb/IIIa Inhibition vs. Switch to Bivalirudin Alone
Comparing Consistent therapy on Enox + GPIIb/IIIa Inhibition vs. Switch to Bivalirudin Alone
Consistent vs. SwitchConsistent vs. SwitchConsistent vs. SwitchConsistent vs. Switch
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
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 toSwitch to Bivalirudin alone (N = 765)
White HD, et al. J Am Coll Cardiol 2008;51:1734–41
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ACUITY – Switch ACUITY – Switch Consistent vsConsistent vs. . Switch High RiskSwitch High Risk
ACUITY – Switch ACUITY – Switch Consistent vsConsistent vs. . Switch High RiskSwitch High Risk
Comparing Consistent UFH/Enox vs Switch Bivalirudin Comparing Consistent UFH/Enox vs Switch Bivalirudin
ConsistentConsistentUFH/EnoxUFH/Enox
N = 1581N = 1581
SwitchSwitchBivalirudinBivalirudin
N = 1496N = 1496RRRR
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]
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
High Risk PatientsHigh Risk Patients
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ACUITY – SWITCH ACUITY – SWITCH Consistent vs. SwitchConsistent vs. Switch Patients Undergoing PCIPatients Undergoing PCI
Comparing Consistent UFH/Enox vs Switch Bivalirudin Comparing Consistent UFH/Enox vs Switch 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]
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
PCI PatientsPCI Patients
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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 Net Clinical OutcomeOutcome
0.93 (0.75-1.16)0.93 (0.75-1.16)Composite Composite
IschemiaIschemia
Switch to Bivalirudin BetterSwitch to Bivalirudin Better Consistent UFH/Enox + IIb/IIIa Consistent UFH/Enox + IIb/IIIa BetterBetter
ACUITY: SwitchACUITY: SwitchACUITY: SwitchACUITY: Switch
30 Days30 Days
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
0 1 2
White HD, et al. J Am Coll Cardiol 2008;51:1734–41
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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 Net Clinical OutcomeOutcome
1.11 (0.83-1.49)1.11 (0.83-1.49)Composite Composite
IschemiaIschemia
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)
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
0 1 2
White HD, et al. J Am Coll Cardiol 2008;51:1734–41
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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
White HD. In Press JACCWhite HD. In Press JACC
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
ACUITY – Switch ACUITY – Switch ACUITY PCI: Switch from Prior AntithrombinACUITY PCI: Switch from Prior Antithrombin
0.10.1 11 10100.10.1 11 1010
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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]
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
0
5
10
15
20
Net clinicaloutcome
Ischemiccomposite
Majorbleeding
30 d
ay e
ven
ts (
%)
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)
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ACUITY – Switch LimitationsACUITY – Switch LimitationsACUITY – Switch LimitationsACUITY – Switch Limitations
► Post-hoc subgroup analysisPost-hoc subgroup analysis
► Pre-randomization use of anti-thrombin Pre-randomization use of anti-thrombin was not stratifiedwas not stratified
► Timing and dose of last UFH and Enox Timing and dose of last UFH and Enox was not collected in the CRFwas not collected in the CRF
► Post-hoc subgroup analysisPost-hoc subgroup analysis
► Pre-randomization use of anti-thrombin Pre-randomization use of anti-thrombin was not stratifiedwas not stratified
► Timing and dose of last UFH and Enox Timing and dose of last UFH and Enox was not collected in the CRFwas not collected in the CRF
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
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Randomize
Protocol 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 patients (N=6,002)1
Overall population: Urgent or elective PCI patients (N=6,002)1
UFH 65 U/kg with planned GP IIb/IIIa
(n=3,008)1
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 AnalysisREPLACE-2: SWITCH AnalysisREPLACE-2: SWITCH Analysis
1. Lincoff ML et al. JAMA. 2004;292:696-703.2. Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.
AT=antithrombin.
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
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†
Protocol Major/Minor Bleeding by Protocol Major/Minor Bleeding by SWITCH and Randomized TherapySWITCH and Randomized TherapyProtocol 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 decreased Regardless of prior heparin or not, patients administered bivalirudin had decreased bleedingbleeding
There was a significant increase in major/minor protocol bleeding in patients There was a significant increase in major/minor protocol bleeding in patients administered UFH with prior heparin therapyadministered UFH with prior heparin therapy
Regardless of prior heparin or not, patients administered bivalirudin had decreased Regardless of prior heparin or not, patients administered bivalirudin had decreased bleedingbleeding
There was a significant increase in major/minor protocol bleeding in patients There was a significant increase in major/minor protocol bleeding in patients administered UFH with prior heparin therapyadministered UFH with prior heparin therapy
*P=NS for all 3-way comparisons versus bivalirudin alone; †P<.05 vs prior treatment with UFH or enoxaparin; ‡naïve=no prior AT therapy in preceding 48 hours.
Pro
toco
l maj
or/
min
or
ble
ed
Naïve→Bivalirudin‡
(n=2,345)
LMWH→Bivalirudin
(n=258)
UFH→Bivalirudin
(n=287)
LMWH→UFH + GP IIb/IIIa
(n=313)
Naïve→ UFH +
GP IIb/IIIa‡
(n=2,325)
UFH→UFH + GP IIb/IIIa
(n=349)
*
Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
15.6% 15.3% 16.7%
28.6%
33.8% 34.8%
0%
5%
10%
15%
20%
25%
30%
35%
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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 Patients switched from UFH or enoxaparin to bivalirudin had the lowest rates of TIMI bleeding bleeding
Patients administered UFH had higher rates of bleeding, with highest rates in patients Patients administered UFH had higher rates of bleeding, with highest rates in patients switching between heparinsswitching between heparins
Patients switched from UFH or enoxaparin to bivalirudin had the lowest rates of TIMI Patients switched from UFH or enoxaparin to bivalirudin had the lowest rates of TIMI bleeding bleeding
Patients administered UFH had higher rates of bleeding, with highest rates in patients Patients administered UFH had higher rates of bleeding, with highest rates in patients switching between heparinsswitching between heparins
TIM
I maj
or/
min
or
ble
ed
Naïve→Bivalirudin†
(n=2,345)
LMWH → Bivalirudin
(n=258)
UFH→Bivalirudin
(n=287)
LMWH→UFH+ GP IIb/IIIa
(n=313)
Naïve→UFH + GP IIb/IIIa†
(n=2,325)
UFH→UFH + GP IIb/IIIa
(n=349)
*
*P=NS for all 3-way comparisons versus bivalirudin alone; †naïve=no prior AT therapy in preceding 48 hours.
Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
1.9%1.4%
4.3%
5.4%
1.9%
3.5%
0%
1%
2%
3%
4%
5%
6%
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SWITCHSWITCH
Waksman et al. J Invasive Cardiol 2006;18:370
p = 0.39p = 0.39
n = 30n = 30 n = 31n = 31n = 30n = 30
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
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 %
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4.8% 5.2%
8.5%7.5%
0%
2%
4%
6%
8%
10%
UFH pretreatment(n=2,553)
No UFHpretreatment
(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 pretreatment(n=2,553)
No UFHpretreatment
(n=1,042)
30-D
ay M
AC
E
Bivalirudin with "provisional" GP IIb/IIIa Heparin + GP IIb/IIIa
PPintint=0.08=0.08PPintint=0.47=0.47
HORIZONS AMI Switching DataHORIZONS AMI 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
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
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]
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How to SwitchHow to Switch
From UFH to BivalirudinFrom UFH to Bivalirudin From UFH to BivalirudinFrom UFH to Bivalirudin
• • Discontinue LMWH for 8 hours before Discontinue LMWH for 8 hours before starting bivalirudinstarting 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• Discontinue UFH for 30 minutes before Discontinue UFH for 30 minutes before starting bivalirudinstarting bivalirudin
From LMWH to BivalirudinFrom LMWH to BivalirudinFrom LMWH to BivalirudinFrom LMWH to Bivalirudin
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
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ConclusionsConclusions
► Switching to bivalirudin is safeSwitching to bivalirudin is safe Switching from any heparin to bivalirudin Switching from any heparin to bivalirudin
monotherapy is not associated with an monotherapy is not associated with an increased risk for ischemic eventsincreased risk for ischemic events
► FurthermoreFurthermore Switch to bivalirudin provides patients the Switch to bivalirudin provides patients the
50% bleeding advantage of bivalirudin50% bleeding advantage of bivalirudin
► Switching to bivalirudin is safeSwitching to bivalirudin is safe Switching from any heparin to bivalirudin Switching from any heparin to bivalirudin
monotherapy is not associated with an monotherapy is not associated with an increased risk for ischemic eventsincreased risk for ischemic events
► FurthermoreFurthermore Switch to bivalirudin provides patients the Switch to bivalirudin provides patients the
50% bleeding advantage of bivalirudin50% bleeding advantage of bivalirudin
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
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Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, NZ
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Keith A A FoxKeith A A Fox
Edinburgh Centre for Cardiovascular ScienceEdinburgh Centre for Cardiovascular Science
Role of Bleeding Reduction in ACSRole of Bleeding Reduction in ACSImpact on Outcomes and CostsImpact on Outcomes and Costs
The Role and Implications of Bleeding in ACS
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..
Potential conflicts of interestPotential conflicts of interestPotential conflicts of interestPotential conflicts of interest
Speaker’s name: Keith A A Fox
I have the following potential conflicts of interest to report:
Consulting
Research grants/speaker honoraria: sanofi-aventis, Bristol-Myers Squibb, and GlaxoSmithKline
Stockholder of a healthcare company
Owner of a healthcare company
Other(s)
I do not have any potential conflict of interest
Speaker’s name: Keith A A Fox
I have the following potential conflicts of interest to report:
Consulting
Research grants/speaker honoraria: sanofi-aventis, Bristol-Myers Squibb, and GlaxoSmithKline
Stockholder of a healthcare company
Owner of a healthcare company
Other(s)
I do not have any potential conflict of interest
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Bleeding in ACSBleeding in ACS
► How common is major bleeding in ACS?► What are the risk factors for bleeding?► The impact of anti-thrombotic therapy?► What are the consequences of bleeding?
• Net clinical outcome• Costs
► How common is major bleeding in ACS?► What are the risk factors for bleeding?► The impact of anti-thrombotic therapy?► What are the consequences of bleeding?
• Net clinical outcome• Costs
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Reduced Thrombotic Reduced Thrombotic and Embolic Eventsand Embolic Events
Factors Contributing to the Balance of RisksFactors Contributing to the Balance of Risks
Cerebral and Systemic Cerebral and Systemic Bleeding EventsBleeding Events
AnticoagulantsAnticoagulantsAnti-plateletsAnti-plateletsAnti-thrombinsAnti-thrombinsACE / ARBACE / ARBHypertension &Hypertension & lipid controllipid controlSmoking cessationSmoking cessation
AnticoagulantsAnticoagulantsAnti-plateletsAnti-plateletsAnti-thrombinsAnti-thrombinsRenal dysfunctionRenal dysfunctionPoor hypertensionPoor hypertension controlcontrol
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Hierarchy of Bleeding RiskHierarchy of Bleeding Risk
Fatal bleedFatal bleed
Intra-cerebral bleedIntra-cerebral bleed
Life-threatening bleedLife-threatening bleed
Bleed with hemodynamic disturbanceBleed with hemodynamic disturbanceor requiring transfusionor requiring transfusion
or prolonging hospital stayor prolonging hospital stay
Minor bleedsMinor bleedsTIMI “ Major Bleed”: >5gm Hb drop or 5U transfusion or ICHTIMI “ Major Bleed”: >5gm Hb drop or 5U transfusion or ICH
GUSTO “ severe/life threatening”: ICH or GUSTO “ severe/life threatening”: ICH or hemodynamic compromise requiring treatmenthemodynamic compromise requiring treatment
A consistent definition A consistent definition of bleeding is requiredof bleeding is required
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Major Bleeding in ACS: GRACE RegistryMajor Bleeding in ACS: GRACE RegistryP
atie
nts
%P
atie
nts
%
• Life threatening bleeding requiring a transfusion of 2+ units
• Bleeding resulting in an absolute decrease in hematocrit of ≥ 10%
• Bleeding resulting in death
n= 24,045 patients
Definition Definition of bleeding:of bleeding:
European Heart Journal (2003) 24, 1815–1823
3.9
2.3
4.7 4.8
0
1
2
3
4
5
6
Major bleeding
Overall ACS
Unstable angina
Non-ST MI
ST-MI
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Multivariate Risk (Non-ST MI) Multivariate Risk (Non-ST MI) Major Bleeding (1)Major Bleeding (1)
Hosomer-Lemeshow p value 0.70, C statistic 0.73Hosomer-Lemeshow p value 0.70, C statistic 0.73
Moscucci et al Eur Heart J 2003
Odds RatioOdds Ratio (95% CI)(95% CI)
Thrombolytic + Thrombolytic + IIb/IIIaIIb/IIIa 4.194.19 1.68-10.01.68-10.0
IIb/IIIaIIb/IIIa 1.861.86 1.43-2.431.43-2.43
History of BleedingHistory of Bleeding 2.182.18 1.17-4.081.17-4.08
Renal InsufficiencyRenal Insufficiency 1.531.53 1.13-2.081.13-2.08
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Multivariate Risk (Non-ST MI) Multivariate Risk (Non-ST MI) Major BleedingMajor Bleeding
Hosomer-Lemeshow p value 0.70, C statistic 0.73
Moscucci et al Eur Heart J 2003Moscucci et al Eur Heart J 2003
Odds RatioOdds Ratio (95% CI)(95% CI)
Age (10yr)Age (10yr) 1.221.22 1.10-1.351.10-1.35
FemaleFemale 1.361.36 1.07-1.731.07-1.73
Inotropes (iv)Inotropes (iv) 1.881.88 1.35-2.621.35-2.62
Renal InsufficiencyRenal Insufficiency 2.012.01 1.38-2.911.38-2.91
DiureticsDiuretics 1.911.91 1.46-2.491.46-2.49
Mean Arterial Pressure Mean Arterial Pressure (20mm (20mm ))
1.041.04 1.14-1.271.14-1.27
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GUSTO I Predictors of BleedingGUSTO I Predictors of Bleeding
Berkowitz, Berkowitz, CirculationCirculation 1997;95:2508-2516 1997;95:2508-2516 12 12
VariableVariable Odds RatioOdds Ratio 95% CI95% CI 22
Patients treated Patients treated in USin US 1.761.76 (1.08, 2.85)(1.08, 2.85) 521521
Age (60 v 50y)Age (60 v 50y) 1.301.30 (1.26, 1.35)(1.26, 1.35) 222222
Weight (75 v Weight (75 v 85kg)85kg) 1.231.23 (1.18, 1.28)(1.18, 1.28) 164164
FemaleFemale 1.421.42 (1.31, 1.53)(1.31, 1.53) 7373
African AncestryAfrican Ancestry 1.331.33 (1.12, 1.57)(1.12, 1.57) 1010
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Bleeding and Outcome?Bleeding and Outcome?
The Role and Implications of Bleeding in ACS
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log rank p-value for all four categories <0.0001log-rank p-value for no bleeding vs. mild bleeding = 0.02log-rank p-value for mild vs. moderate bleeding <0.0001log-rank p-value for moderate vs. severe <0.001
Bleeding and Outcomes in ACSBleeding and Outcomes in ACS
Rao SV, et al. Am J Cardiol. 2005 Nov 1;96(9):1200-6.
Kaplan Meier Curves for 30-Day Death, Stratified by Bleed SeverityKaplan Meier Curves for 30-Day Death, Stratified by Bleed SeverityN=26,452 ACS patients from GUSTO IIb, PARAGON A, PARAGON B, & PURSUIT N=26,452 ACS patients from GUSTO IIb, PARAGON A, PARAGON B, & PURSUIT
Kaplan Meier Curves for 30-Day Death, Stratified by Bleed SeverityKaplan Meier Curves for 30-Day Death, Stratified by Bleed SeverityN=26,452 ACS patients from GUSTO IIb, PARAGON A, PARAGON B, & PURSUIT N=26,452 ACS patients from GUSTO IIb, PARAGON A, PARAGON B, & PURSUIT
NoneMildModerateSevere
NoneMildModerateSevere
0 5 10 15 20 25 30 0 5 10 15 20 25 30
1.00
0.95
0.90
0.85
0.80
0.75
0.70
1.00
0.95
0.90
0.85
0.80
0.75
0.70
Days to DeathDays to Death
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6-month Death/MI (Adjusted)According to Severity of Bleeding
6-month Death/MI (Adjusted)According to Severity of Bleeding
Rao SV, et. al., ACC 2005Rao SV, et. al., ACC 2005
1.01.0
GUSTO MildGUSTO Mild
GUSTO ModerateGUSTO Moderate
GUSTO SevereGUSTO Severe
1.31.3
2.02.0
5.15.1
5.05.0
Odds ratioOdds ratio
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30 Day Death According to BleedingOASIS Registry, OASIS-2, CURE
30 Day Death According to BleedingOASIS Registry, OASIS-2, CURE
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 3271032710470470 459459 440440 430430 420420 410410 408408
Cum
ulat
ive
Eve
nts,
%C
umul
ativ
e E
vent
s, %
DaysDays
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The impact of renal dysfunctionThe impact of renal dysfunction
The Role and Implications of Bleeding in ACS
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SYNERGY: Clinical Outcomes and ProceduresCreatinine Clearance (CrCl)
SYNERGY: Clinical Outcomes and ProceduresCreatinine Clearance (CrCl)
P-value from logistic regression with CrCl as continuous variableP-value from logistic regression with CrCl as continuous variable* in-hospital* in-hospital
CrCl < 30CrCl < 30N=156N=156
CrCl 30-60CrCl 30-60N=2732N=2732
CrCl CrCl 60 60 N=7011N=7011
p-valuep-value
30-Day Outcomes30-Day Outcomes
Death/MIDeath/MI 24.4%24.4% 17.3%17.3% 12.7%12.7% <0.0001<0.0001
DeathDeath 15.4%15.4% 5.7%5.7% 1.8%1.8% <0.0001<0.0001
Cardiac CathCardiac Cath 80.1%80.1% 88.8%88.8% 93.7%93.7% <0.0001<0.0001
PCIPCI 35.0%35.0% 42.4%42.4% 51.5%51.5% <0.0001<0.0001
CSBGCSBG 17.1%17.1% 20.0%20.0% 20.2%20.2% 0.840.84
In-Hospital In-Hospital BleedingBleeding
GUSTO SevereGUSTO Severe 7.7%7.7% 3.7%3.7% 1.8%1.8% <0.0001<0.0001
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Increased Risks Associated with Transfusion
Increased Risks Associated with Transfusion
The Role and Implications of Bleeding in ACSThe Role and Implications of Bleeding in ACS
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CRUSADE Bleeding Risks CRUSADE Bleeding Risks Transfusion by AgeTransfusion by Age
CRUSADE Bleeding Risks CRUSADE Bleeding Risks Transfusion by AgeTransfusion by Age
Through Q2 2004 (n=74,271)Through Q2 2004 (n=74,271)
-- Yang, J Am Coll Cardiol 2005;46:1490-5
14.9% overall14.9% overall10.3% non-CABG10.3% non-CABG
4.5
10.3
14.1
9.7
17.9 18.5
0
5
10
15
20
<65 yrs 65-75 yrs > 75 yrs
% R
BC
Tra
nsf
usi
on
Non-CABG Overall
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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, & nadir HCTpropensity, & nadir HCT
3.83.8
3.53.5
3.93.9
Odds RatioOdds Ratio
-- Rao SV, et. al., JAMA 2004
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Does Prevention of Bleeding Improve Long-term Outcome?Does Prevention of Bleeding
Improve Long-term Outcome?
The Role and Implications of Bleeding in ACSThe Role and Implications of Bleeding in ACS
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1-Year Mortality1-Year Mortality
Multivariate Logistic ModelMultivariate Logistic Model
PredictorPredictor OddsOddsRatioRatio
95%Confidence95%ConfidenceIntervalInterval p-valuep-value
CrCl <30 ml/minCrCl <30 ml/min 7.97.9 2.7-22.42.7-22.4
<0.001<0.001CrCl 30-60 CrCl 30-60
ml/minml/min 3.83.8 2.2-6.62.2-6.6
CrCl 60-90 CrCl 60-90 ml/minml/min 1.71.7 1.0-2.71.0-2.7
Major BleedMajor Bleed 3.673.67 2.1-6.52.1-6.5 <0.001<0.001
Non-Q MINon-Q MI 2.582.58 1.5-4.41.5-4.4 0.0040.004
DiabetesDiabetes 1.741.74 1.3-2.61.3-2.6 0.0050.005
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Attributable deaths = N deathsAttributable deaths = N deathsamong pts with the time updatedamong pts with the time updatedevent (attribute) X (adj. HR – 1)/adj. HRevent (attribute) X (adj. HR – 1)/adj. HRMehran RM et al. SubmittedMehran RM et al. Submitted
Influence of Major Bleeding and MI in the First Influence of Major Bleeding and MI in the First 30 Days on Risk of Death 30 Days on Risk of Death Over 1 YearOver 1 Year
Cox model adjusted for baseline predictors, with MI and major bleeding (non-CABG) as time-updated covariates
Cox model adjusted for baseline predictors, with MI and major bleeding (non-CABG) as time-updated covariates
Of 13,819 enrolled pts, 524 (3.8%) died within 1 yearOf 13,819 enrolled pts, 524 (3.8%) died within 1 year
Myocardial infarctionMyocardial infarction 2.51 (1.95-3.25)2.51 (1.95-3.25) <0.0001<0.0001
Major bleeding without or Major bleeding without or before transfusionbefore transfusion 2.00 (1.30-3.06)2.00 (1.30-3.06) <0.0001<0.0001
Major bleeding after Major bleeding after transfusiontransfusion 3.93 (2.95-5.24)3.93 (2.95-5.24) <0.0001<0.0001
HR ± 95% CIHR ± 95% CI P-valueP-valueHR (95% CI)HR (95% CI)AttributableAttributable
deathsdeaths
51.5*51.5*
66.5**66.5**
*9.8% of all deaths*9.8% of all deaths**12.7% of all deaths**12.7% of all deaths
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P-valueP-valueRR (95% CI)RR (95% CI)Risk ratio ± 95% CIRisk ratio ± 95% CI
Predictors of Major BleedingPredictors of Major Bleeding
Age Age >>75 (vs. 55-75)75 (vs. 55-75)
AnemiaAnemia
CrCl <60mL/minCrCl <60mL/min
DiabetesDiabetes
Female genderFemale gender
High-risk (ST / biomarkers)High-risk (ST / biomarkers)
HypertensionHypertension
No prior PCINo prior PCI
Prior antithrombotic therapyPrior antithrombotic therapy
Heparin(s) + GPI (vs. Bivalirudin)Heparin(s) + GPI (vs. Bivalirudin)
1.56 (1.19-2.04)1.56 (1.19-2.04) 0.00090.0009
1.89 (1.48-2.41)1.89 (1.48-2.41) <0.0001<0.0001
1.68 (1.29-2.18)1.68 (1.29-2.18) <0.0001<0.0001
1.30 (1.03-1.63)1.30 (1.03-1.63) 0.02480.0248
2.08 (1.68-2.57)2.08 (1.68-2.57) <0.0001<0.0001
1.42 (1.06-1.90)1.42 (1.06-1.90) 0.01780.0178
1.33 (1.03-1.70)1.33 (1.03-1.70) 0.02870.0287
1.47 (1.15-1.88)1.47 (1.15-1.88) 0.00190.0019
1.23 (0.98-1.55)1.23 (0.98-1.55) 0.07680.0768
2.08 (1.56-2.76)2.08 (1.56-2.76) <0.0001<0.0001
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
Results: The ACUITY Trial — PCI PopulationResults: The ACUITY Trial — PCI PopulationResults: The ACUITY Trial — PCI PopulationResults: The ACUITY Trial — PCI Population
0 1 2 3
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Days
Cum
ulat
ive
Haz
ard
0.0
0.01
0.02
0.03
0.04
0 5 10 15 20 25 30
Major Bleeding at 30 DaysMajor Bleeding at 30 DaysUFH/Enox versus FondaparinuxUFH/Enox versus Fondaparinux
UFH/Enoxaparin
Fondaparinux
HR 0.6795% CI 0.59-0.76
P<0.00001
HR 0.6795% CI 0.59-0.76
P<0.00001
OASIS 5 & 6OASIS 5 & 6
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Mortality: Day 30Mortality: Day 30
Days
Cum
ulat
ive
Haz
ard
0.0
0.01
0.02
0.03
0 3 6 9 12 15 18 21 24 27 30
HR 0.83 HR 0.83 95% CI 0.71-0.9795% CI 0.71-0.97
P=0.022P=0.022
EnoxaparinEnoxaparinEnoxaparinEnoxaparin
FondaparinuxFondaparinuxFondaparinuxFondaparinux
OASIS 5OASIS 5
Yusuf et al NEJM 2006Yusuf et al NEJM 2006
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Relative Impact of MI, Refractory Ischemia or Bleeding on Mortality
Relative Impact of MI, Refractory Ischemia or Bleeding on Mortality
Crude Odds Ratio for Crude Odds Ratio for DeathDeath (95% CI)(95% CI)
30 Days30 Days 30 to 180 Days30 to 180 Days 180 Days180 Days
Nonfatal MINonfatal MI 9.9 (8.0-12.3)9.9 (8.0-12.3) 2.3 (1.6-3.3)2.3 (1.6-3.3) 5.7 (4.7-6.9)5.7 (4.7-6.9)
Refractory Refractory IschemiaIschemia 4.1 (3.0-5.7)4.1 (3.0-5.7) 1.4 (0.8-2.4)1.4 (0.8-2.4) 2.7 (2.0-3.6)2.7 (2.0-3.6)
Major BleedsMajor Bleeds 6.6 (5.2-8.3)6.6 (5.2-8.3) 2.2 (1.6-3.2)2.2 (1.6-3.2) 4.2 (3.5-5.1)4.2 (3.5-5.1)
Minor BleedsMinor Bleeds 3.0 (2.1-4.3)3.0 (2.1-4.3) 1.6 (1.0-2.5)1.6 (1.0-2.5) 2.2 (1.7-3.0)2.2 (1.7-3.0)
OASIS 5OASIS 5
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Minimizing the Risks of Bleeding?Minimizing the Risks of Bleeding?
The Role and Implications of Bleeding in ACSThe Role and Implications of Bleeding in ACS
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Excessive Dosing of Anticoagulants by AgeExcessive Dosing of Anticoagulants by Age
12.5
28.7
8.512.5
3733.1
16.5
38.5
64.5
0
10
20
30
40
50
60
70
LMW Heparin UF Heparin GP IIb/IIIa
% E
xce
ssiv
e D
ose
< 65 yrs 65-75 yrs >75 yrs
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Dosing Combinations and Transfusions Heparin + GP IIb-IIIa Inhibitors*
Dosing Combinations and Transfusions Heparin + GP IIb-IIIa Inhibitors*
* Among patients receiving both Heparin (UFH or LMWH) and GP IIb-IIIa Inhibitors* Among patients receiving both Heparin (UFH or LMWH) and GP IIb-IIIa Inhibitors
4.1
9
18.5
0
2
4
6
8
10
12
14
16
18
20
Both Right 1 Excessive Both Excessive
% R
BC
Tra
nsfu
sion
s
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Bleeding and Resource UseBleeding and Resource Use Predictors of Total CostsPredictors of Total Costs
Model C-index=0.87Model C-index=0.87
Adjusted for patient characteristicsAdjusted for patient characteristics
Model C-index=0.87Model C-index=0.87
Adjusted for patient characteristicsAdjusted for patient characteristicsRao SV, et. al. AHJ 2008.
N=1235 pts from GUSTO IIbN=1235 pts from GUSTO IIbN=1235 pts from GUSTO IIbN=1235 pts from GUSTO IIb
$3,370
$1,158$2,164
$7,188
$12,409
$2,488
$5,255
$2,436
$1,336
0
2,000
4,000
6,000
8,000
10,000
12,000
14,000
Mod/SevBld
UA Cath PCI CABG Pacemaker IABP ICU day Non-ICUday
$
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ConclusionsConclusions
► In ACS bleeding is important as it is a harbinger of adverse In ACS bleeding is important as it is a harbinger of adverse outcomes, including deathoutcomes, including death Major bleeding and recurrent MI have a similar risk of deathMajor bleeding and recurrent MI have a similar risk of death
► Older age, chronic kidney disease, female gender, anemia, Older age, chronic kidney disease, female gender, anemia, diabetes: consistently associated with bleeding and blood diabetes: consistently associated with bleeding and blood transfusiontransfusion
► Major bleeding is associated with adverse outcomes and Major bleeding is associated with adverse outcomes and increased costsincreased costs
► Both ESC and ACC/AHA Guidelines in ACS highlight the Both ESC and ACC/AHA Guidelines in ACS highlight the importance of bleeding reduction in ACS careimportance of bleeding reduction in ACS care
► In ACS bleeding is important as it is a harbinger of adverse In ACS bleeding is important as it is a harbinger of adverse outcomes, including deathoutcomes, including death Major bleeding and recurrent MI have a similar risk of deathMajor bleeding and recurrent MI have a similar risk of death
► Older age, chronic kidney disease, female gender, anemia, Older age, chronic kidney disease, female gender, anemia, diabetes: consistently associated with bleeding and blood diabetes: consistently associated with bleeding and blood transfusiontransfusion
► Major bleeding is associated with adverse outcomes and Major bleeding is associated with adverse outcomes and increased costsincreased costs
► Both ESC and ACC/AHA Guidelines in ACS highlight the Both ESC and ACC/AHA Guidelines in ACS highlight the importance of bleeding reduction in ACS careimportance of bleeding reduction in ACS care
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Translating Advances in NSTEMI and STEMI into Real World
Institutional Practice
Translating Advances in NSTEMI and STEMI into Real World
Institutional Practice
Harold L. Dauerman, MDDirector, Cardiovascular Catheterization
LaboratoriesProfessor of MedicineUniversity of Vermont
Fletcher Allen Health Care
Harold L. Dauerman, MDDirector, Cardiovascular Catheterization
LaboratoriesProfessor of MedicineUniversity of Vermont
Fletcher Allen Health Care
The Science and Medicine of ACSThe Science and Medicine of ACS
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Potential conflicts of interestPotential conflicts of interest
Speaker’s name: Harold L. Dauerman, MD
I have the following potential conflicts of interest to report:
Consulting: The Medicines Company, Abbott Vascular
Employment in industry
Stockholder of a healthcare company
Owner of a healthcare company
Other(s)
I do not have any potential conflict of interest
Speaker’s name: Harold L. Dauerman, MD
I have the following potential conflicts of interest to report:
Consulting: The Medicines Company, Abbott Vascular
Employment in industry
Stockholder of a healthcare company
Owner of a healthcare company
Other(s)
I do not have any potential conflict of interest
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University of Vermont Post-PCI Bleeding and Vascular Complication Rates
University of Vermont Post-PCI Bleeding and Vascular Complication Rates
NNE Rate: 2.0% in 2006
Any Transfusion, RPH or Repair = Bleeding ComplicationAny Transfusion, RPH or Repair = Bleeding Complication Any Transfusion, RPH or Repair = Bleeding ComplicationAny Transfusion, RPH or Repair = Bleeding Complication
Introduction ofIntroduction of Bivalirudin to Cath LabBivalirudin to Cath Lab
Introduction ofIntroduction of Bivalirudin to Cath LabBivalirudin to Cath Lab
Introduction of Introduction of Upstream BivalirudinUpstream Bivalirudin
Introduction of Introduction of Upstream BivalirudinUpstream Bivalirudin
0
0.5
1
1.5
2
2.5
3
3.5
4
2001 2002 2003 2004 2005 2006 2007
Ble
edin
g C
ompl
icat
ion,
%
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Incorporation of Bivalirudin in Cath Lab for NSTEMI in 2003—A Cautious Beginning
Incorporation of Bivalirudin in Cath Lab for NSTEMI in 2003—A Cautious Beginning
82%18%
Drug Eluting Bare Metal
82%18%
Drug Eluting Bare Metal
42%
25% 33%
Bivalirudin
GP IIb/IIIa Inhibitor
UFH alone
Bivalirudin
GP IIb/IIIa Inhibitor
UFH alone
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P < 0.001 for temporal trendP < 0.001 for temporal trend
Arterial injury and/or arterial injury related bleeding N= 36,631 Patients Undergoing PCI, NNE RegistryArterial injury and/or arterial injury related bleeding N= 36,631 Patients Undergoing PCI, NNE Registry
Signs of Hope Since 2004Signs of Hope Since 2004
Dauerman, Applegate and Cohen, JACC 2007
3.2
2.51
2.111.96
3.37
0
0.5
1
1.5
2
2.5
3
3.5
4
2002 2003 2004 2005 2006
Maj
or V
ascu
lar
Com
plic
atio
ns,
%*
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How We Introduced Upstream and Downstream Bivalirudin: The UVMC Time Line
How We Introduced Upstream and Downstream Bivalirudin: The UVMC Time Line
2003: Put bivalirudin on the cath lab shelf as an option for NSTEMI
2007: Educational programs for fellows, floor staff and attendings
We did not remove GPI option
We did NOT involve community hospitals in this decision. They can do whatever they want as long as they transfer and don’t overdose patients.
2008: A standardized STEMI bivalirudin approach
For upstream AMI utilization, bivalirudin ordered from pharmacy
In collaboration with ED (EDICT for ACS Strategy)
2003: Put bivalirudin on the cath lab shelf as an option for NSTEMI
2007: Educational programs for fellows, floor staff and attendings
We did not remove GPI option
We did NOT involve community hospitals in this decision. They can do whatever they want as long as they transfer and don’t overdose patients.
2008: A standardized STEMI bivalirudin approach
For upstream AMI utilization, bivalirudin ordered from pharmacy
In collaboration with ED (EDICT for ACS Strategy)
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NSTEMI Transfers, Upstream
Strategies, andResults of Clinical Trials
NSTEMI Transfers, Upstream
Strategies, andResults of Clinical Trials
Non ST-Elevation Myocardial InfarctionNon ST-Elevation Myocardial Infarction
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What We Really Do With Transfers? September 24, 2007 email from me
What We Really Do With Transfers? September 24, 2007 email from me
To: Sullivan, Claudia A.Cc: Ades, Philip A.Subject: Transfer of John XXXXX, DOB 11/08/25
81M with NSTEMI/old LBBB, Tn 3.0 Pain free, but with NSVT. ASA/clopidogrel 300 po/enoxaparin. From Adirondack Medical Center.
Class I transfer. Change to bivalirudin on arrival. DNR—reverse POLST (wants a cath, but no CABG). Echo today, cath tomorrow (or today if unstable).
Thanks,Harry
To: Sullivan, Claudia A.Cc: Ades, Philip A.Subject: Transfer of John XXXXX, DOB 11/08/25
81M with NSTEMI/old LBBB, Tn 3.0 Pain free, but with NSVT. ASA/clopidogrel 300 po/enoxaparin. From Adirondack Medical Center.
Class I transfer. Change to bivalirudin on arrival. DNR—reverse POLST (wants a cath, but no CABG). Echo today, cath tomorrow (or today if unstable).
Thanks,Harry
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Protocol Major/Minor Bleed by SWITCH and Randomized Therapy
Protocol Major/Minor Bleed by SWITCH and Randomized Therapy
*P=NS for all 3-way comparisons versus bivalirudin alone; †P<.05 vs prior treatment with UFH or enoxaparin; ‡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
NaïveNaïve→→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→ 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)
*
†
Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.
15.6% 15.3%16.7%
28.6%
33.8% 34.8%
0%
5%
10%
15%
20%
25%
30%
35%
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Transfer to Cardiology FloorTransfer to Cardiology Floor
► Enoxaparin held—wait 8 hours from community hospital last dose.
► Then, start upstream bivalirudin
► Patient pain free—1st case next A.M
► DES, no eptifibatide, closure device, 150 mg clopidogrel
► Ambulate at 6 hours► D/C following 0900 A.M.
► Enoxaparin held—wait 8 hours from community hospital last dose.
► Then, start upstream bivalirudin
► Patient pain free—1st case next A.M
► DES, no eptifibatide, closure device, 150 mg clopidogrel
► Ambulate at 6 hours► D/C following 0900 A.M.
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Not Thienopyridine ExposedNot Thienopyridine Exposed
If Patient is not Clopidogrel Exposed, Do We Use Bivalirudin? Definitions?
If Patient is not Clopidogrel Exposed, Do We Use Bivalirudin? Definitions?
RR [95%CI]RR [95%CI]
0.81 (0.68-0.96)0.81 (0.68-0.96)
RR [95%CI] RR [95%CI]
0.96 (0.77-1.20)0.96 (0.77-1.20)
RR [95%CI] RR [95%CI]
0.50 (0.37-0.67)0.50 (0.37-0.67)
RR [95%CI] RR [95%CI]
1.07 (0.83-1.39)1.07 (0.83-1.39)
RR [95%CI] RR [95%CI]
1.37 (1.00-1.88)1.37 (1.00-1.88)
RR [95%CI] RR [95%CI]
0.61 (0.39-0.97)0.61 (0.39-0.97)
Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16 Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16
Thienopyridine ExposedThienopyridine Exposed
13.8%
8.4%7.2%
8.1%
11.1%
3.6%
Net clinicaloutcomes
Ischemiccomposite
Major bleeding
UFH/Enoxaparin + IIb/IIIa (N=1722)
Bivalirudin Alone (N=1789)
11.8%
7.5%
5.7%
3.5%
12.7%
10.3%
Net clinicaloutcomes
Ischemiccomposite
Major bleeding
UFH/Enoxaparin + IIb/IIIa (N=811)
Bivalirudin Alone (N=804)
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Risk ratio (RR) ±95% CI for the triple ischemic endpoint(death, MI, unplanned revascularization)
Risk ratio (RR) ±95% CI for the triple ischemic endpoint(death, MI, unplanned revascularization)
Bivalirudin alone betterBivalirudin alone better Heparin + GPIIb/IIIa better Heparin + GPIIb/IIIa better
Peri-PCI Clopidogrel N=1044, RR 1.26 [95% CI 0.82,1.92]
Peri-PCI Clopidogrel N=1044, RR 1.26 [95% CI 0.82,1.92]
Post-PCI Clopidgrel(> 30 minutes After PCI)
N=519 RR 1.48 [95% CI 0.89, 2.47]
Post-PCI Clopidgrel(> 30 minutes After PCI)
N=519 RR 1.48 [95% CI 0.89, 2.47]
Pre-PCI clopidogrel N=3429, RR 0.92 [95% CI 0.74,1.15]
Pre-PCI clopidogrel N=3429, RR 0.92 [95% CI 0.74,1.15]
No Clopidogrel N=88 RR 2.62 [95% CI 0.89, 7.72]
No Clopidogrel N=88 RR 2.62 [95% CI 0.89, 7.72]
pinteraction = 0.35pinteraction = 0.35
00 11 22 33 44 55 66 77 88
Timing of Clopidogrel Administration and 30-Day Risk of Ischemic Outcomes
Timing of Clopidogrel Administration and 30-Day Risk of Ischemic Outcomes
S. Steinhubl TCT 2007S. Steinhubl TCT 2007
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Does Periprocedural Infarct Increase With Upstream and Downstream Bivalirudin? No!Does Periprocedural Infarct Increase With
Upstream and Downstream Bivalirudin? No!
ACS PCI OutcomesACS PCI Outcomes20052005
Bival 61%Bival 61%N=373N=373
20072007Bival 91%Bival 91%
N=361N=361P valueP value
Any Transfusion (%)Any Transfusion (%) 2.02.0 1.01.0 NSNS
Death (%)Death (%) 3.03.0 1.01.0 0.080.08
Urgent revascularization (%)Urgent revascularization (%) 2.02.0 1.01.0 NSNS
MI, 50% CK-MB Rise (%)MI, 50% CK-MB Rise (%) 4.04.0 1.01.0 0.020.02
Mechanical Complication (%)Mechanical Complication (%) 8.08.0 6.06.0 NSNS
Clopidogrel preload in approx 60% of PCI patientsCK-MB on all patients the day after PCI (University of Vermont data)
Submitted, TCT 2008Submitted, TCT 2008
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STEMI Switching, Clopidogrel and
Stent Thrombosis
STEMI Switching, Clopidogrel and
Stent Thrombosis
ST-Elevation Myocardial Infarction ST-Elevation Myocardial Infarction
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Primary PCI for STEMI N= 7,629
Bivalirudin and GPIIbIIIa PCIN=177 (55%)
No Bivalirudin PCI N= 7,309
ClopidogrelN=171 (97%)
GP IIbIIIa Inhibitor useN=6,873 (94%)
Prior to PCI N=37 (21%)
Not Prior to PCI N= 140 (79%)
Prior to PCI N=2,489 (36%)
Not Prior to PCI N= 4,384 (64%)
Abciximab N=64 (36%)Eptifibatide N=93 (52%)Tirofiban N=1 (1%)Unkown N=19 (11%)
Abciximab N=2,283 (33%)Eptifibatide N=3,551 (52%)Tirofiban N=154 (2%)Unknown N= 885 (13%)
AbciximabN=8 (22%)EptifibatideN=27 (73%)TirofibanN=1 (3%)Unknown N=1 (2%)
AbciximabN=622 (25%)EptifibatideN=1621 (65%)TirofibanN=99 (4%)Unknown N=147 (6%)
AbciximabN=56 (40%)EptifibatideN=66 (47%)TirofibanN=0 (0%)Unknown N=18 (13%)
AbciximabN=1661 (38%)EptifibatideN=1930 (44%)TirofibanN=55 (1%)Unknown N=738 (17%)
Bivalirudin Alone N=143 (45%)
ClopidogrelPrior to PCI N=41 (24%)
ClopidogrelN=137 (96%)
Prior to PCI N=31 (23%)
ClopidogrelN=6878 (94%)
Clopidogrel Prior to PCI
N=1466 (21%)
Bivalirudin PCIN=320 (4%)
Dauerman and French, Coronary Artery Disease, 2006
The Standard of Care for STEMI PCI in 2005:The Standard of Care for STEMI PCI in 2005:National Registry of Myocardial Infarction-5National Registry of Myocardial Infarction-5
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Implementation of HORIZONS AMI PCI Pharmacologic Aspects of Management
Implementation of HORIZONS AMI PCI Pharmacologic Aspects of Management
Unfractionated heparin 60 U/kg IV*; subsequent boluses titrated by nomogram to ACT 200-250
secs; terminated at procedure end unless prolonged antithrombin needed
Bivalirudin at the REPLACE-2 Dosing (NOT ACUITY) Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to ACT;
terminated at procedure end unless prolonged antithrombin needed (0.25 mg/kg/hr infusion)
Glycoprotein IIb/IIIa inhibitors Routine use in UFH arm; recommended only for giant thrombus or
refractory no reflow in bivalirudin arm Abciximab or double bolus eptifibatide as per investigator discretion –
dosing per FDA label, renal adjusted; continued for 12 (abciximab) or 12-18 (eptifibatide)
Unfractionated heparin 60 U/kg IV*; subsequent boluses titrated by nomogram to ACT 200-250
secs; terminated at procedure end unless prolonged antithrombin needed
Bivalirudin at the REPLACE-2 Dosing (NOT ACUITY) Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to ACT;
terminated at procedure end unless prolonged antithrombin needed (0.25 mg/kg/hr infusion)
Glycoprotein IIb/IIIa inhibitors Routine use in UFH arm; recommended only for giant thrombus or
refractory no reflow in bivalirudin arm Abciximab or double bolus eptifibatide as per investigator discretion –
dosing per FDA label, renal adjusted; continued for 12 (abciximab) or 12-18 (eptifibatide)
* If pre randomization UFH administered, ACT is checked first* If pre randomization UFH administered, ACT is checked first** If pre randomization UFH administered, started 30’ after last bolus** If pre randomization UFH administered, started 30’ after last bolus
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Primary PCI for STEMI: Community Hospital AlgorithmPrimary PCI for STEMI: Community Hospital AlgorithmASA, Clopidogrel and UFH and then Switch to Bivalirudin at UVMASA, Clopidogrel and UFH and then Switch to Bivalirudin at UVM
Time from ED Presentation at NWMC to Open Artery at FAHC: 88 Minutes
Time from ED Presentation at NWMC to Open Artery at FAHC: 88 Minutes
27 miles, on interstate highway27 miles, on interstate highway
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UFH + GP UFH + GP
IIb/IIIaIIb/IIIa(N=1802)(N=1802)
BivalirudinBivalirudin(N=1800)(N=1800)
UFH pre randomizationUFH pre randomization 65.6%65.6% 65.6%65.6%
Antithrombin in CCLAntithrombin in CCL
UFHUFH 98.9%98.9% 4.1%4.1%
BivalirudinBivalirudin 0.4%0.4% 96.9%96.9%
Peak ACTPeak ACT 264 [228, 320]264 [228, 320] 357 [300, 402]357 [300, 402]
GP IIb/IIIa in CCLGP IIb/IIIa in CCL 94.5%*94.5%* 7.2%*7.2%*
Bail-out per protocol**Bail-out per protocol** -- 4.4%4.4%
AbciximabAbciximab 49.9%49.9% 4.0%4.0%
EptifibatideEptifibatide 44.4%44.4% 3.1%3.1%
TirofibanTirofiban 0.2%0.2% 0.1%0.1%
Do I Have to Load Bivalirudin in the ED or Can I Start in the Cath Lab? The HORIZONS AMI Switching Perspective
Do I Have to Load Bivalirudin in the ED or Can I Start in the Cath Lab? The HORIZONS AMI Switching Perspective
*97.7% and 7.5% during PCI. ** For giant thrombus or refractory no reflow after *97.7% and 7.5% during PCI. ** For giant thrombus or refractory no reflow after PCI. CCL = cardiac catheterization laboratoryPCI. CCL = cardiac catheterization laboratory
G Stone TCT 2007G Stone TCT 2007
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Bivalirudin Improves Mortality in STEMI Bivalirudin Improves Mortality in STEMI
Dea
th (
%)
Dea
th (
%)
Dea
th (
%)
Dea
th (
%)
Time in DaysTime in DaysTime 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)
G Stone TCT 2007G Stone TCT 2007
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The UVM STEMI Order SheetOne Pathway for Primary PCI and ED Collaboration
The UVM STEMI Order SheetOne Pathway for Primary PCI and ED Collaboration
TESTS AND MEDICATIONSEKG: EKG for diagnosis performed within 10 minutes of ED arrival. No further EKG required.
LABORATORY:7. CBC,lytes, BUN, CR, PT, PTT, Lipids, LFT’s, CK, CK-MB and TnI sent immediately on arrival: STAT8. Other labs: MEDICATIONS: Weight: __kg Estimated / Actual (Circle one) Check patient not allergic to aspirin9. Aspirin Non- Enteric Coated 325 mg PO Daily 10. Clopidogrel 600 mg PO x one11. Bivalirudin bolus 0.75 mg/kg IV, then infusion 1.75 mg/kg/hr (STAT from Pharmacy)12. Saline Lock with routine flushes every 8 hours
OPTIONAL:13. Nitroglycerin infusion: 400 mcg/ml infusion at _______ mcg/kg/min IV Titrate to chest pain, keep systolic BP >90. 14. Lopressor 5 mg IVP x 1 if HR > 80 and SBP > 140
TESTS AND MEDICATIONSEKG: EKG for diagnosis performed within 10 minutes of ED arrival. No further EKG required.
LABORATORY:7. CBC,lytes, BUN, CR, PT, PTT, Lipids, LFT’s, CK, CK-MB and TnI sent immediately on arrival: STAT8. Other labs: MEDICATIONS: Weight: __kg Estimated / Actual (Circle one) Check patient not allergic to aspirin9. Aspirin Non- Enteric Coated 325 mg PO Daily 10. Clopidogrel 600 mg PO x one11. Bivalirudin bolus 0.75 mg/kg IV, then infusion 1.75 mg/kg/hr (STAT from Pharmacy)12. Saline Lock with routine flushes every 8 hours
OPTIONAL:13. Nitroglycerin infusion: 400 mcg/ml infusion at _______ mcg/kg/min IV Titrate to chest pain, keep systolic BP >90. 14. Lopressor 5 mg IVP x 1 if HR > 80 and SBP > 140
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The Bivalirudin Strategy for STEMI PCIThe Bivalirudin Strategy for STEMI PCI
ASA, clopidogrel 600 po x 1, bivalirudin and stent
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What About The Stent Thrombosis Risk? What About The Stent Thrombosis Risk?
*Protocol definition of stent thrombosis, CEC adjudicated*Protocol definition of stent thrombosis, CEC adjudicated*Protocol definition of stent thrombosis, CEC adjudicated*Protocol definition of stent thrombosis, CEC adjudicated
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
G Stone TCT 2007G Stone TCT 2007
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Sianos, G. et al. J Am Coll Cardiol 2007;50:573-583
Risk Stratification For STEMI Stent ThrombosisRisk Stratification For STEMI Stent ThrombosisThe Importance of Thrombus BurdenThe Importance of Thrombus Burden
Large thrombus burden (LTB), defined as thrombus burden > 2 vessel diameters: Approx 25% of STEMI
Large thrombus burden (LTB), defined as thrombus burden > 2 vessel diameters: Approx 25% of STEMI
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Sianos, G. et al. J Am Coll Cardiol 2007;50:573-583
Drug Eluting Stent Thrombosis and Large Thrombus Drug Eluting Stent Thrombosis and Large Thrombus Burden: Modifying Strategy In Highest Risk PatientsBurden: Modifying Strategy In Highest Risk Patients
Large Thrombus Burden> 5 fold Increased Risk of
30 Day Stent Thrombosis
Large Thrombus Burden> 5 fold Increased Risk of
30 Day Stent Thrombosis
ThrombectomyProlonged BivalirudinGPI
ThrombectomyProlonged BivalirudinGPI
LTB vs. STB, p<0.001LTB vs. STB, p<0.001
Total PopulationTotal Population
STBSTB
LTBLTB
2.7%2.7%3.2%3.2%
5.8%5.8%
8.2%8.2%
1.1%1.1% 1.4%1.4%2.1%2.1% 3.2%3.2%
0.5%0.5% 0.7%0.7% 0.7%0.7%1.3%1.3%
0 1 3 6 9 12 15 18 21 240 1 3 6 9 12 15 18 21 24
15
12
9
6
3
0
15
12
9
6
3
0
Months of follow-upMonths of follow-up
Cum
ulat
ive
IRA
-ST
Rat
e (%
)C
umul
ativ
e IR
A-S
T R
ate
(%)
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ACUITYACUITYHeparinHeparin + IIb/IIIa+ IIb/IIIa(N=222)(N=222)
Bivalirudin Bivalirudin + + IIb/IIIaIIb/IIIa
(N=241)(N=241)
Bivalirudin Bivalirudin
alonealone(N=249)(N=249)
P valueP value3-way3-way
Any thrombotic Any thrombotic complication post complication post
PCIPCI8.6%8.6% 3.7%3.7% 5.6%5.6% 0.090.09
Final TIMI flow 3Final TIMI flow 3 90.5%90.5% 93.7%93.7% 90.7%90.7% 0.370.37
Final blush grade 3Final blush grade 3 81.5%81.5% 79.0%79.0% 79.5%79.5% 0.780.78
ACUITY and Large Thrombus DataThe Rationale for Selective Adjunctive GPI
ACUITY and Large Thrombus DataThe Rationale for Selective Adjunctive GPI
* New or ↑ thrombus, abrupt closure, no reflow, or distal embolization * New or ↑ thrombus, abrupt closure, no reflow, or distal embolization
G. Stone AHA 2006G. Stone AHA 2006
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Projecting What Happens if You Use GPI in 25% of Your Bivalirudin STEMI Patients
Projecting What Happens if You Use GPI in 25% of Your Bivalirudin STEMI Patients
Assumes Bival + GPI bleeding rate of 6.8%Assumes Bival + GPI bleeding rate of 6.8%
P < 0.001
Still P < 0.001Still P < 0.001
HORIZONS 7%HORIZONS 7% UVM Implemented HORIZONS—25%UVM Implemented HORIZONS—25%
4.9 5.2
8.3 8.3
0
1
2
3
4
5
6
7
8
9
Maj
or B
leed
ing,
%
Bival +UFH + GPI
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Incorporation of HORIZONS AMI and Large Thrombus Data—STEMI Algorithm
Incorporation of HORIZONS AMI and Large Thrombus Data—STEMI Algorithm
► ED STEMI—25% of PatientsED STEMI—25% of Patients► ASA/clopidogrel 600 mg po ASA/clopidogrel 600 mg po
load and bivalirudinload and bivalirudin► Bolus and infusion of Bolus and infusion of
eptifibatide after wiring eptifibatide after wiring vessel shows Large vessel shows Large Thrombus BurdenThrombus Burden
► Angiojet and Bare Metal Angiojet and Bare Metal StentStent
► 150 mg clopidogrel and 18 150 mg clopidogrel and 18 hours of eptifibatidehours of eptifibatide
► No ambulation until No ambulation until eptifibatide off (18 hours)eptifibatide off (18 hours)
► D/C on Day 3 postD/C on Day 3 post MI
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STEMI:STEMI:Within 24 Hours CPWithin 24 Hours CP
UFH (60 U/Kg)UFH (60 U/Kg)Beta Blockers only if HTNBeta Blockers only if HTN
UFH or Bivalirudin:UFH or Bivalirudin:GPI Optional: Avoid if High Bleed RiskGPI Optional: Avoid if High Bleed Risk
B Blockers ONLY if HTNB Blockers ONLY if HTN
PCI Capability or < 60 minute Transfer Time
No PCI Capability and > 60 minute Transfer Time
Primary PCI with Stenting:Primary PCI with Stenting:GPI/Thrombectomy if Large ThrombusGPI/Thrombectomy if Large Thrombus
or as Bailout; Otherwise, Bivalirudin Aloneor as Bailout; Otherwise, Bivalirudin Alone
90 minutesTo Open
Artery Lytic Lytic ContraindicatedContraindicated
Emergent Transfer
TNK and UFHTNK and UFH
Transfer Transfer from from Community ERCommunity ER
To PCI SiteTo PCI Site
If no CP and less than 50% If no CP and less than 50% ST Elevations, PCI at 12-24ST Elevations, PCI at 12-24
Hours with StentHours with Stent
If Reperfusion Fails,If Reperfusion Fails,Emergent PCI with stentEmergent PCI with stent
ASA/ClopidogrelASA/ClopidogrelStatinStatin
Groin ClosureGroin ClosureCardiac RehabCardiac Rehab
Lopressor 12.5 bidLopressor 12.5 bid
Transfer
Rescue PCI:
Class I Indication
The NSTEMI Paradigm
of 4-48 Hours
ASA 325 po
ClopidogrelClopidogrel600 po600 po
Clopidogrel Clopidogrel 300 po300 po
Continue bivalirudin for 2 hours after PCI
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Conclusions Key Implementation Points
Conclusions Key Implementation Points
► Bivalirudin can be safely instituted across the spectrum of PCI patients, including those with NSTE-ACS and STEMI.
► Clopidogrel 600 mg po load may be done in ED or immediately after PCI.
► Community referring hospitals may use antithrombotic therapy of choice—then switch to bivalirudin on arrival to PCI institution.
► STEMI requires an algorithm for care and bivalirudin is the baseline strategy. But, bivalirudin may be instituted in the ED or the cath lab, depending upon local issues.
► Enhanced management of large thrombus burden should be considered especially during the most “vulnerable” 2 hours after PCI.
► Bivalirudin can be safely instituted across the spectrum of PCI patients, including those with NSTE-ACS and STEMI.
► Clopidogrel 600 mg po load may be done in ED or immediately after PCI.
► Community referring hospitals may use antithrombotic therapy of choice—then switch to bivalirudin on arrival to PCI institution.
► STEMI requires an algorithm for care and bivalirudin is the baseline strategy. But, bivalirudin may be instituted in the ED or the cath lab, depending upon local issues.
► Enhanced management of large thrombus burden should be considered especially during the most “vulnerable” 2 hours after PCI.
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Questions for the PanelQuestions for the Panel
► Does a consistent, unified upstream strategy for anticoagulation across the STEMI and NSTE-ACS risk spectrum make sense? When does it? When doesn’t it?
► Given that bleeding appears to be a driver of MACE events, including mortality, in ACS and STEMI, and since switching to bivalirudin appears to decrease bleeding, should this switching strategy be promulgated in patients undergoing PCI?
► What are the best ways, from an institutional/process-of-care perspective, to establish a consistent antithrombotic strategy for this patient population?
► Other issues? We’ll answer your questions!
► Does a consistent, unified upstream strategy for anticoagulation across the STEMI and NSTE-ACS risk spectrum make sense? When does it? When doesn’t it?
► Given that bleeding appears to be a driver of MACE events, including mortality, in ACS and STEMI, and since switching to bivalirudin appears to decrease bleeding, should this switching strategy be promulgated in patients undergoing PCI?
► What are the best ways, from an institutional/process-of-care perspective, to establish a consistent antithrombotic strategy for this patient population?
► Other issues? We’ll answer your questions!