introduction and objectives issues and challenges in acs

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

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


The LandscapeThe Landscape

• A changing pattern of care for all A changing pattern of care for all high-risk ACShigh-risk ACS

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



• ……and outcomes which are and outcomes which are improvingimproving

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

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)




• A growing level of complexityA growing level of complexity

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

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!

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




• A growing level of complexityA growing level of complexity• Use and timing of interventions Use and timing of interventions

impact therapeutic choicesimpact therapeutic choices



• ……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 !

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

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

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

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

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.

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.

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

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

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

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



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

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

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

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.

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

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

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


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.

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)


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


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%


0.3%0.2%

Cardiac

Non cardiac

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

P=0.029


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


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%


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


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

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

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

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

HR [95% CI] P-valueAttributable

DeathsRisk Factor


- - CompleteComplete model with MACE components and major bleeding - model with MACE components and major bleeding -


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]

HR [95% CI] P-valueAttributable

DeathsRisk Factor


- - CompleteComplete model in 3,124 pts with successfully implanted stents - model in 3,124 pts with successfully implanted stents -


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]

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.

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

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


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


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

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


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

► 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


SWITCHSWITCH

DefinitionsDefinitions

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

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)

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

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


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


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)


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]


High Risk PatientsHigh Risk Patients

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]


PCI PatientsPCI Patients

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

Prior Antithrombin TherapyPrior Antithrombin Therapy

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

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


0 1 2


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)


0 1 2


PCIPCI (n=2528)(n=2528)

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

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

Switch to Switch to Bivalirudin Bivalirudin

betterbetter

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

Switch to Switch to Bivalirudin Bivalirudin

betterbetter

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

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

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

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

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

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

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]


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)

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


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.


†

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%

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%

SWITCHSWITCH

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

p = 0.39p = 0.39

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


13%13%

3%3%

7%7%

0%0%

5%5%

10%10%

15%15%

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

Time from last enoxaparin doseTime from last enoxaparin dose

Maj

or

Ble

edin

g %

Maj

or

Ble

edin

g %

4.8% 5.2%

8.5%7.5%

0%

2%

4%

6%

8%

10%

UFH 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


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]

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


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


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

..

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)


Speaker’s name: Keith A A Fox


Consulting

Research grants/speaker honoraria: sanofi-aventis, Bristol-Myers Squibb, and GlaxoSmithKline



Other(s)


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

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

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

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

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

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

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

Bleeding and Outcome?Bleeding and Outcome?


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

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

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

The impact of renal dysfunctionThe impact of renal dysfunction


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

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

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

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

Does Prevention of Bleeding Improve Long-term Outcome?Does Prevention of Bleeding

Improve Long-term Outcome?


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

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



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

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

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

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

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

Minimizing the Risks of Bleeding?Minimizing the Risks of Bleeding?


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

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

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

$

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

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

Potential conflicts of interestPotential conflicts of interest

Speaker’s name: Harold L. Dauerman, MD


Consulting: The Medicines Company, Abbott Vascular

Employment in industry



Other(s)


Speaker’s name: Harold L. Dauerman, MD


Consulting: The Medicines Company, Abbott Vascular

Employment in industry



Other(s)


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,

%

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

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,

%*

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)

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

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

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%

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.

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)

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

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

STEMI Switching, Clopidogrel and

Stent Thrombosis

STEMI Switching, Clopidogrel and

Stent Thrombosis

ST-Elevation Myocardial Infarction ST-Elevation Myocardial Infarction

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%)




Bivalirudin Alone N=143 (45%)

ClopidogrelPrior to PCI N=41 (24%)


Prior to PCI N=31 (23%)


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

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

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

UFH + GP UFH + GP

IIb/IIIaIIb/IIIa(N=1802)(N=1802)


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

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)


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

The Bivalirudin Strategy for STEMI PCIThe Bivalirudin Strategy for STEMI PCI

ASA, clopidogrel 600 po x 1, bivalirudin and stent

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)


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


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

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

(%)

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

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

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

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

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.

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!

introduction and objectives issues and challenges in acs

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