Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Program Chairman Chairman, Department of Emergency...

Charles V. Pollack Jr, MA, MD, FACEP, FAAEMCharles V. Pollack Jr, MA, MD, FACEP, FAAEMProgram ChairmanProgram Chairman

Chairman, Department of Emergency MedicineChairman, Department of Emergency MedicinePennsylvania HospitalPennsylvania Hospital

Professor of Emergency MedicineProfessor of Emergency MedicineUniversity of PennsylvaniaUniversity of Pennsylvania

School of MedicineSchool of MedicinePhiladelphia, PennsylvaniaPhiladelphia, Pennsylvania





Cardiovascular Emergencies—Cardiovascular Emergencies—New Dimensions and New Dimensions and

Critical Practice AdvancesCritical Practice Advances

Cardiovascular Emergencies—Cardiovascular Emergencies—New Dimensions and New Dimensions and

Critical Practice AdvancesCritical Practice Advances

Evidence-Based Management of Acute Coronary Syndromes: Evidence-Based Management of Acute Coronary Syndromes: Optimizing Patient Outcomes in the Complex and Challenging Optimizing Patient Outcomes in the Complex and Challenging

Sphere of Cardiovascular Emergency CareSphere of Cardiovascular Emergency Care

Evidence-Based Management of Acute Coronary Syndromes: Evidence-Based Management of Acute Coronary Syndromes: Optimizing Patient Outcomes in the Complex and Challenging Optimizing Patient Outcomes in the Complex and Challenging

Sphere of Cardiovascular Emergency CareSphere of Cardiovascular Emergency Care

Getting in the Stream of ThingsGetting in the Stream of ThingsGetting in the Stream of ThingsGetting in the Stream of Things

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

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

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

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

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

Welcome and Program OverviewWelcome and Program Overview

Program Educational ObjectivesProgram Educational ObjectivesProgram Educational ObjectivesProgram Educational Objectives

As a result of this session, emergency physicians will:As a result of this session, emergency physicians will: ► Learn to identify signs, symptoms, and prognostic features of Learn to identify signs, symptoms, and prognostic features of

acute coronary syndromes and related cardiovascular acute coronary syndromes and related cardiovascular emergencies.emergencies.

► Learn to assess and implement optimal pharmacologic Learn to assess and implement optimal pharmacologic interventions, especially antithrombotic therapy in the interventions, especially antithrombotic therapy in the upstream setting, for patients presenting with manifestations of upstream setting, for patients presenting with manifestations of ACS and related cardiovascular disease emergencies.ACS and related cardiovascular disease emergencies.

► Learn to characterize, identify, and evaluate the safety, efficacy, Learn to characterize, identify, and evaluate the safety, efficacy, and side effects of myriad therapeutic options used for acute and side effects of myriad therapeutic options used for acute ischemic coronary syndromes including, aspirin, antiplatelet ischemic coronary syndromes including, aspirin, antiplatelet agents, direct thrombin inhibitors, UFH, LMWHs, and factor Xa agents, direct thrombin inhibitors, UFH, LMWHs, and factor Xa inhibitors — with a focus on new 2007 ACC/AHA UA/NSTEMI inhibitors — with a focus on new 2007 ACC/AHA UA/NSTEMI GuidelinesGuidelines

As a result of this session, emergency physicians will:As a result of this session, emergency physicians will: ► Learn to identify signs, symptoms, and prognostic features of Learn to identify signs, symptoms, and prognostic features of

acute coronary syndromes and related cardiovascular acute coronary syndromes and related cardiovascular emergencies.emergencies.

► Learn to assess and implement optimal pharmacologic Learn to assess and implement optimal pharmacologic interventions, especially antithrombotic therapy in the interventions, especially antithrombotic therapy in the upstream setting, for patients presenting with manifestations of upstream setting, for patients presenting with manifestations of ACS and related cardiovascular disease emergencies.ACS and related cardiovascular disease emergencies.

► Learn to characterize, identify, and evaluate the safety, efficacy, Learn to characterize, identify, and evaluate the safety, efficacy, and side effects of myriad therapeutic options used for acute and side effects of myriad therapeutic options used for acute ischemic coronary syndromes including, aspirin, antiplatelet ischemic coronary syndromes including, aspirin, antiplatelet agents, direct thrombin inhibitors, UFH, LMWHs, and factor Xa agents, direct thrombin inhibitors, UFH, LMWHs, and factor Xa inhibitors — with a focus on new 2007 ACC/AHA UA/NSTEMI inhibitors — with a focus on new 2007 ACC/AHA UA/NSTEMI GuidelinesGuidelines

Program FacultyProgram Faculty

Program ChairmanProgram Chairman

Charles V. Pollack Jr, MA, Charles V. Pollack Jr, MA, MD, FACEP, FAAEMMD, FACEP, FAAEMChairman, Department of Chairman, Department of Emergency MedicineEmergency MedicinePennsylvania HospitalPennsylvania HospitalProfessor of Emergency MedicineProfessor of Emergency MedicineUniversity of Pennsylvania School University of Pennsylvania School of Medicineof MedicinePhiladelphia, PennsylvaniaPhiladelphia, Pennsylvania

Program ChairmanProgram Chairman

Charles V. Pollack Jr, MA, Charles V. Pollack Jr, MA, MD, FACEP, FAAEMMD, FACEP, FAAEMChairman, Department of Chairman, Department of Emergency MedicineEmergency MedicinePennsylvania HospitalPennsylvania HospitalProfessor of Emergency MedicineProfessor of Emergency MedicineUniversity of Pennsylvania School University of Pennsylvania School of Medicineof MedicinePhiladelphia, PennsylvaniaPhiladelphia, Pennsylvania

Distinguished PresentersDistinguished Presenters

Judd E. Hollander, MDJudd E. Hollander, MDProfessor and Clinical Research DirectorProfessor and Clinical Research DirectorDepartment of Emergency MedicineDepartment of Emergency MedicineUniversity of PennsylvaniaUniversity of Pennsylvania

Philadelphia, PennsylvaniaPhiladelphia, Pennsylvania Sunil Rao, MD, FACCSunil Rao, MD, FACCDirector of Interventional CardiologyDirector of Interventional CardiologyVeterans Administration Medical CenterVeterans Administration Medical CenterAssistant ProfessorAssistant ProfessorDivision of Cardiovascular MedicineDivision of Cardiovascular MedicineDuke University Medical CenterDuke University Medical CenterDurham, North Carolina Durham, North Carolina

Distinguished PresentersDistinguished Presenters

Judd E. Hollander, MDJudd E. Hollander, MDProfessor and Clinical Research DirectorProfessor and Clinical Research DirectorDepartment of Emergency MedicineDepartment of Emergency MedicineUniversity of PennsylvaniaUniversity of Pennsylvania

Philadelphia, PennsylvaniaPhiladelphia, Pennsylvania Sunil Rao, MD, FACCSunil Rao, MD, FACCDirector of Interventional CardiologyDirector of Interventional CardiologyVeterans Administration Medical CenterVeterans Administration Medical CenterAssistant ProfessorAssistant ProfessorDivision of Cardiovascular MedicineDivision of Cardiovascular MedicineDuke University Medical CenterDuke University Medical CenterDurham, North Carolina Durham, North Carolina

COI Faculty DisclosuresCOI Faculty Disclosures

Charles V. Pollack Jr, MA, MD, FACEP, FAAEMCharles V. Pollack Jr, MA, MD, FACEP, FAAEMGrant/Research Support: GlaxoSmithKlineConsultant: The Medicines Co., Schering-Plough, Sanofi-Aventis, BMS, GenentechSpeaker’s Bureau: Schering-Plough, Sanofi-Aventis, BMS, Genentech

Judd E. Hollander, MDJudd E. Hollander, MDGrant/Research Support: Sanofi-Aventis, Biosite, Scios, The Medicines CompanyGrant/Research Support: Sanofi-Aventis, Biosite, Scios, The Medicines CompanyConsultant: Sanofi-Aventis, Biosite, Scios, The Medicines CompanyConsultant: Sanofi-Aventis, Biosite, Scios, The Medicines CompanySpeaker’s Bureau: Sanofi-Aventis, Biosite, Scios, The Medicines CompanySpeaker’s Bureau: Sanofi-Aventis, Biosite, Scios, The Medicines Company

Sunil Rao, MD, FACCSunil Rao, MD, FACCGrant/Research Support: CordisGrant/Research Support: CordisConsultant: Sanofi-Aventis, The Medicines CompanyConsultant: Sanofi-Aventis, The Medicines CompanySpeaker’s Bureau: Sanofi-Aventis, The Medicines Company, CordisSpeaker’s Bureau: Sanofi-Aventis, The Medicines Company, Cordis

Charles V. Pollack Jr, MA, MD, FACEP, FAAEMCharles V. Pollack Jr, MA, MD, FACEP, FAAEMGrant/Research Support: GlaxoSmithKlineConsultant: The Medicines Co., Schering-Plough, Sanofi-Aventis, BMS, GenentechSpeaker’s Bureau: Schering-Plough, Sanofi-Aventis, BMS, Genentech

Judd E. Hollander, MDJudd E. Hollander, MDGrant/Research Support: Sanofi-Aventis, Biosite, Scios, The Medicines CompanyGrant/Research Support: Sanofi-Aventis, Biosite, Scios, The Medicines CompanyConsultant: Sanofi-Aventis, Biosite, Scios, The Medicines CompanyConsultant: Sanofi-Aventis, Biosite, Scios, The Medicines CompanySpeaker’s Bureau: Sanofi-Aventis, Biosite, Scios, The Medicines CompanySpeaker’s Bureau: Sanofi-Aventis, Biosite, Scios, The Medicines Company

Sunil Rao, MD, FACCSunil Rao, MD, FACCGrant/Research Support: CordisGrant/Research Support: CordisConsultant: Sanofi-Aventis, The Medicines CompanyConsultant: Sanofi-Aventis, The Medicines CompanySpeaker’s Bureau: Sanofi-Aventis, The Medicines Company, CordisSpeaker’s Bureau: Sanofi-Aventis, The Medicines Company, Cordis

Acute Coronary SyndromeAcute Coronary SyndromeThe 2007 ACC/AHA UA/NSTEMI Guidelines The 2007 ACC/AHA UA/NSTEMI Guidelines

From the ED to CCU and Cath Lab — From the ED to CCU and Cath Lab — Adherence Yields Better OutcomesAdherence Yields Better Outcomes

Acute Coronary SyndromeAcute Coronary SyndromeThe 2007 ACC/AHA UA/NSTEMI Guidelines The 2007 ACC/AHA UA/NSTEMI Guidelines

From the ED to CCU and Cath Lab — From the ED to CCU and Cath Lab — Adherence Yields Better OutcomesAdherence Yields Better Outcomes





Getting in the (Up)Stream of ThingsGetting in the (Up)Stream of ThingsGetting in the (Up)Stream of ThingsGetting in the (Up)Stream of Things

Changing the Calculation Changing the Calculation Assessing Adherence to GuidelinesAssessing Adherence to Guidelines

Changing the Calculation Changing the Calculation Assessing Adherence to GuidelinesAssessing Adherence to Guidelines

Anderson HV, Bach RG, J Am Coll Cardiol 2005;46:1488-9.

““We need to invert the current equation We need to invert the current equation

to calculate an opportunity score for ACS to calculate an opportunity score for ACS

patients rather than a risk score. Patients patients rather than a risk score. Patients

with higher baseline risks, such as the with higher baseline risks, such as the

elderly, would have higher opportunity elderly, would have higher opportunity

scores for benefit, even allowing for scores for benefit, even allowing for

some of the greater risks from the some of the greater risks from the

treatment.”treatment.”

““We need to invert the current equation We need to invert the current equation

to calculate an opportunity score for ACS to calculate an opportunity score for ACS

patients rather than a risk score. Patients patients rather than a risk score. Patients

with higher baseline risks, such as the with higher baseline risks, such as the

elderly, would have higher opportunity elderly, would have higher opportunity

scores for benefit, even allowing for scores for benefit, even allowing for

some of the greater risks from the some of the greater risks from the

treatment.”treatment.”

++++

Ischemic Discomfort at Rest

Ischemic Discomfort at Rest

No ST-segment Elevation

No ST-segment Elevation

Non-Q-wave MIUnstable Angina

Q-wave MI

ST-segment Elevation

ST-segment Elevation

++ ++

( : positive cardiac biomarker)

EmergencyEmergencyDepartmentDepartment

In-hospitalIn-hospital6-24hrs6-24hrs

PresentationPresentation

Acute Coronary SyndromesAcute Coronary SyndromesClinical Spectrum and PresentationClinical Spectrum and Presentation

Acute Coronary SyndromesAcute Coronary SyndromesClinical Spectrum and PresentationClinical Spectrum and Presentation

NSTEMINSTEMI

SYNERGY

LMWHLMWH

ESSENCEESSENCE

19941994 19951995 19961996 19971997 19981998 19991999 20002000 20022002 20032003 20042004 20052005 2006200620012001

CURECURE

ClopidogrelClopidogrel

Bleeding riskBleeding risk

Ischemic riskIschemic risk

GP IIb/IIIa GP IIb/IIIa blockersblockers

PRISM-PLUSPRISM-PLUS

PURSUITPURSUIT

ACUITYTACTICS TIMI-18TACTICS TIMI-18

Early invasiveEarly invasive

PCIPCI ~ 5% stents~ 5% stents ~85% stents~85% stents Drug-eluting stentsDrug-eluting stents

ISAR-REACT 2

Milestones in ACS Management

OASIS-5

[ Fondaparinux ][ Fondaparinux ]

Anti-Thrombin RxAnti-Thrombin Rx

Anti-Platelet RxAnti-Platelet Rx

Treatment StrategyTreatment Strategy

HeparinHeparin

AspirinAspirin

ConservativeConservative

ICTUS

BivalirudinBivalirudin

REPLACE 2REPLACE 2

Adapted from and with the courtesy of Steven Manoukian, MDAdapted from and with the courtesy of Steven Manoukian, MDAdapted from and with the courtesy of Steven Manoukian, MDAdapted from and with the courtesy of Steven Manoukian, MD

We Must Risk Stratify PatientsWe Must Risk Stratify Patientswith Chest Painwith Chest Pain

Three levels of risk stratification are pertinentThree levels of risk stratification are pertinent to Emergency Department Management to Emergency Department Management

LowLow, intermediate, or high risk, intermediate, or high risk that ischemic symptoms that ischemic symptoms are a result of CADare a result of CAD

Low, intermediateLow, intermediate, or , or high riskhigh risk of short-term death or of short-term death or nonfatal MI from ACSnonfatal MI from ACS

Dynamic, ongoing risk-oriented evaluationDynamic, ongoing risk-oriented evaluation of low- or of low- or intermediate-risk patients for “conversion” to high-risk intermediate-risk patients for “conversion” to high-risk status status that is linked to intensity of treatmentthat is linked to intensity of treatment

Three levels of risk stratification are pertinentThree levels of risk stratification are pertinent to Emergency Department Management to Emergency Department Management

LowLow, intermediate, or high risk, intermediate, or high risk that ischemic symptoms that ischemic symptoms are a result of CADare a result of CAD

Low, intermediateLow, intermediate, or , or high riskhigh risk of short-term death or of short-term death or nonfatal MI from ACSnonfatal MI from ACS

Dynamic, ongoing risk-oriented evaluationDynamic, ongoing risk-oriented evaluation of low- or of low- or intermediate-risk patients for “conversion” to high-risk intermediate-risk patients for “conversion” to high-risk status status that is linked to intensity of treatmentthat is linked to intensity of treatment

““Dynamic Risk Stratification” ToolsDynamic Risk Stratification” Tools““Dynamic Risk Stratification” ToolsDynamic Risk Stratification” Tools

► History and PhysicalHistory and Physical

► Standard EKG and non-standard EKG leadsStandard EKG and non-standard EKG leads 15-lead ECGs should, perhaps, be “standard” in all but very-15-lead ECGs should, perhaps, be “standard” in all but very-

low-risk patientslow-risk patients

► BiomarkersBiomarkers CPK-MB, Troponins I and T, MyoglobinCPK-MB, Troponins I and T, Myoglobin Ischemia-Modified AlbuminIschemia-Modified Albumin

► Non-Invasive ImagingNon-Invasive Imaging EchocardiogramEchocardiogram Stress testingStress testing Technetium-99m-sestamibi Technetium-99m-sestamibi

► Predictive Indices/SchemesPredictive Indices/Schemes Better as research tools than for real-time clinical decision-Better as research tools than for real-time clinical decision-

makingmaking

► History and PhysicalHistory and Physical

► Standard EKG and non-standard EKG leadsStandard EKG and non-standard EKG leads 15-lead ECGs should, perhaps, be “standard” in all but very-15-lead ECGs should, perhaps, be “standard” in all but very-

low-risk patientslow-risk patients

► BiomarkersBiomarkers CPK-MB, Troponins I and T, MyoglobinCPK-MB, Troponins I and T, Myoglobin Ischemia-Modified AlbuminIschemia-Modified Albumin

► Non-Invasive ImagingNon-Invasive Imaging EchocardiogramEchocardiogram Stress testingStress testing Technetium-99m-sestamibi Technetium-99m-sestamibi

► Predictive Indices/SchemesPredictive Indices/Schemes Better as research tools than for real-time clinical decision-Better as research tools than for real-time clinical decision-

makingmaking

► Braunwald E, Antman EM, Beasley JW, et al: ACC/AHA Braunwald E, Antman EM, Beasley JW, et al: ACC/AHA guidelines for the management of patients with unstable guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial angina and non-ST-segment elevation myocardial infarction: a report of the American College of infarction: a report of the American College of Cardiology/American Heart Association Task Force on Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Practice Guidelines (Committee on the Management of Patients with Unstable Angina). Patients with Unstable Angina). J Am Coll CardiolJ Am Coll Cardiol 2000;36:970-1062 (2002 update at 2000;36:970-1062 (2002 update at www.acc.org; ; summary in summary in CirculationCirculation 2002;106:1893-1900) 2002;106:1893-1900)

► Pollack CV, Roe MT, Peterson ED: 2002 Update to the Pollack CV, Roe MT, Peterson ED: 2002 Update to the ACC/AHA guidelines for the management of patients ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation with unstable angina and non-ST-segment elevation myocardial infarction: Implications for emergency myocardial infarction: Implications for emergency department practice. department practice. Ann Emerg MedAnn Emerg Med 2003;41:355-69 2003;41:355-69

► Braunwald E, Antman EM, Beasley JW, et al: ACC/AHA Braunwald E, Antman EM, Beasley JW, et al: ACC/AHA guidelines for the management of patients with unstable guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial angina and non-ST-segment elevation myocardial infarction: a report of the American College of infarction: a report of the American College of Cardiology/American Heart Association Task Force on Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Practice Guidelines (Committee on the Management of Patients with Unstable Angina). Patients with Unstable Angina). J Am Coll CardiolJ Am Coll Cardiol 2000;36:970-1062 (2002 update at 2000;36:970-1062 (2002 update at www.acc.org; ; summary in summary in CirculationCirculation 2002;106:1893-1900) 2002;106:1893-1900)

► Pollack CV, Roe MT, Peterson ED: 2002 Update to the Pollack CV, Roe MT, Peterson ED: 2002 Update to the ACC/AHA guidelines for the management of patients ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation with unstable angina and non-ST-segment elevation myocardial infarction: Implications for emergency myocardial infarction: Implications for emergency department practice. department practice. Ann Emerg MedAnn Emerg Med 2003;41:355-69 2003;41:355-69

NSTE ACS — Optimal Therapy: 2002NSTE ACS — Optimal Therapy: 2002NSTE ACS — Optimal Therapy: 2002NSTE ACS — Optimal Therapy: 2002

http://www.pbase.com/es839145/animated_water


► Anderson JL, Adams CD, Antman EM, et al. 2007 Anderson JL, Adams CD, Antman EM, et al. 2007 guidelines for the management of patients with unstable guidelines for the management of patients with unstable angina/non-ST-segment-elevation myocardial infarction: a angina/non-ST-segment-elevation myocardial infarction: a report of the American College of Cardiology/American report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Heart Association Task Force on Practice Guidelines. J J Am Coll CardiolAm Coll Cardiol 2007;50:e1-e157, and 2007;50:e1-e157, and CirculationCirculation 2007;116:e148-e304, and at 2007;116:e148-e304, and at www.acc.org and at and at www.americanheart.org. .

► Pollack CV, Braunwald E: 2007 Update to the ACC/AHA Pollack CV, Braunwald E: 2007 Update to the ACC/AHA guidelines for the management of patients with unstable guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial angina and non-ST-segment elevation myocardial infarction: Implications for emergency department infarction: Implications for emergency department practice. practice. Ann Emerg MedAnn Emerg Med 2007, in press. 2007, in press.

NSTE ACS — Optimal Therapy, 2007NSTE ACS — Optimal Therapy, 2007NSTE ACS — Optimal Therapy, 2007NSTE ACS — Optimal Therapy, 2007



II IIaIIa IIbIIb IIIIII

““The Guidelines”The Guidelines”Classes of RecommendationsClasses of Recommendations

““The Guidelines”The Guidelines”Classes of RecommendationsClasses of Recommendations

Intervention is useful and effectiveIntervention is useful and effective

Evidence supportive; awaiting Evidence supportive; awaiting confirming dataconfirming data

Evidence conflicts/opinions differ; Evidence conflicts/opinions differ; neutral statementneutral statement

Intervention is not useful/effective and Intervention is not useful/effective and may be harmfulmay be harmful

Intervention is useful and effectiveIntervention is useful and effective

Evidence supportive; awaiting Evidence supportive; awaiting confirming dataconfirming data

Evidence conflicts/opinions differ; Evidence conflicts/opinions differ; neutral statementneutral statement

Intervention is not useful/effective and Intervention is not useful/effective and may be harmfulmay be harmful

Evidence-Based Approach to ACS Evidence-Based Approach to ACS Weighing the EvidenceWeighing the Evidence

► Class I:Class I: Benefit > > Risk Benefit > > Risk

► Class IIa:Class IIa: Benefit > Risk Benefit > Risk

► Class IIb:Class IIb: Benefit Benefit >> Risk Risk

► Class III:Class III: Risk Risk >> Benefit Benefit

► Class I:Class I: Benefit > > Risk Benefit > > Risk

► Class IIa:Class IIa: Benefit > Risk Benefit > Risk

► Class IIb:Class IIb: Benefit Benefit >> Risk Risk

► Class III:Class III: Risk Risk >> Benefit Benefit

““The Guidelines”The Guidelines”Weighing the EvidenceWeighing the Evidence

Weight of Evidence GradesWeight of Evidence Grades

= Data from many large, randomized = Data from many large, randomized

trials trials

== Data from fewer, smaller randomized Data from fewer, smaller randomized trials, careful analyses of trials, careful analyses of nonrandomized studies, nonrandomized studies, observational registriesobservational registries

== Expert consensusExpert consensus

What Do The Guidelines MeanWhat Do The Guidelines Meanfor Emergency Medicine Practice?for Emergency Medicine Practice?


► Objective approach to risk stratification and Objective approach to risk stratification and

treatmenttreatment

► Driven by risk, not patient geographyDriven by risk, not patient geography

► MultidisciplinaryMultidisciplinary

► Provides a foundation for communication, Provides a foundation for communication,

collaboration, and continuum of care from ED collaboration, and continuum of care from ED

to cardiology serviceto cardiology service

► 2007 Guidelines push for that continuum to be 2007 Guidelines push for that continuum to be

compressed in durationcompressed in duration

► Objective approach to risk stratification and Objective approach to risk stratification and

treatmenttreatment

► Driven by risk, not patient geographyDriven by risk, not patient geography

► MultidisciplinaryMultidisciplinary

► Provides a foundation for communication, Provides a foundation for communication,

collaboration, and continuum of care from ED collaboration, and continuum of care from ED

to cardiology serviceto cardiology service

► 2007 Guidelines push for that continuum to be 2007 Guidelines push for that continuum to be

compressed in durationcompressed in duration

AcuteAcute

CoronaryCoronary

SyndromeSyndrome

AcuteAcute

CoronaryCoronary

SyndromeSyndrome


AcuteAcute

ControversyControversy

SyndromeSyndrome

AcuteAcute

ControversyControversy

SyndromeSyndrome



AcuteAcute

ConfusionalConfusional

SyndromeSyndrome

AcuteAcute

ConfusionalConfusional

SyndromeSyndrome


Acute Confounded SyndromeAcute Confounded Syndrome

“ “The Writing Committee believes that The Writing Committee believes that inadequate inadequate unconfounded, comparative information is availableunconfounded, comparative information is available to to recommend a preferred [anticoagulation] regimen when recommend a preferred [anticoagulation] regimen when an early, invasive strategy is used for UA/NSTEMI, and an early, invasive strategy is used for UA/NSTEMI, and physician and health care system preference, together physician and health care system preference, together with individualized patient application, is advised.”with individualized patient application, is advised.”

Acute Confounded SyndromeAcute Confounded Syndrome

“ “The Writing Committee believes that The Writing Committee believes that inadequate inadequate unconfounded, comparative information is availableunconfounded, comparative information is available to to recommend a preferred [anticoagulation] regimen when recommend a preferred [anticoagulation] regimen when an early, invasive strategy is used for UA/NSTEMI, and an early, invasive strategy is used for UA/NSTEMI, and physician and health care system preference, together physician and health care system preference, together with individualized patient application, is advised.”with individualized patient application, is advised.”

UA/NSTEMI Strategy OverviewUA/NSTEMI Strategy OverviewUA/NSTEMI Strategy OverviewUA/NSTEMI Strategy Overview

ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.

AcuteAcute

ContentiousnessContentiousness

SyndromeSyndrome

AcuteAcute

ContentiousnessContentiousness

SyndromeSyndrome



AcuteAcute

CollaborationCollaboration

SyndromeSyndrome

AcuteAcute

CollaborationCollaboration

SyndromeSyndrome



Big Picture: Early Invasive Vs. Big Picture: Early Invasive Vs. Initial Conservative TherapyInitial Conservative Therapy

““An early invasive strategy (i.e., diagnostic angiography with intent to An early invasive strategy (i.e., diagnostic angiography with intent to perform revascularization) is indicated in initially stabilized UA/NSTEMI perform revascularization) is indicated in initially stabilized UA/NSTEMI patients (without serious comorbidities or contraindications to such patients (without serious comorbidities or contraindications to such procedures) procedures) who have an elevated risk for clinical eventswho have an elevated risk for clinical events.”.”

““In initially stabilized patients, an In initially stabilized patients, an initially conservative (i.e., a selectively initially conservative (i.e., a selectively invasive) strategy may be consideredinvasive) strategy may be considered as a treatment strategy for as a treatment strategy for UA/NSTEMI patients (without serious comorbidities or contraindications UA/NSTEMI patients (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events, to such procedures) who have an elevated risk for clinical events, including those who are troponin positiveincluding those who are troponin positive.”.”

““The decision to implement an initial conservative (vs. initial invasive) The decision to implement an initial conservative (vs. initial invasive) strategy in these patients may be made by strategy in these patients may be made by considering physician and considering physician and patient preferencepatient preference.” .”

Big Picture: Early Invasive Vs. Big Picture: Early Invasive Vs. Initial Conservative TherapyInitial Conservative Therapy

““An early invasive strategy (i.e., diagnostic angiography with intent to An early invasive strategy (i.e., diagnostic angiography with intent to perform revascularization) is indicated in initially stabilized UA/NSTEMI perform revascularization) is indicated in initially stabilized UA/NSTEMI patients (without serious comorbidities or contraindications to such patients (without serious comorbidities or contraindications to such procedures) procedures) who have an elevated risk for clinical eventswho have an elevated risk for clinical events.”.”

““In initially stabilized patients, an In initially stabilized patients, an initially conservative (i.e., a selectively initially conservative (i.e., a selectively invasive) strategy may be consideredinvasive) strategy may be considered as a treatment strategy for as a treatment strategy for UA/NSTEMI patients (without serious comorbidities or contraindications UA/NSTEMI patients (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events, to such procedures) who have an elevated risk for clinical events, including those who are troponin positiveincluding those who are troponin positive.”.”

““The decision to implement an initial conservative (vs. initial invasive) The decision to implement an initial conservative (vs. initial invasive) strategy in these patients may be made by strategy in these patients may be made by considering physician and considering physician and patient preferencepatient preference.” .”

UA/NSTEMI Strategy OverviewUA/NSTEMI Strategy OverviewUA/NSTEMI Strategy OverviewUA/NSTEMI Strategy Overview

ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.Circulation.ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.Circulation.

Algorithm for Evaluation and Management of Algorithm for Evaluation and Management of Patients Suspected of Having ACSPatients Suspected of Having ACS

ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.

AASymptoms Suggestive Symptoms Suggestive of ACSof ACS

Symptoms Suggestive Symptoms Suggestive of ACSof ACS

NoncardiacNoncardiacDiagnosisDiagnosis

NoncardiacNoncardiacDiagnosisDiagnosis

UnstableUnstableAnginaAngina

UnstableUnstableAnginaAngina

Treatment as Treatment as indicated by indicated by alternative alternative diagnosisdiagnosis

Treatment as Treatment as indicated by indicated by alternative alternative diagnosisdiagnosis

See ACC/AHA See ACC/AHA Guidelines for Guidelines for Chronic Stable Chronic Stable

AnginaAngina

See ACC/AHA See ACC/AHA Guidelines for Guidelines for Chronic Stable Chronic Stable

AnginaAngina

BIBI B2B2

Possible Possible ACSACS

Possible Possible ACSACS

DefiniteDefiniteACSACS

DefiniteDefiniteACSACS

B3B3 B4B4


Possible ACSPossible ACSPossible ACSPossible ACS

Nondiagnostic ECGNondiagnostic ECGNormal initial serum cardiac biomarkersNormal initial serum cardiac biomarkers

Nondiagnostic ECGNondiagnostic ECGNormal initial serum cardiac biomarkersNormal initial serum cardiac biomarkers

OBSERVEOBSERVE12 hours or more 12 hours or more

from symptom onsetfrom symptom onset

OBSERVEOBSERVE12 hours or more 12 hours or more

from symptom onsetfrom symptom onset

No recurrent pain, No recurrent pain, negative follow-up negative follow-up

studiesstudies

No recurrent pain, No recurrent pain, negative follow-up negative follow-up

studiesstudies

Recurrent pain, positive Recurrent pain, positive follow-up studiesfollow-up studies

Diagnosis OF ACS Diagnosis OF ACS confirmedconfirmed

Recurrent pain, positive Recurrent pain, positive follow-up studiesfollow-up studies

Diagnosis OF ACS Diagnosis OF ACS confirmedconfirmed

Admit to hospitalAdmit to hospitalManage via acute Manage via acute ischemia pathwayischemia pathway

Admit to hospitalAdmit to hospitalManage via acute Manage via acute ischemia pathwayischemia pathway

Stress study to provoke ischemiaStress study to provoke ischemiaConsider evaluation of LV function if Consider evaluation of LV function if

ischemia is present (tests may be ischemia is present (tests may be performed either prior to discharge performed either prior to discharge

or as outpatientor as outpatient




D1D1

E1E1

F2F2F1F1

G1G1

H3H3



PositivePositive

Diagnosis of ACS Diagnosis of ACS confirmed or highly confirmed or highly

likelylikely

PositivePositive

Diagnosis of ACS Diagnosis of ACS confirmed or highly confirmed or highly

likelylikely

Admin to hospitalAdmin to hospital

Manage via Manage via acute ischemia acute ischemia

pathwaypathway

Admin to hospitalAdmin to hospital

Manage via Manage via acute ischemia acute ischemia

pathwaypathway

H2H2 H3H3







G1G1

NegativeNegativePotential diagnoses:Potential diagnoses:

Nonischemic Nonischemic discomfort; low-risk discomfort; low-risk

ACSACS

NegativeNegativePotential diagnoses:Potential diagnoses:

Nonischemic Nonischemic discomfort; low-risk discomfort; low-risk

ACSACS

Arrangements for Arrangements for outpatient follow-upoutpatient follow-upArrangements for Arrangements for

outpatient follow-upoutpatient follow-up

H1H1

I1I1


Specific Recommendations, Class Specific Recommendations, Class Designation, and Levels Of Designation, and Levels Of

EvidenceEvidence

Initial Invasive Strategy: What’s New?Initial Invasive Strategy: What’s New?

Specific Recommendations, Class Specific Recommendations, Class Designation, and Levels Of Designation, and Levels Of

EvidenceEvidence

Initial Invasive Strategy: What’s New?Initial Invasive Strategy: What’s New?

UA/NSTEMI Strategy OverviewUA/NSTEMI Strategy Overview

New Strategies: AnticoagulantsNew Strategies: Anticoagulants

““Two new anticoagulants, Two new anticoagulants, fondaparinux and fondaparinux and bivalirudinbivalirudin, have undergone , have undergone favorable testing in favorable testing in

clinical trials and are recommendedclinical trials and are recommended as alternatives as alternatives to unfractionated heparin (UFH) and low-molecular-to unfractionated heparin (UFH) and low-molecular-

weight heparins (LMWHs) for specific or more weight heparins (LMWHs) for specific or more general applications.”general applications.”







Algorithm for Patients With UA/NSTEMI Algorithm for Patients With UA/NSTEMI Managed by an Initial Invasive StrategyManaged by an Initial Invasive Strategy

Diagnosis of UA/NSTEMI is Likely or DefiniteDiagnosis of UA/NSTEMI is Likely or DefiniteDiagnosis of UA/NSTEMI is Likely or DefiniteDiagnosis of UA/NSTEMI is Likely or Definite

ASA (Class I, LOE:A)* ASA (Class I, LOE:A)* Clopidogrel if ASA intolerant (Class I, LOE: A)Clopidogrel if ASA intolerant (Class I, LOE: A)

ASA (Class I, LOE:A)* ASA (Class I, LOE:A)* Clopidogrel if ASA intolerant (Class I, LOE: A)Clopidogrel if ASA intolerant (Class I, LOE: A)

Select Management StrategySelect Management Strategy††Select Management StrategySelect Management Strategy††

Invasive StrategyInvasive StrategyInitiate anticoagulant therapy (Class I, LOE: A): Initiate anticoagulant therapy (Class I, LOE: A): Acceptable options*: enoxaparin or UFH (Class Acceptable options*: enoxaparin or UFH (Class

I, LOE: A), bivalirudin or fondaparinux are I, LOE: A), bivalirudin or fondaparinux are preferable (Class I, LOE: B)preferable (Class I, LOE: B)

Invasive StrategyInvasive StrategyInitiate anticoagulant therapy (Class I, LOE: A): Initiate anticoagulant therapy (Class I, LOE: A): Acceptable options*: enoxaparin or UFH (Class Acceptable options*: enoxaparin or UFH (Class

I, LOE: A), bivalirudin or fondaparinux are I, LOE: A), bivalirudin or fondaparinux are preferable (Class I, LOE: B)preferable (Class I, LOE: B)

InitialInitialConservative Conservative

StrategyStrategy

InitialInitialConservative Conservative

StrategyStrategy

AAAA

B1B1B1B1


Algorithm for Patients With UA/NSTEMI Algorithm for Patients With UA/NSTEMI Managed by an Initial Invasive StrategyManaged by an Initial Invasive Strategy

Prior to AngiographyPrior to AngiographyInitiate at least one (Class I, LOE: A) orInitiate at least one (Class I, LOE: A) or

Both (Class IIa, LOE: B) of the following:Both (Class IIa, LOE: B) of the following:

Clopidogrel* Clopidogrel* ‡‡ IV GP IIb/IIIa inhibitor* IV GP IIb/IIIa inhibitor* ‡‡

Factors favoring administration of both Factors favoring administration of both clopidogrel and GP IIb/IIIa inhibitor include:clopidogrel and GP IIb/IIIa inhibitor include:

Delay to angiographyDelay to angiographyHigh risk featuresHigh risk features

Early recurrent ischemic discomfortEarly recurrent ischemic discomfort

Prior to AngiographyPrior to AngiographyInitiate at least one (Class I, LOE: A) orInitiate at least one (Class I, LOE: A) or

Both (Class IIa, LOE: B) of the following:Both (Class IIa, LOE: B) of the following:

Clopidogrel* Clopidogrel* ‡‡ IV GP IIb/IIIa inhibitor* IV GP IIb/IIIa inhibitor* ‡‡

Factors favoring administration of both Factors favoring administration of both clopidogrel and GP IIb/IIIa inhibitor include:clopidogrel and GP IIb/IIIa inhibitor include:

Delay to angiographyDelay to angiographyHigh risk featuresHigh risk features

Early recurrent ischemic discomfortEarly recurrent ischemic discomfort

Diagnostic AngiographyDiagnostic AngiographyDiagnostic AngiographyDiagnostic Angiography

B2B2B2B2


Welcome To This Program!Welcome To This Program!

► Move from confusion, controversy, and Move from confusion, controversy, and

contentiousness to contentiousness to collaboration and collaboration and

more evidence-based caremore evidence-based care

► Give emergency physicians familiarity Give emergency physicians familiarity

they need with ACC/AHA 2007 they need with ACC/AHA 2007

UA/NSTEMI Guidelines in order to:UA/NSTEMI Guidelines in order to: (1) Treat patients optimally and; (1) Treat patients optimally and;

(2) Work effectively and collegially with (2) Work effectively and collegially with

their cardiology consultantstheir cardiology consultants

► Move from confusion, controversy, and Move from confusion, controversy, and

contentiousness to contentiousness to collaboration and collaboration and

more evidence-based caremore evidence-based care

► Give emergency physicians familiarity Give emergency physicians familiarity

they need with ACC/AHA 2007 they need with ACC/AHA 2007

UA/NSTEMI Guidelines in order to:UA/NSTEMI Guidelines in order to: (1) Treat patients optimally and; (1) Treat patients optimally and;

(2) Work effectively and collegially with (2) Work effectively and collegially with

their cardiology consultantstheir cardiology consultants

Recent Clinical Trials in STEMI Recent Clinical Trials in STEMI and NSTEMIand NSTEMI

What New Evidence Tells Us and Implications What New Evidence Tells Us and Implications for ED Cardiovascular Managementfor ED Cardiovascular Management

Recent Clinical Trials in STEMI Recent Clinical Trials in STEMI and NSTEMIand NSTEMI

What New Evidence Tells Us and Implications What New Evidence Tells Us and Implications for ED Cardiovascular Managementfor ED Cardiovascular Management

Judd E. Hollander, MDJudd E. Hollander, MDProfessor and Clinical Research DirectorProfessor and Clinical Research Director

Department of Emergency MedicineDepartment of Emergency MedicineUniversity of PennsylvaniaUniversity of Pennsylvania

Getting in the Stream of ThingsGetting in the Stream of Things

ACS: Recent Clinical Trials in ACS: Recent Clinical Trials in STEMISTEMI and NSTEMI and NSTEMI

ACS: Recent Clinical Trials in ACS: Recent Clinical Trials in STEMISTEMI and NSTEMI and NSTEMI

Getting in the (Up)Stream of ThingsGetting in the (Up)Stream of Things

8.57.3 7.2

22.0

2.0

7.24.9

2.8

6.8

1.0

0.0

5.0

10.0

15.0

20.0

25.0

Death DeathSHOCK

excl.

Reinfarction Recurrentischemia

Stroke

Per

cen

t (%

)

Lysis

PCI

8.57.3 7.2

22.0

2.0

7.24.9

2.8

6.8

1.0

0.0

5.0

10.0

15.0

20.0

25.0

Death DeathSHOCK

excl.

Reinfarction Recurrentischemia

Stroke

Per

cen

t (%

)

Lysis

PCI

PCI PCI versusversus Fibrinolysis FibrinolysisSystematic Overview Systematic Overview

Short term (4-6 weeks)

Keeley EC, Boura JA, Grines CL. Lancet. 2003.

P=0.0002P=0.0002P=0.0003P=0.0003 P<0.0001P<0.0001

P<0.0001P<0.0001

P=0.0004P=0.0004

(23 RCTs, n=7,739)(23 RCTs, n=7,739)(23 RCTs, n=7,739)(23 RCTs, n=7,739)

5.9%

2.2%

3.7%

5.7%

0%

2%

4%

6%

8%

10%

<2 Hrs(n=460)

>2 Hrs(n=374)

30-d

ay m

ort

alit

y

Pre-hosp tPAPCI

5.9%

2.2%

3.7%

5.7%

0%

2%

4%

6%

8%

10%

<2 Hrs(n=460)

>2 Hrs(n=374)

30-d

ay m

ort

alit

y

Pre-hosp tPAPCI

7.4%

15.3%

7.3%6.0%

0%

5%

10%

15%

20%

<3 Hrs(n=551)

>3 Hrs(n=299)

30-d

ay m

ort

alit

y

Lytic (SK)Transfer for PCI

7.4%

15.3%

7.3%6.0%

0%

5%

10%

15%

20%

<3 Hrs(n=551)

>3 Hrs(n=299)

30-d

ay m

ort

alit

y

Lytic (SK)Transfer for PCI

Early Presenting Patients — Early Presenting Patients — Primary PCI Primary PCI versusversus Fibrinolytics Fibrinolytics

Early Presenting Patients — Early Presenting Patients — Primary PCI Primary PCI versusversus Fibrinolytics Fibrinolytics

p=0.058p=0.058 p=0.47p=0.47

CAPTIMCAPTIM

p<0.02p<0.02

PRAGUE-2PRAGUE-2

Widimsky P, et al. Eur Heart J. 2003;24(1):94-104. Steg PG, et al. Circulation. 2003;108(23):2851-2856.

Mortality Rates with Primary PCI as aMortality Rates with Primary PCI as aFunction of PCI Time DelayFunction of PCI Time Delay

Mortality Rates with Primary PCI as aMortality Rates with Primary PCI as aFunction of PCI Time DelayFunction of PCI Time Delay

PP=.006=.006

Circle sizes =Circle sizes = sample size of the studysample size of the study

Solid line = weighted metaregressionSolid line = weighted metaregression

Nallamothu BK, Bates ER. Am J Cardiol. 2003;92:824-826.

62 min62 min BenefitBenefitFavors PCIFavors PCI

HarmHarmFavors LysisFavors Lysis

For every 10 min delay to PCI: 1% reduction in mortality difference towards lyticsFor every 10 min delay to PCI: 1% reduction in mortality difference towards lytics

55

1010

1515

00

Ab

solu

te r

isk

dif

fere

nce

in

dea

th (

%)

Ab

solu

te r

isk

dif

fere

nce

in

dea

th (

%)

––5500 2020 4040 6060 8080 100100PCI-related time delay (door to balloon - door to needle)PCI-related time delay (door to balloon - door to needle)

Can We Improve STEMI CareCan We Improve STEMI CareWith Fibrinolysis?With Fibrinolysis?

Can We Improve STEMI CareCan We Improve STEMI CareWith Fibrinolysis?With Fibrinolysis?

Optimizing STEMI OutcomesOptimizing STEMI Outcomes

Adjunctive Medications —Adjunctive Medications —No Effect in STEMINo Effect in STEMI

► Double-bolus t-PADouble-bolus t-PA

► TNKTNK

► rPArPA

► nPAnPA

► GP IIb/IIIa inhibition GP IIb/IIIa inhibition +lytic+lytic

► Oral GP IIb/IIIaOral GP IIb/IIIa

► Double-bolus t-PADouble-bolus t-PA

► TNKTNK

► rPArPA

► nPAnPA

► GP IIb/IIIa inhibition GP IIb/IIIa inhibition +lytic+lytic

► Oral GP IIb/IIIaOral GP IIb/IIIa

► HirudinHirudin

► PexulizamabPexulizamab

► MagnesiumMagnesium

► AdenosineAdenosine

► PSGLPSGL

► GIKGIK

► HirudinHirudin

► PexulizamabPexulizamab

► MagnesiumMagnesium

► AdenosineAdenosine

► PSGLPSGL

► GIKGIK

USEFUL ADJUNCTSUSEFUL ADJUNCTS

AspirinEnoxaparinClopidogrel

USEFUL ADJUNCTSUSEFUL ADJUNCTS

AspirinEnoxaparinClopidogrel

CLARITY–TIMI 28CLARITY–TIMI 28CLARITY–TIMI 28CLARITY–TIMI 28

Double-blind, randomized, placebo-controlled trial inDouble-blind, randomized, placebo-controlled trial in3491 Patients, aged 183491 Patients, aged 18––75 yr, with STEMI <12 hr 75 yr, with STEMI <12 hr

Double-blind, randomized, placebo-controlled trial inDouble-blind, randomized, placebo-controlled trial in3491 Patients, aged 183491 Patients, aged 18––75 yr, with STEMI <12 hr 75 yr, with STEMI <12 hr

Fibrinolytic, ASA, heparinFibrinolytic, ASA, heparin

Clopidogrel300 + 75 mg qd

Coronary angiogramCoronary angiogram(2(2––8 days)8 days)

Primary endpointPrimary endpointOccluded artery Occluded artery (TIMI flow grade (TIMI flow grade 0/1) or death/MI 0/1) or death/MI by time of angioby time of angio

Randomized

Placebo

StudyStudydrugdrug

30-d clinical follow-up30-d clinical follow-up

Open-labelOpen-labelclopidogrelclopidogrelper MD inper MD in

both groupsboth groups

Sabatine MS, et al. N Engl J Med. 2005;352:1179-1189.

PlaceboClopidogrel

PP=.001=.001

Odds Ratio: 0.64Odds Ratio: 0.64(95% CI, 0.53-0.76)(95% CI, 0.53-0.76)

1.00.4 0.6 0.8 1.2 1.6

ClopidogrelBetter

PlaceboBetter

n=1752 n=1739

36%Odds Reduction

15.0

21.7

Occ

lud

ed A

rter

y o

r D

eath

/MI

(%)

0

5

10

15

20

25


CLARITY–TIMI 28CLARITY–TIMI 28

CV Death, MI, and Urgent CV Death, MI, and Urgent RevascularizationRevascularization

CV Death, MI, and Urgent CV Death, MI, and Urgent RevascularizationRevascularization

Days

En

dp

oin

t (%

)

0

5

10

15

0 5 10 15 20 25 30

PlaceboPlacebo

ClopidogrelClopidogrel

Odds Ratio: 0.80Odds Ratio: 0.80(95% CI, 0.65(95% CI, 0.65––0.97)0.97)

PP=.03=.03

20%20%


CLARITY–TIMI 28: BleedingCLARITY–TIMI 28: BleedingCLARITY–TIMI 28: BleedingCLARITY–TIMI 28: Bleeding

NSNS7.27.27.57.5In those undergoing CABGIn those undergoing CABG

NSNS7.97.99.19.1CABG w/in 5 d of study medCABG w/in 5 d of study med

0.90.9

1.71.7

0.70.7

0.50.5

1.11.1

Placebo Placebo (%)(%)

Placebo Placebo (%)(%)

NSNS

NSNS

NSNS

NSNS

NSNS

PPPP

1.91.9TIMI majorTIMI major

1.61.6

0.50.5

1.01.0

1.31.3

Clopidogrel Clopidogrel (%)(%)

Clopidogrel Clopidogrel (%)(%)

TIMI minorTIMI minor

ICHICH

Through 30 daysThrough 30 days

TIMI minorTIMI minor

TIMI majorTIMI major

Through angiographyThrough angiography

OutcomeOutcomeOutcomeOutcome


STEMI < 6 hoursSTEMI < 6 hoursLytic eligibleLytic eligible

Lytic choice by MDLytic choice by MD(TNK, tPA, rPA, SK)(TNK, tPA, rPA, SK)

ENOXAPARIN

< 75 y: 30 mg IV bolus SC 1.0 mg / kg q 12 h (Hosp DC)

≥ 75 y: No bolus

SC 0.75 mg / kg q 12 h (Hosp DC)

CrCl < 30: 1.0 mg / kg q 24 h

Double-blind, double-dummyDouble-blind, double-dummy

ASAASA

Day 30Day 3011°° Efficacy Endpoint: Death or Nonfatal MI Efficacy Endpoint: Death or Nonfatal MI1° Safety Endpoint: TIMI Major Hemorrhage1° Safety Endpoint: TIMI Major Hemorrhage

EXTRACT: TIMI 25EXTRACT: TIMI 25EXTRACT: TIMI 25EXTRACT: TIMI 25

UFH60 U / kg bolus (4000 U)

Inf 12 U / kg / h (1000 U / h)Duration: at least 48 hCont’d at MD discretion

Primary End Point (ITT) — Primary End Point (ITT) — Death or Nonfatal MIDeath or Nonfatal MI

Primary End Point (ITT) — Primary End Point (ITT) — Death or Nonfatal MIDeath or Nonfatal MI

0

3

6

9

12

15

0 5 10 15 20 25 30

Pri

ma

ry E

nd

Po

int

(%)

Pri

ma

ry E

nd

Po

int

(%)

ENOX

UFH

Relative RiskRelative Risk0.83 (0.77 to 0.90)0.83 (0.77 to 0.90)

P<0.0001P<0.0001

Days Days

9.9%

12.0%

Lost to follow up = 3 Lost to follow up = 3

17% RRR

Antman EM, et al. Antman EM, et al. NEJMNEJM 354:1477-1488 354:1477-1488 Antman EM, et al. Antman EM, et al. NEJMNEJM 354:1477-1488 354:1477-1488

Death or Nonfatal MI — Day 30Death or Nonfatal MI — Day 30Medical Therapy vs Any PCIMedical Therapy vs Any PCI

Death or Nonfatal MI — Day 30Death or Nonfatal MI — Day 30Medical Therapy vs Any PCIMedical Therapy vs Any PCI

0.00040.00040.0010.001

%

% E

ven

tsE

ven

ts

0

5

10

15

Any PCI Medical Rx

N = 15,223 (75%) N = 4,676 (23%)

P ValueP Value

9.79.7

RRR RRR 16%16%

11.411.413.813.8

10.710.7

RRR RRR 23%23%

EnoxaparinEnoxaparin

UFHUFH


UFHUFH


Death or Nonfatal MI — Day 30Death or Nonfatal MI — Day 30Clopidogrel UseClopidogrel Use

Death or Nonfatal MI — Day 30Death or Nonfatal MI — Day 30Clopidogrel UseClopidogrel Use

0.00050.0005 0.00060.0006

%

% E

ven

tsE

ven

ts

0

5

10

15

No Clopidogrel Clopidogrel Use*

N = 14,752 (78%) N = 5,727 (28%) P ValueP Value

10.410.4

RRRRRR15%15%

12.212.211.411.4

8.78.7

RRRRRR24%24%

* 2546 clopidogrel treated patients did not undergo PCI


UFHUFH


UFHUFH


Net Clinical Benefit at 30 DaysNet Clinical Benefit at 30 DaysNet Clinical Benefit at 30 DaysNet Clinical Benefit at 30 Days

11 1.251.250.90.90.80.8

Death or Nonfatal MI or Death or Nonfatal MI or Nonfatal ICHNonfatal ICH

Death or Nonfatal MI or Death or Nonfatal MI or Nonfatal Major BleedNonfatal Major Bleed

Death or Nonfatal MI orDeath or Nonfatal MI or Nonfatal Disabl. Stroke Nonfatal Disabl. Stroke

ENOX BetterENOX Better UFH BetterUFH BetterRRRR

UFH (%)UFH (%) ENOX (%)ENOX (%) RRR (%)RRR (%)

12.312.3 10.110.1 1818

12.812.8 11.011.0 1414

12.212.2 10.110.1 1717

Prespecified DefinitionsPrespecified Definitions

P <0.0001P <0.0001

P <0.0001P <0.0001

P <0.0001P <0.0001


Trial Results In Perspective —Trial Results In Perspective —PCI vs Lysis for STEMIPCI vs Lysis for STEMI

7

2.2

3.4

0

2

4

6

8

10

% E

ven

ts%

Eve

nts

(3

0-42

Da

ys)

(30-

42 D

ays

)

ReinfarctionReinfarction

Lytic Arms (UFH) PCI

ArmsENOX

Overview of 23 RCTsOverview of 23 RCTs Overview of 23 RCTsOverview of 23 RCTs

The advance in adjunctive therapy with enoxaparin has narrowed the The advance in adjunctive therapy with enoxaparin has narrowed the

gap between PCI and Lysis as reperfusion for STEMIgap between PCI and Lysis as reperfusion for STEMI The advance in adjunctive therapy with enoxaparin has narrowed the The advance in adjunctive therapy with enoxaparin has narrowed the

gap between PCI and Lysis as reperfusion for STEMIgap between PCI and Lysis as reperfusion for STEMI


12,000 Patients with STEMI < 12 h of symptom onsetInclusion: ST 2 mm prec leads or 1 mm limb leads

Exclusion: Contraindicated. For anticoagulant, INR > 1.8, pregnancy, ICH<12 mo

UFH notindicatedUFH not indicated

Study Design: Randomized, Double Study Design: Randomized, Double Blind, Double DummyBlind, Double Dummy

Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion (eg. late)

Stratification

UFH indicatedUFH indicatedRandomization Randomization

Fondaparinux2.5 mg Placebo

Fondaparinux2.5 mg UFH


Primary Efficacy OutcomePrimary Efficacy OutcomeDeath/MI at 30 DaysDeath/MI at 30 Days

DaysDays

Cu

mu

lati

ve H

azar

dC

um

ula

tive

Haz

ard

0.0

0.0

0.02

0.02

0.04

0.04

0.06

0.06

0.08

0.08

0.10

0.10

0.12

0.12

00 33 66 99 1212 1515 1818 2121 2424 2727 3030

UFH/PlaceboUFH/Placebo

FondaparinuxFondaparinux

HR 0.86 HR 0.86 95% CI 0.77-95% CI 0.77-0.960.96

P=0.008P=0.008


Efficacy of Fondaparinux by StrataEfficacy of Fondaparinux by Strataon Death/MIon Death/MI

0.760.76--1.021.020.880.8811.211.212.712.7Stratum II (n = 6434)Stratum II (n = 6434)

(Fonda vs. UFH)(Fonda vs. UFH)

0.760.76--0.990.990.870.8715.915.917.317.3Stratum I (n = 5658)Stratum I (n = 5658)

(Fonda vs. Placebo)(Fonda vs. Placebo)

95% CI95% CIHRHRFondaFondaControlControl

No. of Events (%)No. of Events (%)

Interaction P=0.88Interaction P=0.88


STEMI — ConclusionsSTEMI — Conclusions

► There is still a role for fibrinolytic There is still a role for fibrinolytic therapy in STEMItherapy in STEMI

► Adjuvant clopidogrel and/or Adjuvant clopidogrel and/or enoxaparin improve outcomes in enoxaparin improve outcomes in combination with fibrinolyticscombination with fibrinolytics

► Fondaparinux improves outcomes Fondaparinux improves outcomes relative to placeborelative to placebo

ACS: Recent Clinical Trials inSTEMI and NSTEMI

ACS: Recent Clinical Trials inSTEMI and NSTEMI

Getting in the (Up) Stream of Things Getting in the (Up) Stream of Things

5.955.956.336.33

5.165.16 5.075.07 4.974.974.634.63

4.164.16 4.174.17

0

1

22

33

44

55

66

7

Hospital Composite Quality Quartiles

% In

-ho

spit

al M

ort

alit

y

Every 10% Every 10% in guidelines adherence = in guidelines adherence =11% 11% in mortality (OR=0.89, 95% CI, 0.81-0.98) in mortality (OR=0.89, 95% CI, 0.81-0.98)

Peterson ED et al. J Am Coll Cardiol. 2004;43(suppl A):406A. Abstract 1077-71.

The Link Between Guideline The Link Between Guideline Implementation and Mortality Is ClearImplementation and Mortality Is Clear

The Link Between Guideline The Link Between Guideline Implementation and Mortality Is ClearImplementation and Mortality Is Clear

25% 25%–50% 50%–75% 75%

Adjusted

UnadjustedUnadjusted

Antithrombotic and AntiplateletAntithrombotic and AntiplateletTherapy in ACSTherapy in ACS

Antithrombotic and AntiplateletAntithrombotic and AntiplateletTherapy in ACSTherapy in ACS

ACC/AHA Guideline Update for UA and NSTEMI. 2002.

CURE: CURE: CClopidogrel in lopidogrel in UUnstable Angina nstable Angina

to Prevent to Prevent RRecurrent ecurrent EEventsvents

CURE: Primary End Point:CURE: Primary End Point:MI/Stroke/CV Death (N=12,562*)MI/Stroke/CV Death (N=12,562*)

CURE SafetyCURE SafetyCURE SafetyCURE Safety

SYNERGY DesignSYNERGY Design

At least 2 of 3 required:

• Age 60

• ST (transient) or

• (+) CK-MB or troponin

Primary endpoint: Death or MI at 30 days

High-riskHigh-riskACS PatientsACS Patients

Early invasive strategyOther therapy per ACC/AHA guidelines

(ASA, -blocker, ACE, clopidogrel, GP IIb/IIIa)

Enoxaparin IV UFH

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

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

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

Death and MI at 30 DaysDeath and MI at 30 DaysDeath and MI at 30 DaysDeath and MI at 30 Days

1

Hazard Ratio (95% CI)

Enoxaparin UFHBetter Better

30-day Death/MI30-day Death/MI

0.8 1.01.2

HR 0.96 (0.86 – 1.06)

HR 0.96 (0.86 – 1.06)

1.11.1

0 5 10 15 20 25 300.8

0.9

0.95

1.0

Fre

edo

m f

rom

Dea

th /

MI

Days from Randomization

0.85EnoxaparinUFHEnoxaparinUFH


6-Month Survival — Death/MI6-Month Survival — Death/MI(Intention-to-Treat)(Intention-to-Treat)

HR (95% CI) = 0.978 (0.891, 1.075)HR (95% CI) = 0.978 (0.891, 1.075)

0 3030 6060 9090 120120 150150 1801800.7

0.750.75

0.80.8

0.850.85

0.90.9

0.950.95

1Fr

eedo

m fr

om D

eath

/ M

I at 6

Mon

ths


UFHUFH



Bleeding EventsBleeding EventsBleeding EventsBleeding Events

GUSTO severe 2.7 2.2 0.08

TIMI major (clinical): 9.1 7.6 0.008CABG-related 6.8 5.9 0.08Non-CABG-related 2.4 1.8 0.03

Hb/HCT drop (algorithm) 15.2 12.5 < 0.001

Any RBC transfusion 17.0 16.0 0.16

ICH < 0.1 < 0.1 NS

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

—%——%—


► Enoxaparin was not superior to unfractionated Enoxaparin was not superior to unfractionated heparin but was noninferior for non–ST-segment heparin but was noninferior for non–ST-segment elevation ACSelevation ACS

► More bleeding was observed with enoxaparinMore bleeding was observed with enoxaparin► Enoxaparin was an alternative to unfractionated Enoxaparin was an alternative to unfractionated

heparin for non–ST-segment elevation ACS in high-heparin for non–ST-segment elevation ACS in high-risk patients being managed with a rapid transition to risk patients being managed with a rapid transition to interventionintervention

► Do not change fromDo not change from UFH to Enoxaparin, orUFH to Enoxaparin, or

Enoxaparin to UFHEnoxaparin to UFH ► Stay with the agent initiated in the EDStay with the agent initiated in the ED

CollaborationCollaboration PathwaysPathways Bivalirudin may be exceptionBivalirudin may be exception

SYNERGY: Conclusions/CaveatsSYNERGY: Conclusions/Caveats

OASIS-5 Study DesignOASIS-5 Study DesignOASIS-5 Study DesignOASIS-5 Study Design

Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76

Patients w/ NSTE ACSPatients w/ NSTE ACS Chest pain < 24 hours2/3:

Age > 60ST-segment ∆

↑ cardiac markers

Chest pain < 24 hours2/3:

Age > 60ST-segment ∆

↑ cardiac markers

ASA, clopidogrel, IIb/IIIa, planned cath per local

practice

ASA, clopidogrel, IIb/IIIa, planned cath per local

practice

ExcludeAge < 21

Contraindication to enoxHemorrhagic stroke < 12 moCreat > 3 mg/dL (265 umol/L)

ExcludeAge < 21

Contraindication to enoxHemorrhagic stroke < 12 moCreat > 3 mg/dL (265 umol/L)

RandomizeRandomize

n = 20,000n = 20,000

Fondaparinux2.5 mg sc qd

Fondaparinux2.5 mg sc qd

Enoxaparin 1 mg/kg sc bid

Enoxaparin 1 mg/kg sc bid

PCI < 6 h: IV fondaparinux 2.5 mg w/o IIb/IIIa, 0 w/ IIb/IIIa

PCI > 6h: IV fondaparinux 5 mg w/o IIb/IIIa, 2.5 mg w/ IIb/IIIa

PCI < 6 h: IV fondaparinux 2.5 mg w/o IIb/IIIa, 0 w/ IIb/IIIa

PCI > 6h: IV fondaparinux 5 mg w/o IIb/IIIa, 2.5 mg w/ IIb/IIIa

Primary Efficacy: Death, MI, refractory ischemia at 9 days Safety: Major bleeding at 9 days Risk/Benefit: Death, MI, refractory ischemia and major bleeding at 9 days

Secondary Above and each component separately at day 30 and 6 months

Primary Efficacy: Death, MI, refractory ischemia at 9 days Safety: Major bleeding at 9 days Risk/Benefit: Death, MI, refractory ischemia and major bleeding at 9 days

Secondary Above and each component separately at day 30 and 6 months

PCI < 6 h: no UFHPCI > 6h: IV UFH

100 U/kg w/o IIb/IIIa60 U/kg w/ IIb/IIIa

PCI < 6 h: no UFHPCI > 6h: IV UFH

100 U/kg w/o IIb/IIIa60 U/kg w/ IIb/IIIaOutcomesOutcomes

OASIS–5: Efficacy at Day 9OASIS–5: Efficacy at Day 9

EnoxEnox FondaFonda————%——%——

Death/MI/RIDeath/MI/RI 5.85.8 5.95.9

Death/MIDeath/MI 4.14.1 4.14.1

DeathDeath 1.91.9 1.81.8

MIMI 2.72.7 2.72.7

Refract IschRefract Isch 1.91.9 2.052.05

0.80.8 11 1.21.2

Non-inferiorityNon-inferiorityMargin = 1.185Margin = 1.185

Hazard RatioHazard Ratio

Fonda BetterFonda Better Enox BetterEnox Better


OASIS–5: Bleeding Rates at Day 9OASIS–5: Bleeding Rates at Day 9OASIS–5: Bleeding Rates at Day 9OASIS–5: Bleeding Rates at Day 9

OutcomeOutcome EnoxEnox FondaFonda HR (95% CI)HR (95% CI) PP

No. RandomizedNo. Randomized 10,02110,021 10,05710,057

Total Bleed (%)Total Bleed (%) 7.07.0 3.23.2 0.44 (0.39 – 0.51)0.44 (0.39 – 0.51) < 0.0001< 0.0001

Major Bleed (%)Major Bleed (%) 4.04.0 2.12.1 0.53 (0.45 – 0.62)0.53 (0.45 – 0.62) < 0.0001< 0.0001

TIMI Major Bleed (%)TIMI Major Bleed (%) 1.31.3 0.70.7 0.54 (0.41 – 0.73)0.54 (0.41 – 0.73) < 0.0001< 0.0001

Minor Bleed (%)Minor Bleed (%) 3.13.1 1.11.1 0.35 (0.28 – 0.43)0.35 (0.28 – 0.43) < 0.0001< 0.0001


Efficacy End Points at 6 MonthsEfficacy End Points at 6 Months

End point End point EnoxaparinEnoxaparin FondaparinuxFondaparinux P valueP value

Death/MI/ refractory Death/MI/ refractory ischemia ischemia 13.2%13.2% 12.3%12.3% 0.060.06

Death/MI Death/MI 11.4%11.4% 10.5%10.5% 0.050.05

Death Death 6.5%6.5% 5.8%5.8% 0.050.05

MI MI 6.6%6.6% 6.3%6.3% NSNS

Stroke Stroke 1.7%1.7% 1.3%1.3% 0.040.04

Death/MI/stroke*Death/MI/stroke* 12.5%12.5% 11.3%11.3% 0.0070.007


PCI — Procedural ComplicationsPCI — Procedural ComplicationsPCI — Procedural ComplicationsPCI — Procedural Complications

Events (30 Days)Events (30 Days) Enoxaparin Enoxaparin n=3089n=3089

Fondaparinux Fondaparinux n=3118n=3118 P valueP value

Any UFH during PCI Any UFH during PCI 53.8%53.8% 18.8%18.8%

Any procedural Any procedural complication complication 8.6%8.6% 9.6%9.6% 0.180.18

Abrupt closureAbrupt closure 1.1%1.1% 1.5%1.5% 0.200.20

Catheter thrombus Catheter thrombus 0.5%0.5% 1.3%1.3% 0.0010.001

Vascular access Vascular access 8.1%8.1% 3.3%3.3% <0.0001<0.0001

Pseudo-aneurysmPseudo-aneurysm 1.6%1.6% 1.0%1.0% 0.390.39

Large hematomaLarge hematoma 4.4%4.4% 1.6%1.6% <0.0001<0.0001


Moderate-high risk

ACS

ACUITY Study Design – First Randomization

ACUITY Study Design – First Randomization

► Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819)


An

gio

gra

ph

y w

ith

in 7

2h

Aspirin in allAspirin in allClopidogrelClopidogrel

dosing and timingdosing and timingper local practiceper local practice

UFH orEnoxaparin+ GP IIb/IIIa

Bivalirudin+ GP IIb/IIIa

BivalirudinAlone

R*

ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

Medicalmanagement

PCI

CABG

Primary endpoint: “Net Clinical Composite”

Death, MI, TVR, Bleeding



Moderate-high risk

ACS

ACUITY Study Design – Second RandomizationACUITY Study Design – Second Randomization



An

gio

gra

ph

y w

ith

in 7

2h


Aspirin in allClopidogrel

dosing and timingper local practice

Medicalmanagement

PCI

CABG

BivalirudinAlone

UFH or EnoxaparinRoutine upstream

GPI in all ptsGPI started in

CCL for PCI only

R

Bivalirudin

R

Routine upstream GPI in all ptsGPI started in

CCL for PCI only

1. Composite net clinical benefit =

2. Ischemic composite

or

3. Major bleeding

3 Primary Endpoints (at 30 Days)3 Primary Endpoints (at 30 Days)

Death from any cause Myocardial infarction

- During medical Rx: Any biomarker elevation >ULN

- Post PCI: CKMB >ULN with new Q waves or >3x ULN w/o Q waves

- Post CABG: CKMB >5x ULN with new Q waves, >10x ULN w/o Q waves

Unplanned revascularization for ischemia

Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16. Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16.

1. Composite net clinical benefit =

2. Ischemic composite

or

3. Major bleeding

3 Primary Endpoints (at 30 Days)3 Primary Endpoints (at 30 Days)

Non CABG related bleeding

– – Intracranial bleeding or intraocular bleedingIntracranial bleeding or intraocular bleeding

– – Retroperitoneal bleedingRetroperitoneal bleeding

– – Access site bleed requiring intervention/surgeryAccess site bleed requiring intervention/surgery

– – Hematoma ≥5 cmHematoma ≥5 cm

– – Hgb Hgb ≥3g/dL with an overt source or ≥3g/dL with an overt source or ≥4g/dL w/o overt source≥4g/dL w/o overt source

– – Blood product transfusionBlood product transfusion

-–-– Reoperation for bleedingReoperation for bleeding


Ischemic Composite EndpointIschemic Composite EndpointIschemic Composite EndpointIschemic Composite Endpoint

0

5

10

15

0 5 10 15 20 25 30 35

Cu

mu

lati

ve E

ven

ts (

%)


EstimateEstimatePP

(log rank)(log rank)

7.3%7.3%UFH/Enoxaparin + IIb/IIIa (N=4603)UFH/Enoxaparin + IIb/IIIa (N=4603)

Bivalirudin + IIb/IIIa (N=4604)Bivalirudin + IIb/IIIa (N=4604) 0.370.377.7%7.7%

Bivalirudin alone (N=4612)Bivalirudin alone (N=4612) 0.300.307.8%7.8%


Major Bleeding EndpointMajor Bleeding EndpointMajor Bleeding EndpointMajor Bleeding Endpoint

0

5

10

15

0 5 10 15 20 25 30 35

Cu

mu

lati

ve E

ven

ts (

%)


EstimateEstimate PP




Bivalirudin alone (N=4612)Bivalirudin alone (N=4612) <0.0001<0.00013.0%3.0%

Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16.

Net Clinical OutcomeNet Clinical OutcomeNet Clinical OutcomeNet Clinical Outcome

0

5

10

15

0 5 10 15 20 25 30 35

Cu

mu

lati

ve E

ven

ts (

%)


EstimateEstimatePP




Bivalirudin alone (N=4612)Bivalirudin alone (N=4612) 0.0140.01410.1%10.1%


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

4

5

Mo

rtal

ity

(%)


2

1

ACUITY Mortality at 1-yearACUITY Mortality at 1-yearACUITY Mortality at 1-yearACUITY Mortality at 1-year

UFH/Enoxaparin + IIb/IIIaBivalirudin + IIb/IIIa

Bivalirudin alone

EstimateP

(log rank)

1.4%0.531.6%0.391.6%

—

EstimateP

(log rank)

4.4%0.934.2%0.663.8%

1 year

—

p=0.90

Bivalirudin+GPI vs. Hep+GPIHR [95% CI] = 0.99 (0.80-1.22)

30 day

3

Bivalirudin alone vs. Hep+GPIHR [95% CI] = 0.95 (0.77-1.18)


► Bivalirudin plus IIb/IIIa had similar ischemic Bivalirudin plus IIb/IIIa had similar ischemic outcomes, similar bleeding, and similar net outcomes, similar bleeding, and similar net clinical benefit to heparin plus IIb/IIIaclinical benefit to heparin plus IIb/IIIa

► Bivalirudin alone (with provisional IIb/IIIa use) Bivalirudin alone (with provisional IIb/IIIa use) had similar ischemic outcomes, less bleeding, had similar ischemic outcomes, less bleeding, and superior net clinical benefit to heparin plus and superior net clinical benefit to heparin plus IIb/IIIaIIb/IIIa

► Whether or not reductions in bleeding will Whether or not reductions in bleeding will translate into longer-term reductions in translate into longer-term reductions in mortality is yet to be determinedmortality is yet to be determined

► Bivalirudin plus IIb/IIIa had similar ischemic Bivalirudin plus IIb/IIIa had similar ischemic outcomes, similar bleeding, and similar net outcomes, similar bleeding, and similar net clinical benefit to heparin plus IIb/IIIaclinical benefit to heparin plus IIb/IIIa

► Bivalirudin alone (with provisional IIb/IIIa use) Bivalirudin alone (with provisional IIb/IIIa use) had similar ischemic outcomes, less bleeding, had similar ischemic outcomes, less bleeding, and superior net clinical benefit to heparin plus and superior net clinical benefit to heparin plus IIb/IIIaIIb/IIIa

► Whether or not reductions in bleeding will Whether or not reductions in bleeding will translate into longer-term reductions in translate into longer-term reductions in mortality is yet to be determinedmortality is yet to be determined

ACUITY — ConclusionsACUITY — ConclusionsACUITY — ConclusionsACUITY — Conclusions

NSTEMI ConclusionsNSTEMI ConclusionsNSTEMI ConclusionsNSTEMI Conclusions

► Old and new options for ACSOld and new options for ACS UFH or EnoxaparinUFH or Enoxaparin BivalirudinBivalirudin Fondaparinux (not tested adequately in cath lab)Fondaparinux (not tested adequately in cath lab)

► Balance ischemic efficacy and safetyBalance ischemic efficacy and safety Customize approach for patient and institutionCustomize approach for patient and institution

► Many choicesMany choices Collaborate with IC and CARD on clinical pathwaysCollaborate with IC and CARD on clinical pathways

► Adapt ACC/AHA 2007 Guidelines to Clinical Adapt ACC/AHA 2007 Guidelines to Clinical Practice in ED (Endorsed by SAEM)Practice in ED (Endorsed by SAEM)

► Old and new options for ACSOld and new options for ACS UFH or EnoxaparinUFH or Enoxaparin BivalirudinBivalirudin Fondaparinux (not tested adequately in cath lab)Fondaparinux (not tested adequately in cath lab)

► Balance ischemic efficacy and safetyBalance ischemic efficacy and safety Customize approach for patient and institutionCustomize approach for patient and institution

► Many choicesMany choices Collaborate with IC and CARD on clinical pathwaysCollaborate with IC and CARD on clinical pathways

► Adapt ACC/AHA 2007 Guidelines to Clinical Adapt ACC/AHA 2007 Guidelines to Clinical Practice in ED (Endorsed by SAEM)Practice in ED (Endorsed by SAEM)

Acute Coronary SyndromeAcute Coronary SyndromeThe 2007 ACC/AHA UA/NSTEMI Guidelines — The 2007 ACC/AHA UA/NSTEMI Guidelines —

From the ED to the CCU and Cath LabFrom the ED to the CCU and Cath Lab

Adherence as the Road to Better OutcomesAdherence as the Road to Better Outcomes

Acute Coronary SyndromeAcute Coronary SyndromeThe 2007 ACC/AHA UA/NSTEMI Guidelines — The 2007 ACC/AHA UA/NSTEMI Guidelines —

From the ED to the CCU and Cath LabFrom the ED to the CCU and Cath Lab

Adherence as the Road to Better OutcomesAdherence as the Road to Better Outcomes


Charles V. Pollack Jr, MA, MD, FACEP, FAAEMCharles V. Pollack Jr, MA, MD, FACEP, FAAEMChairman, Department of Emergency MedicineChairman, Department of Emergency Medicine

Pennsylvania HospitalPennsylvania HospitalProfessor of Emergency MedicineProfessor of Emergency Medicine

University of PennsylvaniaUniversity of PennsylvaniaSchool of MedicineSchool of Medicine

Philadelphia, PennsylvaniaPhiladelphia, Pennsylvania

Charles V. Pollack Jr, MA, MD, FACEP, FAAEMCharles V. Pollack Jr, MA, MD, FACEP, FAAEMChairman, Department of Emergency MedicineChairman, Department of Emergency Medicine

Pennsylvania HospitalPennsylvania HospitalProfessor of Emergency MedicineProfessor of Emergency Medicine

University of PennsylvaniaUniversity of PennsylvaniaSchool of MedicineSchool of Medicine

Philadelphia, PennsylvaniaPhiladelphia, Pennsylvania

19901990 19921992 19941994 19961996 19981998 20002000 20022002

19901990ACC/AHAACC/AHA

AMI AMI R. GunnarR. Gunnar

19941994AHCPR/NHLBIAHCPR/NHLBI

UA UA E. BraunwaldE. Braunwald

19961996 1999 1999 RevisedRevised UpdatedUpdated

ACC/AHA AMI ACC/AHA AMI T. Ryan T. Ryan

2004 20072004 2007 Revised UpdatedRevised Updated

ACC/AHA STEMI ACC/AHA STEMI E. AntmanE. Antman

2004 20072004 2007 Revised UpdatedRevised Updated

ACC/AHA STEMI ACC/AHA STEMI E. AntmanE. Antman

2000 2002 2000 2002 20072007 Revised UpdatedRevised Updated RevisedRevised

ACC/AHA UA/NSTEMIACC/AHA UA/NSTEMI E. Braunwald J. AndersonE. Braunwald J. Anderson

2000 2002 2000 2002 20072007 Revised UpdatedRevised Updated RevisedRevised

ACC/AHA UA/NSTEMIACC/AHA UA/NSTEMI E. Braunwald J. AndersonE. Braunwald J. Anderson

20042004 20072007

Evolution of Guidelines for ACSEvolution of Guidelines for ACSEvolution of Guidelines for ACSEvolution of Guidelines for ACS

Sea and Stream Changes in ACSSea and Stream Changes in ACSSea and Stream Changes in ACSSea and Stream Changes in ACS

The 2007 Guidelines have created a “Sea The 2007 Guidelines have created a “Sea Change” in the Change” in the EDED and and ICIC TTherapeutic herapeutic approach to care of patients with UA/NSTEMIapproach to care of patients with UA/NSTEMI

New “Streams” of care, with new New “Streams” of care, with new anticoagulants, are in playanticoagulants, are in play

Clopidogrel use has been liberalizedClopidogrel use has been liberalized Bleeding end points play a more important Bleeding end points play a more important

role in drug selectionrole in drug selection Dogmatism is out, customization is inDogmatism is out, customization is in Collaboration is emphasizedCollaboration is emphasized

Class I Benefit >>> Risk

Procedure/ Treatment SHOULD be performed/ administered

Class IIa Benefit >> RiskAdditional studies with focused objectives needed

IT IS REASONABLE to perform procedure/administer treatment

Class IIb Benefit ≥ RiskAdditional studies with broad objectives needed; Additional registry data would be helpful

Procedure/Treatment MAY BE CONSIDERED

Class III Risk ≥ BenefitNo additional studies needed

Procedure/Treatment should NOT be performed/administered SINCE IT IS NOT HELPFUL AND MAY BE HARMFUL

ShouldShouldIs recommendedIs recommendedIs indicatedIs indicatedIs useful/effective/ Is useful/effective/

beneficialbeneficial

Is reasonableIs reasonableCan be Can be

useful/effective/ useful/effective/ beneficialbeneficial

Is probably Is probably recommended or recommended or indicatedindicated

May/might be May/might be consideredconsidered

May/might be May/might be reasonablereasonable

Usefulness/Usefulness/effectiveness is effectiveness is

unknown/unclear/ unknown/unclear/ uncertain or not well uncertain or not well established established

Is not recommendedIs not recommendedIs not indicatedIs not indicatedShould notShould notIs not useful/effective/ Is not useful/effective/

beneficialbeneficialMay be harmfulMay be harmful

Applying Classification of Applying Classification of RecommendationsRecommendations

Applying Classification of Applying Classification of RecommendationsRecommendations

CRUSADE: A NationalCRUSADE: A NationalQuality Improvement InitiativeQuality Improvement Initiative

CRUSADE: A NationalCRUSADE: A NationalQuality Improvement InitiativeQuality Improvement Initiative

CCan an RRapid Risk Stratification of apid Risk Stratification of UUnstable nstable

Angina Patients Angina Patients SSuppress uppress ADADverse Outcomes verse Outcomes

with with EEarly Implementation arly Implementation

of the ACC/AHA Guidelinesof the ACC/AHA Guidelines

2002-20072002-2007

CCan an RRapid Risk Stratification of apid Risk Stratification of UUnstable nstable

Angina Patients Angina Patients SSuppress uppress ADADverse Outcomes verse Outcomes

with with EEarly Implementation arly Implementation

of the ACC/AHA Guidelinesof the ACC/AHA Guidelines

2002-20072002-2007

Management Strategies: 2002 GuidelinesManagement Strategies: 2002 GuidelinesConservative Conservative versusversus Invasive Strategies Invasive Strategies

Management Strategies: 2002 GuidelinesManagement Strategies: 2002 GuidelinesConservative Conservative versusversus Invasive Strategies Invasive Strategies

Early (within 48h) invasive strategy inEarly (within 48h) invasive strategy inhigh-risk patients with any of the high-risk patients with any of the following:following:

Recurrent ischemia, despite medsRecurrent ischemia, despite meds Elevated Troponin I or TElevated Troponin I or T New ST-segment depressionNew ST-segment depression New CHF symptomsNew CHF symptoms High-risk stress test findingsHigh-risk stress test findings LV dysfunction (EF < 40%)LV dysfunction (EF < 40%) Hemodynamic instability, sustained VTHemodynamic instability, sustained VT PCI within 6 months, prior CABGPCI within 6 months, prior CABG

Early (within 48h) invasive strategy inEarly (within 48h) invasive strategy inhigh-risk patients with any of the high-risk patients with any of the following:following:

Recurrent ischemia, despite medsRecurrent ischemia, despite meds Elevated Troponin I or TElevated Troponin I or T New ST-segment depressionNew ST-segment depression New CHF symptomsNew CHF symptoms High-risk stress test findingsHigh-risk stress test findings LV dysfunction (EF < 40%)LV dysfunction (EF < 40%) Hemodynamic instability, sustained VTHemodynamic instability, sustained VT PCI within 6 months, prior CABGPCI within 6 months, prior CABG


Either strategy in low- to moderate-risk Either strategy in low- to moderate-risk patients without contraindications to patients without contraindications to revascularizationrevascularization

Early invasive strategy for patients with Early invasive strategy for patients with repeated ACS presentations, without repeated ACS presentations, without high-risk features or ongoing ischemiahigh-risk features or ongoing ischemia

Either strategy in low- to moderate-risk Either strategy in low- to moderate-risk patients without contraindications to patients without contraindications to revascularizationrevascularization

Early invasive strategy for patients with Early invasive strategy for patients with repeated ACS presentations, without repeated ACS presentations, without high-risk features or ongoing ischemiahigh-risk features or ongoing ischemia


Management Strategies — 2002 GuidelinesManagement Strategies — 2002 GuidelinesConservative Conservative versusversus Invasive Strategies Invasive Strategies

Management Strategies — 2002 GuidelinesManagement Strategies — 2002 GuidelinesConservative Conservative versusversus Invasive Strategies Invasive Strategies

Invasive Procedures in 2006Invasive Procedures in 2006(Among Patients Without Contraindications To Cath)(Among Patients Without Contraindications To Cath)

Invasive Procedures in 2006Invasive Procedures in 2006(Among Patients Without Contraindications To Cath)(Among Patients Without Contraindications To Cath)

Median TimesMedian Times

• Cath - 22 hrsCath - 22 hrs

• PCI - 21 hrsPCI - 21 hrs

• CABG - 69 hrsCABG - 69 hrs

83%

67%

53%

38%

12%

0%

20%

40%

60%

80%

100%

Cath Cath < 48 hr PCI PCI < 48 hr CABG

Management Strategies — 2007Management Strategies — 2007Early Invasive Early Invasive versusversus Initial Conservative Initial Conservative


► Early invasive:Early invasive: Diagnostic angiography with Diagnostic angiography with intent to perform revascularizationintent to perform revascularization Cath anticipated within 4-24 hoursCath anticipated within 4-24 hours Follows a foundation of risk-directed medical Follows a foundation of risk-directed medical

therapytherapy

► Early ConservativeEarly Conservative (or (or selectively invasiveselectively invasive):): Invasive evaluation only if optimal medical Invasive evaluation only if optimal medical management failsmanagement fails

► Note: from ED perspective, both strategies Note: from ED perspective, both strategies involve risk-directed, evidence-based medical involve risk-directed, evidence-based medical therapytherapy

► Early invasive:Early invasive: Diagnostic angiography with Diagnostic angiography with intent to perform revascularizationintent to perform revascularization Cath anticipated within 4-24 hoursCath anticipated within 4-24 hours Follows a foundation of risk-directed medical Follows a foundation of risk-directed medical

therapytherapy

► Early ConservativeEarly Conservative (or (or selectively invasiveselectively invasive):): Invasive evaluation only if optimal medical Invasive evaluation only if optimal medical management failsmanagement fails

► Note: from ED perspective, both strategies Note: from ED perspective, both strategies involve risk-directed, evidence-based medical involve risk-directed, evidence-based medical therapytherapy

EIS is indicated in initially stabilized EIS is indicated in initially stabilized UA/NSTEMI patients (without UA/NSTEMI patients (without contraindications) contraindications) who have an elevated who have an elevated risk for clinical eventsrisk for clinical events

EIS is indicated in UA/NSTEMI patients EIS is indicated in UA/NSTEMI patients (without contraindications) (without contraindications) who have who have refractory angina or hemodynamic or refractory angina or hemodynamic or electrical instabilityelectrical instability

ICS ICS may be considered in initially may be considered in initially stabilized patientsstabilized patients who have an elevated who have an elevated risk for clinical events (including risk for clinical events (including ↑Tn)↑Tn)

EIS is indicated in initially stabilized EIS is indicated in initially stabilized UA/NSTEMI patients (without UA/NSTEMI patients (without contraindications) contraindications) who have an elevated who have an elevated risk for clinical eventsrisk for clinical events

EIS is indicated in UA/NSTEMI patients EIS is indicated in UA/NSTEMI patients (without contraindications) (without contraindications) who have who have refractory angina or hemodynamic or refractory angina or hemodynamic or electrical instabilityelectrical instability

ICS ICS may be considered in initially may be considered in initially stabilized patientsstabilized patients who have an elevated who have an elevated risk for clinical events (including risk for clinical events (including ↑Tn)↑Tn)




EIS is indicated in initially stabilized EIS is indicated in initially stabilized UA/NSTEMI patients (without UA/NSTEMI patients (without contraindications) who have an elevated contraindications) who have an elevated risk for clinical eventsrisk for clinical events

EIS is indicated in UA/NSTEMI patients EIS is indicated in UA/NSTEMI patients (without contraindications) who have (without contraindications) who have refractory angina or hemodynamic or refractory angina or hemodynamic or electrical instabilityelectrical instability

ICS may be considered in initially ICS may be considered in initially stabilized patients who have an elevated stabilized patients who have an elevated risk for clinical events (including risk for clinical events (including ↑Tn)↑Tn)

EIS is indicated in initially stabilized EIS is indicated in initially stabilized UA/NSTEMI patients (without UA/NSTEMI patients (without contraindications) who have an elevated contraindications) who have an elevated risk for clinical eventsrisk for clinical events

EIS is indicated in UA/NSTEMI patients EIS is indicated in UA/NSTEMI patients (without contraindications) who have (without contraindications) who have refractory angina or hemodynamic or refractory angina or hemodynamic or electrical instabilityelectrical instability

ICS may be considered in initially ICS may be considered in initially stabilized patients who have an elevated stabilized patients who have an elevated risk for clinical events (including risk for clinical events (including ↑Tn)↑Tn)


Management Strategies — 2007Management Strategies — 2007Early Invasive vs Initial InvasiveEarly Invasive vs Initial Invasive

The decision to employ an EIS vs ICS The decision to employ an EIS vs ICS may be made may be made by considering physician by considering physician and patient preferenceand patient preference

Invasive strategy may be preferable in Invasive strategy may be preferable in patients with CKDpatients with CKD

EIS if patient:EIS if patient:► Will not consent to revascularizationWill not consent to revascularization► Has too many comorbiditiesHas too many comorbidities► Is low riskIs low risk

The decision to employ an EIS vs ICS The decision to employ an EIS vs ICS may be made may be made by considering physician by considering physician and patient preferenceand patient preference

Invasive strategy may be preferable in Invasive strategy may be preferable in patients with CKDpatients with CKD

EIS if patient:EIS if patient:► Will not consent to revascularizationWill not consent to revascularization► Has too many comorbiditiesHas too many comorbidities► Is low riskIs low risk




Benefits of Early CatheterizationBenefits of Early Catheterizationby Risk Groupby Risk Group

Benefits of Early CatheterizationBenefits of Early Catheterizationby Risk Groupby Risk Group

0

2

4

6

8

10

12

Low Risk Moderate Risk High Risk

Early Cath No Early Cath

Bhatt AHA 2002.

% I

nhos

pita

l Mor

talit

y%

Inh

ospi

tal M

orta

lity

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

40 50 60 70 80 90

Age (years)

Per

cen

tag

e U

se

Cath

PCI

CABG

Invasive Procedure Use by AgeInvasive Procedure Use by AgeInvasive Procedure Use by AgeInvasive Procedure Use by Age

Alexander KA, J Am Coll Cardiol 2005;46:1479-87.

Medical Management — 2002 GuidelinesMedical Management — 2002 GuidelinesAntithrombotic Therapy Antithrombotic Therapy


Immediate aspirinImmediate aspirin

Clopidogrel, if aspirin contraindicatedClopidogrel, if aspirin contraindicated

Heparin (IV unfractionated, LMW) with Heparin (IV unfractionated, LMW) with antiplatelet agents listed aboveantiplatelet agents listed above

Enoxaparin preferred over UFH unless Enoxaparin preferred over UFH unless CABG is planned within 24 hoursCABG is planned within 24 hours

Immediate aspirinImmediate aspirin

Clopidogrel, if aspirin contraindicatedClopidogrel, if aspirin contraindicated

Heparin (IV unfractionated, LMW) with Heparin (IV unfractionated, LMW) with antiplatelet agents listed aboveantiplatelet agents listed above

Enoxaparin preferred over UFH unless Enoxaparin preferred over UFH unless CABG is planned within 24 hoursCABG is planned within 24 hours

IIII IIaIIaIIaIIa IIbIIbIIbIIb IIIIIIIIIIII

Acute (first 24 hours)Acute (first 24 hours)Antithrombotic TherapiesAntithrombotic Therapies

Acute (first 24 hours)Acute (first 24 hours)Antithrombotic TherapiesAntithrombotic Therapies

91% 90% 89% 90%84%

78% 75% 78%

0%

20%

40%

60%

80%

100%

All Patients Females Age > 75 Diabetes

Aspirin Anticoagulant (heparin or LMWH)91% 90% 89% 90%

84%78% 75% 78%

0%

20%

40%

60%

80%

100%

All Patients Females Age > 75 Diabetes

Aspirin Anticoagulant (heparin or LMWH)

Medical Management — 2007 GuidelinesMedical Management — 2007 GuidelinesAntiThrombotic Therapy AntiThrombotic Therapy

In EIS:In EIS:

► Enoxaparin or UFHEnoxaparin or UFH

► Bivalirudin* or fondaparinuxBivalirudin* or fondaparinux

In ICS:In ICS:► Enoxaparin or UFHEnoxaparin or UFH

► FondaparinuxFondaparinux

In ICS with In ICS with ↑ risk of bleeding: ↑ risk of bleeding: FondaparinuxFondaparinux

In EIS:In EIS:

► Enoxaparin or UFHEnoxaparin or UFH

► Bivalirudin* or fondaparinuxBivalirudin* or fondaparinux

In ICS:In ICS:► Enoxaparin or UFHEnoxaparin or UFH

► FondaparinuxFondaparinux

In ICS with In ICS with ↑ risk of bleeding: ↑ risk of bleeding: FondaparinuxFondaparinux


If ICS selected, either enoxaparin or If ICS selected, either enoxaparin or fondaparinuxfondaparinux is preferred over UFH is preferred over UFH unless CABG is anticipated withinunless CABG is anticipated within24 hours24 hours

If ICS selected, either enoxaparin or If ICS selected, either enoxaparin or fondaparinuxfondaparinux is preferred over UFH is preferred over UFH unless CABG is anticipated withinunless CABG is anticipated within24 hours24 hours


Relevant new studies for antithrombotic therapy:Relevant new studies for antithrombotic therapy:

SYNERGY, SYNERGY, JAMA JAMA 20042004

OASIS-5, OASIS-5, NEJMNEJM 2006 2006

ACUITY, ACUITY, NEJMNEJM 2006 2006

Relevant new studies for antithrombotic therapy:Relevant new studies for antithrombotic therapy:

SYNERGY, SYNERGY, JAMA JAMA 20042004

OASIS-5, OASIS-5, NEJMNEJM 2006 2006

ACUITY, ACUITY, NEJMNEJM 2006 2006



SYNERGY: Primary Efficacy OutcomeSYNERGY: Primary Efficacy OutcomeSYNERGY: Primary Efficacy OutcomeSYNERGY: Primary Efficacy Outcome

Enoxaparin is as effective as UFH in the treatment of high-risk patientswith ACS undergoing a rapid invasive strategy

SYNERGY Trial Investigators, JAMA 2004;292:45.

1

Hazard Ratio (95% CI)

Enoxaparin UFHBetter Better

30-day Death/MI30-day Death/MI

0.8 1.01.2

HR 0.96(0.86 – 1.06)

HR 0.96(0.86 – 1.06)

1.11.1

0 5 10 15 20 25 300.8

0.9

0.95

1.0

Fre

edo

m f

rom

Dea

th /

MI


0.85EnoxaparinUFH

OASIS-5OASIS-5

OASIS-5: Death/MI/RI at Day 9OASIS-5: Death/MI/RI at Day 9OASIS-5: Death/MI/RI at Day 9OASIS-5: Death/MI/RI at Day 9

DaysDays

Cu

mu

lati

ve H

aza

rdC

um

ula

tive

Ha

zard

0.00.0

0.0

10

.01

0.0

20

.02

0.0

30

.03

0.0

40

.04

0.0

50

.05

0.0

60

.06

00 11 22 33 44 55 66 77 88 99



HR 1.01 HR 1.01 95% CI 0.9095% CI 0.90- 1.131.13

OASIS-5 Major Bleeding at 9 DaysOASIS-5 Major Bleeding at 9 Days

Days

Cu

mu

lati

ve H

azar

d

0.0

0.01

0.02

0.03

0.04

0 1 2 3 4 5 6 7 8 9

HR 0.52 95% CI 0.44-0.61

P<0.001



OASIS-5OASIS-5OASIS-5OASIS-5

OASIS-5: 30-Day MortalityOASIS-5: 30-Day Mortality

Days

Cu

mu

lati

ve H

azar

d0.

00.

010.

020.

03

0 3 6 9 12 15 18 21 24 27 30

HR 0.83 HR 0.83 95% CI 0.7195% CI 0.7195% CI 0.71--0.970.97

P=0.02



OASIS-5OASIS-5OASIS-5OASIS-5

Patients Undergoing PCI within the first Patients Undergoing PCI within the first 8 Days of Randomization8 Days of Randomization

Patients Undergoing PCI within the first Patients Undergoing PCI within the first 8 Days of Randomization8 Days of Randomization

0.0013.59 (1.64-7.84)29 (0.9%)8 (0.4%)All catheter-related thrombi

0.082.99 (0.81-11.04)9 (0.3%)3 (0.1%)Catheter-related thrombus not resulting in clinical complications

1.16 (0.94-1.42)188 (6.0%)161 (5.2%)Abrupt closure, new thrombus with reduced flow, dissection, or no reflow

0.211.11 (0.94-1.29)299 (9.5%)268 (8.6%)Any complication

PCI-related coronary complication

0.36 (0.26-0.49)50 (1.6%)138 (4.4%)Large hematoma

0.63 (0.40-0.98)31 (1.0%)49 (1.6%)Pseudoaneurysm

<0.0010.41 (0.33-0.51)103 (3.3%)251 (8.1%)Any complication

No. of events (% of patients)Complications involving the vascular access site

P Value

Relative Risk

(95% CI)Fondaparinux

(n=3135)Enoxaparin

(n=3104)

““The ACUITY study, which tested bivalirudin for The ACUITY study, which tested bivalirudin for UA/NSTEMI, has led to a UA/NSTEMI, has led to a guidelines change to guidelines change to allow bivalirudin as an anticoagulant optionallow bivalirudin as an anticoagulant option.”.”


ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.Circulation.ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.Circulation.

ACUITY: Primary Results – 30 daysACUITY: Primary Results – 30 days

UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin AloneUFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone

7.3%5.7%

11.7%

5.3%

11.8%

7.7% 7.8%

10.1%

3.0%

Net clinical outcome Composite ischemia Major bleeding (non-CABG)

30 d

ay e

ven

ts (

%)

UFH/Enox+ GP IIb/IIIa (N=4603) Bivalirudin+GP IIb/IIIa (N=4604) Bivalirudin alone (N=4612)

PNI <0.001PSup = 0.015

PNI = 0.011 PSup = 0.32

PNI <0.001PSup <0.001

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

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

5

15

25

Isch

emic

Co

mp

osi

te (

%)


10

20 UFH/Enoxaparin + IIb/IIIaBivalirudin + IIb/IIIa

Bivalirudin alone

EstimateP

(log rank)

30 day

7.4%0.367.8%0.347.9%

—

EstimateP

(log rank)

16.3%0.3816.5%0.3116.4%

1 year

—

p=0.55



Ischemic Composite EndpointIschemic Composite Endpoint(Death, MI, unplanned revascularization for ischemia)(Death, MI, unplanned revascularization for ischemia)

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

Stone GW. ACC 2007 presentation

ACUITY Trial — Troponin PositiveACUITY Trial — Troponin PositivePCI Subgroup (N= 2949)PCI Subgroup (N= 2949)

13.4%

8.1%7.0%

9.1%

12.4%

4.2%

Net clinicaloutcomes

Ischemiccomposite

Major bleeding

30

da

y e

ve

nts

(%

)

UFH/Enoxaparin + IIb/IIIa Bivalirudin Alone

UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone

Stone GW et al, www.thelancet.com Vol 369 March 17, 2007.

RR [95%CI]

0.93 [0.77-1.12]

RR [95%CI]

1.12 [0.88-1.42]

RR [95%CI]

0.59 [0.44-0.80]


No Thienopyridine Exposure – PCI pts*No Thienopyridine Exposure – PCI pts*30 Day Primary Endpoint Adverse Events30 Day Primary Endpoint Adverse Events

11.8%

7.5%5.7%

10.3%

12.7%

3.5%

Net clinicaloutcomes

Ischemiccomposite

Major bleeding

30

da

y e

ve

nts

(%

)

UFH/Enoxaparin + IIb/IIIa (N=811)

Bivalirudin Alone (N=804)

*Thienopyridine at any time, any dose, up to time of PCI (Including 87 patients not receiving thienopyridine at any time)

RR [95%CI] 0.61 (0.39-0.97)

RR [95%CI] 1.37 (1.00-1.88)

RR [95%CI] 1.07 (0.83-1.39)

ACUITY PCI as presented at TCT 2006.

0 1 2

Composite Ischemia at 1 YearComposite Ischemia at 1 Year

Hazard ratio±95% CI


Bivalalone

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

HR (95% CI)HR (95% CI) PPintint

0.670.67

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

19.8%19.8% 19.2%19.2% 1.09 (0.96-1.23)1.09 (0.96-1.23)

21.1%21.1% 20.7%20.7% 1.04 (0.79-1.36)1.04 (0.79-1.36)

9.0%9.0% 9.6%9.6% 0.97 (0.76-1.24)0.97 (0.76-1.24)

Actual Treatment

PCI (n=5179)

CABG (n=1040)

Medical (n=2994)

17.7%17.7%

14.6%14.6%

16.4%16.4%

16.1%16.1%

1.14 (0.99-1.30)1.14 (0.99-1.30)

0.95 (0.80-1.14)0.95 (0.80-1.14)0.110.11

Biomarkers (CK/Trop)

Elevated (n=5072)

Normal (n=3402)

16.2%16.2%

16.4%16.4%

17.2%17.2%

14.3%14.3%

0.97 (0.86-1.11)0.97 (0.86-1.11)

1.20 (1.01-1.44)1.20 (1.01-1.44)0.070.07

Pre Thienopyridine

Yes (n=5751)

No (n=3305)

UFH/Enoxaparin + GPIIb/IIIa vs. Bivalirudin alone

1 yr KM estimate1 yr KM estimate

ACUITY 1-Year Data as presented at ACC 2007.

P value interaction

only between subgroups

► Unfractionated Heparin (UFH)Unfractionated Heparin (UFH) Pro:Pro: Familiarity, reversibility Familiarity, reversibility Con:Con: Adverse PK Adverse PK

► EnoxaparinEnoxaparin Pro:Pro: Ease of use, predictability, familiarity Ease of use, predictability, familiarity Con:Con: Bleeding concerns, transition to cath Bleeding concerns, transition to cath

lab, needs dose adjustment for CKD, lab, needs dose adjustment for CKD, increased bleeding risk noted especially in increased bleeding risk noted especially in patients with renal dysfunction (OASIS-5)patients with renal dysfunction (OASIS-5)

► Unfractionated Heparin (UFH)Unfractionated Heparin (UFH) Pro:Pro: Familiarity, reversibility Familiarity, reversibility Con:Con: Adverse PK Adverse PK

► EnoxaparinEnoxaparin Pro:Pro: Ease of use, predictability, familiarity Ease of use, predictability, familiarity Con:Con: Bleeding concerns, transition to cath Bleeding concerns, transition to cath

lab, needs dose adjustment for CKD, lab, needs dose adjustment for CKD, increased bleeding risk noted especially in increased bleeding risk noted especially in patients with renal dysfunction (OASIS-5)patients with renal dysfunction (OASIS-5)

Upstream Antithrombotic Therapy: IAUpstream Antithrombotic Therapy: IAUpstream Antithrombotic Therapy: IAUpstream Antithrombotic Therapy: IA

► FondaparinuxFondaparinux Pro:Pro: Ease of use, once daily Ease of use, once daily Con:Con: Need additional anticoagulant (UFH? Need additional anticoagulant (UFH?

bivalirudin?) in cath lab (“clot on the wire”), lack of bivalirudin?) in cath lab (“clot on the wire”), lack of familiarity in ED, label, not studied in CrCl < 30, not familiarity in ED, label, not studied in CrCl < 30, not accepted by IC community for PCI despite Guidelinesaccepted by IC community for PCI despite Guidelines

► BivalirudinBivalirudin Pro:Pro: Comfort level in cath lab, short half-life, can omit Comfort level in cath lab, short half-life, can omit

GP IIb/IIIa’s (more to follow) in most patients, reduced GP IIb/IIIa’s (more to follow) in most patients, reduced bleeding risk, can switch to bivalirudin from other bleeding risk, can switch to bivalirudin from other anticoaglants and antithromboticsanticoaglants and antithrombotics

Con:Con: Lack of familiarity in ED, limited data on Lack of familiarity in ED, limited data on prolonged infusion, cost of prolonged infusion, label, prolonged infusion, cost of prolonged infusion, label, not studied in CrCl < 30not studied in CrCl < 30

► FondaparinuxFondaparinux Pro:Pro: Ease of use, once daily Ease of use, once daily Con:Con: Need additional anticoagulant (UFH? Need additional anticoagulant (UFH?

bivalirudin?) in cath lab (“clot on the wire”), lack of bivalirudin?) in cath lab (“clot on the wire”), lack of familiarity in ED, label, not studied in CrCl < 30, not familiarity in ED, label, not studied in CrCl < 30, not accepted by IC community for PCI despite Guidelinesaccepted by IC community for PCI despite Guidelines

► BivalirudinBivalirudin Pro:Pro: Comfort level in cath lab, short half-life, can omit Comfort level in cath lab, short half-life, can omit

GP IIb/IIIa’s (more to follow) in most patients, reduced GP IIb/IIIa’s (more to follow) in most patients, reduced bleeding risk, can switch to bivalirudin from other bleeding risk, can switch to bivalirudin from other anticoaglants and antithromboticsanticoaglants and antithrombotics

Con:Con: Lack of familiarity in ED, limited data on Lack of familiarity in ED, limited data on prolonged infusion, cost of prolonged infusion, label, prolonged infusion, cost of prolonged infusion, label, not studied in CrCl < 30not studied in CrCl < 30

Upstream Antithrombotic Therapy: IBUpstream Antithrombotic Therapy: IBUpstream Antithrombotic Therapy: IBUpstream Antithrombotic Therapy: IB

Oral Antiplatelet Therapy — Oral Antiplatelet Therapy — 2002 Clopidogrel Guidance2002 Clopidogrel Guidance

Oral Antiplatelet Therapy — Oral Antiplatelet Therapy — 2002 Clopidogrel Guidance2002 Clopidogrel Guidance

Aspirin + clopidogrel, for up to 1 month*Aspirin + clopidogrel, for up to 1 month*

Aspirin + clopidogrel, for up to 9 months*Aspirin + clopidogrel, for up to 9 months*

Withhold clopidogrel for 5-7 days for CABGWithhold clopidogrel for 5-7 days for CABG

Aspirin + clopidogrel, for up to 1 month*Aspirin + clopidogrel, for up to 1 month*

Aspirin + clopidogrel, for up to 9 months*Aspirin + clopidogrel, for up to 9 months*

Withhold clopidogrel for 5-7 days for CABGWithhold clopidogrel for 5-7 days for CABG


* For patients managed with an early conservative strategy, and * For patients managed with an early conservative strategy, and those who are planned to undergo early PCIthose who are planned to undergo early PCI* For patients managed with an early conservative strategy, and * For patients managed with an early conservative strategy, and those who are planned to undergo early PCIthose who are planned to undergo early PCI

Guidelines do not specify initial timing of using Guidelines do not specify initial timing of using clopidogrel when coronary anatomy is unknownclopidogrel when coronary anatomy is unknown

Guidelines do not specify initial timing of using Guidelines do not specify initial timing of using clopidogrel when coronary anatomy is unknownclopidogrel when coronary anatomy is unknown

Acute (< 24 hrs) Antiplatelet Acute (< 24 hrs) Antiplatelet Therapies for High-Risk NSTE ACSTherapies for High-Risk NSTE ACS

Acute (< 24 hrs) Antiplatelet Acute (< 24 hrs) Antiplatelet Therapies for High-Risk NSTE ACSTherapies for High-Risk NSTE ACS

43%43%

10%10%

20%20%

30%30%

40%40%

50%50%

60% 60% 52%52%

34%34%

GP IIb/IIIa Clopidogrel GP IIb/IIIa + NeitherGP IIb/IIIa Clopidogrel GP IIb/IIIa + Neither ClopidogrelClopidogrel

CRUSADE Q4 2003 data.

29%29%

Antiplatelet Therapy Antiplatelet Therapy Year 2007 Clopidogrel GuidanceYear 2007 Clopidogrel GuidanceAntiplatelet Therapy Antiplatelet Therapy Year 2007 Clopidogrel GuidanceYear 2007 Clopidogrel Guidance


Clopidogrel with full loading dose in Clopidogrel with full loading dose in ASA-allergic patientsASA-allergic patients

EIS: Clopidogrel or IIb/IIIa administered EIS: Clopidogrel or IIb/IIIa administered upstreamupstream

ICS: Clopidogrel initiated “as soon as ICS: Clopidogrel initiated “as soon as possible” and continued for at least possible” and continued for at least one month . . .and preferably for one one month . . .and preferably for one yearyear

Clopidogrel with full loading dose in Clopidogrel with full loading dose in ASA-allergic patientsASA-allergic patients

EIS: Clopidogrel or IIb/IIIa administered EIS: Clopidogrel or IIb/IIIa administered upstreamupstream

ICS: Clopidogrel initiated “as soon as ICS: Clopidogrel initiated “as soon as possible” and continued for at least possible” and continued for at least one month . . .and preferably for one one month . . .and preferably for one yearyear

Antiplatelet Therapy: 2007Antiplatelet Therapy: 2007Platelet GP IIb/IIIa InhibitorsPlatelet GP IIb/IIIa Inhibitors



ICS with recurrent ischemia on ASA, ICS with recurrent ischemia on ASA, clopidogrel, and anticoag: Addclopidogrel, and anticoag: AddIIb/IIIa upstreamIIb/IIIa upstream

EIS: It is reasonable to give both EIS: It is reasonable to give both clopidogrel and IIb/IIIa upstreamclopidogrel and IIb/IIIa upstream

EIS: Can omit IIb/IIIa if bivalirudin is EIS: Can omit IIb/IIIa if bivalirudin is anticoagulant and at least 300mg anticoagulant and at least 300mg clopidogrel given clopidogrel given >> 6h prior to cath 6h prior to cath

Antiplatelet Drug TargetsAntiplatelet Drug TargetsAntiplatelet Drug TargetsAntiplatelet Drug Targets

PlateletThrombin

ADP

Thromboxane A2

Epinephrine

Serotonin

Collagen

PAR-1

PAR-4

P2Y1

P2Y12

TXA2-R

5HT2A

Anionicphospholipidsurfaces

GP IIbGP IIbGP IIIaGP IIIa

GP VI

Platelet

GP IIIaGP IIIaGP IIbGP IIb

Fibrinogen

GP Ia

TRA

Clopidogrel Prasugrel

Aspirin

Gp IIb/IIIa inhibitors

PAR - 1

P2Y12

3 h 8 h 18-24 h3 h 8 h 18-24 h

Gurbel PA, et al. Circulation. 2005;111:1153-1159.

Clear PlateletsClear PlateletsClear PlateletsClear Platelets

*Pla

tele

t In

hib

itio

nP

late

let

Inh

ibit

ion

*

‡

Pla

tele

t In

hib

itio

nP

late

let

Inh

ibit

ion

*

0

20%

40%

60%

80%

100%

0

20%

40%

60%

80%

100%

Group A: Clopidogrel 300 mg (n = 30) Group B: Clopidogrel 600 mg (n = 30)

Group C: Clopidogrel 300 mg + eptifibatide (n = 30) Group D: Clopidogrel 600 mg + eptifibatide (n = 30)

†

5 µmol/L ADP 20 µmol/L ADP† †

*(P ≤ 0.001), Group A vs B; †(P ≤ 0.001), Group C or D vs Group A or B.

*(P = 0.09), Group A vs B; †(P = 0.01), Group A vs B; ‡(P < 0.001), Groups C and D vs Group A and B; §(P -0.05), Groups C vs D.

†

‡ ‡§

Choices between dual (ASA+clopidogrel), dual Choices between dual (ASA+clopidogrel), dual (ASA+IIb/IIIa) and triple (ASA+clopidogrel+IIb/IIIa) (ASA+IIb/IIIa) and triple (ASA+clopidogrel+IIb/IIIa) antiplatelet therapy are driven by risk and upon antiplatelet therapy are driven by risk and upon consideration of a bivalirudin only EIS:consideration of a bivalirudin only EIS:

Ischemic riskIschemic risk• Conventional consideration in EDConventional consideration in ED• Prefer triple therapy unless . . .Prefer triple therapy unless . . .

Bleeding riskBleeding risk• In ED: Female, elderly, CKD, anemic, In ED: Female, elderly, CKD, anemic, proper proper

dosing, use of bivalirudin only EISdosing, use of bivalirudin only EIS CABG riskCABG risk

• In ED, can’t accurately quantifyIn ED, can’t accurately quantify• Small-molecule IIb/IIIa is reversible; clopidogrel is Small-molecule IIb/IIIa is reversible; clopidogrel is

notnot

Choices between dual (ASA+clopidogrel), dual Choices between dual (ASA+clopidogrel), dual (ASA+IIb/IIIa) and triple (ASA+clopidogrel+IIb/IIIa) (ASA+IIb/IIIa) and triple (ASA+clopidogrel+IIb/IIIa) antiplatelet therapy are driven by risk and upon antiplatelet therapy are driven by risk and upon consideration of a bivalirudin only EIS:consideration of a bivalirudin only EIS:

Ischemic riskIschemic risk• Conventional consideration in EDConventional consideration in ED• Prefer triple therapy unless . . .Prefer triple therapy unless . . .

Bleeding riskBleeding risk• In ED: Female, elderly, CKD, anemic, In ED: Female, elderly, CKD, anemic, proper proper

dosing, use of bivalirudin only EISdosing, use of bivalirudin only EIS CABG riskCABG risk

• In ED, can’t accurately quantifyIn ED, can’t accurately quantify• Small-molecule IIb/IIIa is reversible; clopidogrel is Small-molecule IIb/IIIa is reversible; clopidogrel is

notnot

Antiplatelet Therapy Driven By RiskAntiplatelet Therapy Driven By RiskAntiplatelet Therapy Driven By RiskAntiplatelet Therapy Driven By Risk

Parenteral Antiplatelet Therapy: 2002Parenteral Antiplatelet Therapy: 2002Platelet GP IIb/IIIa InhibitorsPlatelet GP IIb/IIIa Inhibitors


Any GP IIb/IIIa inhibitor + ASA/Heparin Any GP IIb/IIIa inhibitor + ASA/Heparin for all patients, if cath/PCI plannedfor all patients, if cath/PCI planned

Eptifibatide or tirofiban + ASA/Heparin Eptifibatide or tirofiban + ASA/Heparin for high-risk* patients in whom early for high-risk* patients in whom early cath/PCI is not plannedcath/PCI is not planned

Any GP IIb/IIIa inhibitor for patients Any GP IIb/IIIa inhibitor for patients already on ASA + Heparin + clopidogrel, already on ASA + Heparin + clopidogrel, if cath/PCI is plannedif cath/PCI is planned

Any GP IIb/IIIa inhibitor + ASA/Heparin Any GP IIb/IIIa inhibitor + ASA/Heparin for all patients, if cath/PCI plannedfor all patients, if cath/PCI planned

Eptifibatide or tirofiban + ASA/Heparin Eptifibatide or tirofiban + ASA/Heparin for high-risk* patients in whom early for high-risk* patients in whom early cath/PCI is not plannedcath/PCI is not planned

Any GP IIb/IIIa inhibitor for patients Any GP IIb/IIIa inhibitor for patients already on ASA + Heparin + clopidogrel, already on ASA + Heparin + clopidogrel, if cath/PCI is plannedif cath/PCI is planned


* High-risk: Age > 75; prolonged, ongoing CP; hemodynamic instability; rest CP w/ ST ; VT; positive cardiac markers * High-risk: Age > 75; prolonged, ongoing CP; hemodynamic instability; rest CP w/ ST ; VT; positive cardiac markers

Eptifibatide or tirofiban + ASA/Heparin Eptifibatide or tirofiban + ASA/Heparin for patients without continuing for patients without continuing ischemia in whom PCI is not planned ischemia in whom PCI is not planned

Abciximab for patients in whom PCI is Abciximab for patients in whom PCI is not plannednot planned

Eptifibatide or tirofiban + ASA/Heparin Eptifibatide or tirofiban + ASA/Heparin for patients without continuing for patients without continuing ischemia in whom PCI is not planned ischemia in whom PCI is not planned

Abciximab for patients in whom PCI is Abciximab for patients in whom PCI is not plannednot planned







All patients receive ASAAll patients receive ASA

EIS: Upstream clopidogrel or IIb/IIIaEIS: Upstream clopidogrel or IIb/IIIa

EIS: Upstream IIb/IIIa should beEIS: Upstream IIb/IIIa should besmall-moleculesmall-molecule

ICS: If medical management fails, add ICS: If medical management fails, add IIb/IIIa or clopidogrel . . . upstreamIIb/IIIa or clopidogrel . . . upstream


ICS with recurrent ischemia on ASA, ICS with recurrent ischemia on ASA, clopidogrel, and anticoagulant: Addclopidogrel, and anticoagulant: AddIIb/IIIa upstreamIIb/IIIa upstream

EIS: It is reasonable to give both EIS: It is reasonable to give both clopidogrel and IIb/IIIa upstreamclopidogrel and IIb/IIIa upstream

EIS: EIS: Can omit IIb/IIIa if bivalirudin is Can omit IIb/IIIa if bivalirudin is anticoagulant and at least 300mg anticoagulant and at least 300mg clopidogrel given clopidogrel given >> 6h prior to cath 6h prior to cath



ISAR-REACT-2, ISAR-REACT-2, JAMAJAMA 2006 2006

(ACUITY, (ACUITY, NEJMNEJM 2006) 2006)

Both of these studies have Both of these studies have risk considerationsrisk considerations that are important to upstream therapythat are important to upstream therapy

ISAR-REACT-2, ISAR-REACT-2, JAMAJAMA 2006 2006

(ACUITY, (ACUITY, NEJMNEJM 2006) 2006)

Both of these studies have Both of these studies have risk considerationsrisk considerations that are important to upstream therapythat are important to upstream therapy

Relevant New Studies Focusing onRelevant New Studies Focusing onAntiplatelet TherapyAntiplatelet Therapy

Relevant New Studies Focusing onRelevant New Studies Focusing onAntiplatelet TherapyAntiplatelet Therapy

ISAR-REACT 2: Troponin StatusISAR-REACT 2: Troponin StatusISAR-REACT 2: Troponin StatusISAR-REACT 2: Troponin Status

4.6% 4.6%

%

5%

10%

15%

20%

Abciximab Placebo

Troponin negative Troponin negative ( <0.03µg/L, n=973)( <0.03µg/L, n=973)

Pri

mar

y E

ven

tsP

rim

ary

Ev

ents

p=0.98

Kastrati A, Mehilli J , et al. JAMA. 2006 Apr 5;295(13):1531-8.

13.1%

18.3%

%

5%

10%

15%

20%

Abciximab Placebo

Troponin positive Troponin positive (>0.03 µg/L, n=1049)(>0.03 µg/L, n=1049)

p=0.02

In-hospital Major and Minor Bleeding (%)p=NS

ISAR-REACT 2 : BleedingISAR-REACT 2 : BleedingISAR-REACT 2 : BleedingISAR-REACT 2 : Bleeding

Kastrati A, Mehilli J , et al. JAMA. 2006 Apr 5;295(13):1531-8.

0 1 2

ACUITY Composite Ischemia at 1-YearACUITY Composite Ischemia at 1-YearUFH/Enoxaparin + GPIIb/IIIa vs. Bivalirudin Alone



Bivalalone

UFH/Enox+ IIb/IIIa

HR (95% CI) Pint

0.67

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

19.8% 19.2% 1.09 (0.96-1.23)

21.1% 20.7% 1.04 (0.79-1.36)

9.0% 9.6% 0.97 (0.76-1.24)

Actual Treatment

PCI (n=5179)

CABG (n=1040)

Medical (n=2994)

17.7%

14.6%

16.4%

16.1%

1.14 (0.99-1.30)

0.95 (0.80-1.14)0.11

Biomarkers (CK/Trop)

Elevated (n=5072)

Normal (n=3402)

16.2%

16.4%

17.2%

14.3%

0.97 (0.86-1.11)

1.20 (1.01-1.44)0.07

Pre Thienopyridine

Yes (n=5751)

No (n=3305)

1 yr KM estimate

ACUITY 1-Year Data as presented at ACC 2007.

P value interaction

only between subgroups

0 1 2

Death at One Year — Death at One Year — Interaction AnalysisInteraction Analysis

UFH/Enoxaparin + GPIIb/IIIa vs. Bivalirudin aloneUFH/Enoxaparin + GPIIb/IIIa vs. Bivalirudin alone

Hazard ratioHazard ratio±95% CI±95% CI

Hazard ratioHazard ratio±95% CI±95% CI

BivalBivalalonealone

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

HR (95% CI)HR (95% CI) PPintint

0.960.96

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

3.2%3.2% 4.0%4.0% 0.95 (0.70-1.29)0.95 (0.70-1.29)

6.8%6.8% 6.7%6.7% 1.03 (0.64-1.66)1.03 (0.64-1.66)

4.0%4.0% 4.3%4.3% 0.95 (0.66-1.37)0.95 (0.66-1.37)

Actual TreatmentActual Treatment

PCI (n=5179)PCI (n=5179)

CABG (n=1040)CABG (n=1040)

Medical (n=2994)Medical (n=2994)

4.8%4.8%

2.4%2.4%

5.0%5.0%

3.6%3.6%

1.04 (0.80-1.34)1.04 (0.80-1.34)

0.84 (0.55-1.28)0.84 (0.55-1.28)0.400.40

Biomarkers (CK/Trop)Biomarkers (CK/Trop)

Elevated (n=5072)Elevated (n=5072)

Normal (n=3402)Normal (n=3402)

3.5%3.5%

4.0%4.0%

4.2%4.2%

4.4%4.4%

0.90 (0.68-1.18)0.90 (0.68-1.18)

1.05 (0.74-1.48)1.05 (0.74-1.48)0.520.52

Pre ThienopyridinePre Thienopyridine

Yes (n=5751)Yes (n=5751)

No (n=3305)No (n=3305)

1 yr KM estimate1 yr KM estimate



ICS with recurrent ischemia on ASA, ICS with recurrent ischemia on ASA, clopidogrel, and anticoag: addclopidogrel, and anticoag: addIIb/IIIa upstreamIIb/IIIa upstream

EIS: it is reasonable to give both EIS: it is reasonable to give both clopidogrel and IIb/IIIa upstreamclopidogrel and IIb/IIIa upstream


ICS with recurrent ischemia on ASA, ICS with recurrent ischemia on ASA, clopidogrel, and anticoag: addclopidogrel, and anticoag: addIIb/IIIa upstreamIIb/IIIa upstream

EIS: it is reasonable to give both EIS: it is reasonable to give both clopidogrel and IIb/IIIa upstreamclopidogrel and IIb/IIIa upstream


CREDO: 15 hrs (not 6 hrs) Until Clinical CREDO: 15 hrs (not 6 hrs) Until Clinical Benefit Seen with 300 mg LoadBenefit Seen with 300 mg Load

CREDO: 15 hrs (not 6 hrs) Until Clinical CREDO: 15 hrs (not 6 hrs) Until Clinical Benefit Seen with 300 mg LoadBenefit Seen with 300 mg Load

Steinhubl S et al, J Am Coll Cardiol 2006;47:939-943.

Death, MI, UTVR (%)Death, MI, UTVR (%)Death, MI, UTVR (%)Death, MI, UTVR (%)

Placebo Pretreatment (N_915)Placebo Pretreatment (N_915)Placebo Pretreatment (N_915)Placebo Pretreatment (N_915)

Clopidogrel Pretreatment < 15 hours (N=645)Clopidogrel Pretreatment < 15 hours (N=645)Clopidogrel Pretreatment < 15 hours (N=645)Clopidogrel Pretreatment < 15 hours (N=645)

Clopidogrel Pretreatment Clopidogrel Pretreatment >> 15 hours (N=202) 15 hours (N=202)Clopidogrel Pretreatment Clopidogrel Pretreatment >> 15 hours (N=202) 15 hours (N=202)

8.3%8.3%8.3%8.3%

7.8%7.8%7.8%7.8%

3.5%3.5%3.5%3.5%

0 5 10 15 20 250 5 10 15 20 250 5 10 15 20 250 5 10 15 20 25

DaysDaysDaysDays

1010

88

66

44

22

00

1010

88

66

44

22

00

Quadruple Composite

Ischemic Composite

ACUITY Major Bleeding

1.00 (0.89-1.11)1.00 (0.89-1.11)

1.12 (0.97-1.29)1.12 (0.97-1.29)

0.80 (0.67-0.95)0.80 (0.67-0.95)

0 1 2Deferred

GP IIb-IIIa better (n=4,602)

Upstream GP IIb-IIIa better

(n=4,605)

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

Risk ratio ±95% CI

ACUITY Timing Analysis (N=9,207)ACUITY Timing Analysis (N=9,207)

ACUITY as presented at ACC 2006.

Excessive Dosing of AcuteExcessive Dosing of AcuteMedications by AgeMedications by Age

Excessive Dosing of AcuteExcessive Dosing of AcuteMedications by AgeMedications 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

xces

sive

Do

se

< 65 yrs 65-75 yrs >75 yrs

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

xces

sive

Do

se

< 65 yrs 65-75 yrs >75 yrs

Alexander KA, JAMA 2005;294:3108-16.

8

6.7

4.4

10.4

8.8

13.3

0

2

4

6

8

10

12

14

UF Heparin LMWH GP IIb-IIIa

Recommended Excess

RBC Transfusions by Excess DosingRBC Transfusions by Excess DosingRBC Transfusions by Excess DosingRBC Transfusions by Excess DosingR

BC

Tra

nsf

usi

on

(%

)R

BC

Tra

nsf

usi

on

(%

)


Death Death

Death or Re-MIDeath or Re-MI

Death Death

Death or Re-MIDeath or Re-MI

11 2.02.0

Adjusted Risk of In-Hospital Outcomes Adjusted Risk of In-Hospital Outcomes By Transfusion Status*By Transfusion Status*

Adjusted Risk of In-Hospital Outcomes Adjusted Risk of In-Hospital Outcomes By Transfusion Status*By Transfusion Status*

* Non-CABG patients onlyYang X, J Am Coll Cardiol 2005;46:1490-5.

Cumulative Effects of Dosing Errors Cumulative Effects of Dosing Errors Combined Use of Heparin and GP IIb-IIIaCombined Use of Heparin and GP IIb-IIIa

Cumulative Effects of Dosing Errors Cumulative Effects of Dosing Errors Combined Use of Heparin and GP IIb-IIIaCombined Use of Heparin and GP IIb-IIIa

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

ns

fus

ion

s


Hospital Link Between Overall Hospital Link Between Overall Guidelines Adherence and MortalityGuidelines Adherence and Mortality

Hospital Link Between Overall Hospital Link Between Overall Guidelines Adherence and MortalityGuidelines Adherence and Mortality

Peterson et al, JAMA 2006;295:1863-1912.

5.95

5.16 4.97

4.16

5.064.63

4.15

6.31

0

1

2

3

4

5

6

7

<=25% 25 - 50% 50 - 75% >=75%


% I

n-H

osp

Mo

rtal

ity

Adjusted Unadjusted

5.95

5.16 4.97

4.16

5.064.63

4.15

6.31

0

1

2

3

4

5

6

7

<=25% 25 - 50% 50 - 75% >=75%


% I

n-H

osp

Mo

rtal

ity

Adjusted Unadjusted

Every 10% Every 10% in guidelines adherence in guidelines adherence 10% 10% in mortality (OR=0.90, 95% CI: 0.84-0.97) in mortality (OR=0.90, 95% CI: 0.84-0.97)

► We should be using optimal medical therapy for We should be using optimal medical therapy for NSTE ACS in the ED, just as in the CCU or the NSTE ACS in the ED, just as in the CCU or the cath lab. cath lab.

► There are new agents that will change the ED There are new agents that will change the ED and the cath lab approach to ACS management, and the cath lab approach to ACS management, both in terms of pharmacologic stabilization both in terms of pharmacologic stabilization (antithrombotic and antiplatelet therapy) and (antithrombotic and antiplatelet therapy) and invasive management (namely, the speed with invasive management (namely, the speed with which the patient goes to the cath lab).which the patient goes to the cath lab).

Conclusions: NSTE ACS - 2007Conclusions: NSTE ACS - 2007Conclusions: NSTE ACS - 2007Conclusions: NSTE ACS - 2007

► We must work with our colleagues in We must work with our colleagues in cardiology to develop pathways for optimal cardiology to develop pathways for optimal use of antithrombotic and antiplatelet use of antithrombotic and antiplatelet therapy at all levels, to facilitate early therapy at all levels, to facilitate early invasive management whenever feasible, invasive management whenever feasible, and to address issues related to bleeding and to address issues related to bleeding risk as well as ischemic risk.risk as well as ischemic risk.

► New “(up)streams” of care have been New “(up)streams” of care have been introduced and require consideration in EDintroduced and require consideration in ED

► In ACS management, one size clearly does In ACS management, one size clearly does NOTNOT fit all! fit all!

Conclusions: NSTE ACSConclusions: NSTE ACSConclusions: NSTE ACSConclusions: NSTE ACS

► ECG and ASA within 10 minECG and ASA within 10 min STEMI patients directed to their pathwaySTEMI patients directed to their pathway

► Risk stratificationRisk stratification Focused history and physical, biomarkers, Focused history and physical, biomarkers,

serial ECGs, risk score, and bleeding riskserial ECGs, risk score, and bleeding risk

► Patients with high ischemic risk should go for EIS Patients with high ischemic risk should go for EIS (Class I) or, in a minority of cases, for ICS (Class (Class I) or, in a minority of cases, for ICS (Class IIa), but only IIa), but only after medical stabilizationafter medical stabilization

► ECG and ASA within 10 minECG and ASA within 10 min STEMI patients directed to their pathwaySTEMI patients directed to their pathway

► Risk stratificationRisk stratification Focused history and physical, biomarkers, Focused history and physical, biomarkers,

serial ECGs, risk score, and bleeding riskserial ECGs, risk score, and bleeding risk

► Patients with high ischemic risk should go for EIS Patients with high ischemic risk should go for EIS (Class I) or, in a minority of cases, for ICS (Class (Class I) or, in a minority of cases, for ICS (Class IIa), but only IIa), but only after medical stabilizationafter medical stabilization

Summary 2007 Guidelines: Upstream Summary 2007 Guidelines: Upstream Management of Suspected ACSManagement of Suspected ACS

► AnticoagulationAnticoagulation EIS: Enoxaparin (I-A), UFH (I-A), or bivalirudin (I-B)EIS: Enoxaparin (I-A), UFH (I-A), or bivalirudin (I-B)

• Strong support for bivalirudin when time to lab is Strong support for bivalirudin when time to lab is quick and/or when bleeding risk is higher (screen quick and/or when bleeding risk is higher (screen for patients at hgher risk for bleeding)for patients at hgher risk for bleeding)

ECS: Enoxaparin (I-A), UFH (I-A), or fondaparinux ECS: Enoxaparin (I-A), UFH (I-A), or fondaparinux (I-B)(I-B)

• Strong support for fondaparinux when bleeding risk Strong support for fondaparinux when bleeding risk is higher, but more problematic if catheterization is higher, but more problematic if catheterization later requiredlater required

Individual patient characteristics (ischemic risk, Individual patient characteristics (ischemic risk, bleeding risk, time to cath) should drive choices, which bleeding risk, time to cath) should drive choices, which should be made collaboratively by EM and cardiologyshould be made collaboratively by EM and cardiology

Summary 2007 Guidelines: Upstream Summary 2007 Guidelines: Upstream Medical StabilizationMedical Stabilization

► AnticoagulationAnticoagulation

““The Writing Committee believes that The Writing Committee believes that inadequate inadequate unconfounded, comparative information is unconfounded, comparative information is availableavailable to recommend a preferred to recommend a preferred [anticoagulation] regimen when an early, [anticoagulation] regimen when an early, invasive strategy is used for UA/NSTEMI, and invasive strategy is used for UA/NSTEMI, and physician and health care system preference, physician and health care system preference, together with individualized patient application, together with individualized patient application, is advised.”is advised.”

Summary 2007 GuidelinesSummary 2007 Guidelines Upstream Medical Stabilization Upstream Medical Stabilization

Summary 2007 GuidelinesSummary 2007 Guidelines Upstream Medical Stabilization Upstream Medical Stabilization

► Antiplatelet therapyAntiplatelet therapy Everybody gets ASAEverybody gets ASA

Clopidogrel use much more strongly supportedClopidogrel use much more strongly supported in in 2007 Guidelines than in 2002, but CABG caveat still 2007 Guidelines than in 2002, but CABG caveat still operative!operative!

Clopidogrel OR a GPI upstream (I-A) for high risk Clopidogrel OR a GPI upstream (I-A) for high risk patients, and consider BOTH (IIa-B) patients, and consider BOTH (IIa-B)

Collaboration again critical, as choice of Collaboration again critical, as choice of anticoagulant may impact choice of antiplatelet anticoagulant may impact choice of antiplatelet therapy, and institutional posture re: pretreatment therapy, and institutional posture re: pretreatment with clopidogrel may override other concernswith clopidogrel may override other concerns

► Antiplatelet therapyAntiplatelet therapy Everybody gets ASAEverybody gets ASA

Clopidogrel use much more strongly supportedClopidogrel use much more strongly supported in in 2007 Guidelines than in 2002, but CABG caveat still 2007 Guidelines than in 2002, but CABG caveat still operative!operative!

Clopidogrel OR a GPI upstream (I-A) for high risk Clopidogrel OR a GPI upstream (I-A) for high risk patients, and consider BOTH (IIa-B) patients, and consider BOTH (IIa-B)

Collaboration again critical, as choice of Collaboration again critical, as choice of anticoagulant may impact choice of antiplatelet anticoagulant may impact choice of antiplatelet therapy, and institutional posture re: pretreatment therapy, and institutional posture re: pretreatment with clopidogrel may override other concernswith clopidogrel may override other concerns

Summary 2007 GuidelinesSummary 2007 Guidelines Upstream Medical StabilizationUpstream Medical Stabilization

Summary 2007 GuidelinesSummary 2007 Guidelines Upstream Medical StabilizationUpstream Medical Stabilization

► Earlier use of clopidogrelEarlier use of clopidogrel

► New antithrombotics—bivalirudin (for invasive) New antithrombotics—bivalirudin (for invasive) and fondaparinux for conservative—and new and fondaparinux for conservative—and new antithrombotic/antiplatelet combinationsantithrombotic/antiplatelet combinations

► Faster time to cath for NSTE ACS patientsFaster time to cath for NSTE ACS patients

► More emphasis by cardiologists on bleeding More emphasis by cardiologists on bleeding risk . . . sometimes prompting different risk . . . sometimes prompting different considerations in the EDconsiderations in the ED

► Earlier use of clopidogrelEarlier use of clopidogrel

► New antithrombotics—bivalirudin (for invasive) New antithrombotics—bivalirudin (for invasive) and fondaparinux for conservative—and new and fondaparinux for conservative—and new antithrombotic/antiplatelet combinationsantithrombotic/antiplatelet combinations

► Faster time to cath for NSTE ACS patientsFaster time to cath for NSTE ACS patients

► More emphasis by cardiologists on bleeding More emphasis by cardiologists on bleeding risk . . . sometimes prompting different risk . . . sometimes prompting different considerations in the EDconsiderations in the ED

Summary 2007 Guidelines Summary 2007 Guidelines Changes Likely to Impact the EDChanges Likely to Impact the EDSummary 2007 Guidelines Summary 2007 Guidelines

Changes Likely to Impact the EDChanges Likely to Impact the ED

Why Bleeding Matters: A Cautionary Note For The Emergency

Medicine Specialist

Importance of Multi-specialty ED and IC Therapeutic (EDICT) Alignment of Upstream

Care for ACS

Sunil Rao, MD, FACCSunil Rao, MD, FACCDirector of Interventional CardiologyDirector of Interventional Cardiology

Veterans Administration Medical CenterVeterans Administration Medical CenterAssistant ProfessorAssistant Professor

Division of Cardiovascular MedicineDivision of Cardiovascular MedicineDuke University Medical CenterDuke University Medical Center

Why Bleeding Matters: A Cautionary Note For The Emergency

Medicine Specialist

Importance of Multi-specialty ED and IC Therapeutic (EDICT) Alignment of Upstream

Care for ACS

Sunil Rao, MD, FACCSunil Rao, MD, FACCDirector of Interventional CardiologyDirector of Interventional Cardiology

Veterans Administration Medical CenterVeterans Administration Medical CenterAssistant ProfessorAssistant Professor

Division of Cardiovascular MedicineDivision of Cardiovascular MedicineDuke University Medical CenterDuke University Medical Center


ACS Case PresentationACS Case PresentationACS Case PresentationACS Case Presentation

► 77 year old female presents to ED with 2 weeks of 77 year old female presents to ED with 2 weeks of progressive angina, one episode lasting 90 minutesprogressive angina, one episode lasting 90 minutes History of Type 2 DM, HTN, cigarette smokingHistory of Type 2 DM, HTN, cigarette smoking Weight 65 kgWeight 65 kg

► ECG non-specific, POS TnI 0.79 (ULN 0.5), nl CKMB, ECG non-specific, POS TnI 0.79 (ULN 0.5), nl CKMB, CrCL 40 ml/min, Hgb 9.7 g/dlCrCL 40 ml/min, Hgb 9.7 g/dl

► Given ASA, 300 mg clopidogrel, 5 mg IV metoprolol, Given ASA, 300 mg clopidogrel, 5 mg IV metoprolol, IV NTGIV NTG

► Continued chest painContinued chest pain Anticoagulation options in the ED?Anticoagulation options in the ED? Risk stratification strategy?Risk stratification strategy? Which upstream strategy makes most sense?Which upstream strategy makes most sense? Collaboration with cardiology colleagues?Collaboration with cardiology colleagues?

Medical Rx(cath)

Time

Admission Cath Discharge

No Cath

Cath PCI

Surgery

Medical Rx (no cath)

Medical Rx

No disease

(82 % of total)

(18 % of total)

(52% of total, 63% of those undergoing cath)

40 % < 48 hrs

12 % > 48 hrs

(12% of total, 15% of those undergoing cath)

63 % < 48 hrs

19 % > 48 hrs

CRUSADERegistry

10/04-9/05n=35,897

Patient X

ACS Management Pathways

Cath

Medical Rx

Ischemic Complications

Ischemic Complications

Hemorrhage HIT

Hemorrhage HIT

► Death

► MI

► Urgent TVR

► Death

► MI

► Urgent TVR

► Major Bleeding

► Minor Bleeding

► Thrombocytopenia

► Major Bleeding

► Minor Bleeding

► Thrombocytopenia

Composite Adverse Event EndpointsComposite Adverse Event Endpoints

Evolving ED Paradigm for Evaluating Evolving ED Paradigm for Evaluating ACS Management StrategiesACS Management Strategies

Evolving ED Paradigm for Evaluating Evolving ED Paradigm for Evaluating ACS Management StrategiesACS Management Strategies

Although these complications usuallyAlthough these complications usually

are not seen in the ED, choices made are not seen in the ED, choices made in the EDin the ED

influence the likelihood of these adverse events!influence the likelihood of these adverse events!

Although these complications usuallyAlthough these complications usually

are not seen in the ED, choices made are not seen in the ED, choices made in the EDin the ED

influence the likelihood of these adverse events!influence the likelihood of these adverse events!

Options for NSTE-ACS Therapy in 2007Options for NSTE-ACS Therapy in 2007Options for NSTE-ACS Therapy in 2007Options for NSTE-ACS Therapy in 2007

► Antiplatelet therapiesAntiplatelet therapies ASA, ClopidogrelASA, Clopidogrel Glycoprotein IIb/IIIa inhibitorsGlycoprotein IIb/IIIa inhibitors

► Antithrombin therapyAntithrombin therapy UFHUFH EnoxaparinEnoxaparin FondaparinuxFondaparinux BivalirudinBivalirudin

► Risk stratificationRisk stratification ConservativeConservative InvasiveInvasive

► Antiplatelet therapiesAntiplatelet therapies ASA, ClopidogrelASA, Clopidogrel Glycoprotein IIb/IIIa inhibitorsGlycoprotein IIb/IIIa inhibitors

► Antithrombin therapyAntithrombin therapy UFHUFH EnoxaparinEnoxaparin FondaparinuxFondaparinux BivalirudinBivalirudin

► Risk stratificationRisk stratification ConservativeConservative InvasiveInvasive

Risk of events

Risk of bleeding

ThrombosisHemostasis

Two sides of the same coin

Degree of Anticoagulation

Ris

k

Balancing Ischemic Events and Balancing Ischemic Events and Bleeding RiskBleeding Risk

Balancing Ischemic Events and Balancing Ischemic Events and Bleeding RiskBleeding Risk

CRUSADE In-Hospital Outcomes: 2006CRUSADE In-Hospital Outcomes: 2006CRUSADE In-Hospital Outcomes: 2006CRUSADE In-Hospital Outcomes: 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)

ACS-related Bleeding —Relevant QuestionsACS-related Bleeding —Relevant Questionsfor the Emergency Medicine Specialistfor the Emergency Medicine Specialist

► Who bleeds? Can we risk stratify?Who bleeds? Can we risk stratify?

► Should bleeding risk affect upstream Should bleeding risk affect upstream antithrombotic care? If so, how?antithrombotic care? If so, how?

► Is bleeding bad or a necessary evil?Is bleeding bad or a necessary evil?

► Can blood transfusion “correct” risks Can blood transfusion “correct” risks associated with bleeding?associated with bleeding?

► Does bleeding affect resource use?Does bleeding affect resource use?

► What options do we have to balance efficacy What options do we have to balance efficacy (reduced risk for ischemic outcomes) and (reduced risk for ischemic outcomes) and safety (reduced bleeding)?safety (reduced bleeding)?

Bleeding in ACS — Identification

Questions to be answered —

1] Who bleeds?1] Who bleeds?

2] What risk factors are predictive of 2] What risk factors are predictive of bleeding?bleeding?

3] How should initial choices for3] How should initial choices for upstream care be influenced by upstream care be influenced by bleeding risk?bleeding risk?

Questions to be answered —

1] Who bleeds?1] Who bleeds?

2] What risk factors are predictive of 2] What risk factors are predictive of bleeding?bleeding?

3] How should initial choices for3] How should initial choices for upstream care be influenced by upstream care be influenced by bleeding risk?bleeding risk?

Independent Independent predictors of predictors of major major bleeding bleeding in marker- in marker- positive positive acute acute coronary coronary syndromessyndromes

Moscucci, GRACE Registry, Eur Heart J. 2003 Oct;24(20):1815-23.

Predictors of Major Bleeding in ACSPredictors of Major Bleeding in ACS

► Older AgeOlder Age

► Female GenderFemale Gender

► Renal FailureRenal Failure

► History of BleedingHistory of Bleeding

► Right Heart CatheterizationRight Heart Catheterization

► GPIIb-IIIa AntagonistsGPIIb-IIIa Antagonists

0 1 2 3

P-valueRR (95% CI)Risk ratio ± 95% CI

Predictors of Major BleedingPredictors of Major Bleeding

Age >75 (vs. 55-75)

Anemia

CrCl <60mL/min

Diabetes

Female gender

High-risk (ST / biomarkers)

Hypertension

No prior PCI

Prior antithrombotic therapy

Heparin(s) + GPI (vs. Bivalirudin)

1.56 (1.19-2.04) 0.0009

1.89 (1.48-2.41) <0.0001

1.68 (1.29-2.18) <0.0001

1.30 (1.03-1.63) 0.0248

2.08 (1.68-2.57) <0.0001

1.42 (1.06-1.90) 0.0178

1.33 (1.03-1.70) 0.0287

1.47 (1.15-1.88) 0.0019

1.23 (0.98-1.55) 0.0768

2.08 (1.56-2.76) <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 4 5

P-valueRR (95% CI)

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

Heparin(s) + GPI (vs. Heparin(s) + GPI (vs. BivalirudinBivalirudin))

1.420 (1.055-1.910)1.420 (1.055-1.910) 0.00600.0060

3.764 (2.919-4.855)3.764 (2.919-4.855) <0.0001<0.0001

2.097 (1.568-2.803)2.097 (1.568-2.803) <0.0001<0.0001

1.560 (1.209-2.014)1.560 (1.209-2.014) 0.00600.0060

2.233 (1.739-2.867)2.233 (1.739-2.867) <0.0001<0.0001

1.754 (1.297-2.372)1.754 (1.297-2.372) 0.00030.0003

1.457 (1.051-2.020)1.457 (1.051-2.020) 0.02410.0241

1.728 (1.256-2.379)1.728 (1.256-2.379) 0.00070.0007

Predictors of TransfusionPredictors of Transfusion

Risk ratio ± 95% CI

Results: The ACUITY TrialResults: The ACUITY TrialResults: The ACUITY TrialResults: The ACUITY Trial


► Older age, chronic kidney disease, female Older age, chronic kidney disease, female gender are consistently associated with gender are consistently associated with bleeding and blood transfusionbleeding and blood transfusion

► Analysis of large randomized trials have also Analysis of large randomized trials have also identified novel risk factors for bleeding such identified novel risk factors for bleeding such as diabetes and anemiaas diabetes and anemia

► These risk factors can readily be identified These risk factors can readily be identified during the ED evaluation of a patient with ACSduring the ED evaluation of a patient with ACS

Bleeding Predictors — ConclusionsBleeding Predictors — Conclusions

Questions to be answered —Questions to be answered —

1] Is bleeding bad or a necessary evil?1] Is bleeding bad or a necessary evil?

2] What is the relationship between 2] What is the relationship between bleeding and patient outcomes in ACS?bleeding and patient outcomes in ACS?

3] What initial choices can the ED 3] What initial choices can the ED physician make that are compatible withphysician make that are compatible with guidelines and that will reduce bleeding?guidelines and that will reduce bleeding?

Questions to be answered —Questions to be answered —

1] Is bleeding bad or a necessary evil?1] Is bleeding bad or a necessary evil?

2] What is the relationship between 2] What is the relationship between bleeding and patient outcomes in ACS?bleeding and patient outcomes in ACS?

3] What initial choices can the ED 3] What initial choices can the ED physician make that are compatible withphysician make that are compatible with guidelines and that will reduce bleeding?guidelines and that will reduce bleeding?

Bleeding in ACS — ConsequencesBleeding in ACS — ConsequencesBleeding in ACS — ConsequencesBleeding in ACS — Consequences

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

P<0.001

5.13.0

5.37.0

18.616.1 15.3

22.8

0.0

10.0

20.0

30.0

40.0

No Bleed

Bleed

Overall Unstable NSTEMI STEMIOverall Unstable NSTEMI STEMI ACS AnginaACS Angina

Pat

ien

ts (

%)

Pat

ien

ts (

%)

Major Bleeding PredictsMajor Bleeding PredictsMortality in ACSMortality in ACS

Major Bleeding PredictsMajor Bleeding PredictsMortality in ACSMortality in ACS

24,045 ACS patients in the GRACE registry, in-hospital death24,045 ACS patients in the GRACE registry, in-hospital death24,045 ACS patients in the GRACE registry, in-hospital death24,045 ACS patients in the GRACE registry, in-hospital death

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 ACSBleeding and Outcomes in ACSBleeding and Outcomes in ACS

Rao SV, et al. Am J Cardiol. 2005 Nov 1;96(9):1200-6. Epub 2005 Sep 12.

Kaplan Meier Curves for 30-Day Death, Stratified by Bleed SeverityKaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity

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

26,452 patients from PURSUIT, PARAGON A, 26,452 patients from PURSUIT, PARAGON A, PARAGON B, GUSTO IIb NSTPARAGON B, GUSTO IIb NST

Bleeding severity and adjusted hazard of deathBleeding severity and adjusted hazard of death

*p<0.0001*p<0.0001

Bleeding and Outcomes in NSTE-ACS Bleeding and Outcomes in NSTE-ACS Bleeding and Outcomes in NSTE-ACS Bleeding and Outcomes in NSTE-ACS

Bleeding SeverityBleeding Severity 30d Death30d Death 30d Death/MI30d Death/MI 6 mo. Death6 mo. Death

Mild*Mild* 1.6 1.6 1.31.3 1.41.4

Moderate*Moderate* 2.7 2.7 3.33.3 2.12.1

Severe*Severe* 10.610.6 5.65.6 7.57.5

*Bleeding as a time-dependent covariate*Bleeding as a time-dependent covariate

Rao SV, et al. Am J Cardiol. 2005 Nov 1;96(9):1200-6. Epub 2005 Sep 12.

► Bleeding is associated with adverse short- and Bleeding is associated with adverse short- and long-term outcomes among patients with ACS long-term outcomes among patients with ACS and those undergoing PCIand those undergoing PCI

Mortality rates are higher among those who bleedMortality rates are higher among those who bleed

MI rates are higher among those who bleedMI rates are higher among those who bleed

► The risk is “dose-dependent” with worse bleeding The risk is “dose-dependent” with worse bleeding associated with worse outcomesassociated with worse outcomes

► This relationship is persistent after robust This relationship is persistent after robust statistical adjustment for confoundersstatistical adjustment for confounders

► Decisions made in the ED may affect subsequent Decisions made in the ED may affect subsequent bleeding risk, and in turn, clinical outcomesbleeding risk, and in turn, clinical outcomes

Bleeding and Outcomes — ConclusionsBleeding and Outcomes — ConclusionsBleeding and Outcomes — ConclusionsBleeding and Outcomes — Conclusions

Bleeding in ACSBleeding in ACSBleeding in ACSBleeding in ACS

Question To Be AnsweredQuestion To Be Answered

Can blood transfusionCan blood transfusion

“correct” adverse outcomes “correct” adverse outcomes

associate with bleeding?associate with bleeding?


Can blood transfusionCan blood transfusion

“correct” adverse outcomes “correct” adverse outcomes

associate with bleeding?associate with bleeding?

30-Day Survival By Transfusion Group30-Day Survival By Transfusion Group

Rao SV, et. al., JAMA 2004;292:1555–1562.

Transfusion in ACSTransfusion in ACSTransfusion in ACSTransfusion in ACS

N=24,111N=24,111N=24,111N=24,111

*Transfusion as a time-dependent covariate*Transfusion as a time-dependent covariate

Cox Model for 30-day DeathCox Model for 30-day DeathCox Model for 30-day DeathCox Model for 30-day Death

N=24,111N=24,111N=24,111N=24,111

Rao SV, et. al., JAMA 2004;292:1555–1562.

PRBC Transfusion Among NSTE ACS PatientsPRBC Transfusion Among NSTE ACS Patients PRBC Transfusion Among NSTE ACS PatientsPRBC Transfusion Among NSTE ACS Patients

Adjusted Risk of In-Hospital Outcomes Adjusted Risk of In-Hospital Outcomes

By Transfusion Status*By Transfusion Status*

*Non-CABG patients only

Yang X, J Am Coll Cardiol 2005;46:1490–5.

N=74,271 ACS patients from CRUSADE N=74,271 ACS patients from CRUSADE

9.4%

2.3%

18.8%

11.0%

29.2%

4.8%7.1%

1.3%

IschemicComposite

Death MI (all) UnplannedRevasc

30 d

ay e

ven

ts (

%)

Transfusion (N=319, 2.3%) No Transfusion (N=13500, 97.7%)

Transfusion, Ischemic Endpoints,Transfusion, Ischemic Endpoints,and Mortality in ACUITY Trialand Mortality in ACUITY Trial

9.4%

2.3%

18.8%

11.0%

29.2%

4.8%7.1%

1.3%

IschemicComposite

Death MI (all) UnplannedRevasc

30

da

y e

ve

nts

(%

)

Transfusion (N=319, 2.3%) No Transfusion (N=13500, 97.7%)

P<0.0001 for all


Results: The ACUITY Trial (N=13,819)Results: The ACUITY Trial (N=13,819)Results: The ACUITY Trial (N=13,819)Results: The ACUITY Trial (N=13,819)

Increased 1-year mortality in transfused patientsIncreased 1-year mortality in transfused patientsAdjusted Odds Ratio 4.26 (2.25–8.08)Adjusted Odds Ratio 4.26 (2.25–8.08)

Transfusion Post PCI — Transfusion Post PCI — REPLACE 2 One Year MortalityREPLACE 2 One Year Mortality

Transfusion Post PCI — Transfusion Post PCI — REPLACE 2 One Year MortalityREPLACE 2 One Year Mortality

1.9%

13.9%

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

14.0%

16.0%

Non-Transfused Transfused

P<0.0001

Manoukian SV, Voeltz MD, Attubato MJ, Bittl JA, Feit F, Lincoff AM. CRT 2005. Abstract.

► Blood transfusion is independently Blood transfusion is independently associated with death and re-MIassociated with death and re-MI

► Transfusion does not correct the Transfusion does not correct the adverse impact bleeding and is not an adverse impact bleeding and is not an “insurance policy” for choices made in “insurance policy” for choices made in the EDthe ED

► Blood transfusion is best avoided in Blood transfusion is best avoided in ACS patients whenever possibleACS patients whenever possible

► Decisions regarding bleeding risk Decisions regarding bleeding risk should be part of ED decision-making should be part of ED decision-making processprocess

Blood Transfusion — Conclusions

Bleeding in ACSBleeding in ACS


Does bleeding impact resource use?Does bleeding impact resource use?


Does bleeding impact resource use?Does bleeding impact resource use?

Bleeding and Resource Use: Predictors of Total CostsBleeding and Resource Use: Predictors of Total CostsBleeding and Resource Use: Predictors of Total CostsBleeding and Resource Use: Predictors of Total Costs

3370

11582164

7188

12409

2488

5255

24361336

0

2000

4000

6000

8000

10000

12000

14000

Mod/SevBld

UA Cath PCI CABG Pacemaker IABP ICU day Non-ICUday

$

Mod/sev bleedMod/sev bleed

Per patient cost - $530Per patient cost - $530

Transfusion - $2080, P < 0.01Transfusion - $2080, P < 0.01


Mod/sev bleedMod/sev bleed


Transfusion - $2080, P < 0.01Transfusion - $2080, P < 0.01


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. ACC 2007.

N=1235 pts from GUSTO IIbN=1235 pts from GUSTO IIbN=1235 pts from GUSTO IIbN=1235 pts from GUSTO IIb

► The available costs data clearly show that The available costs data clearly show that a balance must be struck between a balance must be struck between ischemia reduction and bleedingischemia reduction and bleeding Both ischemic complications and bleeding are Both ischemic complications and bleeding are

associated with increased costs such that any associated with increased costs such that any cost savings realized by reducing one is offset cost savings realized by reducing one is offset by cost increases associated with the otherby cost increases associated with the other

► Although these costs are not realized in Although these costs are not realized in the ED, the choices made there impact the ED, the choices made there impact costs downstreamcosts downstream

Bleeding and Costs — ConclusionsBleeding and Costs — Conclusions

What therapeutic options do ED What therapeutic options do ED physicans and cardiologists have to physicans and cardiologists have to

balance efficacy (reduced risk for balance efficacy (reduced risk for ischemic outcomes) and safety ischemic outcomes) and safety

(bleeding)?(bleeding)?

Bleeding in ACSBleeding in ACSBleeding in ACSBleeding in ACS


X

Xa

II

IIa

(Thrombin)

(Prothrombin)TF VIIa

IX IXa

Xa Inhibitors - Fondaparinux

Xa Inhibitors - Fondaparinux

Direct Thrombin Inhibitors - Bivalirudin

Direct Thrombin Inhibitors - Bivalirudin

Va

Targets for InterventionTargets for InterventionTargets for InterventionTargets for Intervention

OASIS 5 — Study DesignOASIS 5 — Study DesignOASIS 5 — Study DesignOASIS 5 — Study Design

NSTE ACS patientsNSTE ACS patients2 of 3: Age > 60, ECG ∆, 2 of 3: Age > 60, ECG ∆, Markers Markers

N=20,000N=20,000

NSTE ACS patientsNSTE ACS patients2 of 3: Age > 60, ECG ∆, 2 of 3: Age > 60, ECG ∆, Markers Markers

N=20,000N=20,000

Fondaparinux 2.5 mg SC QDFondaparinux 2.5 mg SC QDFondaparinux 2.5 mg SC QDFondaparinux 2.5 mg SC QD Enoxaparin 1 mg/kg SC BIDEnoxaparin 1 mg/kg SC BIDEnoxaparin 1 mg/kg SC BIDEnoxaparin 1 mg/kg SC BID

Death-MI-ischemia at 9dDeath-MI-ischemia at 9d

Major bleeding* at 9dMajor bleeding* at 9d

Death-MI-ischemia at 9dDeath-MI-ischemia at 9d

Major bleeding* at 9dMajor bleeding* at 9d

*ICH, RP, IO, Transfusion, *ICH, RP, IO, Transfusion, Hgb 3 gm/dl Hgb 3 gm/dl*ICH, RP, IO, Transfusion, *ICH, RP, IO, Transfusion, Hgb 3 gm/dl Hgb 3 gm/dl

Patients with NSTE ACS, Chest discomfort < 24 hours2 of 3: Age>60, ST Segment Δ, cardiac markers

Patients with NSTE ACS, Chest discomfort < 24 hoursPatients with NSTE ACS, Chest discomfort < 24 hours2 of 3: Age>60, ST Segment 2 of 3: Age>60, ST Segment ΔΔ, , cardiac markerscardiac markers

Fondaparinux2.5 mg sc once daily

FondaparinuxFondaparinux2.5 mg sc once daily2.5 mg sc once daily

Study Design: Randomized, Double Blind

ASA, Clop, GP IIb/IIIa, planned Cath/PCI as per

local practice

ASA, Clop, GP ASA, Clop, GP IIb/IIIaIIb/IIIa, , planned planned CathCath/PCI as per /PCI as per

local practicelocal practice

RandomizeRandomize

Enoxaparin1 mg/kg sc twice daily

EnoxaparinEnoxaparin1 mg/kg sc twice daily1 mg/kg sc twice daily

Primary: Efficacy: Death, MI, refractory ischemia at 9 days Safety: Major bleeding at 9 daysRisk benefit: Death, MI, refractory ischemia, major bleeds 9 days

Secondary: Above & each component separately at day 30 & 6 monthsHypothesis: First test non-inferiority, then test superiority

Primary:Primary: EfficacyEfficacy:: Death, MI, refractory ischemiaDeath, MI, refractory ischemia at 9 days at 9 days SafetySafety:: Major bleeding at 9 daysMajor bleeding at 9 daysRisk benefitRisk benefit:: Death, MI, refractory ischemia, major bleeds 9 daysDeath, MI, refractory ischemia, major bleeds 9 days

SecondarySecondary:: Above & each component Above & each component separatelyseparately at day 30 & 6 monthsat day 30 & 6 monthsHypothesisHypothesis:: First test nonFirst test non--inferiority, then test superiorityinferiority, then test superiority

Outcomes

PCI< 6 hPCI< 6 h,, No additional UFHNo additional UFHPCI >6 hPCI >6 h,, IV UFHIV UFHWith With IIb/IIIaIIb/IIIa 65 U/kg65 U/kgWithout Without IIb/IIIaIIb/IIIa 100 U/kg100 U/kg

PCI <6 hPCI <6 h:: IV Fonda 2.5 mgIV Fonda 2.5 mgwithout without IIb/IIIaIIb/IIIa, 0 with , 0 with IIb/IIIaIIb/IIIaPCI> 6 hPCI> 6 h:: IV Fonda 2.5 mg withIV Fonda 2.5 mg withand 5.0 mg without and 5.0 mg without IIb/IIIaIIb/IIIa

ExcludeAge < 21Any contra-ind to EnoxHem stroke< 12 mo.Creat> 3 mg/dL/265 umol/L

N=20,000

Death/MI/RI: Day 9

Days

Cum

ulat

ive

Ha

zard

0.0

0.0

10

.02

0.0

30

.04

0.0

50

.06

0 1 2 3 4 5 6 7 8 9

Enoxaparin

Fondaparinux

HR 1.01 95% CI 0.90-1.13

Major Bleeding: 9 Days

Days

Cu

mu

lati

ve H

azar

d

0.0

0.01

0.02

0.03

0.04

0 1 2 3 4 5 6 7 8 9

HR 0.53 95% CI 0.45-0.62

P<<0.00001

Enoxaparin

Fondaparinux

Mortality: Day 30

Days

Cu

mu

lati

ve H

aza

rd0.

00.

010.

020.

03

0 3 6 9 12 15 18 21 24 27 30

HR 0.83 HR 0.83 95% CI 0.7195% CI 0.71--0.970.97

P=0.022P=0.022

Enoxaparin

Fondaparinux

OASIS 5OASIS 5OASIS 5OASIS 5

Patients Undergoing PCIPatients Undergoing PCIOASIS 5 and 6OASIS 5 and 6

Patients Undergoing PCIPatients Undergoing PCIOASIS 5 and 6OASIS 5 and 6

OASIS 5 Investigators NEJM 2006OASIS 6 Investigators JAMA 2006OASIS 5 Investigators NEJM 2006OASIS 6 Investigators JAMA 2006

RxRx

None None (n=2867)(n=2867)

Lysis Lysis (n=5436)(n=5436)

1° PCI 1° PCI (n=3789)(n=3789)

1.0 2.00.5

Favors FondaparinuxFavors Fondaparinux Favors UFH or PlaceboFavors UFH or Placebo

0.30.2

1.2

0.7

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Before Heparin After Heparin

%

Enox

Fonda

Catheter ThrombusCatheter Thrombus

Moderate-high risk

ACS

ACUITY Study Design – ACUITY Study Design – First RandomizationFirst Randomization

ACUITY Study Design – ACUITY Study Design – First RandomizationFirst Randomization

► Moderate-high risk unstable angina or NSTEMI Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819)undergoing an invasive strategy (N = 13,819)

An

gio

gra

ph

y w

ith

in 7

2h

Aspirin in allAspirin in allClopidogrelClopidogrel

dosing and timingdosing and timingper local practiceper local practice

UFH orEnoxaparin+ GP IIb/IIIa

Bivalirudin+ GP IIb/IIIa

BivalirudinAlone

R*


Medicalmanagement

PCI

CABG





ACUITY: Primary results – 30 daysACUITY: Primary results – 30 days

UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin AloneUFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone

7.3%5.7%

11.7%

5.3%

11.8%

7.7% 7.8%

10.1%

3.0%

Net clinical outcome Composite ischemia Major bleeding (non-CABG)

30 d

ay e

ven

ts (

%)

UFH/Enox+ GP IIb/IIIa (N=4603) Bivalirudin+GP IIb/IIIa (N=4604) Bivalirudin alone (N=4612)

PNI <0.001PSup = 0.015

PNI = 0.011 PSup = 0.32

PNI <0.001PSup <0.001

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

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

4

5

Mo

rtal

ity

(%)


2

1

Mortality: 524 Total Deaths at 1-yearMortality: 524 Total Deaths at 1-yearMortality: 524 Total Deaths at 1-yearMortality: 524 Total Deaths at 1-year

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

UFH/Enoxaparin + IIb/IIIaBivalirudin + IIb/IIIa

Bivalirudin alone

EstimateP

(log rank)

1.4%0.531.6%0.391.6%

—

EstimateP

(log rank)

4.4%0.934.2%0.663.8%

1 year

—

p=0.90


30 day

3



ACUITY PCI: High Risk* PatientsACUITY PCI: High Risk* PatientsACUITY PCI: High Risk* PatientsACUITY PCI: High Risk* Patients

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)

UFH/Enox+ IIb/IIIa betterUFH/Enox+ IIb/IIIa better

* High risk = ↑Tn, CKMB or ECG Δ’s

0.1 1 10

Bivalirudin betterBivalirudin better Bivalirudin betterBivalirudin better

30 day Results 1 year Results

Composite Composite ischemiaischemia

1.08 (0.88-1.08 (0.88-1.32)1.32)

Major Major bleedingbleeding

0.55 (0.42-0.55 (0.42-0.72)0.72)

MortalityMortality 0.94 (0.67-1.31)0.94 (0.67-1.31)

UFH/Enox+ IIb/IIIa betterUFH/Enox+ IIb/IIIa better

Mo

rtal

ity

(%)


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

5

15

30

10

25

20

1 yearEstimate

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

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

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

28.9%

12.5%

8.6%

3.4%

Day 0 – 2 after MI 12.6 (7.8-20.4) 29 (37.6) <0.0001

Day 3 – 7 after MI 5.3 (2.7-10.4) 11 (14.3) <0.0001

Day 8 – 35 after MI 1.6 (0.8-3.1) 12 (15.6) 0.18

Day > 35 after MI 1.2 (0.8-1.9) 25 (32.5) 0.34

Day 0 – 2 after Major Bleed 3.0 (1.6-5.6) 12 (12.9) 0.0009

Day 3 – 7 after Major Bleed 4.0 (2.1-7.5) 15 (16.1) <0.0001

Day 8 – 35 after Major Bleed 4.5 (2.8-7.4) 25 (26.9) <0.0001

Day > 35 after Major Bleed 2.2 (1.5-3.2) 41 (44.1) <0.0001

P-valueP-valueDeaths (n/%)Deaths (n/%)HR ± 95% CIHR ± 95% CI

0.5 1 2 4 8 16

HR (CI)HR (CI)

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

ACS Case PresentationACS Case Presentation

► 77 year-old female presented to ED with 2 weeks 77 year-old female presented to ED with 2 weeks of progressive angina, one episode lasting 90 of progressive angina, one episode lasting 90 minutesminutes History of Type 2 DM, HTN, cigarette smokingHistory of Type 2 DM, HTN, cigarette smoking Weight 65 kgWeight 65 kg

► ECG non-specific, POC TnI 0.79 (ULN 0.5), nl ECG non-specific, POC TnI 0.79 (ULN 0.5), nl CKMB, CrCL 40 ml/min, Hgb 9.7 g/dlCKMB, CrCL 40 ml/min, Hgb 9.7 g/dl

► Given ASA, 300 mg clopidogrel, 5 mg IV Given ASA, 300 mg clopidogrel, 5 mg IV metoprolol, IV NTGmetoprolol, IV NTG

► Continued chest painContinued chest pain Anticoagulant choices in ED?Anticoagulant choices in ED? Risk stratification strategy?Risk stratification strategy?

► Decision made to pursue rapid invasive risk Decision made to pursue rapid invasive risk stratificationstratification High-risk featuresHigh-risk features

• Elevated troponinElevated troponin• Ongoing chest pain despiteOngoing chest pain despite

medical therapymedical therapy

► Antithrombin therapy choicesAntithrombin therapy choices Risk for bleedingRisk for bleeding

• Age, Female sex, renalAge, Female sex, renalinsufficiency, anemiainsufficiency, anemia

Bivalirudin bolus and gtt initiatedBivalirudin bolus and gtt initiated

► AngiographyAngiography

Case PresentationCase Presentation

Addressing the Challenge of Addressing the Challenge of Selecting an Anticoagulation StrategySelecting an Anticoagulation Strategy

Bleeding RiskBleeding RiskBleeding RiskBleeding Risk

Ischemic RiskIschemic RiskIschemic RiskIschemic Risk

Renal functionRenal functionRenal functionRenal functionAgeAgeAgeAge

Time to cathTime to cathTime to cathTime to cath

CostCostCostCost

Ease of useEase of useEase of useEase of use

PCI vs CABG vs Med RxPCI vs CABG vs Med RxPCI vs CABG vs Med RxPCI vs CABG vs Med Rx

Bleeding Among PatientsBleeding Among Patientswith ACS Conclusionswith ACS Conclusions

► There are several therapeutic There are several therapeutic pathways for NSTE ACS carepathways for NSTE ACS care

► The “(up)stream” of care begins in the The “(up)stream” of care begins in the emergency departmentemergency department

► Choices made in the ED impactChoices made in the ED impactdownstream eventsdownstream events Ischemic complicationsIschemic complications Bleeding complicationsBleeding complications

Conclusions—Bleeding in ACS Conclusions—Bleeding in ACS Conclusions—Bleeding in ACS Conclusions—Bleeding in ACS

► Certain patient and PCI procedure characteristics Certain patient and PCI procedure characteristics predict bleedingpredict bleeding

Age, female gender, CKD Age, female gender, CKD Diabetes and anemia are newly identified risk factors Diabetes and anemia are newly identified risk factors

for bleeding among ACS patientsfor bleeding among ACS patients

►Bleeding is associated with worse short and long-Bleeding is associated with worse short and long-term outcomes including death and MIterm outcomes including death and MI

►Blood transfusion is associated with increased Blood transfusion is associated with increased mortality in ACS patients mortality in ACS patients

►In addition to clinical outcomes, bleeding is In addition to clinical outcomes, bleeding is associated with increased cost of careassociated with increased cost of care

► Certain patient and PCI procedure characteristics Certain patient and PCI procedure characteristics predict bleedingpredict bleeding

Age, female gender, CKD Age, female gender, CKD Diabetes and anemia are newly identified risk factors Diabetes and anemia are newly identified risk factors

for bleeding among ACS patientsfor bleeding among ACS patients

►Bleeding is associated with worse short and long-Bleeding is associated with worse short and long-term outcomes including death and MIterm outcomes including death and MI

►Blood transfusion is associated with increased Blood transfusion is associated with increased mortality in ACS patients mortality in ACS patients

►In addition to clinical outcomes, bleeding is In addition to clinical outcomes, bleeding is associated with increased cost of careassociated with increased cost of care

Conclusions — Bleeding in ACS Conclusions — Bleeding in ACS

►Coordination of care through cooperation Coordination of care through cooperation between ED and IC Treatment (EDICT for ACS) between ED and IC Treatment (EDICT for ACS) is essential to navigate the new landscapeis essential to navigate the new landscape

►ACC/AHA guidelines ACC/AHA guidelines now recognize the value now recognize the value of bleeding reduction in ACS careof bleeding reduction in ACS care

► Bivalirudin is a Class I (Bivalirudin is a Class I (Level of evidence: Level of evidence: B)B) recommended antithrombin agent for recommended antithrombin agent for NSTE ACS patients undergoing an invasive NSTE ACS patients undergoing an invasive strategystrategy

► ACUITY demonstrates that bivalirudin ACUITY demonstrates that bivalirudin provides protection from ischemic events provides protection from ischemic events while reducing bleeding riskwhile reducing bleeding risk

►Coordination of care through cooperation Coordination of care through cooperation between ED and IC Treatment (EDICT for ACS) between ED and IC Treatment (EDICT for ACS) is essential to navigate the new landscapeis essential to navigate the new landscape

►ACC/AHA guidelines ACC/AHA guidelines now recognize the value now recognize the value of bleeding reduction in ACS careof bleeding reduction in ACS care

► Bivalirudin is a Class I (Bivalirudin is a Class I (Level of evidence: Level of evidence: B)B) recommended antithrombin agent for recommended antithrombin agent for NSTE ACS patients undergoing an invasive NSTE ACS patients undergoing an invasive strategystrategy

► ACUITY demonstrates that bivalirudin ACUITY demonstrates that bivalirudin provides protection from ischemic events provides protection from ischemic events while reducing bleeding riskwhile reducing bleeding risk

UPSTREAM ACS CAREUPSTREAM ACS CARECollaborations, Models, and ProtocolsCollaborations, Models, and Protocols

UPSTREAM ACS CAREUPSTREAM ACS CARECollaborations, Models, and ProtocolsCollaborations, Models, and Protocols

The Mandate to Cooperate The Mandate to Cooperate and Collaborateand Collaborate

The Mandate to Cooperate The Mandate to Cooperate and Collaborateand Collaborate

EDED

EmergencyEmergencyDepartmentDepartment

ICIC

InterventionalInterventionalCardiologyCardiology

++TT

TherapeuticTherapeuticTeamsTeams

++ ACSACSforfor

PCI

PCI

77

Fond

apar

inux

Fond

apar

inux

66

Biv

aliru

din

Biv

aliru

din 55

Enox

apar

in

+ G

PI

Enox

apar

in

+ G

PI

44

UFH + GPI

UFH + GPI

33

Clopidogrel

Clopidogrel

22A

SAASA

11

ASAASA PCIPCI

Bleeding risk factors

CABG likely or planned

► Bleeding risk factors

► Renal dysfunction

PCI

Year 2007 ACC-AHA NSTEMI GuidelinesYear 2007 ACC-AHA NSTEMI GuidelinesSeven Streams of Success Early Invasive TherapySeven Streams of Success Early Invasive Therapy

Year 2007 ACC-AHA NSTEMI GuidelinesYear 2007 ACC-AHA NSTEMI GuidelinesSeven Streams of Success Early Invasive TherapySeven Streams of Success Early Invasive Therapy

+ Clopidogrel+ Clopidogrel

No clopidogrelpretreatment

Aspirinallergy









Biv

aliru

din

PCI

PCIClopidogrel+ ASA+

UFH/EnoxaparinBivalirudin +

Clopidogrel/ASA

SwitchingSwitching




ACS (Acute Controversy Syndrome): ACS (Acute Controversy Syndrome): Cardiovascular Emergency Case Cardiovascular Emergency Case

Studies — Emergency Medicine and Studies — Emergency Medicine and Cardiovascular Specialists Engage Cardiovascular Specialists Engage

in the “Acute Collaboration in the “Acute Collaboration Syndrome”Syndrome”

From ACS Risk Profiles to Patient Care: Case Studies From ACS Risk Profiles to Patient Care: Case Studies in ACS—Doing the Right Thing in the Right Patient in ACS—Doing the Right Thing in the Right Patient

ACS (Acute Controversy Syndrome): ACS (Acute Controversy Syndrome): Cardiovascular Emergency Case Cardiovascular Emergency Case

Studies — Emergency Medicine and Studies — Emergency Medicine and Cardiovascular Specialists Engage Cardiovascular Specialists Engage

in the “Acute Collaboration in the “Acute Collaboration Syndrome”Syndrome”

From ACS Risk Profiles to Patient Care: Case Studies From ACS Risk Profiles to Patient Care: Case Studies in ACS—Doing the Right Thing in the Right Patient in ACS—Doing the Right Thing in the Right Patient

Getting in the Stream of ThingsGetting in the Stream of Things

Case Studies in Case Studies in Acute Coronary SyndromesAcute Coronary Syndromes

Case Studies in Case Studies in Acute Coronary SyndromesAcute Coronary Syndromes

Acknowledgement is made to Dr. Steven Manoukian, Acknowledgement is made to Dr. Steven Manoukian, MD and CMEducation Resources, LLC for patient cases MD and CMEducation Resources, LLC for patient cases

studies, cineangiograms, and/or assistance in studies, cineangiograms, and/or assistance in preparation of case studies for this segment of the preparation of case studies for this segment of the

program program

Acknowledgement is made to Dr. Steven Manoukian, Acknowledgement is made to Dr. Steven Manoukian, MD and CMEducation Resources, LLC for patient cases MD and CMEducation Resources, LLC for patient cases

studies, cineangiograms, and/or assistance in studies, cineangiograms, and/or assistance in preparation of case studies for this segment of the preparation of case studies for this segment of the

program program

Case #1: History and FindingsCase #1: History and Findings

► A 76 year-old white male with h/o stent to LAD 1 A 76 year-old white male with h/o stent to LAD 1 year agoyear ago

► Presents with multiple episodes of recurrent Presents with multiple episodes of recurrent chest pain including rest pain over 2 dayschest pain including rest pain over 2 days

► Pain similar to time of PCI in pastPain similar to time of PCI in past► Symptoms relieved in ED with sl NTGSymptoms relieved in ED with sl NTG► PMH: IDDM, HTN, CHOL elevationPMH: IDDM, HTN, CHOL elevation► PE: benign (weight 84 kg).PE: benign (weight 84 kg).► Labs: Labs: Hgb 10.7Hgb 10.7, , Cr 1.9,Cr 1.9, CK 173/2, Tr <0.03. CK 173/2, Tr <0.03.► ECG (next slide)ECG (next slide)

► A 76 year-old white male with h/o stent to LAD 1 A 76 year-old white male with h/o stent to LAD 1 year agoyear ago

► Presents with multiple episodes of recurrent Presents with multiple episodes of recurrent chest pain including rest pain over 2 dayschest pain including rest pain over 2 days

► Pain similar to time of PCI in pastPain similar to time of PCI in past► Symptoms relieved in ED with sl NTGSymptoms relieved in ED with sl NTG► PMH: IDDM, HTN, CHOL elevationPMH: IDDM, HTN, CHOL elevation► PE: benign (weight 84 kg).PE: benign (weight 84 kg).► Labs: Labs: Hgb 10.7Hgb 10.7, , Cr 1.9,Cr 1.9, CK 173/2, Tr <0.03. CK 173/2, Tr <0.03.► ECG (next slide)ECG (next slide)

New anterior and lateral ST / T changes.

Case #1: ECGCase #1: ECG

Based on your clinical assessment, this patient’s risk of Based on your clinical assessment, this patient’s risk of short-term (30-Day) ischemic events is:short-term (30-Day) ischemic events is:

A.A. LowLow

B.B. ModerateModerate

C.C. HighHigh

D.D. Very highVery high

Case #1Case #1

Which of this patient’s baseline factors do you Which of this patient’s baseline factors do you consider most important for determining this patient’s consider most important for determining this patient’s

ischemic risk?ischemic risk?

A.A. Advanced age Advanced age

B.B. Anginal pattern Anginal pattern

C.C. ECG findings ECG findings

D.D. Biomarkers Biomarkers

*

Case #1Case #1

Based on your clinical assessment, this patient’s risk of Based on your clinical assessment, this patient’s risk of incurring a short-term (30-Day) hemorrhagic event related incurring a short-term (30-Day) hemorrhagic event related

to PCI is:to PCI is:

A.A. LowLow

B.B. ModerateModerate

C.C. HighHigh

D.D. Very highVery high

Case #1Case #1

Which of this patient’s baseline factors do you consider Which of this patient’s baseline factors do you consider most important for determining hemorrhagic risk?most important for determining hemorrhagic risk?


B.B. Hypertension Hypertension

C.C. Impaired creatinine clearance Impaired creatinine clearance

D.D. Anemia Anemia

*

Case #1Case #1

In ACS patients, do you alter your choice of In ACS patients, do you alter your choice of anticoagulant/ antithrombotic therapy based upon an anticoagulant/ antithrombotic therapy based upon an

assessment of the individual patient’s risk of assessment of the individual patient’s risk of hemorrhagic complications?hemorrhagic complications?

A.A. Yes Yes

B.B. No No

*

Case #1Case #1

Among those of you who Among those of you who wouldwould alter or customize alter or customize antithrombotic therapy based on an ACS patient’s risk antithrombotic therapy based on an ACS patient’s risk

for hemorrhage in the setting of PCI, which of the for hemorrhage in the setting of PCI, which of the following baseline characteristics would you consider following baseline characteristics would you consider

most important in supporting the use of a “hemorrhage-most important in supporting the use of a “hemorrhage-minimizing” anithrombotic regimen:minimizing” anithrombotic regimen:

A.A. Elderly and femaleElderly and female

B.B. Renal insufficiency and positive Renal insufficiency and positive biomarkersbiomarkers

C.C. Anemia and high risk ischemic featuresAnemia and high risk ischemic features

*

Case #1Case #1

What would you likely use for anticoagulation in this What would you likely use for anticoagulation in this patient, prior to catheterization, if you anticipated patient, prior to catheterization, if you anticipated catheterization would occur in catheterization would occur in 4 hours or less?4 hours or less?

A.A. Unfractionated heparin alone Unfractionated heparin alone

B.B. Enoxaparin alone Enoxaparin alone

C.C. Bivalirudin alone Bivalirudin alone

D.D. A heparin with a GP IIb/IIIa inhibitor A heparin with a GP IIb/IIIa inhibitor

E.E. FondaparinuxFondaparinux

*

Case #1Case #1

What would your choice of upstream anticoagulation What would your choice of upstream anticoagulation therapy be, if you anticipated cardiac catheterization therapy be, if you anticipated cardiac catheterization the the

same day (within 12 hours)?same day (within 12 hours)?






*

Case #1Case #1

What would your choice of upstream anticoagulation What would your choice of upstream anticoagulation therapy be, if you anticipated cardiac catheterization therapy be, if you anticipated cardiac catheterization the the

next day (within 24 hours)?next day (within 24 hours)?






*

Case #1Case #1

At this point, your anticoagulation regimen for PCI in At this point, your anticoagulation regimen for PCI in this patient would be?this patient would be?

A.A. Additional heparin Additional heparin

B.B. Switch to enoxaparin Switch to enoxaparin

C.C. Switch to bivalirudin Switch to bivalirudin

D.D. Additional heparin plus GP IIb/IIIa inhibitor Additional heparin plus GP IIb/IIIa inhibitor

*

Case #1Case #1

Case #2: HistoryCase #2: History

► 77 year-old white female without prior cardiac 77 year-old white female without prior cardiac historyhistory

► Multiple short episodes of chest pain todayMultiple short episodes of chest pain today

► Unrelieved with NTG sl and IV; metoprolol IVUnrelieved with NTG sl and IV; metoprolol IV

► PMH: DM, HTN, CHOLPMH: DM, HTN, CHOL

► PE: benign (weight 65 kg).PE: benign (weight 65 kg).

► Labs: Hgb 11.7, Cr 1.1, CK 285/9, Labs: Hgb 11.7, Cr 1.1, CK 285/9, Tr 2.7Tr 2.7

► ECGECG

New inferior changes New lateral changes


Based upon this patient’s overall profile, when selecting Based upon this patient’s overall profile, when selecting an antithrombotic regimen, you are more likely be an antithrombotic regimen, you are more likely be

concerned about:concerned about:

A.A. Ischemic risk Ischemic risk

B.B. Hemorrhagic risk Hemorrhagic risk

*

Case #2Case #2

Which of the following factors would you consider most Which of the following factors would you consider most important when evaluating the need for immediate important when evaluating the need for immediate

catheterization in this patient?catheterization in this patient?


B.B. Positive biomarkers Positive biomarkers

C.C. ECG findings ECG findings

D.D. Refractory discomfort Refractory discomfort

*

Case #2Case #2

Would a plan of immediate versus delayed Would a plan of immediate versus delayed catheterization influence your choice of anticoagulation catheterization influence your choice of anticoagulation

therapy?therapy?

A.A. YesYes

B.B. NoNo

*

Case #2Case #2

If this patient was going for immediate catheterization If this patient was going for immediate catheterization (now), which of the following regimens would you start?(now), which of the following regimens would you start?






*

Case #2Case #2

If catheterization had to be delayed 2-4 hours If catheterization had to be delayed 2-4 hours (availability of lab, transfer, etc.), which of the following (availability of lab, transfer, etc.), which of the following

regimens would you start?regimens would you start?





E.E. Fondaparinux Fondaparinux

*

Case #2Case #2

Case #3: HistoryCase #3: History

► 82 year old white-female with history of MI, 82 year old white-female with history of MI, PTCA/LAD in 1997PTCA/LAD in 1997

► Presents with exertional chest pain as well as Presents with exertional chest pain as well as chest pressure at rest x 72 hours, but is now chest pressure at rest x 72 hours, but is now pain-free in EDpain-free in ED

► PMH: IRDM, HTN, CHOLPMH: IRDM, HTN, CHOL

► PE: 2/6 murmur at apex (weight 58 kg)PE: 2/6 murmur at apex (weight 58 kg)

► Labs: Hgb 11.1, Labs: Hgb 11.1, Cr 1.6Cr 1.6, CK 37/1, , CK 37/1, Tr <0.03Tr <0.03

► ECG.ECG.


No notable findings compared to old ECG.

What would you use for upstream anticoagulation in this What would you use for upstream anticoagulation in this patient whose catheterization is planned for the next patient whose catheterization is planned for the next

day: i.e., within 24 hours?day: i.e., within 24 hours?






*

Case #3Case #3

In general, in an ACS patient with moderate or high risk In general, in an ACS patient with moderate or high risk ischemic features, at what point in the patient’s course would ischemic features, at what point in the patient’s course would

you administer clopidogrel?you administer clopidogrel?

A.A. In the ED, immediately. In the ED, immediately.

B.B. In the catheterization lab, prior to In the catheterization lab, prior to catheterization.catheterization.

C.C. In the catheterization lab, after In the catheterization lab, after catheterization and decision to proceed catheterization and decision to proceed with PCI, but prior to PCI.with PCI, but prior to PCI.

D.D. In the catheterization lab, post-PCI. In the catheterization lab, post-PCI.

*

Concluding QuestionsConcluding Questions

In general, based on my interpretation of the current In general, based on my interpretation of the current evidence for selecting anticoagulation therapy in ACS evidence for selecting anticoagulation therapy in ACS

patients, therapy is best guided by:patients, therapy is best guided by:

A.A. Ischemic risk (reduction of ischemic Ischemic risk (reduction of ischemic endpoints) endpoints)

B.B. Bleeding risk (reduction of bleeding Bleeding risk (reduction of bleeding endpoints)endpoints)

C.C. Balance of ischemic and bleeding risk, and Balance of ischemic and bleeding risk, and selection of a strategy that optimizes “net selection of a strategy that optimizes “net clinical benefit” (optimizes aggregate clinical benefit” (optimizes aggregate reduction of both ischemic and bleeding reduction of both ischemic and bleeding endpoints)endpoints)*

Concluding QuestionsConcluding Questions

1) How do ED specialists incorporate new streams of 1) How do ED specialists incorporate new streams of care for NSTEMI introduced by Year 2007 ACC/AHA care for NSTEMI introduced by Year 2007 ACC/AHA Guidelines for NSTEMI - Bivaliridion for initial invasive Guidelines for NSTEMI - Bivaliridion for initial invasive strategy? Fondaprinux for initial conservative therapy?strategy? Fondaprinux for initial conservative therapy?

2) How do new guidelines affect clopidogrel treatment at 2) How do new guidelines affect clopidogrel treatment at front lines of ED care?front lines of ED care?

3) How do ED specialists and cardiologists synchronize 3) How do ED specialists and cardiologists synchronize on new GLs and newly introduced options?on new GLs and newly introduced options?

4) Questions4) Questions

*

Discussion PointsDiscussion Points

Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Program Chairman Chairman, Department of Emergency...

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