welcome to the edict for acs cardiovascular forum

Welcome to the EDICT for ACS Cardiovascular Forum

Critical Challenges Critical Challenges in in CardiovascularCardiovascular MedicineMedicine

Advancing Management of Acute Coronary Syndromes(ACS)—Advancing Management of Acute Coronary Syndromes(ACS)—Establishing Interventional Cardiology & Emergency Medicine Establishing Interventional Cardiology & Emergency Medicine

Therapeutic Teams Therapeutic Teams

Linking Science and Landmark Studies to the Front Lines of Cardiology PracticeLinking Science and Landmark Studies to the Front Lines of Cardiology Practice

Critical Challenges Critical Challenges in in CardiovascularCardiovascular MedicineMedicine

Advancing Management of Acute Coronary Syndromes(ACS)—Advancing Management of Acute Coronary Syndromes(ACS)—Establishing Interventional Cardiology & Emergency Medicine Establishing Interventional Cardiology & Emergency Medicine

Therapeutic Teams Therapeutic Teams

Linking Science and Landmark Studies to the Front Lines of Cardiology PracticeLinking Science and Landmark Studies to the Front Lines of Cardiology Practice

Steven V. Manoukian, MD, FACCSteven V. Manoukian, MD, FACCDirector, Interventional CardiologyDirector, Interventional Cardiology

Emory-Crawford Long HospitalEmory-Crawford Long HospitalEmory University School of MedicineEmory University School of Medicine

President, American Heart Association, Atlanta Div.President, American Heart Association, Atlanta Div.Atlanta, GAAtlanta, GA




EDICT for ACS Mission Statement:

Bringing together interventional cardiologists and emergency medicine specialists to manage patients collaboratively and seamlessly in order to improve

clinical outcomes in ACS

CME-accredited symposium jointly sponsored by University of CME-accredited symposium jointly sponsored by University of Massachusetts Medical Center, office of CME and CMEducation Massachusetts Medical Center, office of CME and CMEducation Resources, LLCResources, 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, clinical relevance, on-label Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and indications for agents discussed, and emerging evidence and information from recent studiesinformation from recent studies

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

Welcome Welcome

Educational ObjectivesEducational Objectives

► As a result of this session, cardiologists and emergency As a result of this session, cardiologists and emergency physicians will be able to assess and implement optimal physicians will be able to assess and implement optimal antithrombotic strategies for patients with acute coronary antithrombotic strategies for patients with acute coronary syndromes (ACS).syndromes (ACS).

► As a result of this session, attendees will understand impact As a result of this session, attendees will understand impact of specific pharmacologic agents on outcomes, including of specific pharmacologic agents on outcomes, including ischemic endpoints, bleeding, and mortality for patients with ischemic endpoints, bleeding, and mortality for patients with ACS.ACS.

► As a result of this session, attendees are able to discuss the As a result of this session, attendees are able to discuss the impact that new trials are likely to have on future impact that new trials are likely to have on future management of patients with ACS.management of patients with ACS.

► As a result of this session, ED physicians and cardiologists As a result of this session, ED physicians and cardiologists will learn to apply AHA/ACC, ACCP, and other national will learn to apply AHA/ACC, ACCP, and other national guidelines in order to optimize therapy ACS guidelines in order to optimize therapy ACS

► As a result of this session, cardiologists and emergency As a result of this session, cardiologists and emergency physicians will be able to assess and implement optimal physicians will be able to assess and implement optimal antithrombotic strategies for patients with acute coronary antithrombotic strategies for patients with acute coronary syndromes (ACS).syndromes (ACS).

► As a result of this session, attendees will understand impact As a result of this session, attendees will understand impact of specific pharmacologic agents on outcomes, including of specific pharmacologic agents on outcomes, including ischemic endpoints, bleeding, and mortality for patients with ischemic endpoints, bleeding, and mortality for patients with ACS.ACS.

► As a result of this session, attendees are able to discuss the As a result of this session, attendees are able to discuss the impact that new trials are likely to have on future impact that new trials are likely to have on future management of patients with ACS.management of patients with ACS.

► As a result of this session, ED physicians and cardiologists As a result of this session, ED physicians and cardiologists will learn to apply AHA/ACC, ACCP, and other national will learn to apply AHA/ACC, ACCP, and other national guidelines in order to optimize therapy ACS guidelines in order to optimize therapy ACS

Program FacultyProgram Faculty

Steven V. Manoukian, MD, FACCSteven V. Manoukian, MD, FACCDirector, Interventional CardiologyDirector, Interventional CardiologyEmory-Crawford Long HospitalEmory-Crawford Long HospitalEmory University School of MedicineEmory University School of MedicinePresident, American Heart Association, Atlanta Div.President, American Heart Association, Atlanta Div.Atlanta, GAAtlanta, GA

Sunil V. Rao MDSunil V. Rao MDAssistant Professor of MedicineAssistant Professor of MedicineDuke University Medical CenterDuke University Medical CenterDurham VA Medical CenterDurham VA Medical CenterDuke Clinical Research InstituteDuke Clinical Research Institute

James Hoekstra, MDJames Hoekstra, MDProfessor and ChairmanProfessor and ChairmanDepartment of Emergency MedicineDepartment of Emergency MedicineWake Forest University Health CenterWake Forest University Health CenterWinston-Salem, NCWinston-Salem, NC

Steven V. Manoukian, MD, FACCSteven V. Manoukian, MD, FACCDirector, Interventional CardiologyDirector, Interventional CardiologyEmory-Crawford Long HospitalEmory-Crawford Long HospitalEmory University School of MedicineEmory University School of MedicinePresident, American Heart Association, Atlanta Div.President, American Heart Association, Atlanta Div.Atlanta, GAAtlanta, GA

Sunil V. Rao MDSunil V. Rao MDAssistant Professor of MedicineAssistant Professor of MedicineDuke University Medical CenterDuke University Medical CenterDurham VA Medical CenterDurham VA Medical CenterDuke Clinical Research InstituteDuke Clinical Research Institute

James Hoekstra, MDJames Hoekstra, MDProfessor and ChairmanProfessor and ChairmanDepartment of Emergency MedicineDepartment of Emergency MedicineWake Forest University Health CenterWake Forest University Health CenterWinston-Salem, NCWinston-Salem, NC

Financial DisclosuresFinancial Disclosures

Steven V. Manoukian, MD, FACCSteven V. Manoukian, MD, FACCGrant/Research Support: The Medicines CompanyGrant/Research Support: The Medicines CompanySpeaker’s Bureau: The Medicines CompanySpeaker’s Bureau: The Medicines Company

Sunil V. Rao, MDSunil V. Rao, MDConsultant: sanofi-aventis, The Medicines Company, Pfizer, Cordis Consultant: sanofi-aventis, The Medicines Company, Pfizer, Cordis Research funding: Agency for Healthcare Research & Quality, National Research funding: Agency for Healthcare Research & Quality, National Institute for Aging, American College of Cardiology Institute for Aging, American College of Cardiology

James Hoekstra, MDJames Hoekstra, MDGrant/Research Support: Schering-Plough, BiositeGrant/Research Support: Schering-Plough, BiositeConsultant: Schering-Plough, The Medicines Co., sanofi-aventisConsultant: Schering-Plough, The Medicines Co., sanofi-aventisSpeaker’s Bureau: Schering-Plough, BMS, sanofi-aventisSpeaker’s Bureau: Schering-Plough, BMS, sanofi-aventis

Steven V. Manoukian, MD, FACCSteven V. Manoukian, MD, FACCGrant/Research Support: The Medicines CompanyGrant/Research Support: The Medicines CompanySpeaker’s Bureau: The Medicines CompanySpeaker’s Bureau: The Medicines Company

Sunil V. Rao, MDSunil V. Rao, MDConsultant: sanofi-aventis, The Medicines Company, Pfizer, Cordis Consultant: sanofi-aventis, The Medicines Company, Pfizer, Cordis Research funding: Agency for Healthcare Research & Quality, National Research funding: Agency for Healthcare Research & Quality, National Institute for Aging, American College of Cardiology Institute for Aging, American College of Cardiology

James Hoekstra, MDJames Hoekstra, MDGrant/Research Support: Schering-Plough, BiositeGrant/Research Support: Schering-Plough, BiositeConsultant: Schering-Plough, The Medicines Co., sanofi-aventisConsultant: Schering-Plough, The Medicines Co., sanofi-aventisSpeaker’s Bureau: Schering-Plough, BMS, sanofi-aventisSpeaker’s Bureau: Schering-Plough, BMS, sanofi-aventis

NOTENOTE

There will be off-label discussions—indications and There will be off-label discussions—indications and dosing—during this CME symposium, and speakers dosing—during this CME symposium, and speakers will note such off-label information. This information will note such off-label information. This information

does not imply or constitute endorsement of such does not imply or constitute endorsement of such strategies, which must be evaluated on the basis of strategies, which must be evaluated on the basis of

evidence and expert analysis.evidence and expert analysis.

Off-Label Discussion and InformationOff-Label Discussion and Information

EDICT for ACS CD-ROMEDICT for ACS CD-ROM

Comprehensive Comprehensive Cardiovascular CD-ROM Cardiovascular CD-ROM Resource includes:Resource includes:

CME-certified National Experts’ CME-certified National Experts’ SlideCASTs on ACS Clinical SlideCASTs on ACS Clinical Trials and BleedingTrials and Bleeding

EDICT for ACS CME Program EDICT for ACS CME Program SlideCASTSlideCAST

Direct links to CME-certified Direct links to CME-certified WebCASTs in cardiovascular WebCASTs in cardiovascular medicinemedicine

Direct links to CME-certified ACS-Direct links to CME-certified ACS-WRAP and PCI-WRAPWRAP and PCI-WRAP

Landmark trials and guidelines in Landmark trials and guidelines in ACSACS

EDICT for ACS on the WebEDICT for ACS on the Web

Updated Information about ACS Updated Information about ACS Management, Guidelines, and Trials Management, Guidelines, and Trials will be available on:will be available on:

EDICTforACS.comEDICTforACS.com

ClinicalWebcasts.comClinicalWebcasts.com

MedicineCAST.netMedicineCAST.net

CardioCAST.netCardioCAST.net

Updated Information about ACS Updated Information about ACS Management, Guidelines, and Trials Management, Guidelines, and Trials will be available on:will be available on:

EDICTforACS.comEDICTforACS.com

ClinicalWebcasts.comClinicalWebcasts.com

MedicineCAST.netMedicineCAST.net

CardioCAST.netCardioCAST.net

We Request That You…We Request That You…

► Please fill out your Please fill out your question question and answerand answer cards as program cards as program proceeds so we can collect proceeds so we can collect them and discuss during the them and discuss during the Q&A sessionQ&A session

Please fill out the Please fill out the Course Course Survey and EvaluationSurvey and Evaluation forms forms to obtain CME credit, and to obtain CME credit, and hand the form to the staff at hand the form to the staff at the desk outsidethe desk outside

Advancing Management of Acute Coronary Syndromes Advancing Management of Acute Coronary Syndromes Linking Science and Landmark Studies to the Front Lines Linking Science and Landmark Studies to the Front Lines

of Cardiology Practiceof Cardiology Practice

Advancing Management of Acute Coronary Syndromes Advancing Management of Acute Coronary Syndromes Linking Science and Landmark Studies to the Front Lines Linking Science and Landmark Studies to the Front Lines

of Cardiology Practiceof Cardiology Practice

Introduction to EDICT for ACS ForumIntroduction to EDICT for ACS ForumIntroduction to EDICT for ACS ForumIntroduction to EDICT for ACS Forum







Critical Challenges in Cardiovascular Critical Challenges in Cardiovascular Disease—Introduction Disease—Introduction

Fuster V et al. J Am Coll Cardiol 2005;46:937-954.

Co-Existent Stable and Acute LesionsCo-Existent Stable and Acute LesionsCo-Existent Stable and Acute LesionsCo-Existent Stable and Acute Lesions

Chronic Atherosclerosis Acute Thrombosis

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

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

Sites of Antithrombotic Drug ActionSites of Antithrombotic Drug Action

Tissue factorTissue factor

Plasma clottingcascade


ProthrombinProthrombin

ThrombinThrombin

FibrinogenFibrinogen FibrinFibrin

ThrombusThrombus

Platelet aggregationPlatelet aggregation

Platelet activationPlatelet activation

CollagenCollagen

Thromboxane A2Thromboxane A2

ADPADP

ATAT

ATAT

Aspirin

ClopidogrelPrasugrelCangrelor

EptifibatideAbciximabTirofiban

(GPI)BivalirudinHirudin

Argatroban

FactorXa

FactorXa

Heparin LMWHs

Fibrinolytics

FondaparinuxATAT

1992 1995 1998 2001 2004 2007

1997 1999

UFH

LMWH TIMI 11B

2004

SYNERGY

Bivalirudin

2003

REPLACE 2

ASA

IIb/IIIa antagonists

1995

2001

1998

EPISTENT

PURSUIT

2001

ESPRIT

GUSTO 42004

ISAR REACT

Clopidogrel CURE

2000

Anti-thrombotic agents

Anti-platelet agents

Evolving ACS Therapies and Patterns of Antithrombotic Use*

ACUITY

2006

ISAR-REACT 2

* Width of bar represents approximate degree of use of antiplatelet or anticoagulants at a particular time

Thank YouThank You

A Science-to-Strategy Analysis of BleedingIssues in Acute Coronary Syndromes

A Science-to-Strategy Analysis of BleedingIssues in Acute Coronary Syndromes

BLEEDING IN THE SETTING OFACUTE CORONARY SYNDROMES (ACS)

Clinical Implications and Effects on Mortality and Resource Utilization

BLEEDING IN THE SETTING OFACUTE CORONARY SYNDROMES (ACS)

Clinical Implications and Effects on Mortality and Resource Utilization

Sunil V. Rao MDAssistant Professor of MedicineDuke University Medical Center

Durham VA Medical CenterDuke Clinical Research Institute

Sunil V. Rao MDAssistant Professor of MedicineDuke University Medical Center

Durham VA Medical CenterDuke Clinical Research Institute

Ischemic Complications Ischemic

Complications

► Death

► MI

► Urgent TVR

► Death

► MI

► Urgent TVR

Evolving Paradigm for Evaluating ACS Evolving Paradigm for Evaluating ACS Management StrategiesManagement Strategies

Composite Adverse Event EndpointsComposite Adverse Event Endpoints

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




Periprocedural

Complications

Periprocedural

Complications

Clinical BenefitClinical Benefit

► Death

► Major Disability

► Death

► Major Disability

► Cost

► Ease of Use

► Duration of Therapy

► Accounting for Bleeding and Ischemic Endpoints

► Cost

► Ease of Use

► Duration of Therapy

► Accounting for Bleeding and Ischemic Endpoints




DeathDeath 4.3%4.3%

(Re)-Infarction(Re)-Infarction 2.5%2.5%

CHFCHF 8.0%8.0%

Cardiogenic ShockCardiogenic Shock 2.6%2.6%

StrokeStroke 0.8%0.8%

Non-CABG TransfusionNon-CABG Transfusion 9.9%9.9%

Bhatt DL, et al. Bhatt DL, et al. JAMAJAMA. 2004 Nov 3;292(17):2096-104. . 2004 Nov 3;292(17):2096-104.

CRUSADE In-Hospital OutcomesCRUSADE In-Hospital Outcomes

Bleeding in ACS - AgendaBleeding in ACS - Agenda

► Predictors of bleeding in ACSPredictors of bleeding in ACS

► Outcomes associated with bleedingOutcomes associated with bleeding Impact of definition on outcomesImpact of definition on outcomes

► Outcomes associated with blood Outcomes associated with blood transfusiontransfusion

► Special populations at riskSpecial populations at risk ElderlyElderly Chronic kidney diseaseChronic kidney disease AnemiaAnemia

► Cost implications of bleeding Cost implications of bleeding

What predicts bleeding among patients

with ACS ?

What predicts bleeding among patients

with ACS ?

Bleeding in ACS

Question to be answered:Question to be answered:

Independent Independent Predictors of Predictors of Major Bleeding Major Bleeding in Marker Positive in Marker Positive Acute Coronary Acute Coronary SyndromesSyndromes

Moscucci, GRACE Registry, Moscucci, GRACE Registry, Eur Heart JEur Heart J. 2003 Oct;24(20):1815-23. . 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-valueP-valueRR (95% CI)RR (95% CI)Risk ratio ± 95% CIRisk ratio ± 95% CIRisk ratio ± 95% CIRisk ratio ± 95% CI

Predictors of Major BleedingPredictors of Major Bleeding

Age Age >>75 (vs. 55-75)75 (vs. 55-75)

AnemiaAnemia

CrCl <60mL/minCrCl <60mL/min

DiabetesDiabetes

Female genderFemale gender

High-risk (ST / biomarkers)High-risk (ST / biomarkers)

HypertensionHypertension

No prior PCINo prior PCI

Prior antithrombotic therapyPrior antithrombotic therapy

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

1.56 (1.19-2.04)1.56 (1.19-2.04) 0.00090.0009

1.89 (1.48-2.41)1.89 (1.48-2.41) <0.0001<0.0001

1.68 (1.29-2.18)1.68 (1.29-2.18) <0.0001<0.0001

1.30 (1.03-1.63)1.30 (1.03-1.63) 0.02480.0248

2.08 (1.68-2.57)2.08 (1.68-2.57) <0.0001<0.0001

1.42 (1.06-1.90)1.42 (1.06-1.90) 0.01780.0178

1.33 (1.03-1.70)1.33 (1.03-1.70) 0.02870.0287

1.47 (1.15-1.88)1.47 (1.15-1.88) 0.00190.0019

1.23 (0.98-1.55)1.23 (0.98-1.55) 0.07680.0768

2.08 (1.56-2.76)2.08 (1.56-2.76) <0.0001<0.0001

Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

Results: The ACUITY Trial PCI PopulationResults: The ACUITY Trial PCI PopulationResults: The ACUITY Trial PCI PopulationResults: The ACUITY Trial PCI Population

0 1 2 3 4 5

P-valueP-valueRR (95% CI)RR (95% CI)

Age Age >>75 (vs. 55-75)75 (vs. 55-75)

AnemiaAnemia


DiabetesDiabetes




HeparinHeparin(s)(s) + GPI + GPI (vs. Bivalirudin)(vs. Bivalirudin)

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% CIRisk ratio ± 95% CIRisk ratio ± 95% CIRisk ratio ± 95% CI


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

REPLACE-2REPLACE-2Multivariate Predictors of Major BleedingMultivariate Predictors of Major Bleeding

RISK FACTORSRISK FACTORS Odds RatioOdds Ratio 95% CI95% CI p-valuep-value

Baseline risk factorsBaseline risk factors

Age Age >> 75 75 1.4821.482 1.009 to 2.1761.009 to 2.176 0.0450.045

Gender (M vs. F)Gender (M vs. F) 0.6520.652 0.477 to 0.8900.477 to 0.890 0.00720.0072

Prior AnginaPrior Angina 1.5891.589 1.077 to 2.3451.077 to 2.345 0.01970.0197

Creatinine clearance* Creatinine clearance* 0.9930.993 0.987 to 0.9980.987 to 0.998 0.00610.0061

AnemiaAnemia 1.4031.403 1.015 to 1.9391.015 to 1.939 0.04010.0401

Peri-procedural risk factorsPeri-procedural risk factors

Treatment Group (BIV vs. H+GPI)Treatment Group (BIV vs. H+GPI) 0.5080.508 0.352 to 0.7330.352 to 0.733 0.00030.0003

Provisional GPI receivedProvisional GPI received 2.6792.679 1.591 to 4.5121.591 to 4.512 0.00020.0002

Procedure Duration >1hProcedure Duration >1h 2.0492.049 1.217 to 3.4491.217 to 3.449 0.00690.0069

Time to Sheath Removal >6hTime to Sheath Removal >6h 1.6141.614 1.064 to 2.4481.064 to 2.448 0.02440.0244

ICU stay (days)†ICU stay (days)† 1.251.25 1.183 to 1.3211.183 to 1.321 <0.0001<0.0001

IABPIABP 8.7058.705 3.433 to 22.0723.433 to 22.072 <0.0001<0.0001Feit F et al. Unpublished (in manuscript)

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

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

► Procedural characteristics such as procedure duration and sheath dwell time also predict bleeding complications

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

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

► Procedural characteristics such as procedure duration and sheath dwell time also predict bleeding complications

Bleeding Predictors—Conclusions

Does bleeding influence the prognosis

of ACS patients ?

Does bleeding influence the prognosis

of ACS patients ?

Bleeding in ACS


Moscucci M et al. Moscucci M et al. Eur Heart JEur Heart J 2003;24:1815-23. 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 Predicts Mortality in ACSMajor Bleeding Predicts Mortality in ACSMajor Bleeding Predicts Mortality in ACSMajor Bleeding Predicts Mortality 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 & OutcomesBleeding & Outcomes

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

9.3%

3.0%

17.1%

5.4%

24.2%

5.5%7.8%

0.8%

IschemicComposite

Death MI (all) UnplannedRevasc

30 day events (%)

Major Bleeding (N=462, 5.9%) No Major Bleeding (N=7327, 94.1%)

Major Bleeding, Ischemic Endpoints, Major Bleeding, Ischemic Endpoints, and Mortalityand Mortality

9.3%

3.0%

17.1%

5.4%

24.2%

5.5%7.8%

0.8%

IschemicComposite


30 day events (%)


P<0.0001 for all


Results: The ACUITY Trial PCI Population (N=7,789)Results: The ACUITY Trial PCI Population (N=7,789)Results: The ACUITY Trial PCI Population (N=7,789)Results: The ACUITY Trial PCI Population (N=7,789)

4.8%

12.6%

17.1%

0.8%

5.5% 4.8%

MI (all) Non-Q MI Q-MI

30 day events (%)


Major Bleeding and Myocardial InfarctionMajor Bleeding and Myocardial Infarction

4.8%

12.6%

17.1%

0.8%

5.5% 4.8%


30 day events (%)


P<0.0001 for all


Results: The ACUITY Trial PCI Population (N=7,789)Results: The ACUITY Trial PCI Population (N=7,789)Results: The ACUITY Trial PCI Population (N=7,789)Results: The ACUITY Trial PCI Population (N=7,789)

Major and Minor Bleeding in PCIMajor and Minor Bleeding in PCIBleeding Increases Mortality and EventsBleeding Increases Mortality and Events

Kinnaird TD et al. AM J Cardiol 2003;92:930-5.

10,974 patients undergoing PCI, Washington Hospital Center, 1991-2000.

In-Hospital Clinical EventsIn-Hospital Clinical Events

MajorMajor(n=588)(n=588)

MinorMinor(n=1,394)(n=1,394)

NoneNone(n=8,992)(n=8,992)

DeathDeath 7.5%*7.5%*†† 1.8%*1.8%* 0.6%0.6%

Q-wave myocardial infarctionQ-wave myocardial infarction 1.2%*1.2%* 0.7%0.7%‡‡ 0.2%0.2%

Non-Q-wave myocardial infarctionNon-Q-wave myocardial infarction 30.7%*30.7%*†† 16.8%*16.8%* 11.8%11.8%

Repeat lesion angioplastyRepeat lesion angioplasty 1.9%*1.9%*§§ 0.8%0.8%‡‡ 0.3%0.3%

Major adverse cardiac eventMajor adverse cardiac event 6.6%*6.6%*†† 2.2%*2.2%* 0.6%0.6%

Bleeding ComplicationBleeding Complication

* p<0.001 versus none † p<0.001 versus minor ‡ p<0.01 versus none § p<0.05 versus minor

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

Mortality rates are higher among those who bleed

MI rates are higher among those who bleed

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

► This relationship is persistent after robust statistical adjustment for confounders

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

Mortality rates are higher among those who bleed

MI rates are higher among those who bleed

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

► This relationship is persistent after robust statistical adjustment for confounders

Bleeding and Outcomes—Conclusions

How does one assess bleeding

severity?

How does one assess bleeding

severity?

Bleeding in ACS


Bleeding Incidence in ACS Clinical TrialsBleeding Incidence in ACS Clinical Trials

0.4

10

1.2

4

1.5

3.7

9.1

0

2

4

6

8

10

12

GUSTO IIb OASIS-2 PRISM-PLUS PURSUIT PRISM CURE SYNERGY

%

Rao SV, et al. J Am Coll Cardiol. 2006 Feb 21;47(4):809-16. Epub 2006 Jan 26 Rao SV, et al. J Am Coll Cardiol. 2006 Feb 21;47(4):809-16. Epub 2006 Jan 26

Bleeding DefinitionsBleeding Definitions

► TIMI DefinitionTIMI Definition MajorMajor

• ICHICH• Associated with Hgb decrease ≥ 5 g/dl or Associated with Hgb decrease ≥ 5 g/dl or

HCT decrease ≥ 15%HCT decrease ≥ 15% MinorMinor

• Observed blood loss associated with Hgb Observed blood loss associated with Hgb decrease ≥ 3 g/dl or HCT decrease ≥ 10%decrease ≥ 3 g/dl or HCT decrease ≥ 10%

• No identifiable source but Hgb decrease No identifiable source but Hgb decrease ≥ 4 g/dl or HCT decrease ≥ 12%≥ 4 g/dl or HCT decrease ≥ 12%

MinimalMinimal• Overt hemorrhage with Hgb drop < 3 g/dl or Overt hemorrhage with Hgb drop < 3 g/dl or

HCT drop < 9%HCT drop < 9%

Chesebro JH. Chesebro JH. CirculationCirculation 1987. Jul;76(1):142-54. 1987. Jul;76(1):142-54. Chesebro JH. Chesebro JH. CirculationCirculation 1987. Jul;76(1):142-54. 1987. Jul;76(1):142-54.

N Engl J MedN Engl J Med. 1993 Nov 25;329(22):1615-22. Erratum in: . 1993 Nov 25;329(22):1615-22. Erratum in: N Engl J MedN Engl J Med 1994 Feb 17;330(7):516 1994 Feb 17;330(7):516 N Engl J MedN Engl J Med. 1993 Nov 25;329(22):1615-22. Erratum in: . 1993 Nov 25;329(22):1615-22. Erratum in: N Engl J MedN Engl J Med 1994 Feb 17;330(7):516 1994 Feb 17;330(7):516

Bleeding DefinitionsBleeding Definitions

► GUSTO DefinitionGUSTO Definition Severe or life threateningSevere or life threatening

• ICH or hemodynamic compromise ICH or hemodynamic compromise requiring treatmentrequiring treatment

ModerateModerate• Requiring transfusionRequiring transfusion

MildMild• Not meeting criteria for Severe or Not meeting criteria for Severe or

ModerateModerate

Bleeding Incidence Among 15,858 NSTEBleeding Incidence Among 15,858 NSTEACS Patients: Impact of DefinitionACS Patients: Impact of Definition

8.5 8.2

12.7

1.2

11.4

19.2

0

5

10

15

20

25

GUSTOMild

GUSTOMod

GUSTO Sev TIMI Mini TIMI Min TIMI Maj

%


Bleeding Scales Among Bleeding Scales Among NSTE ACS PatientsNSTE ACS Patients


TIMI and GUSTO – Adjusted Hazard of 30 d Death/MI N=15,858TIMI and GUSTO – Adjusted Hazard of 30 d Death/MI N=15,858TIMI and GUSTO – Adjusted Hazard of 30 d Death/MI N=15,858TIMI and GUSTO – Adjusted Hazard of 30 d Death/MI N=15,858

► Clearly defining bleeding severity can be difficult, but there are definitions that have been used in clinical trials and registries

► Not all of these definitions have been validated in terms of prognosis

► TIMI and GUSTO are 2 of the most commonly used definitions

► Bleeding definitions that include clinical events (e.g. GUSTO) are better at predicting outcomes

► Clearly defining bleeding severity can be difficult, but there are definitions that have been used in clinical trials and registries

► Not all of these definitions have been validated in terms of prognosis

► TIMI and GUSTO are 2 of the most commonly used definitions

► Bleeding definitions that include clinical events (e.g. GUSTO) are better at predicting outcomes

Bleeding Definitions—Conclusions

► Do blood transfusions have predictive

value?

► Do blood transfusions correct negative

impact of bleeding?

► Do blood transfusions have predictive

value?

► Do blood transfusions correct negative

impact of bleeding?

Bleeding in ACS

Questions to be answered:Questions to be answered:

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

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

Transfusion 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

PRBC Transfusion Among NSTE ACS Patients:PRBC Transfusion Among NSTE ACS Patients:Cox Model for 30-day DeathCox Model for 30-day Death

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

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

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

By Transfusion Status*By Transfusion Status*

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

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

9.4%

2.3%

18.8%

11.0%

29.2%

4.8%7.1%

1.3%

IschemicComposite


30 day events (%)

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

Transfusion, Ischemic Endpoints, and Transfusion, Ischemic Endpoints, and MortalityMortality

9.4%

2.3%

18.8%

11.0%

29.2%

4.8%7.1%

1.3%

IschemicComposite


30 day events (%)


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)

5.3%

13.8%

18.8%

0.9%

4.8% 3.8%


30 day events (%)


Transfusion and Myocardial InfarctionTransfusion and Myocardial Infarction

5.3%

13.8%

18.8%

0.9%

4.8% 3.8%


30 day events (%)


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

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.

► Although there has never been a randomized trial of blood transfusion in patients with ACS, the available observational data consistently supports a relationship between blood transfusion and increased adverse outcomes, including death, MI, and unplanned revascularization

► Blood transfusion is best avoided in ACS patients whenever possible

► Although there has never been a randomized trial of blood transfusion in patients with ACS, the available observational data consistently supports a relationship between blood transfusion and increased adverse outcomes, including death, MI, and unplanned revascularization

► Blood transfusion is best avoided in ACS patients whenever possible

Blood Transfusion—Conclusions

Are there certain ACS subpopulations

at especially high risk for bleeding,

transfusion, and morbidity/mortality?

Are there certain ACS subpopulations

at especially high risk for bleeding,

transfusion, and morbidity/mortality?

Bleeding in ACS


4.5

10.3

14.1

18.517.9

9.7

0

5

10

15

20

<65 yrs 65–75 yrs > 75 yrs

% RBC Transfusion

Non-CABG Overall

Bleeding Risks—Transfusions by AgeBleeding Risks—Transfusions by Age

Alexander KA, Alexander KA, JAMAJAMA 2005;294:3108–16. 2005;294:3108–16. Alexander KA, Alexander KA, JAMAJAMA 2005;294:3108–16. 2005;294:3108–16.

6,002 patients in REPLACE-26,002 patients in REPLACE-2806 patients (13.4%) classified as elderly, >75 years of age806 patients (13.4%) classified as elderly, >75 years of age

p<0.0001 p=0.0001

2.7%

1.7%

5.0%

6.7%

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

7.0%

8.0%

Major Bleeding Transfusions

REPLACE-2:REPLACE-2:Elderly Patients Have Increased Major Bleeding and Elderly Patients Have Increased Major Bleeding and

TransfusionsTransfusions

= Not Elderly, <75

= Elderly, >75

Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-613. Abstract.

0.5%0.4%

13.0%

15.0%

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

14.0%

16.0%

18.0%

Major Bleeding Transfusions

30-Day Mortality

No

Yes

p<0.0001 p=0.0001

6,002 patients in REPLACE-2.6,002 patients in REPLACE-2. 806 patients (13.4%) classified as elderly, >75 years of age.806 patients (13.4%) classified as elderly, >75 years of age.

Elderly Patients in REPLACE-2:Elderly Patients in REPLACE-2:Increased 30-Day Mortality With Major Bleeding and TransfusionsIncreased 30-Day Mortality With Major Bleeding and Transfusions

Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-613. Abstract.

Excessive Dosing ofExcessive Dosing ofAnticoagulants by AgeAnticoagulants by Age


12.5

28.7

8.5

33.137

12.5

64.5

38.5

16.5

0

10

20

30

40

50

60

70

LMW Heparin UF Heparin GP Iib/IIIa

% R

BC

Tra

nsf

usi

on

<65 yrs 65Š75 yrs >75 yrs

RBC Transfusions by Excess DosingRBC Transfusions by Excess Dosing

8

6.7

4.4

13.3

8.8

10.4

0

3

6

9

12

15

UF Heparin LMWH GP llb-llla

% RBC Transfusion

Recommended Excess


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

5

10

15

20

Both Right 1 Excessive Both Excessive

% RBC Transfusion


Excess Dosing of Gp IIb/IIIa Excess Dosing of Gp IIb/IIIa and Bleeding in Womenand Bleeding in Women

OverallOverallOverallOverall

WomenWomenWomenWomen

MenMenMenMen

1.46 (1.22, 1.73)1.46 (1.22, 1.73)1.46 (1.22, 1.73)1.46 (1.22, 1.73)

1.72 (1.30, 2.28)1.72 (1.30, 2.28)1.72 (1.30, 2.28)1.72 (1.30, 2.28)

1.27 (0.97, 1.66)1.27 (0.97, 1.66)1.27 (0.97, 1.66)1.27 (0.97, 1.66)

0.50.50.50.5 1.01.01.01.0 1.51.51.51.5 2.02.02.02.0 2.52.52.52.5

Excess Dosing More Likely to BleedExcess Dosing More Likely to BleedExcess Dosing More Likely to BleedExcess Dosing More Likely to Bleed

Alexander KP, et. al. Circulation 2006Alexander KP, et. al. Circulation 2006

N=32,601 patients from CRUSADEN=32,601 patients from CRUSADEN=32,601 patients from CRUSADEN=32,601 patients from CRUSADE

Bleeding is Increased in Patients With Bleeding is Increased in Patients With Impaired Renal Function Undergoing PCIImpaired Renal Function Undergoing PCI

≥≥ 60 ml/min60 ml/min N=4824 N=4824

< 60 ml/min< 60 ml/min N=886 N=886 p valuep value

30-d Death30-d Death 5 (0.1%)5 (0.1%) 14 (1.6%)14 (1.6%) < 0.001< 0.001

30-d Myocardial infarction30-d Myocardial infarction 305 (6.3%)305 (6.3%) 75 (8.5%)75 (8.5%) 0.0180.018

30-d urgent revascularization30-d urgent revascularization 61 (1.3%)61 (1.3%) 10 (1.1%)10 (1.1%) 0.7380.738

Triple ischemic endpointTriple ischemic endpoint 338 (7.0%)338 (7.0%) 84 (9.5%)84 (9.5%) 0.0100.010

In-hospital protocol major In-hospital protocol major bleedingbleeding 123 (2.5%)123 (2.5%) 54 (6.1%)54 (6.1%) < 0.001< 0.001

TIMI major + minor bleedingTIMI major + minor bleeding 114 (2.4%)114 (2.4%) 46 (5.2%)46 (5.2%) < 0.001< 0.001

Creatinine ClearanceCreatinine Clearance

Chew DP et al. Am J Cardiol 2005;95:581–585.

Anemia Identifies High-RiskAnemia Identifies High-RiskThe Unrecognized Risk FactorThe Unrecognized Risk Factor

► OlderOlder

► FemaleFemale

► Lower BMILower BMI

► Fewer CaucasiansFewer Caucasians

► Lower Hemoglobin (11.7 vs. 14.3 g/dL)Lower Hemoglobin (11.7 vs. 14.3 g/dL)

► Lower Hematocrit (34.6 vs. 41.8%)Lower Hematocrit (34.6 vs. 41.8%)

► Less Tobacco useLess Tobacco use

► More Diabetes MellitusMore Diabetes Mellitus

► More history of CHF, MI, PCI, CABGMore history of CHF, MI, PCI, CABG

REPLACE-2 Anemic Patient Baseline Characteristics:REPLACE-2 Anemic Patient Baseline Characteristics:(Anemia in 22.7%)(Anemia in 22.7%)

Voeltz MD, Attubato MJ, Feit F, Lincoff AM, Manoukian SV. J Am Coll Cardiol 2005;45(3)[Suppl A]:1037-Voeltz MD, Attubato MJ, Feit F, Lincoff AM, Manoukian SV. J Am Coll Cardiol 2005;45(3)[Suppl A]:1037-13-31A. Abstract.13-31A. Abstract.

Major Bleeding is IncreasedMajor Bleeding is Increasedin Anemic Patients Undergoing PCIin Anemic Patients Undergoing PCI

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

Non-Anemic Anemic

6,010 patients in REPLACE-2.1,362 patients (22.7%) classified as anemic based upon WHO definition.

Major bleeding = 3.2%

Major Bleeding

2.8%

4.9%

P=0.0001

Protocol definition: >3g/dL drop in HgB,

intracranial, retroperitoneal,

2U transfusion

Voeltz MD, Attubato MJ, Feit F, Lincoff AM, Manoukian SV. J Am Coll Cardiol 2005;45(3)[Suppl Voeltz MD, Attubato MJ, Feit F, Lincoff AM, Manoukian SV. J Am Coll Cardiol 2005;45(3)[Suppl A]:1037-13-31A. Abstract.A]:1037-13-31A. Abstract.

NSTE-ACS MortalityNSTE-ACS MortalityStratified by HemoglobinStratified by Hemoglobin

Sabatine MS. Circulation 2005

UnadjustedUnadjusted

Hb (g/dL)Hb (g/dL) nn OROR (95% Cl)(95% Cl) OROR (95% Cl)(95% Cl) P P valuevalue

>17>17 216 216 1.471.47 (1.03–2.10)(1.03–2.10) 1.451.45 (0.94–2.23)(0.94–2.23) 0.0930.093

16–1716–17 812 812 1.211.21 (0.97–1.51)(0.97–1.51) 1.271.27 (0.98–1.65)(0.98–1.65) 0.0660.066

15–1615–16 21302130 1.0 1.0 referencereference 1.0 1.0 referencereference

14–1514–15 33903390 1.061.06 (0.89–1.22)(0.89–1.22) 1.111.11 (0.93–1.33)(0.93–1.33) 0.2510.251

13–1413–14 35203520 1.021.02 (0.88–1.19)(0.88–1.19) 1.041.04 (0.86–1.24)(0.86–1.24) 0.7090.709

12–1312–13 23312331 1.091.09 (0.92–1.28)(0.92–1.28) 1.071.07 (0.88–1.30)(0.88–1.30) 0.5140.514

11–1211–12 976 976 1.201.20 (0.97–1.47)(0.97–1.47) 1.041.04 (0.81–1.34)(0.81–1.34) 0.7550.755

10–1110–11 343 343 1.411.41 (1.05–1.89)(1.05–1.89) 1.291.29 (0.92–1.82)(0.92–1.82) 0.1450.145

9–109–10 342 342 2.442.44 (1.88–3.18)(1.88–3.18) 2.692.69 (2.01–3.60)(2.01–3.60) <0.001<0.001

8–98–9 306 306 2.242.24 (1.69–2.96)(1.69–2.96) 2.452.45 (1.80–3.33)(1.80–3.33) <0.001<0.001

<8<8 137 137 3.973.97 (2.76–5.70)(2.76–5.70) 3.493.49 (2.35–5.20)(2.35–5.20) <0.001<0.001

Abbreviations: CI, confidence interval; Hb, hemoglobin; OR, odds ration. Adapted with permission.Abbreviations: CI, confidence interval; Hb, hemoglobin; OR, odds ration. Adapted with permission.

Unadjusted and adjusted odds ratios for cardiovascular mortality in patientsUnadjusted and adjusted odds ratios for cardiovascular mortality in patientswith non-ST elevation acute coronary syndromes at 30 days stratefied by hemoglobinwith non-ST elevation acute coronary syndromes at 30 days stratefied by hemoglobin

Adjusted for baseline characteristicsAdjusted for baseline characteristics

► Certain ACS patient populations are at especially high risk for bleeding and mortality

Elderly, females, CKD, anemia

► Improper dosing of anticoagulants is a common error and is associated with bleeding risk in the elderly, females, and those with CKD

► Anemia places patients at risk for both bleeding and mortality

► Certain ACS patient populations are at especially high risk for bleeding and mortality

Elderly, females, CKD, anemia

► Improper dosing of anticoagulants is a common error and is associated with bleeding risk in the elderly, females, and those with CKD

► Anemia places patients at risk for both bleeding and mortality

High-Risk Populations—Conclusions

Does bleeding influence the cost of

care for patients with ischemic heart

disease?

Does bleeding influence the cost of

care for patients with ischemic heart

disease?

Bleeding in ACS


8800

27349

1300

5900

0

10000

20000

30000

$$$

Urgent PCI UrgentCABG

Minor bleed Major bleed

Costs Abciximab versus Placebo

ischemic costs: $523

major bleed costs: $458

Abciximab versus Placebo

ischemic costs: $523

major bleed costs: $458

Mark DB, et al. Mark DB, et al. CirculationCirculation. 2000 Feb 1;101(4):366-71 . 2000 Feb 1;101(4):366-71 Mark DB, et al. Mark DB, et al. CirculationCirculation. 2000 Feb 1;101(4):366-71 . 2000 Feb 1;101(4):366-71

Calculating Costs of Ischemia and Bleeding:Calculating Costs of Ischemia and Bleeding:EPIC EQOL Study (Abciximab in PCI)EPIC EQOL Study (Abciximab in PCI)

► The available costs data confirms that a balance must be struck between ischemia reduction and bleeding.

► Both ischemic complications and bleeding are associated with increased costs.

► The available costs data confirms that a balance must be struck between ischemia reduction and bleeding.

► Both ischemic complications and bleeding are associated with increased costs.

Bleeding and Costs—Conclusions

Bleeding Among Patients with ACSBleeding Among Patients with ACSConclusionsConclusions

► Antithrombotic therapies are cornerstone RxAntithrombotic therapies are cornerstone Rx Must balance thrombosis and hemostasisMust balance thrombosis and hemostasis

► Certain patient and PCI procedure Certain patient and PCI procedure characteristics predict bleedingcharacteristics predict bleeding Age, female gender, CKD, procedure time, Age, female gender, CKD, procedure time,

sheath dwell timesheath dwell time

► Diabetes and anemia are newly identified risk Diabetes and anemia are newly identified risk factors for bleeding among ACS patientsfactors for bleeding among ACS patients

Conclusions—Bleeding Conclusions—Bleeding

►Bleeding is associated with worse short and Bleeding is associated with worse short and long-term outcomes including death and MIlong-term outcomes including death and MI

►Assessing bleeding severity is important Assessing bleeding severity is important

► Many definitions have been usedMany definitions have been used

► Definitions that include clinical events Definitions that include clinical events appear to be more useful than those that appear to be more useful than those that include only laboratory parametersinclude only laboratory parameters

►Blood transfusion is associated with increased Blood transfusion is associated with increased mortality in ACS patients mortality in ACS patients

►Bleeding is associated with worse short and Bleeding is associated with worse short and long-term outcomes including death and MIlong-term outcomes including death and MI

►Assessing bleeding severity is important Assessing bleeding severity is important

► Many definitions have been usedMany definitions have been used

► Definitions that include clinical events Definitions that include clinical events appear to be more useful than those that appear to be more useful than those that include only laboratory parametersinclude only laboratory parameters

►Blood transfusion is associated with increased Blood transfusion is associated with increased mortality in ACS patients mortality in ACS patients

Conclusions—Bleeding Conclusions—Bleeding

► 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

► Bleeding costs can offset the savings Bleeding costs can offset the savings realized by reduced ischemic realized by reduced ischemic complicationscomplications

►Given the body of evidence related to bleeding Given the body of evidence related to bleeding and transfusion, therapies that can reduce and transfusion, therapies that can reduce ischemia while minimizing the risk for bleeding ischemia while minimizing the risk for bleeding have the potential to further improve outcomes have the potential to further improve outcomes among patients with ACSamong patients with ACS

► 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

► Bleeding costs can offset the savings Bleeding costs can offset the savings realized by reduced ischemic realized by reduced ischemic complicationscomplications

►Given the body of evidence related to bleeding Given the body of evidence related to bleeding and transfusion, therapies that can reduce and transfusion, therapies that can reduce ischemia while minimizing the risk for bleeding ischemia while minimizing the risk for bleeding have the potential to further improve outcomes have the potential to further improve outcomes among patients with ACSamong patients with ACS

A Science-to-Strategy Analysis of Landmark Trialsin Acute Coronary Syndromes (ACS)

Applying New Data and Established Guidelinesto the Practice of Interventional Cardiology and

Emergency Medicine

A Science-to-Strategy Analysis of Landmark Trialsin Acute Coronary Syndromes (ACS)

Applying New Data and Established Guidelinesto the Practice of Interventional Cardiology and

Emergency Medicine

Critical Challenges in Cardiovascular Medicine

Critical Challenges in Cardiovascular Medicine

Steven V. Manoukian, MD, FACCDirector, Interventional Cardiology

Emory-Crawford Long HospitalEmory University School of Medicine

President, American Heart Association, Atlanta Div.Atlanta, GA

Steven V. Manoukian, MD, FACCDirector, Interventional Cardiology

Emory-Crawford Long HospitalEmory University School of Medicine

President, American Heart Association, Atlanta Div.Atlanta, GA

ACS Program AgendaACS Program Agenda

► Recent landmark clinical trials ICTUS ISAR-REACT 2 SYNERGY OASIS 5 ACUITY

– Antithrombotic strategy– Timing– PCI

Conclusions

► Conclusions about ACS management

► Frequent Questions

► Recent landmark clinical trials ICTUS ISAR-REACT 2 SYNERGY OASIS 5 ACUITY

– Antithrombotic strategy– Timing– PCI

Conclusions

► Conclusions about ACS management

► Frequent Questions

Actions of Thrombin on Blood Cells and Blood Vessels

Actions of Thrombin on Blood Cells and Blood Vessels

EndotheliumEndothelium

NeutrophilNeutrophil

PlateletPlatelet

MonocyteMonocyte

LymphocyteLymphocyte

SmoothMusclecell

ThrombinThrombinCytokinesGrowth factorsAutocoidsProteases

CytokinesGrowth factorsAutocoidsProteases

Shape andpermeabilitychanges

Shape andpermeabilitychanges

Coughlin SR, Nature 2000; 407: 258-264

• Serine protease generated at sites of vascular injury. • Potent platelet activator (PAR-protease activated receptor). • Elicits host of responses in vascular endothelium:

- Shape & permeability changes

- Mobilization of adhesive molecules to endothelial surface

- Stimulation of autocoid and cytokine production. • Chemotactic for monocytes. • Mitogenic for lymphocytes & mesenchymal cells.

Antithrombotic and AntiplateletTherapy in ACS

Antithrombotic and AntiplateletTherapy in ACS

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

ECG and Outcome in TACTICS/TIMI 18ECG and Outcome in TACTICS/TIMI 18

26.3

15.316.4

15.6

0

6

12

18

24

30

26.3

15.316.4

15.6

0

6

12

18

24

30

ST-segment s

( n = 852 )

ST-segment s

( n = 852 )

Death / MI / Rehospitalization at 6 Months

Cannon et al. N Engl J Med 2001; 344: 1879-87Cannon et al. N Engl J Med 2001; 344: 1879-87

No ST-segment s

( n = 1368 )

No ST-segment s

( n = 1368 )


InvasiveInvasive

Risk StratificationRisk Stratification

16.2

10.6

7.9

5.3

0

3

6

9

12

15

18

21

24

27

16.2

10.6

7.9

5.3

0

3

6

9

12

15

18

21

24

27

24.2

12.3

14.8

8.9

0

3

6

9

12

15

18

21

24

27

24.2

12.3

14.8

8.9

0

3

6

9

12

15

18

21

24

27

5.63.1

6

2.9

0

3

6

9

12

15

18

21

24

27

5.63.1

6

2.9

0

3

6

9

12

15

18

21

24

27

14.8

5.2

16.7

4.3

0

3

6

9

12

15

18

21

24

27

14.8

5.2

16.7

4.3

0

3

6

9

12

15

18

21

24

27

Death/MI/hospDeath/MI/hosp

Tn T > 0.01 ng/mlTn T > 0.01 ng/ml

Death/MI/hospDeath/MI/hosp Death/MIDeath/MI

Death/MI/hospDeath/MI/hosp Death/MIDeath/MIDeath/MI/hospDeath/MI/hosp Death/MIDeath/MI

Death/MIDeath/MI

Tn T > 0.01 ng/mlTn T > 0.01 ng/ml

Tn T < 0.01 ng/mlTn T < 0.01 ng/ml Tn T < 0.01 ng/mlTn T < 0.01 ng/ml

6 Months30 Days

Cannon et al. N Engl J Med 2001; 344: 1879-87Cannon et al. N Engl J Med 2001; 344: 1879-87


InvasiveInvasive

Troponin and Outcome in TACTICS/TIMI 18Troponin and Outcome in TACTICS/TIMI 18

Risk StratificationRisk Stratification

<0.001<0.001

0.0020.002

0.800.800.900.90

<0.001<0.001

0.0820.082

0.460.46

0.580.58

CRUSADE: In-Hospital OutcomesCRUSADE: In-Hospital Outcomes

Peterson, E.D. et al. JAMA 2006;295:1912-1920.

No. of Events (%) by Hospital Adherence QuartileNo. of Events (%) by Hospital Adherence Quartile

Population 1 (Lowest) 2 4 4 (Highest) P value

Overall (N = 64775) (n = 12329) (n = 15255) (n = 18364) (n = 18827)

Death 784 (6.36) 772 (5.06) 850 (4.63) 786 (4.17) <.001

Death/MI* 1119 (9.08) 1280 (8.39) 1223 (6.66) 1201 (6.38) <.001

Stroke 96 (0.78) 146 (0.96) 171 (0.93) 134 (0.71) .31

CHF 908 (7.36) 1747 (11.45) 1727 (9.40) 1541 (8.19) .24

NSTEMI (N = 57260) (n = 9892) (n = 12597) (n = 18149) (n = 16622)

Death 760 (7.68) 701 (5.56) 843 (4.64) 718 (4.32) <.001

Death/MI* 1055 (10.67) 1128 (8.95) 1206 (6.64) 1105 (6.65) <.001

Stroke 96 (0.80) 146 (0.98) 171 (0.94) 134 (0.72) .25

CHF 862 (8.71) 1368 (10.68) 1851 (10.20) 1424 (8.57) .13

*Indicates in-hospital death or recurrent MI.

Population 1 (Lowest) 2 4 4 (Highest) P value

Overall (N = 64775) (n = 12329) (n = 15255) (n = 18364) (n = 18827)

Death 784 (6.36) 772 (5.06) 850 (4.63) 786 (4.17) <.001

Death/MI* 1119 (9.08) 1280 (8.39) 1223 (6.66) 1201 (6.38) <.001

Stroke 96 (0.78) 146 (0.96) 171 (0.93) 134 (0.71) .31

CHF 908 (7.36) 1747 (11.45) 1727 (9.40) 1541 (8.19) .24

NSTEMI (N = 57260) (n = 9892) (n = 12597) (n = 18149) (n = 16622)

Death 760 (7.68) 701 (5.56) 843 (4.64) 718 (4.32) <.001

Death/MI* 1055 (10.67) 1128 (8.95) 1206 (6.64) 1105 (6.65) <.001

Stroke 96 (0.80) 146 (0.98) 171 (0.94) 134 (0.72) .25

CHF 862 (8.71) 1368 (10.68) 1851 (10.20) 1424 (8.57) .13

*Indicates in-hospital death or recurrent MI.

The Evolving World of ACS The Evolving World of ACS

Recent Landmark TrialsRecent Landmark Trials

► Science

► Recent Trials

► Clinical Strategies

► Science

► Recent Trials

► Clinical Strategies

Case for Invasive ManagementCase for Invasive Management

► FRISC II

► TACTICS

► FRISC II

► TACTICS

36018090300

Pro

bab

ility

of

dea

thP

rob

abili

ty o

f d

eath

.04

.03

.02

.01

0.00

Non-invasive (n=1235)Non-invasive (n=1235)

Invasive (n=1222)Invasive (n=1222)

Invasive Noninvasive RR (95 % CI) p2.2 % 4.0 % 0.56 (0.35 - 0.89) 0.018

FRISC II Mortality at One-Year Invasive versus Non-invasive Management Strategies

FRISC II Mortality at One-Year Invasive versus Non-invasive Management Strategies

Lancet. 1999; 354:701-7 Lancet. 1999; 354:701-7

0 1 2 3 4 5 6Time (months)Time (months)

0

4

8

12

16

20

% P

ati

ents

% P

ati

ents

CONS

INV

O.R 0.7895% CI (0.62, 0.97)

p=0.025

O.R 0.7895% CI (0.62, 0.97)

p=0.025

19.4%

15.9%

TACTICS Primary Endpoint: Death, MI, Rehosp for ACS at 6 Months

TACTICS Primary Endpoint: Death, MI, Rehosp for ACS at 6 Months

Cannon CP, Weintraub WS. N Engl J Med. 2001 Jun 21;344(25):1879-87. Cannon CP, Weintraub WS. N Engl J Med. 2001 Jun 21;344(25):1879-87.

Recent Clinical Trials Recent Clinical Trials

► ISAR REACT-2

► SYNERGY

► OASIS-5

► ACUITY

► ISAR REACT-2

► SYNERGY

► OASIS-5

► ACUITY

Is a GP IIb/IIIa receptor antagonist required in patients with ACS going to PCI, or is high dose clopidogrel sufficient?

Is a GP IIb/IIIa receptor antagonist required in patients with ACS going to PCI, or is high dose clopidogrel sufficient?

ISAR-REACT 2

Question to be answered: Question to be answered:

ISAR-REACT 2 Trial: Study DesignISAR-REACT 2 Trial: Study Design

Primary Endpoint: Composite of death, MI, and urgent target vessel revascularization (TVR) due to myocardial ischemia within 30 days

Secondary Endpoint: In-hospital major and minor bleeding

Primary Endpoint: Composite of death, MI, and urgent target vessel revascularization (TVR) due to myocardial ischemia within 30 days

Secondary Endpoint: In-hospital major and minor bleeding

2022 patients with an episode of angina within the preceding 48 hours Elevated troponin T or new ST-segment changes or presumed new BBB

Significant lesions in a native vessel or bypass graft undergoing PCI

2022 patients with an episode of angina within the preceding 48 hours Elevated troponin T or new ST-segment changes or presumed new BBB

Significant lesions in a native vessel or bypass graft undergoing PCI

Abciximabn=1012

Abciximabn=1012

Placebon=1010Placebon=1010

Pre-treatment with high dose (600mg) clopidogrel

at least 2 hours pre-procedure

Pre-treatment with high dose (600mg) clopidogrel

at least 2 hours pre-procedure

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

9%

12%

%

5%

10%

15%

Abciximab Placebo

Composite of death, MI, or urgent TVR due to Myocardial Ischemia within 30 days (%)


ISAR-REACT 2: Primary EndpointISAR-REACT 2: Primary Endpoint

p=0.03p=0.03

( n = 2022 )

1.1%

8.1%

1.0%1.6%

10.5%

1.2%

0%

5%

10%

15%

Death MI Urgent TVR

Abciximab

Placebo

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

ISAR-REACT 2 : Individual EndpointsISAR-REACT 2 : Individual Endpoints


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

4.6% 4.6%

%

5%

10%

15%

20%

Abciximab Placebo

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

Pri

mar

y E

ven

tsP

rim

ary

Ev

ents

p=0.98


13.1%

18.3%

%

5%

10%

15%

20%

Abciximab Placebo

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

(>0.03 µg/L, n=1049)

p=0.02

1.4%

4.2%

2.5%

1.4%

3.3%

2.0%

0%

1%

2%

3%

4%

5%

Major Bleeding Minor Bleeding Transfusion

Abciximab Placebo



ISAR-REACT 2 : BleedingISAR-REACT 2 : Bleeding


► Even with clopidogrel pretreatment, heparin therapy alone is inadequate to prevent ischemic events in high risk ACS patients undergoing PCI

► This effect was primarily present in troponin-positive patients

► Even with clopidogrel pretreatment, heparin therapy alone is inadequate to prevent ischemic events in high risk ACS patients undergoing PCI

► This effect was primarily present in troponin-positive patients

ISAR-REACT 2 Trial: Conclusions/Caveats

What is the role of enoxaparin in patients with non–ST segment elevation ACS at high risk for ischemic cardiac complications managed with an early invasive approach ?

What is the role of enoxaparin in patients with non–ST segment elevation ACS at high risk for ischemic cardiac complications managed with an early invasive approach ?

SYNERGY


Study Design

At least 2 of 3 required:

• Age 60

• ST (transient) or • (+) CK-MB or troponin

At least 2 of 3 required:

• Age 60

• ST (transient) or • (+) CK-MB or troponin

Primary endpoint: Death or MI at 30 daysPrimary endpoint: Death or MI at 30 days

High-riskACS Patients

Early invasive strategyOther therapy per ACC/AHA guidelines

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

Early invasive strategyOther therapy per ACC/AHA guidelines

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

Enoxaparin IV UFH

Randomize(n = 10,000)Randomize(n = 10,000)

60 U/kg 12 U/kg/h (aPTT 50 – 70 sec)

60 U/kg 12 U/kg/h (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

SYNERGY: Primary Results (30 Days)SYNERGY: Primary Results (30 Days)

Enoxaparin UFH Unadjusted(n = 4,993) (n = 4,985) P value

Death and MI 14.0% 14.5% 0.40

Death 3.2% 3.1% 0.71

MI 11.7% 12.7% 0.14

Enoxaparin UFH Unadjusted(n = 4,993) (n = 4,985) P value

Death and MI 14.0% 14.5% 0.40

Death 3.2% 3.1% 0.71

MI 11.7% 12.7% 0.14


0.8 1 1.2

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)

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

0 5 10 15 20 25 300.8

0.9

0.95

1.0

Free

dom

from

Dea

th /

MI

Days from Randomization

0.85EnoxaparinUFHEnoxaparinUFH


SYNERGY Bleeding EventsSYNERGY Bleeding Events

GUSTO severe 2.7% 2.2% 0.08

TIMI major (clinical): 9.1% 7.6% 0.008

CABG-related 6.8% 5.9% 0.08

Non-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

Enoxaparin UFH P value (n = 4,993) (n = 4,985)


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

► More bleeding was observed with enoxaparin

► Enoxaparin was an alternative to unfractionated heparin for non–ST-segment elevation ACS in high-risk patients being managed with a rapid transition to intervention

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

► More bleeding was observed with enoxaparin

► Enoxaparin was an alternative to unfractionated heparin for non–ST-segment elevation ACS in high-risk patients being managed with a rapid transition to intervention

SYNERGY: Conclusions/Caveats

Is fondaparinux an alternative to enoxaparin in higher-risk ACS patients?

Is fondaparinux an alternative to enoxaparin in higher-risk ACS patients?

OASIS-5


OASIS-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

practice200

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

practice200

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 and Safety at Day 9OASIS 5 Efficacy and Safety at Day 9


0.00

0.01

0.02

0.03

0.04

0.05

0.06

Hazard ratio 1.01 (95% CI, 0.90-

1.13)

Cu

mu

lati

ve

Ha

zard

Days

0.00

0.01

0.02

0.03

0.04

Cu

mu

lati

ve

Ha

zard

Days

Hazard ratio 0.52 (95% CI, 0.44-0.61)

BleedingBleedingDeath, MI, RIDeath, MI, RI

0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9

FondaparinuxEnoxaparin

Efficacy End Points at 6 MonthsEfficacy End Points at 6 Months

End point Enoxaparin Fondaparinux P value

Death/MI/ refractory ischemia

13.2% 12.3% 0.06

Death/MI 11.4% 10.5% 0.05

Death 6.5% 5.8% 0.05

MI 6.6% 6.3%

Stroke 1.7% 1.3% 0.04

Death/MI/stroke* 12.5% 11.3% 0.007


PCI—Procedural ComplicationsPCI—Procedural Complications

Events (30 Days)Enoxaparin

n=3089Fondaparinux

n=3118P value

Any UFH during PCI 53.8% 18.8%

Any procedural complication

8.6% 9.6% 0.18

Abrupt closure 1.1% 1.5% 0.20

Catheter thrombus 0.5% 1.3% 0.001

Vascular access 8.1% 3.3% <0.0001

Pseudo-aneurysm 1.6% 1.0% 0.39

Large hematoma 4.4% 1.6% <0.0001


► Among patients with NSTE-ACS, fondaparinux was non-inferior for primary composite endpoint of death, MI or refractory ischemia at day 9 compared with enoxaparin.

► There was a significant reduction in the safety endpoint of major bleeding at 9 days and the secondary endpoint of mortality at 30 days and 6 months.

► In the OASIS-5 trial, the relationship between bleeding and mortality requires further investigation

► The optimal approach to using fondaparinux in the catheterization lab has yet to be defined, and therefore, its use in this setting is currently not recommended

► Among patients with NSTE-ACS, fondaparinux was non-inferior for primary composite endpoint of death, MI or refractory ischemia at day 9 compared with enoxaparin.

► There was a significant reduction in the safety endpoint of major bleeding at 9 days and the secondary endpoint of mortality at 30 days and 6 months.

► In the OASIS-5 trial, the relationship between bleeding and mortality requires further investigation

► The optimal approach to using fondaparinux in the catheterization lab has yet to be defined, and therefore, its use in this setting is currently not recommended

OASIS-5: Conclusions/Caveats

Sites of Antithrombotic Drug ActionSites of Antithrombotic Drug Action

Tissue factorTissue factor



ProthrombinProthrombin

Thrombin

FibrinogenFibrinogen FibrinFibrin

ThrombusThrombus

Platelet aggregationPlatelet aggregation

Platelet activationPlatelet activation

CollagenCollagen

Thromboxane A2Thromboxane A2

ADPADP

ATAT

ATAT

Aspirin

ClopidogrelPrasugrelCangrelor

EptifibatideAbciximabTirofiban

(GPI)BivalirudinHirudin

Argatroban

FactorXa

FactorXa

Heparin LMWHs

Fibrinolytics

FondaparinuxATAT

Bivalirudin as an Alternative to UFH/LMWHBivalirudin as an Alternative to UFH/LMWH

►Advantages of the direct thrombin inhibitor bivalirudin No requirement for anti-thrombin III Effective on clot-bound thrombin Inhibits thrombin-mediated platelet activation No interactions with PF-4 Plasma half-life 25 minutes No requirement for anticoagulant monitoring

►Clinical results with bivalirudin in PCI In REPLACE 2, bivalirudin showed similar protection from

ischemic events as UFH + GP IIb/IIIa inhibitors, with markedly reduced bleeding1

►Not previously tested in contemporary ACS patients

►Advantages of the direct thrombin inhibitor bivalirudin No requirement for anti-thrombin III Effective on clot-bound thrombin Inhibits thrombin-mediated platelet activation No interactions with PF-4 Plasma half-life 25 minutes No requirement for anticoagulant monitoring

►Clinical results with bivalirudin in PCI In REPLACE 2, bivalirudin showed similar protection from

ischemic events as UFH + GP IIb/IIIa inhibitors, with markedly reduced bleeding1

►Not previously tested in contemporary ACS patients

REPLACE 2. Lincoff AM et al. JAMA 2003;289:853-863 REPLACE 2. Lincoff AM et al. JAMA 2003;289:853-863

REPLACE-2 ACS SubgroupREPLACE-2 ACS Subgroup

n = 1330n = 1330 n = 1330n = 1330n = 4495n = 4495 n = 4495n = 4495

Rajagopal V, Lincoff AM et al. AHJ 2005.Rajagopal V, Lincoff AM et al. AHJ 2005.

ACSACS No ACSNo ACS00

33

66

99

1212

1515

Death, MI, UR - 30 Days (%)Death, MI, UR - 30 Days (%)

8.78.7

6.86.8 7.47.4

Heparin + GP IIb/IIIaHeparin + GP IIb/IIIa


ACSACS No ACSNo ACS00

11

22

33

44

Death - 1 Year (%)Death - 1 Year (%)

1.51.5

2.52.5

2.02.0

Heparin + GP IIb/IIIaHeparin + GP IIb/IIIa


8.08.01.81.8

► When given by itself (with provisional GP IIb/IIa usage) is a strategy of bivalirudin alone comparable to the use of UFH/enoxaparin plus a GP IIb/IIIa antagonist in moderate and high risk ACS patients managed invasively?

► When given by itself (with provisional GP IIb/IIa usage) is a strategy of bivalirudin alone comparable to the use of UFH/enoxaparin plus a GP IIb/IIIa antagonist in moderate and high risk ACS patients managed invasively?

ACUITY

Questions to be answered:Questions to be answered:

► When given with a GP IIb/IIIa antagonist, does bivalirudin provide benefit over UFH/enoxaparin in moderate and high risk ACS patients managed invasively ?

► When given with a GP IIb/IIIa antagonist, does bivalirudin provide benefit over UFH/enoxaparin in moderate and high risk ACS patients managed invasively ?

Bivalirudin in ACS: HypothesesBivalirudin in ACS: Hypotheses

► In moderate- and high-risk patients patients with ACS undergoing an invasive strategy, compared to UFH or LMWH + GP IIb/IIIa inhibitors:

Bivalirudin + GP IIb/IIIa inhibitors will result in less adverse ischemic events and less bleeding

Bivalirudin alone will result in similar rates of ischemic events and markedly reduced bleeding

► In moderate- and high-risk patients patients with ACS undergoing an invasive strategy, compared to UFH or LMWH + GP IIb/IIIa inhibitors:

Bivalirudin + GP IIb/IIIa inhibitors will result in less adverse ischemic events and less bleeding

Bivalirudin alone will result in similar rates of ischemic events and markedly reduced bleeding

Inclusion/Exclusion Criteria

Age ≥18 years Chest pain ≥10’ within 24h At least one of:

New ST depression or transient ST elevation ≥1 mm

Troponin I, T, or CKMB Documented CAD All other 4 TIMI risk criteria

- Age ≥65 years- Aspirin within 7 days- ≥2 angina episodes w/i 24h- ≥3 cardiac risk factors

Written informed consent

Age ≥18 years Chest pain ≥10’ within 24h At least one of:

New ST depression or transient ST elevation ≥1 mm

Troponin I, T, or CKMB Documented CAD All other 4 TIMI risk criteria

- Age ≥65 years- Aspirin within 7 days- ≥2 angina episodes w/i 24h- ≥3 cardiac risk factors

Written informed consent

Inclusion Criteria Exclusion Criteria No angiography within 72h Acute STEMI or shock Bleeding diathesis or major

bleed within 2 weeks Platelet count ≤100,000/mm3

INR >1.5 control CrCl ≤30 ml/min Abcx or ≥2 prior LMWH doses

Prior UFH, LMWH (1 dose), eptifibatide and tirofiban were allowed

Allergy to drugs, contrast

No angiography within 72h Acute STEMI or shock Bleeding diathesis or major

bleed within 2 weeks Platelet count ≤100,000/mm3

INR >1.5 control CrCl ≤30 ml/min Abcx or ≥2 prior LMWH doses

Prior UFH, LMWH (1 dose), eptifibatide and tirofiban were allowed

Allergy to drugs, contrast

Moderate-high risk unstable angina or NSTEMIModerate-high risk unstable angina or NSTEMI

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

Moderate-high risk

ACS

Study Design – First RandomizationStudy 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*

*Stratified by pre-angiography thienopyridine use or administration


Medicalmanagement

PCI

CABG

Moderate-high risk

ACS

Study Design – Second RandomizationStudy 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

UF Heparin Enoxaparin BivalirudinU/Kg mg/Kg mg/kg*

Bolus 60 1.0 sc bid 0.1 ivInfusion/h 121 0.25 iv

PCIACT

200-250s

0.30 iv bolus2

0.75 iv bolus3

0.50 bolus iv

1.75/h infusion iv4

CABG Per institutionPer

institutionPer institution5

Medical mgt

None6 None6 None6

ACUITY: Study MedicationsACUITY: Study Medications

► Anti-thrombin agents (started pre angiography)► Anti-thrombin agents (started pre angiography)

1 Target aPTT 50-75 seconds2 If last enoxaparin dose ≥8h - <16h before PCI; 3 If maintenance dose discontinued or ≥16h from last dose4 Discontinued at end of PCI with option to continue at 0.25mg/kg for 4-12h if GPIIb/IIIa inhibitor not used5 Bivalirudin option for off-pump same as PCI dose. For on-pump bivalirudin discontinued 2 hours before6 Option to continue with pre-PCI anti-thrombotic regimen at physician discretion

Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16. Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16. * This is an off-label dose used in the

ACUITY Trial* This is an off-label dose used in the

ACUITY Trial

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


Primary Results by TreatmentPrimary Results by Treatment

UFH/Enox + GP IIb/IIIa

Bivalirudin +GP IIb/IIIa

Bivalirudinalone

Endpoint Rate Rate P Value Rate P Value

Net clinical outcome 11.7% 11.8%

<0.001 NI

10.1%0.015 Sup

Ischemic events 7.3% 7.7% 0.007 NI 7.8% 0.011 NI

Major bleeding 5.7% 5.3% 0.001 NI 3.0%

<0.001 Sup

NI = non-inferiority; Sup = superiority

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

Components of the Ischemic CompositeComponents of the Ischemic Composite

7.3%

1.3%

4.9%

2.3% 2.7% 2.4%1.5%

7.7%

5.0%5.4%

7.8%

1.6%

Ischemiccomposite

Death Myocardialinfarction

Unplannedrevasc forischemia

30 day events (%)

UFH/Enox +GPI N=4603 Bivalirudin +GPI N=4604 Bivalirudin alone N =4612

PSup = 0.32

PSup = 0.34

PSup = 0.35

PSup = 0.78


UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin aloneUFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin alone

Ischemic Composite EndpointIschemic Composite Endpoint

0

5

10

15

0 5 10 15 20 25 30 35

Cu

mu

lati

ve E

ven

ts (

%)


EstimateP

(log rank)

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

Bivalirudin + IIb/IIIa (N=4604) 0.377.7%

Bivalirudin alone (N=4612) 0.307.8%

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


Major Bleeding EndpointMajor Bleeding Endpoint

0

5

10

15

0 5 10 15 20 25 30 35

Cu

mu

lati

ve E

ven

ts (

%)


Estimate P

(log rank)



Bivalirudin alone (N=4612) <0.00013.0%



Net Clinical Outcome Composite EndpointNet Clinical Outcome Composite Endpoint

0

5

10

15

0 5 10 15 20 25 30 35

Cu

mu

lati

ve E

ven

ts (

%)


EstimateP

(log rank)



Bivalirudin alone (N=4612) 0.01410.1%



Major Bleeding EndpointsMajor Bleeding Endpoints

PSup=0.38 PSup<0.0001PSup=0.31 PSup<.001

UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin aloneUFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin alone


11.8%

5.7%

11.1%

5.3%

3.0%

9.1%

All major bleeding Non CABG major bleeding (primary endpoint)

30 d

ay e

ven

ts (

%)

Heparin +GPI (N=4603) Bivalirudin +GPI (N=4604) Bivalirudin alone (N=4612)

0 1 2

Net Clinical Outcome CompositeNet Clinical Outcome Composite

UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin AloneUFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone

Men (n=6444)Women (n=2771)

Diabetes (n=2585)No diabetes (n=6630)

CrCl ≥60 (n=6993)CrCl <60 (n=1644)

Age <65 (n=5051)Age ≥65 (n=4164)

Risk ratio±95% CI

Risk ratio±95% CI

BivalAlone

UFH/Enox+ IIb/IIIa

7.8%12.9%

US (n=5224)OUS (n=3991)

10.6%9.5%

8.9%16.1%

10.8%9.8%

9.5%11.6%

9.2%14.7%

11.8%11.5%

10.4%16.8%

13.7%10.9%

10.9%13.5%

P Pint

0.86 (0.71-1.03)0.88 (0.75-1.02)

0.90 (0.77-1.05)0.82 (0.68-0.98)

0.86 (0.74-0.99)0.96 (0.77-1.19)

0.79 (0.64-0.97)0.90 (0.78-1.04)

0.87 (0.75-1.00)0.86 (0.70-1.04)

0.090.09

0.160.03

0.030.71

0.020.16

0.050.12

0.89

0.47

0.43

0.28

0.91

RR (95% CI)

Bivalirudin alone better UFH/Enox + IIb/IIIa better


► ACUITY compares two new strategies against the currently defined standard of care in ACS patients managed with an early invasive strategy

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

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

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

► ACUITY compares two new strategies against the currently defined standard of care in ACS patients managed with an early invasive strategy

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

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

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

ACUITY: Conclusions/Caveats


Is there an advantage to using a GP IIb/IIIa antagonist routinely upstream in rapidly, invasively managed ACS patients, versus selective use in the cath lab for PCI?

Is there an advantage to using a GP IIb/IIIa antagonist routinely upstream in rapidly, invasively managed ACS patients, versus selective use in the cath lab for PCI?

ACUITY Timing Trial

Moderate-high risk

ACS

Study Design – Second RandomizationStudy 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

Stone GW, et al. JAMA 2007; 297:591-602 Stone GW, et al. JAMA 2007; 297:591-602

Upstream llb/llla vs. Selective llb/lllvs. Bivalirudin Alone

Upstream llb/llla vs. Selective llb/lllvs. Bivalirudin Alone

Timing Trial—Net Clinical Outcome Composite Endpoint

Timing Trial—Net Clinical Outcome Composite Endpoint

Stone GW, et al. JAMA 2007; 297:591-602 Stone GW, et al. JAMA 2007; 297:591-602

► The ACUITY Timing trial compared the outcomes with upstream GPI use with the outcomes for selective, in-lab use for PCI in rapidly invasively managed ACS patients; additional comparisons were made to the bivalirudin-alone arm

► Upstream IIb/IIIa use was associated with slightly fewer ischemic events, slightly more bleeding, and identical net clinical benefit to a selective in-lab IIb/IIIa strategy

► In comparison to the IIb/IIIa arms, bivalirudin alone had comparable ischemic outcomes, less bleeding, and superior net clinical benefit.

► Future analyses will need to focus on the duration of therapy, and look more closely at comparisons with the bivalirudin-alone strategy

► The ACUITY Timing trial compared the outcomes with upstream GPI use with the outcomes for selective, in-lab use for PCI in rapidly invasively managed ACS patients; additional comparisons were made to the bivalirudin-alone arm

► Upstream IIb/IIIa use was associated with slightly fewer ischemic events, slightly more bleeding, and identical net clinical benefit to a selective in-lab IIb/IIIa strategy

► In comparison to the IIb/IIIa arms, bivalirudin alone had comparable ischemic outcomes, less bleeding, and superior net clinical benefit.

► Future analyses will need to focus on the duration of therapy, and look more closely at comparisons with the bivalirudin-alone strategy

ACUITY Timing Trial: Conclusions/Caveats


What were the outcomes in the ACUITY patients who underwent PCI?

What were the outcomes in the ACUITY patients who underwent PCI?

ACUITY—PCI Subset

Management Strategy (N=13,819)Management Strategy (N=13,819)

56.4%

11.4% 32.2%CABG (n=1,539)CABG (n=1,539)

Medical Rx (n=4,491)Medical Rx (n=4,491)

PCI (n=7,789)PCI (n=7,789)

Heparin + IIb/IIIaN = 2,561

Heparin + IIb/IIIaN = 2,561

Bivalirudin + IIb/IIIaN = 2,609

Bivalirudin + IIb/IIIaN = 2,609

Bivalirudin aloneN = 2,619

Bivalirudin aloneN = 2,619


ACUITY—PCI Major BleedingACUITY—PCI Major Bleeding


PSup=0.32 PSup<0.0001

6.8% 7.5%

3.5%

Non CABG major bleeding (primary endpoint)

30 d

ay e

ven

ts (

%)

Heparin+GPI (N=2561)

Bivalirudin+GPI (N=2609)

Bivalirudin alone (N=2619)


Components of Ischemia–PCI ptsComponents of Ischemia–PCI pts

Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin AloneHeparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone

*Heparin=unfractionated or enoxaparin*Heparin=unfractionated or enoxaparin

p=0.16 p=0.45 p=0.37 p=0.53 p=0.16 p=0.19 p=0.31 P=0.87

8.2%

0.9%

5.6%

3.2% 3.7% 3.2%

6.6%

9.3%

1.1% 1.1%

8.8%

6.5%

Compositeischemia

Death Myocardialinfarction

Unplannedrevasc forischemia

30 d

ay e

ven

ts (

%)


Heparin+GPI (N=2561)

Bivalirudin+GPI (N=2609)

Bivalirudin alone (N=2619)

13.4%

8.1%7.0%

4.2%

12.4%

9.1%

Net clinicaloutcomes

Ischemiccomposite

Majorbleeding

Heparin + IIb/IIIa (N=1436)

Bivalirudin (N=1513)

Troponin (+) Patients—PCITroponin (+) Patients—PCI

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]


Interaction P values = 0.46, 0.86 and 0.28 respectively

Interaction P values = 0.46, 0.86 and 0.28 respectively


13.8%

8.4%7.2%

8.1%

11.1%

3.6%


Ischemiccomposite

Major bleeding

UFH/Enoxaparin + IIb/IIIa (N=1722)

Bivalirudin Alone (N=1789)

11.8%

7.5%

5.7%

3.5%

12.7%

10.3%


Ischemiccomposite

Major bleeding

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

Bivalirudin Alone (N=804)

Thienopyridine ExposedThienopyridine Exposed Not Thienopyridine Exposed

Thienopyridine Exposure Thienopyridine Exposure

RR [95%CI]

0.81 (0.68-0.96)

RR [95%CI]

0.96 (0.77-1.20)

RR [95%CI]

0.50 (0.37-0.67)

RR [95%CI]

1.07 (0.83-1.39)

RR [95%CI]

1.37 (1.00-1.88)

RR [95%CI]

0.61 (0.39-0.97)

Interaction P values = 0.17, 0.19 and 0.65 respectivelyInteraction P values = 0.17, 0.19 and 0.65 respectivelyStone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16. Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16.

► PCI patients in ACUITY demonstrated outcomes similar to those of the overall trial—i. e., comparable ischemic outcomes, less bleeding, and superior net clinical outcomes

► This was true even in troponin (+) patients, although in this case net clinical outcomes were noninferior with bivalirudin monotherapy

► A controversial subgroup are patients with or without clopidogrel exposure prior to intervention: In patients not exposed to clopidogrel, bivalirudin monotherapy was associated with a slightly higher rate of ischemic events. The significance of this is uncertain at present.

► PCI patients in ACUITY demonstrated outcomes similar to those of the overall trial—i. e., comparable ischemic outcomes, less bleeding, and superior net clinical outcomes

► This was true even in troponin (+) patients, although in this case net clinical outcomes were noninferior with bivalirudin monotherapy

► A controversial subgroup are patients with or without clopidogrel exposure prior to intervention: In patients not exposed to clopidogrel, bivalirudin monotherapy was associated with a slightly higher rate of ischemic events. The significance of this is uncertain at present.

ACUITY—PCI: Conclusions/Caveats

Conclusions—Recent ACS Trials

► ISAR REACT 2—Clopidogrel loading alone is not sufficient in ACS patients; Troponin (+) patients derive significant benefit with GP IIb/IIIa antagonists

► SYNERGY—Enoxaparin is an alternative in invasively managed patients, but may have slightly higher bleeding, especially when UFH is indiscriminately added in the cath lab

► ISAR REACT 2—Clopidogrel loading alone is not sufficient in ACS patients; Troponin (+) patients derive significant benefit with GP IIb/IIIa antagonists

► SYNERGY—Enoxaparin is an alternative in invasively managed patients, but may have slightly higher bleeding, especially when UFH is indiscriminately added in the cath lab

►OASIS 5—Fondaparinux has less bleeding than enoxaparin, non-inferior clinical outcomes at 9 days, and less death and death/MI at 6 months; UFH is probably required in the cath lab—dose unknown.

►ACUITY—Bivalirudin with provisional GPI has less bleeding than UFH/LMWH + GPI, comparable ischemic outcomes, and superior net clinical benefit. Bivalirudin + GPI is comparable to UFH/LMWH + GPI

►OASIS 5—Fondaparinux has less bleeding than enoxaparin, non-inferior clinical outcomes at 9 days, and less death and death/MI at 6 months; UFH is probably required in the cath lab—dose unknown.

►ACUITY—Bivalirudin with provisional GPI has less bleeding than UFH/LMWH + GPI, comparable ischemic outcomes, and superior net clinical benefit. Bivalirudin + GPI is comparable to UFH/LMWH + GPI

Conclusions—Recent ACS Trials

► NSTE-ACS is common and associated with high morbidity and mortality

► Early invasive strategy is preferred in higher-risk individuals

► Early initiation of appropriate antiplatelet and antithrombin therapy is important for reduction of ischemic events

► Balancing the risk of ischemic and bleeding complications is essential to maximize clinical benefit in individual patients

► The evidence base and strategies for optimal management of NSTE-ACS continue to evolve

► NSTE-ACS is common and associated with high morbidity and mortality

► Early invasive strategy is preferred in higher-risk individuals

► Early initiation of appropriate antiplatelet and antithrombin therapy is important for reduction of ischemic events

► Balancing the risk of ischemic and bleeding complications is essential to maximize clinical benefit in individual patients

► The evidence base and strategies for optimal management of NSTE-ACS continue to evolve

Conclusions—ACS Management

Non-ST-Segment ElevationNon-ST-Segment ElevationAcute Coronary Syndrome:Acute Coronary Syndrome:

Initial Presentation and Implications for Selecting Initial Presentation and Implications for Selecting Treatment StrategiesTreatment Strategies

Does One Size Fit All?Does One Size Fit All?

James Hoekstra, MDJames Hoekstra, MDProfessor and ChairmanProfessor and Chairman

Department of Emergency MedicineDepartment of Emergency MedicineWake Forest University Health CenterWake Forest University Health Center

Winston-Salem, NCWinston-Salem, NC

The Emergency Medicine PerspectiveThe Emergency Medicine Perspective

Changing the Calculations for Changing the Calculations for Assessing Guidelines AdherenceAssessing Guidelines Adherence

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

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

calculate an opportunity score for ACS patients calculate an opportunity score for ACS patients

rather than a risk score. Patients with higher rather than a risk score. Patients with higher

baseline risks, such as the elderly, would have baseline risks, such as the elderly, would have

higher opportunity scores for benefit, even higher opportunity scores for benefit, even

allowing for some of the greater risks from the allowing for some of the greater risks from the

treatment.”treatment.”

The Challenge: The Challenge: Balancing Efficacy and SafetyBalancing Efficacy and Safety

► CCurrent guidelines (2002) emphasize reduction urrent guidelines (2002) emphasize reduction of ischemic risk in NSTE ACS—especially for of ischemic risk in NSTE ACS—especially for upstream therapy initiated in the EDupstream therapy initiated in the ED

► Updated guidelines (2007) are expected to Updated guidelines (2007) are expected to include data on the harm that bleeding events include data on the harm that bleeding events cause, diminishing ischemic efficacy in some cause, diminishing ischemic efficacy in some patientspatients

► Emergency physicians are comfortable with Emergency physicians are comfortable with the goal of reducing ischemic risk . . . and the goal of reducing ischemic risk . . . and traditionally have left concern over bleeding to traditionally have left concern over bleeding to “downstream providers”“downstream providers”

The Challenge: The Challenge: Balancing Efficacy and SafetyBalancing Efficacy and Safety

► Emergency physicians are accustomed to Emergency physicians are accustomed to assessing ischemic risk . . . but have little assessing ischemic risk . . . but have little data to guide them in assessing “bleeding data to guide them in assessing “bleeding risk”—a task not previously considered to risk”—a task not previously considered to be in their domainbe in their domain

► More than ever, “balanced” More than ever, “balanced” pharmacotherapy will require pharmacotherapy will require multidisciplinary collaboration, pathways, multidisciplinary collaboration, pathways, anticipation of consistent care (especially anticipation of consistent care (especially time from ED to cath), and individualized time from ED to cath), and individualized patient assessmentpatient assessment

Ischemic Risk StratificationIschemic Risk Stratification

► Three levels of risk strat are pertinent to the Three levels of risk strat are pertinent to the ED:ED:

lowlow, , intermediate, or highintermediate, or high risk that ischemic risk that ischemic symptoms are a result of CADsymptoms are a result of CAD

low, intermediatelow, intermediate, or , or high riskhigh risk of short-term of short-term death or nonfatal MI from ACSdeath or nonfatal MI from ACS

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

Ischemic Risk Stratification ToolsIschemic 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 15-lead ECGs should perhaps be “standard” in all but very-low-risk patients“standard” in all but very-low-risk patients

MarkersMarkers CPK-MB, Troponins I and T, MyoglobinCPK-MB, Troponins I and T, Myoglobin Markers of ischemia and inflammation?Markers of ischemia and inflammation?

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 better as research tools than for real-time

clinical decisionmakingclinical decisionmaking

Guidelines Call for Therapeutic Response to Guidelines Call for Therapeutic Response to Identification of Ischemic RiskIdentification of Ischemic Risk

Anti-ischemic therapyAnti-ischemic therapy Oxygen, nitroglycerin, beta-blockers, Oxygen, nitroglycerin, beta-blockers,

morphinemorphine

Anti-thrombotic therapyAnti-thrombotic therapy ASA, anticoagulantASA, anticoagulant

Anti-platelet therapyAnti-platelet therapy Anti-activation therapy with clopidogrel, anti-Anti-activation therapy with clopidogrel, anti-

aggregation therapy with a GP IIb/IIIa receptor aggregation therapy with a GP IIb/IIIa receptor antagonistantagonist

lowrisklowriskmod

riskmodrisk

highriskhighrisk

Selection of Therapy in the ED is Traditionally Selection of Therapy in the ED is Traditionally Based on Reducing Ischemic RiskBased on Reducing Ischemic Risk

► Escalation of therapy for ischemia in this setting is Escalation of therapy for ischemia in this setting is associated with increased risk of bleedingassociated with increased risk of bleeding

► This “price to be paid” has generally been accepted This “price to be paid” has generally been accepted and tolerated, especially in patients at high ischemic and tolerated, especially in patients at high ischemic risk, who benefit disproportionately from advanced risk, who benefit disproportionately from advanced therapytherapy Enox superior to UFH in patients with higher TIMI Risk Enox superior to UFH in patients with higher TIMI Risk

ScoresScores Clopidogrel + ASA superior to ASA alone in patients with Clopidogrel + ASA superior to ASA alone in patients with

higher TIMI Risk Scoreshigher TIMI Risk Scores GP IIb/IIIa receptor antagonists benefit troponin positive GP IIb/IIIa receptor antagonists benefit troponin positive

patients more than troponin negative patientspatients more than troponin negative patients

Selection of Therapy in the ED Should Selection of Therapy in the ED Should Include Consideration of Bleeding RiskInclude Consideration of Bleeding Risk

► Just as in the Cath Lab and the CCU, we must Just as in the Cath Lab and the CCU, we must also be attentive to the impact of bleeding riskalso be attentive to the impact of bleeding risk

► In the ED, bleeding risk is impacted byIn the ED, bleeding risk is impacted by Choice of therapyChoice of therapy Dosing Dosing Duration and reversibility of therapy and Duration and reversibility of therapy and

impact on selection of downstream therapyimpact on selection of downstream therapy

Selection of Therapy in the ED Must Selection of Therapy in the ED Must Include Consideration of Bleeding RiskInclude Consideration of Bleeding Risk

► AgeAge

► GenderGender

► Renal insufficiencyRenal insufficiency

► Baseline anemiaBaseline anemia

► Expectation of prolonged medical therapyExpectation of prolonged medical therapy

How Do We Balance? One Guy’s Opinion of How Do We Balance? One Guy’s Opinion of Choices for Upstream TherapyChoices for Upstream Therapy

► Pertinent data since 2002 ACC/AHA Guidelines:Pertinent data since 2002 ACC/AHA Guidelines: INTERACTINTERACT SYNERGYSYNERGY OASIS-5OASIS-5 ISAR-REACT-2ISAR-REACT-2 REPLACE-2REPLACE-2 ACUITYACUITY CRUSADE and NRMI dataCRUSADE and NRMI data

How Do We Balance? One Guy’s Opinion of How Do We Balance? One Guy’s Opinion of Choices for Upstream Therapy: AntithromboticsChoices for Upstream Therapy: Antithrombotics

OptionOption PatientPatient Ease of UseEase of Use Ischemic Ischemic EfficacyEfficacy

Reduction of Reduction of Bleeding RiskBleeding Risk

UFHUFH Low riskLow risk not indicatednot indicated

Mod riskMod risk BB BB BB

High riskHigh risk BB BB BB

EnoxEnox Low riskLow risk not indicatednot indicated

Mod riskMod risk AA B*B* CC

High riskHigh risk AA B*B* CC

Bival (not yet Bival (not yet approved in approved in

ED)ED)

Low riskLow risk not indicated upstreamnot indicated upstream

Mod riskMod risk B-B- BB AA

High riskHigh risk B-**B-** B to C+B to C+ AA

* If medical management only, enox is ++++** ease of use higher if no IIb/IIIa is used* If medical management only, enox is ++++** ease of use higher if no IIb/IIIa is used

How Do We Balance? One Guy’s Opinion of How Do We Balance? One Guy’s Opinion of Choices for Upstream Therapy: AntiplateletsChoices for Upstream Therapy: Antiplatelets

OptionOption PatientPatient Ease of UseEase of Use Ischemic Ischemic EfficacyEfficacy

Reduction of Reduction of Bleeding RiskBleeding Risk

ASAASA Low riskLow risk AA AA BB

Mod riskMod risk AA AA BB

High riskHigh risk AA AA BB

clopidogrelclopidogrel Low riskLow risk not indicatednot indicated

Mod riskMod risk AA BB BB

High riskHigh risk AA AA B-C*B-C*

GP IIb/IIIaGP IIb/IIIa Low riskLow risk not indicatednot indicated

Mod riskMod risk not indicatednot indicated

High riskHigh risk BB AA B-B-

* CABG concern* CABG concern

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

ACC/AHA Guidelines for TherapyACC/AHA Guidelines for Therapy

http://www.acc.org/

Hospital CareHospital CareAnti-Thrombotic TherapyAnti-Thrombotic 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

Hospital CareHospital CarePlatelet 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

II IIaIIa IIbIIb IIIIII

* 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

Hospital CareHospital CarePlatelet GP IIb/IIIa InhibitorsPlatelet GP IIb/IIIa Inhibitors

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

II IIaIIa IIbIIb IIIIII

0 1 2

ACUITY—Primary Endpoint Measures (ITT)ACUITY—Primary Endpoint Measures (ITT)ACUITY—Primary Endpoint Measures (ITT)ACUITY—Primary Endpoint Measures (ITT)

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

Risk ratioRisk ratio±95% CI±95% CI

Risk ratioRisk ratio±95% CI±95% CI

PrimaryPrimaryendpointendpoint

BivalBivalalonealone

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

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

Net clinical Net clinical outcomeoutcome

Ischemic Ischemic compositecomposite

Major bleedingMajor bleeding

Upp

er b

oun

dary

non

-infe

riorit

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

0.0150.015

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

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

p valuep value(non inferior)(non inferior)

(superior)(superior)

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


0 1 2

ACUITY—Net Clinical Outcome CompositeACUITY—Net Clinical Outcome Composite


Men (n=6444)Women (n=2771)

Diabetes (n=2585)No diabetes (n=6630)

CrCl ≥60 (n=6993)CrCl <60 (n=1644)

Age <65 (n=5051)Age ≥65 (n=4164)

Risk ratio±95% CI

Risk ratio±95% CI

BivalAlone

UFH/Enox+ IIb/IIIa

7.8%12.9%

US (n=5224)OUS (n=3991)

10.6%9.5%

8.9%16.1%

10.8%9.8%

9.5%11.6%

9.2%14.7%

11.8%11.5%

10.4%16.8%

13.7%10.9%

10.9%13.5%

P Pint

0.86 (0.71-1.03)0.88 (0.75-1.02)

0.90 (0.77-1.05)0.82 (0.68-0.98)

0.86 (0.74-0.99)0.96 (0.77-1.19)

0.79 (0.64-0.97)0.90 (0.78-1.04)

0.87 (0.75-1.00)0.86 (0.70-1.04)

0.090.09

0.160.03

0.030.71

0.020.16

0.050.12

0.89

0.47

0.43

0.28

0.91

RR (95% CI)

Bivalirudin alone betterBivalirudin alone better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa betterStone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16. Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16.

0 1 2


Yes (n=3197)No (n=6008)

Low (0-2) (n=1291)Intermed (3-4) (n=4407)

High (5-7) (n=2449)

Elevated (n=5368)Normal (n=3841)

Risk ratio±95% CI

Risk ratio±95% CI

BivalAlone

UFH/Enox+ IIb/IIIa

9.2%11.3%

12.2%11.1%

P Pint

0.76 (0.65-0.89)1.02 (0.86-1.21)

12.2%7.1%

13.3%9.4%

0.92 (0.80-1.06)0.75 (0.61-0.93)

0.230.01

<0.0010.83

0.35

0.02

0.18

13.0%8.6%

13.7%10.6%

0.96 (0.80-1.14)0.81 (0.69-0.95)

0.610.01 0.42

Biomarkers (CK/Trop)

ST Deviation

TIMI Risk Score

Pre Thienopyridine

6.4% 10.2% 0.63 (0.43-0.91) 0.019.4% 10.2% 0.92 (0.77-1.10) 0.34

13.9% 15.2% 0.92 (0.76-1.11) 0.36

Yes (n=5192)No (n=4023)

RR (95% CI)

Bivalirudin alone betterBivalirudin alone better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa betterStone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16. Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16.

ACUITY—Net Clinical Outcome CompositeACUITY—Net Clinical Outcome Composite

Hospital CareHospital CareClopidogrel TherapyClopidogrel Therapy

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

IIII IIaIIaIIaIIa IIbIIbIIbIIb IIIIIIIIIIII

* 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

CURE: Ischemic Endpoints Were Reduced CURE: Ischemic Endpoints Were Reduced within 24h of Randomizationwithin 24h of Randomization

Adapted from Adapted from Yusuf S, et al. Yusuf S, et al. Circulation.Circulation. 2003;107:966-972. 2003;107:966-972.

Hours After RandomizationHours After Randomization

Cu

mu

lati

ve H

azar

d R

ates

Cu

mu

lati

ve H

azar

d R

ates

0.00.0

0.0050.005

0.0100.010

0.0150.015

0.0200.020

0.0250.025

00 22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424

RR = 0.67RR = 0.67P P = 0.003= 0.003

PlaceboPlacebo+ ASA+ ASA

ClopidogrelClopidogrel+ ASA+ ASA

33%33%RRRRRR

Bleeding Among CABG Patients Receiving ClopidogrelBleeding Among CABG Patients Receiving ClopidogrelExcludes transfers out within 48 hours and contraindicationsExcludes transfers out within 48 hours and contraindications

95% CI Odds Ratio

1.0 2.00.5Clopidogrel WorseClopidogrel Better

Clopidogrel>5 days 1.30 (0.95, 1.78)

Risk-adjusted AnalysesRisk-adjusted Analyses

ClopidogrelWithin 5 days 1.33 (1.12, 1.58)

unpublished CRUSADE data, www.crusadeqi.comunpublished CRUSADE data, www.crusadeqi.com

Factors that Should Influence Choice of Factors that Should Influence Choice of Upstream Therapy for NSTE ACSUpstream Therapy for NSTE ACS

► AgeAge Older patients more likely to have ischemic Older patients more likely to have ischemic

eventsevents Older patients more likely to have bleeding Older patients more likely to have bleeding

eventsevents

► GenderGender Women more likely to present late and atypicallyWomen more likely to present late and atypically Women more likely to have bleeding eventsWomen more likely to have bleeding events

► DiabetesDiabetes Diabetics more likely to present atypically and Diabetics more likely to present atypically and

have ischemic eventshave ischemic events


► Renal statusRenal status Without appropriate adjustment for CrCl, may Without appropriate adjustment for CrCl, may

increase bleeding events associated with UFH, increase bleeding events associated with UFH, enox, and GP IIb/IIIa agentsenox, and GP IIb/IIIa agents

► Anticipated downstream managementAnticipated downstream management PCI, CABG capability and time to cathPCI, CABG capability and time to cath

► TroponinTroponin Troponin + shown to respond better to Troponin + shown to respond better to

• early (vs later) cathearly (vs later) cath• enox (vs UFH)enox (vs UFH)• clopidogrel + ASA (vs ASA monotherapy)clopidogrel + ASA (vs ASA monotherapy)• GP IIb/IIIa therapyGP IIb/IIIa therapy


► H / HH / H Anemic patients more likely to have bleeding Anemic patients more likely to have bleeding

eventsevents

► WeightWeight Smaller patients more likely to be overdosedSmaller patients more likely to be overdosed Larger patients more likely to be underdosed and Larger patients more likely to be underdosed and

may have renal issuesmay have renal issues

► Perceived CABG risk (short-term)Perceived CABG risk (short-term) Impacts timing of clopidogrel dosingImpacts timing of clopidogrel dosing Among GP IIb/IIIa agents, mitigates against Among GP IIb/IIIa agents, mitigates against

abciximababciximab

Example of Multidisciplinary, Example of Multidisciplinary, Collaborative Management: Scenario 1Collaborative Management: Scenario 1

► 64 y/o male with NSTEMI64 y/o male with NSTEMI

► Hemodynamically stable, now pain-freeHemodynamically stable, now pain-free

► CRF: smoking, diabeticCRF: smoking, diabetic

► No cath lab at facility, patient refuses transferNo cath lab at facility, patient refuses transfer

► Optimal management:Optimal management: ASA, enox, clopidogrelASA, enox, clopidogrel consider GP IIb/IIIa if develops pain or becomes consider GP IIb/IIIa if develops pain or becomes

unstableunstable




► CRF: smoking, diabetic, CRF: smoking, diabetic, renal insufficiencyrenal insufficiency

► No cath lab at facility, patient refuses transferNo cath lab at facility, patient refuses transfer

► Optimal management:Optimal management: ASA, enox ASA, enox (adjusted for CrCl)(adjusted for CrCl), clopidogrel, clopidogrel consider GP IIb/IIIa consider GP IIb/IIIa (adjusted for CrCl)(adjusted for CrCl) if if

develops pain or becomes unstabledevelops pain or becomes unstable





► Will go to cath tomorrow morningWill go to cath tomorrow morning

► Optimal management:Optimal management: ASA, ASA, heparinheparin, , consider clopidogrel (or give if consider clopidogrel (or give if

PCI)PCI) consider GP IIb/IIIa if develops pain or becomes consider GP IIb/IIIa if develops pain or becomes

unstableunstable


► 8484 y/o male with NSTEMI y/o male with NSTEMI



► Will go to cath tomorrow morningWill go to cath tomorrow morning

► Optimal management:Optimal management: ASA, ASA, consider bival*, calculate CrClconsider bival*, calculate CrCl consider GP IIb/IIIa if develops pain or becomes consider GP IIb/IIIa if develops pain or becomes

unstableunstable Clopidogrel if PCIClopidogrel if PCI

* Not yet FDA approved* Not yet FDA approved





► Going to cath in next 2-4 hoursGoing to cath in next 2-4 hours

► Optimal management:Optimal management: ASA, ASA, bival*, calculate CrClbival*, calculate CrCl consider GP IIb/IIIa if develops pain or becomes consider GP IIb/IIIa if develops pain or becomes

unstableunstable Clopidogrel if PCIClopidogrel if PCI

* Not yet FDA approved* Not yet FDA approved

► Chest Pain or ACS CommitteeChest Pain or ACS Committee

► Meets quarterly or PRNMeets quarterly or PRN PRN means after . . .PRN means after . . .

• Pertinent, “practice-changing” new study Pertinent, “practice-changing” new study publishedpublished

• ACC / AHA / TCT meetingsACC / AHA / TCT meetings• M & M or sentinel eventM & M or sentinel event• New guidelines publishedNew guidelines published

Optimal Management of NSTE ACS: Optimal Management of NSTE ACS: ED to Cardiology: A Functional ModelED to Cardiology: A Functional Model

► Chest Pain or ACS Committee comprised ofChest Pain or ACS Committee comprised of Emergency physiciansEmergency physicians Interventional cardiologistsInterventional cardiologists Medical cardiologistsMedical cardiologists HospitalistsHospitalists CT surgeonsCT surgeons ED nursingED nursing Cath lab nursingCath lab nursing CCU nursingCCU nursing LabLab imagingimaging

Optimal Management of NSTE ACS: ED Optimal Management of NSTE ACS: ED to Cardiology: A Functional Modelto Cardiology: A Functional Model

► Chest Pain or ACS Committee discusses:Chest Pain or ACS Committee discusses: Protocols / standing ordersProtocols / standing orders Practice variations vs evidencePractice variations vs evidence Reduction of medical errors in ACS careReduction of medical errors in ACS care DTB timesDTB times QI issues (CRUSADE / NRMI / ACTION)QI issues (CRUSADE / NRMI / ACTION) Transfers in, transfers outTransfers in, transfers out New data - - should it impact our protocols New data - - should it impact our protocols

before it is added to guidelines?before it is added to guidelines?

Optimal Management of NSTE ACS: Optimal Management of NSTE ACS: ED to Cardiology: A Functional ModelED to Cardiology: A Functional ModelOptimal Management of NSTE ACS: Optimal Management of NSTE ACS:

ED to Cardiology: A Functional ModelED to Cardiology: A Functional Model

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

We in the ED must work with our colleagues in We in the ED must work with our colleagues in Cardiology to develop pathways for proper use of Cardiology to develop pathways for proper use of antithrombotic and antiplatelet therapy at all levels, to antithrombotic and antiplatelet therapy at all levels, to facilitate early invasive management whenever facilitate early invasive management whenever feasible, and to address issues related to bleeding feasible, and to address issues related to bleeding risk as well as ischemic risk. A seamless transition of risk as well as ischemic risk. A seamless transition of care is most likely to result in good outcomes.care is most likely to result in good outcomes.

Optimal Management of NSTE ACS: Optimal Management of NSTE ACS: ED to CardiologyED to Cardiology

Case Studies inCase Studies inAcute Coronary SyndromesAcute Coronary Syndromes

Moderated by:Moderated by:

Interventional Cardiology Co-ChairmanInterventional Cardiology Co-ChairmanEmergency Medicine Co-ChairmanEmergency Medicine Co-Chairman

Regional Expert Panel MembersRegional Expert Panel Members

Moderated by:Moderated by:

Interventional Cardiology Co-ChairmanInterventional Cardiology Co-ChairmanEmergency Medicine Co-ChairmanEmergency Medicine Co-Chairman

Regional Expert Panel MembersRegional Expert Panel Members

Case #1: HistoryCase #1: History

► 76 year old WM with h/o stent to LAD 1 year ago.76 year old WM with h/o stent to LAD 1 year ago.► Presents with multiple episodes of recurrent chest pain Presents with multiple episodes of recurrent chest pain

including rest pain over 2 days.including rest pain over 2 days.► Pain similar to time of PCI in past.Pain similar to time of PCI in past.► Symptoms relieved in ED with sl NTG.Symptoms relieved in ED with sl NTG.► PMH: IDDM, HTN, CHOL.PMH: IDDM, HTN, CHOL.► PE: benign (weight 84 kg).PE: benign (weight 84 kg).► Labs: Hgb 10.7, Cr 1.9, CK 173/2, Tr <0.03.Labs: Hgb 10.7, Cr 1.9, CK 173/2, Tr <0.03.► ECG.ECG.

Case #1: ECGCase #1: ECG

New anterior and lateral ST / T changes.

This patient’s risk of short-term (30-Day) ischemic This patient’s risk of short-term (30-Day) ischemic events is: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 is most Which of this patient’s baseline factors is most important in determining their ischemic risk?important in determining their 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

This patient’s risk of short-term (30-Day) hemorrhagic This patient’s risk of short-term (30-Day) hemorrhagic events is:events is:

A.A. LowLow


C.C. HighHigh


Case #1Case #1

Which of this patient’s baseline factors is most Which of this patient’s baseline factors is most important in determining their hemorrhagic risk?important in determining their hemorrhagic risk?


B.B. Hypertension Hypertension

C.C. Impaired creatinine clearance Impaired creatinine clearance

D.D. Anemia Anemia

*

Case #1Case #1

0 1 2 3

P-valueP-valueRR (95% CI)RR (95% CI)Risk ratio ± 95% CIRisk ratio ± 95% CI

Results: The ACUITY Trial (N=13819)Results: The ACUITY Trial (N=13819)

Predictors of Major BleedingPredictors of Major Bleeding

Age Age >>75 (vs. 55-75)75 (vs. 55-75)

AnemiaAnemia


DiabetesDiabetes




No prior PCINo prior PCI

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

1.51 (1.21-1.89)1.51 (1.21-1.89) <0.0001<0.0001

1.88 (1.54-2.29)1.88 (1.54-2.29) <0.0001<0.0001

1.54 (1.24-1.90)1.54 (1.24-1.90) <0.0001<0.0001

1.21 (1.00-1.46)1.21 (1.00-1.46) 0.0520.052

1.90 (1.59-2.26)1.90 (1.59-2.26) <0.0001<0.0001

1.67 (1.32-2.11)1.67 (1.32-2.11) <0.0001<0.0001

1.23 (1.00-1.52)1.23 (1.00-1.52) 0.04760.0476

1.36 (1.11-1.67)1.36 (1.11-1.67) 0.00280.0028

2.04 (1.62-2.56)2.04 (1.62-2.56) <0.0001<0.0001

Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

Based upon this patient’s overall profile, I am more Based upon this patient’s overall profile, I am more concerned about:concerned about:

A.A. Ischemic risk Ischemic risk

B.B. Hemorrhagic risk Hemorrhagic risk

Case #1Case #1

In ACS, do you alter your choice of anticoagulant In ACS, do you alter your choice of anticoagulant therapy due to an individual patient’s risk of therapy due to an individual patient’s risk of

hemorrhagic complications?hemorrhagic complications?

A.A. Yes Yes

B.B. No No

*

Case #1Case #1

In this patient, would you select anticoagulant therapy In this patient, would you select anticoagulant therapy primarily basedprimarily based upon the risk of hemorrhagic upon the risk of hemorrhagic

complications?complications?

A.A. Yes Yes

B.B. No No

*

Case #1Case #1

What would you use for anticoagulation in this patient, What would you use for anticoagulation in this patient, prior to catheterization?prior to catheterization?

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

*

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

immediately (within 4 hours)?immediately (within 4 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 the therapy be, if you anticipated cardiac catheterization 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 the therapy be, if you anticipated cardiac catheterization the

next day (within 24 hours)?next day (within 24 hours)?





*

Case #1Case #1

Case #1: Pre-angiographyCase #1: Pre-angiographyHeparin initiated, catheterization 18 h laterHeparin initiated, catheterization 18 h later

ACT 173 seconds.ACT 173 seconds.*

At this point, your anticoagulation regimen for PCI At this point, your anticoagulation regimen for PCI in this patient would be?in 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 #1: Post-AngiographyCase #1: Post-Angiography

*

Do you believe that major hemorrhagic complications Do you believe that major hemorrhagic complications independently increase mortality in ACS?independently increase mortality in ACS?

A.A. Yes Yes

B.B. No No

Case #1Case #1

Results: The ACUITY Trial (N=13819)Results: The ACUITY Trial (N=13819)Major Bleeding, Ischemic Endpoints, and MortalityMajor Bleeding, Ischemic Endpoints, and Mortality

7.6%

2.2%

14.6%

7.3%

23.1%

4.6%6.8%

1.2%

IschemicComposite


30 day events (%)


P<0.0001 for all

Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

Do you believe that major hemorrhagic complications Do you believe that major hemorrhagic complications are more important than MI in influencing mortality in are more important than MI in influencing mortality in

ACS?ACS?

A. Less importantA. Less important

B. Same importanceB. Same importance

C. More importantC. More important

*

Case #1Case #1

Results from The ACUITY Trial (N=13819)Results from The ACUITY Trial (N=13819)

Predictors of Mortality at 30 DaysPredictors of Mortality at 30 Days

Predictors of Mortality at 30 Days in The ACUITY TrialPredictors of Mortality at 30 Days in The ACUITY Trial

VariableVariable OROR 95% CI95% CI p-valuep-value

Major BleedingMajor Bleeding 7.557.55 4.68-12.184.68-12.18 <0.0001<0.0001

MI (within 30 days)MI (within 30 days) 3.963.96 2.45-6.422.45-6.42 <0.0001<0.0001

LVEF LVEF << 50% 50% 2.962.96 1.99-4.391.99-4.39 <0.0001<0.0001

Age Age >> 75 years 75 years 2.552.55 1.68-3.871.68-3.87 <0.0001<0.0001

ECG ChangesECG Changes 2.322.32 1.54-3.501.54-3.50 <0.0001<0.0001

Elevated Cardiac MarkersElevated Cardiac Markers 1.971.97 1.23-3.171.23-3.17 0.0050.005

Prior CVAPrior CVA 1.941.94 1.09-3.441.09-3.44 0.0240.024

PCI (vs. CABG)PCI (vs. CABG) 0.290.29 0.18-0.470.18-0.47 <0.0001<0.0001

Manoukian SV, Feit F, Mehran R, et al. Unpublished.Manoukian SV, Feit F, Mehran R, et al. Unpublished.


► 67 year old WF without prior cardiac history.67 year old WF without prior cardiac history.

► Multiple short episodes of chest pain today.Multiple short episodes of chest pain today.

► Unrelieved with NTG sl, IV; metoprolol IV.Unrelieved with NTG sl, IV; metoprolol IV.

► PMH: DM, HTN, CHOL.PMH: DM, HTN, CHOL.

► PE: benign (weight 65 kg).PE: benign (weight 65 kg).

► Labs: Hgb 11.7, Cr 1.1, CK 285/9, Tr 2.7.Labs: Hgb 11.7, Cr 1.1, CK 285/9, Tr 2.7.

► ECG.ECG.


New inferior changes New lateral changes


A.A. LowLow


C.C. HighHigh


*

Case #2Case #2

Based upon this patient’s overall profile, when selecting Based upon this patient’s overall profile, when selecting an antithrombotic regimen, I am more concerned about:an antithrombotic regimen, I am more concerned about:



*

Case #2Case #2

Which of these factors is most important in considering Which of these factors is most important in considering the need for immediate catheterization in this patient?the need for immediate 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

Does a plan of immediate catheterization influence your Does a plan of immediate catheterization influence your choice of anticoagulation therapy?choice of anticoagulation 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), would you start?(now), 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.), would you start?(availability of lab, transfer, etc.), would you start?





*

Case #2Case #2

Case #2: Pre-AngiographyCase #2: Pre-AngiographyBivalirudin started, immediate catheterizationBivalirudin started, immediate catheterization

Case #2: AngiographyCase #2: Angiography


► 82 year old WF with h/o MI, PTCA/LAD 1997.82 year old WF with h/o MI, PTCA/LAD 1997.

► Exertional and rest chest pressure x 72 hours, Exertional and rest chest pressure x 72 hours, now pain-free in ED.now pain-free in ED.

► PMH: IRDM, HTN, CHOL.PMH: 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, Cr 1.6, CK 37/1, Tr <0.03.Labs: Hgb 11.1, Cr 1.6, CK 37/1, Tr <0.03.

► ECG.ECG.


No notable findings compared to old ECG.


A.A. LowLow


C.C. HighHigh


*

Case #3Case #3

Based upon this patient’s overall profile, I am more Based upon this patient’s overall profile, I am more concerned about:concerned about:



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Case #3Case #3

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: within 24 hours?day: within 24 hours?





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Case #3Case #3

Case #3: Pre-AngiographyCase #3: Pre-AngiographyHeparin initiated, catheterization the next dayHeparin initiated, catheterization the next day

ACT 187 seconds.ACT 187 seconds.

Case #3: AngiographyCase #3: Angiography

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 ischemic features, at what point in the patient’s course

would you administer clopidogrel?would you administer clopidogrel?

A.A. In the ED, immediately. In the ED, immediately.

B.B. In the cath lab, prior to catheterization. In the cath lab, prior to catheterization.

C.C. In the cath lab, after catheterization and In the cath lab, after catheterization and decision to proceed with PCI, but prior to decision to proceed with PCI, but prior to PCI.PCI.

D.D. In the cath lab, post-PCI. In the cath lab, post-PCI.

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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 reduction of clinical benefit” (optimizes reduction of ischemic and bleeding endpoints)ischemic and bleeding endpoints)

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Concluding QuestionsConcluding Questions

INTERACTIVE FORUM

Applying Evidence, Trials, and Clinical Realities to

Multidisciplinary ACS Care

EDICT for ACS INTERACTIVE FORUMEDICT for ACS INTERACTIVE FORUMFaculty, Expert Panel, and ParticipantsFaculty, Expert Panel, and Participants

1.1. How should interventional cardiologists and How should interventional cardiologists and emergency physicians collaborate to deliver emergency physicians collaborate to deliver optimal care for ACS?optimal care for ACS?

• Can and should EDICT therapeutic teams be • Can and should EDICT therapeutic teams be organized, and if so, what form should they take? organized, and if so, what form should they take? Who should be on these teams? Who should be on these teams?

• What are the responsibilities and mandates of such • What are the responsibilities and mandates of such

a team? Policies? Pathways? Therapeutic a team? Policies? Pathways? Therapeutic consistency? consistency?

• How should protocols for EDICT for ACS be • How should protocols for EDICT for ACS be generated? generated?


2.2. Understanding the “mind sets” and action Understanding the “mind sets” and action drivers of EDICT for ACS team members, i.e., drivers of EDICT for ACS team members, i.e., interventional cardiologists (ICs) versus interventional cardiologists (ICs) versus emergency physicians (EPs):emergency physicians (EPs):

• Are emergency physicians “guideline-driven?” Are • Are emergency physicians “guideline-driven?” Are they more likely to adhere strictly to AHA/ACC they more likely to adhere strictly to AHA/ACC guidelines than ICs? Why do they adopt strategies? guidelines than ICs? Why do they adopt strategies?

• Are IC decisions, practices, and protocols driven • Are IC decisions, practices, and protocols driven more by clinical experience, and trial-based data? more by clinical experience, and trial-based data?

• Does this lead to a divergence of treatment • Does this lead to a divergence of treatment approaches for ACS? How can and should these approaches for ACS? How can and should these differences be reconciled? differences be reconciled?


3. In which patient types are IC and EP care 3. In which patient types are IC and EP care strategies for ACS patients most closely strategies for ACS patients most closely aligned currently?aligned currently?

• Medical therapy for low risk groups?• Medical therapy for low risk groups? Where is there agreement? Disagreement? Where is there agreement? Disagreement?

• Moderate or high risk patients going to• Moderate or high risk patients going to catheterization/PCI within 4 hours (relatively catheterization/PCI within 4 hours (relatively immediately)? Agreement? Disagreement? immediately)? Agreement? Disagreement?

• Moderate or high risk groups with anticipated• Moderate or high risk groups with anticipated catheterization within 12-24 hours? catheterization within 12-24 hours? Agreement? Disagreement? Agreement? Disagreement?


4. What clinical outcome measures would an4. What clinical outcome measures would anEDICT for ACS team or review panel followEDICT for ACS team or review panel followto evaluate success or failure of their NSTE-to evaluate success or failure of their NSTE-ACS protocols, processes, and therapies?ACS protocols, processes, and therapies?

• Door to catheterization/PCI time? Measure against• Door to catheterization/PCI time? Measure against CRUSADE findings and benchmarks? Other CRUSADE findings and benchmarks? Other benchmarks? benchmarks?

• Time to onset of antithrombotic therapy?• Time to onset of antithrombotic therapy?

• Length of hospitalization? Cost of hospitalization?• Length of hospitalization? Cost of hospitalization?

• Bleeding complications? Ischemic complications?• Bleeding complications? Ischemic complications?


5.5. Can EDICT for ACS teams develop a quick Can EDICT for ACS teams develop a quick checklist or risk stratification tool to checklist or risk stratification tool to determine importance of bleeding risk?determine importance of bleeding risk?

• What risk factors should suggest bleeding-sparing• What risk factors should suggest bleeding-sparing strategies as dominant antithrombotic strategy? strategies as dominant antithrombotic strategy?

• What are bleeding reduction strategies? When• What are bleeding reduction strategies? When should they take precedence? should they take precedence?

• How should this be incorporated into protocol?• How should this be incorporated into protocol?


6. What specific ACS strategies can this group 6. What specific ACS strategies can this group agree upon as it relates to NSTE-ACS, and agree upon as it relates to NSTE-ACS, and therefore, recommend for adoption by an therefore, recommend for adoption by an EDICT for ACS team?EDICT for ACS team?

• Timing of invasive strategy? ASAP? Depending• Timing of invasive strategy? ASAP? Depending on risk group? on risk group?

• Clopidogrel use: When? In Whom? How much? • Clopidogrel use: When? In Whom? How much? Caveats? Caveats?

• GPIIb/IIIa receptor antagonist: When? Upstream?• GPIIb/IIIa receptor antagonist: When? Upstream? At catheterization? Routine? Provisional? At catheterization? Routine? Provisional?


6. Recommendations for EDICT for ACS 6. Recommendations for EDICT for ACS strategies (continued)?strategies (continued)?

• Direct thrombin inhibitor (bivalirudin)? In which • Direct thrombin inhibitor (bivalirudin)? In which patient populations? Monotherapy? When to patient populations? Monotherapy? When to initiate? Crossovers? When not to initiate? initiate? Crossovers? When not to initiate?

• How should new ACC/AHA guidelines impact • How should new ACC/AHA guidelines impact decisions about bivalirudin? Where would EPs and decisions about bivalirudin? Where would EPs and ICs introduce bivalirudin into process-of-care ICs introduce bivalirudin into process-of-care pathway for ACS? pathway for ACS?


6. Recommendations for ACS strategies 6. Recommendations for ACS strategies (continued)?(continued)? • Enoxaparin? When to use? When not to use?• Enoxaparin? When to use? When not to use? What if consistency cannot be maintained? What if consistency cannot be maintained? Crossovers? Crossovers?

• Heparin? When to use? When not to use?• Heparin? When to use? When not to use? What if consistency cannot be maintained? What if consistency cannot be maintained? Crossovers? Crossovers?

• Fondaparinux?• Fondaparinux?


6.6. Recommendations for EDICT for ACS clinical Recommendations for EDICT for ACS clinical strategies (continued)?strategies (continued)?

• Statins: Should they be initiated in ED as part of • Statins: Should they be initiated in ED as part of EDICT strategy? If so, at what point? What agent? EDICT strategy? If so, at what point? What agent? At what dose? At what dose?

• Beta-blockers?• Beta-blockers?

• ACEIs or ARBs? In certain subsets? Diabetics? • ACEIs or ARBs? In certain subsets? Diabetics? Heart failure? Heart failure?

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7. Practical and process-oriented recommenda-7. Practical and process-oriented recommenda-tions for and EDICT for ACS program:tions for and EDICT for ACS program:

• How often should EDICT for ACS leadership• How often should EDICT for ACS leadership committee meet within an institution? committee meet within an institution?

• What should its goals be? Protocols? • What should its goals be? Protocols? Compliance? Measuring outcomes? Compliance? Measuring outcomes?

• How should findings and recommendations• How should findings and recommendations be disseminated? be disseminated?

• Education? EdictforACS.com? How should it • Education? EdictforACS.com? How should it be used? be used?*


Thank YouThank You

welcome to the edict for acs cardiovascular forum

Documents

therapy acs slide

emergency physicians

acute coronary syndromes

future management of

interventional cardiologists

acs mission statement

acs cardiovascular forum

emergency medicine specialists