Why Bleeding Matters in ACS

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

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

Veterans Administration Medical CenterVeterans Administration Medical CenterAssistant ProfessorAssistant Professor

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

Why Bleeding Matters in ACS

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

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

Veterans Administration Medical CenterVeterans Administration Medical CenterAssistant ProfessorAssistant Professor

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

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

Program Faculty and COIProgram Faculty and COIProgram Faculty and COIProgram Faculty and COI

  

COI DisclosuresCOI Disclosures

Sunil V. Rao, MD, FACCSunil V. Rao, MD, FACCGrant/Research Support:Grant/Research Support: Cordis, The Medicines Cordis, The Medicines CompanyCompanyConsultant:Consultant: sanofi-aventis, Bristol-Myers Squibb, sanofi-aventis, Bristol-Myers Squibb, The Medicines CompanyThe Medicines CompanySpeaker’s Bureau:Speaker’s Bureau: sanofi-aventis, Bristol-Myers sanofi-aventis, Bristol-Myers Squibb, Cordis, The Medicines CompanySquibb, Cordis, The Medicines Company

  

AcuteAcute

CoronaryCoronary

SyndromeSyndrome

AcuteAcute

CoronaryCoronary

SyndromeSyndrome

What Do The Guidelines Mean for ED What Do The Guidelines Mean for ED Physicians and Cardiologists?Physicians and Cardiologists?

AcuteAcute

ControversyControversy

SyndromeSyndrome

AcuteAcute

ControversyControversy

SyndromeSyndrome

What Do The Guidelines Mean for ED What Do The Guidelines Mean for ED Physicians and Cardiologists?Physicians and Cardiologists?

AcuteAcute

ConfoundedConfounded

SyndromeSyndrome

AcuteAcute

ConfoundedConfounded

SyndromeSyndrome

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

What Do The Guidelines Mean for ED What Do The Guidelines Mean for ED Physicians and Cardiologists?Physicians and Cardiologists?

AcuteAcute

ContentiousnessContentiousness

SyndromeSyndrome

AcuteAcute

ContentiousnessContentiousness

SyndromeSyndrome

What Do The Guidelines Mean for ED What Do The Guidelines Mean for ED Physicians and Cardiologists?Physicians and Cardiologists?

AcuteAcute

CollaborationCollaboration

SyndromeSyndrome

AcuteAcute

CollaborationCollaboration

SyndromeSyndrome

What Do The Guidelines Mean for ED What Do The Guidelines Mean for ED Physicians and Cardiologists?Physicians and Cardiologists?

Opportunities for Collaboration between Opportunities for Collaboration between Emergency Medicine and CardiologyEmergency Medicine and Cardiology

► Improve D2R timesImprove D2R times

► More consistency in anticoagulation and antiplatelet More consistency in anticoagulation and antiplatelet

therapy in transition from ED to caththerapy in transition from ED to cath● Familiarity and consistency result in fewer dosing errors, Familiarity and consistency result in fewer dosing errors,

omissions and delays in therapyomissions and delays in therapy

► Improve compliance with evidence-driven best practiceImprove compliance with evidence-driven best practice● CRUSADE and ACTION indicate better patient outcomes; CRUSADE and ACTION indicate better patient outcomes;

new studies suggest further improvement is possiblenew studies suggest further improvement is possible

► Improve D2R timesImprove D2R times

► More consistency in anticoagulation and antiplatelet More consistency in anticoagulation and antiplatelet

therapy in transition from ED to caththerapy in transition from ED to cath● Familiarity and consistency result in fewer dosing errors, Familiarity and consistency result in fewer dosing errors,

omissions and delays in therapyomissions and delays in therapy

► Improve compliance with evidence-driven best practiceImprove compliance with evidence-driven best practice● CRUSADE and ACTION indicate better patient outcomes; CRUSADE and ACTION indicate better patient outcomes;

new studies suggest further improvement is possiblenew studies suggest further improvement is possible

ACS Case PresentationACS Case Presentation

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

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

► Given ASA, 300 mg clopidogrel, 5 mg IV metoprolol, IV Given ASA, 300 mg clopidogrel, 5 mg IV metoprolol, IV NTGNTG

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

Medical Rx(cath)

Time

Admission Cath Discharge

No Cath

Cath PCI

Surgery

Medical Rx (no cath)

Medical Rx

No disease

(82 % of total)

(18 % of total)

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

40 % < 48 hrs

12 % > 48 hrs

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

63 % < 48 hrs

19 % > 48 hrs

CRUSADERegistry

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

Patient X

ACS Management Pathways

Cath

Medical Rx

Ischemic Complications

Ischemic Complications

Hemorrhage HIT

Hemorrhage HIT

► Death

► MI

► Urgent TVR

► Death

► MI

► Urgent TVR

► Major Bleeding

► Minor Bleeding

► Thrombocytopenia

► Major Bleeding

► Minor Bleeding

► Thrombocytopenia

Composite Adverse Event EndpointsComposite Adverse Event Endpoints

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

Although these complications usually

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

influence the likelihood of these adverse events!

Although these complications usually

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

influence the likelihood of these adverse events!

SYNERGY

LMWHLMWH

ESSENCEESSENCE

19941994 19951995 19961996 19971997 19981998 19991999 20002000 2002200220032003 20042004 20052005 2006200620012001

CURECURE

ClopidogrelClopidogrelGP 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

Bleeding riskBleeding risk

Ischemic riskIschemic risk

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.

20072007 20082008

ISAR-REACT 3

OASIS-6

HORIZONS AMI

TRITON TIMI-38

Options for NSTE-ACS Therapy in 2009Options for NSTE-ACS Therapy in 2009

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

► Antithrombin therapyAntithrombin therapy● UFHUFH● EnoxaparinEnoxaparin● FondaparinuxFondaparinux● BivalirudinBivalirudin

► Risk stratificationRisk stratification● ConservativeConservative● InvasiveInvasive

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

► Antithrombin therapyAntithrombin therapy● UFHUFH● EnoxaparinEnoxaparin● FondaparinuxFondaparinux● BivalirudinBivalirudin

► Risk stratificationRisk stratification● ConservativeConservative● InvasiveInvasive

Antiplatelet Tx: 2007Antiplatelet Tx: 2007

II IIaIIa IIbIIb IIIIII

ICS with recurrent ischemia on ASA, ICS with recurrent ischemia on ASA, clopidogrel, and anticoag: add IIb/IIIa clopidogrel, and anticoag: add IIb/IIIa upstreamupstream

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

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

ICS with recurrent ischemia on ASA, ICS with recurrent ischemia on ASA, clopidogrel, and anticoag: add IIb/IIIa clopidogrel, and anticoag: add IIb/IIIa upstreamupstream

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

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

New Guidance on ThienopyridinesNew Guidance on Thienopyridines

II IIaIIa IIbIIb IIIIII

Clopidogrel 75mg/d should be added to Clopidogrel 75mg/d should be added to ASA in STEMI patients if lysed or if not ASA in STEMI patients if lysed or if not reperfusedreperfused

If < 75y/o and lysed or if not reperfused, If < 75y/o and lysed or if not reperfused, add oral load of 300mg clopidogreladd oral load of 300mg clopidogrel

In PPCI, give 600mg clopidogrel as soon In PPCI, give 600mg clopidogrel as soon as possibleas possible

Clopidogrel 75mg/d should be added to Clopidogrel 75mg/d should be added to ASA in STEMI patients if lysed or if not ASA in STEMI patients if lysed or if not reperfusedreperfused

If < 75y/o and lysed or if not reperfused, If < 75y/o and lysed or if not reperfused, add oral load of 300mg clopidogreladd oral load of 300mg clopidogrel

In PPCI, give 600mg clopidogrel as soon In PPCI, give 600mg clopidogrel as soon as possibleas possible

Antman et al, 2007 Focused Update to 2004 ACC/AHA STEMI GLsAntman et al, 2007 Focused Update to 2004 ACC/AHA STEMI GLsKing et al, 2008 Focused Update to 2005 ACC/AHA/SCAI PCI GLsKing et al, 2008 Focused Update to 2005 ACC/AHA/SCAI PCI GLsAntman et al, 2007 Focused Update to 2004 ACC/AHA STEMI GLsAntman et al, 2007 Focused Update to 2004 ACC/AHA STEMI GLsKing et al, 2008 Focused Update to 2005 ACC/AHA/SCAI PCI GLsKing et al, 2008 Focused Update to 2005 ACC/AHA/SCAI PCI GLs

Risk of eventsRisk of events

Risk of bleedingRisk of bleeding

ThrombosisThrombosisHemostasisHemostasis

Two sides of the same coinTwo sides of the same coin

Degree of AnticoagulationDegree of Anticoagulation

Ris

kR

isk

Balancing Ischemic Events and Bleeding RiskBalancing Ischemic Events and Bleeding Risk

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

*Excluding CABG-related transfusionsCRUSADE DATA: January 1, 2006 – December 31, 2006 (n= 29,825)

DeathDeath 3.6%3.6%

(Re)-Infarction(Re)-Infarction 1.8%1.8%

CHFCHF 6.6%6.6%

Cardiogenic ShockCardiogenic Shock 2.2%2.2%

StrokeStroke 0.7%0.7%

RBC Transfusion*RBC Transfusion* 9.1%9.1%

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

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

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

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

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

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

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

Bleeding in ACS—Identification

Questions to be answered —Questions to be answered —

1.1. Who bleeds?Who bleeds?

2.2. What risk factors are predictive of bleeding?What risk factors are predictive of bleeding?

3.3. How should initial choices for upstream care be How should initial choices for upstream care be influenced by bleeding risk?influenced by bleeding risk?

Independent Independent predictors of predictors of major bleeding major bleeding

in marker- in marker- positive positive acute coronary acute coronary

syndromessyndromes

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

Predictors of Major Bleeding in ACSPredictors of Major Bleeding in ACS

► Older AgeOlder Age

► Female GenderFemale Gender

► Renal FailureRenal Failure

► History of BleedingHistory of Bleeding

► Right Heart CatheterizationRight Heart Catheterization

► GPIIb-IIIa AntagonistsGPIIb-IIIa Antagonists

► 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% 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; Manoukian, Feit, Mehran et al., JACC; 2007; 49(12); 1362-68.

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

CrCl <60mL/minCrCl <60mL/min

DiabetesDiabetes

Female genderFemale gender

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

HypertensionHypertension

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

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

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

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

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

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

Bleeding Predictors — Conclusions

Questions to be answeredQuestions to be answered

1.1. Is bleeding bad or a necessary evil?Is bleeding bad or a necessary evil?

2.2. What is the relationship between bleeding and What is the relationship between bleeding and patient outcomes in ACS?patient outcomes in ACS?

3.3. What initial choices can the ED physician make What initial choices can the ED physician make that are compatible with guidelines and that will that are compatible with guidelines and that will reduce bleeding?reduce bleeding?

Bleeding in ACS — Consequences

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

P<0.001P<0.001

5.13.0

5.37.0

18.616.1 15.3

22.8

0.0

10.0

20.0

30.0

40.0No Bleed Bleed

Overall Overall Unstable Unstable NSTEMI NSTEMI STEMISTEMIACS ACS AnginaAngina

Pat

ient

s (%

)P

atie

nts

(%)

Pat

ient

s (%

)P

atie

nts

(%)

Major Bleeding PredictsMajor Bleeding PredictsMortality in ACSMortality in ACS

Major Bleeding PredictsMajor Bleeding PredictsMortality in ACSMortality in ACS

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

log rank p-value for all four categories <0.0001log-rank p-value for no bleeding vs. mild bleeding = 0.02log-rank p-value for mild vs. moderate bleeding <0.0001log-rank p-value for moderate vs. severe <0.001

Bleeding and Outcomes in ACSBleeding and Outcomes in ACS

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

Kaplan Meier Curves for 30-Day Death, Stratified by Bleed SeverityKaplan Meier Curves for 30-Day Death, Stratified by Bleed SeverityN=26,452 ACS patients from GUSTO IIb, PARAGON A, PARAGON B, & PURSUIT N=26,452 ACS patients from GUSTO IIb, PARAGON A, PARAGON B, & PURSUIT

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

26,452 patients from PURSUIT, PARAGON A, PARAGON 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

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

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

Mild*Mild* 1.61.6 1.31.3 1.41.4

Moderate*Moderate* 2.72.7 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*Bleeding as a time-dependent covariate*Bleeding as a time-dependent covariate

Mor

talit

y (%

)M

orta

lity

(%)

Days from RandomizationDays from Randomization

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

5

15

30

10

25

20

1 yearEstimate

Major Bleed only (without MI) (N=551) 12.5%28.9%Both MI and Major Bleed (N=94)

3.4%No MI or Major Bleed (N=12,557)MI only (without Major Bleed) (N=611) 8.6%

Impact of MI and Major Bleeding (non-CABG) in Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Yearthe First 30 Days on Risk of Death Over 1 Year

28.9%

12.5%

8.6%

3.4%

ACUITYACUITY

Stone GW, et al. JAMA 2007; 298:2497-2506 Stone GW, et al. JAMA 2007; 298:2497-2506

Day 0 – 2 after MIDay 0 – 2 after MI 12.6 (7.8-20.4)12.6 (7.8-20.4) 29 (37.6)29 (37.6) <0.0001<0.0001

Day 3 – 7 after MIDay 3 – 7 after MI 5.3 (2.7-10.4)5.3 (2.7-10.4) 11 (14.3)11 (14.3) <0.0001<0.0001

Day 8 – 35 after MIDay 8 – 35 after MI 1.6 (0.8-3.1)1.6 (0.8-3.1) 12 (15.6)12 (15.6) 0.180.18

Day > 35 after MIDay > 35 after MI 1.2 (0.8-1.9)1.2 (0.8-1.9) 25 (32.5)25 (32.5) 0.340.34

Day 0 – 2 after Major BleedDay 0 – 2 after Major Bleed 3.0 (1.6-5.6)3.0 (1.6-5.6) 12 (12.9)12 (12.9) 0.00090.0009

Day 3 – 7 after Major BleedDay 3 – 7 after Major Bleed 4.0 (2.1-7.5)4.0 (2.1-7.5) 15 (16.1)15 (16.1) <0.0001<0.0001

Day 8 – 35 after Major BleedDay 8 – 35 after Major Bleed 4.5 (2.8-7.4)4.5 (2.8-7.4) 25 (26.9)25 (26.9) <0.0001<0.0001

Day > 35 after Major BleedDay > 35 after Major Bleed 2.2 (1.5-3.2)2.2 (1.5-3.2) 41 (44.1)41 (44.1) <0.0001<0.0001

P-valueP-valueP-valueP-valueDeaths (n/%)Deaths (n/%)Deaths (n/%)Deaths (n/%)HR ± 95% CIHR ± 95% CIHR ± 95% CIHR ± 95% CI

0.5 1 2 4 8 16

HR (CI)HR (CI)HR (CI)HR (CI)

Impact of MI and Major Bleeding (non-CABG) in Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Yearthe First 30 Days on Risk of Death Over 1 Year

ACUITY TRIAL—Cox model adjusted for baseline predictors: Bleeding and MI as time updated covariates ACUITY TRIAL—Cox model adjusted for baseline predictors: Bleeding and MI as time updated covariates

Stone, ACC 2007Stone, ACC 2007

In-Hospital Bleeding and Discharge TherapiesIn-Hospital Bleeding and Discharge TherapiesN=2498 pts in PREMIER RegistryN=2498 pts in PREMIER Registry

Less likelyLess likelyLess likelyLess likely More likelyMore likelyMore likelyMore likely

Wang TY, et.al. Wang TY, et.al. Circulation (in press)Circulation (in press)Wang TY, et.al. Wang TY, et.al. Circulation (in press)Circulation (in press)

DischargeDischarge1 Month1 Month6 Months6 Months1 Year1 Year

DischargeDischarge1 Month1 Month6 Months6 Months1 Year1 Year

DischargeDischarge1 Month1 Month6 Months6 Months1 Year1 Year

Aspirin

Thienopyridine

Beta-Blocker

0 0.5 1.0 1.5

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

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

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

► The risk is at least similar to that conferred by MI (maybe The risk is at least similar to that conferred by MI (maybe higher)higher)

► The risk is persistent out to 1 year while the risk from recurrent The risk is persistent out to 1 year while the risk from recurrent ischemia appears limited to 30 daysischemia appears limited to 30 days

► Decisions made in the ED may affect subsequent bleeding risk, Decisions made in the ED may affect subsequent bleeding risk, and in turn, evidence-based therapy and clinical outcomesand in turn, evidence-based therapy and clinical outcomes

Bleeding and Outcomes — Conclusions

Bleeding in ACS

Question To Be AnsweredQuestion To Be Answered

Can blood transfusionCan blood transfusion“correct” adverse outcomes “correct” adverse outcomes

associate with bleeding?associate with bleeding?

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

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

Transfusion in ACSTransfusion in ACS

N=24,111N=24,111

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

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

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

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

PRBC Transfusion Among NSTE ACS PatientsPRBC Transfusion Among NSTE ACS Patients

Adjusted fortransfusion propensity

Adjusted for baseline characteristics

Adjusted for baseline characteristics, bleeding propensity, transfusion propensity, and nadir HCT

Adjusted fortransfusion propensity

Adjusted for baseline characteristics

Adjusted for baseline characteristics, bleeding propensity, transfusion propensity, and nadir HCT

3.77 (3.13, 4.523.77 (3.13, 4.523.77 (3.13, 4.523.77 (3.13, 4.52

3.54 (2.96, 4.23)3.54 (2.96, 4.23)3.54 (2.96, 4.23)3.54 (2.96, 4.23)

3.94 (3.26, 4.75)3.94 (3.26, 4.75)3.94 (3.26, 4.75)3.94 (3.26, 4.75)

-4.0-4.0 1.0 1.0 10.0 10.0-4.0-4.0 1.0 1.0 10.0 10.0

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

*Non-CABG patients only

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

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

DeathDeath

Death or Re-MIDeath or Re-MI

1.01.0 2.02.0

9.4%

2.3%

18.8%

11.0%

29.2%

4.8%7.1%

1.3%

IschemicComposite

Death MI (all) UnplannedRevasc

30 d

ay e

vent

s (%

)

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

9.4%

2.3%

18.8%

11.0%

29.2%

4.8%7.1%

1.3%

IschemicComposite

Death MI (all) UnplannedRevasc

30 d

ay e

vent

s (%

)

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

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

9.4%

2.3%

18.8%

11.0%

29.2%

4.8%7.1%

1.3%

IschemicComposite

Death MI (all) UnplannedRevasc

30

da

y e

ve

nts

(%

)

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

P<0.0001 for all

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

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.

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

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

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

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

Blood Transfusion — Conclusions

Bleeding in ACS

Question To Be AnsweredQuestion To Be Answered

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

Question To Be AnsweredQuestion To Be Answered

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

Bleeding and Resource Use Bleeding and Resource Use Predictors of Total CostsPredictors of Total Costs

$3,370

$1,158

$2,164

$7,188

$12,409

$2,488

$5,255

$2,436

$1,336

0

2,000

4,000

6,000

8,000

10,000

12,000

14,000

Mod/SevBld

UA Cath PCI CABG Pacemaker IABP ICU day Non-ICUday

$

Moderate/severe bleedModerate/severe bleedPer patient cost - $530Per patient cost - $530

Transfusion - $2,080, P < 0.01Transfusion - $2,080, P < 0.01Per patient cost - $287Per patient cost - $287

Moderate/severe bleedModerate/severe bleedPer patient cost - $530Per patient cost - $530

Transfusion - $2,080, P < 0.01Transfusion - $2,080, P < 0.01Per patient cost - $287Per patient cost - $287

Model C-index=0.87Model C-index=0.87

Adjusted for patient characteristicsAdjusted for patient characteristics

Model C-index=0.87Model C-index=0.87

Adjusted for patient characteristicsAdjusted for patient characteristicsRao SV, et. al. AHJ 2008.

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

► The available costs data clearly show that a The available costs data clearly show that a balance must be struck between ischemia balance must be struck between ischemia reduction and bleedingreduction and bleeding

● Both ischemic complications and bleeding are Both ischemic complications and bleeding are associated with increased costs such that any cost associated with increased costs such that any cost savings realized by reducing one is offset by cost savings realized by reducing one is offset by cost increases associated with the otherincreases associated with the other

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

Bleeding and Costs — Conclusions

Risk versus BenefitRisk versus Benefit

ThrombosisThrombosisThrombosisThrombosis

BleedingBleedingBleedingBleeding

► Decision made to pursue rapid invasive risk Decision made to pursue rapid invasive risk stratificationstratification● High-risk featuresHigh-risk features

• Elevated troponinElevated troponin• Ongoing chest pain despiteOngoing chest pain despite

medical therapymedical therapy

► Antithrombin therapy choicesAntithrombin therapy choices● Risk for bleedingRisk for bleeding

• Age, Female sex, renalAge, Female sex, renalinsufficiency, anemiainsufficiency, anemia

● Bivalirudin bolus and gtt initiatedBivalirudin bolus and gtt initiated

► AngiographyAngiography

Case PresentationCase Presentation

Addressing the Challenges of Addressing the Challenges of Selecting an Anticoagulation StrategySelecting an Anticoagulation Strategy

Bleeding RiskBleeding RiskBleeding RiskBleeding Risk

Ischemic RiskIschemic RiskIschemic RiskIschemic Risk

Renal functionRenal functionRenal functionRenal functionAgeAgeAgeAge

Time to cathTime to cathTime to cathTime to cath

CostCostCostCost

Ease of useEase of useEase of useEase of use

PCI vs CABG vs Med RxPCI vs CABG vs Med RxPCI vs CABG vs Med RxPCI vs CABG vs Med Rx

UPSTREAM ACS CAREUPSTREAM ACS CARECollaborations, Models, and ProtocolsCollaborations, Models, and Protocols

UPSTREAM ACS CAREUPSTREAM ACS CARECollaborations, Models, and ProtocolsCollaborations, Models, and Protocols

The Mandate to Cooperate The Mandate to Cooperate and Collaborateand Collaborate

EDED

EmergencyEmergencyDepartmentDepartment

ICIC

InterventionalInterventionalCardiologyCardiology

++TT

TherapeuticTherapeuticTeamsTeams

++ ACSACSforfor