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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
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