Importance and Impact of Importance and Impact of Bleeding on ACS Clinical Bleeding on ACS Clinical

OutcomesOutcomes

Sunil V. Rao MDSunil V. Rao MDAssistant Professor of MedicineAssistant Professor of Medicine

Duke University Medical CenterDuke University Medical Center

Durham VA Medical CenterDurham VA Medical Center

Duke Clinical Research InstituteDuke Clinical Research Institute

DisclosuresDisclosures

Consultant and/or Speaker’s BureauConsultant and/or Speaker’s Bureau Sanofi-AventisSanofi-Aventis The Medicines CompanyThe Medicines Company PfizerPfizer Cordis Cordis

Antithrombotic Pharmacotherapy During PCI: Antithrombotic Pharmacotherapy During PCI: 25 Years of Evolving Therapy25 Years of Evolving TherapyAntithrombotic Pharmacotherapy During PCI: Antithrombotic Pharmacotherapy During PCI: 25 Years of Evolving Therapy25 Years of Evolving Therapy

1970s1970sEmpirical treatment with heparin and Empirical treatment with heparin and aspirinaspirin

1980s1980sRandomized and observational studiesRandomized and observational studies aspirin: no aspirin: no restenosis; but restenosis; but acute complications acute complications heparin: threshold 300 seconds ACTheparin: threshold 300 seconds ACT

1990s1990sEra of stents and platelet blockadeEra of stents and platelet blockade stents: “shotgun” approach stents: “shotgun” approach ASA + ADP-inhibitors ASA + ADP-inhibitors GP IIb/IIIa blockade: antibody and SMIGP IIb/IIIa blockade: antibody and SMI heparin: heparin: doses; LMWH doses; LMWH

2000s2000sTargeted anticoagulants Targeted anticoagulants (DTIs,Anti-Xa)(DTIs,Anti-Xa)Challenge of optimal combinationsChallenge of optimal combinations

1970s1970sEmpirical treatment with heparin and Empirical treatment with heparin and aspirinaspirin

1980s1980sRandomized and observational studiesRandomized and observational studies aspirin: no aspirin: no restenosis; but restenosis; but acute complications acute complications heparin: threshold 300 seconds ACTheparin: threshold 300 seconds ACT

1990s1990sEra of stents and platelet blockadeEra of stents and platelet blockade stents: “shotgun” approach stents: “shotgun” approach ASA + ADP-inhibitors ASA + ADP-inhibitors GP IIb/IIIa blockade: antibody and SMIGP IIb/IIIa blockade: antibody and SMI heparin: heparin: doses; LMWH doses; LMWH

2000s2000sTargeted anticoagulants Targeted anticoagulants (DTIs,Anti-Xa)(DTIs,Anti-Xa)Challenge of optimal combinationsChallenge of optimal combinations

Progressively better outcomes with PCIProgressively better outcomes with PCI

Unadjusted Outcomes after PCI

0

1

2

3

4

5

6

7

8

1977-1981

1985-1986

1990-1994

1997-1998

%

In-hosp Mortality

Emer CABG

From the NHLBI(I), NHLBI (II), NACI, and NHLBIFrom the NHLBI(I), NHLBI (II), NACI, and NHLBI

Dynamic RegistriesDynamic Registries

From the NHLBI(I), NHLBI (II), NACI, and NHLBIFrom the NHLBI(I), NHLBI (II), NACI, and NHLBI

Dynamic RegistriesDynamic Registries

CRUSADE In-Hospital OutcomesCRUSADE In-Hospital Outcomes

Death Death 4.3 4.3 %%

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

CHF CHF 8.0 % 8.0 %

Cardiogenic Shock Cardiogenic Shock 2.6 2.6 %%

Stroke Stroke 0.8 % 0.8 %

Non-CABG TransfusionNon-CABG Transfusion 9.9 % 9.9 %

CRUSADE: Quarter 1, 2004-Quarter 4, 2004 (n=39,933)

Bleeding and ACSBleeding and ACS

Older AgeOlder Age

Female GenderFemale Gender

Renal FailureRenal Failure

History of BleedingHistory of Bleeding

Right Heart CatheterizationRight Heart Catheterization

GPIIbIIIa antagonistsGPIIbIIIa antagonists

IndependentPredictors of MajorBleeding in MarkerPositive Acute Coronary Syndromes

Moscucci, GRACE Registry, Eur H J 2003Moscucci, GRACE Registry, Eur H J 2003

Excess dosing of Gp IIb/IIIa and bleeding in womenExcess dosing of Gp IIb/IIIa and bleeding in womenN=32,601 patients from CRUSADEN=32,601 patients from CRUSADE

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

Procedural factorsProcedural factorsFemoral arterial accessFemoral arterial access

Sherev DA, CCI 2005Sherev DA, CCI 2005

““Major” Bleeding – Incidence in ACS Clinical TrialsMajor” Bleeding – Incidence in ACS Clinical Trials

0

2

4

6

8

10

12

GUSTOIIb

OASIS-2 PRISM-PLUS

PURSUIT PRISM CURE SYNERGY

%

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. 2005Rao SV, et al. Rao SV, et al. Am J CardiolAm J Cardiol. 2005. 2005

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

Bleeding and Outcomes in NSTE ACSBleeding and Outcomes in NSTE ACS 26,452 patients from PURSUIT, PARAGON A, PARAGON B, GUSTO IIb 26,452 patients from PURSUIT, PARAGON A, PARAGON B, GUSTO IIb

NSTNST

Adjusted Hazard Ratios for Mortality by Bleeding SeverityAdjusted Hazard Ratios for Mortality by Bleeding Severity

Bleeding Bleeding severityseverity

30d Death30d Death 6 mo Death6 mo Death

Mild*Mild* 1.61.6 1.41.4

Moderate*Moderate* 2.72.7 2.12.1

Severe*Severe* 10.610.6 7.57.5

*p<0.0001*p<0.0001Bleeding as a time-dependent covariateBleeding as a time-dependent covariate

Rao SV, et.al. Rao SV, et.al. AJC AJC 20052005Rao SV, et.al. Rao SV, et.al. AJC AJC 20052005

Bleeding & Outcomes - Data from CURE TrialBleeding & Outcomes - Data from CURE Trial

Life ThreateningLife ThreateningLife ThreateningLife Threatening

MajorMajorMajorMajor

MinorMinorMinorMinor

No bleedingNo bleedingNo bleedingNo bleeding

Mor

talit

y (%

)M

orta

lity

(%)

Mor

talit

y (%

)M

orta

lity

(%)

25252525

20202020

15151515

10101010

55 55

0000

0000 30303030 60606060 90909090 120120120120 150150150150 180180180180

Eikelboom JW, et. al. Eikelboom JW, et. al. Circulation Circulation 2006 2006Eikelboom JW, et. al. Eikelboom JW, et. al. Circulation Circulation 2006 2006

8.28.5

12.7

1.2

11.4

19.2

0

5

10

15

20

25

GUSTOMild

GUSTOMod

GUSTOSev

TIMI Mini TIMI Min TIMI Maj

%

Bleeding Incidence : Impact of definitionBleeding Incidence : Impact of definitionN=15,858 ACS pts from PURSUIT & PARAGON BN=15,858 ACS pts from PURSUIT & PARAGON B

Rao SV, et.al. Rao SV, et.al. JACC JACC 20062006Rao SV, et.al. Rao SV, et.al. JACC JACC 20062006

Effect of bleeding definition on 30d death/MIEffect of bleeding definition on 30d death/MIN=15,858 ACS patients from PURSUIT & PARAGON BN=15,858 ACS patients from PURSUIT & PARAGON B

Rao SV, et.al. Rao SV, et.al. JACC JACC 20062006Rao SV, et.al. Rao SV, et.al. JACC JACC 20062006

Increased RiskIncreased RiskDecreased RiskDecreased Risk

8800

27349

1300

5900

0

10000

20000

30000

Urgent PCI Urgent CABG Minor bleed Major bleed

$$$

Costs

8800

27349

1300

5900

0

10000

20000

30000

Urgent PCI Urgent CABG Minor bleed Major bleed

$$$

Costs

Mark DB, et al. Circ 1996Mark DB, et al. Circ 1996Mark DB, et al. Circ 1996Mark DB, et al. Circ 1996

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

Abciximab versus Placebo

ischemic costs: $523

major bleed costs: $458

Abciximab versus Placebo

ischemic costs: $523

major bleed costs: $458

Risk versus benefitRisk versus benefit

ThrombosisThrombosis

BleedingBleeding

Bleeding – Immediate clinical consequencesBleeding – Immediate clinical consequences

Cessation of antithrombotic therapyCessation of antithrombotic therapy

HypotensionHypotension

Reversal of antithrombotic therapyReversal of antithrombotic therapy

Blood transfusionBlood transfusion

1.0Less than US More than US

Unadjusted

Adjustedfor baseline

characteristics

Adjustedfor baseline

characteristics and procedures

Adjustedfor baseline

characteristics,procedures, and

bleeding

0.24 (0.19 – 0.30)

0.19 (0.15 – 0.25)

0.69 (0.54 – 0.88)

0.76 (0.59 – 1.00)

Geographic variation in transfusion relative to U.S. N=24,112

Rao SV, et. al. AHA 2005Rao SV, et. al. AHA 2005

Variations in Transfusion Rates for NSTE ACS Across HospitalsVariations in Transfusion Rates for NSTE ACS Across Hospitals

0

5

10

15

20

25

30

0 4 8 12 16 20 24 > 28

0

5

10

15

20

25

30

0 4 8 12 16 20 24 > 28

Percentage of Patients Receiving Blood Transfusions (%)Percentage of Patients Receiving Blood Transfusions (%)

Per

cen

tag

e o

f H

osp

ital

s (%

)P

erce

nta

ge

of

Ho

spit

als

(%)

Yang X, et. al. JACC 2005Yang X, et. al. JACC 2005

Non-CABGNon-CABG

OverallOverall

Cooperative Cardiovascular ProjectCooperative Cardiovascular Project30 day death by transfusion and Hct30 day death by transfusion and Hct

78,974 pts > 65 years with 78,974 pts > 65 years with confirmed MIconfirmed MI

Grouped into categories of Grouped into categories of admission hematocritadmission hematocrit

Excluded pts with bleeding Excluded pts with bleeding and those with CABGand those with CABG

Primary endpoint: 30-day Primary endpoint: 30-day mortalitymortality

Wu W, NEJM 2001Wu W, NEJM 2001

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

<24% 24-27 27-30 30-33 33-36 36-39 >39%

Odds ratio for30 day mortalityOdds ratio for30 day mortality

HigherHigherHigherHigher

LowerLowerLowerLower

HCT< 33 %HCT< 33 %

Transfusion in ACSTransfusion in ACSN=24,111 pts from PURSUIT, PARAGON B, GUSTO IIbN=24,111 pts from PURSUIT, PARAGON B, GUSTO IIb

30 Day Survival By Transfusion Group

0.9

0.92

0.94

0.96

0.98

1

0 5 10 15 20 25 30

Days

Su

rviv

al R

ates

No TransfusionTransfusion

Rao SV, et. al., Rao SV, et. al., JAMA JAMA 20042004

PRBC Transfusion Among NSTE ACS Patients:PRBC Transfusion Among NSTE ACS Patients:Cox model for 30-day Death (N=24,111)Cox model for 30-day Death (N=24,111)

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

1.01.0 1010-4.0-4.0

Adjusted for transfusion Adjusted for transfusion propensitypropensity

Adjusted for baselineAdjusted for baselinecharacteristicscharacteristics

Adjusted for baseline Adjusted for baseline Characteristics, bleedingCharacteristics, bleedingpropensity, transfusion propensity, transfusion Propensity, & nadir HCTPropensity, & nadir HCT

3.77 (3.14, 4.52)3.77 (3.14, 4.52)

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

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

Rao SV, et. al., Rao SV, et. al., JAMA JAMA 20042004

Adjusted Risk of In-Hospital Outcomes

By Transfusion Status*

Adjusted Risk of In-Hospital Outcomes

By Transfusion Status*

* Non-CABG patients onlyYang X, et. al. JACC 2005* Non-CABG patients onlyYang X, et. al. JACC 2005

Death

Death or Re-MI

Death

Death or Re-MI

11 2.02.0

N=74,971 ACS pts. from 478 centersN=74,971 ACS pts. from 478 centers

Properties of PRBCsProperties of PRBCs

Low 2,3 DPG*

High O2 affinity*

Depleted of Nitric Oxide NO plays a fundamental role in O2

exchange†

Low 2,3 DPG*

High O2 affinity*

Depleted of Nitric Oxide NO plays a fundamental role in O2

exchange†

*Welch HG, et. al. *Welch HG, et. al. Ann Int MedAnn Int Med 1992 1992††Stamler JS, et. al. Stamler JS, et. al. Science Science 19971997

Effects of TransfusionEffects of Transfusion

Packed red cells Depleted of NO

Function as NO “sinks” Lead to vasoconstrictionPlatelet aggregationIneffective O2 delivery

Associated with increases in CRP and IL6*

Packed red cells Depleted of NO

Function as NO “sinks” Lead to vasoconstrictionPlatelet aggregationIneffective O2 delivery

Associated with increases in CRP and IL6*

*Fransen E, et. al. *Fransen E, et. al. Chest Chest 19991999

STEEPLESTEEPLEIV enoxaparinIV enoxaparin

STEEPLESTEEPLEIV enoxaparinIV enoxaparin

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

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

Fondaparinux2.5 mg sc once daily

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

Study Design: Randomized, Double Blind

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

local practice

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

local practicelocal practice

RandomizeRandomize

Enoxaparin1 mg/kg sc twice daily

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

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

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

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

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

Outcomes

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

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

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

N=20,000

OASIS 5OASIS 5FondaparinuxFondaparinux

OASIS 5OASIS 5FondaparinuxFondaparinux

REPLACE-2REPLACE-2

ACUITYACUITYBivalirudinBivalirudin

REPLACE-2REPLACE-2

ACUITYACUITYBivalirudinBivalirudin

STEEPLE Investigators. STEEPLE Investigators. NEJMNEJM 2006 2006

OASIS Investigators. OASIS Investigators. NEJMNEJM 2006 2006

Lincoff AM, et. al. Lincoff AM, et. al. JAMA JAMA 20032003

Stone GW. Stone GW. ACCACC 2006 2006

STEEPLE Investigators. STEEPLE Investigators. NEJMNEJM 2006 2006

OASIS Investigators. OASIS Investigators. NEJMNEJM 2006 2006

Lincoff AM, et. al. Lincoff AM, et. al. JAMA JAMA 20032003

Stone GW. Stone GW. ACCACC 2006 2006

Addressing the challenge of selecting an anticoagulation strategyAddressing the challenge of selecting an anticoagulation strategy

Bleeding RiskBleeding RiskBleeding RiskBleeding Risk

Ischemic RiskIschemic RiskIschemic RiskIschemic Risk

Renal functionRenal functionRenal functionRenal functionAgeAgeAgeAge

Time to cathTime to cathTime to cathTime to cath

CostCostCostCost

Ease of useEase of useEase of useEase of use

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

Bleeding and ACS outcomesBleeding and ACS outcomesConclusionsConclusions

Bleeding is more common than we thinkBleeding is more common than we think

Clinical bleeding and transfusion are associated with Clinical bleeding and transfusion are associated with worse outcomes and costworse outcomes and cost

Strategies that maintain an adequate antithrombotic Strategies that maintain an adequate antithrombotic effect to reduce ischemia while minimizing the risk effect to reduce ischemia while minimizing the risk of bleeding may improve survival in patients with of bleeding may improve survival in patients with acute ischemic heart diseaseacute ischemic heart disease The traditional efficacy-safety relationship has The traditional efficacy-safety relationship has

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