Unstable Angina-NSTEMI.ppt

Daniel I. Simon, M.D.Daniel I. Simon, M.D.Chief, Division of Cardiovascular MedicineChief, Division of Cardiovascular Medicine

Director, Heart & Vascular InstituteDirector, Heart & Vascular InstituteUniversity Hospitals Case Medical CenterUniversity Hospitals Case Medical Center

Herman K. Hellerstein Professor of MedicineHerman K. Hellerstein Professor of MedicineCase Western Reserve University School of MedicineCase Western Reserve University School of Medicine

Anti-Thrombotic Therapy in ACS: Update for 2008

Disclosures-Drug

• Accumetrics– Research Grant

• Eli Lilly– Consultant– Speaker honoraria

• Medicines Company– Steering Committee– Speaker bureau

• Millennium– Consultant

• Sanofi-Aventis– Consultant– Speaker honoraria

• Schering-Plough– Scientific Advisory Board– Speaker honoraria– Research grant

Disclosures-DeviceDisclosures-Device

• Boston Scientific/Guidant– TAXUS V DSMB– Speaker honoraria– Live-case transmission support

• Cordis/J&J– Consulting– Speaker honoraria– Fellowship research support– FDA panel team

• Medtronic– Consulting

CaseCase• 44 yo women with 2 days of intermittent 44 yo women with 2 days of intermittent

CP occurring with minimal exertion and at CP occurring with minimal exertion and at rest.rest.

• CRF: HTN, smokerCRF: HTN, smoker• Med: ACEI, thiazide diuretic, ASAMed: ACEI, thiazide diuretic, ASA• PE: WNLPE: WNL• Labs: CPK 54, cTnI 0.13Labs: CPK 54, cTnI 0.13• EKGEKG

Management IssuesManagement Issues

• UFH, LMWH, fondaparinux, or bivalirudinUFH, LMWH, fondaparinux, or bivalirudin

• ClopidogrelClopidogrel– 300 or 600 mg load300 or 600 mg load– DurationDuration

• Invasive or conservative strategyInvasive or conservative strategy

• If invasive, cath <6h or tomorrowIf invasive, cath <6h or tomorrow

• GP IIb/IIIa inhibitor upstream or in cath labGP IIb/IIIa inhibitor upstream or in cath lab

Link Between Overall ACC/AHA Guidelines Adherence and Mortality

Link Between Overall ACC/AHA Guidelines Adherence and Mortality

Peterson et al, ACC 2004Peterson et al, ACC 2004

5.95

5.16 4.97

4.16

5.074.63

4.17

6.33

0

1

2

3

4

5

6

7

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

Hospital Composite Quality Quartiles

% I

n-H

osp

Mo

rtal

ity

Adjusted Unadjusted

5.95

5.16 4.97

4.16

5.074.63

4.17

6.33

0

1

2

3

4

5

6

7

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

Hospital Composite Quality Quartiles

% I

n-H

osp

Mo

rtal

ity

Adjusted Unadjusted

Every 10% Every 10% in guidelines adherence in guidelines adherence 11% 11% in in mortalitymortality

PTCA/stentPTCA/stent

Fatal thrombus

Plaque Rupture:A common substrate for acute coronary syndromes

- Michael Davies- Earling Falk- Paris Constantinides

Clinical

Presentation

% Patients

ACC/NCDR

N=210,158

UFH

+

IIb/IIIa Inhibitor

Bivalirudin UFH

+

clopidogrel

STEMI 13.1% RAPPORT

ISAR-2

ADMIRAL

CADILLAC

HORIZONS

NSTEMI 15.4% CAPTURE

PRISM/PRISM-PLUS

PURSUIT

PARAGON A/B

ACUITY ISAR-REACT 2

Non-inferiority

rejected

USA 35.6% CAPTURE

PRISM/PRISM-PLUS

PURSUIT

PARAGON A/B

ACUITY ISAR-REACT 2

Non-inferiority

rejected

Elective PCI

Low-risk ACS

33.9% EPILOG

EPISTENT

ESPRIT

REPLACE-2 ISAR-REACT

64%

Anti-Thrombotic Strategies in PCI

USA/Non-ST Elevation ACSUSA/Non-ST Elevation ACS

Generally caused by partially occlusive,

platelet-rich thrombus

Unobstructedlumen

thrombus

Results from cross-linking of fibrinogen by platelet GP IIb-

IIIa receptors at sites of plaque rupture

platelet

fibrinogen

Rupturedplaque

GP IIb-IIIa

Artery wall

AspiriAspirinn++

IV heparin/LMWH*IV heparin/LMWH*++

IV platelet IV platelet GP IIb/IIIa GP IIb/IIIa AntagonistAntagonist

++clopidogrelclopidogrel

AspirinAspirin++

SQ LMWH*SQ LMWH*oror

IV heparinIV heparin++

clopidigrelclopidigrel

Possible Possible ACSACS

Likely/Definite Likely/Definite ACSACS

Definite ACSDefinite ACSWith Cath and PCIWith Cath and PCI

AspirinAspirin

Braunwald et al. Braunwald et al. J Am Coll Cardiol.J Am Coll Cardiol. 2000;36:970-1062 2000;36:970-1062

Class I Recommendations for Antithrombotic Therapy

*Class IIa: Enoxaparin preferred over UFH

UA/NSTEMI GUIDELINES – March 15 2002UA/NSTEMI GUIDELINES – March 15 2002

Prior CABGHigh-risk findings on noninvasive stress testing

PCI within 6 monthsRecurrent angina/ischemia with CHF, S3, PE, rales, etc.

Sustained VTST-segment depression

Hemodynamic instabilityElevated TnT or Tnl

Ejection fraction <.40Recurrent angina/ischemia

Class IAn early invasive strategy in patients with UA/NSTEMI and any of the following high-risk indicators (Level of Evidence: A)

Braunwald et al. J Am Coll Cardiol. 2002;40:1366-1374.

ACC/AHA Guidelines for UA/NSTEMI:Early Invasive Strategy

Invasive vs. Conservative Strategy for UA/NSTEMI – All Studies

TIMI IIIBTIMI IIIB

Conservative Invasive

VANQWISHVANQWISHMATEMATE

FRISC IIFRISC II

TACTICS-TIMI 18

TACTICS-TIMI 18

VINOVINO

RITA-3RITA-3

# Pts: 1140 1674 7018

TRUCS TRUCS

ISAR-COOL ISAR-COOL

ICTUSICTUS

Bavry AA, et al. J Am Coll Cardiol 2006;48:1319–1325. Reprinted with permission from Elsevier. CI = confidence interval; RR = relative risk.

Relative Risk of All-Cause Mortality for Early Invasive Therapy Compared With Conservative

Therapy at a Mean Follow-Up of 2 y

0%

2%

4%

6%

8%

10%

PCIPCI

N=2754N=2754PP=0.001=0.001

N=12,296N=12,296PP=0.001=0.001

+24 h +48 h +72 h +24 h +48 h

Boersma et al. Circulation. 1999;100:2045

4.3%4.3%

2.9%2.9%

8.0%8.0%

4.9%4.9%

Dea

th o

r M

ID

eath

or

MI

Medical RxMedical Rx Post PCIPost PCI

Control

GP IIb/IIIa inhibitor

0

GP IIb-IIIa Inhibition:Beneficial pre- and post-PCI

Meta-analysis CAPTURE, PURSUIT, PRISM-PLUS

ESPRIT Sub-study:Procedural risk vs. clinical risk

Tcheng & Simon. 2008

ADP Receptor Blockers:ADP Receptor Blockers:CURE, PCI-CURE, CREDO,CURE, PCI-CURE, CREDO,ISAR-REACT, ISAR-COOL,ISAR-REACT, ISAR-COOL,

ISAR-REACT 2, CHARISMA,ISAR-REACT 2, CHARISMA,TRITONTRITON

Different Mechanisms of ActionDifferent Mechanisms of Action Oral Antiplatelet AgentsOral Antiplatelet Agents

CollagenThrombin

TXA2

Aspirin

ADPADP

(FibrinogenReceptor)

clopidogrel bisulfate

TXA2

ADP

Dipyridamole

Phosphodiesterase

ADP

Gp IIb/IIIa Activation

COXCOX

ticlopidine HCl

ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase.Schafer AI. Am J Med. 1996;101:199–209.

Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events

Aspirin 75-325mg

Aspirin 75-325mg

Plac

ebo

Clopid

ogrel

300m

g

load

ing d

ose

Patients withNon-ST elevation

Acute Coronary

Syndrome

R

1 3 6 9 12 Months

The CURE Trial InvestigatorsThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

3 months double-blind treatment 12 months3 months double-blind treatment 12 months

Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.*

(6259 patients)

Placebo + ASA 75-325 mg q.d.*(6303 patients)

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

Cu

mu

lati

ve H

azar

d R

ate

Clopidogrel Clopidogrel + ASA*+ ASA*

33 66 99

Placebo Placebo + ASA*+ ASA*

Months of Follow-UpMonths of Follow-Up

11.4%11.4%

9.3%9.3%

20% RRR20% RRRPP < 0.001 < 0.001

N = 12,562N = 12,562

00 1212

* In combination with standard therapy

The CURE Trial InvestigatorsThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

Primary End Point: MI/Stroke/CV Death

0.150.15

0.100.10

0.050.05

0.00.0

0 100100 200200 300300 400400Days of follow-upDays of follow-up

12.6%12.6%

8.8%8.8%

31% RRR31% RRRP P = 0.002= 0.002N = 2658N = 2658

ClopidogrelClopidogrel+ ASA*+ ASA*

PlaceboPlacebo+ ASA*+ ASA*

Cu

mu

lati

ve H

azar

d R

ate

Composite of CV death or MI from randomization to end of follow-up

Overall Long-Term ResultsPCI-CURE

Mehta et al. Lancet 2001;358:527-33

Sabatine MS, et al. JAMA 2006

Optimal Timing?

Steinhubl et al. J Am Coll Cardiol 2006;47:939-43

Hours After Randomization

Within 24 hrs of Randomization

Cumulative Hazard Rates

0.0

0.005

0.010

0.015

0.020

0.025

0 2 4 6 8 10 12 14 16 18 20 22 24

p=0.003

Placebo+ ASA

Clopidogrel+ ASA

34%34%Relative RiskRelative Risk

ReductionReduction

MI/Stroke/CV MI/Stroke/CV Death/Severe IschemiaDeath/Severe Ischemia

Yusuf et al. for the CURE Trial Investigators. Yusuf et al. for the CURE Trial Investigators. CirculationCirculation. 2003;107:966. 2003;107:966

Major/Life-Threatening Bleeds Major/Life-Threatening Bleeds within 7 days of CABG Surgerywithin 7 days of CABG Surgery

PlaceboPlacebo ClopidClopid RRRR pp

Stopped Stopped << 5 days 5 days prior to CABGprior to CABG

N = 476N = 476 N = 436N = 436

Pts with Maj/LT BldPts with Maj/LT Bld TIMI MajorTIMI Major

6.3%6.3%2.7%2.7%

9.6%9.6%2.5%2.5%

1.531.530.920.92

0.060.06NSNS

Stopped > 5 days Stopped > 5 days prior to CABGprior to CABG

N = 454N = 454 N = 456N = 456

Pts with Maj/LT Bld Pts with Maj/LT Bld TIMI MajorTIMI Major

5.3%5.3%2.4%2.4%

4.4%4.4%1.8%1.8%

0.830.830.720.72

0.530.53NSNS

Yusuf et al. for the CURE investigators. NEJM. 2001;345:494-502Fox et al. Circulation. 2004;110:1202-08

7.57.2

9.1

7.9

5.96.5

0

2

4

6

8

10

(%)

All <= 5 days >5 days

Clopidogrel

Placebo

Major Bleeding In ThoseUndergoing CABG

All P=NS

n=67 n=69 n=33 n=38 n=34 n=31

Time from d/c of study med to CABG

TARGET: TARGET: Clopidogrel pre-treatmentClopidogrel pre-treatment

Chan et al. J Amer Coll Cardiol 2003; 42:1196

Clopidogrel pre-treatment: RR = 0.61 (0.44-0.84) P=0.003

ISAR-COOL:“cooling” off strategyISAR-COOL:“cooling” off strategyEarly <6h vs. cool-off 3-5d Early <6h vs. cool-off 3-5d

Neumann et al. JAMA 2003;290:1593-9

ASA 100 mg BIDClopidogrel 600 mg load, 75 mg BIDIV heparin 60U/kgTirofiban 10 g/kg, 0.1 g/kg/min

ISAR-CHOICE:300 vs. 600 vs. 900 mg ISAR-CHOICE:300 vs. 600 vs. 900 mg

Von Beckerath et al. Circulation 2005:112:2946-2950

Clopidogrel Non-responsiveness

0

5

10

15

20

25

30

35

%

300 mg 600 mg

P<0.002

28

8

32

8

Gurbel et al. J Amer Coll Cardiol 2005

ADP 5 ADP 20

P<0.002

% Non-responders at 24h

ARMYDA-2:Clopidogrel 300 vs. 600 mg ARMYDA-2:Clopidogrel 300 vs. 600 mg

Patti et al. Circulation 2005:111:2099-2106

Cuisset et al. J Amer Coll Cardiol 2006;48:1339-45

Clopidogrel 300 mg (n=146) or clopidogrel 600 mg (n=146), Clopidogrel 300 mg (n=146) or clopidogrel 600 mg (n=146), platelet reactivity (ADP 10 platelet reactivity (ADP 10 M) and clinical outcomesM) and clinical outcomes

Clopidogrel and Platelet Reactivity

High post-High post-treatment treatment platelet platelet reactivity reactivity (HPPR) > 70%(HPPR) > 70%

25% 300 mg25% 300 mg15% 600 mg15% 600 mgP=0.03P=0.03

CV Event-freeCV Event-freeSurvivalSurvivalHPPR: RR 13.8HPPR: RR 13.8P<0.0001P<0.0001

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

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

Secondary Endpoint: In-hospital major and minor bleedingSecondary Endpoint: In-hospital major and minor bleeding

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

Secondary Endpoint: In-hospital major and minor bleedingSecondary Endpoint: In-hospital major and minor bleeding

2022 patients with an episode of angina within the preceding 48 hours and an elevated troponin T level or new ST-segment depression of ≥0.1 mV or

transient (<20 minutes) ST-segment elevation of ≥0.1 mV or new or presumed new bundle-branch block; significant angiographic lesions in a native

coronary vessel or venous bypass graft amenable to and requiring a PCI Placebo Controlled. Randomized. Blinded.

24% female, mean age 66 years, mean follow-up 30 days

2022 patients with an episode of angina within the preceding 48 hours and an elevated troponin T level or new ST-segment depression of ≥0.1 mV or

transient (<20 minutes) ST-segment elevation of ≥0.1 mV or new or presumed new bundle-branch block; significant angiographic lesions in a native

coronary vessel or venous bypass graft amenable to and requiring a PCI Placebo Controlled. Randomized. Blinded.

24% female, mean age 66 years, mean follow-up 30 days

Abciximab(usual bolus or infusion dose)

n=1012

Abciximab(usual bolus or infusion dose)

n=1012

Placebon=1010

Placebon=1010

Pre-treatment with high dose (600mg) clopidogrel at least 2h pre-procedurePre-treatment with high dose (600mg) clopidogrel at least 2h pre-procedure

Kastrati et al. JAMA 2006;295:1531-8Kastrati et al. JAMA 2006;295:1531-8

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

• The primary The primary composite composite endpoint occurred endpoint occurred less frequently in less frequently in the abciximab the abciximab group compared to group compared to placebo (8.9% vs placebo (8.9% vs 11.9%; relative risk 11.9%; relative risk [RR] 0.75 p=0.03)[RR] 0.75 p=0.03)

8.9%

11.9%

0%

5%

10%

15%

Abciximab Placebo

8.9%

11.9%

0%

5%

10%

15%

Abciximab Placebo

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

p=0.03

Kastrati et al. JAMA 2006;295:1531-8Kastrati et al. JAMA 2006;295:1531-8

Study Design

Double-blind

ACS (STEMI or UA/NSTEMI) & Planned PCI

ASA

PRASUGREL60 mg LD/ 10 mg MD

CLOPIDOGREL300 mg LD/ 75 mg MD

1o endpoint: CV death, MI, Stroke2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch

CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleedsKey Substudies: Pharmacokinetic, Genomic

Median duration of therapy - 12 months

N= 13,600

Healthy VolunteerHealthy VolunteerCrossover StudyCrossover Study

-20-20

00

2020

4040

6060

8080

100100

IPA

at

24 h

ou

rs (

%)

IPA

at

24 h

ou

rs (

%)

Response to Response to Prasugrel 60 mgPrasugrel 60 mg

Response to Response to Clopidogrel 300 mgClopidogrel 300 mg

Clopidogrel ResponderClopidogrel Responder

Clopidogrel Non-responderClopidogrel Non-responder

Inte

rpat

ien

tIn

terp

atie

nt

Var

iab

ility

Var

iab

ility

Interp

atient

Interp

atient

Variab

ilityV

ariability

From Brandt JT AHJ 153: 66e9,2007

N=66

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

HR 0.80P=0.0003

HR 0.77P=0.0001

Days

Pri

ma

ry E

nd

po

int

(%)

12.1(781)

9.9 (643)

Primary EndpointPrimary EndpointCV Death,MI,StrokeCV Death,MI,Stroke

NNT= 46

ITT= 13,608ITT= 13,608 LTFU = 14 (0.1%)LTFU = 14 (0.1%)

Stent ThrombosisStent Thrombosis(ARC Definite + Probable)(ARC Definite + Probable)

0

1

2

3

0 30 60 90 180 270 360 450

HR 0.48P <0.0001

Prasugrel

Clopidogrel2.4

(142)

NNT= 77

1.1 (68)

Days

En

dp

oin

t (%

)

Any Stent at Index PCIAny Stent at Index PCI N= 12,844 N= 12,844

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

Days

En

dp

oin

t (%

)

12.1

9.9

HR 1.32(1.03-1.68)

P=0.03

Prasugrel

Clopidogrel1.82.4

138 events

35 events

Balance of Balance of Efficacy and SafetyEfficacy and Safety

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 46

NNH = 167

1.8

0.9 0.9

0.10.3

2.4

1.41.1

0.4 0.3

0

2

4

TIMI MajorBleeds

LifeThreatening

Nonfatal Fatal ICH

Bleeding EventsBleeding EventsSafety CohortSafety Cohort

(N=13,457)(N=13,457)

% E

ven

ts%

Eve

nts

ARD 0.6%ARD 0.6%HR 1.32HR 1.32P=0.03P=0.03

NNH=167 NNH=167

ClopidogrelClopidogrel

PrasugrelPrasugrel

ARD 0.5%ARD 0.5%HR 1.52HR 1.52P=0.01P=0.01

ARD 0.2%ARD 0.2%P=0.23P=0.23

ARD 0%ARD 0%P=0.74P=0.74

ARD 0.3%ARD 0.3%P=0.002P=0.002

ICH in Pts w ICH in Pts w Prior Stroke/TIA Prior Stroke/TIA

(N=518)(N=518)

Clop 0 (0) %Clop 0 (0) % Pras 6 (2.3)%Pras 6 (2.3)% (P=0.02) (P=0.02)

Net Clinical BenefitNet Clinical BenefitDeath, MI, Stroke, Death, MI, Stroke,

Major Bleed (non CABG)Major Bleed (non CABG)

0

5

10

15

0 30 60 90 180 270 360 450Days

En

dp

oin

t (%

)

HR 0.87P=0.004

13.9

12.2

Prasugrel

ClopidogrelITT= 13,608ITT= 13,608

-23

6

-25

-20

-15

-10

-5

0

5

10

Events per 1000 ptsEvents per 1000 pts

MIMI Major BleedMajor Bleed(non CABG)(non CABG)

++All CauseAll CauseMortalityMortality

Clop 3.2%Clop 3.2%Pras 3.0 %Pras 3.0 %

P=0.64P=0.64

Diabetic SubgroupDiabetic Subgroup

0

2

4

6

8

10

12

14

16

18

0 30 60 90 180 270 360 450

HR 0.70P<0.001

Days

En

dp

oin

t (%

)

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 21

N=3146N=3146

17.0

12.2

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel 2.6

2.5

Net Clinical BenefitNet Clinical BenefitBleeding Risk SubgroupsBleeding Risk Subgroups

OVERALL

>=60 kg

< 60 kg

< 75

>=75

No

Yes

0.5 1 2

Prior Stroke / TIA

Age

Wgt

Risk (%)

+ 37

-16

-1

-16

+3

-14

-13

Prasugrel Better Clopidogrel BetterHR

Pint = 0.006

Pint = 0.18

Pint = 0.36

Post-hoc analysisPost-hoc analysis

Bleeding Risk SubgroupsBleeding Risk SubgroupsTherapeutic ConsiderationsTherapeutic Considerations

Significant Net Clinical Benefit

with Prasugrel80%

MD MD 10 mg10 mg

Reduced MD

Guided by PK

Age > 75 or

Wt < 60 kg

16%

Avo

id

Prasu

grel

Prio

r

CV

A/T

IA4%4%

Anti-platelet Therapy in ACSAnti-platelet Therapy in ACS

0

1 08

Placebo APTC CURE TRITON-TIMI 38

Single Antiplatelet Rx

Dual Antiplatelet Rx

Higher IPA

ASAASA +

Clopidogrel ASA + Prasugrel

- 22%

- 20%

- 19%

+ 60% + 38% + 32%

Reduction in

IschemicEvents

Increase in

Major Bleeds

IIaS

C

Direct antithrombin

LMWH

ATXa

ATXa

Pentasaccharide

= saccharide unit.Konkle BA, Schafer AI. In: Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald’s Heart Disease. 7th ed. Vol 2. Philadelphia: Elsevier Saunders; 2005:2067-2092.

ATIIa

Hep

UFH

Lots of Anticoagulant Choices

Study DesignAt least 2 of 3 required:At least 2 of 3 required:

• Age Age 60 60

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

Enoxaparin IV Heparin

Primary endpoint: Death or MI at 30 days

High-RiskHigh-RiskACS PatientsACS Patients

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

Early invasive strategyOther therapy per AHA/ACC Guidelines

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

60 U/kg 60 U/kg 12 U/kg/hr 12 U/kg/hr (aPTT 50-70 sec)(aPTT 50-70 sec)1 mg/kg SC Q12H1 mg/kg SC Q12H

JAMA 2004;292:45-54

SYNERGY: Primary End Point

0 5 10 15 20 25 300.8

0.85

0.9

0.95

1.0

Free

dom

from

Dea

th /

MI

Days from Randomization

UFHEnoxaparin

HR 0.96 (0.87-1.06)

30-Day Death/MI30-Day Death/MI

0.80.8 11 1.21.2

Hazard Ratio (95% CI)

Enoxaparin

Better

UFH

Better

Mahaffey et al, for the SYNERGY Investigators. JAMA. 2004;292:45-54.Adapted from www.clinicaltrialresults.org.

Hazard Ratio (95% CI)

Enox UFHBetter Better

0.60.6 11 22

Hazard Ratio (95% CI)

Enox UFHBetter Better

0.60.6 11 22

Prior Antithrombin Therapy: Efficacy and Safety

Enox UFH (%) (%)Enox UFH (%) (%)

30-DAY DEATH / MI

30-DAY DEATH / MI

BLEEDINGGUSTO Severe

TIMI Major

BLEEDINGGUSTO Severe

TIMI MajorEnox UFH (%) (%)Enox UFH (%) (%)

2.9 2.42.9 2.4Total(n = 9978)

14.0 14.514.0 14.59.1 7.69.1 7.6

3.1 1.83.1 1.8No Prior Rx(n = 2440)

12.6 14.812.6 14.89.7 6.99.7 6.9

3.1 2.23.1 2.2ConsistentTherapy(n = 6138)

13.3 15.913.3 15.99.3 7.99.3 7.9

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

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

Fondaparinux2.5 mg sc once daily

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

Study Design: Randomized, Double Blind

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

local practice

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

local practicelocal practice

RandomizeRandomize

Enoxaparin1 mg/kg sc twice daily

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

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

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

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

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

Outcomes

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

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

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

N=20,000

Death/MI/RI: Day 9

Days

Cum

ulat

ive

Haz

ard

0.0

0.01

0.02

0.03

0.04

0.05

0.06

0 1 2 3 4 5 6 7 8 9

Enoxaparin

Fondaparinux

HR 1.01 95% CI 0.90-1.13

Major Bleeding: 9 Days

Days

Cu

mu

lati

ve H

azar

d

0.0

0.01

0.02

0.03

0.04

0 1 2 3 4 5 6 7 8 9

HR 0.53 95% CI 0.45-0.62

P<<0.00001

Enoxaparin

Fondaparinux

Mortality: Day 30

Days

Cu

mu

lati

ve H

aza

rd0.

00.

010.

020.

03

0 3 6 9 12 15 18 21 24 27 30

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

P=0.022P=0.022

Enoxaparin

Fondaparinux

OASIS-6 Trial: PCI Substudy at 30 Days

There was no difference in the primary endpoint for patients who were managed with primary PCI (6.1% vs 5.1%, P=.19)

Guiding catheter thrombosis in the primary PCI cohort occurred more often with fondaparinux compared with control (n=22 vs n=0, P <.001)

6.1%

5.1%

0%

2%

4%

6%

8%

Fondaparinux Control

Primary Endpoint of Death or MI in PCI Cohort (%)P =.19

Yusuf S, et al. JAMA. 2006;295:1519-1530.Adapted with permission from www.clinicaltrialresults.org

What about direct thrombin inhibitors in ACS and PCI?

Moderate-to high-

riskACS

ACUITY Study Design:First Randomization

An

gio

gra

ph

y w

ith

in 7

2 h

Aspirin in all,Clopidogrel dosing

and timingper local practice

UFH or enox+ GP IIb/IIIa

n=4603

Bivalirudin+ GP IIb/IIIa

n=4604

Bivalirudinalone

n=4,612

R*

Moderate- to high-risk patients with UA or NSTEMIundergoing an invasive strategy (N = 13,819)

Medicalmanagement

PCI

CABG

Stone et al. N Engl J Med 2006

*Stratified by pre-angiography thienopyridine use or administration.

Moderate-to high-risk ACS

ACUITY Study Design: Second Randomization

Moderate- to high-risk patients with unstable anginaor NSTEMI undergoing an invasive strategy (N = 13,819)

Aspirin in all,Clopidogrel

dosing and timingper local practice

Bivalirudinalone N=4612

UFH or EnoxaparinRoutine upstream GPI in all pts (2294)

GPI started in CCL for PCI only (2309)

R

Bivalirudin

R

Routine upstream GPI in all pts (2311)

GPI started in CCL for PCI only (2293)

UF

H, E

no

xaparin

,o

r Bivaliru

din

Routine upstreamGPI in all pts

n=4603

Deferred GPIfor PCI only

N=4604

vsvs

Primary analysis

Secondary

analysis

Stone et al. N Engl J Med 2006

0 1 2

ACUITY: Primary End Point Measures*

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

Risk ratio±95% CI

Risk ratio±95% CI

Primaryend point

Bivalalone

UFH/Enox+ IIb/IIIa

RR (95% CI)

Net clinical outcome

Ischemic composite

Major bleeding

Up

per

bo

un

dar

y n

on

-in

feri

ori

ty

11.7%10.1% 0.86 (0.77-0.97)<.001.015

7.3%7.8% 1.08 (0.93-1.24).02.32

5.7%3.0% 0.53 (0.43-0.65)<.001<.001

P value(noninferior)

(superior)

UFH/Enoxaparin + GP IIb/IIIa vs Bivalirudin alone

*ITT population.

UFH = unfractionated heparin

Stone et al. N Engl J Med 2006

LBCT March 29, 08

ISAR ISAR REACT 3REACT 3

2,289 Pts

30-day Follow-up

2,281 Pts

UFHBivalirudin

PCI

4,570 Patients

Study Population

LBCT March 29, 08

ISAR ISAR REACT 3REACT 3

Days after randomization

Cumulative incidence (%)

0

2

4

6

8

10

0 5 10 15 20 25 30

Primary (Quadruple) EndpointDeath, MI, UTVR, Major Bleeding

8.3%8.7%

RR=0.94 [95% CI, 0.77-1.15], P=0.57

Bivalirudin

UFH

LBCT March 29, 08

ISAR ISAR REACT 3REACT 3

Cumulative incidence (%)

0

2

4

6

8

10

0 5 10 15 20 25 30

Days after randomization

Secondary (Triple) EndpointDeath, MI, UTVR

5.0%5.9%

RR=1.16 [95% CI, 0.91-1.49], P=0.23

Bivalirudin

UFH

LBCT March 29, 08

ISAR ISAR REACT 3REACT 3

3.1

6.8

1.3

4.6

9.9

1.8

0

2

4

6

8

10

12

Major bleeding Minor bleeding Transfusion

Incidence (%)

P=0.008

Bleeding Events

P=0.0001 P=0.15

BivalirudinUFH

LBCT March 29, 08

ISAR ISAR REACT 3REACT 3 Conclusion

In biomarker negative patients with stable and unstable angina undergoing PCI pretreated with

clopidogrel 600 mg for >2 hours, bivalirudin does not improve “net clinical benefit”

– the quadruple endpoint – at 30 days compared to UFH,

although it significantly reduces bleeding

Major Bleeding Associated With Increased Ischemic Events and Mortality

9.3

3.0

24.2

5.4

17.1

0.8

7.85.5

0

5

10

15

20

25

30

Compositeischemia

Death MI (all)

Major bleeding (n=462) No major bleeding (n=7,327)

P<.001 for all

30-d

ay e

ven

ts (

%)

Data on file. The Medicines Company, Parsippany, NJ.

Unplanned revascularization

Mauri et al. ACC 2008

Mauri et al. ACC 2008

Mauri et al. ACC 2008

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

Proceed to Diagnostic Angiography

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

LOE: A)

Diagnosis of UA/NSTEMI is Likely or Definite

Invasive StrategyInit ACT (Class I, LOE: A)

Acceptable options: enoxaparin or UFH (Class I, LOE: A) bivalirudin or fondaparinux (Class I, LOE: B)

Select Management StrategyProceed with an

Initial Conservative

Strategy

Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Figure 7. ACT = anticoagulation therapy; LOE = level of evidence.

A

B

B1

B2

Prior to AngiographyInit at least one (Class I, LOE: A) or

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

ClopidogrelIV GP IIb/IIIa inhibitor

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

Delay to AngiographyHigh Risk Features

Early recurrent ischemic discomfort

Init clopidogrel (Class I, LOE: A) Consider adding IV eptifibatide or tirofiban (Class

IIb, LOE: B)

Conservative StrategyInit ACT (Class I, LOE: A):

Acceptable options: enoxaparin or UFH (Class I, LOE: A) or fondaparinux (Class I, LOE: B), but

enoxaparin or fondaparinux are preferable (Class IIa, LOE: B)

Select Management Strategy

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

Diagnosis of UA/NSTEMI is Likely or Definite

Algorithm for Patients with UA/NSTEMI Managed by an Initial Conservative Strategy

Proceed with Invasive Strategy

(Continued)Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Figure 8. ACT = anticoagulation therapy; LOE = level of evidence.

C2

C1

A

CaseCase

• 44 yo women with 2 days of intermittent 44 yo women with 2 days of intermittent CP occurring with minimal exertion and at CP occurring with minimal exertion and at rest.rest.

• CRF: HTN, smokerCRF: HTN, smoker• Med: ACEI, thiazide diuretic, ASAMed: ACEI, thiazide diuretic, ASA• PE: WNLPE: WNL• Labs: CPK 54, cTnI 0.13Labs: CPK 54, cTnI 0.13• EKGEKG

4.78.3

13.219.9

26.2

40.9

0

10

20

30

40

50

0/1 2 3 4 5 6/7

D/M

I/U

rg R

evas

c (%

)

Number of Risk Factors% Popl’n: 4.3 17.3 32.0 29.3 13.0 3.4

Antman et al JAMA 2000

TIMI Risk Score For UA/NSTEMI• Age Age >> 65 y 65 y• >> 3 CAD Risk Factors 3 CAD Risk Factors• Prior Stenosis > 50 % Prior Stenosis > 50 % • ST deviationST deviation• >> 2 Anginal events 2 Anginal events << 24 h 24 h• ASA in last 7 daysASA in last 7 days• Elev Cardiac MarkersElev Cardiac Markers

Management IssuesManagement Issues

• UFH, LMWH, fondaparinux, or bivalirudinUFH, LMWH, fondaparinux, or bivalirudin

• ClopidogrelClopidogrel– 300 or 600 mg load300 or 600 mg load– DurationDuration

• Invasive or conservative strategyInvasive or conservative strategy

• If invasive, cath <6h or tomorrowIf invasive, cath <6h or tomorrow

• GP IIb/IIIa inhibitor upstream or in cath labGP IIb/IIIa inhibitor upstream or in cath lab

Ostial Ostial LADLAD

Ostial LADOstial LAD

ClopidogrelClopidogrel600 mg (ER)600 mg (ER)

UFHUFHEptifibatideEptifibatide

andandCypherCypher3.5 x 133.5 x 13

(cath lab)(cath lab)

Post-dilPost-dil4.04.0

16 atm16 atm

FinalFinal

FinalFinal