Anti-Thrombotic Therapy in ACS:

Update for 2008

Daniel I. Simon, M.D.

Chief, Division of Cardiovascular Medicine
Director, Heart & Vascular Institute
University Hospitals Case Medical Center
Herman K. Hellerstein Professor of Medicine
Case Western Reserve University School of Medicine

Disclosures-Drug
Accumetrics
Sanofi-Aventis
Research Grant
Consultant
Eli Lilly
Speaker honoraria
Consultant
Schering-Plough
Speaker honoraria
Scientific Advisory Board
Medicines Company
Speaker honoraria
Steering Committee
Research grant
Speaker bureau
Millennium
Consultant

Disclosures-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

Case
44 yo women with 2 days of intermittent CP
occurring with minimal exertion and at rest.
CRF: HTN, smoker
Med: ACEI, thiazide diuretic, ASA
PE: WNL
Labs: CPK 54, cTnI 0.13
EKG

Management Issues
UFH, LMWH, fondaparinux, or bivalirudin
Clopidogrel
300 or 600 mg load
Duration

Invasive or conservative strategy

If invasive, cath <6h or tomorrow
GP IIb/IIIa inhibitor upstream or in cath lab

Link Between Overall ACC/AHA

Guidelines Adherence and
Mortality

Every 10% in guidelines adherence 11% in

mortality

Peterson et al, ACC 2004

Plaque
Rupture:
A common
substrate for
acute
coronary
syndromes
- Michael Davies
- Earling Falk
- Paris Constantinides

Fatal thrombus

PTCA/stent

Anti-Thrombotic Strategies in PCI

Clinical
Presentation

% Patients
ACC/NCDR
N=210,158

UFH
+
IIb/IIIa Inhibitor

Bivalirudin

UFH
+
clopidogrel

RAPPORT
ISAR-2
ADMIRAL
CADILLAC

HORIZONS

CAPTURE
PRISM/PRISM-PLUS
PURSUIT
PARAGON A/B

ACUITY

ISAR-REACT 2
Non-inferiority
rejected

35.6%

CAPTURE
PRISM/PRISM-PLUS
PURSUIT
PARAGON A/B

ACUITY

ISAR-REACT 2
Non-inferiority
rejected

33.9%

EPILOG
EPISTENT
ESPRIT

REPLACE-2

ISAR-REACT

STEMI

13.1%

NSTEMI

15.4%

USA

Elective PCI
Low-risk ACS

64%

USA/Non-ST Elevation ACS

Generally caused by
partially occlusive,
platelet-rich thrombus
Unobstructed
lumen

Results from cross-linking of

fibrinogen by platelet GP IIbIIIa receptors at sites of plaque
rupture

GP IIb-IIIa
platelet

thrombus
fibrinogen
Ruptured
plaque Artery

wall

UA/NSTEMI GUIDELINES March 15 2002

Class I Recommendations for

Antithrombotic Therapy
Definite ACS
With Cath and PCI

Likely/Definite
ACS

Possible
ACS

Aspirin
+
IV heparin/LMWH*
+
IV platelet
GP IIb/IIIa
Antagonist
+
clopidogrel

Aspirin
+
SQ LMWH*
or
IV heparin
+
clopidigrel

Aspirin

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

*Class IIa: Enoxaparin

preferred over UFH

ACC/AHA Guidelines for UA/NSTEMI:

Early Invasive Strategy

Class I

An early invasive strategy in patients with UA/NSTEMI and any of

the following high-risk indicators (Level of Evidence: A)
Recurrent angina/ischemia

Ejection fraction <.40

Elevated TnT or Tnl

Hemodynamic instability

ST-segment depression

Sustained VT

Recurrent angina/ischemia
with CHF, S3, PE, rales, etc.

PCI within 6 months

High-risk findings on
noninvasive stress testing

Prior CABG

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

Invasive vs. Conservative Strategy

for UA/NSTEMI All Studies
ISAR-COOL

RITA-3
VINO

VANQWISH

TRUCS
MATE
ICTUS

TIMI IIIB

TACTICSTIMI 18

FRISC II

Invasive

Conservative
# Pts: 1140

1674

7018

Relative Risk of All-Cause Mortality for Early

Invasive Therapy Compared With Conservative
Therapy at a Mean Follow-Up of 2 y

Bavry AA, et al. J Am Coll Cardiol 2006;48:13191325. Reprinted with permission from Elsevier. CI = confidence interval; RR = relative risk.

GP IIb-IIIa Inhibition:
Beneficial pre- and post-PCI
Meta-analysis CAPTURE, PURSUIT, PRISM-PLUS

Medical Rx
10%

N=12,296
P=0.001

Death or MI

8%

Post PCI
Control
GP IIb/IIIa inhibitor

N=2754
P=0.001

8.0%

6%
4.9%

4.3%

4%

2.9%

2%
0%
0

+24 h

+48 h

+72 h

+24 h
PCI

Boersma et al. Circulation. 1999;100:2045

+48 h

ESPRIT Sub-study:
Procedural risk vs. clinical risk

Tcheng & Simon. 2008

ADP Receptor Blockers:

CURE, PCI-CURE, CREDO,
ISAR-REACT, ISAR-COOL,
ISAR-REACT 2, CHARISMA,
TRITON

Oral Antiplatelet Agents

Different Mechanisms of Action

clopidogrel bisulfate

Dipyridamole

ADP

ticlopidine HCl

ADP

Phosphodiesterase

ADP

Gp IIb/IIIa
(Fibrinogen
Receptor)

Activation
COX

Collagen
Thrombin
TXA2

TXA2

Aspirin

ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase.

Schafer AI. Am J Med. 1996;101:199209.

C
30 lop
lo 0m id
ad g og
in
re
g
l
do
se

Clopidogrel in Unstable Angina to

Prevent Recurrent Ischemic Events

Aspirin 75-325mg

Patients with
Non-ST elevation
Acute Coronary
Syndrome

Clopidogrel 75mg q.d.

+ ASA 75-325 mg q.d.*
(6259 patients)

3 months double-blind treatment 12 months

Pl
ac
eb

Aspirin 75-325mg

6
9
Months

The CURE Trial Investigators.

Investigators N Engl J Med. 2001;345:494-502.

12

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

Primary End Point:

MI/Stroke/CV Death
Cumulative Hazard Rate

0.14

11.4%

Placebo
+ ASA*

0.12

9.3%

0.10
0.08

Clopidogrel
+ ASA*

0.06
0.04

20% RRR
P < 0.001
N = 12,562

0.02
0.00
0

Months of Follow-Up
* In combination with standard therapy

12

PCI-CURE

Overall Long-Term Results

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

Cumulative Hazard Rate

0.15

12.6%

Placebo
+ ASA*

8.8%

0.10

Clopidogrel
+ ASA*
0.05

31% RRR
P = 0.002
N = 2658

0.0
0

100

200
Days of follow-up

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

300

400

Sabatine MS, et al. JAMA 2006

Optimal Timing?

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

MI/Stroke/CV
Death/Severe Ischemia
Within 24 hrs of Randomization
0.025
Cumulative Hazard Rates
0.020

34%

Relative Risk
Reduction

Placebo
+ ASA

0.015

0.010

Clopidogrel
+ ASA

0.005

p=0.003

0.0
0

10

12

14

16

Hours After Randomization

18

20

22

24

Major/Life-Threatening Bleeds
within 7 days of CABG Surgery
Stopped < 5 days
prior to CABG
Pts with Maj/LT Bld
TIMI Major
Stopped > 5 days
prior to CABG
Pts with Maj/LT Bld
TIMI Major

Placebo

Clopid

N = 476

N = 436

6.3%
2.7%

9.6%
2.5%

N = 454

N = 456

5.3%
2.4%

4.4%
1.8%

RR

1.53
0.92

0.06
NS

0.83
0.72

0.53
NS

Yusuf et al. for the CURE investigators. NEJM. 2001;345:494-502

Fox et al. Circulation. 2004;110:1202-08

Major Bleeding In Those

Undergoing 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: Clopidogrel pre-treatment

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

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

ISAR-COOL:cooling off strategy

Early <6h vs. cool-off 3-5d

ASA 100 mg BID

Clopidogrel 600 mg load, 75 mg BID
IV heparin 60U/kg
Tirofiban 10 g/kg, 0.1 g/kg/min
Neumann et al. JAMA 2003;290:1593-9

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

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

Clopidogrel Non-responsiveness
% Non-responders at 24h
P<0.002

P<0.002

32

28

ADP 5
Gurbel et al. J Amer Coll Cardiol 2005

ADP 20

ARMYDA-2:Clopidogrel 300 vs. 600 mg

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

Clopidogrel and Platelet Reactivity

Clopidogrel 300 mg (n=146) or clopidogrel 600 mg (n=146),
platelet reactivity (ADP 10 M) and clinical outcomes
High posttreatment
platelet
reactivity
(HPPR) > 70%
25% 300 mg
15% 600 mg
P=0.03
CV Event-free
Survival
HPPR: RR 13.8
P<0.0001
Cuisset et al. J Amer Coll Cardiol 2006;48:1339-45

ISAR-REACT 2 Trial: Study Design

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

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

Abciximab
(usual bolus or infusion dose)
n=1012

Placebo
n=1010

Primary Endpoint: Composite

Composite of
of death,
death, MI,
MI, and urgent target vessel
revascularization
revascularization (TVR)
(TVR) due
due to
to myocardial
myocardial ischemia within
within 30
30 days
days
Secondary
Secondary Endpoint:
Endpoint: In-hospital
In-hospital major
major and minor bleeding
Kastrati et al. JAMA 2006;295:1531-8

ISAR-REACT 2: Primary Endpoint

Composite of death, MI, or urgent TVR due to
Myocardial Ischemia within 30 days (%)
p=0.03

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

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

Study Design
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind

CLOPIDOGREL
300 mg LD/ 75 mg MD

PRASUGREL
60 mg LD/ 10 mg MD

Median duration of therapy - 12 months

1o endpoint:
2o endpoints:

CV death, MI, Stroke

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

Healthy Volunteer
Crossover Study
100

Interpatient
Variability

N=66

60

40

20

Interpatient
Variability

IPA at 24 hours (%)

80

Clopidogrel Responder

-20

Clopidogrel Non-responder

Response to
Clopidogrel 300 mg

From Brandt JT AHJ 153: 66e9,2007

Response to
Prasugrel 60 mg

Primary Endpoint
CV Death,MI,Stroke
Primary Endpoint (%)

15
Clopidogrel

10
Prasugrel

HR 0.77
P=0.0001

ITT= 13,608

0 30 60 90

9.9
(643)
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46

HR 0.80
P=0.0003

12.1
(781)

180

Days

270

LTFU = 14 (0.1%)

360

450

Stent Thrombosis
(ARC Definite + Probable)
3

Any Stent at Index PCI

N= 12,844

Endpoint (%)

Clopidogrel

2.4
(142)

1.1
(68)

Prasugrel

HR 0.48
P <0.0001
NNT= 77

0 30 60 90

180

270
Days

360

450

Balance of
Efficacy and Safety
15

138
events

Clopidogrel
12.1

Endpoint (%)

CV Death / MI / Stroke

9.9

10

Prasugrel

TIMI Major
NonCABG Bleeds
0

0 30 60 90

180

Days

HR 0.81
(0.73-0.90)
P=0.0004
NNT = 46

35
events

Prasugrel

2.4 HR 1.32
1.8 (1.03-1.68)
Clopidogrel
P=0.03
270

360

450

NNH = 167

Bleeding Events
Safety Cohort
(N=13,457)
ICH in Pts w
Prior Stroke/TIA
(N=518)

Clopidogrel
Prasugrel
% Events

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

ARD 0.6%
HR 1.32
P=0.03
NNH=167

ARD 0.5%
HR 1.52
P=0.01

ARD 0.2%
P=0.23

ARD 0.3%
P=0.002

ARD 0%
P=0.74

Net Clinical Benefit

Death, MI, Stroke,
Major Bleed (non CABG)
15

Clopidogrel

ITT= 13,608

13.9

Endpoint (%)

12.2

Prasugrel

10

HR 0.87
P=0.004

Events per 1000 pts

+

Major Bleed
(non CABG)

MI

30 60 90

180

Days

270

360

All Cause
Mortality
Clop 3.2%
Pras 3.0 %
P=0.64

450

Diabetic Subgroup
N=3146
18

Clopidogrel

Endpoint (%)

16

17.0

CV Death / MI / Stroke

14

12.2

12
10

Prasugrel

HR 0.70
P<0.001
NNT = 21

8
6

TIMI Major
NonCABG Bleeds

4
2
0

Clopidogrel

2.6
2.5

Prasugrel
0

30 60 90

180

Days

270

360

450

Net Clinical Benefit

Bleeding Risk Subgroups
Post-hoc analysis
Prior
Stroke / TIA

Age

Wgt

Risk (%)

Yes

+ 37

No

Pint = 0.006

-1

>=75
< 75

Pint = 0.18

< 60 kg

-16
+3

>=60 kg

Pint = 0.36

-14

-13

OVERALL
0.5

-16

Prasugrel Better

1
HR

Clopidogrel Better

Bleeding Risk Subgroups

Therapeutic Considerations

16%

4%

MD
10 mg

Significant
Net Clinical Benefit
with Prasugrel
80%

id
Avo rel
sug
Pra
r
Prio IA
/T
CVA

Re
Gu du
c
Ag ided ed
M
W e > by D
t < 75 P K
60 or
kg

Anti-platelet Therapy in ACS

ASA

ASA +
Clopidogrel

ASA +
Prasugrel
Reduction
in
Ischemic
Events

- 22%
- 20%
- 19%

+ 60%

Single
Antiplatelet Rx

+ 38%

Dual
Antiplatelet Rx

+ 32%

Higher
IPA

Increase
in
Major
Bleeds

Lots of Anticoagulant Choices

AT

IIa
S

IIa
Hep

UFH
AT

Xa

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

Direct antithrombin
AT

Xa

Pentasaccharide
= saccharide unit.

High-Risk
ACS Patients

Study Design

Randomize
(n = 10,000)

Enoxaparin
1 mg/kg SC Q12H

At least 2 of 3 required:

Age 60
ST (transient) or
(+) CK-MB or Troponin
IV Heparin
60 U/kg 12 U/kg/hr
(aPTT 50-70 sec)

Early invasive strategy

Other therapy per AHA/ACC Guidelines
(ASA, -blocker, ACE, clopidogrel, GP IIb/IIIa)

Primary endpoint: Death or MI at 30 days

JAMA 2004;292:45-54

SYNERGY: Primary End Point

Freedom from Death / MI

1.0

Hazard Ratio (95% CI)

0.95

30-Day Death/MI

0.9

HR 0.96 (0.87-1.06)

0.85
0.8

0.8

Enoxaparin
UFH
0

5 10 15 20 25
Days from Randomization

Enoxaparin
Better

30

Mahaffey et al, for the SYNERGY Investigators. JAMA. 2004;292:45-54.

Adapted from www.clinicaltrialresults.org.

UFH
Better

1.2

Prior Antithrombin Therapy: Efficacy and Safety

BLEEDING

30-DAY
DEATH
MI CI)
Ratio /(95%
(%) Hazard

GUSTO Severe
Enox UFH
TIMI
Major
Hazard
Ratio
(95% CI) (%) (%)

Enox UFH
(%)
14.0

12.6

13.3

14.5

14.8

Total

2.9

2.4

(n = 9978)

9.1

7.6

No Prior Rx

3.1

1.8

9.7

6.9

3.1

2.2

9.3

7.9

(n = 2440)

Consistent
Therapy

15.9

(n = 6138)
0.6

Enox
Better

UFH
Better

0.6

Enox
Better

UFH
Better

Study Design:
Randomized, Double Blind
Patients with NSTE ACS, Chest discomfort < 24 hours
2 of 3: Age>60, ST Segment
,, cardiac markers

Exclude
Age < 21
Any contra-ind to Enox
Hem stroke< 12 mo.
Creat> 3 mg/dL/265 umol/L

Randomize

ASA, Clop, GP IIb/IIIa,

IIb/IIIa,
planned Cath/PCI
Cath/PCI as per
local practice

Enoxaparin
Fondaparinux
N=20,000
1 mg/kg sc twice daily
2.5 mg sc once daily
PCI< 6 h,
h, No additional UFH
PCI >6 h,
h, IV UFH
With IIb/IIIa 65 U/kg
Without IIb/IIIa 100 U/kg

PCI <6 h:
h: IV Fonda 2.5 mg
without IIb/IIIa,
IIb/IIIa, 0 with IIb/IIIa
PCI> 6 h:
h: IV Fonda 2.5 mg with
and 5.0 mg without IIb/IIIa

Outcomes
Primary:

Efficacy
Death, MI, refractory ischemia at 9 days
Efficacy::
Safety
Major bleeding at 9 days
Safety::
Risk benefit
benefit:: Death, MI, refractory ischemia, major bleeds 9 days
Secondary
Secondary:: Above & each component separately at day 30 & 6 months
Hypothesis
-inferiority, then test superiority
Hypothesis:: First test non
non-inferiority,

0.01 0.02 0.03 0.04 0.05 0.06

HR 1.01
95% CI 0.90-1.13
Enoxaparin
Fondaparinux

0.0

Cumulative Hazard

Death/MI/RI: Day 9

5
Days

Major Bleeding: 9 Days

0.02

0.03

HR 0.53
95% CI 0.45-0.62
P<<0.00001

0.01

Fondaparinux

0.0

Cumulative Hazard

0.04

Enoxaparin

5
Days

Mortality: Day 30

0.02

Fondaparinux

0.01

HR 0.83
95% CI 0.71-0.97
P=0.022

0.0

Cumulative Hazard

0.03

Enoxaparin

12

15

Days

18

21

24

27

30

OASIS-6 Trial: PCI Substudy at 30 Days

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

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)

What about direct thrombin

inhibitors in ACS and PCI?

ACUITY Study Design:

First Randomization
UFH or enox
+ GP IIb/IIIa
n=4603

Moderateto highrisk
ACS

R*

Aspirin in all,
Clopidogrel dosing
and timing
per local practice

Bivalirudin
+ GP IIb/IIIa
n=4604
Bivalirudin
alone
n=4,612

Angiography within 72 h

Moderate- to high-risk patients with UA or NSTEMI

undergoing an invasive strategy (N = 13,819)

*Stratified by pre-angiography thienopyridine use or administration.

Stone et al. N Engl J Med 2006

Medical
management

PCI

CABG

ACUITY Study Design:

Second Randomization
Moderate- to high-risk patients with unstable angina
or NSTEMI undergoing an invasive strategy (N = 13,819)
UFH or Enoxaparin

GPI started in CCL

for PCI only (2309)

Routine upstream
GPI in all pts
n=4603
vs

Bivalirudin

Moderateto highrisk ACS

Aspirin in all,
Clopidogrel
dosing and timing
per local practice

Stone et al. N Engl J Med 2006

Routine upstream
GPI in all pts (2311)
GPI started in CCL
for PCI only (2293)

Bivalirudin
alone
N=4612

Deferred GPI
for PCI only
N=4604

Primary analysis
Secondary
analysis

UFH, Enoxaparin,
or Bivalirudin

Routine upstream
GPI in all pts (2294)

ACUITY: Primary End Point Measures*

UFH/Enoxaparin + GP IIb/IIIa vs Bivalirudin alone

Net clinical
outcome
Ischemic
composite
Major bleeding

Upper boundary non-inferiority

Primary
end point

Risk ratio
95% CI

Bival UFH/Enox
RR (95% CI)
alone + IIb/IIIa

P value
(noninferior)
(superior)

10.1%

11.7% 0.86 (0.77-0.97)

<.001
.015

7.8%

7.3% 1.08 (0.93-1.24)

.02
.32

3.0%

5.7% 0.53 (0.43-0.65)

<.001
<.001

*ITT population.
UFH = unfractionated heparin

Bivalirudin alone better

UFH/Enox + IIb/IIIa better

Stone et al. N Engl J Med 2006

ISAR
REACT 3

Study Population
4,570 Patients
Bivalirudin

UFH

2,289 Pts

2,281 Pts
PCI

30-day Follow-up
LBCT
March 29, 08

ISAR
REACT 3

Primary (Quadruple) Endpoint

Death, MI, UTVR, Major Bleeding
Cumulative incidence (%)
10

UFH
8

Bivalirudin

6
4

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

2
0
0
LBCT
March 29, 08

10

15

20

Days after randomization

25

30

8.7%
8.3%

ISAR
REACT 3

Secondary (Triple) Endpoint

Death, MI, UTVR

Cumulative incidence (%)

10
8

Bivalirudin

UFH

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

2
0
0
LBCT
March 29, 08

10

15

Days after
randomization

20

25

30

5.9%
5.0%

ISAR
REACT 3

Bleeding Events
Bivalirudin
UFH

Incidence (%)
P=0.008

LBCT
March 29, 08

P=0.0001

P=0.15

ISAR
REACT 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

LBCT
March 29, 08

Major Bleeding Associated With

Increased Ischemic Events and Mortality

30-day events (%)

P<.001 for all

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

Mauri et al. ACC 2008

Mauri et al. ACC 2008

Mauri et al. ACC 2008

Diagnosis of UA/NSTEMI is Likely or

Definite

Algorithm for
ASA (Class I, LOE: A)
Patients with
Clopidogrel if ASA intolerant (Class I,
LOE: A)
UA/NSTEMI
Select Management Strategy
Managed by
Invasive Strategy
an Initial
Init ACT (Class I, LOE: A)
Acceptable options: enoxaparin or UFH (Class I, LOE: A)
Invasive
bivalirudin or fondaparinux (Class I, LOE: B)
Strategy
A

Proceed with an
Initial
Conservative
Strategy

B1

Prior to Angiography
Init at least one (Class I, LOE: A) or
both (Class IIa, LOE: B) of the following:
Clopidogrel
IV GP IIb/IIIa inhibitor

B2

Factors favoring admin of both clopidogrel

and GP IIb/IIIa inhibitor include:
Delay to Angiography
High Risk Features
Early recurrent ischemic discomfort
Proceed to Diagnostic Angiography
Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Figure 7. ACT = anticoagulation therapy; LOE = level of evidence.

Algorithm for Patients with UA/NSTEMI

Managed by an Initial Conservative Strategy
Diagnosis of UA/NSTEMI is Likely
or Definite
ASA (Class I, LOE: A)
Clopidogrel if ASA intolerant (Class I, LOE: A)

Proceed with
Invasive
Strategy

Select Management Strategy

Conservative Strategy
Init ACT (Class I, LOE: A):
C1
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)

Init clopidogrel (Class I, LOE: A)

Consider adding IV eptifibatide or tirofiban
(Class IIb, LOE: B)

C2

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

Case
44 yo women with 2 days of intermittent CP
occurring with minimal exertion and at rest.
CRF: HTN, smoker
Med: ACEI, thiazide diuretic, ASA
PE: WNL
Labs: CPK 54, cTnI 0.13
EKG

D/MI/Urg Revasc (%)

TIMI Risk Score For UA/NSTEMI

50
40
30

Age > 65 y
> 3 CAD Risk Factors
Prior Stenosis > 50 %
ST deviation
ASA in last 7 days
Elev Cardiac Markers

26.2
19.9

20
10

40.9

> 2 Anginal events < 24 h

4.7

8.3

13.2

0
0/1
% Popln: 4.3

2
3
4
5
Number of Risk Factors
17.3
32.0
29.3
13.0

6/7
3.4

Antman et al JAMA 2000

Management Issues
UFH, LMWH, fondaparinux, or bivalirudin
Clopidogrel
300 or 600 mg load
Duration

Invasive or conservative strategy

If invasive, cath <6h or tomorrow
GP IIb/IIIa inhibitor upstream or in cath lab

Ostial
LAD

Ostial LAD

Clopidogrel
600 mg (ER)
UFH
Eptifibatide
and
Cypher
3.5 x 13
(cath lab)

Post-dil
4.0
16 atm

Final

Final