Antiplatelet Interventions in Acute Coronary Syndromes

1
Antiplatelet Interventions in Acute Coronary
Syndromes
2
Contents

• Acute Coronary Syndromes Tailoring Treatment to
  Level of Risk
• Thrombus Susceptibility and the Vulnerable
  Plaque Relationship Between Inflammation and
  Thrombosis
• ACC/AHA UA/NSTEMI Guidelines Role of GP IIb/IIIa
  Inhibitors
• Clinical Trials of GP IIb/IIIa Inhibition
• Clinical Insights, Risk Stratification, and
  Enhancing Outcomes
• GP IIb/IIIa Inhibition in STEMI Growing Clinical
  Trial Evidence

3
Acute Coronary Syndromes Tailoring Treatment
to Level of Risk
4
US hospital discharges Unstable angina/NSTEMI
and STEMI
Acute coronary syndromes
1.67 million hospital discharges
STEMI
UA/NSTEMI
1.17 million discharges per year
500,000 discharges per year
STEMI ST-elevation myocardial infarction (MI),
or Q-wave MI NSTEMI nonST-elevation MI, or
nonQ-wave MI
AHA. Heart Disease and Stroke Statistics2005
Update.
5
ACC/AHA 2002 UA/NSTEMI guidelines High-risk
indicators for early invasive strategy
Class I (Level of evidence A)

• Recurrent angina/ischemia on treatment
• Elevated troponin levels
• New ST-segment depression
• Recurrent angina/ischemia with CHF symptoms, S3
  gallop, pulmonary edema, worsening rales, new or
  worsening mitral regurgitation
• High-risk noninvasive test results
• Depressed LV function (EF lt40)
• Sustained ventricular tachycardia
• PCI within 6 months
• Prior CABG

Braunwald E et al. J Am Coll Cardiol.
2002401366-74.
6
Invasive Rx in ACS Early and late mortality
7 trials, N 9212
Cons ()
Inv ()
Favors routineinvasive
Favors selectiveinvasive
Mortality during hospitalization
TIMI 3B
1.9
2.2
VANQWISH
1.3
4.5
MATE
3.3
0.9
FRISC II
0.9
1.1
0.7
1.4
TACTICS
VINO
4.5
1.6
RITA 3
0.7
1.6
OR 1.60, P 0.007
Subtotal
1.1
1.8
Mortality after discharge
TIMI 3B
3.3
2.8
VANQWISH
11.7
13.4
MATE
6.9
10.0
FRISC II
3.0
1.2
TACTICS
2.8
1.9
VINO
9.4
1.6
RITA 3
7.3
5.2
OR 0.76, P 0.01
Subtotal
3.8
4.9
0.1
0.2
0.5
1
2
5
10
Odds ratio (95 CI)
Mehta SR et al. JAMA. 20052932908-17.
7
Invasive management of UA/NSTEMI meta-analysis
Subgroups
7 trials, N 9212
Death or MI at follow-up
Favorsroutineinvasive
Favorsselective invasive
Trial
Selective ()
Odds ratio
P
Routine ()
Before 1999
19.3
19.6
0.92
0.99
After 1999
12.4
9.4
lt0.001
0.73
0.69
Positive troponin
14.0
10.0
0.001
Negative troponin
0.42
6.7
0.89
7.4
0.82
14.7
17.4
Marker positive
0.01
0.90
Marker negative
7.7
8.5
0.40
Overall
12.2
14.4
0.001
0.82
0.5
1.0
2.0
Odds ratio (95 Cl)

• TIMI 3B, VANQWISH, MATE
• FRISC II, TACTICS, VINO, RITA 3
• Data by troponin status available only in FRISC
  II, TACTICS, RITA 3

Mehta SR et al. JAMA. 20052932908-17.
8
RITA 3 Benefit of routine invasive strategy
mainly in high-risk patients
Randomized Intervention Trial of unstable Angina
Based on age, diabetes, prior MI, smoking, ST?,
pulse, grade 3/4 angina, sex, left bundle branch
block, transient ST?
Fox KAA et al. Lancet. 2005366914-20.
9
RITA 3 Greater benefit of early invasive
strategy in men vs women with ACS
n 682 women, 1128 men with UA/NSTEMI
Men
Women
20
20
HR 1.09(95 CI 0.701.71)
HR 0.61(95 CI 0.440.85)
16
16
Invasive
Conservative
Deathor MI()
12
12
8
8
Invasive
Conservative
4
4
0
0
0
1
3
2
0
1
3
2
Time (years)
Time (years)
No. patients
Invasive
545
491
354
189
350
316
228
125
Conservative
583
507
356
194
332
305
230
119

Clayton TC et al.
Eur Heart J. 2004251641-50.
10
FRISC II Men with ACS show greater benefit from
early invasive strategy than women
Fragmin and fast Revascularization during
InStability in Coronary artery disease
n 749 women, 1708 men with UA/NSTEMI
Men
Women
20
20
Noninvasive (n 834)
16
15.8
16
Invasive (n 348)
12.4
P lt 0.001
Death or MI()
12
12
ns
10.5
9.6
8
8
Invasive (n 874)
Noninvasive (n 401)
4
4
0
0
0
60
120
180
240
300
360
0
60
120
180
240
300
360
Time (days)
Time (days)
Lagerqvist B et al. J Am Coll Cardiol.
20013841-8.
11
Release of cardiac troponins and CK-MB in acute
MI
50
Cardiac troponin afterclassic acute MI
20
CK-MB after acute MI
10
Multiples of the upper reference limit
Cardiac troponin aftermicroinfarction
5
2
Upperreference limit
1
0
0
1
2
3
4
5
6
7
8
Days after onset of acute MI
Antman EM. N Engl J Med. 20023462079-82.
12
In-hospital mortality higher with any degree of
troponin elevation in NSTEMI patients
CRUSADE N 23,298
7
6
5
In-hospital mortality ()
4
3
2
1
0
0
1
2
3
4
5
6
7
8
9
10
Maximum troponin ratio
Reference limit maximum troponin ratio 01x
upper limit of normal
Roe MT et al. Arch Intern Med. 20051651870-6.
13
TIMI risk score for UA/NSTEMI

• Age 65 years
• 3 CAD risk factors
• Significant coronary stenosis
• ST-segment deviation
• Severe angina (2 anginal events in last 24
  hours)
• Daily use of aspirin in prior 7 days
• Elevated serum cardiac markers

Family history of CAD, hypertension, elevated
cholesterol, diabetes, current smoker Creatine-ki
nase MB and/or cardiac troponins
Antman EM et al. JAMA. 2000284835-42.
14
TIMI risk score in UA/NSTEMI
45
40.9
35
Death/MI/severe ischemia at 14 days ()
26.2
25
19.9
13.2
15
8.3
4.7
5
0
0/1
2
3
4
5
6/7
Risk factors (n)
Antman EM et al. JAMA. 2000284835-42.
n 1957 ACS patients
15
Multimarker strategy Identifying high-risk
patients by troponin I, CRP, and BNP
OPUS-TIMI 16
TACTICS-TIMI 18
6
6
14
13
P 0.014
P lt 0.001
30-day mortality relative risk
10
4
3.5
5.7
6
1.8
2
1
2.1
2
1
0
0
1
2
3
0
1
2
3
0
Elevated cardiac biomarkers (n)
Elevated cardiac biomarkers (n)
67
150
155
78
504
717
324
90
n
BNP B-type natriuretic peptide CRP C-reactive
protein
Sabatine MS et al. Circulation. 20021051760-3.
16
Multimarker approach in ACS
Myocyte necrosis
Troponin
Hemodynamic stress
Inflammation
hs-CRP, CD40L
BNP, NT-proBNP
Vasculardamage
A1C
CrClMicroalbuminuria
Blood glucose
Independentpredictor of risk
Useful in multimarker strategy
Therapeuticimplication
Biomarker
Giugliano RP et al. J Am Coll Cardiol.
200546906-19.
17
Thrombus Susceptibilityand the Vulnerable Plaque

• Relationship Between Inflammation and Thrombosis

18
Interaction between inflammation and hemostasis
in vulnerable plaque
Wagner DD. Arterioscler Thromb Vasc Biol.
2005251321-4.
19
Txnip links shear stress to inflammation

• No shear
• Txnip
• Thioredoxin inactive

• Normal shear
• Txnip
• Thioredoxin active

Txnip thioredoxin interacting protein (vitamin
D upregulating protein 1)ASK
apoptosis-signaling kinase JNK Jun-terminal
kinase
Harrison DG. Nat Med. 200511375-6.
20
Platelet adhesion and aggregation
InactiveGP IIb/IIIa
Unactivatedplatelet
R
TXA2 ADP
R
NO
Fibrinogen
ActiveGP IIb/IIIa
GPIb-IX-V
Disrupted endothelium
vWf
Subendothelial matrix
ADP adenosine diphosphate NO nitric oxide
R platelet receptors TXA2 thromboxane A2
vWf von Willebrand factor
Freedman JE. Circulation. 20051122725-34.
21
Platelets release soluble CD40 ligand (sCD40L)
after thrombin stimulation
10
Thrombin
sCD40L(ng/mL)
5
Thrombin
0
0
50
100
150
200
250
300
350
Time (minutes)
Chakrabarti S et al. Arterioscler Thromb Vasc
Biol. 2005252428-34.
22
Recombinant sCD40L enhances platelet release of
reactive oxygen species
Platelets Dihydrorhodamine
Unstimulated
TRAP
TRAP rsCD40L
Chakrabarti S. et al. Arterioscler Thromb Vasc
Biol. 2005252428-34.
TRAP Thrombin receptor-activated platelets
23
GP IIb/IIIa antagonists block sCD40L release
from platelets
Activated platelet
Unstimulated platelet
André P et al. Circulation. 2002106896-9.
24
Points of action for antithrombotics
Aspirin
ThromboxaneA2
Collagen
Thrombin
ADP
UFHLMWHsDirect thrombininhibitors
TiclopidineClopidogrel
Fibrinogen
GP IIb/IIIa activation
AbciximabTirofibanEptifibatide
von Willebrand factor
Platelet aggregation
Fibrin
Thrombus formation
Thrombolytics
Curran MP, Keating GM. Drugs. 2005652009-35.
25
Proposed model for optimal use of GP IIb/IIIa
inhibitors
GP IIb/IIIa PCI80 occupancy
GP IIb/IIIa No PCIlt80 occupancygt12 hours
Antman EM. Am Heart J. 2003146(suppl)S18-22.
26
Potential mechanisms for reduction of
thrombo-inflammation with GP IIb/IIIa inhibition

• Inhibit platelet activation
• Reduce sCD40L in ACS and PCI
• Blunt CRP increase in ACS and PCI
• Reverse endothelial dysfunction induced by PCI
• Reduce leukocyte-platelet aggregation in ACS

Furman MI et al. J Thromb Haemost.
20053312-20. Giugliano RP, Braunwald E. J Am
Coll Cardiol. 200546906-19.
27
ACC/AHA UA/NSTEMI Guidelines Role of GP
IIb/IIIa Inhibitors
28
ACC/AHA guidelines for UA/NSTEMI GP IIb/IIIa
inhibitors
A platelet GP IIb/IIIa antagonist should be
administered in addition to ASA and heparin to
patients in whom cardiac catheterization and PCI
are planned. GP IIb/IIIa antagonists may also be
administered just prior to PCI.
Eptifibatide or tirofiban should be administered
in addition to ASA and heparin in patients with
continuing ischemia, elevated troponin, or other
high-risk features in whom an invasive management
strategy is not planned.
A platelet GP IIb/IIIa antagonist should be
administered to patients already receiving
heparin, ASA, and clopidogrel in whom cardiac
catheterization and PCI are planned. GP IIb/IIIa
antagonists may also be administered just prior
to PCI.
Braunwald E et al. J Am Coll Cardiol.
2002401366-74.
29
ACC/AHA UA/NSTEMI Guidelines Management of
high-risk patients

• High-risk patients
• Signs of ischemia at rest gt20 minutes AND
  ST-segment depression and/or elevated cardiac
  biomarkers

Diagnostic catheterization and revascularization
within 2448 hours (Class Ia)
Adapted from Braunwald E et al. J Am Coll
Cardiol. 2002401366-74.
30
Mortality risk is lower with early (lt24-hour) GP
IIb/IIIa inhibition
Adjusted OR (95 Cl)
Favorsearly GP IIb/IIIa inhibitor
Favors no early GP IIb/IIIa inhibitor
6 RCTs ACS (N 31,402)
0.91 (0.811.02)
CRUSADE ACS (N 49,378)
0.93 (0.831.05)
CRUSADE Tn (n 32,290)
0.88 (0.771.01)
NRMI NSTEMI (n 60,770)
0.88 (0.790.97)
0.5
1.0
2.0
Odds ratio
Boersma E et al. Lancet. 2002359189-98. Hoekstra
JW et al. Acad Emerg Med. 200512431-8.
RCT randomized control trial Tn troponin
positive
31
Recommended therapies for UA/NSTEMI
Acute therapies (lt24h)
Discharge therapies

• Aspirin
• ?-Blocker
• Heparin (UFH or LMWH)
• GP IIb/IIIa inhibitor (all receiving PCI/cath)
• Clopidogrel (all receiving PCI)
• Catheterization/revascularization 48 hours

• Aspirin
• Clopidogrel
• ?-Blocker
• ACE inhibitor
• Statin/lipid lowering
• Smoking cessation
• Cardiac rehabilitation

Braunwald E et al. J Am Coll Cardiol.
2002401355-74.
32
Majority of ACS patients undergo catheterization
CRUSADE registry data October 1, 2004September
30, 2005 (n 35,897)
Cath
Cath
PCI
PCIlt48 hr
CABG
lt48 hr
CRUSADE. www.crusadeqi.com
Without contraindication to catheterization
33
Clinical Trials of GP IIb/IIIa Inhibition

• Major Trials of GP IIb/IIIa Inhibitors in ACS
• GP IIb/IIIa Inhibitors in PCI
• GP IIb/IIIa Inhibition in Patients With Diabetes

34
Clinical Trials of GP IIb/IIIa Inhibition

• Major Trials of GP IIb/IIIa Inhibitors in ACS

35
Efficacy of GP IIb/IIIa inhibition on death or
MI in PCI or ACS
Death or MI at 30 days
FavorsGP IIb/IIIa
Favorsplacebo
Trial
N
EPIC 2099 IMPACT II 4010 EPILOG 2792
CAPTURE 1265 RESTORE 2139 EPISTENT 2399
PRISM 3231 PRISM-PLUS 1570 PARAGON 2282
PURSUIT 10,948 Overall 30,366
Elective PCI
ACS
0.79 (0.730.85)P lt 109
1
2
0
Odds ratio (95 CI)
Does not include 345 patients In the tirofiban
only group, which was stopped prematurely
Antman EM et al. Am Heart J. 2003146S18-S22.
36
PRISM-PLUS Study design
Platelet-Receptor Inhibition for ischemic
Syndrome Management in Patients Limited by
Unstable Signs and symptoms (PRISM-PLUS)
N 1915 with unstable angina or nonQ-wave
MIRandomized, double-blind study
Tirofibann 345
Heparinn 797
Tirofiban heparinn 773
Infusion for 71.3 20 hoursAngiography
angioplasty during Tx after 48 hours (prn)
Primary outcomeDeath, MI, refractory ischemia
7 days
PRISM-PLUS Investigators. N Engl J Med.
19983381488-97.
Stopped prematurely due to high mortality at 7
days
37
PRISM-PLUS Benefits at 30 days similar
with/without PCI
Death or MI
Death/MI/RI
30
30
24.7
25
25
21.3
18.7
20
20
18.1
15
15
Outcomesat 30 days
13.0
11.5
8.9
8.3
10
10
5
5
0
0
No PCI n 1069
PCI n 501
No PCI n 1069
PCI n 501
23? 0.501.12
36? 0.341.08
RRR (95 CI)
12? 0.631.15
27? 0.441.04
Heparin
Tirofiban heparin
Morrow DA et al. Am J Cardiol. 200494774-6.
RI recurrent ischemia
38
PRISM-PLUS Benefit of GP IIb/IIIa inhibition by
risk profile
Death/MI/RI
Favorstirofiban/heparin
Favorsheparin
H
TH
OR
P
No PCI
High risk (n 664)
Low risk (n 405)
PCI
High risk (n 280)
Low risk (n 221)
0.1
1
10
Odds ratio (95 CI)
H heparin T tirofiban High risk TIMI risk
score 4RI refractory ischemia
Morrow DA et al. Am J Cardiol. 200494774-6.
39
PURSUIT Study design
Platelet Glycoprotein IIb/IIIa in Unstable
Angina Receptor Suppression Using Integrilin
Therapy
N 10,948 Chest pain lt24 hours ECG changes
of ischemia orElevated CK-MB gtULN for
hospital Randomized, double-blind study
High-dose eptifibatide 180-µg/kg bolus, then
2.0 µg/kg per min for 72 h (96 h with coronary
intervention)n 4722
Placebon 4739
Primary outcomeComposite death/nonfatal MI 30
days
Lower-dose eptifibatide (n 1487) stopped after
safety of high-dose was shown
PURSUIT Trial Investigators. N Engl J Med.
1998339436-43.
40
PURSUIT Pre-PCI GP IIb/IIIa inhibition prevents
early MI
10
HR 0.29 P lt 0.001
Placebo
5.5
Pre-PCI MI ()
5
Eptifibatide
1.7
0
1
3
0
2
Days from enrollment

Kleiman NS et al. Circulation. 2000101751-7.
41
PURSUIT GP IIb/IIIa inhibition prevents death
with/without early PCI
Death or myocardial reinfarction

Favors eptifibatide
Favors placebo
Placebo
Eptifibatide
96 Hours Early PCI 15.3 9.2 No early
PCI 7.7 5.5 7 Days Early PCI 16.0 9.9 No
early PCI 10.8 8.8 30 Days Early
PCI 16.7 11.2 No early PCI 15.0 12.2 6
Months Early PCI 19.8 15.1 No early
PCI 18.6 15.3
0.5
1
2
OR (95 CI)
Early PCI n 450No early PCI n 1316
Lincoff AM et al. Circulation 20001021093-100.
42
PURSUIT Importance of timing GP IIb/IIIa
inhibition on outcomes
3.0
2.8
2.3
2.5
Difference in rate of death or MI, eptifibatide
vs placebo()
2.0
1.7
1.5
1.0
0.5
0
0.0
lt6
612
1224
gt24
Time to treatment (hours)
N 9471
Bhatt DL et al. JAMA. 20002841549-58.
.
43
TACTICS-TIMI 18 Study design
Treat angina with Aggrastat and determine Cost of
Therapy with an Invasive or Conservative
StrategyThrombolysis In Myocardial Infarction
N 2220 with unstable angina/NSTEMI
ASAUnfractionated heparinTirofiban 0.4 µg/kg
per min over 30 min, then 0.1 µg/kg per min for
48 h, including 12 h post-PCI
Conservative approach ETT/cath/PCI for recurrent
or demonstrated ischemia
Invasive approach Cath within 448 hours with
revascularization if anatomy suitable
Primary outcomeDeath, MI, rehospitalization for
ACS
ETT exercise tolerance test
Cannon CP et al. N Engl J Med. 20013441879-87.
44
TACTICS-TIMI 18 vs TIMI IIIB Effects of early
PCI GP IIb/IIIa inhibition
P 0.003
Deaths/MI/ACS at 6 months
39
40
P 0.005
38 ? in death/MI/ACS in TACTICS-TIMI 18 vs
TIMI IIIB (P lt 0.0001)
P lt 0.0001
30
24
23
22
Events ()
18
20
12
10
0
Intermediate (34)
Low (02)
High (57)
TIMI risk score category
TIMI IIIB
TACTICS-TIMI 18
Sabatine MS et al. Circulation. 2004109874-80.
Adjusted for baseline differences
45
TACTICS-TIMI 18 Duration of GP IIb/IIIa
inhibitor pre-PCI influences TIMI flow
P 0.013
50
43.4
40

• Longer infusion
• TIMI myocardial perfusion grade 3 OR 0.52 (P
  0.012)
• TIMI flow grade 3 OR 0.61 (P 0.054)
• Minimum diameter (P 0.032)

TIMI myocardial perfusion grade 3 ()
29.9
30
20
10
0
lt21
gt21
Treatment duration (hours)
Gibson CM et al. Am J Cardiol. 200494492-4.
Controlled for baseline troponin T
46
Clinical Trials of GP IIb/IIIa Inhibition

• GP IIb/IIIa Inhibitors in Planned PCI

47
ESPRIT Study design
Enhanced Suppression of the Platelet IIb/IIIa
Receptor with Integrilin Therapy
Assess effect of novel, double-bolus dose
eptifibatide in coronary stenting N 2064
undergoing stent implantation Randomized,
controlled study
Eptifibatide 180-µg/kg double-bolus 10 min apart
continuous infusion 2.0 µg/kg per min for
1824 h
Placebo
Aspirin heparin thienopyridine
Primary outcomeDeath, MI, urgent
revascularization and thrombotic bailout after
GP IIb/IIIa inhibitor 48 h
Secondary outcomeDeath/MI/urgent
revascularization at 30 days
ESPRIT Investigators. Lancet. 20003562037-44.
48
ESPRIT Outcomes at 48 hours
Eptifibatidebetter
Placebo better
Eptifibatide
Placebo
RR
P
6.6
10.5
0.63
0.0015
Primary endpoint
6.0
9.3
0.65
0.0045
Death/MI/UTVR
5.5
9.2
0.60
0.0013
Death/MI
3.4
5.1
0.67
0.053
Death/Large MI
3.3
4.9
0.67
0.064
Large MI
5.4
9.0
0.60
0.0015
All MI
0.6
1.0
0.60
0.30
UTVR
1.0
2.1
0.48
0.029
Thrombotic bailout
5.4
0.1
0.2
0.50
0.55
Death
0.5
1.5
0
1
2
Relative Risk
N 2064 UTVR urgent target vessel
revascularization
ESPRIT Investigators. Lancet. 20003652037-44.
49
ESPRIT Primary outcome over time
Death/MI/TVR/thrombotic bailout within 48 hours
RR 0.76 (95 Cl 0.630.93) P 0.0068
25
20
RR 0.65 (95 Cl 0.490.87) P 0.0034
RR 0.65 (95 Cl 0.470.87) P 0.0045
Primary endpoint ()
15
10
5
0
30 days
12 months
48 hours
Placebo
Eptifibatide
Granada JF, Kleiman NS. Am J Cardiovasc Drugs.
2004431-41.
TVR target vessel revascularization
50
GP IIb/IIIa inhibition in planned PCI
Death, MI, or urgent revasc at 30 days
P
Placebo ()
GP IIb/IIIa ()
EPIC
Favors GP IIb/IIIa
Favors placebo
12.8
11.4
0.430
Abciximab B
12.8
8.3
0.008
Abciximab BI
EPILOG
11.7
5.2
lt0.001
Abciximab LDH
11.7
5.4
lt0.001
Abciximab SDH
EPISTENT
10.8
5.3
lt0.001
Abciximab stent
10.8
6.9
0.007
Abciximab PCI
IMPACT II
11.4
9.2
0.063
Eptifibatide 135/.5
11.4
9.9
0.220
Eptifibatide 135/.75
RESTORE
10.5
8.0
0.052
Tirofiban
CAPTURE
15.9
11.3
0.012
Abciximab
RAPPORT
11.2
5.8
0.030
Abciximab
0.25
1.0
4.0
Odds ratio (95 CI)
B bolus BI bolus infusion LDH low-dose
heparin SDH standard-dose heparin
Lincoff AM et al. J Am Coll Cardiol.
2000351103-15.
51
Timing of catheterization Weekday vs weekend
hospital admission
N 56,352 with UA/NSTEMI (CRUSADE)
60
Weekday
50
40
Proportion undergoing cardiac catheterization
()
Weekend
30
20
P lt 0.001 by log-rank statistic
10
0
0
6
12
18
24
30
36
42
48
54
60
66
72
78
Time from admission (hours)
Ryan JW et al. Circulation. 20051123049-57.
52
Weekend delay in catheterization does not
increase adverse events
N 56,352 with UA/NSTEMI (CRUSADE)
Weekend patients (n 10 804)
Weekday patients (n 45 548)
Adjusted OR (95 CI)
In-Hospital Outcomes
1.02 (0.921.13)
4.4
4.1
Death
0.96 (0.861.07)
2.9
3.0
Reinfarction
0.98 (0.911.07)
6.6
6.6
Death or MI
1.05 (0.921.21)
2.8
2.6
Cardiogenic shock
0.96 (0.861.07)
0.8
0.8
Stroke
1.00 (0.931.08)
9.2
8.6
CHF
1.00 (0.941.06)
15.1
14.5
Any adverse event
Ryan JW et al. Circulation. 20051123049-57.
53
Clinical Trials of GP IIb/IIIa Inhibition

• GP IIb/IIIa Inhibition in Patients With Diabetes

54
Accelerated CAD progression in diabetes
Inflammation hsCRP?, IL-6?. VCAM-1?, ICAM-1?,
P-selectin?, sCD40L?, TNF-??, TSP-1?
Prothrombotic state GP IIb/IIIa
receptors? Platelet factor 4? Fibrinogen?, TF?,
vWf? PAI-1? Protein C?
CAD progression and/orworse outcomes post-PCI
Restenosis Hyperinsulinemia RAGE/AGE? PPAR-?
modulation TSP-1?
Endothelial dysfunction Hyperglycemia Free fatty
acids Insulin resistance RAGE/AGE? Dyslipidemia
Associated conditions Renal dysfunction LV
dysfunction Peripheral vascular disease
Atherosclerotic burden Diffuse disease Multivessel
disease Negative remodeling
Roffi M, Topol EJ. Eur Heart J. 200425190-8.
RAGE receptor for advanced glycation
end-products (AGE)TSP-1 thrombospondin-1
55
Altered platelet functions in diabetes

• ? Membrane fluidity
• Altered Ca2 and Mg2 homeostasis
• ? Arachidonic acid metabolism
• ? Thromboxane A2 synthesis

• ? Prostacyclin production
• ? NO production
• ? Antioxidants
• ? Activation-dependent adhesion molecules (eg,
  GP IIb/IIIa, P-selectin)

These changes contribute to increased platelet
aggregability and adhesiveness in diabetes
Colwell JA, Nesto RW. Diabetes Care.
2003262181-8.
56
PURSUIT Outcomes in diabetic vs nondiabetic US
patients
30-day death or MI
Placebo better
Eptifibatide better
Diabetes
No diabetes
0.33
1.0
3.0
Odds ratio (95 CI)
Lincoff AM et al. Circulation. 20001021093-100.
57
PRISM-PLUS Outcomes in diabetic NSTEMI patients
by treatment strategy
Tirofiban heparin()
Heparin()
30-day outcomes
Composite
All diabetic patients undergoing
PCI
21.2
25.4
25.6
CABG
44.9
Medical management
22.5
17.7
MI/Death
All diabetic patients undergoing
PCI
1.9
12.7
CABG
26.5
2.6
Medical management
11.2
7.6
0.1
1
5
10
0.5
Risk ratio (95 CI)
Théroux P et al. Circulation. 20001022466-72.
58
TACTICS-TIMI 18 Death/MI/ACS in ACS patients
with/without diabetes
30
Invasive
27.7
27
Conservative
25
13
20.1
20
Event rate at 6 months ()
16.4
14.2
15
10
5
0
Diabetes
No diabetes
Death, MI, rehospitalization for ACSPatients
treated with aspirin, clopidogrel, and tirofiban
Roffi M et al. Eur Heart J. 200425190-8.
59
EPISTENT, ESPRIT Effect on 1-year mortality in
planned PCI by diabetes status
Evaluation of Platelet Inhibition in STENTing
Enhanced Suppression of the Platelet IIb/IIIa
Receptor with Integrilin Therapy
5
EPISTENT(Abciximab)
ESPRIT(Eptifibatide)
4.1
4
3.5
1-year mortality ()
3
1.9
2
1.5
1.4
1.3
1.2
1.0
1
0
Diabetes
No diabetes
Diabetes
No diabetes
GP IIb/IIIa inhibitor
Placebo
Lincoff AM. Circulation. 20031071556-9.
60
PCI in patients with ACS and diabetes

• Patients with ACS plus diabetes are at higher
  risk for recurrent events but derive greater
  benefit from aggressive therapy

• Mainstays of acute-phase therapy in diabetic ACS

• Triple antiplatelet therapy Aspirin,
  clopidogrel, GP IIb/IIIa inhibition
• Heparin or LMWH
• Early invasive assessment and, if appropriate,
  stent-based PCI

• Despite sharp declines in restenosis rates with
  drug-eluting stents, patients with ACS plus
  diabetes remain at high risk for repeat
  revascularization

Roffi M, Topol EJ. Eur Heart J. 200425190-8.
61
Clinical Insights, Risk Stratification, and
Enhancing Outcomes
62
CRUSADE National quality improvement initiative
Can Rapid risk stratification of Unstable angina
patients Suppress ADverse outcomes with Early
implementation of the ACC/AHA guidelines

• Academic collaboration among cardiology and
  emergency medicine initiated in 2001
• Cross collaboration with ACC and AHA
• Multi-industry sponsor
• Goal Improve adherence to ACC/AHA guidelines
  for managing patients with ACS

CRUSADE. www.crusadeqi.com
63
CRUSADE In-hospital mortality by age and acute
treatment
20
Age gt75 yrs
17.6
18
Age lt75 yrs
16
14
12
10.4
10.7

10
8.7
8
6.7
6.5
5.2
6
3.5
3.5
3.1
4
2.7
1.8
1
2
0.6
0
0
1
2
3
4
5
6
Number of recommended therapies
Aspirin, ß-blockers, UFH/LMWH, GP IIb/IIIa
inhibitors, clopidogrel lt24 hours, PCI lt48 hours
N 105,619 registry patients
Boden WE et al. Circulation. 2005112II-745.
64
CRUSADE Post-admission MI vs use of recommended
therapies
7
6.7

6
Adjusted OR 0.91 (95 CI 0.880.95)
5
4.2

4
3.4
2.9
3
2.6
2.5
2.2
2
1
0
1
2
3
4
5
6
Number of recommended therapies
Aspirin, ß-blockers, UFH/LMWH, GP IIb/IIIa
inhibitors, clopidogrel lt24 hours, PCI lt48 hours
N 105,619 registry patients
Boden WE et al. Circulation. 2005112II-745.
65
CRUSADE Impact of early aggressive management
strategy on in-hospital mortality
N 17,926 registry patients
Acute medical therapy (lt24 h)
In-hospital mortality ? 32 P lt 0.001
P lt 0.001
94
100
89
88
78
74
80
72
8
60
51
51
6

40
3.7

4
26
2.5
14
20
2
0
0
Aspirin
?-Blocker
Clopidogrel
Heparin
GP IIb/IIIa inhibitor
No early invasive care (n 9889)
Early invasive care (cardiac cath lt48 h, n
8037)
Bhatt DL et al. JAMA. 20042922096-104.
Adjusted for clinical differences and propensity
score
66
CRUSADE NSTE ACS dosing of antithromboticsStudy
overview
Objective Investigate association between
dosing UFH, LMWH, and GP IIb/IIIa inhibitors and
major clinical outcomes Design Prospective
observational analysis Population Registry
patients with NSTE ACS receiving antithrombotic
agents Primary outcome Relation between
excessive dosing of UFH, LMWH, and GP IIb/IIIa
inhibitors and major bleeding, in-hospital
mortality, and length of stay
NSTE ACS nonST-segment elevation acute
coronary syndromes
Alexander KP et al. JAMA. 20052943108-16.
67
Major predictors of overdosing
Older age(65 years)
Renalinsufficiency
Female
Patients vulnerable to overdosing
Low bodyweight
Diabetes
CHF
Alexander KP et al. JAMA. 20052943108-16.
68
Results Excess dosing by age
70
P lt 0.001 for all treatment groups
60
50
Excessdose()
40
30
20
10
0
UFH
LMWH
GP IIb/IIIa inhibitors
Patient age (years)
lt65
75
6574
Alexander KP et al. JAMA. 20052943108-16.
69
Results Antithrombotic therapy dose and major
bleeding
35
30
25
Majorbleeding()
P lt 0.001
P 0.25
P lt 0.001
20
15
10
5
0
UFH
LMWH
GP IIb/IIIa inhibitors
2074
2063
2073
714
2327
3998
922
237
5879
1955
178
N
Underdosed
Recommended
Mild excess
Major excess
Data are for noncoronary bypass grafting and
nontransfer population
Alexander KP et al. JAMA. 20052943108-16.
70
Recommended dosing of antithrombotic agents
Alexander KP et al. JAMA. 20052943108-16.
71
Creatinine clearance vs age
80
70
60
Median creatinine clearance (cc/min)
50
40
30
20
10
0
6574
7584
gt84
lt65
Age (years)
Peterson ED et al. ACC. March 2005 Orlando,
Fla. Data on file at Duke Clinical Research
Institute. Jan 2001Dec 2004.
72
Clinical implications

• Early use of antithrombotic agents plays a key
  role in management of NSTE ACS, but dosing
  errors are common

• Dosing errors occur more often in elderly and
  others already vulnerable to bleeding

• Dosing errors predict an increased risk of major
  bleeding

• Altering dosing based on weight and renal
  function minimizes bleeding while preserving
  therapeutic benefit

• Patients receiving recommended doses of heparin
  and GP IIb/IIIa inhibitors alone or in
  combination have the lowest rates of bleeding

Proper dosing of antithrombotic therapies is
necessary to prevent bleeding complications in
vulnerable patients
Alexander KP et al. JAMA. 20052943108-16.
73
Clinical Insights, Risk Stratification, and
Enhancing Outcomes

• Combination Therapy

74
INTERACT Study design
INTegrilin and Enoxaparin Randomized Assessment
of Acute Coronary Syndrome Treatment
Evaluate safety and efficacy of GP IIb/IIIa
inhibitors enoxaparin vs UFH N 746 with
ischemic chest symptoms and ECG or CK-MB evidence
of ACS Prospective, randomized multicenter study
Enoxaparin 1 mg/kg per 12 h for 48 h
UFH 70 U/kg IV bolus, then 15 U/kg per h for 48 h
Eptifibatide 180 µg/kg bolus, then 2.0 µg/kg per
min for 48 h
Primary safety outcome96 h nonCABG-related
major hemorrhage
Primary efficacy outcomeRecurrent ischemia
detected by continuous ECG evaluation within 96 h
Goodman SG et al. Circulation. 2003107238-44.
UFH unfractionated heparin
75
INTERACT LMWH/UFH plus GP IIb/IIIa inhibitor in
UA/NSTEMIPrimary outcomes
Ischemia
Bleeding (96 h)
35
5
35
P 0.03
P 0.003
30
30
P 0.0002
P lt 0.0001
4
25
25
3
20
20
Patients ()
15
15
2
10
10
1
5
5
0
0
0
Major
Minor
4896 h
Initial 48 h
322
302
n 357
357
n 380
366
380
366
Heparin
Enoxaparin
Enoxaparin 1 mg/kg SC q 12 h for 48 h UFH
70-U/kg bolus 15-U/kg per h infusion for 48
h All patients Eptifibatide 180-?g/kg bolus
2-?g/kg per min infusion NonCABG-related
Goodman SG et al. Circulation. 2003107238-44.
76
INTERACT LMWH/UFH plus GP IIb/IIIa inhibition in
UA/NSTEMI
Effect on 30-day death/MI
UFH GP IIb/IIIa inhibitor
0.10
0.08
P 0.031
0.06
Proportion of patients
0.04
Enoxaparin GP IIb/IIIa inhibitor
0.02
0
15
20
25
30
10
5
0
Days since randomization
Enoxaparin 1 mg/kg SC q 12 h for 48 hUFH
70-U/kg bolus 15-U/kg per h infusion for 48
h All patients Eptifibatide 180-?g/kg bolus
2-?g/kg per min infusion
Goodman SG et al. Circulation. 2003107238-44.
77
SYNERGY Study design
Superior Yield of the New Strategy of Enoxaparin,
Revascularization and GlYcoprotein IIb/IIIa
Inhibitors
Compare enoxaparin vs UFH and define role of
enoxaparin N 10,027 high-risk NSTEMI patients
managed with early PCI Prospective, randomized,
open-label, multicenter study
Enoxaparin
UFH
GP IIb/IIIa inhibitor, aspirin, and clopidogrel
Primary outcomeDeath or MI 30 days
Primary safety outcomeMajor bleeding or stroke
SYNERGY Trial Investigators. JAMA. 200429245-54.
78
SYNERGY Enoxaparin vs UFH with GP IIb/IIIa
inhibition in ACS with early PCI
Primary outcome (death or MI)
Concomitant medications
() Aspirin 95.2 94.7 Clopidogrel
62.5 63.3 GP IIb/IIIa inhibitor
56.5 58.2 b-Blocker 86.4 85.9 ACE
inhibitor 63.8 62.2 Statin 69.2 70.0
0.2
Enoxn 4993
UFHn 4985
UFH
Enoxaparin
14.5
14.0
Proportion of patients
0.1
HR 0.96(95 Cl 0.861.06)
0
10
20
30
0
Days from randomization
No. at Risk
UFH
4920
4458
4343
4301
4279
4261
3509
Enoxaparin
4936
4508
4375
4338
4313
4300
3550
SYNERGY Trial Investigators. JAMA. 200429245-54.
79
PCI-CURE Substudy design
Percutaneous Coronary Intervention substudy of
Clopidogrel in Unstable angina to prevent
Recurrent ischemic Events
Evaluate pre/post-PCI benefit of clopidogrel N
2658 with NSTEMI Double-blind, placebo-controlled,
multicenter prespecified post-randomization
analysis
Clopidogrel 300 mg pre-PCI, Open-label
thienopyridine 24 wk, Clopidogrel 312 mo
Placebo pre-PCI,Open-label thienopyridine 24
wk, Placebo 312 mo
Aspirin 75325 mg (all patients)
Primary outcomeCV death, MI, revascularization
at 30 days
Follow-up 1 month
Mehta SR et al. Lancet. 2001358527-33.
80
PCI-CURE Reduction in primary outcome at 30 days
CV death, MI, or urgent target vessel
revascularization
0.08
30 RRRP 0.03
Placebo
0.06
Cumulative hazard rates
0.04
Clopidogrel
0.02
P 0.03
0
0
5
10
15
20
25
30
Days of follow-up
Mehta SR et al. Lancet. 2001358527-33.
Unadjusted
81
ISAR-REACT Study design
Intracoronary Stenting and Antithrombotic
RegimenRapid Early Action for Coronary Treatment
Evaluate abciximab clopidogrel loading dose in
PCI N 2159 undergoing elective
PCI Double-blind, randomized, placebo-controlled
multicenter study
Clopidogrel 600 mg 2 h prior to PCIAspirin
325500 mg
Abciximab 0.25 mg/kg bolus, then0.125 µg/kg per
min for 12 h UFH 70 U/kg
Placebo UFH 140 U/kg
Primary outcomeAll-cause death, MI, urgent
revascularization
Follow-up 1 month
Kandzari DE et al. J Am Coll Cardiol.
2004442133-6.
82
ISAR-REACT Timing of loading dose and primary
outcome
All-cause death, MI, urgent revascularization
Major bleeding () 1.6 0.5 0.4 1.1
10
lt3 h
36 h
8
612 h
Death, MI, urgent revascularization()
6
gt12 h
4
2
P 0.79
0
0
5
10
15
20
25
30
Time from randomization (days)
Kandzari DE et al. J Am Coll Cardiol.
2004442133-6.
83
ISAR-CHOICE No additional platelet effect with
doses gt600 mg
Intracoronary Stenting and Antithrombotic
Regimen Choose Between 3 High Oral Doses for
Immediate Clopidogrel Effect
Maximal ADP-induced platelet aggregation after 4
hours
120
P 0.001
100
ADP(5 µmol/L)-inducedaggregation()
80
60
40
20
P 0.01
P 0.59
0
300 mg
600 mg
900 mg
Clopidogrel (loading dose)
von Beckerath N et al. Circulation.
20051122946-50.
84
ISAR-SWEET Study design
Intracoronary Stenting and Antithrombotic
Regimen Is Abciximab a Superior Way to Eliminate
Elevated Thrombotic Risk in Diabetics
Evaluate abciximab clopidogrel loading dose in
PCI N 701 with diabetes, undergoing elective
PCI Double-blind, randomized, placebo-controlled
multicenter study
Clopidogrel 600 mg 2 h prior to PCIAbciximab
0.25 mg/kg bolus, then0.125 µg/kg per min for 12
hn 351
Clopidogrel 600 mg 2 h prior to PCI Placebon
350
Aspirin 500 mg and heparin
Primary outcomeAll-cause death and MI at 1 year
Mehilli J et al. Circulation. 20041103627-35.
TVR target vessel revascularization
85
ISAR-SWEET Neutral effect on primary outcome in
diabetes
10
RR 0.97(0.581.62)P 0.91
8
6
All-cause death, MI()
Abciximab
4
Placebo
2
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Time from randomization (months)
Mehilli J et al. Circulation. 20041103627-35.
86
ISAR-SWEET Reduction in restenosis and target
vessel revascularization in diabetes
RRR 24
P 0.01
RRR 22
37.8
40
P 0.03
30.4
28.9
30
23.2
Incidence()
20
10
0
Angiographicrestenosis
Target lesionrevascularization
Abciximab
Placebo
Mehilli J et al. Circulation. 20041103627-35.
87
CLEAR PLATELETS Study design
Clopidogrel Loading with Eptifibatide to Arrest
the Reactivity of PLATELETS
Compare effects of antiplatelet regimens on
platelet reactivity and occurrence of myocardial
necrosis N 120 undergoing elective stenting 2 x
2 factorial study
Clopidogrel 300 mg
Clopidogrel 300 mg eptifibatide
Clopidogrel 600 mg eptifibatide
Clopidogrel 600 mg
Primary aimCompare effects of four regimens
Secondary aimEffect of treatment on platelet
reactivity and postprocedural myocardial necrosis
Loading dose immediately after stenting, then 75
mg/d Double bolus (180 ?g/kg) followed by
infusion (2 ?g/kg per min) for 1824 hours
postprocedure
Gurbel PA et al. Circulation. 20051111153-9.
88
CLEAR PLATELETS Platelet effects vs clopidogrel
dose and GP IIb/IIIa inhibition
Platelet reactivity
Platelet inhibition
70
120
60




100
D
50
C
Relative inhibition ()
Aggregation ()
80
40

30
60

B

20
40
A
?
10
20
0
0
A
B
C
D
1824 h
3 h
8 h
Group
Time (post-stenting)
P 0.001 C or D vs A or B P 0.001 A vs B
P 0.002 A vs B ?P lt 0.001 C or D vs A or B
A Clopidogrel 300 mg B Clopidogrel 600 mg C
Clopidogrel 300 mg eptifibatide D Clopidogrel
600 mg eptifibatide

Gurbel PA et al. Circulation. 20051111153-9.
Response to adenosine diphosphate 5 ?mol/L
89
CLEAR PLATELETS Effect of clopidogrel dose and
GP IIb/IIIa inhibition on cardiac biomarkers
CK-MB release
Troponin release
20
30
20
Patients ()
10

10



0
0
CK-MB (gt3x ULN)
Troponin-I (gt ULN)
Clopidogrel 300 mg Clopidogrel 600
mg Clopidogrel 300 mg eptifibatide Clopidogrel
600 mg eptifibatide
P lt 0.05 vs clopidogrel 300 or 600 mg P 0.04
vs clopidogrel 300 mg P 0.08 vs clopidogrel
600 mg ULN upper limit of normal
Gurbel PA et al. Circulation. 20051111153-9.
90
Clopidogrel response variability 300 mg vs 600
mg
N 190
33
300 mg clopidogrel
Resistance 600 mg 8
30
600 mg clopidogrel
Resistance 300 mg 28
27
24
Nonresponsiveness
21
Patients()
18
15
12
9
6
3
0
-30
(-20,-10
(0,10
(20,30
(40,50
(60,70
(-30,-20
(-10,0
(10,20
(30,40
(50,60
gt 70
D Platelet aggregation (5 µM ADP-induced) at 24
hours
Gurbel PA. J Am Coll Cardiol. 2005451392-96.
91
Clopidogrel resistance associated with increased
CV risk
ADP-induced platelet aggregation
Recurrent CV events at 6 months
40
Clopidogrel resistance
40
120
P 0.007
35
1st Q
100
30
80
25
2nd Q
60


20
3rd Q
15
40
4th Q
6.7
10
20
5
0
0
0
0
1stn 15
2ndn 15
3rdn 15
4thn 15
1
2
3
4
5
6
Days
Quartiles
Matetzky S et al. Circulation. 20041093171-5.
92
REPLACE-2 Study design
Randomized Evaluation in PCI Linking Angiomax to
Reduced Clinical Events
Evaluate bivalirudin vs heparin GP IIb/IIIa
blockade post-PCI N 6010 undergoing
PCI Randomized, double-blind multicenter study
Bivalirudin 0.75 mg/kg bolus, 1.75 mg/kg per h
during PCIProvisional GP IIb/IIIa inhibitor
Heparin 65 U/kg bolusPlanned GP IIb/IIIa
inhibitor
Primary outcomeDeath, MI, repeat
revascularization, or in-hospital major bleeding
in 30 days
Secondary outcomeDeath, MI, repeat
revascularization 30 days
Lincoff AM et al. JAMA. 2003289853-63.
93
REPLACE-2 Death, MI, urgent revascularization,
major bleeding
P 0.32
P 0.26
P 0.23
P 0.44
P lt 0.001
10.0
10
9.2
Heparin GP IIb/IIIa inhibitor(n 3008)
8
7.0
6.2
Bivalirudin(n 2994)
6

4.1
4
2.4
2
1.4
1.2
0.4
0.2
0
Death
MI
Urgent revasc
Major bleed
Composite
Lincoff AM et al. JAMA. 2003289853-63.
94
GP IIb/IIIa Inhibition in STEMI Growing Clinical
Trial Evidence
95
PCI vs fibrinolysis in STEMI patients
Short-term clinical outcomes
Meta-analysis of 23 trials N 7739
25
20
Frequency ()
15
10
5
0
Recur ischemia
Death no SHOCKdata
Total stroke
Hem stroke
Major bleed
Death, MI, stroke
Death
ReMI
PCI
Fibrinolysis
Antman EM et al. Circulation. 2004110588-636. Mo
dified from Keeley EC et al. Lancet.
200336113-20.
96
PCI vs fibrinolysis in STEMI patients Long-term
clinical outcomes
Meta-analysis of 23 trials
35
30
25
Frequency ()
20
15
10
5
0

Death MI stroke
Death
Death, no SHOCK data
RecurMI
Recur ischemia
PCI
Fibrinolysis
Antman EM et al. Circulation. 2004110588-636. Mo
dified from Keeley EC et al. Lancet.
200336113-20.
97
ACC/AHA STEMI guidelines Assessing reperfusion
options
Fibrinolysis
Primary PCI

• Early presentation (3 hours from symptom onset)
• Invasive strategy not an option
• Delay to invasive strategy
• Door-to-balloon exceeds door-to-needle time by gt1
  hour
• gt90 minutes to balloon time

• High-volume lab with surgical backup
• High risk from STEMI
• Fibrinolysis contraindicated (excessive
  bleeding/ICH)
• Late presentation
• Symptoms gt3 hours prior
• STEMI diagnosis in doubt

ICH intracranial hemorrhage
Antman EM et al. Circulation. 20041092480-6.


98
TIMI flow grade
TIMI 0 Complete occlusion TIMI 1
Penetration of obstruction by contrast but no
distal perfusion TIMI 2 Perfusion of
entire artery but delayed flow TIMI 3
Full perfusion, normal flow
Mortality is reduced with better flow
Chesebro JH et al. Circulation. 198776142-54.
99
Mortality benefit of primary PCI declines with
PCI-related time delay
Meta-regression analysis of 21 trials
15
Circle sizes reflect study sample size Solid
line weighted meta-regression
10
Absolute risk difference in death ()
P 0.006
5
62 minutes
BenefitFavors PCI
0
HarmFavors lytics
5
0
20
40
60
80
100
PCI-related time delay (minutes)
Nallamothu BK, Bates ER. Am J Cardiol.
200392824-6.
100
Major considerations for pharmacologic approaches
to facilitate primary PCI

• Delay between presentation with STEMI and primary
  PCI vs progressive nature of ischemia-related
  necrosis

• Inverse relationship between time-to-reperfusion
  and extent of salvaged myocardium and survival

• Relationship between restoration of coronary flow
  and recovery of contractility and survival after
  STEMI

• Facilitated PCI strategy utilizing GP IIb/IIIa
  inhibition or fibrinolytic therapy provides a
  degree of coronary reperfusion when PCI is not
  immediately available

Beygui F, Montalescot G. Eur Heart J.
20057(suppl)110-4.
101
INTAMI pilot trial Early eptifibatide improves
TIMI 3 flow before PCI for STEMI
INTegrilin in Acute Myocardial Infarction
80
67.4
70
P 0.01
58.4
60
50
Patency ()
40
34.0
30
22.4
20
10.2
7.6
10
0
TIMI 3
TIMI 2
TIMI 0/1
Early administration (n 53)
Late or no administration (n 49)

Zeymer
U et al. Eur Heart J. 2005261971-7.
102
TIMI 3 patency before PCI in trials of early vs
late/no GP IIb/IIIa inhibitors in STEMI
40
Abciximab
Tirofiban
Eptifibatide
30
TIMI 3patency before PCI ()
20
10
0
Zorman
Reo-Mobile
ERAMI
ReoPro-bridging
ADMIRAL
Cutlip
TIGER-PA
On-TIME
INTAMI
TITAN
N 109 100 69 55 300 60 100 487 102 316
Early
Late or no GP IIb/IIIa inhibitor
Zeymer U et al. Eur Heart J. 2005261971-7. www.t
imi.org
103
GP IIb/IIIa inhibitors for primary PCI
30-day death, recurrent MI, or urgent
revascularization
P 0.01
16
14.6
P 0.03
14
P 0.02
P 0.04
11.2
12
10.5
10.5
10

8
6
5.8
5
6
4.5
4
2
0
RAPPORT
ISAR-2
ADMIRAL
ACE
N
483
401
300
400
Placebo
GP IIb/IIIa inhibitor
Brener SH et al. Circulation. 199898734-41. Neum
ann FJ et al. J Am Coll Cardiol.
200035915-21. Montalescot G et al. N Engl J
Med. 20013441895-1903. Antoniucci D et al. J Am
Coll Cardiol. 2003421879-85.
Outcome also includes stroke
104
Facilitated PCI in STEMI

• Early administration of GP IIb/IIIa inhibitors is
  associated with significant flow restoration,
  potentially better myocardial reperfusion, and no
  significant increase in major bleeding

• Early GP IIb/IIIa facilitation strategy may be
  recommended in STEMI patients who are candidates
  for primary PCI

• Benefits of GP IIb/IIIa therapy in primary PCI
  for STEMI demonstrated in large clinical trials
  include improvement in pre-PCI coronary flow,
  angiographic parameters, and ischemic outcomes
  and mortality

• More data from large-scale clinical trials are
  needed to determine the risks and benefits of
  facilitated PCI with GP IIb/IIIa inhibitors
  fibrinolytics

Beygui F, Montalescot G. Eur Heart J Suppl.
20057(suppl I)I10-4.