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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
Clinical Trials of
GP IIb/IIIa Inhibition
• Major Trials of GP IIb/IIIa Inhibitors in ACS
VBWG
Efficacy of GP IIb/IIIa inhibition
on death or MI in PCI or ACS
Death or MI at 30 days
Trial
Elective PCI
ACS
N
EPIC
2099
IMPACT II
4010
EPILOG
2792
CAPTURE
1265
RESTORE
2139
EPISTENT
2399
PRISM
3231
PRISM-PLUS
PARAGON
Favors
GP IIb/IIIa
Favors
placebo
1570*
2282
PURSUIT
10,948
Overall
30,366
0.79 (0.73–0.85)
P < 10–9
0
*Does not include 345 patients In the tirofiban only
group, which was stopped prematurely
1
Odds ratio (95% CI)
2
Antman EM et al. Am Heart J. 2003;146:S18-S22.
VBWG
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 non–Q-wave MI
Randomized, double-blind study
Tirofiban*
n = 345
Heparin
n = 797
Tirofiban + heparin
n = 773
Infusion for 71.3 ± 20 hours
Angiography + angioplasty during Tx after 48 hours (prn)
Primary outcome:
Death, MI, refractory ischemia ≤7 days
*Stopped prematurely due to high mortality at 7 days
PRISM-PLUS Investigators. N Engl J Med.
1998;338:1488-97.
VBWG
PRISM-PLUS: Benefits at 30 days
similar with/without PCI
Death or MI
Outcomes
at 30 days
Death/MI/RI
30
30
25
25
20
20
15
10
8.9
8.3
5
0
0
18.1
No PCI
n = 1069
PCI
n = 501
No PCI
n = 1069
PCI
n = 501
23%↓
0.50–1.12
36%↓
0.34–1.08
12%↓
0.63–1.15
27%↓
0.44–1.04
Heparin
RI = recurrent ischemia
18.7
10
5
RRR
(95% CI)
21.3
15
13.0
11.5
24.7
Tirofiban + heparin
Morrow DA et al. Am J Cardiol. 2004;94:774-6.
VBWG
PRISM-PLUS: Benefit of GP IIb/IIIa inhibition
by risk profile
Death/MI/RI
Favors
tirofiban/heparin
Favors
heparin
H
No PCI
High risk (n = 664)
8.7 13.6 1.6
PCI
High risk (n = 280)
P
0.1
32.4 22.2 0.60 0.06
Low risk (n = 221)
H = heparin; T = tirofiban
High risk = TIMI risk score ≥4
RI = refractory ischemia
OR
28.2 21.9 0.69 0.04
Low risk (n = 405)
0.1
T+H
13.7 13.4 0.98 0.9
1
10
Odds ratio (95% CI)
Morrow DA et al. Am J Cardiol. 2004;94:774-6.
VBWG
PURSUIT: Study design
Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using
Integrilin Therapy
N = 10,948
Chest pain <24 hours + ECG changes of ischemia
or
Elevated CK-MB >ULN 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
Placebo
n = 4739
Primary outcome:
Composite 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. 1998;339:436-43.
VBWG
PURSUIT: Pre-PCI GP IIb/IIIa inhibition prevents
early MI
10
HR = 0.29
P < 0.001
Placebo
Pre-PCI
5
MI
(%)
5.5%
Eptifibatide
1.7%
0
0
1
2
3
Days from enrollment
Kleiman NS et al. Circulation. 2000;101:751-7.
VBWG
PURSUIT: GP IIb/IIIa inhibition
prevents death with/without early PCI
%
Placebo Eptifibatide
96 Hours
Early PCI
No early PCI
7 Days
Early PCI
No early PCI
30 Days
Early PCI
No early PCI
6 Months
Early PCI
No early PCI
15.3
7.7
9.2
5.5
16.0
10.8
9.9
8.8
16.7
15.0
11.2
12.2
19.8
18.6
15.1
15.3
Death or myocardial reinfarction
Favors eptifibatide
0.5
Early PCI: n = 450
No early PCI: n = 1316
Favors placebo
1
OR (95% CI)
2
Lincoff AM et al. Circulation 2000;102:1093-100.
VBWG
PURSUIT: Importance of timing
GP IIb/IIIa inhibition on outcomes
3.0
2.8
2.3
2.5
Difference in rate 2.0
of death or MI,
eptifibatide
1.5
vs placebo
(%)
1.0
1.7
0.5
0
0.0
<6
6–12
12–24
>24
Time to treatment (hours)
N = 9471
.
Bhatt DL et al. JAMA. 2000;284:1549-58.
VBWG
TACTICS-TIMI 18: Study design
Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or
Conservative Strategy–Thrombolysis In Myocardial Infarction
N = 2220 with unstable angina/NSTEMI
ASA
Unfractionated heparin
Tirofiban 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
Invasive approach
ETT/cath/PCI for recurrent or
demonstrated ischemia
Cath within 4–48 hours with
revascularization if anatomy suitable
Primary outcome:
Death, MI, rehospitalization for ACS
ETT = exercise tolerance test
Cannon CP et al. N Engl J Med. 2001;344:1879-87.
VBWG
TACTICS-TIMI 18 vs TIMI IIIB:
Effects of early PCI GP IIb/IIIa inhibition
Deaths/MI/ACS at 6 months
39
40
30
Events*
20
(%)
P = 0.003
P = 0.005
P < 0.0001
24
23
22
18
12
38%  in
death/MI/ACS in
TACTICS-TIMI
18 vs TIMI IIIB
(P < 0.0001)
10
0
Low
(0–2)
Intermediate
(3–4)
High
(5–7)
TIMI risk score category
TIMI IIIB
*Adjusted for baseline differences
TACTICS-TIMI 18
Sabatine MS et al. Circulation. 2004;109:874-80.
VBWG
TACTICS-TIMI 18: Duration of GP IIb/IIIa inhibitor
pre-PCI influences TIMI flow
50
P = 0.013
43.4
40
Longer infusion*
TIMI
myocardial
perfusion
grade 3
(%)
30
29.9
TIMI myocardial perfusion grade 3:
OR 0.52 (P = 0.012)
20
TIMI flow grade 3:
OR 0.61 (P = 0.054)
10
Minimum diameter
(P = 0.032)
0
<21
>21
Treatment duration (hours)
*Controlled for baseline troponin T
Gibson CM et al. Am J Cardiol. 2004;94:492-4.
Clinical Trials of
GP IIb/IIIa Inhibition
• GP IIb/IIIa Inhibitors in Planned PCI
VBWG
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 18–24 h
Placebo
Aspirin + heparin + thienopyridine
Primary outcome:
Death, MI, urgent revascularization
and thrombotic bailout after GP IIb/IIIa inhibitor ≤48 h
Secondary outcome:
Death/MI/urgent revascularization at 30 days
ESPRIT Investigators. Lancet. 2000;356:2037-44.
VBWG
ESPRIT: Outcomes at 48 hours
Eptifibatide
better
Placebo
better
Eptifibatide
Placebo
RR
P
Primary endpoint
6.6
10.5
0.63
0.0015
Death/MI/UTVR
6.0
9.3
0.65
0.0045
Death/MI
5.5
9.2
0.60
0.0013
Death/Large MI
3.4
5.1
0.67
0.053
Large MI
3.3
4.9
0.67
0.064
All MI
5.4
9.0
0.60
0.0015
UTVR
0.6
1.0
0.60
0.30
1.0
2.1
0.48
0.029
0.1
0.2
0.50
0.55
Thrombotic bailout
5.4
Death
0
0.5
1
1.5
Relative Risk
N = 2064
UTVR = urgent target vessel revascularization
2
ESPRIT Investigators. Lancet. 2000;365:2037-44.
VBWG
ESPRIT: Primary outcome over time
25
20
Primary
endpoint 15
(%)
10
Death/MI/TVR/thrombotic bailout within 48 hours
RR = 0.76
(95% Cl 0.63–0.93)
P = 0.0068
RR = 0.65
(95% Cl 0.47–0.87)
P = 0.0045
RR = 0.65
(95% Cl 0.49–0.87)
P = 0.0034
48 hours
30 days
5
0
Placebo
TVR = target vessel revascularization
12 months
Eptifibatide
Granada JF, Kleiman NS. Am J Cardiovasc Drugs.
2004:4:31-41.
VBWG
GP IIb/IIIa inhibition in planned PCI
GP IIb/IIIa (%) Placebo (%)
EPIC
Abciximab B
Abciximab B+I
EPILOG
Abciximab LDH
Abciximab SDH
EPISTENT
Abciximab + stent
Abciximab + PCI
IMPACT II
Eptifibatide 135/.5
Eptifibatide 135/.75
RESTORE
Tirofiban
CAPTURE
Abciximab
RAPPORT
Abciximab
P
11.4
8.3
12.8
12.8
0.430
0.008
5.2
5.4
11.7
11.7
<0.001
<0.001
5.3
6.9
10.8
10.8
<0.001
0.007
9.2
9.9
11.4
11.4
0.063
0.220
8.0
10.5
0.052
11.3
15.9
0.012
5.8
11.2
0.030
Death, MI, or urgent revasc at 30 days
Favors GP IIb/IIIa Favors placebo
0.25
B = bolus; B+I = bolus + infusion; LDH = low-dose
heparin; SDH = standard-dose heparin
1.0
Odds ratio (95% CI)
4.0
Lincoff AM et al. J Am Coll Cardiol. 2000;35:1103-15.
VBWG
Timing of catheterization: Weekday vs weekend
hospital admission
N = 56,352 with UA/NSTEMI (CRUSADE)
60
Weekday
50
40
Proportion
undergoing
30
cardiac
catheterization
(%)
20
Weekend
P < 0.001 by
log-rank statistic
10
0
0
6
12
18 24 30 36 42 48 54 60
Time from admission (hours)
66
72
78
Ryan JW et al. Circulation. 2005;112:3049-57.
VBWG
Weekend delay in catheterization does not
increase adverse events
N = 56,352 with UA/NSTEMI (CRUSADE)
In-Hospital
Outcomes
Weekday
patients
(n = 45 548)
Weekend
patients
(n = 10 804)
Adjusted OR (95% CI)
Death
4.1
4.4
1.02 (0.92–1.13)
Reinfarction
3.0
2.9
0.96 (0.86–1.07)
Death or MI
6.6
6.6
0.98 (0.91–1.07)
Cardiogenic shock
2.6
2.8
1.05 (0.92–1.21)
Stroke
0.8
0.8
0.96 (0.86–1.07)
CHF
8.6
9.2
1.00 (0.93–1.08)
Any adverse event
14.5
15.1
1.00 (0.94–1.06)
Ryan JW et al. Circulation. 2005;112:3049-57.
Clinical Trials of
GP IIb/IIIa Inhibition
• GP IIb/IIIa Inhibition in Patients With Diabetes
VBWG
Accelerated CAD progression in diabetes
Inflammation
hsCRP, IL-6. VCAM-1,
ICAM-1, P-selectin, sCD40L,
TNF-, TSP-1
Endothelial dysfunction
Hyperglycemia
Free fatty acids
Insulin resistance
RAGE/AGE
Dyslipidemia
Prothrombotic state
GP IIb/IIIa receptors
Platelet factor 4
Fibrinogen, TF, vWf
PAI-1
Protein C
CAD progression and/or
worse outcomes post-PCI
Associated conditions
Renal dysfunction
LV dysfunction
Peripheral vascular disease
RAGE = receptor for advanced glycation end-products (AGE)
TSP-1 = thrombospondin-1
Restenosis
Hyperinsulinemia
RAGE/AGE
PPAR- modulation
TSP-1
Atherosclerotic burden
Diffuse disease
Multivessel disease
Negative remodeling
Roffi M, Topol EJ.
Eur Heart J. 2004;25:190-8.
VBWG
Altered platelet functions in diabetes
 Membrane fluidity
 Prostacyclin production
Altered Ca+2 and Mg+2
homeostasis
 NO production
 Arachidonic acid
metabolism
 Thromboxane A2
synthesis
 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. 2003;26:2181-8.
VBWG
PURSUIT: Outcomes in diabetic vs nondiabetic
US patients
30-day death or MI
Eptifibatide better
Placebo better
Diabetes
No diabetes
0.33
1.0
3.0
Odds ratio (95% CI)
Lincoff AM et al. Circulation. 2000;102:1093-100.
VBWG
PRISM-PLUS: Outcomes in diabetic NSTEMI
patients by treatment strategy
Heparin
(%)
30-day outcomes
Composite
Tirofiban
+ heparin
(%)
All diabetic patients undergoing
PCI
CABG
Medical management
MI/Death
25.4
44.9
22.5
21.2
25.6
17.7
All diabetic patients undergoing
PCI
CABG
Medical management
0.1
0.5
1
5
12.7
26.5
11.2
1.9
2.6
7.6
10
Risk ratio (95% CI)
Théroux P et al. Circulation. 2000;102:2466-72.
VBWG
TACTICS-TIMI 18: Death/MI/ACS
in ACS patients with/without diabetes
30
27%
Invasive
27.7
Conservative
25
20
Event
rate* at 6
months
(%)
20.1
13%
16.4
14.2
15
10
5
0
Diabetes
*Death, MI, rehospitalization for ACS
Patients treated with aspirin, clopidogrel, and tirofiban
No diabetes
Roffi M et al. Eur Heart J. 2004;25:190-8.
VBWG
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)
4.1
4
1-year
mortality
(%)
ESPRIT
(Eptifibatide)
3.5
3
1.9
2
1.2
1
1.0
1.3
1.5
1.4
0
Diabetes
No diabetes
Placebo
Diabetes
No diabetes
GP IIb/IIIa inhibitor
Lincoff AM. Circulation. 2003;107:1556-9.
VBWG
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 drugeluting stents, patients with ACS plus diabetes remain
at high risk for repeat revascularization
Roffi M, Topol EJ. Eur Heart J. 2004;25:190-8.