Clinical Trials of GP IIbIIIa Inhibition

1
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

2
Clinical Trials of GP IIb/IIIa Inhibition

• Major Trials of GP IIb/IIIa Inhibitors in ACS

3
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.
4
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
5
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
6
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.
7
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.
8
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.
9
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.
10
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.
.
11
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.
12
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
13
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
14
Clinical Trials of GP IIb/IIIa Inhibition

• GP IIb/IIIa Inhibitors in Planned PCI

15
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.
16
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.
17
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
18
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.
19
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.
20
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.
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Clinical Trials of GP IIb/IIIa Inhibition

• GP IIb/IIIa Inhibition in Patients With Diabetes

22
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
23
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.
24
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.
25
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.
26
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.
27
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.
28
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.