clinical trials of gp iib/iiia inhibition major trials of gp iib/iiia inhibitors in acs gp iib/iiia...
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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
Antman EM et al. Am Heart J. 2003;146:S18-S22.
Death or MI at 30 days
*Does not include 345 patients In the tirofiban only group, which was stopped prematurely
Efficacy of GP IIb/IIIa inhibition on death or MI in PCI or ACS
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
Trial N
Odds ratio (95% CI)
FavorsGP IIb/IIIa
Favorsplacebo
1 2
0.79 (0.73–0.85)P < 10–9
Elective PCI
ACS
0
VBWG
PRISM-PLUS: Study design
Tirofiban*n = 345
Heparinn = 797
Tirofiban + heparinn = 773
N = 1915 with unstable angina or non–Q-wave MIRandomized, double-blind study
Infusion for 71.3 ± 20 hoursAngiography + angioplasty during Tx after 48 hours (prn)
Primary outcome:Death, MI, refractory ischemia ≤7 days
PRISM-PLUS Investigators. N Engl J Med. 1998;338:1488-97. *Stopped prematurely due to high mortality at 7 days
Platelet-Receptor Inhibition for ischemic Syndrome Management in Patients Limited by Unstable Signs and symptoms (PRISM-PLUS)
VBWG
Morrow DA et al. Am J Cardiol. 2004;94:774-6.RI = recurrent ischemia
30
25
20
15
10
5
0
Heparin
Death or MI
11.58.9
13.0
8.3
Tirofiban + heparin
No PCIn = 1069
PCIn = 501
23%↓0.50–1.12
36%↓0.34–1.08
RRR(95% CI)
30
25
20
15
10
5
0
Death/MI/RI
21.318.7
24.7
18.1
No PCIn = 1069
PCIn = 501
12%↓0.63–1.15
27%↓0.44–1.04
Outcomesat 30 days
PRISM-PLUS: Benefits at 30 days similar with/without PCI
VBWG
H = heparin; T = tirofibanHigh risk = TIMI risk score ≥4RI = refractory ischemia Morrow DA et al. Am J Cardiol. 2004;94:774-6.
H T+H OR P
No PCIHigh risk (n = 664)
Low risk (n = 405)
High risk (n = 280)
Low risk (n = 221)
0.04
0.1
0.06
0.9
0.69
1.6
0.60
0.98
21.9
13.6
22.2
13.4
28.2
8.7
32.4
13.7
0.1 1 10
Favorstirofiban/heparin
Favorsheparin
Odds ratio (95% CI)
PCI
Death/MI/RI
PRISM-PLUS: Benefit of GP IIb/IIIa inhibition by risk profile
VBWG
PURSUIT: Study design
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
N = 10,948 Chest pain <24 hours + ECG changes of ischemia
orElevated CK-MB >ULN for hospitalRandomized, double-blind study
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.
Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy
VBWG
HR = 0.29P < 0.001
Kleiman NS et al. Circulation. 2000;101:751-7.
Days from enrollment
Pre-PCI MI (%)
1.7%
5.5%5
10
0
0 1 2 3
Placebo
Eptifibatide
PURSUIT: Pre-PCI GP IIb/IIIa inhibition prevents early MI
VBWG
Lincoff AM et al. Circulation 2000;102:1093-100.Early PCI: n = 450No early PCI: n = 1316
%
96 Hours Early PCI 15.3 9.2 No early PCI 7.7 5.57 Days Early PCI 16.0 9.9 No early PCI 10.8 8.830 Days Early PCI 16.7 11.2 No early PCI 15.0 12.26 Months Early PCI 19.8 15.1 No early PCI 18.6 15.3
Favors eptifibatide Favors placeboPlacebo Eptifibatide
Death or myocardial reinfarction
0.5 1 2OR (95% CI)
PURSUIT: GP IIb/IIIa inhibition prevents death with/without early PCI
VBWG
.
Bhatt DL et al. JAMA. 2000;284:1549-58.
2.8
2.3
1.7
00.0
0.5
1.0
1.5
2.0
2.5
3.0
Difference in rate of death or MI,
eptifibatide vs placebo
(%)
<6 6–12 12–24 >24
Time to treatment (hours)
PURSUIT: Importance of timing GP IIb/IIIa inhibition on outcomes
N = 9471
VBWG
TACTICS-TIMI 18: Study design
Conservative approach
ETT/cath/PCI for recurrent or demonstrated ischemia
Invasive approach
Cath within 4–48 hours with revascularization if anatomy suitable
N = 2220 with unstable angina/NSTEMI
ASAUnfractionated 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
ETT = exercise tolerance test Cannon CP et al. N Engl J Med. 2001;344:1879-87.
Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy–Thrombolysis In Myocardial Infarction
Primary outcome:Death, MI, rehospitalization for ACS
VBWG
Sabatine MS et al. Circulation. 2004;109:874-80.*Adjusted for baseline differences
Deaths/MI/ACS at 6 months
38% in death/MI/ACS in TACTICS-TIMI 18 vs TIMI IIIB (P < 0.0001)
Events* (%)
22 23
39
12
18
24
0
10
20
30
40
Intermediate(3–4)
Low(0–2)
High(5–7)
TIMI risk score category
P < 0.0001 P = 0.005
P = 0.003
TIMI IIIB TACTICS-TIMI 18
TACTICS-TIMI 18 vs TIMI IIIB: Effects of early PCI GP IIb/IIIa inhibition
VBWG
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)
Gibson CM et al. Am J Cardiol. 2004;94:492-4.*Controlled for baseline troponin T
TIMI myocardialperfusiongrade 3
(%)
Treatment duration (hours)
P = 0.013
<21 >21
10
30
50
0
20
40
29.9
43.4
TACTICS-TIMI 18: Duration of GP IIb/IIIa inhibitor pre-PCI influences TIMI flow
Clinical Trials of GP IIb/IIIa Inhibition
• GP IIb/IIIa Inhibitors in Planned PCI
VBWG
ESPRIT: Study design
Eptifibatide 180-µg/kg double-bolus 10 min apart
+ continuous infusion 2.0 µg/kg per min for 18–24 hPlacebo
Assess effect of novel, double-bolus dose eptifibatide in coronary stenting N = 2064 undergoing stent implantation
Randomized, controlled study
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
Aspirin + heparin + thienopyridine
ESPRIT Investigators. Lancet. 2000;356:2037-44.
Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy
VBWG
ESPRIT Investigators. Lancet. 2000;365:2037-44.N = 2064UTVR = urgent target vessel revascularization
Eptifibatide Placebo RR PEptifibatide
betterPlacebo better
Primary endpoint
Death/MI/UTVR
Death/MI
Death/Large MI
Large MI
All MI
UTVR
Thrombotic bailout
0.5 1.50 1 2
Death5.4
6.6 10.5 0.63 0.0015
6.0 9.3 0.65 0.0045
5.5 9.2 0.60 0.0013
3.4 5.1 0.67 0.053
5.4 9.0 0.60 0.0015
0.6 1.0 0.60 0.30
1.0 2.1 0.48 0.029
0.1 0.2 0.50 0.55
3.3 4.9 0.67 0.064
Relative Risk
ESPRIT: Outcomes at 48 hours
VBWG
Granada JF, Kleiman NS. Am J Cardiovasc Drugs. 2004:4:31-41.TVR = target vessel revascularization
Death/MI/TVR/thrombotic bailout within 48 hours
Placebo Eptifibatide
RR = 0.76(95% Cl 0.63–0.93)
P = 0.0068
RR = 0.65(95% Cl 0.49–0.87)
P = 0.0034
RR = 0.65(95% Cl 0.47–0.87)
P = 0.0045
48 hours 30 days 12 months
Primary endpoint
(%)
0
5
10
15
20
25
ESPRIT: Primary outcome over time
VBWG
Lincoff AM et al. J Am Coll Cardiol. 2000;35:1103-15.B = bolus; B+I = bolus + infusion; LDH = low-dose heparin; SDH = standard-dose heparin
Death, MI, or urgent revasc at 30 daysP
0.430Abciximab BEPIC
0.008Abciximab B+I
<0.001Abciximab LDHEPILOG
<0.001Abciximab SDH
<0.001Abciximab + stentEPISTENT
0.007Abciximab + PCI
0.063Eptifibatide 135/.5IMPACT II
0.220Eptifibatide 135/.75
0.052TirofibanRESTORE
0.030AbciximabRAPPORT
0.25 1.0 4.0
Favors GP IIb/IIIa Favors placebo
0.012AbciximabCAPTURE
Odds ratio (95% CI)
Placebo (%)
12.812.8
11.711.7
10.810.8
11.411.4
10.5
11.2
15.9
GP IIb/IIIa (%)
11.48.3
5.25.4
5.36.9
9.29.9
8.0
5.8
11.3
GP IIb/IIIa inhibition in planned PCI
VBWG
Ryan JW et al. Circulation. 2005;112:3049-57.
N = 56,352 with UA/NSTEMI (CRUSADE)
60
50
40
30
20
10
00 6 12 18 24 30 36
Time from admission (hours)
Proportion undergoing
cardiac catheterization
(%) P < 0.001 bylog-rank statistic
42 48 54 60 66 72 78
Weekend
Weekday
Timing of catheterization: Weekday vs weekend hospital admission
VBWG
Weekend delay in catheterization does not increase adverse events
Ryan JW et al. Circulation. 2005;112:3049-57.
1.00 (0.94–1.06)15.114.5Any adverse event
1.00 (0.93–1.08)9.28.6CHF
0.96 (0.86–1.07)0.80.8Stroke
1.05 (0.92–1.21)2.82.6Cardiogenic shock
0.98 (0.91–1.07)6.66.6Death or MI
0.96 (0.86–1.07)2.93.0Reinfarction
1.02 (0.92–1.13)4.44.1Death
Adjusted OR (95% CI)
Weekend patients
(n = 10 804)
Weekday patients
(n = 45 548)In-Hospital Outcomes
N = 56,352 with UA/NSTEMI (CRUSADE)
Clinical Trials of GP IIb/IIIa Inhibition
• GP IIb/IIIa Inhibition in Patients With Diabetes
VBWG
CAD progression and/orworse outcomes post-PCI
Roffi M, Topol EJ. Eur Heart J. 2004;25:190-8.
RAGE = receptor for advanced glycation end-products (AGE)TSP-1 = thrombospondin-1
Accelerated CAD progression in diabetes
InflammationhsCRP, IL-6. VCAM-1,
ICAM-1, P-selectin, sCD40L, TNF-, TSP-1
Prothrombotic stateGP IIb/IIIa receptors
Platelet factor 4Fibrinogen, TF, vWf
PAI-1Protein C
Associated conditionsRenal dysfunction
LV dysfunctionPeripheral vascular disease
Atherosclerotic burdenDiffuse disease
Multivessel diseaseNegative remodeling
RestenosisHyperinsulinemia
RAGE/AGEPPAR- modulation
TSP-1
Endothelial dysfunctionHyperglycemiaFree fatty acids
Insulin resistanceRAGE/AGEDyslipidemia
VBWG
Colwell JA, Nesto RW. Diabetes Care. 2003;26:2181-8.
Altered platelet functions in diabetes
Membrane fluidity
Altered Ca+2 and Mg+2 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
VBWG
Lincoff AM et al. Circulation. 2000;102:1093-100.
30-day death or MI
No diabetes
Diabetes
0.33 1.0 3.0
Placebo betterEptifibatide better
PURSUIT: Outcomes in diabetic vs nondiabetic US patients
Odds ratio (95% CI)
VBWG
Théroux P et al. Circulation. 2000;102:2466-72.
Heparin(%)
Tirofiban + heparin
(%)30-day outcomes
Composite
MI/Death
Medical managementCABG
PCI
All diabetic patients undergoing
Medical managementCABG
PCI
All diabetic patients undergoing
0.1 1 5 100.5
25.4
22.544.9
12.726.511.2
21.2
17.725.6
1.92.67.6
Risk ratio (95% CI)
PRISM-PLUS: Outcomes in diabetic NSTEMI patients by treatment strategy
VBWG
Roffi M et al. Eur Heart J. 2004;25:190-8.
Event rate* at 6 months
(%)
*Death, MI, rehospitalization for ACSPatients treated with aspirin, clopidogrel, and tirofiban
0
5
10
15
20
25
30
Diabetes No diabetes
14.216.4
13%
27%
20.1
27.7 Invasive
Conservative
TACTICS-TIMI 18: Death/MI/ACS in ACS patients with/without diabetes
VBWG
Lincoff AM. Circulation. 2003;107:1556-9.
1-year mortality
(%)
Evaluation of Platelet Inhibition in STENTing Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy
0
1
2
3
4
5
Diabetes
4.1
1.2
No diabetes
EPISTENT(Abciximab)
ESPRIT(Eptifibatide)
1.9
1.0
Diabetes
3.5
1.3
No diabetes
1.5 1.4
Placebo GP IIb/IIIa inhibitor
EPISTENT, ESPRIT: Effect on 1-year mortality in planned PCI by diabetes status
VBWG
Roffi M, Topol EJ. Eur Heart J. 2004;25:190-8.
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