Intravenous GP IIb/IIIa Inhibitors
• Abciximab (c7E3 Fab, ReoPro) = Human-murine chimeric monoclonal Fab antibody fragment
• Eptifibatide (Integrilin) = A cyclic heptapeptide based on the Lys-Gly-Asp (KGD) amino acid sequence
• Tirofiban (Aggrastat) = Tyrosine derivative non-peptide mimetic inhibitor
Intravenous GP IIb/IIIa InhibitorsAbciximab (ReoPro)
• Has a rapid, high affinity to platelets within minutes
• Dissociation slowly from GP IIb/IIIa receptor
• Clears rapidly from plasma but remains bound to circulating platelets up to 21 days
• Binding to IIb/IIIa receptor is non-specific and has equal affinity for the vitronectin receptor which appears to play a role in cell adhesion, migration and proliferation
Intravenous GP IIb/IIIa Inhibitors
Reopro Integrilin Aggrastat
Structure Monoclonal antibody
Peptide Non-peptide Tyrosine derivative
Specificity to IIb/IIIa receptor
Also binds to vitronectin
Very Very
Platelet bound t1/2 Hours Seconds Seconds
Platelet recovery 12-36 Hrs 4 Hrs 4 Hrs
Plasma t1/2 Minutes 2.5 Hrs 1.8 Hrs
% of dose in bolus 75% <2-16% <2-5%
IV IIb/IIIa Inhibitors and Time course of Action on Platelets
N = 2099 N = 2792N = 1265
Pts referred for elective or urgent PTCAPts referred for elective or urgent PTCAwho are also stent candidateswho are also stent candidates
PTCA alone +PTCA alone +Abciximab Bolus + infusion +Abciximab Bolus + infusion +
Low Dose Heparin Low Dose Heparin (70 U/kg to ACT (70 U/kg to ACT >> 200 s)200 s)
N = 796N = 796
PTCA + Stent PTCA + Stent ++
Standard Dose Heparin Standard Dose Heparin (100 U/kg to ACT (100 U/kg to ACT >> 300 s)300 s)
N = 794N = 794
PTCA + Stent PTCA + Stent ++
Abciximab Bolus + infusion +Abciximab Bolus + infusion +Low Dose Heparin Low Dose Heparin
(70 U/kg to ACT (70 U/kg to ACT >> 200 s)200 s)N = 809N = 809
30 day and 6 month composite endpoint of death, MI, and recurren30 day and 6 month composite endpoint of death, MI, and recurrent revascularizationt revascularization
Protocol DesignProtocol DesignEPISTENTEPISTENT
EPISTENTEPISTENT
Placebo/StentPlacebo/Stent AbxAbx/Stent/Stent AbxAbx/Balloon/Balloon
No. PatientsNo. Patients
Stent Placed (%)Stent Placed (%)
No. Stents/Pt (%)No. Stents/Pt (%)
11
22
33
44
Maximum BalloonMaximum Balloon
Inflation Pressure (mm)Inflation Pressure (mm)
809
95.3
69.6
21.9
5.7
2.7
16.0
794
96.9
73.8
20.2
4.5
1.6
16.0
796
19.1
66.4
23.0
7.2
3.3
16.0
Stent Placement
EPISTENTEPISTENT o1 Endpoint: Death, MI, or Urgent Intervention
10.812.1
5.36.46.8
9.2
0
3
6
9
12
15
30 day 6 months
Inci
den
ce (
%)
Placebo/Stent Abciximab/Stent Abciximab/PTCA
p < 0.001
p = 0.051
p < 0.001
p = 0.007
ReductionReductionvsvs Stent OnlyStent OnlyAbciximab + StentAbciximab + StentAbciximab OnlyAbciximab Only
47%47%24%24%
51%51%37%37%
EPISTENTEPISTENT
9.310.2
11.4
4.2 4.75.65.2
5.8
7.8
0
3
6
9
12
24 Hours 30 Days 6 months
Inci
denc
e (%
)Stent Only (n = 809) Abciximab + Stent (n = 794)
Abciximab Only (n = (796)
EPISTENTEPISTENT M yocardial InfarctionM yocardial Infarction
9.610.3
4.55.25.3
6.6
0
3
6
9
12
30 day 6 months
Inci
denc
e (%
)Placebo/Stent Abciximab/Stent Abciximab/PTCA
EPISTENTEPISTENT T a r g e t V e s s e lT a r g e t V e s s e l R e v a s c u la r iz a tio nR e v a s c u la r iz a tio n (T V R )(T V R )
2.9
10.6
2.3
8.7
3.5
15.4
0
5
10
15
20
30 day 6 months
Inci
denc
e (%
)Placebo/Stent Abciximab/Stent Abciximab/PTCA
EPISTENTEPISTENT
Diabetes and Diabetes and StentingStenting
1Circ 1997;96:1454 2Ann Int Med 1993;118:3443JACC Abstracts 1997;29:188A 4JACC Abstracts 1997;29:455A
Study
Van Belle1
Carozza 2
Elezi 3
Yokoi 4
No.Lesions
300
230
1469
1031
Diabetes
25
55
40
29
No Diabetes
27
20
24
23
Restenosis Rates (%)
EPISTENTEPISTENT Death, M I, or TVR at 6 m onthsDeath, M I, or TVR at 6 m onths
25.2
16.5
13.0 13.0
23.4
19.9
0
5
10
15
20
25
30
Diabetics Nondiabetics
Inci
denc
e (%
)Placebo/Stent Abciximab/Stent Abciximab/PTCA
EPISTENTEPISTENT T V R a t 6 m o n th sT V R a t 6 m o n th s
16.6
9.08.1 8.8
18.4
14.6
0
5
10
15
20
Diabetics Nondiabetics
Inci
denc
e (%
)Placebo/Stent Abciximab/Stent Abciximab/PTCA
EPISTENTEPISTENT
6 Month Outcome 6 Month Outcome -- Diabetic Patients (N=491)Diabetic Patients (N=491)
Days from Randomization
TVR
Days from Randomization
Death or MI
0
5
0 30 60 90 120 150 180
Placebo + Stent
Abciximab + Stent
Abciximab + PTCA
% of Pts, Death or MI
12.7%
p = 0.041
7.8%
6.2%
p = 0.128
0
5
10
15
20
0 30 60 90 120 150 180
Placebo + Stent
Abciximab + Stent
Abciximab + PTCA
% of Pts, Any TVR
8.1%
16.6%
18.4%
p = 0.021
EPISTENTEPISTENT
1 Year Mortality 1 Year Mortality -- DiabetesDiabetes
4.1
1.2
2.6
0
1
2
3
4
5
PlacStent
AbcixStent
AbcixPTCA
% Death
Diabetic (N = 491)
1.9 2.0
1.0
0
1
2
3
4
5
PlacStent
AbcixStent
AbcixPTCA
% Death
Non Diabetic (N = 1908)
World Wide Effect of Reopro if Used in All PTCA Procedures - Extrapolation
from EPISTENT
No. of Lives Saves: >2500
No. of MIs Prevented: >40,000
No. of emergency Revascularisation >6500
Prevented:
IMPACT II - Eptifibatide (Integrillin) For Elective or Urgent PTCA
R = Revascularisation.
11.4
9.29.9
Treatment Arms0
2
4
6
8
10
12
14
Co
mp
os i
te E
nd
po
int %
(Dea
th, M
I, U
r ge n
t R
Placebo
135/0.5 Dose
135/0.75 Dosep=0.06 p=0.0.22
19% 16%
N = 4010Treatment was given for 24 hrsBaseline characteristics or risk stratification were not predictive of treatment effectThe differences in death and MI rates was maintained over 6 months but the rate of revascularisation remained unchangedSubgroup angiography study of 900 pts should no effect on restenosis
RESTORE Trial - Tirofiban for Patients with UA or acute MI undergoing PTCA
R = Revascularisation.
10.5
8
Treatment Arms0
2
4
6
8
10
12
Co
mp
os
ite
En
dp
oin
t %
(D
ea
th,
MI,
Urg
en
t R
Placebo
Tirofibinp=0.05224%
N = 2139Treatment was given for 36 hrsBaseline characteristics or risk stratification were not predictive of treatment effectThe differences in death and MI rates was maintained over 6 months but the rate of revascularisation remained unchangedSubgroup angiography study of 600 pts should no effect on restenosis
Overview of Randomised Trials of GP IIb/IIIa Inhibitors During Coronary Intervention
RAPPORT TRIAL - Reopro For Primary PTCA
Endpoint A= Death, recurrent MI, urgent repeat TVR at 30 days. B= Death, recurrent MI, any repeat TVR (inc elective ones) at 6 month
11.2
28.2
9.5
5.8
28.1
16.6
Endpoint A Endpoint BBleeding Complications0
5
10
15
20
25
30
35
Eve
nt R
ate
(%
)
Placebo
Reopro
p= 0.03848% 0.02
N = 483
GP IIb/IIIa Inhibitors for Coronary Intervention
• In >15,000 patients GP IIb/IIIIa blockade shown to reduce risk of important acute ischaemic events by >50-60% during coronary intervention
• The treatment effect extends to each of the components of the composite clinical endpoints (Death, MI, and emergency revascularisation)
• The inhibition of ischaemic events is achieved early (12-48 hrs) and maintained up to 3 yrs
• All patients regardless of their demographics, clinical, angiograhic, or procedural characteristic benefit
• Patients with UAP and Diabetics obtain the greatest benefit
• There may be heterogeneity among the different IIb/IIIa inhibitors. The greatest impact has been shown with Reopro. This may be due to its non-specific binding ability and its different pharmocokinetic profile
GP IIb/IIIa Inhibitors for Coronary Intervention
• Reopro may be specially effective in reducing TVR and therefore restenosis in diabetes in association with coronary stenting but influence of GP IIb/IIIa inhibitors on restenosis in other groups remain unclear
• Safety of these drugs is increased by keeping ACT ~200 during procedure and avoiding post-procedural heparin with early sheath removal
• Economical aspects of this therapy needs to be evaluated
GP IIb/IIIa Inhibitors for Coronary Intervention
Who should have Reopro during Coronary Intervention
• Patients with UAP at rest with ECG changes, or Refractory angina or Post MI angina particularly if:– Diabetic– Clot present– TIMI 3 flow not achieved– Troponin level is raised
• ? In Rescue / Salvage PTCA
EPISTENTEPISTENT
1.4
2.1
5.8
0.91.5
2.01.5
1.1
2.6
0
2
4
6
8
Inci
denc
e (%
)Stent Only (n = 809)
Abciximab + Stent (n = 794)
Abciximab Only (n = (796)
D e a th , M I, o r T V RD e a th , M I, o r T V R
11.4
18.3
6.1
13.0
8.0
20.5
0
5
10
15
20
25
30 day 6 months
Inci
denc
e (%
)Placebo/Stent Abciximab/Stent Abciximab/PTCAEPISTENTEPISTENT
EPISTENTEPISTENT
6 Month Death or MI 6 Month Death or MI -- DiabetesDiabetes
15
Days from Randomization
Placebo + Stent
Abciximab + Stent
Abciximab + PTCA
% of Pts, Death or MI
0
5
10
0 30 60 90 120 150 180
12.7%
p = 0.041
7.8%
6.2%
p = 0.128
Diabetic (N = 49)
Days from Randomization
0
5
10
15
0 30 60 90 120 150 180
% of Pts, Death or MI
5.4%
p <0.001
11.0%
7.8%p = 0.049
Abciximab + Stent
Abciximab + PTCA
Placebo + Stent
Non Diabetic (N = 1908)
EPISTENTEPISTENT
Month TVR Month TVR -- DiabetesDiabetesDiabetic (N = 491) Non Diabetic (N = 1908)
Days from Randomization
Placebo + Stent
Abciximab + Stent
Abciximab + PTCA
% of Pts, Any TVR
1800
5
10
15
20
0 30 60 90 120 150
8.1%
16.6%
18.4%
p = 0.021
Days from Randomization
% of Pts, Any TVR
0
5
10
15
20
0 30 60 90 120 150 180
14.6%
9.0%
8.8%p = 0.002
Abciximab + Stent
Placebo + Stent
Abciximab + PTCA
EPISTENTEPISTENT
6 Month TVR Post 6 Month TVR Post StentingStenting -- DiabetesDiabetes
Days from Randomization
Diabetic (N = 335)
Days from Randomization
900
5
10
15
20
0 30 60 120 150 180
% of Pts, Any TVR
9.0%
8.8%
Placebo + Stent
Abciximab + Stent
Non Diabetic (N = 1267)
0
5
10
15
20
0 30 60 90 120 150 180
Placebo + Stent
Abciximab + Stent
% of Pts, Any TVR
8.1%
16.6%
p = 0.021
EPISTENTEPISTENT
6 Month Death or MI 6 Month Death or MI -- Diabetic PatientsDiabetic Patients
1.7
6.2
0.6
6.27.8
1.3
6.5
11.012.7
0
2
4
6
8
10
12
14
Death + MI Death MI
% o
f pat
ient
s
Plac +Stent Abcix + Stent Abcix + PTCA
(N = 491)