intravenous gp iib/iiia inhibitors abciximab (c7e3 fab, reopro) = human- murine chimeric monoclonal...

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)