Learning from the Recently Completed Oral Glycoprotein

IIb/IIIa Receptor Antagonist Trials

Christopher Cannon, M.D.

Brigham and Women’s Hospital

Boston, MA

Need for Long-Term Antiplatelet Therapy

• Markers of platelet activation persist at 1 month post ACS– Ault K, et al. P selectin in the TIMI 12 trial. J

Am Coll Cardiol 1999;33:634-639.• Events persist beyond acute period:

In the TIMI 3 Registry, Death/MI/Rec Ischemia – In-hospital = 10.5%– One year = 28.3%

• Benefit of IIb/IIIa inhibition achieved only during IV infusion period (PURSUIT, PRISM-PLUS)

1. Platelet Adhesion

2. Platelet Activation

Platelet

GP Ib

Plaque rupture

Activated Platelet GP IIb/IIIa

3. Platelet AggregationASA,

Clopidogrel/Ticlopidine

ASA, Clopidogrel/Ticlopidine

GP IIb/IIIa Inhibitors

GP IIb/IIIa Inhibitors in PCI and ACS

Odds Ratio & 95% CI

Placebo BetterIIb/IIIa Better

Trial Placebo IIb/IIIaN

Overall 30,336 11.1% 9.0%0.79 (0.73, 0.85)p < 10 -9

0 1 2

IMPACT-IIEPIC

4,010

2,099

8.4%10.1%

7.1%7.0%

RESTORECAPTURE

2,139

1,265

6.3%9.0%

5.1%4.8%

EPILOG 2,792 9.1% 4.0%

PURSUIT 10,948 15.7% 14.2%

PRISM 3,231 7.0% 5.7%PRISM PLUS 1,570 11.9% 8.7%PARAGON 2,282 11.7% 11.3%

Topol EJ Topol EJ Lancet Lancet 1999;353:227-231.1999;353:227-231.

Death/MI at 30 Days

EPISTENT 2,399 10.2% 5.2%

0

10

20

30

40

ASA 3 5 7 10 5 10 15

TIMI-12: Oral IIb/IIIa Inhibition in ACSTIMI-12: Oral IIb/IIIa Inhibition in ACS

n=52 11 69 59 72 5 9 47

Pat

ien

ts (

%)

mg bid mg qd

Cannon et al. Circulation 1998;97:340Cannon et al. Circulation 1998;97:340

Major or Minor BleedingMajor or Minor Bleeding

6

Study DesignStudy Design

ASA 150-162 mg daily

Orbofiban50 mg BID

Orbo 50 mg BID x 30 daysthen Orbo 30 mg BID

Placebo BID

Other Meds, Cath/Revasc per MD

F/U Day 14, Day 30

Follow-up visit every 3 months

Primary endpoint to 30 days + follow-up

Death, MIUrgent Revasc,

Ischemia -> Rehosp,or Stroke

Randomize 1:1:1

Patient with Unstable Coronary Syndrome <72 hours N=10,302

Primary Endpoint - Through F/U (300 days)

No. Pts

Composite

(%)

Death

MI

Urg revasc

Rehosp

Stroke

Placebo

20.3

3.1

5.5

8.0

11.3

0.9

Orbo

50/30*

20.2

4.4

5.1

6.1

12.1

1.1

Orbo

50/50

20.1

4.1

5.4

6.1

11.2

1.1

P valuesEach Dose vs. Placebo

Data as of Jun 10 1999

NS

0.002 / 0.03

NS

0.001 / 0.003

NS

NS

*Orbofiban 50mg bid x 30 days, then 30mg bid

Cause of Deaths within 30 Days (Preliminary Review)

Data as of Jun 10 1999

No. Deaths

reviewed

Progressive

Sudden

Non-Ischemic

Bleeding

New Thrombotic

Event

35

7

11

7

2

8

69

19

15

5

5

25

43

9

9

1

3

21

Orbo 50/50Placebo Orbo 50/30

Bleeding Events and Thrombocytopenia (F/U)

No. Pts

Severe

ICH

Major

Major/Sev

Platelets

50-80,000

20-50,000

<20,000

Placebo

0.4

0.1

1.7

1.9

0.1

0.1

0.0

Orbo

50/30

1.2

0.2

2.2

3.3

0.6

0.3

0.3

Orbo

50/50

0.7

0.1

3.1

3.7

0.6

0.3

0.3

P valueEach Dosevs. Placebo

Data as of Jun 10 1999

0.0001 / 0.04

NS

NS / 0.0002

< 0.0001

0.0003

0.01 / 0.02

0.01/0.01

Safety (Mean 2 year F/U)CAPRIECAPRIE

•GI hemorrhage 2.0% 2.7% P < 0.05

•Hospitalizationdue to GI hemorrhage 0.7% 1.1% P = 0.012

•GI ulcers 0.7% 1.2% P < 0.001

•Intracranial hemorrhage 0.4% 0.5% P = NS

•Severe Neutropenia 0.04% 0.02% P = NS

*Patients with a history of GI bleed and peptic ulcers were excluded from CAPRIE.

ClopidogrelClopidogrel Aspirin*Aspirin* (n = 9599) (n = 9599) (n = 9586) (n = 9586)

Primary Endpoint to F/UPatients-> PCI on study drug

Primary Endpoint to F/UPatients-> PCI on study drug

Time (days)0 50 100 150 200 250 300

05

10

15

20

25

30

% Patients

placebo50-30 mg50-50 mg

F/U pl v. 50-30: p=0.14pl v. 50-50: p=0.02

30d pl v. 50-30: p=0.73pl v. 50-50: p=0.08

Data as of Jun 10 1999

Summary

First large global trial in ACS of oral IIb/IIIa inhibitor

Orbofiban: minimal efficacy benefit with small excess in mortality

Major bleeding and thrombocytopenia rates were low but higher than placebo

Greater benefit and no harm was seen in subgroups with normal renal function and without heart failure.

30% benefit in PCI patients on study drug

Xemilofiban 10 mg TID

Xemilofiban 20 mg TID

Placebo TID

Randomization

Xemilofiban 20 mg

Placebo

PTCR

30 to 90 min prior to PTCR

Stented patients were assigned to receive either ticlopidine (if assigned to the placebo arm) or ticlopidine placebo (if assigned to an active therapy arm ) for 2 to 4 weeks. ASA was taken by all patients at doses between 80-325 mg per day

6 Month Follow-up

The EXCITE Trial

Treatment

Placebo

Xemilofiban 10 mg

Xemilofiban 20 mg

Cu

mu

lati

ve E

ven

t R

ate

Month from Randomization10 2 3 4 5 6 7

0

0.05

0.10

0.15

0.20

Primary Efficacy AnalysisPrimary Efficacy Analysis (Death, MI, and Urgent Revascularization)(Death, MI, and Urgent Revascularization)

4

65

8

9.8 10.1 10.0

05

1015

TIMI 12 SYMPHONY 1

% o

f P

atie

nts

ASALowMedHigh

TIMI 12 / Symphony I TrialsTIMI 12 / Symphony I TrialsSibrafibanSibrafiban

6 weeks 3 months D/MI/RI Death/MI

IV vs. Oral GP IIb/IIIa inhibitionIV vs. Oral GP IIb/IIIa inhibition

00

2525

5050

7575

100100

00 6h6h 12h12h 24h24h

% i

nh

ibit

ion

(A

DP

)%

in

hib

itio

n (

AD

P)

36h36h

IV infusion:IV infusion:(Eptifibatide 180 ug/kg (Eptifibatide 180 ug/kg

+ 2.0 ug/kg/min)+ 2.0 ug/kg/min)(mean +/- Std. Dev) (mean +/- Std. Dev)

N=48N=48

IntravenousIntravenous OralOral

Data on File, COR/Key Ferguson et al JACC 1998;31:185A (abstract)

00

5050

100100

0h0h 6h6h 0h 0h 6h 6h

8080

Oral :Oral :(Orbofiban (Orbofiban 50 mg BID)50 mg BID)

= Mean= Mean

ADP-Inducted Activation of Platelets from Patients Treated with Orbofiban

Platelet Degranulation/P Selectin

2.0 µM ADP

Randomization 1 Month

P-s

elec

tin

Exp

ress

ion

(per

cen

tag

e o

f p

late

lets

)

0

20

40

60

80

100p < 0.05

__

Fibrinogen Binding

0.2 µM ADP

Randomization 1 Month

Fib

rin

og

en B

ind

ing

(per

cen

tag

e o

f p

late

lets

)

0

20

40

60

80

100

p < 0.01

__

Holmes et al. Am J Cardiol (in press)

0

2

4

6

8

10

12

14

0 0 0.01 0.1 1 10

Abciximab dose (ug/ml)

% P

late

lets

bin

din

g F

gnFibrinogen Binding and Platelet

Aggregation with IIb/IIIa Inhibitor

Fibrinogen Binding and Platelet Aggregation with IIb/IIIa Inhibitor

0

25

50

75

100

None P2 Ab Abcix 0.1ug/ml

% P

late

let

Ag

gre

gat

ion P=0.001

Fibrinogen Binding Platelet Aggregation

Peter et al, Blood 1998;92:3230-9.

Hypothesis: Intrinsic Activating Property of IIb/IIIa Inhibition

GP IIb/IIIa GP IIb/IIIa ReceptorReceptor IIb/IIIa inhibitorIIb/IIIa inhibitor

ActivatedActivatedUnactivatedUnactivated

PlateletPlateletAdapted: Peter et al., Blood 1998;92:3230-9.

Dissociation of competitive inhibitor

FGNFGN

Binding IIb/IIIa inhibitor

Allows Binding of Fibrinogen +Plt Aggreg

Activation ofIIb/IIIa receptor

“Outside-In Signaling Platelet Activation

FGNFGN

Exploratory Analyses: Exploratory Analyses: Lessons LearnedLessons Learned

Exploratory Analyses: Exploratory Analyses: Lessons LearnedLessons Learned

Fixed-dosing with a competitive oral IIb/IIIa inhibitor:

Peaks/troughs in % inhibition and high inter-patient variability

Low blood levels at some time periods

Too low to prevent events

? Proaggregatory effects (Peter et al, Blood 1998)

High blood levels in some patients ( creat.)

Potential for excess bleeding

? Plaque hemorrhage -> increased events

Scorecard - Comparing Oral Agents

Roxifiban Orbofiban Sibrafiban Xemilofiban

Trial Rocket OPUS-TIMI16 Symphony EXCITEIIb/IIIa selective +++ +++ +++ +++Binding Tightly Competitive Competitive Competitive

bound “Off rate” 7 mins seconds seconds secondsPeak of Onset 3-6h 4-6h 4-6h 2-3hHalf-life 24 h 8-10h 11h 4-5hExcretion Plt. Dissoc. Renal Renal RenalDosing QD BID BID TIDLow Peak/trough +++ ++ ++ +Intra-pt variability + ++ ++ ++Inter-pt variability ++ ++ ++ ++Plts < 50,000 <0.5% 0.6% <0.5% 0.5%Plts Pro-aggreg. No Yes - Yes

2nd Generation 1st Generation Oral IIb/IIIa inhibitors

Conclusions - Oral Antiplatelet Therapy at the End of the Millennium

Future Directions - Oral IIb/IIIa inhibitors:1. Need to optimize dosing

Mimic stable effect of IV drugsReduce inter- and intra-patient variability? Use bedside platelet test to adjust dose

2. Test “second generation” drugs (tight IIb/IIIa binding)

ASA and ADP antagonists Proven benefit in large trials Both decrease platelet activation Combination ASA/Clopidogrel being tested