(and www.circ.ahajournals.org r23-r35).

A Phase 3 International, Randomized, Double-Blind,

Placebo-Controlled Trial Evaluating the Efficacy and Safety

Of Orbofiban in Patients with Unstable Coronary Syndromes

A Phase 3 International, Randomized, Double-Blind,

Placebo-Controlled Trial Evaluating the Efficacy and Safety

Of Orbofiban in Patients with Unstable Coronary Syndromes

Cannon CP et al. Circulation 2000;102:149-156

Need for Long-Term Antiplatelet Therapy

Need for Long-Term Antiplatelet Therapy

Markers of platelet activation persist 1 month post ACS- Ault K, et al. P selectin in TIMI 12 trial. JACC 1999;33:634-

639. Angioscopy: Thrombus persists 1 month post ACS

- Van Belle, et al. Circulation 1998;97:26-33 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)

U.S. U.S. 27042704 BelgiumBelgium 232 232 Switzerl.Switzerl. 6565

CanadaCanada 20642064 Germany Germany 224 224 MexicoMexico 6060

IsraelIsrael 784784 PolandPoland 218 218 ItalyItaly 5252

Netherl.Netherl. 674674 U.K.U.K. 202 202 DenmarkDenmark 3232

SpainSpain 568 568 AustraliaAustralia 168 168 NorwayNorway 22 22 Czech R.Czech R. 532 532 FranceFrance 163 163 AustriaAustria 2121ArgentinaArgentina 316 316 ChileChile 145 145 FinlandFinland 1919BrazilBrazil 277277 S AfricaS Africa 130 130 N ZealandN Zealand 1616RussiaRussia 266 266 IrelandIreland 99 99 PortugalPortugal 14 14 HungaryHungary 235 235

Patients Randomized = 10,288Patients Randomized = 10,288

Cannon CP et al. Circulation 2000;102:149-156

TIMI Study Chairman’s OfficeTIMI Study Chairman’s Office Eugene Braunwald, MD Eugene Braunwald, MD Christopher Cannon, MDChristopher Cannon, MD Carolyn McCabe, BSCarolyn McCabe, BS

Nottingham Clinical Trial Nottingham Clinical Trial Allan Skene, PhD Allan Skene, PhDData CentreData Centre Robert Wilcox, MD Robert Wilcox, MD

Andrew FoxleyAndrew Foxley Andrew CharlesworthAndrew Charlesworth

Sponsor - G.D. Searle:Sponsor - G.D. Searle: John Alexander, MD John Alexander, MD Robert Anders, PharmDRobert Anders, PharmD Daniel BurnsDaniel Burns

Central UnitsCentral Units

Cannon CP et al. Circulation 2000;102:149-156

Eligibility CriteriaEligibility Criteria

Inclusion Criteria:Inclusion Criteria:

Rest ischemic pain Rest ischemic pain >> 5 mins within 72 hrs 5 mins within 72 hrs with any 1with any 1:: ECG changes, Positive enzymes, (Hx coronary, ECG changes, Positive enzymes, (Hx coronary,

peripheral or cerebrovasc disease, diabetes)peripheral or cerebrovasc disease, diabetes)

Major Exclusion Criteria:Major Exclusion Criteria: Age < 18 years Age < 18 years Renal insufficiency (creatinine >1.6 mg/dl or a Renal insufficiency (creatinine >1.6 mg/dl or a

estimated creatinine clearance of <40 cc/min)estimated creatinine clearance of <40 cc/min) Increased bleeding risk (Hx. Plts, GI bleed)Increased bleeding risk (Hx. Plts, GI bleed) Need for warfarin, chronic NSAIDsNeed for warfarin, chronic NSAIDs ReoPro/IIb/IIIa inhibitor Rx for index eventReoPro/IIb/IIIa inhibitor Rx for index event

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

30 days: orbofiban vs. placebo p=0.01

F/U: each dose vs. placebo p=0.02

N=10,288

Baseline CharacteristicsBaseline Characteristics

Plac. Orbo50/30

Orbo50/50

P value

No Pts. 3421 3537 3330

Age (yrs) 60.2 60.5 60.7 0.27

Female (%) 27.5 28.2 28.0 0.80

Prior MI (%) 27.4 26.3 28.4 0.16

Prior PAD (%) 6.8 6.9 6.9 0.96

Prior CVA/TIA (%) 3.0 2.5 2.6 0.50

Diabetes (%) 21.1 20.4 21.6 0.47

Killip Class II/IV 8.7 8.1 9.2 0.74

MI as index event 61.2 60.1 60.4 0.63

Day 30 OutcomesDay 30 Outcomes

Plac. Orbo50/30

Orbo50/50

Orbo(All)

P value

Death 1.4 2.3 1.6 2.0 0.02

MI 2.9 2.8 2.8 2.8 0.89

Urg Rev 4.4 2.4 3.0 2.7 <0.0001

Isch- rehosp 2.8 3.2 2.7 3.0 0.71

ICH

Non-ICH

0.1

0.4

0.1

0.5

0.1

0.7

0.1

0.6

0.79

0.28

Composite 10.8 10.0 9.9 9.9 0.12

Death /MI 3.9 4.6 4.2 4.4 0.31Cannon CP et al. Circulation 2000;102:149-156

10 Month Outcomes10 Month Outcomes

Plac. Orbo50/30

Orbo50/50

50/30vs. P

50/50 vs.Plac

Death 3.7 5.1 4.5 0.009 0.12

MI 5.0 5.8 6.1 0.75 0.28

Urg Rev 7.7 5.7 6.2 0.0003 0.01

Isch- rehosp 9.7 10.2 9.0 0.61 0.47

ICH Non-ICH

0.21.0

0.21.1

0.11.2

0.390.82

0.740.31

Composite 22.9 23.1 22.8 0.41 0.59

Death /MI 8.1 9.7 9.5 0.18 0.12

Cannon CP et al. Circulation 2000;102:149-156

TIMI Classification - Underlying Event Leading to Death

TIMI Classification - Underlying Event Leading to Death

No. Deaths

Progressive

Sudden

Non-Ischemic

Bleeding

New Thrombotic

Event

Unclassified

98

10

28

19

4

24

13

144

22

30

21

9

43

19

118

11

25

20

4

40

18

Orbo 50/50Placebo Orbo 50/30

* *

*p=0.03Cannon CP et al. Circulation 2000;102:149-156

Bleeding - Day 30Bleeding - Day 30

Plac. Orbo50/30

Orbo50/50

50/30vs. P

50/50 vs.Plac

Severe 0.2 0.3 0.3 0.50 0.43

Major 1.2 2.0 2.3 0.007 0.0006

Severe / major 1.4 2.4 2.6 0.003 0.0005

Minor 5.8 11.0 11.9 <0.0001 <0.0001

Bleed -> D/Cstudy drug

3.0 8.5 8.9 <0.0001 <0.0001

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Bleeding - 10 MonthsBleeding - 10 Months

Plac. Orbo50/30

Orbo50/50

50/30vs. Plac

50/50 vs.Plac

Severe 0.3 0.5 0.4 0.26 0.62

Major 1.7 3.3 4.2 0.0008 <0.0001

Severe / major 2.0 3.7 4.5 <0.0001 <0.0001

Minor 9.4 16.4 20.5 <0.0001 <0.0001

Bleed -> D/Cstudy drug

5.0 13.4 16.9 <0.0001 <0.0001

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Thrombocytopenia by Study DrugThrombocytopenia by Study Drug

30 Day

50-80,000 (%)

20-50,000 (%)

<20,000 (%)

10 Months

50-80,000 (%)

20-50,000 (%)

<20,000 (%)

Placebo

0

0.1

0

0.1

0.1

0

Orbo

50/30

0.2

0

0.3

0.4

0

0.3

Orbo

50/50

0.4

0.2

0.3

0.5

0.2

0.3

P value

0.009 / 0.0004

NS / 0.08

0.003 / 0.002

0.06 / 0.006

NS / 0.05

0.01 / 0.01Cannon CP et al. Circulation 2000;102:149-156

Day 2 ResultsDay 2 Results

Plac. Orbo50/30

Orbo50/50

50/30vs. P

50/50 vs.Plac

Death 0.2 0.7 0.3 0.004 0.76

MI 0.9 0.6 0.4 0.17 0.01

Urg Rev 1.17 0.7 1.1 0.0001 0.03

Composite 3.0 2.1 1.8 0.02 0.003

Death /MI 1.1 1.1 0.7 0.85 0.06

D/MI,Urev 2.8 1.8 1.7 0.005 0.003

Cannon CP et al. Circulation 2000;102:149-156

Day 2 ResultsDay 2 Results

Plac. Orbo50/30

Orbo50/50

50/30vs. P

50/50 vs.Plac

Heparin/LMWH

Death 0.3 0.8 0.2 0.02 0.78

Composite 3.7 2.5 2.1 0.01 0.0009

NoHep/LMWH

Death 0.2 0.6 0.4 0.11 0.37

Composite 1.3 1.3 1.3 0.91 0.97

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Plac Orbo Int. P0.86 0.872.26 3.91 0.12

1.34 1.611.40 2.89 0.14

1.34 1.781.73 5.45 0.005

1.90 2.180.67 1.72 0.04

1.15 1.523.40 6.68 0.31

Age < 65Age > 65

MenWomen

No prior CHFPrior CHF

Acute MIUA

Killiip IKillip II-IV

Relative Risk0.1 1 10

Subgroups: 30 Day MortalitySubgroups: 30 Day Mortality

Orbo better Orbo WorseCirculation 2000;102:149-156

Subgroups: 30 Day MortalitySubgroups: 30 Day Mortality

0.84 0.691.92 3.13 0.09

1.22 1.231.42 2.31 0.22

2.07 0.301.27 2.13 0.003

1.53 0.911.28 2.37 0.005

30 Day MortalityPlac Orbo Int P.

CC > 100CC < 100

No HeparinHeparin

PCI pre-RNo PCI

PCI pre/postNo PCI

Orbo Better Orbo Worse

Relative Risk0.1 1 10

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Subgroups: 10 Month CompositeSubgroups: 10 Month Composite

Plac Orbo Int. P20.9 19.626.7 28.9 0.07

21.6 22.126.4 25.2 0.52

22.2 21.934.8 41.7 0.09

21.2 21.124.9 24.8 0.92

22.5 21.827.7 34.7 0.03

Age < 65Age > 65

MenWomen

No prior CHFPrior CHF

Acute MIUA

Killiip IKillip II-IV

Relative Risk

0 1 2

Orbo better Orbo WorseCannon CP et al. Circulation 2000;102:149-156

20.8 19.425.1 26.9 0.38

19.6 19.624.4 24.5 0.43

21.4 19.123.0 23.3 0.36

27.5 22.921.0 23.0 0.006

CC > 100CC < 100

No HeparinHeparin

PCI pre-RNo PCI

PCI pre/postNo PCI

Orbo Better Orbo Worse

Plac Orbo Int. PRelative Risk

0 1

2

Subgroups: 10 Month CompositeSubgroups: 10 Month Composite

Cannon CP et al. Circulation 2000;102:149-156

SummarySummary

Orbofiban:

Minimal efficacy benefit overall in ACS

Greater benefit in PCI

Substudies: P-selectin, FGN binding

mortality,

Small absolute %

thrombotic events

-> ? Prothrombotic, ?Unstable patients

Major bleeding, thrombocytopenia higher, but in acceptable range

Cannon CP et al. Circulation 2000;102:149-156

Potential Explanations - Future Directions

Potential Explanations - Future Directions

PK/PD variability, peak trough -

Longer T1/2, ? Adjust with platelet monitoring

Only modest benefit in non-PCI ACS patients

Recurrent events not platelet -mediated?- unlikely

Concomitant Rx beyond ASA?

? Clopidogrel to Platelet Activation,

? Antithrombin to inhibit clotting cascade

? Prothrombotic effects:

Need drugs with tight binding

Cannon CP et al. Circulation 2000;102:149-156