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A Phase 3 International, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Efficacy and Safety Of O rbofiban in P atients with U nstable Coronary S yndromes. (and www.circ.ahajournals.org r23-r35). Cannon CP et al. Circulation 2000;102:149-156.

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A Phase 3 International, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Efficacy and Safety Of Orbofiban in Patients with Unstable Coronary Syndromes

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

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)
patients randomized 10 288

Patients Randomized = 10,288

U.S. 2704 Belgium 232 Switzerl. 65

Canada 2064 Germany 224 Mexico 60

Israel 784 Poland 218 Italy 52

Netherl. 674 U.K. 202 Denmark 32

Spain 568 Australia 168 Norway 22

Czech R. 532 France 163 Austria 21

Argentina 316 Chile 145 Finland 19

Brazil 277 S Africa 130 N Zealand 16

Russia 266 Ireland 99 Portugal 14 Hungary 235

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

central units

TIMI Study Chairman’s Office Eugene Braunwald, MD

Christopher Cannon, MD

Carolyn McCabe, BS

Nottingham Clinical Trial Allan Skene, PhD

Data Centre Robert Wilcox, MD

Andrew Foxley

Andrew Charlesworth

Sponsor - G.D. Searle: John Alexander, MD

Robert Anders, PharmD

Daniel Burns

Central Units

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

eligibility criteria
Eligibility Criteria
  • Inclusion Criteria:
    • Rest ischemic pain > 5 mins within 72 hrs with any 1:
    • ECG changes, Positive enzymes, (Hx coronary, peripheral or cerebrovasc disease, diabetes)
  • Major Exclusion Criteria:
    • Age < 18 years
    • Renal insufficiency (creatinine >1.6 mg/dl or a estimated creatinine clearance of <40 cc/min)
    • Increased bleeding risk (Hx. Plts, GI bleed)
    • Need for warfarin, chronic NSAIDs
    • ReoPro/IIb/IIIa inhibitor Rx for index event
study design
Study Design

Patient with Unstable Coronary Syndrome <72 hours

N=10,288

ASA 150-162 mg daily

Randomize 1:1:1

Orbofiban

50 mg BID

Placebo

BID

Orbo 50 mg BID x 30 days

then Orbo 30 mg BID

Other Meds, Cath/Revasc per MD

Primary endpoint to 30 days + follow-up

Death, MI

Urgent Revasc,

Ischemia -> Rehosp,

or Stroke

30 days: orbofiban vs. placebo p=0.01

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

F/U Day 14, Day 30

Follow-up visit every 3 months

day 30 outcomes

Plac.

Orbo

Orbo

Orbo

P value

50/30

50/50

(All)

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

0.1

0.1

0.1

0.1

0.79

Non-ICH

0.4

0.5

0.7

0.6

0.28

Composite

10.8

10.0

9.9

9.9

0.12

Death /MI

3.9

4.6

4.2

4.4

0.31

Day 30 Outcomes

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

10 month outcomes
10 Month Outcomes

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

timi classification underlying event leading to death

Placebo

Orbo 50/30

Orbo 50/50

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

TIMI Classification - Underlying Event Leading to Death

*

*

*p=0.03

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

bleeding day 30
Bleeding - Day 30

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

bleeding 10 months
Bleeding - 10 Months

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

thrombocytopenia by study drug

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

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

0.009 / 0.0004

NS / 0.08

0.003 / 0.002

0.06 / 0.006

NS / 0.05

0.01 / 0.01

Thrombocytopenia by Study Drug

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

day 2 results
Day 2 Results

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

day 2 results1
Day 2 Results

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

subgroups 30 day mortality

Relative Risk

10

0.1

1

Int

Plac Orbo

. P

Age

<

65

0.86 0.87

Age > 65

2.26 3.91 0.12

Men

1.34 1.61

Women

1.40 2.89 0.14

No prior

CHF

1.34 1.78

Prior CHF

1.73 5.45 0.005

Acute MI

1.90 2.18

UA

0.67 1.72 0.04

Killiip

I

1.15 1.52

Killip

II-IV

3.40 6.68 0.31

Subgroups: 30 Day Mortality

Orbo better Orbo Worse

Circulation 2000;102:149-156

subgroups 30 day mortality1

Relative Risk

0.1

10

1

CC > 100

CC

<

100

No Heparin

Heparin

PCI pre-R

No PCI

PCI pre/post

No PCI

Orbo

Orbo

Better

Worse

Subgroups: 30 Day Mortality

30 Day Mortality

Plac Orbo

Int P

.

0.84 0.69

1.92 3.13 0.09

1.22 1.23

1.42 2.31 0.22

2.07 0.30

1.27 2.13 0.003

1.53 0.91

1.28 2.37 0.005

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

subgroups 10 month composite

Relative Risk

1

Plac Orbo

Int

. P

2

0

20.9 19.6

Age

<

65

26.7 28.9 0.07

Age > 65

21.6 22.1

Men

26.4 25.2 0.52

Women

22.2 21.9

No prior CHF

34.8 41.7 0.09

Prior CHF

21.2 21.1

Acute MI

24.9 24.8 0.92

UA

22.5 21.8

Killiip

I

27.7 34.7 0.03

Killip

II-IV

Orbo better Orbo Worse

Subgroups: 10 Month Composite

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

subgroups 10 month composite1

Relative Risk

1

2

Plac Orbo

Int

. P

0

20.8 19.4

CC > 100

25.1 26.9 0.38

CC

<

100

19.6 19.6

No Heparin

24.4 24.5 0.43

Heparin

21.4 19.1

PCI pre-R

23.0 23.3 0.36

No PCI

27.5 22.9

PCI pre/post

21.0 23.0 0.006

No PCI

Orbo

Orbo

Better

Worse

Subgroups: 10 Month Composite

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

summary
Summary
  • 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