(and r23-r35). a phase 3 international, randomized, double-blind, placebo-controlled trial...
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(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
Cannon CP et al. Circulation 2000;102:149-156
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
Cannon CP et al. Circulation 2000;102:149-156
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
Cannon CP et al. Circulation 2000;102:149-156
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
Cannon CP et al. Circulation 2000;102:149-156
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