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David J. Moliterno, MD, MPH Chief, Cardiovascular Medicine
Professor & Vice-Chair of MedicineUniversity of Kentucky
Co-Director - Gill Heart InstituteLexington, KY
TRA-PCITRA-PCIUpdate on the New Antiplatelet Agents:Update on the New Antiplatelet Agents:
PAR-1 InhibitorsPAR-1 Inhibitors
Platelet-Thrombin Platelet-Thrombin InteractionInteraction
ThrombinThrombin
XXaa+V+Vaa+II+II
ThrombusThrombus
FibrinFibrin
FibrinogenFibrinogen
Platelet Platelet ReceptorsReceptors
Platelet
ThrombinThrombin
ADPADP
EpinephrineEpinephrine
CollagenCollagen Anionicphospholipid
surfaces
GPGPIIb/IIIaIIb/IIIa
Platelet
Fibrinogen
GP Ia
P2Y1
GP VI
PAR-4
TBX ATBX A22 TBXA2-R
SerotoninSerotonin 5HT2A
P2Y12
PAR-1
GPGPIIb/IIIaIIb/IIIa
EPI-R
TRA BackgroundTRA Background
SCH 530348 is an oral, potent, selective thrombin receptor SCH 530348 is an oral, potent, selective thrombin receptor antagonist (TRA) being developed for the prevention and antagonist (TRA) being developed for the prevention and treatment of atherothrombosis. treatment of atherothrombosis.
Preclinical and early clinical studies have demonstrated SCH Preclinical and early clinical studies have demonstrated SCH 530348 to have antithrombotic properties, with no increase in 530348 to have antithrombotic properties, with no increase in bleeding time or clotting times (aPTT, PT, ACT).bleeding time or clotting times (aPTT, PT, ACT).
SCH 530348 is an oral, potent, selective thrombin receptor SCH 530348 is an oral, potent, selective thrombin receptor antagonist (TRA) being developed for the prevention and antagonist (TRA) being developed for the prevention and treatment of atherothrombosis. treatment of atherothrombosis.
Preclinical and early clinical studies have demonstrated SCH Preclinical and early clinical studies have demonstrated SCH 530348 to have antithrombotic properties, with no increase in 530348 to have antithrombotic properties, with no increase in bleeding time or clotting times (aPTT, PT, ACT).bleeding time or clotting times (aPTT, PT, ACT).
Galbulimima baccataGalbulimima baccata
Himbicine derivativeHimbicine derivative Bark of the Australian RhododendronBark of the Australian Rhododendron Found in the tropical zones of eastern Found in the tropical zones of eastern
Malaysia, New Guinea, northern Malaysia, New Guinea, northern Australia and the Solomon Islands.Australia and the Solomon Islands.
Study DesignStudy Design
Non-Urgent PCI or Cath possible PCI (All Receive Aspirin)
Randomization #1 — 3:1 SCH530348:Placebo (Single Loading Dose)
Sequential Groups: 1=10 mg; 2=20 mg; 3=40 mg, or Placebo
No PCI** No PCI**
Randomization #2 1:1:1Maintenance Therapy Once Daily for ~ 60 days
SCH 530348 Loading Dose SCH 530348Or Placebo Loading Dose Placebo
Safety: TIMI Major plus Minor BleedingEfficacy: Death/MACE
Safety: TIMI Major plus Minor Bleeding
* Primary Evaluable Cohort* Primary Evaluable Cohort **Secondary Evaluable Cohort**Secondary Evaluable Cohort
Cardiac Catheterization
Planned PCI (All Receive Clopidogrel and Antithrombin)
CABG
Quantify Postoperative Chest-Tube Drainage,
Transfusions, and Re-exploration
Medical Management
0.5 mgn~100
1 mgn~100
2.5 mgn~100
Placebon~100
SCH 530348
PlaceboPlaceboSCH 530348SCH 530348
AllAll 10 mg10 mg 20 mg20 mg 40 mg40 mg
All RandomizedAll Randomized 257257 773773 222222 238238 313313
Primary Cohort (PCI) Primary Cohort (PCI) 151151 422422 129129 120120 173173
Secondary CohortSecondary Cohort 106106 351351 9393 118118 140140
Secondary Cohort Secondary Cohort with CABGwith CABG 2424 5252 1010 1818 2424
MaleMale 80%80% 70%70% 72%72% 66%66% 72%72%
Age (mean, years)Age (mean, years) 6262 6363 6565 6363 6363
Weight (mean, kg)Weight (mean, kg) 9191 9090 8989 9292 9090
Diabetes MellitusDiabetes Mellitus 30%30% 34%34% 37%37% 32%32% 33%33%
Prior MIPrior MI 37%37% 35%35% 35%35% 38%38% 32%32%
Prior RevascularizationPrior Revascularization 47%47% 48%48% 50%50% 46%46% 48%48%
DemographicDemographicss
PlaceboPlacebo(n = 151)(n = 151)
SCH 530348SCH 530348
All All n = 422n = 422
10 mg 10 mg n = 129n = 129
20 mg20 mgn = 120n = 120
40 mg40 mgn = 173n = 173
AspirinAspirin 148 (98%)148 (98%) 416 (99%)416 (99%) 127 (98%)127 (98%) 117 (98%)117 (98%) 172 (99%)172 (99%)
ClopidogrelClopidogrel
All All 146 (97%)146 (97%) 408 (97%)408 (97%) 127 (98%)127 (98%) 117 (98%)117 (98%) 164 (95%)164 (95%)
75 mg75 mg 73 (48%)73 (48%) 191 (45%)191 (45%) 56 (43%)56 (43%) 52 (43%)52 (43%) 83 (48%)83 (48%)
300 mg300 mg 30 (20%)30 (20%) 85 (20%)85 (20%) 34 (26%)34 (26%) 21 (18%)21 (18%) 30 (17%)30 (17%)
600 mg 600 mg 40 (26%)40 (26%) 125 (30%)125 (30%) 36 (28%)36 (28%) 39 (33%)39 (33%) 50 (29%)50 (29%)
Antithrombin AgentAntithrombin Agent
HeparinHeparin 61 (40%)61 (40%) 181 (43%)181 (43%) 53 (41%)53 (41%) 52 (43%)52 (43%) 76 (44%)76 (44%)
BivalirudinBivalirudin 76 (50%)76 (50%) 196 (46%)196 (46%) 65 (50%)65 (50%) 51 (43%)51 (43%) 80 (46%)80 (46%)
GP IIb/IIIaGP IIb/IIIa 7 (5%)7 (5%) 37 (9%)37 (9%) 7 (5%) 7 (5%) 14 (12%)14 (12%) 16 (9%)16 (9%)
PCI Cohort MedicationsPCI Cohort Medications
TIMI Major/Minor BleedingTIMI Major/Minor Bleeding
4%4%
00
2%2%
All TRAAll TRAn=422n=422
2.8%2.8%
PCI CohortPCI Cohort
1%1%
3%3%
5%5%
PlaceboPlacebon=151n=151
3.3%3.3%
10 mg10 mgn=129n=129
20 mg20 mgn=120n=120
40 mg40 mgn=173n=173
1.6%1.6%
2.5%2.5%
4.0%4.0%
SCH 530348SCH 530348
p = 0.77
p = 0.35
p = 0.70
p = 0.73
p- value relative to placebo
PlaceboPlacebo
(n=24)(n=24)
SCH 530348SCH 530348
AllAll
(n=52)(n=52)10 mg10 mg
(n = 10)(n = 10)20 mg20 mg
(n = 18)(n = 18)40 mg40 mg
(n=24)(n=24)
Any BleedAny Bleed 2424 5252 1010 1818 2424
TIMI Major/MinorTIMI Major/Minor 19 (79%)19 (79%) 48 (92%)48 (92%) 9 (90%)9 (90%) 17 (94%)17 (94%) 22 (92%)22 (92%)
Non-TIMINon-TIMI 8 (33%)8 (33%) 18 (35%)18 (35%) 3 (30%)3 (30%) 6 (33%)6 (33%) 9 (39%)9 (39%)
TransfusionTransfusion
PRBCPRBC 11 (46%)11 (46%) 32 (62%)32 (62%) 8 (80%)8 (80%) 9 (50%)9 (50%) 15 (63%)15 (63%)
>2 Units>2 Units 55 99 22 22 55
Chest Tube Chest Tube Drainage (ml)Drainage (ml) 996996 988988 13931393 10151015 870870
Re-explorationRe-exploration 33 22 11 00 11
CABG Cohort BleedingCABG Cohort Bleeding
PlaceboPlacebon= 151n= 151
SCH 530348SCH 530348
AllAlln=422n=422
10 mg10 mgn= 129n= 129
20 mg20 mgn=120n=120
40 mg40 mgn=173n=173
Death/MACE/StrokeDeath/MACE/Stroke 13 (8.6%)13 (8.6%) 26 (6.2%)26 (6.2%) 12 (9.3%)12 (9.3%) 6 (5.0%)6 (5.0%) 8 (4.6%)8 (4.6%)
Death/MACE*Death/MACE* 13 (8.6%)13 (8.6%) 25 (5.9%)25 (5.9%) 11 (8.5%)11 (8.5%) 6 (5.0%)6 (5.0%) 8 (4.6%)8 (4.6%)
Death/MIDeath/MI 11 (7.3%)11 (7.3%) 19 (4.5%)19 (4.5%) 7 (5.4%)7 (5.4%) 5 (4.2%)5 (4.2%) 7 (4.0%)7 (4.0%)
DeathDeath 00 2 (0.5%)2 (0.5%) 1 (0.8%)1 (0.8%) 00 1 (0.6%)1 (0.6%)
MACEMACE 13 (8.6%)13 (8.6%) 24 (5.7%)24 (5.7%) 11 (8.5%)11 (8.5%) 6 (5.0%)6 (5.0%) 7 (4.0%)7 (4.0%)
MIMI 11 (7.3%)11 (7.3%) 18 (4.3%)18 (4.3%) 7 (5.4%)7 (5.4%) 5 (4.2%)5 (4.2%) 6 (3.5%)6 (3.5%)
Recurrent ischemiaRecurrent ischemia 1 (0.7%)1 (0.7%) 1 (0.2%)1 (0.2%) 1 (0.8%)1 (0.8%) 00 00
RevascularizationRevascularization 1 (0.7%)1 (0.7%) 6 (1.4%)6 (1.4%) 3 (2.3%)3 (2.3%) 1 (0.8%)1 (0.8%) 2 (1.2%)2 (1.2%)
StrokeStroke 00 1 (0.2%)1 (0.2%) 1 (0.8%)1 (0.8%) 00 00MACE = Major Adverse Cardiac Event (myocardial infarction, ischemia requiring hospitalization, coronary revascularization) MI = Myocardial Infarction * = primary efficacy endpoint
PCI Cohort MACE ResultsPCI Cohort MACE Results
60-Day Death or MACE60-Day Death or MACE
8%8%
00
4%4%
All TRAAll TRAn=422n=422
PCI CohortPCI Cohort
2%2%
6%6%
10%10%
PlaceboPlacebon=151n=151
8.6%8.6%
10 mg10 mgn=129n=129
20 mg20 mgn=120n=120
40 mg40 mgn=173n=173
8.5%8.5%
5.0%5.0%4.6%4.6%
SCH 530348SCH 530348
5.9%5.9%p = 0.26
p = 0.98
p = 0.25p = 0.15
p- value relative to placebo
60-Day Death or MI60-Day Death or MI
8%8%
00
4%4%
All TRAAll TRAn=422n=422
4.5%4.5%
PCI CohortPCI Cohort
2%2%
6%6%
10%10%
PlaceboPlacebon=151n=151
7.3%7.3%
10 mg10 mgn=129n=129
20 mg20 mgn=120n=120
40 mg40 mgn=173n=173
5.4%5.4%
4.2%4.2%4.0%4.0%
SCH 530348SCH 530348
p = 0.19p = 0.53
p = 0.28p = 0.20
p- value relative to placebo
PCI PCI CohortCohort
Myocardial InfarctionMyocardial Infarction
8%8%
00
4%4%
2%2%
6%6%
10%10%
PlaceboPlacebo 40mg40mg20mg20mg10mg10mg
11 7722 33 44 55 6600
DaysDays
p = 0.52
p = 0.28
p = 0.12
80%80%
00
40%40%
Platelet Aggregation SubstudyPlatelet Aggregation Substudy
20%20%
60%60%
100%100%
PlaceboPlacebon=23n=23
10 mg10 mgn=15n=15
20 mg20 mgn=18n=18
40 mg40 mgn=33n=33
2929
SCH 530348SCH 530348
00 00 00 00 00 00
5353
6868
8282
9696
46465454
66
4343
2121
30 minutes30 minutes
60 minutes60 minutes
90 minutes90 minutes
120 minutes120 minutes
Subjects with >80% IPA to 15 Subjects with >80% IPA to 15 M TRAPM TRAP
PlaceboPlacebo
SCH 530348SCH 530348
AllAll 0.5 mg0.5 mg 1.0 mg1.0 mg 2.5 mg2.5 mg
NumberNumber 149149 413413 136136 139139 138138
TIMI Major/MinorTIMI Major/Minor 00 4 (1.0%)4 (1.0%) 2 (1.5%)2 (1.5%) 00 2 (1.4%)2 (1.4%)
TIMI MajorTIMI Major 00 2 (0.5%)2 (0.5%) 1 (0.7%)1 (0.7%) 00 1 (0.7%)1 (0.7%)
TIMI MinorTIMI Minor 00 2 (0.5%)2 (0.5%) 1 (0.7%)1 (0.7%) 00 1 (0.7%)1 (0.7%)
Non-TIMI bleedingNon-TIMI bleeding 8 (5.4%)8 (5.4%) 25 (6.1%)25 (6.1%) 8 (5.9%)8 (5.9%) 6 (4.3%)6 (4.3%) 11 (8.0%)11 (8.0%)
PCI Cohort Results after Day 60PCI Cohort Results after Day 60
80%80%
00
40%40%
Platelet AggregationPlatelet Aggregation
20%20%
60%60%
100%100%
0.5 mg0.5 mg 1.0 mg1.0 mg 2.5 mg2.5 mg
SCH 530348SCH 530348
100100 10010030 days30 days
60 days60 days
Subjects with >80% IPA to 15 Subjects with >80% IPA to 15 M TRAPM TRAP
100100 100100
9191 9191
PlaceboPlacebo
111199
ConclusionConclusionss TRA was not associated with an increase inTRA was not associated with an increase in
TIMI major, minor, or non-TIMI bleedingTIMI major, minor, or non-TIMI bleeding
Using 15 Using 15 M TRAP-induced platelet aggregation:M TRAP-induced platelet aggregation: 40 mg loading dose of SCH 530348 achieved40 mg loading dose of SCH 530348 achieved
≥ 80% IPA in 1-2 hours in 68-96% subjects≥ 80% IPA in 1-2 hours in 68-96% subjects 1 mg and 2.5 mg maintenance doses sustained 1 mg and 2.5 mg maintenance doses sustained
≥ 80≥ 80% IPA at 30 and 60 days in all subjects% IPA at 30 and 60 days in all subjects
While not statistically significant, SCH 530348 While not statistically significant, SCH 530348 was associated with:was associated with: Death/MACE: Death/MACE: 32% overall; 32% overall; 46% with 40 mg46% with 40 mg MI: MI: 41% overall; 41% overall; 52% with 40 mg52% with 40 mg
TRA was not associated with an increase inTRA was not associated with an increase inTIMI major, minor, or non-TIMI bleedingTIMI major, minor, or non-TIMI bleeding
Using 15 Using 15 M TRAP-induced platelet aggregation:M TRAP-induced platelet aggregation: 40 mg loading dose of SCH 530348 achieved40 mg loading dose of SCH 530348 achieved
≥ 80% IPA in 1-2 hours in 68-96% subjects≥ 80% IPA in 1-2 hours in 68-96% subjects 1 mg and 2.5 mg maintenance doses sustained 1 mg and 2.5 mg maintenance doses sustained
≥ 80≥ 80% IPA at 30 and 60 days in all subjects% IPA at 30 and 60 days in all subjects
While not statistically significant, SCH 530348 While not statistically significant, SCH 530348 was associated with:was associated with: Death/MACE: Death/MACE: 32% overall; 32% overall; 46% with 40 mg46% with 40 mg MI: MI: 41% overall; 41% overall; 52% with 40 mg52% with 40 mg
TRATRA••CERCER
• • 1-Year Cardiovascular Death, MI, Stroke, Recurrent 1-Year Cardiovascular Death, MI, Stroke, Recurrent Ischemia with Rehosp, Urgent Coronary Revas •Ischemia with Rehosp, Urgent Coronary Revas •
• • 1-Year Cardiovascular Death, MI, Stroke, Recurrent 1-Year Cardiovascular Death, MI, Stroke, Recurrent Ischemia with Rehosp, Urgent Coronary Revas •Ischemia with Rehosp, Urgent Coronary Revas •
www.clinicaltrials.govwww.clinicaltrials.gov
NSTEACSNSTEACSN = 10,000N = 10,000
SCH 530348SCH 53034840 mg bolus, 2.5 mg daily40 mg bolus, 2.5 mg daily
n=5000n=5000
PlaceboPlacebo(and usual therapy)(and usual therapy)
n=5000n=5000
TThrombin hrombin RReceptor eceptor AAntagonist for ntagonist for CClinical linical EEvent vent RReduction in Acute Coronary Syndromeeduction in Acute Coronary Syndrome
TRATRA••2P—TIMI 502P—TIMI 50
• • 1-Year Cardiovascular Death, MI, Stroke, Recurrent 1-Year Cardiovascular Death, MI, Stroke, Recurrent Ischemia with Rehosp, Urgent Coronary Revas •Ischemia with Rehosp, Urgent Coronary Revas •
• • 1-Year Cardiovascular Death, MI, Stroke, Recurrent 1-Year Cardiovascular Death, MI, Stroke, Recurrent Ischemia with Rehosp, Urgent Coronary Revas •Ischemia with Rehosp, Urgent Coronary Revas •
www.clinicaltrials.govwww.clinicaltrials.gov
Hx MI, CVA, PVDHx MI, CVA, PVDN ~ 18,000N ~ 18,000
SCH 530348SCH 5303482.5 mg daily2.5 mg daily
N~9,000N~9,000
PlaceboPlacebo(and usual therapy)(and usual therapy)
N~9000N~9000
TThrombin hrombin RReceptor eceptor AAntagonistntagonistfor for 22º º PPreventionrevention