Emerging Antiplatelet Therapies and the Latest Clinical Trials

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Emerging Antiplatelet Therapies and the Latest
Clinical Trials
Robert A. Harrington, MD Professor of
Medicine Director, Duke Clinical Research
Institute Duke University Medical Center
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Ongoing Trials Evaluating Novel Antiplatelet
Drugs or Strategies in ACS and PCI

• CURRENT (dosing)
• TRITON (new ADP)
• PLATO (new ADP)
• CHAMPION (IV ADP)
• ERASE (IV to po ADP)
• EARLY ACS (IIb/IIIa timing)
• TRACER and 2P (TRA)

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Study Design
Patients with UA/NSTEMI planned for early
invasive strategy, i.e. intend for PCI as early
as possible within 24 hrs
RANDOMIZE
Clopidogrel High-Dose Group Clopidogrel 600 mg
loading dose Day 1 followed by 150 mg from Day 2
to 7 75 mg from Day 8 to 30
Clopidogrel Standard-Dose Group Clopidogrel 300
mg ( placebo) Day 1 followedby 75 mg (
placebo) from Day 2 to 775 mg from Day 8 to 30
RANDOMIZE
RANDOMIZE
ASA low-dose group At least 300 mg Day 1 75-100
mgfrom Day 2 to 30
ASA high-dose group At least 300 mg Day
1 300-325 mgfrom Day 2 to 30
ASA high-dose group At least 300 mg Day
1 300-325 mgfrom Day 2 to 30
ASA low-dose group At least 300 mg Day 1 75-100
mgfrom Day 2 to 30
PCI percutaneous coronary intervention
UA/NSTEMI unstable angina/non-ST-segment
elevation myocardial infarction
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Study Design
ACS (STEMI or UA/NSTEMI) Planned PCI
ASA
N 13,000
Double-blind
PRASUGREL
CLOPIDOGREL
Median duration of therapy 12 months
1o endpoint CV death, MI, Stroke 2o
endpoints CV death, MI, Stroke, Rehosp
Re-isch CV death, MI, UTVR
Wiviott SD et al. Am Heart J. 2006152627-35.
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Patients ACS, Moderate-High Risk UA/NSTEMI/STEMI
PCI, Medically Managed, or CABG All Receiving
ASA Clopidogrel Treated or Naïve
N 18,000 pts
Clopidogrel If pretreated, no additional load if
naïve, standard 300 mg load, then 75 mg/d
maintenance additional 300 mg permitted pre-PCI
AZD6140 180 mg load, then 90mg/d
maintenance additional 90 mg pre-PCI

12 month maximum exposure (Min 6 mo, max 12
mo, mean 11 mo)
Primary EndpointCVD/MI/stroke Secondary EP
CVD/MI/Stroke/Revascularization with PCI
CVD/MI/Stroke, Severe recurrent ischemia
ClinicalTrials.gov Identifier  NCT00391872.
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Cangrelor Phase III RCTs
1O Endpoint 48 hr death/MI/IDR
vs. Clopidogrel 600 mg
vs. Placebo ( usual care)
Est. 4,400 pts
Est. 9,000 pts
ClinicalTrials.gov Identifier  NCT00385138.
ClinicalTrials.gov Identifier  NCT00305162.
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ERASE-MI Early Rapid ReversAl of Platelet
ThromboSis with Intravenous PRT060128 Before PCI
to Optimize REperfusion in Acute MI
ClinicalTrials.gov Identifier  NCT00546260.
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Study Design

• 2 of 3 criteria
• Age gt60 yo
• CKMB or TNT/I
• ST ? or transient ST ?

High-risk NSTE ACS N 10,500
Placebo
Eptifibatide (180/2/180)
Randomize within 8 hours Early invasive strategy
no sooner than next calendar day
1? Endpoint 96-hr Death/MI/Urgent
Revasc/Thrombotic bailout 2? Endpoint 30 d
Death/MI
ClinicalTrials.gov Identifier  NCT00089895.
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Platelet Receptors
Platelet
Platelet
Thrombin
Fibrinogen
GP IIb/IIIa
ADP
GP IIb/IIIa
EPI-R
Epinephrine
Collagen
Anionic phospholipid surfaces
GP Ia
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Study Design
Non-Urgent PCI or Cath possible PCI (All Receive
Aspirin) Randomization 1 31 SCH530348Placebo
(Single Loading Dose) Sequential Groups 110 mg
220 mg 340 mg, or Placebo
Cardiac Catheterization Planned PCI (All Receive
Clopidogrel and Antithrombin)
No PCI
Randomization 2 111 Maintenance Therapy Once
Daily for 60 days SCH 530348 Loading Dose ? SCH
530348 Or Placebo Loading Dose ? Placebo
CABG
Medical Management
Quantify Postoperative Chest-Tube Drainage,
Transfusions, and Re-exploration
SCH 530348
0.5 mg n100
1 mg n100
2.5 mg n100
Placebo n100
Safety TIMI Major plus Minor Bleeding Efficacy
Death/MACE
Safety TIMI Major plus Minor Bleeding
Secondary Evaluable Cohort
Primary Evaluable Cohort
Moliterno DJ et al. Presented at ACC 2007.
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PCI Patient Results (Primary Cohort)
Moliterno DJ et al. Presented at ACC 2007.
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PCI Cohort
60-Day Death or MI
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P value relative to placebo
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P 0.53
P 0.19
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P 0.28
4.5
P 0.20
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2
0
All TRA n 422
Placebo n 151
10 mg n 129
20 mg n 120
40 mg n 173
SCH 530348
Moliterno DJ et al. Presented at ACC 2007.
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Thrombin Receptor Antagonism
TRA Program (29,500 pts)
NSTE ACS 10,000 pts
2º Prevention 19,500 pts
TRA
Placebo
TRA
Placebo
F/U 1 yr minimum
1o EP Composite of CV death, MI, stroke, and
urgent revascularization
1o EP Composite of CV death, MI, stroke, urgent
revascularization and recurrent ischemia w/
rehospitalization
ClinicalTrials.gov Identifier  NCT00526474.
ClinicalTrials.gov Identifier  NCT00527943.
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Emerging Antiplatelet Therapies/Strategies and
Ongoing RCTs Conclusions

• While antiplatelet therapies are the cornerstone
  of CAD care, there are many unresolved questions
  and opportunities for improving patient
  care/outcomes.
• Current and ongoing trials will enroll gt90,000
  patients over the next few years in attempts to
  test new strategies and agents.
• Global collaboration and participation in RCTs is
  critical to advancing patient care.