emerging antiplatelet therapies and the latest clinical trials
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Emerging Antiplatelet Therapies Emerging Antiplatelet Therapies and the Latest Clinical Trialsand the Latest Clinical Trials
Robert A. Harrington, MDRobert A. Harrington, MDProfessor of MedicineProfessor of Medicine
Director, Duke Clinical Research InstituteDirector, Duke Clinical Research InstituteDuke University Medical CenterDuke University Medical Center
Ongoing Trials Evaluating Novel Antiplatelet Ongoing Trials Evaluating Novel Antiplatelet Drugs or Strategies in ACS and PCIDrugs or Strategies in ACS and PCI
CURRENT (dosing)CURRENT (dosing)
TRITON (new ADP)TRITON (new ADP)
PLATO (new ADP)PLATO (new ADP)
CHAMPION (IV ADP)CHAMPION (IV ADP)
ERASE (IV to po ADP)ERASE (IV to po ADP)
EARLY ACS (IIb/IIIa timing)EARLY ACS (IIb/IIIa timing)
TRACER and 2P (TRA)TRACER and 2P (TRA)
Study DesignStudy Design
Clopidogrel High-Dose GroupClopidogrel 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 GroupClopidogrel 300 mg (+ placebo) Day 1 followed
by 75 mg (+ placebo) from Day 2 to 7;75 mg from Day 8 to 30
RANDOMIZE RANDOMIZE
ASA low-dose groupAt least 300 mg Day 1;
75-100 mgfrom Day 2 to 30
ASA high-dose groupAt least 300 mg Day 1;
300-325 mgfrom Day 2 to 30
ASA high-dose groupAt least 300 mg Day 1;
300-325 mgfrom Day 2 to 30
ASA low-dose groupAt least 300 mg Day 1;
75-100 mgfrom Day 2 to 30
Patients with UA/NSTEMI planned for early invasivestrategy, i.e. intend for PCI as early as possible within 24 hrs
RANDOMIZE
PCI = percutaneous coronary intervention; UA/NSTEMI = unstable angina/non-ST-segment elevation myocardial infarction
Double-blind
ACS (STEMI or UA/NSTEMI) & Planned PCI
ASA
PRASUGREL CLOPIDOGREL
1o endpoint: CV death, MI, Stroke2o endpoints: CV death, MI, Stroke, Rehosp Re-isch
CV death, MI, UTVR
Median duration of therapy – 12 months
N = 13,000
Wiviott SD et al. Am Heart J. 2006;152:627-35.
Study DesignStudy DesignStudy DesignStudy Design
Patients: ACS, Moderate-High Risk Patients: ACS, Moderate-High Risk UA/NSTEMI/STEMI UA/NSTEMI/STEMI
PCI, Medically Managed, or CABGPCI, Medically Managed, or CABGAll Receiving ASAAll Receiving ASA
Clopidogrel Treated* or NaïveClopidogrel Treated* or Naïve
ClopidogrelIf pretreated, no additional load;if naïve, standard 300 mg load,
then 75 mg/d maintenance;additional 300 mg permitted pre-PCI
Primary Endpoint:CVD/MI/strokeSecondary EP: CVD/MI/Stroke/Revascularization with PCI;
CVD/MI/Stroke, Severe recurrent ischemia
12 month maximum exposure(Min = 6 mo, max = 12 mo, mean = 11 mo)
N = 18,000 pts
AZD6140180 mg load, then
90mg/d maintenance;additional 90 mg pre-PCI
ClinicalTrials.gov Identifier: NCT00391872.
Cangrelor Phase III RCTs
1O Endpoint: 48 hr death/MI/IDR
vs. Clopidogrel 600 mg vs. Placebo (+ usual care)
Est. 9,000 pts Est. 4,400 pts
ClinicalTrials.gov Identifier: NCT00385138.ClinicalTrials.gov Identifier: NCT00305162.
VIGOURVIGOUR
ERASE-MI:ERASE-MI: EEarlyarly RapidRapid RReverseversAAll of of Platelet ThromboPlatelet ThromboSSisis with Intravenous with Intravenous
PRT060128 Before PCI to Optimize PRT060128 Before PCI to Optimize REREperfusion in Acute perfusion in Acute MI MI
ClinicalTrials.gov Identifier: NCT00546260.
Study DesignStudy Design
High-risk NSTE ACS
N = 10,500
High-risk NSTE ACS
N = 10,500
1 Endpoint: 96-hr Death/MI/Urgent Revasc/Thrombotic bailout
2 Endpoint: 30 d Death/MI
1 Endpoint: 96-hr Death/MI/Urgent Revasc/Thrombotic bailout
2 Endpoint: 30 d Death/MI
PlaceboPlaceboEptifibatide (180/2/180)Eptifibatide (180/2/180)
Randomize within 8 hours
Early invasive strategy: no sooner than next calendar day
Randomize within 8 hours
Early invasive strategy: no sooner than next calendar day
2 of 3 criteria:1. Age >60 yo2. + CKMB or TNT/I3. ST or transient ST
ClinicalTrials.gov Identifier: NCT00089895.
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
Study DesignStudy DesignNon-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
Moliterno DJ et al. Presented at ACC 2007.
PlaceboPlacebo
SCH 530348SCH 530348
AllAll 10 mg10 mg 20 mg20 mg 40 mg40 mg
NumberNumber 151151 422422 129129 120120 173173
TIMI Major/MinorTIMI Major/Minor 5 (3.3%)5 (3.3%) 12 (2.8%)12 (2.8%) 2 (1.6%)2 (1.6%) 3 (2.5%)3 (2.5%) 7 (4.0%)7 (4.0%)
TIMI MajorTIMI Major 2 (1.3%)2 (1.3%) 3 (0.7%)3 (0.7%) 2 (1.6%)2 (1.6%) 00 1 (0.6%)1 (0.6%)
TIMI MinorTIMI Minor 3 (2.0%)3 (2.0%) 9 (2.1%)9 (2.1%) 00 3 (2.5%)3 (2.5%) 6 (3.4%)6 (3.4%)
Non-TIMI bleedingNon-TIMI bleeding 48 (32%)48 (32%) 170 (40%)170 (40%) 46 (36%)46 (36%) 51 (43%)51 (43%) 73 (42%)73 (42%)
PCI Patient Results (Primary Cohort)PCI Patient Results (Primary Cohort)
Moliterno DJ et al. Presented at ACC 2007.
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
Moliterno DJ et al. Presented at ACC 2007.
TRA Program(29,500 pts)
1o EP: Composite of CV death, MI, stroke, and
urgent revascularization
Thrombin Receptor Antagonism
CER
NSTE ACS10,000 pts
2º Prevention19,500 pts
TRA Placebo TRA Placebo
F/U 1 yr minimum
1o EP: Composite of CV death, MI, stroke, urgent
revascularization and recurrent ischemia w/
rehospitalization
ClinicalTrials.gov Identifier: NCT00526474.ClinicalTrials.gov Identifier: NCT00527943.
While antiplatelet therapies are the While antiplatelet therapies are the cornerstone of CAD care, there are many cornerstone of CAD care, there are many unresolved questions and opportunities for unresolved questions and opportunities for improving patient care/outcomes.improving patient care/outcomes.
Current and ongoing trials will enroll Current and ongoing trials will enroll >90,000 patients over the next few years in >90,000 patients over the next few years in attempts to test new strategies and agents.attempts to test new strategies and agents.
Global collaboration and participation in Global collaboration and participation in RCTs is critical to advancing patient care.RCTs is critical to advancing patient care.
Emerging Antiplatelet Therapies/Strategies Emerging Antiplatelet Therapies/Strategies and Ongoing RCTs: and Ongoing RCTs: ConclusionsConclusions