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UA/NSTEMIUA/NSTEMI
RanolazineIV to PO
Placebo Matched IV/PO
RANDOMIZE (1:1)Double-blind
Follow-upQ4 mo
(Avg 8-12 mo)
Holter at enrollment x 7dHolter at enrollment x 7d
Follow-up Visits: Day 14, Month 4,
Q4 Months
Primary Endpoint: CV death, MI or Recurrent Ischemia
Final Visit
N = ~ 6500
ETT Month 8
MERLIN – TIMI 36MERLIN – TIMI 36Metabolic Efficiency with Ranolazine for Less Ischemia in
Non-ST Elevation Acute Coronary Syndromes
Morrow DA, Am Heart J 2006;1186:1-9
TIMI 37ATIMI 37A
STEMI within 12hSTEMI within 12hw/ planned 1w/ planned 1°° PCI PCI
INO-1001*IVB x 1
CONTROLIVB x 1
RANDOMIZE (3:1)RANDOMIZE (3:1)Single-blindSingle-blind
F/U at F/U at 14 & 30 days14 & 30 days
Endpoints/MeasuresPharmacokinetics
PharmacodynamicsCK-MB, cTn, BNP
Death/CHF/dysrhythmia
Endpoints/MeasuresPharmacokinetics
PharmacodynamicsCK-MB, cTn, BNP
Death/CHF/dysrhythmia
ASA Standard Rx
*Dose EscalationDose #1 x 1 (N = 10)Dose #2 x 1 (N = 10)Dose #3 x 1 (N = 10)
N = 40
37A
PrimaryPrimaryPCIPCI
Samples forSamples forPK/PD/BiomarkersPK/PD/Biomarkers
A Dose Ranging Trial of the Poly (ADP-ribose) Polymerase (PARP) Inhibitor INO-1001 to Reduce Reperfusion Injury After Primary PCI
TITAN
Double-blind
ACS (STEMI or UA/NSTEMI) & Planned PCIACS (STEMI or UA/NSTEMI) & Planned PCI
ASA
PRASUGRELPRASUGREL CLOPIDOGRELCLOPIDOGREL
11oo endpoint: endpoint: CV death, MI, StrokeCV death, MI, Stroke22oo endpoints: endpoints: CV death, MI, Stroke, Re-ischemiaCV death, MI, Stroke, Re-ischemia
CV death, MI, UTVRCV death, MI, UTVR
Median duration of therapy - 12 months
N= 13,000
TRITON – TIMI 38TRITON – TIMI 38A Comparison of Prasugrel and Clopidogrel in Acute
Coronary Syndrome Patients Who Are To Undergo Percutaneous Coronary Intervention
Wiviott SD, Am Heart J 2006;152:627-35
TITAN
10,500 Patients with> 2 of the following:
1. MB or Tn 2. New STD > 1mm 3. Age > 60
Eptifibatide 180/2/180 Matching Placebo
Angiography > 12 Hrs Later
Optional Study Drug in Cath LabBlinded Placebo / Eptifibatide
Primary Endpoint: D/MI/UR/TBO at 96hSecondary Endpoint: D/MI at 30 days
n=10,500
EARLY ACS – TIMI 39EARLY ACS – TIMI 39Early (<8h) Eptifibatide in Pts with High-Risk ACS
Giugliano RP, Am Heart J 2005;149:994-1002
ASA + Standard Medical TherapyASA + Standard Medical Therapy
Simvastatin 40 mgSimvastatin 40 mg Vytorin 10/40 mgVytorin 10/40 mg
Duration: Minimum 2 1/2 year follow-up (>2955 events)Duration: Minimum 2 1/2 year follow-up (>2955 events)
Primary Endpoint: CV Death, MI, Hospital Admission for UA, Primary Endpoint: CV Death, MI, Hospital Admission for UA, revascularization (> 30 days after randomization), or Strokerevascularization (> 30 days after randomization), or Stroke Primary Endpoint: CV Death, MI, Hospital Admission for UA, Primary Endpoint: CV Death, MI, Hospital Admission for UA, revascularization (> 30 days after randomization), or Strokerevascularization (> 30 days after randomization), or Stroke
Double-blindDouble-blind
Patients stabilized post Acute Coronary Syndrome < 10 daysLDL < 125 mg/dL (or < 100 mg/dL if prior statin)
N=10,000N=10,000
Follow-Up Visit Day 30, Every 4 MonthsFollow-Up Visit Day 30, Every 4 Months
IMPROVE IT – TIMI 40IMPROVE IT – TIMI 40IMProved Reduction of Outcomes: Vytorin Efficacy International Trial
®
AZD6140 180mg bid (option for 90mg bid)
Clopidogrel 300/600mg load: 75mg od
V1 V2 V3 V4 V5 V6End of
TreatmentFollow-up
Onset of chest pain <24h
1 mo
3 mo
6 mo
6 to 12 mo
EOT + 1 mo
* N=9000 per treatment arm
9 mo
12 mo
PLATO – TIMI 41PLATO – TIMI 41A Study of PLATelet inhibition and Patient Outcomes
42
Mod-to-High Risk NSTE ACS w/ Planned Early Inv StrategyMod-to-High Risk NSTE ACS w/ Planned Early Inv Strategy
OtamixGroup 1(n=450)
OtamixGroup 1(n=450)
RAspirin +
clopidogrel
Bail-out eptifibatide in otamixaban
groups if rec. ischemia or thrombotic
complic. during PCI
Study druguntil end of PCI,
as clin. indicated, until Day 4 or hospital d/c,whichever comes first
1° EP: Death, MI, Urgent Revasc, Bail-out IIb/IIIa thru 7 d1° EP: Death, MI, Urgent Revasc, Bail-out IIb/IIIa thru 7 d
Coronary angiography PCI (Day 1-3)Coronary angiography PCI (Day 1-3)
OtamixGroup 2(n=450)
OtamixGroup 2(n=450)
OtamixGroup 4(n=450)
OtamixGroup 4(n=450)
OtamixGroup 5(n=450)
OtamixGroup 5(n=450)
OtamixGroup 3(n=450)
OtamixGroup 3(n=450)
UFH + Eptifi.(n=450)
UFH + Eptifi.(n=450)
at randomization
Day 30 Visit, Day 90 Tel f/up, Day 180 Tel. f/upDay 30 Visit, Day 90 Tel f/up, Day 180 Tel. f/up
SEPIA-ACS 1 – TIMI 42SEPIA-ACS 1 – TIMI 42Dose Ranging Study of Otomixaban - a Novel, Intravenous, Direct Xa Inhibitor
Standard Medical Therapy
Patients post ACS with ↑ natriuretic peptides N= 1100
4 wks
End of Study
NT-proBNP
Blinded Therapy
Dose up-titration over 2 wks
Primary Endpoint - Δ NT-proBNP from baseline to week 8
Aliskiren PlaceboValsartan Combo Rx
Dose up-titration of 2nd agent over 2 wks(placebo in 3 arms and active in Combo arm)
NT-proBNP
AVANT GARDE – TIMI 43AVANT GARDE – TIMI 43Aliskiren and Valsartan to reduce NT-proBNP viarenin-angiotensin-aldosterone-system blockade
4 wks
Planned Elective PCIAggregometry and Biomarkers
ASA
Clopidogrel-naive
Clopidogrel600 mg
Prasugrel 60 mg
0.5,hour post-LD Aggregometry and biomarkers
Diagnostic catheterization anatomy suitable for PCI Post cath aggregometry
n < 180
n = 100 PCI
Post-PCI aggregometry, biomarkers
Primary Endpoint: Mean IPA (6h) in all treated subjectsAdditional Platelet Measures, Myonecrosis, Inflammation
Planned GP IIb/IIIaprohibited
PRINCIPLE – TIMI 44PRINCIPLE – TIMI 44Phase I: Loading
Prasugrel10 mg x 14d
14 d clinical events, biomarkers, aggregometry, CROSSOVER
Clopidogrel 150 mg x 14d
Prasugrel10 mg x 14d
30 d clinical events, biomarkers, aggregometry
Primary Endpoint: Mean IPA (2&4 wks) in all treated subjectsAdditional Platelet Measures, Inflammation, Clinical Events
PCI
Clopidogrel 150 mg x 14d
Phase II: Maintenance
PRINCIPLE – TIMI 44PRINCIPLE – TIMI 44
Enroll within 12 hrs of AngiographyBlood Draw for % Platelet Inhibition and Aspirin Responsiveness
Day 1Blood Draw for % Platelet Inhibition
Pre-op DayBlood Draw for % Platelet Inhibition
Day of CABGObtain Data from Procedure
Post-op DayFollow Course for Complications
VERIFY NOW – TIMI 45VERIFY NOW – TIMI 45Platelet Function Testing for Bleeding Management in Patients
Treated with Clopidogrel and Undergoing Coronary Artery Bypass Grafting
PRIMARY OUTCOME
Correlation of % platelet inhibition
immediately prior to surgery to the risk of TIMI major blood loss peri-operatively (fall in hgb > 5 or hct
> 15%)
Day XBlood Draw for % Platelet Inhibition
Recent ACS PatientsStabilized 1-7 Days Post-Index Event
STRATUM 1STRATUM 1 STRATUM 2STRATUM 2
Primary Endpoint: TIMI Significant Bleeding
MD Decision to Treat with ClopidogrelMD Decision to Treat with Clopidogrel
Dose Levels5, 10, & 20 mg
N ~ 1,350
RIVAQD
3 Dose Levels
RIVAQD
3 Dose Levels
PLACEBO
PLACEBO
RIVABID
3 Dose Levels
RIVABID
3 Dose Levels
RIVAQD
3 Dose Levels
RIVAQD
3 Dose Levels
PLACEBO
PLACEBO
RIVABID
3 Dose Levels
RIVABID
3 Dose Levels
Treat for 6 MonthsTreat for 6 Months
YESNO
ATLAS – TIMI 46ATLAS – TIMI 46STAGE 1: Dose Escalation
RIVA = Rivaroxaban
Recent ACS PatientsStabilized 1-7 Days Post-Index Event
STRATUM 1STRATUM 1 STRATUM 2STRATUM 2
Primary Endpoint: Death, MI, Stroke, or Recurrent Ischemia Requiring Revascularization
MD Decision to Treat with ClopidogrelMD Decision to Treat with Clopidogrel
N ~ 2,100
RIVAQD
RIVAQD
PLACEBO
PLACEBO
RIVABID
RIVABID
RIVAQD
RIVAQD
PLACEBO
PLACEBO
RIVABID
RIVABID
Treat for 6 MonthsTreat for 6 Months
NO YES
ATLAS – TIMI 46ATLAS – TIMI 46STAGE 2: Dose Confirmation
RIVA = Rivaroxaban
Protocol DesignSTEMI within 6 hours STEMI within 6 hours Eligible for primary PCIEligible for primary PCI
ASA 160-325 mg; Clopidogrel 300-600 mgASA 160-325 mg; Clopidogrel 300-600 mgUFH; IV Eptifibatide (double bolus and infusion)UFH; IV Eptifibatide (double bolus and infusion)
IC Eptifibatide90 g/Kg bolusIC Eptifibatide90 g/Kg bolus
N=180
RandomizeBaseline angiographyBaseline angiography
Advance wire and balloon without crossing the lesionAdvance wire and balloon without crossing the lesion
IC salinebolus
IC salinebolus
Angiography (assess stenosis, flow and perfusion)Angiography (assess stenosis, flow and perfusion)
PCIPCI
Primary EndpointImprovement in % diameter stenosis
pre and post Eptifibatide
Primary EndpointImprovement in % diameter stenosis
pre and post Eptifibatide
Secondary EndpointImprovement in pre and post
Eptifibatide CTFC
Secondary EndpointImprovement in pre and post
Eptifibatide CTFC
Angiography Angiography (assess epicardial flow and myocardial perfusion)(assess epicardial flow and myocardial perfusion)
2 : 1
Intracoronary Treatment with Integrilin To Improve Angiographic OutcomesIC-TITAN – TIMI 47IC-TITAN – TIMI 47
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