UA/NSTEMI Ranolazine IV to PO Placebo Matched IV/PO RANDOMIZE (1:1) Double-blind Follow-up Q4 mo (Avg 8-12 mo) Holter at enrollment x 7d Follow-up Visits:

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)


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)









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

Documents

UA/NSTEMI Ranolazine IV to PO Placebo Matched IV/PO RANDOMIZE (1:1) Double-blind Follow-up Q4 mo (Avg 8-12 mo) Holter at enrollment x 7d Follow-up Visits: