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Relationships Relevant to this Presentation Research grants/contracts to DCRI NHLBI, ACC, AHA, sanofi-aventis, Lilly, Daiichi- Sankyo, GSK, TMC, BMS, Astra, J&J, BI, Portola, Novartis, Merck, Regado Consulting Sanofi-aventis, BMS, Novartis, Merck, Portola, Regado Full listing of all relationships with industry http://www.dcri.duke.edu/research/coi.jsp

New Antithrombotics in Coronary Artery Disease Robert A. Harrington, MD, FACC, FAHA, FESC Richard Sean Stack MD Distinguished Professor Director, Duke Clinical Research Institute Duke University Medical Center

New Antithrombotics in CAD: Topics to Consider and Discuss The big picture: global CV disease burden, societal costs, need for evidence Increasing patient complexity Complexities in decision making Antithrombotic therapies: current options and what s in development Personalized medicine

Global Cardiovascular Disease Burden 20 15 CVD deaths (millions) 10 5 1990: 25% of all deaths were from CVD. 2020: 40% of all deaths will be from CVD. In developing countries, MI and CVD deaths occur 10 20 years earlier. CVD deaths < 70 y.o. in developing countries: 50% CVD deaths < 70 y.o. in Western countries: 20% 0 Reddy KS. NEJM 2004

Thrombosis-Dependent Cardiovascular Diseases: Acute and Chronic Syndromes Acute coronary syndromes STE AMI NSTE AMI/UA Coronary revasc PCI CABG Acute CVA/TIA Acute peripheral occlusion Secondary prevention CAD/ACS CVA/TIA PAD Heart failure Atrial fibrillation Mechanical valves

Antithrombotics: Anticoagulants and Antiplatelets-Available and in Development UFH LMWHs VKAs DTIs (po/iv) FXa inhibitors (po/sq) FIXa inhibitors Aspirin ADP blockers (po/iv) GP IIb/IIIa inhibitors TRA Anti-vWF

Recent Advances in Antithrombotic Therapy ACS (NSTE, STE PCI): prasugrel* ACS (NSTE, STE): ticagrelor** AF (versus VKA): dabigatran* AF (versus ASA): apixiban AF (versus VKA): rivaroxaban *Approved for use by US FDA and in EU **Approved for use in EU

Co-morbidities among Patients with CAD: Baseline Characteristics STEMI and NSTEMI Variable STEMI (n=28,614 ) NSTEMI (n=44,528 ) M e a n + as g D e ( y r s ) 6 0+ 14 6 7 + 1 4 F e m a l e s e x 3 0 % 3 8% D i a b e t e s m e l l i t u 2 s4 % 3 6 % P r i o r M I 1 9% 2 9 % P r i o r C H F 5 % 1 7% P r i o r P C I 2 0% 2 6 % P r i o r C A B G 7 % 1 9 % P r i o r S t r o k e 5 % 1 0 % P r i o r P A D 6 % 1 2% ACTION Registry-GWTG DATA: July 1, 2009 June 30, 2010

Top 10 Number of people with diabetes (20-79 years), 2010 and 2030

NSTEMI Invasive Cardiac Procedures ACTION Registry-GWTG DATA: July 1, 2009 June 30, 2010

NSTEMI Discharge Clopidogrel Use by Revascularization Strategies 1 0,8 0,6 0,4 0,2 0 ACTION Registry-GWTG DATA: July 1, 2009 June 30, 2010

NSTEMI Acute Medication Overdosing Trends * Infusion (> 15 units/kg/hr) or bolus (> 70 units/kg) # Initial dose (> 1.05 mg/kg) or total 24 hr dose (> 10 mg over recommended) ACTION Registry-GWTG DATA: July 1, 2009 June 30, 2010

Antithrombotics for ACS: More and More Choices (and Combinations) Factor Xa Direct TIs Lytics Clopidogrel GP IIb/IIIa inhibitors LMWH Heparin Aspirin

Choices Impacting Antithrombotic Therapy Anticoagulants: UFH LMWH Fonda Bival Antiplatelets: ASA (dose) ADP (which/time/dose) IV antiplatelets: None Abcix Ept/Tiro (timing) Cath strategy: Early Delayed Never > 100 Different Combinations! Balance thrombosis versus bleeding

Issues Under Study With Antithrombotics Among Patients with CAD Optimal dosing of ADP blockers and ASA Includes drug interactions and genotyping Novel ADP blockers (oral and IV) Novel antiplatelet targets Novel anticoagulants Post-ACS oral anticoagulants & antiplatelets Other secondary prevention settings (CVD and PAD) Reversible anticoagulants Health policy: comparative effectiveness

Stent Thrombosis (ARC Definite + Probable) 3 Any Stent at Index PCI N= 12,844 Clopidogrel 2.4 (142) Endpoint (%) 2 1 Prasugrel 1.1 (68) HR 0.48 P <0.0001 0 0 3 0 6 0 9 0 1 8 Days 2 7 3 1818 6 NNT= 77 4 5

12 Bleeding Events Safety Cohort (N=13,457) 10 Clopidogrel Prasugrel ICH in Pts w Prior Stroke/TIA (N=518) % Events 8 6 Clop 0 (0) % Pras 6 (2.3)% (P=0.02) 4 2 0 ARD 0.6% HR 1.32 P=0.03 NNH=167 ARD 0.5% HR 1.52 P=0.01 ARD 0.2% P=0.23 ARD 0.3% P=0.002 ARD 0% P=0.74

TRILOGY ACS Study Design Medically Managed UA/NSTEMI Patients N 10, 300 Randomization Stratified by: Age, Country, Prior Clopidogrel Rx (Primary analysis cohort Age < 75 yrs) < 75 yrs = 7800 75 yrs ~ 2500 Med Management Decision 72 hrs (No Prior Clopidogrel Given) Med Management Decision 10 days (Clopidogrel Started 72 hrs OR on Chronic Clopidogrel) Clopidogrel 300 mg LD + 75 mg MD Low Dose ASA + Low Dose ASA + Prasugrel 30 mg LD + 5* or 10 mg MD Clopidogrel 75 mg MD www.clinicaltrials.gov Identifier: Prasugrel 5* or 10 mg MD Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 months * For subjects < 60 kg or 75 years Primary Efficacy Endpoint: CV Death, MI, Stroke

K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke) Cumulative incidence (%) 13 12 11 10 9 8 7 6 5 4 3 2 1 0 Clopidogrel Ticagrelor HR 0.84 (95% CI 0.77 0.92), p=0.0003 11.7 9.8 0 60 120 180 240 300 360 No. at risk Days after randomisation Ticagrelor 9,333 8,628 8,460 8,219 6,743 5,161 4,147 Clopidogrel 9,291 8,521 8,362 8,124 6,743 5,096 4,047 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval Wallentin L et al. NEJM Aug 30, 2009

Secondary efficacy endpoints over time Myocardial infarction Cardiovascular death Cumulative incidence (%) 7 6 5 4 3 2 1 0 Clopidogre l Ticagrelo r HR 0.84 (95% CI 0.75 0.95), p=0.005 6.9 5.8 Cumulative incidence (%) 7 6 5 4 3 2 1 0 Clopidogre l Ticagrelo r HR 0.79 (95% CI 0.69 0.91), p=0.001 5.1 4.0 0 60 120 180 240 300 360 0 60 120 180 240 300 360 No. at risk Days after randomisation Days after randomisation Ticagrelor 9,333 8,678 8,520 8,279 6,796 5,210 4,191 9,333 8,294 8,822 8,626 7119 5,482 4,419 Clopidogrel 9,291 8,560 8,405 8,177 6,703 5,136 4,109 9,291 8,865 8,780 8,589 7079 5,441 4,364 Wallentin L et al. NEJM Aug 30, 2009

Stent thrombosis Stent thrombosis, % Ticagrelor (n=6,732) Clopidogrel (n=6,676) HR for ticagrelor (95% CI) p value* Definite 1.0 1.6 0.62 (0.45 0.85) 0.003 Probable or definite 1.7 2.3 0.72 (0.56 0.93) 0.01 Possible, probable, or definite 2.2 3.1 0.72 (0.58 0.90) 0.003 Evaluated in patients with any stent during the study Time-at-risk is calculated from the date of first stent insertion in the study or date of randomization * By univariate Cox model Cannon CP et al. Lancet 2010

Primary efficacy endpoint by clopidogrel loading dose Characterist ic Hazard Ratio (95% CI) Clopidogrel loading dose (Pre-rand. + Study drug) 93 14 40 91 300 mg 600 mg 0 0.. Ticagrelor 2 5 better Total Patien ts 1. 0 KM % at Month T C 12 i l.. 9 8. 5. 0 11.29. 5 2. Clopidogrel 0 better Cannon CP et al. Lancet 2010 HR (95% CI) Invasive p value (Interactio n) 0.9 17 0.85 (0.74, 0.96) 0.83 (0.67, 1.03)

Time to non-procedure-related PLATO major bleeding 4 Completeness of follow-up 99.97% = five patients lost to followup K-M estimated rate (% per year) 3 2 1 0 Ticagrelor Clopidogrel HR 1.31 (95% CI 1.08 1.60), p=0.006 3.06 2.31 0 60 120 180 240 300 360 No. at risk Days from first IP dose Ticagrelor 9,235 7,641 7,247 6,979 5,496 4,067 3,698 Clopidogrel 9,186 7,718 7,371 7,134 5,597 4,147 3,764 Wallentin L et al. NEJM Aug 30, 2009

Trial Schema N ~ 21,000 Stable pts with history of MI 1-3 yrs prior + 1 additional atherothrombosis risk factor* RANDOMIZE DOUBLE BLIND * Age >65 yrs, diabetes, 2nd prior MI, multivessel CAD, or chronic non-end stage renal dysfunction Planned treatment with ASA 75 150 mg & Standard background care Ticagrelor 90 mg bid Ticagrelor 60 mg bid Placebo Click to edit Master subtitle style Follow-up Visits Q4 mos for 1st yr, then Q6 mos Min 12 mos and median 26 mos follow-up Event-driven trial Primary Efficacy Endpoint: CV Death, MI, or Stroke Primary Safety Endpoint: TIMI Major Bleeding

4 Cangrelor THE CHAMPION PROGRAM COMPLETED PHASE III STUDIES

Summary of clinical efficacy (includes post hoc analyses) 48 hour Events PLATFORM OR [95% CI] P value Death/MI/IDR (primary) 0.87 (0.71,1.07) 0.175 Death/Q-MI/IDR 0.55 (0.33,0.93) 0.024 Death/Q-MI/ST 0.38 (0.20,0.72) 0.003 PCI Death/MI/IDR (primary) 1.05 (0.89,1.24) 0.571 Death/Q-MI/IDR 0.66 (0.42,1.05) 0.080 Death/Q-MI/ST 0.74 (0.43,1.27) 0.268 COMBINED DATA Death/MI/IDR 0.97 (0.86,1.11) 0.679 Death/Q-MI/IDR 0.61 (0.43,0.86) 0.005 0.2 0.5 1.0 Death/Q-MI/ST Cangrelor Better Comparator Better 0.55 (0.36,0.83) 0.004 2.0 5.0

4 Cangrelor CHAMPION PHOENIX

PHOENIX Synopsis Design Study Population Endpoints Cangrelor Dose Regimen Comparator Statistics Superiority, 85% power SA/NSTE-ACS/ STEMI requiring PCI (35% troponin elevated at baseline) Thienopyridine naïve GPI bailout Primary: Death, MI, IDR, ST at 48hr Key Secondary: ST at 48 hr; also GPI as bailout MI def: Universal (UMI) ST def: ARC 30+4 for 2 hours Clopidogrel during procedure per standard of care (i.e. 300mg or 600mg) event rate of 5.1% in the clopidogrel arm and 3.9% in the cangrelor arm (24.5% reduction in odds ratio). N= 10700

Properties of Elinogrel The only reversible and competitive P2Y12 receptor antagonist Direct-acting: no metabolic activation required Available for intravenous and oral administration, enabling acute and chronic use Immediate and near maximal platelet inhibition achieved with IV Duration of action Half-life: 12 hours No major CYP metabolism low potential for drug-drug interactions (including PPIs) Balanced clearance: 50% renal; 50% hepatic (10% metabolized to pharmacologically inactive metabolite)

Phase 3 Chronic CHD Trial Sponsored by Novartis Patients with Prior MI (~24,000 pts) 6-mos to 5 yrs post-index event Background ASA PLACEBO ELINOGREL (low exposure dose) ELINOGREL (high exposure dose) Study is event driven, expected mean duration is ~29 months PRIMARY EFFICACY ENDPOINT: CV Death, MI, Stroke

TRA Background Vorapaxar is an oral, potent, selective thrombin receptor antagonist (TRA) being developed for the prevention and treatment of atherothrombosis. Preclinical and early clinical studies have demonstrated vorapaxar to have antithrombotic properties, with no increase in bleeding time or clotting times (aptt, PT, ACT). Galbulimima baccata Himbacine derivative Bark of the Australian Magnolia Found in the tropical zones of eastern Malaysia, New Guinea, northern Australia and the Solomon Islands.

TRA CER and TRA 2P TIMI-50 Tricocci et al. Am Heart J. 2009:158:327-334.e4. Morrow et al. Am Heart J. 2009:158:325-341.e3. 37

Thrombin Receptor Antagonism TRA Development 37,500 patients Vorapaxar Placebo Vorapaxar Placebo F/U: 30 Days, 4, 8, 12 months and 6 months thereafter F/U 1 yr minimum Primary EP: Composite of CV Death, MI, Stroke, RI with Rehosp, Urgent Revascularization Primary EP: Composite of CV Death, MI, Stroke and Urgent Revascularization

Recent Acute Coronary Syndrome (STEMI or NSTE-ACS) N~15,00 0 Randomize 1:1 Double blind Aspirin Other Antiplatelet up to MD Apixaban Placebo Start study drug ASAP after acute care stabilization / parenteral anticoagulation Event Driven Primary: Death, MI, Severe Recurrent Ischemia, Ischemic Stroke Secondary: Death, MI, Ischemic stroke Safety: Major Bleeding

ATLAS 2 TIMI 51 PHASE III DESIGN Recent ACS Patients (Event driven trial: 13,500 to 16,000 pts) Stabilized 1-7 Days Post-Index Event Stratified by thienopyridine use PLACEBO RIVAROXABAN 2.5 mg BID RIVAROXABAN 5.0 mg BID Study is event driven---expected duration is 33 months PRIMARY EFFICACY ENDPOINT: CV Death, MI, Stroke Gibson CM, AHA 42

Phase II RE-DEEM Overview Randomised, double blind, placebo controlled, dose escalation study ST elevation or non-st elevation ACS with 1 additional risk factor for CV complications, on aspirin & clopidogrel at randomisation Randomisation within 14 days Placebo b.d N=373 Dabigatran 50 mg b.d N=372 Dabigatran 75 mg b.d N=371 Study treatment for 6 months Dabigatran 110 mg b.d N=411 Dabigatran 150 mg b.d N=351 Dose adjustments:patients with moderate renal impairment (GFR 30-50 ml/min) randomised to 75, 110 or 150 mg were analysed as part of that dose group but were treated with the next lower dose.

Aptamer-antidote Pairs Aptamers Encode their Own Antidotes Monoclonal Antibody Aptamer Aptamer Antidote

Neutralization of PD Effect Injection of Antidote (RB007) at 3 Hours 1. 0 Circulation 114; 2006

RB007 Active Control 80 70 Activated Partial Thromboplastin Time (seconds) 60 50 40 30 20 Inject RB007 Place bo 2 : 1 : 0.5 1 :1 0.2 :1 0.125 :1 0 1 2 3 4 5 6 7 8 Chan, M et al, JTH Time Post RB006 Administration (hrs) 46

RADAR Trial Design NSTE-ACS, Planned Catheterization w/i 24 hrs n=800 UFH / LMWH + GP IIb/IIIa n=200 Randomize RB006 1mg /kg IV n=600 Femoral Cardiac Catheterization / Percutaneous Intervention Standard Care RB007 100% n=200 RB007 75% n=100 RB007 50% n=100 RB007 25% n=200 Primary Outcome: ACUITY major bleeding Secondary Outcomes: Ischemic events / stent thrombosis Total bleeding, bailout RB007 dosing

Variability in Inter-Individual Clopidogrel Response Hochholzer, et al. Circulation. 2005;111:2560-2564.

CYP 2C19 Polymorphisms and Stent Thrombosis Hulot. JACC 2010:56:134-143.

Primary endpoint in the clopidogrel group in relation to any CYP2C19 LOF allele (K-M estimate) K-M estimate (%) 12 10 8 6 4 Clopidogrel LOF Clopidogrel No LOF p=0.2 5 11. 2 10. 0 2 p=0.02 8 No. at risk Clopidogrel LOF Clopidogrel No LOF 0 0 60 120 180 240 300 360 Days from randomization 1,388 1,275 1,259 1,226 1,027 801 658 3,516 3,321 3,256 3,186 2,691 2,123 1,757 50 Wallentin L et al Lancet 2010: 376, Online Aug 29, 2010

Primary endpoint in the ticagrelor group in relation to any CYP2C19 LOF allele (K-M estimate) 12 K-M estimate (%) 10 8 6 4 Ticagrelor No LOF Ticagrelor LOF 8. 8. 8 6 2 No. at risk Ticagrelor LOF Ticagrelor No LOF 0 0 60 120 180 240 300 360 Days from randomization 1,384 1,305 1,274 1,250 1,053 834 683 3,554 3,352 3,301 3,222 2,718 2,127 1,761 51 Wallentin L et al Lancet 2010: 376, Online Aug 29, 2010

Higher Doses of Clopidogrel in Carriers with History of Stent Thrombosis Pena. Circulation 2009;119: 2854-2857.

-AHJ 2009

GRAVITAS Study Design Elective or Urgent PCI with DES* VerifyNow P2Y12 Test 12-24 hours post-pci PRU 230 R High-Dose Clopidogrel clopidogrel 600-mg, then clopidogrel 150-mg daily X 6 months Standard-Dose Clopidogrel clopidogrel 75-mg daily X 6 months Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 mo Key Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 mo Pharmacodynamics: Repeat VerifyNow P2Y12 at 1 and 6 months *Peri-PCI clopidogrel per protocol-mandated criteria to ensure steady-state at 12-24 hrs placebo-controlled All patients received aspirin (81-162mg daily)

Pharmacodynamics: Effect of SD vs HD Clopidogrel 500 Standard-Dose P = 0.98 High-Dose P < 0.001 PRU value 400 300 200 Persistently high reactivity @ 30 days: 62% vs 40%, p<0.001 100 0 N=1105 N=1013 N=940 N=1109 N=1012 N=944 ITT population Post-PCI 30 d 6 mo Post-PCI 30 d 6 mo

Primary Endpoint: CV Death, MI, Stent Thrombosis Observed event rates are listed; P value by log rank test.

New Antithrombotics in CAD: Conclusions Thrombosis key mechanism in large variety of cardiovascular diseases Multiple choices now available for antithrombotics in management of CAD Challenges with increasing patient complexity along with understanding nuances of various combinations and interface with care strategies Research needed to aid clinical decision making, including forays into personalized medicine choices based on genetics and phenotypes of response

To develop and share knowledge that improves the care of patients around the world through innovative clinical research Click to edit Master subtitle style...an Academic Research Organization