Relationships Relevant to this Presentation

Transcription

1 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

2 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

3 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

4 Global Cardiovascular Disease Burden CVD deaths (millions) : 25% of all deaths were from CVD. 2020: 40% of all deaths will be from CVD. In developing countries, MI and CVD deaths occur 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

5 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

6 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

7 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

8 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 ) 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

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

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

11 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

12

13 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

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

15 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

16 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

17

18 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 < Days NNT=

19 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) 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

20 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 = 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 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

21

22 K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke) Cumulative incidence (%) Clopidogrel Ticagrelor HR 0.84 (95% CI ), p= 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

23 Secondary efficacy endpoints over time Myocardial infarction Cardiovascular death Cumulative incidence (%) Clopidogre l Ticagrelo r HR 0.84 (95% CI ), p= Cumulative incidence (%) Clopidogre l Ticagrelo r HR 0.79 (95% CI ), p= 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, ,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, ,441 4,364 Wallentin L et al. NEJM Aug 30, 2009

24 Stent thrombosis Stent thrombosis, % Ticagrelor (n=6,732) Clopidogrel (n=6,676) HR for ticagrelor (95% CI) p value* Definite ( ) Probable or definite ( ) 0.01 Possible, probable, or definite ( ) 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

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

26 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) Ticagrelor Clopidogrel HR 1.31 (95% CI ), p= 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

27 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 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

28 4 Cangrelor THE CHAMPION PROGRAM COMPLETED PHASE III STUDIES

29 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) Death/Q-MI/IDR 0.55 (0.33,0.93) Death/Q-MI/ST 0.38 (0.20,0.72) PCI Death/MI/IDR (primary) 1.05 (0.89,1.24) Death/Q-MI/IDR 0.66 (0.42,1.05) Death/Q-MI/ST 0.74 (0.43,1.27) COMBINED DATA Death/MI/IDR 0.97 (0.86,1.11) Death/Q-MI/IDR 0.61 (0.43,0.86) Death/Q-MI/ST Cangrelor Better Comparator Better 0.55 (0.36,0.83)

30 4 Cangrelor CHAMPION PHOENIX

31 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

32 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)

33 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

34

35

36 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.

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

38 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

39

40 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

41

42 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

43 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 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.

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

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

46 RB007 Active Control Activated Partial Thromboplastin Time (seconds) Inject RB007 Place bo 2 : 1 : :1 0.2 : : Chan, M et al, JTH Time Post RB006 Administration (hrs) 46

47 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 RB % 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

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

49 CYP 2C19 Polymorphisms and Stent Thrombosis Hulot. JACC 2010:56:

50 Primary endpoint in the clopidogrel group in relation to any CYP2C19 LOF allele (K-M estimate) K-M estimate (%) Clopidogrel LOF Clopidogrel No LOF p= p= No. at risk Clopidogrel LOF Clopidogrel No LOF Days from randomization 1,388 1,275 1,259 1,226 1, ,516 3,321 3,256 3,186 2,691 2,123 1, Wallentin L et al Lancet 2010: 376, Online Aug 29, 2010

51 Primary endpoint in the ticagrelor group in relation to any CYP2C19 LOF allele (K-M estimate) 12 K-M estimate (%) Ticagrelor No LOF Ticagrelor LOF No. at risk Ticagrelor LOF Ticagrelor No LOF Days from randomization 1,384 1,305 1,274 1,250 1, ,554 3,352 3,301 3,222 2,718 2,127 1, Wallentin L et al Lancet 2010: 376, Online Aug 29, 2010

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

53 -AHJ 2009

54 GRAVITAS Study Design Elective or Urgent PCI with DES* VerifyNow P2Y12 Test 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 hrs placebo-controlled All patients received aspirin (81-162mg daily)

55 Pharmacodynamics: Effect of SD vs HD Clopidogrel 500 Standard-Dose P = 0.98 High-Dose P < PRU value Persistently high 30 days: 62% vs 40%, p< 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

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

57 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

58 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