1. John H. Alexander, MD, MHS Associate Professor of Medicine Director, Cardiovascular Research Duke Clinical Research Institute Duke Medicine Update on antithrombotics in acute coronary syndromes Oral Anti-Xa Agents A new opportunity? www.escardio.org

2. Disclosure n I am on the faculty of the Duke University School of Medicine and Duke Clinical Research Institute. I conduct research on antithrombotic therapies in patients with atrial fibrillation and acute coronary syndromes. n Research Support: Bristol-Myers Squibb, CSL Behring, U.S. NIH, Pfizer, Phyxius Pharmaceuticals, Regado Biosciences n Consultant: Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Jannsen, Orexigen, Pfizer, U.S. VA CSP, Xoma Conflict of interest disclosures available at http://www.dcri.duke.edu/research/coi www.escardio.org

3. op·por·tu·ni·ty Definitions n n a favorable juncture of circumstances n n a good chance for advancement or progress www.escardio.org Oral Anti-Xa Agents post ACS, a new opportunity?

4. Primary Efficacy Endpoint CV Death, MI, Stroke Days after randomisation 060120180240300360 12 11 10 9 8 7 6 5 4 3 2 1 0 13 Cumulative incidence (%) 11.7 Clopidogrel Wallentin NEJM 2009;361:1045-57 4-5% per year Post-Acute Acute www.escardio.org

5. Combination Better Trials Aspirin Better 10.52 0.1 10 Odds Ratio & 95% CI N All studies 1425,307 16.618.0 Bleeding14 25,307 10.110.9 Extracranial1012,488 9.612.2 Intracranial 1012,488 16.716.5 Death/MI/Stroke107,836 9.412.3 Bleeding107,836 2.61.1 Extracranial73,820 2.30.9 Intracranial73,820 0.30.0005 ComboAspirin % Andreotti EHJ 2006;27:519-26 Warfarin After Acute Coronary Syndrome * non-fatal thromboembolic 50.2 Death/MI/Stroke* Studies with INR 2-3 www.escardio.org

6. Antithrombotic Therapy Post-ACS Where Are We Now? Dose? Duration? Familiar Drugs Aspirin Clopidogrel New Drugs Prasugrel Ticagrelor Vorapaxar* Apixaban* Rivaroxaban* Bleeding Common Clinically important Individualization Weight Renal function Regional Genetic polymorphisms Drug interactions Insurance www.escardio.org *Not approved in US

7. Tissue factor Plasma clotting cascade * Prothrombin * Thrombin * FibrinogenFibrin Thrombus Platelet aggregation Conformational activation of GPIIb/IIIa Collagen Thrombin Tx A 2 ADP Aspirin Clopidogrel Prasugrel Ticagrelor Ximeligatran Dabigatran Factor Xa * Rivaroxaban Apixaban Darexaban PAR1 Vorapaxar Atopaxar Warfarin * Post-ACS Antithrombotic Therapy Multiple Targets www.escardio.org

8. New Oral Anticoagulants in ACS Phase 2 DrugTrialTargetPhase 2 ACS Published XimeligatranESTEEMFIIa2003 ApixabanAPPRAISEFXa2009 RivaroxabanATLAS-ACSFXa2009 DabigatranREDEEMFIIa2011 DarexabanRUBY-1FXa2011 www.escardio.org

9. Study Design Phase 2 Clinical Trials of New Anticoagulants Post-ACS NOAC Dose A Safety Outcome: Major or CRNM Bleeding Efficacy Outcome: Ischemic Event Composite Randomize Aspirin Clopidogrel Placebo Recent (≤7days) Acute Coronary Syndrome (STEMI or NSTE-ACS) NOAC Dose B NOAC Dose C NOAC Dose D Revasc 6 Month Treatment Period Parallel or Dose escalation www.escardio.org

10. Phase 2 Conclusions n Adding an anticoagulant to dual antiplatelet therapy post-ACS consistently results in a dose related 2 to 4 fold increase in bleeding ● ESTEEM, REDEEM (IIa); APPRAISE, ATLAS, RUBY (Xa) ■ Suggestion of a potential reduction in ischemic events in some (ESTEEM, APPRAISE, ATLAS) but not other (REDEEM, RUBY) phase 2 clinical trials ● Benefits less apparent with dual antiplatelet therapy ■ Adequately powered phase 3 trial are needed ■ What is the right dose(s) to take forward in phase 3? ● Higher (more efficacy/more bleeding?) ● Lower (less efficacy/less bleeding?) www.escardio.org

11. Apixaban 5 mg BID CrCl<40 ml/min 2.5 mg BID Primary Outcome: CV Death, MI, Ischemic Stroke Safety: TIMI Major Bleeding Randomize 1:1 Double blind Aspirin Other antiplatelet therapy N=10,800 Placebo Recent (≤7days) Acute Coronary Syndrome (STEMI or NSTE-ACS) At Least 2 Additional Risk-Factors Design Alexander NEJM 2011;365:699-708 www.escardio.org

12. Index ACS Event Characteristic Apixaban (n=3705) Placebo (n=3687) Time from index ACS event to rand, days 6.0 (4.0, 7.0) Elevated biomarkers (CKMB or Troponin)81.2 Index ACS event type ST-elevation MI 39.839.4 Non-ST-elevation MI 41.441.8 Unstable angina18.218.1 Index event ACS management Coronary angiography 51.952.3 PCI43.844.2 Medical therapy only55.6 55.2 Dual antiplatelet therapy80.180.4 Alexander NEJM 2011;365:699-708 www.escardio.org

13. Trial Stopped Prematurely On November 15, 2010 the Data Monitoring Committee recommended that the trial be stopped due to an excess of clinically important bleeding in the apixaban arm without a counterbalancing reduction in ischemic events. Patients = 7048 Median f/u = 3.5 months Primary Events = 412 (44%) Alexander NEJM 2011;365:699-708 www.escardio.org

14. Primary Outcome CV Death, MI, Ischemic Stroke Apixaban279 (7.5%) Placebo293 (7.9%) HR 0.95; 95% CI 0.80-1.11; p=0.509 Alexander NEJM 2011;365:699-708 www.escardio.org

15. Other Efficacy Outcomes Apixaban N=3705 Placebo N=3687 p-value CV death, MI, ischemic stroke7.57.90.509 CV death, MI, ischemic stroke, UA9.5 100.430 Death4.23.90.514 CV death2.82.90.754 Myocardial infarction4.95.30.509 Ischemic stroke0.60.90.145 Unstable angina2.32.40.670 Definite stent thrombosis0.91.30.150 Alexander NEJM 2011;365:699-708 www.escardio.org

16. Primary Outcome CV Death, MI, Stroke — Subgroups *HR not calculated for subgroups with ≤10 events Alexander NEJM 2011;365:699-708 www.escardio.org

17. TIMI Major Bleeding Apixaban 48 (1.3%) Placebo 18 (0.5%) HR 2.59; 95% CI 1.50–4.46; p=0.001 Alexander NEJM 2011;365:699-708 www.escardio.org

18. TIMI Major Bleeding Subgroups *HR not calculated for subgroups with ≤10 events Alexander NEJM 2011;365:699-708 www.escardio.org

19. Recent ACS: STEMI, NSTEMI, UA Stabilized 1-7 Days Post-Index Event Exclusions: increased bleeding risk, warfarin use, ICH, prior stroke if on ASA + thienopyridine PRIMARY ENDPOINTS: EFFICACY: CV Death, MI, Stroke (Ischemic, Hemorrhagic, or Uncertain Origin) SAFETY: TIMI major bleeding not associated with CABG Rivaroxaban 5.0 mg BID n=5,176 Stratified by Thienopyridine Use at MD Discretion ASA 75 to 100 mg/day Placebo n=5,176 Rivaroxaban 2.5 mg BID n=5,174 Event driven trial with 1,002 primary efficacy events Mega NEJM 2012;366:9-19 www.escardio.org

20. Months After Randomization Primary Efficacy Endpoint CV DeathMI/Stroke Rivaroxaban (both doses) HR 0.84 (0.74-0.96) mITT p = 0.008 ITT p = 0.002 ARR 1.8% NNT = 56 10.7% 8.9% Estimated Cumulative Incidence (%) Placebo 5113 4307 3470 2664 1831 1079 421 10229 8502 6753 5137 3554 2084 831 Placebo Rivaroxaban 2 Yr KM Estimate No. at Risk www.escardio.org Mega NEJM 2012;366:9-19

21. Months Estimated Cumulative Incidence (%) Placebo Rivaroxaban 5 mg BID 0 8.8% 10.7% “Low Dose” Rivaroxaban 5.0 mg BID 24 Cardiovascular Death CV Death / MI / Stroke HR 0.94 mITT p=0.63 ITT p=0.57 Months 0 24 4.0% 4.1% Placebo Rivaroxaban 5 mg BID HR 0.85 mITT p=0.028 ITT p=0.010 NNT=53 www.escardio.org Mega NEJM 2012;366:9-19

22. “Very Low Dose” Rivaroxaban 2.5 mg BID 0 24 Cardiovascular Death Months CV Death / MI / Stroke Estimated Cumulative incidence (%) HR 0.84 mITT p=0.020 ITT p=0.007 HR 0.66 mITT p=0.002 ITT p=0.005 10.7% 9.1% 0 24 Placebo Months 4.1% 2.7% Rivaroxaban 2.5 mg BID Rivaroxaban 2.5 mg BID Placebo NNT = 71NNT = 63 12 12% 5% www.escardio.org Mega NEJM 2012;366:9-19

23. Primary Efficacy Endpoint - Subgroups CV Death / MI / Stroke Consistent Benefit Mono / Dual Age Sex Weight Renal function Prior MI Prior Stroke Diabetes STEMI / NSTEMI Region www.escardio.org Mega NEJM 2012;366:9-19

24. TIMI Major Bleeding Overall HR=3.96 (2.46-6.38) P<0.001 Riva 5 BID HR=4.47 (2.71-7.36) P<0.001 Riva 2.5 BID HR=3.46 (2.08-5.77) P<0.001 www.escardio.org Mega NEJM 2012;366:9-19 Intracranial Hemorrhage Riva 2.5 BID: HR 2.8 (1.0-7.9) Riva 5.0 BID: HR 3.7 (1.4-10.1)

25. TIMI Major Bleeding - Subgroups Consistent Risk Mono / Dual Age Sex Weight Renal function Prior MI Prior Stroke Diabetes STEMI / NSTEMI Region www.escardio.org Mega NEJM 2012;366:9-19

26. www.escardio.org APPRAISE-2 and ATLAS-2 Comparing Efficacy Results n Different drugs l apixaban vs. rivaroxaban n Different doses l 5.0 bid vs. 2.5 bid / 5.0 bid n Different populations l High-risk vs. broad inclusive n Duration of treatment / follow-up l Mean 8 months vs. 13 months n Chance l Bias introduced by early study discontinuation

27. Apixaban279 (7.5%) Placebo293 (7.9%) HR 0.95; 95% CI 0.80-1.11 p=0.509 Efficacy event rate higher in APPRAISE-2 at 6 months; similar treatment effect

28. Development of Oral Anti-Thrombotic Therapy Post-ACS Reduction in Ischemic Events ASA Prasugrel Ticagrelor No Tx Clopidogrel Vorapaxar Anticoagulant Increases in Bleeding www.escardio.org

29. DoseDose CombinationsCombinations DurationDuration The Sweet Spot for Post-ACS Antithrombotics PatientFactorsPatientFactors Ischemic Events Ischemic stroke Myocardial infarction Unstable angina CV death Revascularization Bleeding Intracranial Major bleeding Transfusion Minor bleeding www.escardio.org

30. op·por·tu·ni·ty Definitions n n a favorable juncture of circumstances n n a good chance for advancement or progress www.escardio.org Oral Anti-Xa Agents post ACS, a new opportunity? My answer: certainly yes.

31. Summing it Up n Adding an oral fXa inhibitor to dual antiplatelet therapy post-ACS… l A definite ~3-4 fold (1.5% absolute) increase in major bleeding, including ICH. l A less certain ~15% (2.0% absolute) decrease in important ischemic events, including total mortality. n These findings (risks & benefits) appear consistent across a wide spectrum of patients. n Whether similar risks and benefits would be observed in patients taking new P2Y12 antagonists is unknown. n Whether and how factor Xa inhibitors are integrated into post-ACS care will depend largely on the relative importance given to ischemic events and bleeding.

32. “Humanity’s greatest advances are not in its discoveries – but in how those discoveries are applied…” Harvard 2007 www.escardio.org

33. THANK YOU! Update on antithrombotics in acute coronary syndromes Oral Anti-Xa Agents A new opportunity? www.escardio.org