1. John H. Alexander, MD, MHS on behalf of the APPRAISE-2 Investigators Apixaban with Antiplatelet Therapy After Acute Coronary Syndrome: Results of the APPRAISE-2 Trial Sponsored by Bristol-Myers Squibb and Pfizer

2. Disclosures for John H. Alexander In compliance with AMA requirements, ISTH makes the following disclosures to the session audience: Research Support/P.I. Bristol-Myers Squibb, Pfizer, Merck-Schering Plough Employee No relevant conflicts of interest to declare Consultant Bristol-Myers Squibb, Pfizer, Polymedix Major Stockholder No relevant conflicts of interest to declare Speakers Bureau No relevant conflicts of interest to declare Honoraria No relevant conflicts of interest to declare Scientific Advisory Board Bristol-Myers Squibb, Regado Biosciences, Ortho-McNeil-Jannsen Presentation includes discussion of the following off-label use of a drug or medical device: Apixaban (Eliquis, Bristol-Myers Squibb)

3. Background Patients with ACS have recurrent ischemic events despite revascularization and antiplatelet therapy. Vitamin K antagonists have been shown to reduce recurrent events on a background of aspirin. Apixaban, an oral, direct, selective factor Xa inhibitor, reduces venous thromboembolism in patients undergoing orthopedic surgery and prevents thromboembolic events in patients with atrial fibrillation who are not candidates for oral vitamin K antagonists. The benefits of apixaban on a background of contemporary antiplatelet therapy following ACS are not known. Wallentin L. N Engl J Med 2009;361:1045–57. Andreotti F. Eur Heart J 2006 Mar;27:519–26. Hansen ML. Arch Intern Med 2010;170:1433–41. Wong PC. J Thromb Haemost 2008;6:820–9. Lassen MR. Lancet 2010;375:807–15. Lassen MR. N Engl J Med 2010;363:2487–98. Connolly SJ. N Engl J Med 2011;364:806–17.

4. APPRAISE-1 Trial Phase 2, 1715 patients, recent acute coronary syndrome Alexander JH. Circulation 2009;119:2877–85. Apixaban 2.5 mg BID, 10 mg QD, 10 mg BID, 20 mg QD, placebo Apixaban 10 mg BID & 20 mg QD stopped due to excess bleeding ISTH Major or CRNM Bleeding CV Death, MI, Stroke, Sev Recurrent Ischemia HR 2.45 (1.31-4.61) p=0.005 HR: 0.61 (0.35-1.04) p=0.07 HR: 0.73 (0.44-1.19) p=0.21 HR 1.78 (0.91-3.48) p=0.09

5. 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 Risk Factors Age ≥65 years Diabetes mellitus Prior MI within 5 years Cerebrovascular disease Peripheral vascular disease Clinical heart failure or LV EF <40% Renal dysfunction (CrCl <60 mL/min) No revascularization for ACS event Projected event rate: 8% / year, median f/u 1.25 years Event driven: 938 patients with the primary outcome 80% power to detect a 20% risk reduction at a one-sided α of 0.005 93% power to detect a 20% risk reduction at a one-sided α of 0.025 Analysis: time to first event (stratified: single vs. dual antiplatelet therapy) Key subgroups: single / dual antiplatelet therapy, revascularized / not revascularized

6. Objective To determine whether apixaban 5mg twice daily reduces the composite of cardiovascular death, MI or stroke at an acceptable risk of bleeding in patients at high-risk for recurrent ischemic events receiving contemporary antiplatelet therapy following an acute coronary syndrome

7. 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%)

8. Enrollment 7392 patients, 858 sites, 39 countries Canada: 254 United States: 935 Mexico: 322 Finland: 7 Denmark: 71 Hungary: 241 Netherlands: 97 Ukraine: 258 Sweden: 105 Norway: 51 U.K.: 45 Belgium: 97 France: 40 Spain: 160 Austria: 114 Italy: 44 Israel: 139 Poland: 353 Czech Rep: 108 Chile: 56 Peru: 132 Colombia: 88 Brazil: 250 Argentina: 256 South Africa: 133 Russia: 1082 China: 75 India: 794 Korea: 177 Singapore: 25 Australia: 38 Germany: 160 Japan: 186 Romania: 158 Turkey: 20 Bulgaria: 202 Slovak Republic: 59 Switzerland: 38 New Zealand: 22

9. Baseline Characteristics Characteristic Apixaban (n=3705) Placebo (n=3687) Age, years67 (59, 73)67 (58, 74) Women, %32.631.7 Inclusion criteria risk factors, % Age > 65 y58.859.0 Diabetes mellitus48.747.0 MI within 5 years36.038.1 Cerebrovascular disease10.19.9 Peripheral vascular disease17.918.3 Heart failure or LVEF <40%49.950.7 Impaired renal function15.716.2 No revasc for index ACS event55.655.2 History of…, % Hypertension79.977.4 Revascularization27.828.7

10. 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 CABG0.6 Medical therapy only55.6 55.2 Dual antiplatelet therapy80.180.4

11. 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

12. 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

13. Primary Outcome CV Death, MI, Stroke — Subgroups *HR not calculated for subgroups with ≤10 events

14. TIMI Major Bleeding Apixaban 48 (1.3%) Placebo 18 (0.5%) HR 2.59; 95% CI 1.50–4.46; p=0.001

15. Other Bleeding Scales Apixaban N=3705 Placebo N=3687 p-value TIMI major1.30.50.001 TIMI major or minor2.2 0.8<0.001 ISTH major2.71.1<0.001 ISTH major or clinically relevant non-major 3.21.2<0.001 GUSTO severe1.00.30.001 Intracranial0.30.10.030 Fatal bleeding: Apixaban = 5 vs. Placebo = 0 ISTH major bleeding = bleeding leading to death, occurring in a critical location, or associated with a ≥2 g/dL drop in hemoglobin or transfusion of 2 or more units of PRBC.

16. TIMI Major Bleeding Subgroups *HR not calculated for subgroups with ≤10 events

17. Conclusions APPRAISE-2 Summary: The addition of apixaban to contemporary antiplatelet therapy increases major bleeding without any significant reduction in ischemic events in high-risk patients following an ACS. Limitations: Because of the early termination of the trial, with accrual of two-thirds of the expected events and a median follow-up of 8 months, some uncertainty regarding efficacy remains. Clinical Implications: The addition of an anticoagulant to currently recommended anti-platelet treatment post-ACS should be used cautiously and only in patients with clear indications for both an anticoagulant and antiplatelet therapy. Future Directions: Further research is needed to explore different antithrombotic combinations and doses that might have a different risk-benefit balance.

18. Acknowledgement Executive Committee: RA Harrington (co-chair), L Wallentin (co-chair), JH Alexander (PI), S James (co-PI), RD Lopes (CEC chair), P Mohan and D Liaw (BMS). Steering Committee: R Diaz, J Amerena, K Huber, F Cools, J Nicolau, D Raev, S Goodman, R Corbalan, Y Huo, M Urina-Triana, P Jansky, S Husted, K Niemela, G Montalescot, H Darius, M Keltai,; P Pais, B Lewis, R De Caterina, H Ogawa, SJ Park, JL Leiva-Pons, J Cornel, F Verheugt, H White, D Atar, A Gallegos-Cazorla, W Ramos, W Ruzyllo, D Vinereanu, M Ruda, RS Tan, V Fridrich, H Du Truit Theron, J Lopez-Sendon, T Jernberg, T Luscher, C Erol, M Flather, A Parkhomenko, D Bhatt, J Miller. Data Monitoring Committee: M Simoons (chair), P Armstrong, J DeLemos, T Kimura, A Maggioni, S Pocock. CEC: R Lopes, K Mahaffey, S Al-Khatib, A Hernandez, B Kolls, S Leonardi, R Mehta, C Melloni, LK Newby, M Roe, B Shah, L Szczech, P Tricoci, A Truffa, J Vavalle, AB Cavalcanti, L Echenique, C Gonzaga, HP Guimaraes, L Armaganijan. DCRI: L Hatch, M Banks, A Handler, L Perkins, A Heath, Y Lokhnygina, S Dickerson, A Stone, K Lee, J Garg. BMS / Pfizer: D Liaw, P Mohan, M Hanna, F Fiedorek, JM Bocquet, N Kolivodiakos, L Rossi, R Braceras, H Pouleur, N Jackson, D Hessinger. PPD: V Ponder-Lee, K Griffith, T Dremsizov, A Bevan, C Murphy, M Okabe, J Knoll, A Burr. The APPRAISE-2 Investigators, Coordinators and Patients

19. APPRAISE-2 Publication

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