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Apixaban with Antiplatelet Therapy After Acute Coronary Syndrome: Results of the APPRAISE-2 Trial

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

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Apixaban with Antiplatelet Therapy After Acute Coronary Syndrome: Results of the APPRAISE-2 Trial

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

  2. Disclosures forJohn H. Alexander In compliance with AMA requirements, ISTH makes the following disclosures to the session audience: 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 TrialPhase 2, 1715 patients, recent acute coronary syndrome Apixaban 2.5 mg BID, 10 mg QD, 10 mg BID, 20 mg QD, placeboApixaban 10 mg BID & 20 mg QD stopped due to excess bleeding CV Death, MI, Stroke, Sev Recurrent Ischemia ISTH Major or CRNM Bleeding HR 2.45 (1.31-4.61) p=0.005 HR: 0.73 (0.44-1.19) p=0.21 HR: 0.61 (0.35-1.04) p=0.07 HR 1.78 (0.91-3.48) p=0.09 Alexander JH. Circulation 2009;119:2877–85.

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

  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. Enrollment7392 patients, 858 sites, 39 countries Poland: 353 Finland: 7 Slovak Republic: 59 Sweden: 105 Norway: 51 Hungary: 241 Romania: 158 Russia: 1082 Canada: 254 Ukraine: 258 Denmark: 71 U.K.: 45 Bulgaria: 202 Netherlands: 97 Turkey: 20 United States: 935 Japan: 186 Belgium: 97 China: 75 Korea: 177 Germany: 160 Mexico: 322 India: 794 France: 40 Spain: 160 Switzerland: 38 Czech Rep: 108 Colombia: 88 Austria: 114 Singapore: 25 Italy: 44 Brazil: 250 Peru: 132 Israel: 139 Chile: 56 Australia: 38 South Africa: 133 Argentina: 256 New Zealand: 22

  9. Baseline Characteristics

  10. Index ACS Event

  11. Primary OutcomeCV Death, MI, Ischemic Stroke Apixaban 279 (7.5%) Placebo 293 (7.9%) HR 0.95; 95% CI 0.80-1.11; p=0.509

  12. Other Efficacy Outcomes

  13. Primary OutcomeCV 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 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 BleedingSubgroups *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

  20. Thank you to our hosts.Congratulations to the Soccer World Cup Champions!

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