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Antithrombotic Therapy in Patients with Atrial Fibrillation and Acute Coronary Syndrome: AUGUSTUS Trial

The AUGUSTUS trial studied the safety and efficacy of different antithrombotic regimens in atrial fibrillation patients with recent acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI). Apixaban without aspirin resulted in less bleeding, fewer hospitalizations, and no significant differences in ischemic events compared to regimens with a vitamin K antagonist, aspirin, or both. This analysis focused on three subgroups: ACS patients treated medically, ACS patients treated with PCI, and patients undergoing elective PCI.

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Antithrombotic Therapy in Patients with Atrial Fibrillation and Acute Coronary Syndrome: AUGUSTUS Trial

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  1. Antithrombotic Therapy in Patients with Atrial Fibrillation and Acute Coronary Syndrome Treated Medically or with Percutaneous Coronary Intervention or Undergoing Elective Percutaneous Coronary Intervention Stephan Windeckeron behalf of the AUGUSTUS Investigators

  2. Background • AUGUSTUS trial — AF patients with recent ACS or PCI • Apixaban without aspirin resulted in • less bleeding • fewer hospitalizations • no significant differences in ischemic events than regimens that included a VKA, aspirin, or both

  3. Background • AUGUSTUS trial — AF patients with recent ACS or PCI • Apixaban without aspirin resulted in • less bleeding • fewer hospitalizations • no significant differences in ischemic events than regimens that included a vitamin K antagonist, aspirin, or both • The safety and efficacy of antithrombotic regimens may differ between patients with AF who have ACS treated medically or with PCI, and those undergoing elective PCI

  4. Pre-Specified Analysis • Using a 2×2 factorial design apixaban was compared with VKA and aspirin with placebo in patients with AF who had ACS or were undergoing PCI and were receiving a P2Y12 inhibitor • We explored bleeding, death, and hospitalization as well as death and ischemic events by antithrombotic strategy in three mutually exclusive, pre-specified subgroups: • Patients with ACS treated medically (ACS Medical) • Patients with ACS treated with PCI (ACS PCI) • Patients undergoing elective PCI (Elective PCI)

  5. Trial Design Randomize n=4600 patients • INCLUSION • AF (prior, persistent, >6 hr) • Physician decision for OAC • ACS or PCI • Planned P2Y12 inhibitor for ≥6 months • EXCLUSION • Contraindication to DAPT • Other reason for VKA (prosthetic valve, moderate / severe mitral stenosis) Apixaban 5 mg BID Apixaban 2.5 mg BID in selected patients VKA (INR 2–3) Open Label Aspirin for all on the day of ACS or PCI Aspirin versus placebo after randomization Double Blind Double Blind Aspirin Aspirin Placebo Placebo • Randomization was stratified by indication at time of enrollment • ACS versus elective PCI • Patients with ACS were managed medically or with PCI according to local practice Lopes RD, et al. Am Heart J. 2018;200:17-23.

  6. Trial Organization DATA SAFETY MONITORING BOARD Lars Wallentin (Chair) Robert Harrington Stuart Pocock Statistical Support—Uppsala Clinical Research CLINICAL EVENTS CLASSIFICATION (CEC) COMMITTEE Duke Clinical Research Institute ACADEMIC COORDINATING CENTER Duke Clinical Research Institute CONTRACT RESEARCH ORGANIZATION Pharmaceutical Product Development (PPD) SPONSORS Bristol-Myers Squibb/Pfizer EXECUTIVE COMMITTEE John Alexander (Chair) Renato Lopes (PI) Roxana Mehran (USA) Christopher Granger (USA) Shaun Goodman (Canada) Harald Darius (Germany) Stephan Windecker (Switzerland) Ronald Aronson (BMS)

  7. Outcomes Primary outcomes: • ISTH major bleeding • Clinically relevant non-major bleeding Secondary outcomes: • Death or hospitalization • Death or ischemic events • Stroke • Myocardial infarction • ARC definite or probable stent thrombosis • Urgent revascularization

  8. Statistical Analysis • Baseline characteristics were summarized for each of the three subgroups (ACS Medical, ACS PCI, Elective PCI) by anticoagulant therapy and antiplatelet therapy. • For each of the outcomes, the proportion of patients with at least one event was calculated and summarized. • The differences between anticoagulant regimens within each of the three subgroups were tested and characterized by hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) from a Cox proportional hazards model adjusted by antiplatelet regimen. • Likewise for the testing of the antiplatelet regimen where adjustment was done by the anticoagulant factor. • The effects of the randomization factor, ACS or PCI status, and their interaction, wastested using a Cox proportional hazards model.

  9. Patient Allocation 4614 patients (492 sites, 33 countries) Elective PCI 38.8% (n=1784) ACS 61.2% (n=2811) Randomization stratified by ACS vs. elective PCI ACS Medical 39.0% (n=1097) ACS PCI 61.0% (n=1714) Patients with ACS were managed medically or with PCI according to local practice 19 pts with missing information about ACS and PCI

  10. CONSORT Diagram Total Randomized N=4614 OAC Aspirin/Placebo Randomized to ApixabanN=2297 Randomized to VKAN=2298 Randomized to AspirinN=2293 Randomized to PlaceboN=2302 Patients with ACS treated medically 547 (23.8%) • 550 (23.9%) • 547 (23.9%) • 550 (23.9%) Patients with ACS treated with PCI • 873 (38.0%) • 841 (36.6%) • 844 (36.8%) • 870 (37.8%) Patient undergoing elective PCI • 877 (38.2%) • 907 (39.5%) • 902 (39.3%) • 882 (38.3%)

  11. Baseline Characteristics

  12. Primary Endpoint: ISTH and CRNM BleedingApixaban vs VKA ACS Medical N=1097 ACS PCI N=1714 Elective PCI N=1784 P for Interaction (ACS Medical, ACS PCI, Elective PCI) = 0.052 HR 0.44 (95% CI 0.28–0.68) HR 0.68 (95% CI 0.52–0.89) HR 0.82 (95% CI 0.64–1.04) VKA VKA VKA Cumulative incidence of event Apixaban Apixaban Apixaban Days since start of intervention Days since start of intervention Days since start of intervention

  13. Ischemic Outcomes—Apixaban vs VKA

  14. Primary Endpoint: ISTH and CRNM BleedingAspirin vs Placebo ACS Medical N=1097 ACS PCI N=1714 Elective PCI N=1784 P for Interaction (ACS Medical, ACS PCI, Elective PCI) = 0.479 HR 1.49 (95% CI 0.98–2.26) HR 2.02 (95% CI 1.53–2.67) HR 1.91 (95% CI 1.48–2.47) Aspirin Aspirin Aspirin Cumulative incidence of event Placebo Placebo Placebo Days since start of intervention Days since start of intervention Days since start of intervention

  15. Ischemic Outcomes—Aspirin vs Placebo

  16. ACS Medical ISTH/CRNM Bleeding Death/Hospitalization Apixaban + Placebo vs. VKA + Aspirin:10% absolute risk reduction (NNT=10) Apixaban + Placebo vs. VKA + Aspirin:10% absolute risk reduction (NNT=10) — VKA + Aspirin (%) — VKA + Placebo (%) — Apixaban + Aspirin (%) — Apixaban + Placebo (%) — VKA + Aspirin (%) — VKA + Placebo (%) — Apixaban + Aspirin (%) — Apixaban + Placebo (%) Event rate Event rate Time from earliest treatment start date (days) Time from randomization start date (days)

  17. ACS PCI ISTH/CRNM Bleeding Death/Hospitalization Apixaban + Placebo vs. VKA + Aspirin:12% absolute risk reduction (NNT=8) Apixaban + Placebo vs. VKA + Aspirin:3.5% absolute risk reduction (NNT=29) — VKA + Aspirin (%) — VKA + Placebo (%) — Apixaban + Aspirin (%) — Apixaban + Placebo (%) Event rate Event rate — VKA + Aspirin (%) — VKA + Placebo (%) — Apixaban + Aspirin (%) — Apixaban + Placebo (%) Time from earliest treatment start date (days) Time from randomization start date (days)

  18. Elective PCI ISTH/CRNM Bleeding Death/Hospitalization Apixaban + Placebo vs. VKA + Aspirin:11% absolute risk reduction (NNT=9) Apixaban + Placebo vs. VKA + Aspirin:3.9% absolute risk reduction (NNT=26) — VKA + Aspirin (%) — VKA + Placebo (%) — Apixaban + Aspirin (%) — Apixaban + Placebo (%) — VKA + Aspirin (%) — VKA + Placebo (%) — Apixaban + Aspirin (%) — Apixaban + Placebo (%) Event rate Event rate Time from randomization start date (days) Time from earliest treatment start date (days)

  19. Limitations • The trial was powered for the primary safety endpoint (ISTH major/CRNM bleeding). The data for three reported subgroups are underpowered. • All patients received aspirin during their hospitalization for the index ACS and/or PCI and for a median of 6–9 days prior to randomization. Therefore, the term dual antithrombotic therapy refers to the period after randomization. • The present study does not address the optimal treatment duration for the combined anticoagulation and P2Y12 inhibitor regimen, as all patients were treated for 6 months. • The present study does not address the optimal short-term treatment duration of aspirin after PCI before initiation of dual antithrombotic therapy.

  20. Conclusions • The overall results of the AUGUSTUS trial are consistent across the three clinically important subgroups (ACS medical, ACS PCI, elective PCI). • Accordingly, anticoagulation with apixaban, at the dose approved for stroke prevention in patients with AF, combined with a P2Y12 inhibitor without aspirin should be preferred in patients with AF and ACS irrespective of management with medical therapy or PCI, and those undergoing elective PCI than regimens that include VKAs, aspirin, or both.

  21. Acknowledgement Thank you to the national leaders, investigators, study coordinators, and study participants who made AUGUSTUS possible.

  22. Circulation. 2019; [published online ahead of print]. DOI: 10.1161/CIRCULATIONAHA.119.043308 • Antithrombotic Therapy in Patients with Atrial Fibrillation and Acute Coronary Syndrome Treated Medically or with Percutaneous Coronary Intervention or Undergoing Elective Percutaneous Coronary Intervention: Insights from the AUGUSTUS Trial • Stephan Windecker; Renato D. Lopes; Tyler Massaro; Charlotte Jones-Burton; Christopher B. Granger; Ronald Aronson; Gretchen Heizer; Shaun G. Goodman; Harald Darius; W. Schuyler Jones; Michael Aschermann; David Brieger; Fernando Cura; Thomas Engstrøm;ViliamFridrich; Sigrun Halvorsen; Kurt Huber; Hyun-Jae Kang; Jose L. Leiva-Pons; Basil S. Lewis; German Malaga; Nicolas Meneveau; Bela Merkely; Davor Milicic; João Morais; Tatjana S. Potpara; DimitarRaev; Manel Sabaté; Suzanne de Waha-Thiele; Robert C. Welsh; Denis Xavier; Roxana Mehran; John H. Alexander ; on behalf of the AUGUSTUS Investigators • Circulation • https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.119.043308

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