Stephan Windecker on behalf of the AUGUSTUS Investigators 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 Windecker on behalf of the AUGUSTUS Investigators

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

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

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)

Trial Design Randomize n=4600 patients Apixaban 5 mg BID VKA Open INCLUSION AF (prior, persistent, >6 hr) Physician decision for OAC ACS or PCI Planned P2Y12 inhibitor for ≥6 months Randomize n=4600 patients 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 Open Label VKA (INR 2–3) Aspirin for all on the day of ACS or PCI Aspirin versus placebo after randomization Aspirin Placebo Double Blind Aspirin Placebo Double Blind 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.

Trial Organization 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) 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

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

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, was tested using a Cox proportional hazards model.

Patient Allocation 4614 patients (492 sites, 33 countries) ACS 61.2% Elective PCI 38.8% (n=1784) 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

CONSORT Diagram Total Randomized OAC Aspirin/Placebo 547 (23.8%) Randomized to Apixaban N=2297 Randomized to VKA N=2298 Randomized to Aspirin N=2293 Randomized to Placebo N=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%)

Baseline Characteristics ACS Medical N=1097 ACS PCI N=1714 Elective PCI N=1784 Age, median (25th, 75th), yrs 70 (64, 77) 71 (64.0, 77.3) 71 (65, 77) Female 39% 27% 25% Diabetes mellitus 32% 35% 41% CrCl, median (25th, 75th), mL/min 72 (54, 91) 76 (57, 96) 76 (59, 98) Heart failure 57% 38% CHA2DS2-VASc score, median (25th, 75th) 4 (3, 5) HAS-BLED score, median (25th, 75th) 2 (2, 3) 3 (2, 3) Prior OAC 48% 42% P2Y12 inhibitor Clopidogrel 98% 90% 93% Prasugrel 0.2% 1.7% 1.2% Ticagrelor 2.1% 8.7% 6.3% Number of days to rand., median (25th, 75th) 9 (6, 12) 5 (3, 9) 5 (2, 9)

Primary Endpoint: ISTH and CRNM Bleeding Apixaban 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) Days since start of intervention Cumulative incidence of event VKA Apixaban

Ischemic Outcomes—Apixaban vs VKA

Primary Endpoint: ISTH and CRNM Bleeding Aspirin 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) Cumulative incidence of event Days since start of intervention Placebo Aspirin Aspirin Aspirin Placebo Placebo

Ischemic Outcomes—Aspirin vs Placebo

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)

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)

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 earliest treatment start date (days) Time from randomization start date (days)

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.

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.

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

Circulation. 2019; [published online ahead of print]. DOI: 10 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;Viliam Fridrich; 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; Dimitar Raev; 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