1. 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

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

4. 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

5. 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)

6. 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.

7. 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

8. 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

9. 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.

10. 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

11. 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%)

12. 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)

13. 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

14. Ischemic Outcomes—Apixaban vs VKA

15. 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

16. Ischemic Outcomes—Aspirin vs Placebo

17. 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)

18. 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)

19. 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)

20. 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.

21. 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.

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

23. Circulation. 2019; [published online ahead of print]. DOI: 10
Circulation. 2019; [published online ahead of print]. DOI: /CIRCULATIONAHA
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