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Randomized Controlled Trial
. 2022 Jul 1;7(7):682-689.
doi: 10.1001/jamacardio.2022.1166.

Apixaban or Warfarin and Aspirin or Placebo After Acute Coronary Syndrome or Percutaneous Coronary Intervention in Patients With Atrial Fibrillation and Prior Stroke: A Post Hoc Analysis From the AUGUSTUS Trial

M Cecilia Bahit  1 , Amit N Vora  2   3 , Zhuokai Li  3 , Daniel M Wojdyla  3 , Laine Thomas  3 , Shaun G Goodman  4   5 , Ronald Aronson  6 , J Dedrick Jordan  7 , Brad J Kolls  3   7 , Keith E Dombrowski  8 , Dragos Vinereanu  9 , Sigrun Halvorsen  10 , Otavio Berwanger  11 , Stephan Windecker  12 , Roxana Mehran  13   14 , Christopher B Granger  3 , John H Alexander  3 , Renato D Lopes  3
Affiliations
Randomized Controlled Trial

Apixaban or Warfarin and Aspirin or Placebo After Acute Coronary Syndrome or Percutaneous Coronary Intervention in Patients With Atrial Fibrillation and Prior Stroke: A Post Hoc Analysis From the AUGUSTUS Trial

M Cecilia Bahit et al. JAMA Cardiol. .

Abstract

Importance: Data are limited regarding the risk of cerebrovascular ischemic events and major bleeding in patients with atrial fibrillation (AF) and recent acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI).

Objective: Determine the efficacy and safety of apixaban or vitamin K antagonists (VKA) and aspirin or placebo according to prior stroke, transient ischemic attack (TIA), or thromboembolism (TE).

Design, setting, and participants: In this prospective, multicenter, 2-by-2 factorial, randomized clinical trial, post hoc parallel analyses were performed to compare randomized treatment regimens according to presence or absence of prior stroke/TIA/TE using Cox proportional hazards models. Patients with AF, recent ACS or PCI, and planned use of P2Y12 inhibitors for 6 months or longer were included; 33 patients with missing data about prior stroke/TIA/TE were excluded.

Interventions: Apixaban (5 mg or 2.5 mg twice daily) or VKA and aspirin or placebo.

Main outcomes and measures: Major or clinically relevant nonmajor (CRNM) bleeding.

Results: Of 4581 patients included, 633 (13.8%) had prior stroke/TIA/TE. Patients with vs without prior stroke/TIA/TE were older; had higher CHA2DS2-VASC and HAS-BLED scores; and more frequently had prior bleeding, heart failure, diabetes, and prior oral anticoagulant use. Apixaban was associated with lower rates of major or CRNM bleeding and death or hospitalization than VKA in patients with (hazard ratio [HR], 0.69; 95% CI, 0.46-1.03) and without (HR, 0.68; 95% CI, 0.57-0.82) prior stroke/TIA/TE. Patients without prior stroke/TIA/TE receiving aspirin vs placebo had higher rates of bleeding; this difference appeared less substantial among patients with prior stroke/TIA/TE (P = .01 for interaction). Aspirin was associated with numerically lower rates of death or ischemic events than placebo in patients with (HR, 0.71; 95% CI, 0.42-1.20) and without (HR, 0.93; 95% CI, 0.72-1.21) prior stroke/TIA/TE (not statistically significant).

Conclusions and relevance: The safety and efficacy of apixaban compared with VKA was consistent with the AUGUSTUS findings, irrespective of prior stroke/TIA/TE. Aspirin increased major or CRNM bleeding, particularly in patients without prior stroke/TIA/TE. Although aspirin may have some benefit in patients with prior stroke, our findings support the use of apixaban and a P2Y12 inhibitor without aspirin for the majority of patients with AF and ACS and/or PCI, regardless of prior stroke/TIA/TE status.

Trial registration: ClinicalTrials.gov Identifier: NCT02415400.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Bahit reported other fees from Bristol Myers Squibb and Pfizer during the conduct of the study and other from Merck Sharp & Dohme, CSL Behring, Vifor, and Boehringer Ingelheim outside the submitted work. Dr Vora reported grants from Medtronic outside the submitted work. Dr Thomas reported grants from Akili Interactive Labs, Amgen, Gilead, and Novartis. Dr Goodman reported grants and other fees from Amgen, Bristol Myers Squibb/Pfizer, Bayer, Boehringer Ingelheim, Anthos Therapeutics, AstraZeneca, CSL Behring, Daiichi-Sankyo, Eli Lilly, Esperion, Fenix Group International, Ferring Pharmaceuticals, GlaxoSmithKline, HLS Therapeutics, Janssen/Johnson & Johnson, Luitpold Pharmaceuticals, Matrizyme, Merck, Novartis, Novo Nordisk, Pendopharm, Regeneron, Sanofi, Servier, Tenax Therapeutics, and Valeo Pharma outside the submitted work and salary support and honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto, Canadian Heart Research Centre, MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Center for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Centre, PERFUSE Research Institute, and TIMI Study Group (Brigham Health). Dr Aronson reported being a salaried employee of Bristol Myers Squibb during the conduct of the study and owning stock in Bristol Myers Squibb outside the submitted work. Dr Kolls reported grants from Pfizer and Bristol Myers Squibb during the conduct of the study. Dr Vinereanu reported grants from Bristol Myers Squibb and Pfizer during the conduct of the study and grants and/or personal fees from Bayer, Boehringer Ingelheim, Pfizer, Novartis, and Daiichi Sankyo outside the submitted work. Dr Halvorsen reported personal fees from Bayer, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Sanofi, and Merck outside the submitted work. Dr Berwanger reported grants and consulting fees from AstraZeneca, Bayer, Pfizer, Servier, Amgen, Novartis, and Boehringer Ingelheim and consulting fees from Sanofi and Novo Nordisk outside the submitted work. Dr Windecker reported institutional research and educational grants from Abbott, Amgen, AstraZeneca, Bristol Myers Squibb, Bayer, Biotronik, Boston Scientific, Cardinal Health, Cardiovalve, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Guerbet, InfraRedx, Johnson & Johnson, Medicure, Medtronic, Novartis, Polares, OrPha Suisse, Pfizer, Regeneron, Sanofi-Aventis, Sinomed, Terumo, and V-Wave outside the submitted work; reported serving as unpaid advisory board member and/or unpaid member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Biotronik, Cardiovalve, Edwards Lifesciences, Janssen, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, V-Wave and Xeltis; and reported being a member of the steering/executive committee group of several investigator-initiated trials that receive funding by industry without impact on his personal remuneration. Dr Mehran reported grants from Abbott, Abiomed, Alleviant, AM Pharma, Applied Therapeutics, Arena, AstraZeneca, Bayer, Beth Israel Deaconess, Biosensors, Biotronik, Boston Scientific, Bristol Myers Squibb/Sanofi, CardiaWave, CellAegis, CeloNova, CERC, Chiesi, Concept Medical, CSL Behring, DSI, Duke University, Eli Lilly/Daiichi Sankyo, Humacyte, Insel Gruppe, Janssen, Medtronic, Novartis, OrbusNeich, Philips, Vivasure, and Zoll; and personal and other fees from Abbott Vascular, Boston Scientific, CIRM, Cine-Med Research, Janssen, WebMD, Idorsia Pharmaceuticals, Medscape, Medtronic, Novartis, Philips, Siemens Medical Solutions, Roivant Sciences, Sanofi, Spectranetics/Philips/Volcano Corporation, Bristol Myers Squibb, Novartis, Watermark Research, American Medical Association Scientific Advisory Board, SCAI Women in Innovations, and Biosensors Scientific Advisory Board (spouse); equity of less than 1% from Applied Therapeutics, Claret Medical, Elixir Medical, STEL, ControlRad (spouse); and being an executive committee member for Janssen Pharmaceuticals and Bristol Myers Squibb outside the submitted work. Dr Granger reported research grants from Akros, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Janssen, Pfizer, Armetheon, US Food and Drug Administration, GlaxoSmithKline, The Medicines Company, Medtronic Foundation, Medtronic, and Novartis and consulting fees from Abiomed, Alnylam Pharma, Anthos, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardionomic, Celecor Therapeutics, Correvio, Daiichi Sankyo, Espero, Janssen, Pfizer, Philips, AbbVie, Armetheon, AstraZeneca, Eli Lilly, Gilead, GlaxoSmithKline, HengRui, Hoffmann-La Roche, The Medicines Company, National Institutes of Health, Novartis, Sirtex, Reata, Verseon, Apple, Medscape, Medtronic, Merck, Novo Nordisk, Roche Diagnostics, Rho Pharmaceuticals, and Tenac.io. Dr Alexander reported grants from Bristol Myers Squibb during the conduct of the study and grants and/or personal fees from AbbVie, Akros, AtriCure, Bayer, Bristol Myers Squibb, CryoLife, CSL Behring, Ferring, Humacyte, Janssen, Pfizer, and Portola outside the submitted work. Dr Lopes reported grants from Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi and personal consulting fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Pfizer, Portolz, and Sanofi outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Kaplan-Meier Curves for Outcomes by Presence of Prior Stroke, Transient Ischemic Attack (TIA), or Thromboembolism (TE)
ISTH indicates International Society on Thrombosis and Haemostasis.
Figure 2.
Figure 2.. Treatment Effect of Apixaban vs Vitamin K Antagonist (VKA) on Outcomes by Presence of Prior Stroke, Transient Ischemic Attack (TIA), or Thromboembolism (TE)
CRNM indicates clinically relevant nonmajor; HR, hazard ratio; ISTH, International Society on Thrombosis and Haemostasis.
Figure 3.
Figure 3.. Treatment Effect of Aspirin vs Placebo on Outcomes by Presence of Prior Stroke, Transient Ischemic Attack (TIA), or Thromboembolism (TE)
CRNM indicates clinically relevant nonmajor; HR, hazard ratio; ISTH, International Society on Thrombosis and Haemostasis.
See this image and copyright information in PMC

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