Antithrombotic Strategies According to Age: Insights from the AUGUSTUS Trial - 26/07/24

Doi : 10.1016/j.amjmed.2024.06.001

Patricia O. Guimarães, MD, PhD ^a,^b, Renato D. Lopes, MD, PhD ^a,^⁎ , Daniel M. Wojdyla, MS ^a, John H. Alexander, MD, MHS ^a, Shaun G. Goodman, MD ^c,^d, Ronald Aronson, MD ^e, Sigrun Halvorsen, MD, PhD ^f, Peter Sinnaeve, MD, PhD ^g,^h, Dragos Vinereanu, MD, PhD ^i,^j, Robert F. Storey, MD ^k,^l, Otavio Berwanger, MD, PhD ^b,^m,ⁿ, Stephan Windecker, MD ^o, Roxana Mehran, MD ^p, Christopher B. Granger, MD ^a, Karen P. Alexander, MD ^a
for the
AUGUSTUS Investigators
^a Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC
^b Hospital Israelita Albert Einstein, São Paulo-SP, Brazil
^c St. Michael's Hospital, Unity Health Toronto, University of Toronto, Toronto, Ontario, Canada
^d Canadian VIGOUR Centre, University of Alberta, Edmonton, Canada
^e Bristol Myers Squibb, Lawrenceville, NJ
^f University of Oslo, Oslo, Norway
^g Department of Cardiovascular Medicine, University Hospitals Leuven, Leuven, Belgium
^h University of Leuven, Leuven, Belgium
ⁱ University of Medicine and Pharmacy Carol Davila University, Bucharest, Romania
^j Emergency Hospital of Bucharest, Bucharest, Romania
^k Division of Clinical Medicine, University of Sheffield, Sheffield, UK
^l NIHR Sheffield Biomedical Research Centre, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK
^m George Institute for Global Health UK, London, UK
ⁿ Imperial College London, London, UK
^o Department of Cardiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
^p Icahn School of Medicine at Mount Sinai, NY

^⁎Requests for reprints should be addressed to Renato D. Lopes, MD, PhD, Duke Clinical Research Institute, P.O. Box 17969, Durham, NC 27715.Duke Clinical Research InstituteP.O. Box 17969DurhamNC27715

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Abstract

Objective

We aimed to evaluate the safety and efficacy of antithrombotic strategies by age in patients with atrial fibrillation and acute coronary syndrome and/or percutaneous coronary intervention in AUGUSTUS.

Methods

Patients were stratified into 3 age groups: <65, 65-74, and ≥75 years. Outcomes of interest were major or clinically relevant non-major bleeding, major bleeding, death or rehospitalization, and ischemic events. Treatment effects of apixaban vs. vitamin K antagonist (VKA) and aspirin vs. placebo were assessed across age groups using Cox models.

Results

Of 4614 patients, 1267 (27.5%) were <65, 1802 (39.0%) were 65-74, and 1545 (33.5%) were ≥75 years. Apixaban was associated with lower rates of major or clinically relevant non-major bleeding than VKA (<65: HR 0.69 [0.47-1.00]; 65-74: HR 0.57 [0.43-0.75]; ≥75: HR 0.81 [0.63-1.04]). Death or hospitalization occurred less often with apixaban, regardless of age. No differences were observed in rates of ischemic events between apixaban and VKA according to age. Aspirin was associated with higher rates of bleeding than placebo (<65: HR 1.67 [1.15-2.43]; 65-74: HR 2.32 [1.73-3.10]; ≥75: HR 1.69 [1.31-2.19]). Rates of death or rehospitalization and ischemic events were similar among patients receiving aspirin or placebo across age groups.

Conclusions

Apixaban was associated with greater absolute reduction in bleeding than VKA in older age groups, reflecting their higher hemorrhagic risk. Aspirin increased bleeding in all age groups vs. placebo. Our findings support the use of apixaban plus a purinergic receptor P2Y₁₂ (P2Y₁₂) inhibitor without aspirin in patients with atrial fibrillation and recent acute coronary syndrome/percutaneous coronary intervention, regardless of age.

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Keywords : Acute coronary syndrome, Age, Antithrombotic strategies, Apixaban, Aspirin, Atrial fibrillation, Percutaneous coronary intervention, Vitamin K antagonist

Plan

Methods

Patients and Study Design

Study Outcomes

Statistical Analysis

Results

Patient Characteristics

Efficacy and Safety of Apixaban vs. VKA According to Age

Efficacy and Safety of Aspirin vs. Placebo According to Age

Discussion

Conclusions

	Trial registration: ClinicalTrials.gov (NCT02415400).
	Funding: The AUGUSTUS trial was sponsored by Bristol Myers Squibb and Pfizer. Although Bristol Myers Squibb assisted with data management, all statistical analyses were performed independently at the Duke Clinical Research Institute (Durham, NC). The initial draft of the manuscript was written by the first author and revised on the basis of comments from the other authors.
	Conflict of Interest: Guimarães: None. Lopes: Research grants or contracts from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, Sanofi-Aventis; funding for educational activities or lectures from Pfizer, Daiichi Sankyo, and Novo Nordisk; and funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Novo Nordisk. Wojdyla: None. J.H. Alexander: Research grants from Bristol Myers Squibb, Boehringer Ingelheim, AstraZeneca, CryoLife, CSL Behring, US Food and Drug Administration, National Institutes of Health, Sanofi, VoluMetrix; consulting fees from Pfizer, Bristol Myers Squibb, AbbVie Pharmaceuticals, CSL Behring, Novo Nordisk, Portola Pharmaceuticals, Quantum Genomics, Teikoku Pharmaceuticals, VA Cooperative Studies, Zafgen. Goodman: Research grant support and/or speaker/consulting honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, 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 A/C, Pfizer, Regeneron, Sanofi, Servier, Tenax Therapeutics, Heart and Stroke Foundation of Ontario/University of Toronto, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Duke Clinical Research Institute, PERFUSE. Aronson: Employee of Bristol Myers Squibb. Halvorsen: Speaker´s honoraria from Sanofi, Pfizer/BMS, Novartis, Novo Nordisk Norway AS. Sinnaeve: Institutional speaker's and consultancy fees from Pfizer, BMS, Boehringer, Daiichi Sankyo. Vinereanu: Research support from Pfizer/Bristol Myers Squibb. Storey: Institutional research grants/support from AstraZeneca and Cytosorbents; and personal fees from Alfasigma, AstraZeneca, Chiesi, Cytosorbents, Daiichi Sankyo, Idorsia, Novartis, Novo Nordisk, Pfizer, PhaseBio and Tabuk. Berwanger: Research grants from AstraZeneca, Pfizer, Bayer, Amgen, Novartis, Servier, and Boehringer-Ingelheim. Windecker: Institutional research and educational grants from Abbott, Amgen, Bayer, BMS, CSL Behring, Boston Scientific, Biotronik, Edwards Lifesciences, Medtronic, Polares, Sinomed. Mehran: Institutional research grants from AstraZeneca, Bayer, Beth Israel Deaconess, Bristol Myers Squibb/Sanofi, CSL Behring, Eli Lilly/Daiichi Sankyo, Medtronic, Novartis, and OrbusNeich; consulting fees from Boston Scientific, Abbott Vascular, Medscape, Siemens Medical Solutions, Roivant Sciences Inc, and Sanofi; consulting (no fees) for Regeneron Pharmaceuticals Inc; institutional consulting fees from Abbott Vascular, Spectranetics/Phillips/Volcano Corporation, Bristol Myers Squibb, Novartis, and Watermark Research; Executive committee member for Janssen Pharmaceuticals and Bristol Myers Squibb; <1% equity in Claret Medical and Elixir Medical. Granger: Research grants from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Janssen, Pfizer, Armetheon, AstraZeneca, US Food and Drug Administration, GlaxoSmithKline, The Medicines Company, Medtronic Foundation, Medtronic Inc, Novartis; consulting fees from Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo, Janssen, Pfizer, Abbvie, Armetheon, AstraZeneca, Eli Lilly, Gilead, GlaxoSmithKline, Hoffmann-La Roche, The Medicines Company, National Institutes of Health, Novartis, Sirtex, Verseon, Apple, Medscape, LLC, Merck, Novo Nordisk, Roche Diagnostics, Rho Pharmaceuticals. K.P. Alexander: None.
	Authorship: POG: Conceptualization; methodology; visualization; writing—original draft & reviewing and editing. RDL: Conceptualization; investigation; funding acquisition; methodology; project administration; resources; supervision; visualization; writing—original draft & reviewing and editing. DMW: Conceptualization; data curation; formal analysis; methodology; software; validation; visualization; writing—original draft & reviewing and editing. JHA: Conceptualization; funding acquisition; investigation; methodology; visualization; writing—reviewing and editing. SGG: Investigation; writing—reviewing and editing. RA: Investigation; project administration; writing—reviewing and editing. SH: Investigation; writing—reviewing and editing. PS: Investigation; writing—reviewing and editing. DV: Investigation; writing—reviewing and editing. RFS: Investigation; writing—reviewing and editing. OB: Investigation; writing—reviewing and editing. SW: Investigation; writing—reviewing and editing. RM: Investigation; writing—reviewing and editing. CBG: Investigation; writing—original draft & reviewing and editing. KPA: Supervision; writing—reviewing and editing.