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Aspirin-free strategies in cardiovascular disease and cardioembolic stroke prevention

Abstract

In patients with manifestations of cardiovascular disease, acetylsalicylic acid (popularly known as aspirin) has been the mainstay of treatment for decades owing to its capacity to reduce the risk of ischaemic events. Accordingly, novel antithrombotic therapies have been traditionally tested on a background of acetylsalicylic acid therapy. Although the adjunctive use of such antithrombotic therapies can potentially further reduce the risk of ischaemic events, these agents are also inevitably associated with an increased risk of bleeding. However, acetylsalicylic acid also increases the risk of bleeding, challenging the paradigm that this agent should remain the cornerstone of antiplatelet treatment when alternative antithrombotic agents are also used. Many antithrombotic compounds are characterized by increased potency and consistent efficacy, which might lessen the need for concomitant acetylsalicylic acid. Accordingly, numerous investigations are testing the hypothesis that acetylsalicylic acid-sparing regimens based on newer antithrombotic agents might have an increased net benefit for individual patients owing to the reduction in bleeding risk, without a trade-off in efficacy. This Review summarizes the state of the art relating to antithrombotic approaches with and without acetylsalicylic acid for the prevention of cardiovascular disease and cardioembolic stroke. Discussion of the scientific rationale, from bench to bedside, for ongoing studies of acetylsalicylic acid-free pharmacological strategies is included.

Key points

  • Most new antithrombotic treatment strategies aimed at further outcome improvement have been developed with acetylsalicylic acid as background therapy.

  • Given that acetylsalicylic acid increases bleeding risk, a number of studies are exploring the possibility of avoiding this drug in the presence of other antithrombotic agents.

  • Pharmacodynamic investigations indicate that no other antithrombotic agent can replace the cyclooxygenase 1-selective, platelet-inhibitory effects of acetylsalicylic acid; however, many newer antithrombotic therapies might have greater antithrombotic efficacy.

  • Given the established role of acetylsalicylic acid in cardiovascular disease management and prevention, favourable results from large-scale clinical trials are warranted before acetylsalicylic acid-free strategies are recommended for routine clinical practice.

  • Acetylsalicylic acid is cost effective and has favourable noncardiac effects, which are under ongoing investigation and need to be taken into account when considering acetylsalicylic acid-free approaches.

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Fig. 1: Uncertainties surrounding the use of acetylsalicylic acid for secondary prevention.
Fig. 2: Trials of antithrombotic approaches in cardiovascular diseases.
Fig. 3: Platelet activation mechanisms.
Fig. 4: In the presence of strong P2Y12 receptor blockade, acetylsalicylic acid provides little additional inhibition of platelet aggregation.

Adapted with permission from ref.81, John Wiley and Sons.

Fig. 5: Synergy of oral anticoagulant and antiplatelet therapy.
Fig. 6: ADD-ASPIRIN trial schema.

Adapted from ref.131, CC-BY-4.0.

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Acknowledgements

D.J.A. is the recipient of funding from the Scott R. MacKenzie Foundation and the US National Institutes of Health (NIH) National Center for Advancing Translational Sciences Clinical and Translational Science Award to the University of Florida UL1 TR000064 and NIH National Human Genome Research Institute U01 HG007269.

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Nature Reviews Cardiology thanks G. Lip, L. Wallentin, and U. Zeymer for their contribution to the peer review of this work.

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D.J.A. and D.C. researched data for the article and wrote the manuscript. All authors contributed substantially to discussions of the article content and undertook reviewing and/or editing of the manuscript before submission.

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Correspondence to Dominick J. Angiolillo.

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D.J.A. declares that he has received consulting fees or honoraria from Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Janssen, Merck, PLx Pharma, Pfizer, Sanofi, and The Medicines Company and has received payments for participation in review activities from CeloNova and St Jude Medical. D.J.A. also declares that his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, and Renal Guard Solutions. D.L.B. declares that he has received research funding from Abbott, Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi Aventis, and The Medicines Company. He also declares that he is an advisory board member for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences and was on the Board of Directors of the Boston VA Research Institute and the Society of Cardiovascular Patient Care; he was Chair of the American Heart Association Quality Oversight Committee and is on the Data Monitoring Committees of the Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, and Population Health Research Institute; he was a Trustee of the American College of Cardiology (ACC), from whom he receives honoraria for his roles as Senior Associate Editor (Clinical Trials and News) at ACC.org and Vice Chair of the ACC Accreditation Committee. He is a member of the clinical trial steering committees of Duke Clinical Research Institute Population Health Research Institute and Harvard Clinical Research Institute. He was Secretary and Treasurer of the Society of Cardiovascular Patient Care, a member of the Continuing Medical Education steering committee for WebMD, and Chair of the National Cardiovascular Data Registry ACTION Registry Steering Committee and of the VA Clinical Assessment, Reporting, and Tracking Research and Publications Committee. He also acts as site co-investigator for Biotronik, Boston Scientific, and St Jude Medical (now Abbott) and conducts unfunded research for FlowCo, Merck, PLx Pharma, and Takeda. Finally, he is Editor in Chief of the Harvard Heart Letter and the Journal of Invasive Cardiology, a guest editor and associate editor of the Journal of the American College of Cardiology, Chief Medical Editor of Cardiology Today’s Intervention, and Deputy Editor of Clinical Cardiology; he receives royalties from Elsevier for his role as Editor of Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease. D.C. declares that he has received speaker’s fees or consulting honoraria from AstraZeneca, Bayer, and Sanofi. J.-P.C. declares that he has received research grants from Bristol-Myers Squibb, Boston Scientific, Federation Française de Cardiologie, Medtronic, and Société Française de Cardiologie; consulting fees from Bristol-Myers Squibb and Sanofi Aventis; and lecture fees from AstraZeneca, Bayer Health Care, Bristol-Myers Squibb, and Daiichi-Sankyo. G.D. declares that he has received honoraria from Bayer. C.M.G. declares that he has received honoraria from Bayer, Janssen Pharmaceuticals, Johnson and Johnson, and Portola Pharmaceuticals. H.-C.G. declares that he has received consulting fees from Medtronic and research grants from Abbott Vascular, Biotronik, Boston Scientific, and Medtronic. T.K. declares that he has received honoraria from Sanofi and research grants from Abbott Vascular. R.D.L. declares that he has received research support from Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, and Pfizer and consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, and Portola. R.M. declares that she has received consulting fees from Abbott Vascular, Abiomed, Boston Scientific, Bristol-Myers Squibb, Cardiovascular Systems, Elixir, Medscape, Shanghai Bracco Sine Pharmaceutical, and The Medicines Company and executive committee fees from Janssen Pharmaceuticals and Osprey Medical. She also declares that her institution receives funding from AstraZeneca, Bayer, Beth Israel Deaconess, Bristol-Myers Squibb, CardioKinetix, Claret Medical, CSL Behring, Eli Lilly/DSI, Medtronic, Novartis Pharmaceuticals, OrbusNeich, Spectranetics, and Watermark Research Partners. P.W.S. declares that he has received consulting fees and honoraria from Abbott Vascular, Biosensors, Medtronic, Micell Technologies, QualiMed, Sinomed, St Jude Medical, Stentys, Svelte, Philips/Volcano, and Xeltis. P.G.S. declares that he has received research grants from Bayer, Merck, Sanofi, and Servier and has received speaker’s fees or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, Merck, Novartis, Pfizer, Regeneron, Sanofi, and Servier. R.F.S. declares that he has received consultancy fees from Actelion, Avacta, AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, Idorsia, Novartis, PlaqueTec, and The Medicines Company; research grants from AstraZeneca and PlaqueTec; and honoraria from AstraZeneca and Bayer. M.V. declares that he has received research grants from AstraZeneca and Terumo and has received honoraria from Abbott Vascular, Amgen, AstraZeneca, Bayer, Biosensors, Cardinal Health, Daiichi-Sankyo, and Terumo. P.V. declares that he has received speaker’s fees or consulting fees from AstraZeneca, Bayer Health Care, and Daiichi-Sankyo. S.W. declares that he has received institutional research funding from Abbott, Amgen, Boston Scientific, Biotronik, and St Jude Medical. U.B., F.F., and F.R. declare no competing interests.

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Capodanno, D., Mehran, R., Valgimigli, M. et al. Aspirin-free strategies in cardiovascular disease and cardioembolic stroke prevention. Nat Rev Cardiol 15, 480–496 (2018). https://doi.org/10.1038/s41569-018-0049-1

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