Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Role of aspirin in primary prevention of cardiovascular disease

Abstract

The benefits of aspirin therapy for the secondary prevention of cardiovascular disease clearly outweigh the risks of bleeding, and low-dose aspirin is uniformly recommended in this setting. However, no clear consensus exists about whether, and if so in whom, aspirin therapy is appropriate for the primary prevention of cardiovascular disease. Three trials of low-dose aspirin versus placebo in three populations at increased risk of myocardial infarction or ischaemic stroke in the absence of established cardiovascular disease were reported in 2018. The ASPREE trial in elderly people was terminated early for futility because aspirin had no effect on disability-free survival but significantly increased the risk of major haemorrhage and, unexpectedly, all-cause mortality. In the ASCEND trial in patients with diabetes mellitus and no evidence of vascular disease, aspirin significantly reduced serious vascular events but increased major bleeding. In the ARRIVE trial in people with multiple risk factors for cardiovascular disease, aspirin had no effect on major cardiovascular events but increased gastrointestinal bleeding. The aim of this Review is to place these new results in the context of previous evidence on aspirin for the primary prevention of cardiovascular disease and to appraise whether the new evidence is likely to enable the more targeted use of aspirin in particular individuals for whom the net benefit is both clinically worthwhile and statistically definite.

Key points

  • The benefits of aspirin therapy for the secondary prevention of cardiovascular disease (CVD) clearly outweigh the risks of bleeding, but whether to recommend low-dose aspirin for primary prevention of CVD is controversial.

  • Use of risk scores for vascular events and major extracranial bleeds to classify individual participant data from a meta-analysis shows that individuals at the highest risk of vascular events are also at the highest risk of bleeding.

  • In 2018, results from three trials of low-dose aspirin in three populations at increased risk of myocardial infarction or ischaemic stroke in the absence of established CVD added to the evidence base.

  • Overall, other than for myocardial infarction, the effects of aspirin on the other major efficacy and safety outcomes seem similar in all the primary prevention trials, including the three (ASPREE, ASCEND and ARRIVE) completed in 2018.

  • The main challenge when assessing the net benefit of aspirin is that benefits and risks are strongly correlated; therefore, identifying large numbers of people at high risk of vascular ischaemia but low risk of bleeding is difficult.

  • New approaches are required to overcome this challenge, perhaps combining coronary imaging to identify apparently healthy people at substantially increased risk of vascular events with gastroprotectant therapy to reduce the risk of bleeding.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Mechanism of action of aspirin.
Fig. 2: Molecular basis of the antiplatelet pharmacodynamics of aspirin.
Fig. 3: Effects of gastroprotectant drugs on the risk of gastrointestinal bleeding.
Fig. 4: Risk of major coronary events versus risk of bleeding.

References

  1. Patrono, C., García Rodríguez, L. A., Landolfi, R. & Baigent, C. Low-dose aspirin for the prevention of atherothrombosis. N. Engl. J. Med. 353, 2373–2383 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Patrono, C. Low-dose aspirin in primary prevention: cardioprotection, chemoprevention, both or neither? Eur. Heart J. 34, 2403–2411 (2013).

    Article  CAS  Google Scholar 

  3. Cleland, J. G. Is aspirin useful in primary prevention? Eur. Heart J. 34, 3412–3418 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Peto, R. et al. Randomised trial of prophylactic daily aspirin in British male doctors. BMJ 296, 313–316 (1988).

    Article  CAS  PubMed  Google Scholar 

  5. Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing Physicians’ Health Study. N. Engl. J. Med. 321, 129–135 (1989).

    Article  Google Scholar 

  6. Vandvik, P. O. et al. Primary and secondary prevention of cardiovascular disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141 (Suppl. 2), e637S–e668S (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rydén, L. et al. ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, prediabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur. Heart J. 34, 3035–3087 (2013).

    Article  PubMed  Google Scholar 

  8. American Diabetes Association. 10. Cardiovascular disease and risk management: Standards of medical care in diabetes. Diabetes Care 42 (Suppl. 1), S103–S123 (2019).

    Article  Google Scholar 

  9. Piepoli, M. F. et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention and Rehabilitation (EACPR). Eur. Heart J. 37, 2315–2381 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Bibbins-Domingo, K. & U.S. Preventive Services Task Force. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann. Intern. Med. 164, 836–845 (2016).

    Article  PubMed  Google Scholar 

  11. Arnett, D. K. et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease. J. Am. Coll. Cardiol. https://doi.org/10.1016/j.jacc.2019.03.010 (2019).

  12. McNeil, J. J. et al. Effect of aspirin on disability-free survival in the healthy elderly. N. Engl. J. Med. 379, 1499–1508 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. McNeil, J. J. et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N. Engl. J. Med. 379, 1509–1518 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. McNeil, J. J. et al. Effect of aspirin on all-cause mortality in the healthy elderly. N. Engl. J. Med. 379, 1519–1528 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. The ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. N. Engl. J. Med. 379, 1529–1539 (2018).

    Article  Google Scholar 

  16. Gaziano, J. M. et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. Lancet 392, 1036–1046 (2018).

    Article  CAS  PubMed  Google Scholar 

  17. Patrignani, P. & Patrono, C. Aspirin and cancer. J. Am. Coll. Cardiol. 68, 967–976 (2016).

    Article  CAS  PubMed  Google Scholar 

  18. Patrono, C. The multifaceted clinical read-outs of platelet inhibition by low-dose aspirin. J. Am. Coll. Cardiol. 66, 74–85 (2015).

    Article  CAS  PubMed  Google Scholar 

  19. Loll, P. J., Picot, D. & Garavito, R. M. The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase. Nat. Struct. Biol. 2, 637–643 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Patrignani, P. et al. Reappraisal of the clinical pharmacology of low-dose aspirin by comparing novel direct and traditional indirect biomarkers of drug action. J. Thromb. Haemost. 12, 1320–1330 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Patrignani, P., Filabozzi, P. & Patrono, C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J. Clin. Invest. 69, 1366–1372 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pedersen, A. K. & FitzGerald, G. A. Dose-related kinetics of aspirin: presystemic acetylation of platelet cyclooxygenase. N. Engl. J. Med. 311, 1206–1211 (1984).

    Article  CAS  PubMed  Google Scholar 

  23. Patrono, C., Baigent, C., Hirsh, J. & Roth, G. Antiplatelet drugs: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 133, 199S–233S (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Rocca, B. et al. Antithrombotic therapy and body mass: an expert position paper of the ESC Working Group on Thrombosis. Eur. Heart J. 39, 1672–1686f (2018).

    Article  CAS  PubMed  Google Scholar 

  25. Giaretta, A., Rocca, B., Di Camillo, B., Toffolo, G. M. & Patrono, C. In silico modeling of the antiplatelet pharmacodynamics of low-dose aspirin in health and disease. Clin. Pharmacol. Ther. 102, 823–831 (2017).

    Article  CAS  PubMed  Google Scholar 

  26. Pascale, S. et al. Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target. Blood 119, 3595–3603 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Rocca, B. et al. The recovery of platelet cyclooxygenase activity explains interindividual variability in responsiveness to low-dose aspirin in patients with and without diabetes. J. Thromb. Haemost. 10, 1220–1230 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. Tefferi, A., Vannucchi, A. M. & Barbui, T. Essential thrombocythemia treatment algorithm 2018. Blood Cancer J. 8, 2 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Murata, T. et al. Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature 388, 678–682 (1997).

    Article  CAS  PubMed  Google Scholar 

  30. Coxib and traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 382, 769–779 (2013).

    Article  CAS  Google Scholar 

  31. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02697916 (2019).

  32. Ridker, P. M. et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N. Engl. J. Med. 352, 1293–1304 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Hansson, L. et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 351, 1755–1762 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Kassoff, A. et al. Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early treatment diabetic retinopathy study report 14. JAMA 268, 1292–1300 (1992).

    Article  Google Scholar 

  35. Belch, J. et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 337, a1840 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ogawa, H. et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA 300, 2134–2141 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Fowkes, F. G. et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. JAMA 303, 841–848 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. de Gaetano, G. et al. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Lancet 357, 89–95 (2001).

    Article  PubMed  Google Scholar 

  39. The Medical Research Council’s General Practice Research Framework. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 351, 233–241 (1998).

    Article  Google Scholar 

  40. Ikeda, Y. et al. Low-dose aspirin for primary prevention of cardiovascular events in Japanese patients 60 years or older with atherosclerotic risk factors: a randomized clinical trial. JAMA 312, 2510–2520 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. Antithrombotic Trialists’ (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 373, 1849–1860 (2009).

    Article  CAS  Google Scholar 

  42. Guirguis-Blake, J. M., Evans, C. V., Senger, C. A., O’Connor, E. A. & Whitlock, E. P. Aspirin for the primary prevention of cardiovascular events: a systematic evidence review for the U.S. Preventive Services Task Force. Ann. Intern. Med. 164, 804–813 (2016).

    Article  PubMed  Google Scholar 

  43. Whitlock, E. P., Burda, B. U., Williams, S. B., Guirguis-Blake, J. M. & Evans, C. V. Bleeding risks with aspirin use for primary prevention in adults: a systematic review for the U.S. Preventive Services Task Force. Ann. Intern. Med. 164, 826–835 (2016).

    Article  PubMed  Google Scholar 

  44. Baigent, C. Aspirin for disease prevention: public policy or personal choice? Ann. Intern. Med. 164, 846–847 (2016).

    Article  PubMed  Google Scholar 

  45. Davì, G. et al. Thromboxane biosynthesis and platelet function in type-II diabetes mellitus. N. Engl. J. Med. 322, 1769–1774 (1990).

    Article  PubMed  Google Scholar 

  46. Zheng, S. L. & Roddick, A. J. Association of aspirin use for primary prevention with cardiovascular events and bleeding events. A systematic review and meta-analysis. JAMA 321, 277–287 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. García Rodríguez, L. A., Hernández-Díaz, S. & de Abajo, F. J. Association between aspirin and upper gastrointestinal complications: systematic review of epidemiologic studies. Br. J. Clin. Pharmacol. 52, 563–571 (2001).

    Article  PubMed  Google Scholar 

  48. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high-risk patients. BMJ 324, 71–86 (2002).

    Article  Google Scholar 

  49. Lanas, A. & Chan, F. K. L. Peptic ulcer disease. Lancet 390, 613–624 (2017).

    Article  PubMed  Google Scholar 

  50. Moayyedi, P. et al. Pantoprazole to prevents gastroduodenal events in patients receiving rivaroxaban and/or aspirin in a randomized, double-blind, placebocontrolled trial.Gastroenterology https://doi.org/10.1053/j.gastro.2019.04.041 (2019).

    Article  PubMed  Google Scholar 

  51. Scally, B. et al. Effects of gastroprotectant drugs for the prevention and treatment of peptic ulcer disease and its complications: a meta-analysis of randomised trials. Lancet Gastroenterol. Hepatol. 3, 231–241 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Focks, J. J. et al. Concomitant use of clopidogrel and proton pump inhibitors: impact on platelet function and clinical outcome- a systematic review. Heart 99, 520–527 (2013).

    Article  PubMed  Google Scholar 

  53. Yu, E. W., Bauer, S. R., Bain, P. A. & Bauer, D. C. Proton pump inhibitors and risk of fractures: a meta analysis of 11 international studies. Am. J. Med. 124, 519–526 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Janarthanan, S., Ditah, I., Adler, D. G. & Ehrinpreis, M. N. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. Am. J. Gastroenterol. 107, 1001–1010 (2012).

    Article  CAS  PubMed  Google Scholar 

  55. Greenland, P., Blaha, M. J., Budoff, M. J., Erbel, R. & Watson, K. E. Coronary calcium score and cardiovascular risk. J. Am. Coll. Cardiol. 72, 434–447 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dehmer, S. P., Maciosek, M. V., Flottemesch, T. J., LaFrance, A. B. & Whitlock, E. P. Aspirin for the primary prevention of cardiovascular disease and colorectal cancer: a decision analysis for the US Preventive Services Task Force. Ann. Intern. Med. 164, 777–786 (2016).

    Article  PubMed  Google Scholar 

  57. Dorresteijn, J. A. N. et al. Aspirin for primary prevention of vascular events in women: individualized prediction of treatment effects. Eur. Heart J. 32, 2962–2969 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. van Kruijsdijk, R. C. M. et al. Individualized prediction of alternate-day aspirin treatment on the combined risk of cancer, cardiovascular disease and gastro-intestinal bleeding in healthy women. Heart 101, 369–376 (2015).

    Article  CAS  PubMed  Google Scholar 

  59. Bonaca, M. P. et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N. Engl. J. Med. 372, 1791–1800 (2015).

    Article  PubMed  Google Scholar 

  60. Eikelboom, J. W. et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N. Engl. J. Med. 377, 1319–1330 (2017).

    Article  CAS  PubMed  Google Scholar 

  61. Lin, J. S. et al. Nontraditional risk factors in cardiovascular disease risk assessment: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA 320, 281–297 (2018).

    Article  PubMed  Google Scholar 

  62. Gachet, C. Antiplatelet drugs: which targets for which treatments? J. Thromb. Haemost. 13 (Suppl. 1), S313–S322 (2015).

    Article  CAS  PubMed  Google Scholar 

  63. De Stefano, V. et al. The Aspirin Regimens in Essential Thrombocythemia (ARES) phase II randomized trial design: implementation of the serum thromboxane B2 assay as an evaluation tool of different dosing regimens in the clinical setting. Blood. Cancer J. 8, 49 (2018).

    Google Scholar 

  64. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02520921 (2009).

  65. Rocca, B. & Patrono, C. Determinants of the interindividual variability in response to antiplatelet drugs. J. Thromb. Haemost. 8, 1597–1602 (2005).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

Both authors researched data for the article, discussed its content, wrote the manuscript and reviewed and edited it before submission.

Corresponding author

Correspondence to Carlo Patrono.

Ethics declarations

Competing interests

C.P. reports consulting and lecture fees from Acticor Biotech, Amgen, Bayer, GlaxoSmithKline and Zambon and institutional research grants from Bayer, Cancer Research UK (Catalyst Award — Aspirin for Cancer Prevention Collaboration), the European Commission and the Italian Drug Agency (AIFA); he serves as chairperson of the Scientific Advisory Board of the International Aspirin Foundation. C.B. reports grants from Boehringer Ingelheim, the British Heart Foundation, the Medical Research Council and the UK National Institute for Health Research.

Additional information

Peer review information

Nature Reviews Cardiology thanks P. Gurbel, and the other anonymous reviewer(s), for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

ADAPTABLE trial: https://theaspirinstudy.org

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Patrono, C., Baigent, C. Role of aspirin in primary prevention of cardiovascular disease. Nat Rev Cardiol 16, 675–686 (2019). https://doi.org/10.1038/s41569-019-0225-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41569-019-0225-y

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing