Skip to main content
SpringerLink
Log in

Benefits and Risks Associated with Low-Dose Aspirin Use for the Primary Prevention of Cardiovascular Disease: A Systematic Review and Meta-Analysis of Randomized Control Trials and Trial Sequential Analysis

  • Systematic Review
  • Published:
American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

Abstract

Background

The role of aspirin in cardiovascular primary prevention remains controversial. Moreover, evidence for the potential benefits of aspirin in patients with high cardiovascular risk remains limited.

Objective

The aim of this study was to explore the role of low-dose aspirin in primary prevention.

Methods

The PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov databases were searched for randomized clinical trials (RCTs) from the date of inception to August 2021. The efficacy outcomes were major adverse cardiovascular events (MACE), myocardial infarction (MI), ischemic stroke (IS), all-cause mortality, and cardiovascular mortality, whereas safety outcomes were major bleeding, intracranial hemorrhage, and gastrointestinal (GI) bleeding. Subgroup analyses were based on different cardiovascular risks and diabetes statuses. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using the fixed- and random-effects models, and trial sequential analysis (TSA) was conducted to determine the robustness of the results.

Results

A total of 10 RCTs fulfilled the inclusion criteria. The use of aspirin was associated with a significant reduction in the risk of MACE (RR 0.89, 95% CI 0.84–0.93), MI (RR 0.86, 95% CI 0.78–0.95), and IS (RR 0.84, 95% CI 0.76–0.93); however, aspirin also increased the risk of safety outcomes, i.e. major bleeding (RR 1.42, 95% CI 1.26–1.60), intracranial hemorrhage (RR 1.33, 95% CI 1.11–1.59), and GI bleeding (RR 1.91, 95% CI 1.44–2.54). Subgroup analyses revealed that in the absence of a statistically significant interaction, a trend toward a net benefit of lower incidence of cardiovascular events (number needed to treat of MACE: high risk: 682 vs. low risk: 2191) and lesser risk of bleeding events (number needed to harm of major bleeding: high risk: 983 vs. low risk: 819) was seen in the subgroup of high cardiovascular risk. Meanwhile, the greater MACE reduction was also detected in the high-risk group of diabetes or nondiabetes patients. Furthermore, a post hoc subgroup analysis indicated a significant rate reduction in patients aged ≤ 70 years but not in patients aged > 70 years. TSA confirmed the benefit of aspirin for MACE up to a relative risk reduction of 10%.

Conclusion

The current study demonstrated that the cardiovascular benefits of low-dose aspirin were equally balanced by major bleeding events. In addition, the potential beneficial effects might be seen in the population ≤ 70 years of age with high cardiovascular risk and no increased risk of bleeding.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Dagenais GR, Leong DP, Rangarajan S, et al. Variations in common diseases, hospital admissions, and deaths in middle-aged adults in 21 countries from five continents (PURE): a prospective cohort study. Lancet. 2020;395:785–94.

    Article  PubMed  Google Scholar 

  2. Zhao D, Liu J, Wang M, et al. Epidemiology of cardiovascular disease in China: current features and implications. Nat Rev Cardiol. 2019;16:203–12.

    Article  PubMed  Google Scholar 

  3. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Circulation. 2019;140:e596–646.

    PubMed  PubMed Central  Google Scholar 

  4. Jones WS, Mulder H, Wruck LM, et al. Comparative effectiveness of aspirin dosing in cardiovascular disease. N Engl J Med. 2021;384:1981–90.

    Article  CAS  PubMed  Google Scholar 

  5. 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. 2002;324:71–86.

    Article  Google Scholar 

  6. Gaziano JM, Brotons C, Coppolecchia R, 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. 2018;392:1036–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bowman L, Mafham M, Wallendszus K, et al. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med. 2018;379:1529–39.

    Article  CAS  PubMed  Google Scholar 

  8. Mcneil JJ, Nelson MR, Woods RL, et al. Effect of Aspirin on All-Cause Mortality in the Healthy Elderly. N Engl J Med. 2018;379:1519–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mcneil JJ, Wolfe R, Woods RL, et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med. 2018;379:1509–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zheng SL, Roddick AJ. Association of aspirin use for primary prevention with cardiovascular events and bleeding events a systematic review and meta-analysis. JAMA. 2019;321:277–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Xie W, Luo Y, Liang X, et al. The efficacy and safety of aspirin as the primary prevention of cardiovascular disease: an updated meta-analysis. Ther Clin Risk Manag. 2019;15:1129–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shah R, Khan B, Latham SB, et al. A meta-analysis of aspirin for the primary prevention of cardiovascular diseases in the context of contemporary preventive strategies. Am J Med. 2019;132:1295-1304.e3.

    Article  CAS  PubMed  Google Scholar 

  13. Lin M-H, Lee C-H, Lin C, et al. Low-dose aspirin for the primary prevention of cardiovascular disease in diabetic individuals: a meta-analysis of randomized control trials and trial sequential analysis. J Clin Med. 2019;8:609.

    Article  CAS  PubMed Central  Google Scholar 

  14. Gelbenegger G, Postula M, Pecen L, et al. Aspirin for primary prevention of cardiovascular disease: a meta-analysis with a particular focus on subgroups. BMC Med. 2019;17:198.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Nudy M, Cooper J, Ghahramani M, et al. Aspirin for primary atherosclerotic cardiovascular disease prevention as baseline risk increases a meta-regression analysis. Am J Med. 2020;133:1056–64.

    Article  CAS  PubMed  Google Scholar 

  16. Belch J, Maccuish A, Campbell I, 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. 2008;337: a1840.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Fowkes FG, Price JF, Stewart MC, et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. JAMA. 2010;303:841–8.

    Article  CAS  PubMed  Google Scholar 

  18. Masson W, Barbagelata L, Lavalle-Cobo A, et al. Low-doses aspirin in the primary prevention of cardiovascular disease in patients with diabetes: meta-analysis stratified by baseline cardiovascular risk. Diabetes Metab Syndr. 2022;16: 102391.

    Article  PubMed  Google Scholar 

  19. Masson G, Lobo M, Masson W, et al. Aspirin in primary prevention. Meta-analysis stratified by baseline cardiovascular risk. Arch Cardiol Mex. 2020;90:293–9.

    PubMed  Google Scholar 

  20. Zhao B, Wu Q, Wang L, et al. Pros and cons of aspirin for the primary prevention of cardiovascular events: a secondary study of trial sequential analysis. Front Pharmacol. 2020;11: 592116.

    Article  CAS  PubMed  Google Scholar 

  21. Yusuf S, Joseph P, Dans A, et al. Polypill with or without aspirin in persons without cardiovascular disease. N Engl J Med. 2021;384:216–28.

    Article  CAS  PubMed  Google Scholar 

  22. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339: b2700.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Guirguis-Blake JM, Evans CV, Senger CA, et al. Aspirin for the primary prevention of cardiovascular events: a systematic evidence review for the us preventive services task force. Ann Intern Med. 2016;164:804–13.

    Article  PubMed  Google Scholar 

  25. Mahmoud AN, Gad MM, Elgendy AY, et al. Efficacy and safety of aspirin for primary prevention of cardiovascular events: a meta-analysis and trial sequential analysis of randomized controlled trials. Eur Heart J. 2019;40:607–17.

    Article  CAS  PubMed  Google Scholar 

  26. Piepoli MF, Hoes AW, Agewall S, 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. 2016;37:2315–81.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021;42:3227–337.

    Article  PubMed  Google Scholar 

  28. Kulinskaya E, Wood J. Trial sequential methods for meta-analysis. Res Synth Methods. 2014;5:212–20.

    Article  PubMed  Google Scholar 

  29. Brok J, Thorlund K, Gluud C, et al. Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses. J Clin Epidemiol. 2008;61:763–9.

    Article  PubMed  Google Scholar 

  30. Wetterslev J, Jakobsen JC, Gluud C. Trial sequential analysis in systematic reviews with meta-analysis. BMC Med Res Methodol. 2017;17:39.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Wetterslev J, Thorlund K, Brok J, et al. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol. 2008;61:64–75.

    Article  PubMed  Google Scholar 

  32. Kang H. Trial sequential analysis: novel approach for meta-analysis. Anesth Pain Med. 2021;16:138–50.

    Article  Google Scholar 

  33. Saito Y, Okada S, Ogawa H, et al. Low-dose aspirin for primary prevention of cardiovascular events in patients with type 2 diabetes mellitus: 10-year follow-up of a randomized controlled trial. Circulation. 2017;135:659–70.

    Article  CAS  PubMed  Google Scholar 

  34. Ikeda Y, Shimada K, Teramoto T, 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. 2014;312:2510–20.

    Article  PubMed  Google Scholar 

  35. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005;352:1293–304.

    Article  CAS  PubMed  Google Scholar 

  36. Roncaglioni MC. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Lancet. 2001;357:89–95.

    Article  CAS  Google Scholar 

  37. Meade TW, Wilkes HC, Kelleher CC, et al. 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. 1998;351:233–41.

    Article  Google Scholar 

  38. Hansson L, Zanchetti A, Carruthers SG, 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. 1998;351:1755–62.

    Article  CAS  PubMed  Google Scholar 

  39. Chinese Society of Cardiology of Chinese Medical Association, et al. Chinese guideline on the primary prevention of cardiovascular diseases [in Chinese]. Zhonghua Xin Xue Guan Bing Za Zhi. 2020;48:1000–38.

    Google Scholar 

  40. Anonymous. Aspirin use to prevent cardiovascular disease: preventive medication. Available at: www.uspreventiveservicestaskforce.org/uspstf/draft-recommendation/aspirin-use-to-prevent-cardiovascular-disease-preventive-medication#fullrecommendationstart.;375

  41. Mahase E. US taskforce advises against low dose aspirin for primary prevention of cardiovascular disease. BMJ. 2021;375: n2521.

    Article  PubMed  Google Scholar 

  42. Draznin B, Aroda VR, Bakris G, et al. 10. Cardiovascular disease and risk management: standards of medical care in diabetes—2022. Diabetes Care. 2022;45:S144-s174.

    Article  Google Scholar 

  43. Chen Y, Yin C, Li Q, et al. Misuse of aspirin and associated factors for the primary prevention of cardiovascular disease. Front Cardiovasc Med. 2021;8: 720113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Christensen MB, Jimenez-Solem E, Ernst MT, et al. Low-dose aspirin for primary and secondary prevention of cardiovascular events in Denmark 1998–2018. Sci Rep. 2021;11:13603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hira RS, Gosch KL. Potential impact of the 2019 ACC/AHA guidelines on the primary prevention of cardiovascular disease recommendations on the inappropriate routine use of aspirin and aspirin use without a recommended indication for primary prevention of cardiovascular disease in cardiology practices: insights from the NCDR PINNACLE Registry. Circ Cardiovasc Qual Outcomes. 2022;15(3): e007979.

    Article  PubMed  Google Scholar 

  46. Kotseva K, De Backer G, De Bacquer D, et al. Primary prevention efforts are poorly developed in people at high cardiovascular risk: a report from the European Society of Cardiology EURObservational Research Programme EUROASPIRE V survey in 16 European countries. Eur J Prev Cardiol. 2021;28(4):370–9.

    Article  PubMed  Google Scholar 

  47. Maiello M, Cecere A, Zito A, et al. Low-dose aspirin for primary prevention of cardiovascular events in postmenopausal women with type-2 diabetes: the prescriptive approach in the real world. Int J Prev Med. 2021;12:140.

    PubMed  PubMed Central  Google Scholar 

  48. Bugiardini R, Pavasović S, Yoon J, et al. Aspirin for primary prevention of ST segment elevation myocardial infarction in persons with diabetes and multiple risk factors. EClinicalMedicine. 2020;27: 100548.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Joseph P, Roshandel G, Gao P, et al. Fixed-dose combination therapies with and without aspirin for primary prevention of cardiovascular disease: an individual participant data meta-analysis. Lancet. 2021;398:1133–46.

    Article  CAS  PubMed  Google Scholar 

  50. Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373:1849–60.

    Article  PubMed  Google Scholar 

  51. Burns RB, Pignone M, Michos ED. Would you recommend aspirin to this patient for primary prevention of atherosclerotic cardiovascular disease? Grand rounds discussion from Beth Israel Deaconess Medical Center. Ann Intern Med. 2021;174:1439–46.

    Article  PubMed  Google Scholar 

  52. Chou R, Dana T, Blazina I, et al. Statins for prevention of cardiovascular disease in adults: evidence report and systematic review for the US Preventive Services task force. JAMA. 2016;316:2008–24.

    Article  PubMed  Google Scholar 

  53. Oh YJ, Kim AJ, Ro H, et al. Low-dose aspirin was associated with an increased risk of cardiovascular events in patients with chronic kidney disease patients and low bodyweight: results from KNOW-CKD study. Sci Rep. 2021;11:6691.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ. 2000;321:1183–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Palmer RH. Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants. Clin Gastroenterol Hepatol. 2015;13:2023–4.

    Article  PubMed  Google Scholar 

  56. Siller-Matula JM, Delle-Karth G. Addition of omeprazole to dual antiplatelet therapy with clopidogrel plus aspirin lowers the risk of upper gastrointestinal bleeding. Evid Based Med. 2011;16:144–5.

    Article  PubMed  Google Scholar 

  57. Ingram CA, Giang G, Mccrory K, et al. Yosprala: coordinated delivery of a proton pump inhibitor and aspirin. J Pharm Technol. 2020;36:78–83.

    Article  PubMed  Google Scholar 

  58. Khodayar S, Bardania H, Shojaosadati SA, et al. Optimization and characterization of aspirin encapsulated nano-liposomes. Iran J Pharm Res. 2018;17:11–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Mollace R, Gliozzi M, Macrì R. Efficacy and safety of novel aspirin formulations: a randomized, double-blind, placebo-controlled study. Pharmaceutics. 2022;14:187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rothwell PM, Cook NR, Gaziano JM, et al. Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials. Lancet. 2018;392:387–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Christiansen M, Grove EL, Hvas A-M. Primary prevention of cardiovascular events with aspirin: toward more harm than benefit—a systematic review and meta-analysis. Semin Thromb Hemost. 2019;45:478–89.

    Article  CAS  PubMed  Google Scholar 

  62. Altman DG, Bland JM. Interaction revisited: the difference between two estimates. BMJ. 2003;326:219.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Harrington D, D’agostino RB Sr, Gatsonis C, et al. New guidelines for statistical reporting in the journal. N Engl J Med. 2019;381:285–6.

    Article  PubMed  Google Scholar 

  64. Bangalore S, Kumar S, Wetterslev J, et al. Angiotensin receptor blockers and risk of myocardial infarction: meta-analyses and trial sequential analyses of 147 020 patients from randomised trials. BMJ. 2011;342: d2234.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China

    Mingming Wang

  2. Department of Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, Liaoning, China

    Haijie Yu

  3. School of Medical Devices, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China

    Zuojing Li

  4. Department of Smart Hospital Administrative, The First Affiliated Hospital of China Medical University, Shenyang, 110001, Liaoning, China

    Daxin Gong

  5. School of Business Administration, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China

    Xiaoxi Liu

Authors
  1. Mingming Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haijie Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zuojing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daxin Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaoxi Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiaoxi Liu.

Ethics declarations

Ethics approval

As this was a systematic review of meta-analyses, no ethical approval was required.

Funding

The authors received no support from any organizations for the submitted work.

Conflict of interest

Mingming Wang, Haijie Yu, Zuojing Li, Daxin Gong, and Xiaoxi Liu have no financial or proprietary interests in any material discussed in this article.

Research involving human participants and/or animals

This article does not contain any studies with human participants or animals performed by any of the authors

Consent to participate

Not applicable (meta-analysis).

Consent for publication

Not applicable.

Code availability

Not applicable.

Data availability

The authors confirm that the data supporting the findings of this study are available in the article and its online supplementary material.

Author contributions

MW and HY were engaged in the design of the study, interpretation of the data, statistical analyses, and drafting of the manuscript. ZL and DG were responsible for data extraction, statistical analyses, interpretation of the data, and administrative and technical support. MW and XL were responsible for the conception and critical revision of the manuscript. All authors read and approved the final version of manuscript.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 3231 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, M., Yu, H., Li, Z. et al. Benefits and Risks Associated with Low-Dose Aspirin Use for the Primary Prevention of Cardiovascular Disease: A Systematic Review and Meta-Analysis of Randomized Control Trials and Trial Sequential Analysis. Am J Cardiovasc Drugs 22, 657–675 (2022). https://doi.org/10.1007/s40256-022-00537-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40256-022-00537-6

Search

Navigation