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Current Diabetes Reports

, 19:107 | Cite as

Aspirin for Primary Prevention of Cardiovascular Disease in Diabetes: a Review of the Evidence

  • Mohammed E. Al-Sofiani
  • Robert Derenbecker
  • Michael Quartuccio
  • Rita R. KalyaniEmail author
Macrovascular Complications in Diabetes (VR Aroda and A Getaneh, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Macrovascular Complications in Diabetes

Abstract

Purpose of Review

People with diabetes are at a higher risk of atherosclerotic cardiovascular disease (ASCVD) compared with those without diabetes. Though aspirin has been shown to have an overall net clinical benefit when used for secondary prevention of ASCVD in people with and without diabetes, the evidence for primary prevention, especially in those with diabetes, remains inconsistent. In this article, we review the latest studies examining the risks and benefits of aspirin use for primary prevention of ASCVD in adults with diabetes, discuss key aspects in assessing the risk-benefit ratio of aspirin use for primary prevention of ASCVD, and summarize current guidelines from professional societies on aspirin use for primary prevention in adults with diabetes.

Recent Findings

In the general population, past studies have shown no difference in the beneficial effect of aspirin for primary cardiovascular disease prevention by diabetes status. However, several randomized controlled studies and meta-analyses in adults with diabetes have shown lack of net clinical benefit of aspirin use for primary prevention of ASCVD. The recent ASCEND trial documented cardiovascular benefit of aspirin for primary prevention in adults with diabetes but suggested that the increased risk of bleeding may outweigh the cardiovascular benefit.

Summary

The decision to initiate aspirin for primary prevention of ASCVD must be considered carefully on an individual basis to balance the cardiovascular benefit and bleeding risk in all patients, especially those with diabetes. A multifactorial approach that focuses on managing ASCVD risk factors such as hypertension, dyslipidemia, dysglycemia, and smoking is recommended in all patients. More research is needed to identify subgroups of people with diabetes who are more likely to benefit from aspirin use for primary prevention of ASCVD and develop better antithrombotic strategies that shift the risk-benefit balance toward an overall net clinical benefit.

Keywords

Primary cardiovascular prevention Diabetes Aspirin Atherosclerotic cardiovascular disease 

Notes

Acknowledgements

The Saudi Government Scholarship from King Saud University, Riyadh, Saudi Arabia provided fellowship training support to Dr. Al-Sofiani. Dr. Kalyani had funding provided by the National Institutes of Health/NIDDK (R03 DK109163).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA. 1979;241(19):2035–8.CrossRefGoogle Scholar
  2. 2.
    Sobel BE. Effects of glycemic control and other determinants on vascular disease in type 2 diabetes. Am J Med. 2002;113(Suppl 6A):22S.Google Scholar
  3. 3.
    Kalyani RR, Lazo M, Ouyang P, et al. Sex differences in diabetes and risk of incident coronary artery disease in healthy young and middle-aged adults. Diabetes Care. 2014;37(3):830–8.  https://doi.org/10.2337/dc13-1755.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Winocour PD. Platelet abnormalities in diabetes mellitus. Diabetes. 1992;41(Suppl 2):26–31.  https://doi.org/10.2337/diab.41.2.s26.CrossRefPubMedGoogle Scholar
  5. 5.
    Davi G, Catalano I, Averna M, et al. Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Engl J Med. 1990;322(25):1769–74.  https://doi.org/10.1056/NEJM199006213222503.CrossRefPubMedGoogle Scholar
  6. 6.
    Di Carli MF, Janisse J, Grunberger G, Ager J. Role of chronic hyperglycemia in the pathogenesis of coronary microvascular dysfunction in diabetes. J Am Coll Cardiol. 2003;41(8):1387–93.CrossRefGoogle Scholar
  7. 7.
    Makimattila S, Virkamaki A, Groop PH, et al. Chronic hyperglycemia impairs endothelial function and insulin sensitivity via different mechanisms in insulin-dependent diabetes mellitus. Circulation. 1996;94(6):1276–82.CrossRefGoogle Scholar
  8. 8.
    Calverley DC, Hacker MR, Loda KA, Brass E, Buchanan TA, Tsao-Wei DD, et al. Increased platelet Fc receptor expression as a potential contributing cause of platelet hypersensitivity to collagen in diabetes mellitus. Br J Haematol. 2003;121(1):139–42.CrossRefGoogle Scholar
  9. 9.
    Ostermann H, van de Loo J. Factors of the hemostatic system in diabetic patients. A survey of controlled studies. Haemostasis. 1986;16(6):386–416.  https://doi.org/10.1159/000215317.CrossRefPubMedGoogle Scholar
  10. 10.
    Saito I, Folsom AR, Brancati FL, Duncan BB, Chambless LE, McGovern PG. Nontraditional risk factors for coronary heart disease incidence among persons with diabetes: the Atherosclerosis Risk in Communities (ARIC) Study. Ann Intern Med. 2000;133(2):81–91.CrossRefGoogle Scholar
  11. 11.
    Gray RP, Patterson DL, Yudkin JS. Plasminogen activator inhibitor activity in diabetic and nondiabetic survivors of myocardial infarction. Arterioscler Thromb. 1993;13(3):415–20.CrossRefGoogle Scholar
  12. 12.
    McGill JB, Schneider DJ, Arfken CL, Lucore CL, Sobel BE. Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients. Diabetes. 1994;43(1):104–9.  https://doi.org/10.2337/diab.43.1.104.CrossRefPubMedGoogle Scholar
  13. 13.
    Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, et al. IDF diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018;138:271–81.CrossRefGoogle Scholar
  14. 14.
    Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047–53.  https://doi.org/10.2337/diacare.27.5.1047.CrossRefGoogle Scholar
  15. 15.
    Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. ETDRS Investigators. JAMA. 1992;268(10):1292–300.Google Scholar
  16. 16.
    Ogawa H, Nakayama M, Morimoto T, et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA. 2008;300(18):2134–41.  https://doi.org/10.1001/jama.2008.623.CrossRefPubMedGoogle Scholar
  17. 17.
    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(7):659–70.  https://doi.org/10.1161/CIRCULATIONAHA.116.025760.CrossRefPubMedGoogle Scholar
  18. 18.
    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.  https://doi.org/10.1136/bmj.a1840.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    •• Antithrombotic Trialists’ (ATT) Collaboration, Baigent C, Blackwell L, 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(9678):1849–60.  https://doi.org/10.1016/S0140-6736(09)60503-1. Findings from this study showed that aspirin decreased the risk of vascular events by 12% in both the general population and in those with diabetes with no significant interaction by diabetes status. CrossRefGoogle Scholar
  20. 20.
    •• Al-Sofiani ME, Yanek LR, Faraday N, et al. Diabetes and platelet response to low-dose aspirin. J Clin Endocrinol Metab. 2018;103(12):4599–608.  https://doi.org/10.1210/jc.2018-01254. A comprehensive examination of the in vivo and in vitro platelet activation and response to aspirin by diabetes status was performed in this study. CrossRefPubMedGoogle Scholar
  21. 21.
    Vinik AI, Erbas T, Park TS, Nolan R, Pittenger GL. Platelet dysfunction in type 2 diabetes. Diabetes Care. 2001;24(8):1476–85.  https://doi.org/10.2337/diacare.24.8.1476.CrossRefPubMedGoogle Scholar
  22. 22.
    Ferroni P, Basili S, Falco A, Davi G. Platelet activation in type 2 diabetes mellitus. J Thromb Haemost. 2004;2(8):1282–91.  https://doi.org/10.1111/j.1538-7836.2004.00836.x.CrossRefPubMedGoogle Scholar
  23. 23.
    Ferreiro JL, Angiolillo DJ. Diabetes and antiplatelet therapy in acute coronary syndrome. Circulation. 2011;123(7):798–813.  https://doi.org/10.1161/CIRCULATIONAHA.109.913376.CrossRefPubMedGoogle Scholar
  24. 24.
    Peto R, Gray R, Collins R, et al. Randomised trial of prophylactic daily aspirin in British male doctors. Br Med J (Clin Res Ed). 1988;296(6618):313–6.  https://doi.org/10.1136/bmj.296.6618.313.CrossRefPubMedCentralGoogle Scholar
  25. 25.
    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. 1989;321(3):129–35.  https://doi.org/10.1056/NEJM198907203210301.CrossRefGoogle Scholar
  26. 26.
    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. The Medical Research Council’s General Practice Research Framework. Lancet. 1998;351(9098):233–241Google Scholar
  27. 27.
    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(9118):1755–62.CrossRefGoogle Scholar
  28. 28.
    de Gaetano G. Collaborative Group of the Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Collaborative Group of the Primary Prevention Project. Lancet. 2001;357(9250):89–95.CrossRefGoogle Scholar
  29. 29.
    Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JAE, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005;352(13):1293–304.CrossRefGoogle Scholar
  30. 30.
    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(9):841–8.  https://doi.org/10.1001/jama.2010.221.CrossRefPubMedGoogle Scholar
  31. 31.
    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(23):2510–20.  https://doi.org/10.1001/jama.2014.15690.CrossRefPubMedGoogle Scholar
  32. 32.
    •• ASCEND Study Collaborative Group, Bowman L, Mafham M, et al. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med. 2018;379(16):1529–39.  https://doi.org/10.1056/NEJMoa1804988. A recent trial that showed cardiovascular benefit of aspirin for primary prevention in people with diabetes but also suggested that the increased risk of bleeding may outweigh the cardiovascular benefit. CrossRefGoogle Scholar
  33. 33.
    Gaziano JM, Brotons C, Coppolecchia R, Cricelli C, Darius H, Gorelick PB, 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(10152):1036–46.CrossRefGoogle Scholar
  34. 34.
    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(16):1519–28.  https://doi.org/10.1056/NEJMoa1803955.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    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(3):277–87.  https://doi.org/10.1001/jama.2018.20578.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Pignone M, Alberts MJ, Colwell JA, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: a position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation. Circulation. 2010;121(24):2694–701.  https://doi.org/10.1161/CIR.0b013e3181e3b133.CrossRefPubMedGoogle Scholar
  37. 37.
    Rothwell PM, Cook NR, Gaziano JM, Price JF, Belch JFF, Roncaglioni MC, 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(10145):387–99.CrossRefGoogle Scholar
  38. 38.
    Becker DM, Segal J, Vaidya D, et al. Sex differences in platelet reactivity and response to low-dose aspirin therapy. JAMA. 2006;295(12):1420–7.CrossRefGoogle Scholar
  39. 39.
    Simpson SH, Abdelmoneim AS, Omran D, Featherstone TR. Prevalence of high on-treatment platelet reactivity in diabetic patients treated with aspirin. Am J Med. 2014;127(1):95.e9.  https://doi.org/10.1016/j.amjmed.2013.09.019.CrossRefGoogle Scholar
  40. 40.
    Bertoluci MC, Rocha VZ. Cardiovascular risk assessment in patients with diabetes. Diabetol Metab Syndr. 2017;9:1. eCollection 2017.  https://doi.org/10.1186/s13098-017-0225-1.CrossRefGoogle Scholar
  41. 41.
    Allan GM, Nouri F, Korownyk C, Kolber MR, Vandermeer B, McCormack J. Agreement among cardiovascular disease risk calculators. Circulation. 2013;127(19):1948–56.  https://doi.org/10.1161/CIRCULATIONAHA.112.000412.CrossRefPubMedGoogle Scholar
  42. 42.
    Goff DC, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):49.  https://doi.org/10.1161/01.cir.0000437741.48606.98.CrossRefGoogle Scholar
  43. 43.
    Rana JS, Tabada GH, Solomon MD, Lo JC, Jaffe MG, Sung SH, et al. Accuracy of the atherosclerotic cardiovascular risk equation in a large contemporary, Multiethnic Population. J Am Coll Cardiol. 2016;67(18):2118–30.CrossRefGoogle Scholar
  44. 44.
    Coleman RL, Stevens RJ, Retnakaran R, Holman RR. Framingham, SCORE, and DECODE risk equations do not provide reliable cardiovascular risk estimates in type 2 diabetes. Diabetes Care. 2007;30(5):1292–3.CrossRefGoogle Scholar
  45. 45.
    Stevens RJ, Kothari V, Adler AI, Stratton IM. United Kingdom Prospective Diabetes Study (UKPDS) Group. The UKPDS risk engine: a model for the risk of coronary heart disease in type II diabetes (UKPDS 56). Clin Sci (Lond). 2001;101(6):671–9.CrossRefGoogle Scholar
  46. 46.
    Simmons RK, Coleman RL, Price HC, et al. Performance of the UK Prospective Diabetes Study Risk Engine and the Framingham risk equations in estimating cardiovascular disease in the EPIC- Norfolk cohort. Diabetes Care. 2009;32(4):708–13.  https://doi.org/10.2337/dc08-1918.CrossRefPubMedGoogle Scholar
  47. 47.
    Fox CS, Golden SH, Anderson C, et al. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation. 2015;132(8):691–718.  https://doi.org/10.1161/CIR.0000000000000230.CrossRefPubMedGoogle Scholar
  48. 48.
    Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease. Circulation. 2019:CIR0000000000000678.  https://doi.org/10.1161/CIR.0000000000000678.
  49. 49.
    American Diabetes Association. 10. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S123.  https://doi.org/10.2337/dc19-S010.CrossRefGoogle Scholar
  50. 50.
    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. 2016;164(12):836–45.  https://doi.org/10.7326/M16-0577.CrossRefPubMedGoogle Scholar
  51. 51.
    Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V RW, et al. ESC Scientific Document Group. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2019;31. pii: ehz486.  https://doi.org/10.1093/eurheartj/ehz486.
  52. 52.
    Bell AD, Roussin A, Cartier R, et al. The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society guidelines. Can J Cardiol. 2011;27(Suppl A):1.  https://doi.org/10.1016/j.cjca.2010.12.015.CrossRefGoogle Scholar
  53. 53.
    De Berardis G, Lucisano G, D'Ettorre A, et al. Association of aspirin use with major bleeding in patients with and without diabetes. JAMA. 2012;307(21):2286–94.  https://doi.org/10.1001/jama.2012.5034.CrossRefPubMedGoogle Scholar
  54. 54.
    Zhang Z, Zhai Z, Yang Y, et al. Diabetes mellitus is associated with increased bleeding in pulmonary embolism receiving conventional anticoagulant therapy: findings from a “real-world” study. J Thromb Thrombolysis. 2017;43(4):540–9.  https://doi.org/10.1007/s11239-017-1473-5.CrossRefPubMedGoogle Scholar
  55. 55.
    Overvad TF, Skjoth F, Lip GY, et al. Duration of diabetes mellitus and risk of thromboembolism and bleeding in atrial fibrillation: nationwide cohort study. Stroke. 2015;46(8):2168–74.  https://doi.org/10.1161/STROKEAHA.115.009371.CrossRefPubMedGoogle Scholar
  56. 56.
    Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093–100.  https://doi.org/10.1378/chest.10-0134.CrossRefPubMedGoogle Scholar
  57. 57.
    Gage BF, Yan Y, Milligan PE, Waterman AD, Culverhouse R, Rich MW, et al. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J. 2006;151(3):713–9.CrossRefGoogle Scholar
  58. 58.
    Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin-associated hemorrhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) study. J Am Coll Cardiol. 2011;58(4):395–401.  https://doi.org/10.1016/j.jacc.2011.03.031.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Gurbel PA, Bliden KP, DiChiara J, Newcomer J, Weng W, Neerchal NK, et al. Evaluation of dose-related effects of aspirin on platelet function: results from the aspirin-induced platelet effect (ASPECT) study. Circulation. 2007;115(25):3156–64.CrossRefGoogle Scholar
  60. 60.
    Capodanno D, Patel A, Dharmashankar K, et al. Pharmacodynamic effects of different aspirin dosing regimens in type 2 diabetes mellitus patients with coronary artery disease. Circ Cardiovasc Interv. 2011;4(2):180–7.  https://doi.org/10.1161/CIRCINTERVENTIONS.110.960187.CrossRefPubMedGoogle Scholar
  61. 61.
    Bethel MA, Harrison P, Sourij H, et al. Randomized controlled trial comparing impact on platelet reactivity of twice-daily with once-daily aspirin in people with Type 2 diabetes. Diabet Med. 2016;33(2):224–30.  https://doi.org/10.1111/dme.12828.CrossRefPubMedGoogle Scholar
  62. 62.
    Brandle M, Davidson MB, Schriger DL, Lorber B, Herman WH. Cost effectiveness of statin therapy for the primary prevention of major coronary events in individuals with type 2 diabetes. Diabetes Care. 2003;26(6):1796–801.  https://doi.org/10.2337/diacare.26.6.1796.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Mohammed E. Al-Sofiani
    • 1
    • 2
  • Robert Derenbecker
    • 3
  • Michael Quartuccio
    • 1
  • Rita R. Kalyani
    • 1
    Email author
  1. 1.Division of Endocrinology, Diabetes & MetabolismThe Johns Hopkins UniversityBaltimoreUSA
  2. 2.Endocrinology Division, College of MedicineKing Saud UniversityRiyadhSaudi Arabia
  3. 3.General Internal MedicineThe Johns Hopkins UniversityBaltimoreUSA

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