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Thromb Haemost 2020; 120(02): 199-206
DOI: 10.1055/s-0039-3400294
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Aspirin Therapy for Primary Prevention: The Case for Continuing Prescribing to Patients at High Cardiovascular Risk—A Review

Raffaele De Caterina 
1   Cardiovascular Division, Pisa University Hospital, University of Pisa, Pisa, Italy
,
Alberto Aimo
1   Cardiovascular Division, Pisa University Hospital, University of Pisa, Pisa, Italy
,
Paul M. Ridker
2   Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
› Author Affiliations
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Publication History

21 July 2019

01 October 2019

Publication Date:
30 December 2019 (online)

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Abstract

Current evidence supports the use of low-dose aspirin for secondary cardiovascular prevention. By contrast, the benefit-to-risk ratio of aspirin use in primary prevention is debated: three contemporary randomized control trials have been conflicting, and meta-analyses have concluded for an unclear clinical benefit, based on the consideration that the reduction in thromboembolic events is counterbalanced by increased bleeding. The primary prevention setting is, however, a heterogeneous mix of subjects at highly variable cardiovascular risk. One possible explanation for the uncertainty of data interpretation is the progressive reduction in risk of major adverse cardiovascular events (MACEs) in primary prevention that has accompanied global education programs, leading patients to smoke less, exercise more, and increasingly take lipid-lowering therapies. Based on a meta-regression of the benefits and harm of aspirin therapy in primary prevention as a function of the 10-year risk of MACE, we favor a nuanced approach still, however, based on the evaluation of cardiovascular risk, acknowledging differences between patients and emphasizing an individualized assessment of both benefits and harm. After optimal control of cardiovascular risk factors, and when patients are less than 70 years of age, clinicians should assess the risk of MACE and base decision on such stratification, considering the risk of bleeding and patient preferences. Clinicians would then advise the use of aspirin in primary prevention patients at the highest risk of MACE who do not have a prohibitive risk of bleeding, and in the majority of cases after initiation of properly titrated statin therapy.

Keywords

aspirin - primary cardiovascular prevention - bleeding - major acute cardiovascular events - MACE - benefit–risk balance

Supplementary Material

 

  • References

  • 1 Elwood PC, Cochrane AL, Burr ML. , et al. A randomized controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infarction. BMJ 1974; 1 (5905): 436-440
    CrossrefPubMedSearch in Google Scholar
  • 2 The Coronary Drug Project Research Group. Aspirin in coronary heart disease. J Chronic Dis 1976; 29 (10) 625-642
    CrossrefPubMedSearch in Google Scholar
  • 3 Breddin K, Loew D, Lechner K, Uberla K, Walter E. Secondary prevention of myocardial infarction: a comparison of acetylsalicylic acid, placebo and phenprocoumon. Haemostasis 1980; 9 (06) 325-344
    PubMedSearch in Google Scholar
  • 4 Elwood PC, Sweetnam PM. Aspirin and secondary mortality after myocardial infarction. Lancet 1979; 2 (8156-8157): 1313-1315
    PubMedSearch in Google Scholar
  • 5 The Persantine-aspirin Reinfarction Study (PARIS) Research Group. Persantine and aspirin in coronary heart disease. Circulation 1980; 62: 449-461
    CrossrefPubMedSearch in Google Scholar
  • 6 The Aspirin Myocardial Infarction Study research group. A randomized, controlled trial of aspirin in persons recovered from myocardial infarction. JAMA 1980; 243 (07) 661-669
    CrossrefPubMedSearch in Google Scholar
  • 7 Aspirin after myocardial infarction. Lancet 1980; 1 (8179): 1172-1173
    PubMedSearch in Google Scholar
  • 8 Montinari MR, Minelli S, De Caterina R. The first 3500 years of aspirin history from its roots - a concise summary. Vascul Pharmacol 2019; 113: 1-8
    CrossrefPubMedSearch in Google Scholar
  • 9 Lewis Jr HD, Davis JW, Archibald DG. , et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med 1983; 309 (07) 396-403
    CrossrefPubMedSearch in Google Scholar
  • 10 Cairns JA, Gent M, Singer J. , et al. Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial. N Engl J Med 1985; 313 (22) 1369-1375
    CrossrefPubMedSearch in Google Scholar
  • 11 ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2 (8607): 349-360
    PubMedSearch in Google Scholar
  • 12 Baigent C, Blackwell L, Collins R. , et al; 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 2009; 373 (9678): 1849-1860
    CrossrefPubMedSearch in Google Scholar
  • 13 Ridker PM. Should aspirin be used for primary prevention in the post-statin era?. N Engl J Med 2018; 379 (16) 1572-1574
    CrossrefPubMedSearch in Google Scholar
  • 14 Gaziano JM, Brotons C, Coppolecchia R. , et al; ARRIVE Executive Committee. 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): 1036-1046
    CrossrefPubMedSearch in Google Scholar
  • 15 Bowman L, Mafham M, Wallendszus K. , et al; ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med 2018; 379 (16) 1529-1539
    CrossrefPubMedSearch in Google Scholar
  • 16 McNeil JJ, Nelson MR, Woods RL. , et al; ASPREE Investigator Group. Effect of aspirin on all-cause mortality in the healthy elderly. N Engl J Med 2018; 379 (16) 1519-1528
    CrossrefPubMedSearch in Google Scholar
  • 17 McNeil JJ, Wolfe R, Woods RL. , et al; ASPREE Investigator Group. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med 2018; 379 (16) 1509-1518
    CrossrefPubMedSearch in Google Scholar
  • 18 McNeil JJ, Woods RL, Nelson MR. , et al; ASPREE Investigator Group. Effect of aspirin on disability-free survival in the healthy elderly. N Engl J Med 2018; 379 (16) 1499-1508
    CrossrefPubMedSearch in Google Scholar
  • 19 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 (03) 277-287
    CrossrefPubMedSearch in Google Scholar
  • 20 Mahmoud AN, Gad MM, Elgendy AY, Elgendy IY, Bavry AA. 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 (07) 607-617
    CrossrefPubMedSearch in Google Scholar
  • 21 Khan SU, Ul Abideen Asad Z, Khan MU. , et al. Aspirin for primary prevention of cardiovascular outcomes in diabetes mellitus: an updated systematic review and meta-analysis. Eur J Prev Cardiol 2019; 2047487319825510
    PubMedSearch in Google Scholar
  • 22 Piepoli MF, Hoes AW, Agewall S. , et al; ESC Scientific Document Group. 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 & Rehabilitation (EACPR). Eur Heart J 2016; 37 (29) 2315-2381
    CrossrefPubMedSearch in Google Scholar
  • 23 Arnett DK, Blumenthal RS, Albert MA. , et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019; 74 (10) 1376-1414
    CrossrefPubMedSearch in Google Scholar
  • 24 Capodanno D, Angiolillo DJ. Aspirin for primary cardiovascular risk prevention and beyond in diabetes mellitus. Circulation 2016; 134 (20) 1579-1594
    CrossrefPubMedSearch in Google Scholar
  • 25 Belch J, MacCuish A, Campbell I. , et al; Prevention of Progression of Arterial Disease and Diabetes Study Group; Diabetes Registry Group; Royal College of Physicians Edinburgh. 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
    CrossrefPubMedSearch in Google Scholar
  • 26 Fowkes FG, Price JF, Stewart MC. , et al; Aspirin for Asymptomatic Atherosclerosis Trialists. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. JAMA 2010; 303 (09) 841-848
    CrossrefPubMedSearch in Google Scholar
  • 27 Halvorsen S, Andreotti F, ten Berg JM. , et al. Aspirin therapy in primary cardiovascular disease prevention: a position paper of the European Society of Cardiology working group on thrombosis. J Am Coll Cardiol 2014; 64 (03) 319-327
    CrossrefPubMedSearch in Google Scholar
  • 28 Patrignani P, Patrono C. Aspirin and cancer. J Am Coll Cardiol 2016; 68 (09) 967-976
    CrossrefPubMedSearch in Google Scholar
  • 29 ETDRS Investigators. Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. JAMA 1992; 268 (10) 1292-1300
    CrossrefPubMedSearch in Google Scholar
  • 30 D'Agostino Sr RB, Vasan RS, Pencina MJ. , et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation 2008; 117 (06) 743-753
    CrossrefPubMedSearch in Google Scholar
  • 31 Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease. Lancet 2013; 382 (9907): 1762-1765
    CrossrefPubMedSearch in Google Scholar
  • 32 Eikelboom JW, Connolly SJ, Bosch J. , et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017; 377 (14) 1319-1330
    CrossrefPubMedSearch in Google Scholar
  • 33 Criqui MH, Langer RD, Fronek A. , et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992; 326 (06) 381-386
    CrossrefPubMedSearch in Google Scholar
  • 34 Halliday A, Harrison M, Hayter E. , et al; Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. 10-year stroke prevention after successful carotid endarterectomy for asymptomatic stenosis (ACST-1): a multicentre randomised trial. Lancet 2010; 376 (9746): 1074-1084
    CrossrefPubMedSearch in Google Scholar
  • 35 Nielsen LH, Bøtker HE, Sørensen HT. , et al. Prognostic assessment of stable coronary artery disease as determined by coronary computed tomography angiography: a Danish multicentre cohort study. Eur Heart J 2017; 38 (06) 413-421
    PubMedSearch in Google Scholar
  • 36 Detrano R, Guerci AD, Carr JJ. , et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med 2008; 358 (13) 1336-1345
    CrossrefPubMedSearch in Google Scholar
  • 37 Lanas A, Polo-Tomás M, Casado-Arroyo R. The aspirin cardiovascular/gastrointestinal risk calculator--a tool to aid clinicians in practice. Aliment Pharmacol Ther 2013; 37 (07) 738-748
    CrossrefPubMedSearch in Google Scholar
  • 38 Scally B, Emberson JR, Spata E. , 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 2018; 3 (04) 231-241
    CrossrefPubMedSearch in Google Scholar
  • 39 Moayyedi P, Eikelboom JW, Bosch J. , et al; COMPASS Investigators. Safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin. Gastroenterology 2019; 157 (03) 682-691.e2
    CrossrefPubMedSearch in Google Scholar
  • 40 Vandvik PO, Lincoff AM, Gore JM. , 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 2012; 141: e637S-e668S
    CrossrefPubMedSearch in Google Scholar
  • 41 Cosentino F, Grant PJ, Aboyans V. , et al; ESC Scientific Document Group. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2019; 2019: ehz486
    PubMedSearch in Google Scholar
  • 42 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 (03) 129-135
    CrossrefPubMedSearch in Google Scholar
  • 43 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): 313-316
    CrossrefPubMedSearch in Google Scholar
  • 44 Hansson L, Zanchetti A, Carruthers SG. , et al; HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998; 351 (9118): 1755-1762
    CrossrefPubMedSearch in Google Scholar
  • 45 Ogawa H, Nakayama M, Morimoto T. , et al; Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial Investigators. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA 2008; 300 (18) 2134-2141
    CrossrefPubMedSearch in Google Scholar
  • 46 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) 2510-2520
    CrossrefPubMedSearch in Google Scholar
  • 47 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. Lancet 2001; 357 (9250): 89-95
    CrossrefPubMedSearch in Google Scholar
  • 48 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 1998; 351 (9098): 233-241
    CrossrefPubMedSearch in Google Scholar
  • 49 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 (13) 1293-1304
    CrossrefPubMedSearch in Google Scholar