There are numerous national and international guidelines on the use of aspirin for the primary prevention of cardiovascular disease. Given the uncertainties about aspirin in primary prevention, our aim was to compare the recommendations and the reported evidence in guidelines for the treatment with aspirin of subjects free of cardiovascular disease with or without diabetes.
Methods and Results
Guidelines were retrieved through Medline and other electronic databases and through a web-based search for guideline development organizations. The content of the recommendations and the underlying evidence were analysed with qualitative and bibliometric methods. In addition, we searched for recent studies to assess whether they underscore the current recommendations. We included 12 guidelines: six European, three North American, and one each from New Zealand, Australia, and the World Health Organization. Recommendations differ with regard to outcome (morbidity, mortality), time span (years of risk), cut-off percentage between high and low risk, and the dose of aspirin. Most guidelines are not in line with recent evidence, which show that aspirin is of uncertain net value as the reduction in absolute risk for occlusive CV events needs to be weighed against an increase in the risk of major bleeds.
Conclusion
We found conflicting recommendations in various guidelines about the use of aspirin for the primary prevention of cardiovascular events, which reflect differences in selection of the evidence and in the timing of publication. According to recent evidence, in general, the use of aspirin seems no longer justifiable in primary prevention in patients with or without diabetes.
BaigentCBlackwellLCollinsR. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet2009; 373: 1849–1860.
2.
AjaniUAFordESGreenlandKJ. Aspirin use among U.S. adults: behavioral risk factor surveillance system. Am J Prev Med2006; 30: 74–77.
3.
Lopez-CarmonaDBernal-LopezMMancera-RomeroJ. Compliance with cardiovascular drug prevention measures in a general population: the Multidisciplinary Intervention in Primary Care (IMAP) study. Eur J Prev Cardiol2012; 19: 1074–1081.
4.
BergerJSRoncaglioniMCAvanziniF. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA2006; 295: 306–313.
5.
PerkJDe BackerGGohlkeH. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): the Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur J Prev Cardiol2012; 19: 585–667.
6.
GeorgGSeroussiBBouaudJ. Extending the GEM model to support knowledge extraction from textual guidelines. Int J Med Inf2005; 74: 79–87.
7.
Clinical Knowledge Summaries. Antiplatelet treatment – Management. When should antiplatelet treatment be prescribed for primary prevention of cardiovascular disease? National Institute for Health and Clinical Excellence, 2009.
8.
JBS 2: Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005; 91 Suppl 5: v1–v52.
9.
Scottish Intercollegiate Guidelines Network. Risk estimation and the prevention of cardiovascular disease. Edinburgh: SIGN, 2007, guideline 97.
Nederlandse Huisartsen Genootschap. Cardiovasculair Risicomanagement. Nederlandse Huisartsen Genootschap, Utrecht, 2006.
12.
Domus Medica. Globaal Cardiovasculair risicobeheer. Domus Medica, Antwerpen, 2007.
13.
Calonge N, Petitti DB, DeWitt TG, et al. Aspirin for the prevention of cardiovascular disease: U.SPreventive Services Task Force recommendation statement. Ann Intern Med2009; 150: 396–404.
14.
GoldsteinLBBushnellCDAdamsRJ. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke2011; 42: 517–584.
15.
Gilpin VL. Review of an article: aspirin for primary prevention of cardiovascular events in people with diabetes. (2010). A position statement of the American Diabetes Association (ADA), a scientific statement of the American Heart Association (AHA), and an expert consensus document of the American College of Cardiology Foundation (ACCF). J Vasc Nurs 2010; 28: 154–155.
16.
17.
Berard L, Booth G, Capes S, et al. Clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2008; 32 Supplement 1.
18.
New Zealand Guidelines Group. New Zealand Cardiovascular guidelines handbook. New Zealand Guidelines Group, New Zealand Ministry of Health, 2009.
19.
HungJfor the Medical Issues Committee of the National Heart Foundation of AustraliaAspirin for primary prevention. Med J Aust2003; 179: 147–152.
20.
Diabetes Australia. Diabetes management in general practice guidelines for type 2 diabetes. Diabetes Australia, Royal Australian College of General Practitioners, Australia, 2011/12.
21.
22.
AlgraAGrevingJP. Aspirin in primary prevention: sex and baseline risk matter. Lancet2009; 373: 1821–1822.
23.
FowkesFGPriceJFStewartMC. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. JAMA2010; 303: 841–848.
24.
EvangelistaVTotaniLRotondoS. Prevention of cardiovascular disease in type-2 diabetes: how to improve the clinical efficacy of aspirin. Thromb Haemost2005; 93: 8–16.
25.
De BerardisGSaccoMStrippoliGF. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials. BMJ2009; 339: b4531–b4531.
26.
BelchJMacCuishACampbellI. 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. BMJ2008; 337: a1840–a1840.
27.
OgawaHNakayamaMMorimotoT. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA2008; 300: 2134–2141.
28.
PignoneMAlbertsMJColwellJA. Aspirin for primary prevention of cardiovascular events in people with diabetes. J Am Coll Cardiol2010; 55: 2878–2886.
29.
Seshasai SR, Wijesuriya S, Sivakumaran R, et al. Effect of aspirin on vascular and nonvascular outcomes: meta-analysis of randomized controlled trials. Arch Intern Med 2012; 172: 209–216.
30.
YounisNWilliamsSAmmoriB. Role of aspirin in the primary prevention of cardiovascular disease in diabetes mellitus: a meta-analysis. Expert Opin Pharmacother2010; 11: 1459–1466.
31.
BartolucciAATenderaMHowardG. Meta-analysis of multiple primary prevention trials of cardiovascular events using aspirin. Am J Cardiol2011; 107: 1796–1801.
32.
ZhangCSunAZhangP. Aspirin for primary prevention of cardiovascular events in patients with diabetes: a meta-analysis. Diabetes Res Clin Pract2010; 87: 211–218.
33.
CalvinADAggarwalNRMuradMH. Aspirin for the primary prevention of cardiovascular events: a systematic review and meta-analysis comparing patients with and without diabetes. Diabetes Care2009; 32: 2300–2306.
34.
Kassoff A, Buzney S, McMeel W, et al. Aspirin effects on mortality and morbidity in patients with diabetes mellitusEarly Treatment Diabetic Retinopathy Study report 14. ETDRS Investigators. JAMA1992; 268: 1292–1300.
35.
Baigent C, Sudlow C and Collins R. 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.
36.
EidelmanRSHebertPRWeismanSM. An update on aspirin in the primary prevention of cardiovascular disease. Arch Intern Med2003; 163: 2006–2010.
37.
Hankey GJ, Sudlow CL and Dunbabin DW. Thienopyridine derivatives (ticlopidine, clopidogrel) versus aspirin for preventing stroke and other serious vascular events in high vascular risk patients. Cochrane Database Syst Rev 2000; issue 1: Article Id CD001246.
38.
HanssonLZanchettiACarruthersSG. 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. Lancet1998; 351: 1755–1762.
39.
HaydenMPignoneMPhillipsC. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med2002; 136: 161–172.
40.
RidkerPMCookNRLeeIM. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med2005; 352: 1293–1304.
41.
SaccoMPellegriniFRoncaglioniMC. Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial. Diabetes Care2003; 26: 3264–3272.
42.
SanmuganathanPSGhahramaniPJacksonPR. Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials. Heart2001; 85: 265–271.
43.
Belanger C, Buring JE, Cook N, et al. Final report on the aspirin component of the ongoing Physicians’ Health StudySteering Committee of the Physicians’ Health Study Research Group. N Engl J Med1989; 321: 129–135.
44.
PetoRGrayRCollinsR. Randomised trial of prophylactic daily aspirin in British male doctors. Br Med J (Clin Res Ed)1988; 296: 313–316.
45.
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 riskThe Medical Research Council’s General Practice Research Framework. Lancet1998; 351: 233–241.
46.
de GaetanoG. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Collaborative Group of the Primary Prevention Project. Lancet2001; 357: 89–95.
47.
HartRGHalperinJLMcBrideR. Aspirin for the primary prevention of stroke and other major vascular events: meta-analysis and hypotheses. Arch Neurol2000; 57: 326–332.
48.
BaigentC. Aspirin for everyone older than 50? Against. BMJ2005; 330: 1442–1443.
49.
PearsonTABlairSNDanielsSR. AHA Guidelines for primary prevention of cardiovascular disease and stroke: 2002 update: consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases. American Heart Association Science Advisory and Coordinating Committee. Circulation2002; 106: 388–391.
50.
Collins R, Peto R, Baigent C, et al. Collaborative overview of randomised trials of antiplatelet therapy I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patientsAntiplatelet Trialists’ Collaboration. BMJ1994; 308: 81–106.
51.
US Preventative Services Task Force. Aspirin for the primary prevention of cardiovascular events: recommendation and rationale. Ann Intern Med 2002; 136: 157–160.
52.
KellyJPKaufmanDWJurgelonJM. Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product. Lancet1996; 348: 1413–1416.
53.
DerrySLokeYK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ2000; 321: 1183–1187.
54.
Garcia RodriguezLAHernandez-DiazSde AbajoFJ. Association between aspirin and upper gastrointestinal complications: systematic review of epidemiologic studies. Br J Clin Pharmacol2001; 52: 563–571.
55.
De BerardisGSaccoMEvangelistaV. Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D): design of a randomized study of the efficacy of low-dose aspirin in the prevention of cardiovascular events in subjects with diabetes mellitus treated with statins. Trials2007; 8: 21–21.
56.
British Heart Foundation. ASCEND: A Study of Cardiovascular Events in Diabetes. Available at: http://www.ctsu.ox.ac.uk/ascend (accessed 16 December 2009).
57.
WolffTMillerTKoS. Aspirin for the primary prevention of cardiovascular events: an update of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med2009; 150: 405–410.
58.
Hernandez-DiazSGarcia RodriguezLA. Cardioprotective aspirin users and their excess risk of upper gastrointestinal complications. BMC Med2006; 4: 22–22.
59.
Hernandez-DiazSRodriguezLA. Incidence of serious upper gastrointestinal bleeding/perforation in the general population: review of epidemiologic studies. J Clin Epidemiol2002; 55: 157–163.
60.
WilsonPWD’AgostinoRBLevyD. Prediction of coronary heart disease using risk factor categories. Circulation1998; 97: 1837–1847.
61.
WolfPAD’AgostinoRBBelangerAJ. Probability of stroke: a risk profile from the Framingham Study. Stroke1991; 22: 312–318.
62.
PatronoCCollerBFitzGeraldGA. Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest2004; 126: 234S–264S.
63.
ThomTHaaseNRosamondW. Heart disease and stroke statistics 2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation2006; 113: e85–e151.
64.
BuseJBGinsbergHNBakrisGL. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation2007; 115: 114–126.
65.
GoldsteinLBAdamsRAlbertsMJ. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation2006; 113: e873–e923.
66.
Centers for Disease Control and Prevention. National diabetes fact sheet. General information and national estimates on diabetes in the United States, 2007. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, 2008.
67.
SilvaJAEscobarACollinsTJ. Unstable angina. A comparison of angioscopic findings between diabetic and nondiabetic patients. Circulation1995; 92: 1731–1736.
68.
NatarajanAZamanAGMarshallSM. Platelet hyperactivity in type 2 diabetes: role of antiplatelet agents. Diab Vasc Dis Res2008; 5: 138–144.
69.
ReuschJE. Diabetes, microvascular complications, and cardiovascular complications: what is it about glucose?. J Clin Invest2003; 112: 986–988.
70.
HeJWheltonPKVuB. Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials. JAMA1998; 280: 1930–1935.
71.
LaiKCLamSKChuKM. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med2002; 346: 2033–2038.
72.
PedersenAKFitzGeraldGA. Dose-related kinetics of aspirin. Presystemic acetylation of platelet cyclooxygenase. N Engl J Med1984; 311: 1206–1211.
73.
PatronoC. Aspirin as an antiplatelet drug. N Engl J Med1994; 330: 1287–1294.
74.
ColwellJAHalushkaPVSarjiK. Altered platelet function in diabetes mellitus. Diabetes1976; 25: 826–831.
75.
DaviGPatronoC. Platelet activation and atherothrombosis. N Engl J Med2007; 357: 2482–2494.
76.
WatalaCGolanskiJPlutaJ. Reduced sensitivity of platelets from type 2 diabetic patients to acetylsalicylic acid (aspirin) its relation to metabolic control. Thromb Res2004; 113: 101–113.
77.
LevEI. Aspirin resistance transient laboratory finding or important clinical entity?. J Am Coll Cardiol2009; 53: 678–680.
78.
SantilliFRoccaBDe CristofaroR. Platelet cyclooxygenase inhibition by low-dose aspirin is not reflected consistently by platelet function assays: implications for aspirin ‘resistance’. J Am Coll Cardiol2009; 53: 667–777.
79.
PignoneMEarnshawSTiceJA. Aspirin, statins, or both drugs for the primary prevention of coronary heart disease events in men: a cost-utility analysis. Ann Intern Med2006; 144: 326–336.
80.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP)Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA2001; 285: 2486–2497.
81.
KearneyPMBlackwellLCollinsR. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet2008; 371: 117–125.
82.
TurnbullFNealBAlgertC. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med2005; 165: 1410–1419.
83.
EikelboomJWHirshJWeitzJI. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation2002; 105: 1650–1655.
84.
RidkerPMCushmanMStampferMJ. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med1997; 336: 973–979.
85.
RexrodeKMLeeIMCookNR. Baseline characteristics of participants in the Women’s Health Study. J Womens Health Gender-Based Med2000; 9: 19–27.
86.
MorimotoTFukuiTLeeTH. Application of U.S. guidelines in other countries: aspirin for the primary prevention of cardiovascular events in Japan. Am J Med2004; 117: 459–468.
87.
BergerJLalaAKrantzMJ. Aspirin for the prevention of cardiovascular events in patients without clinical cardiovascular disease: A meta-analysis of randomized trials. Am Heart J2011; 162: 115–124.
88.
De BerardisGLucisanoGD’EttorreA. Association of aspirin use with major bleeding in patients with and without diabetes. JAMA2012; 307: 2286–2294.
89.
SiontisGCTzoulakiISiontisKC. Comparisons of established risk prediction models for cardiovascular disease: systematic review. BMJ2012; 344: e3318–e3318.
90.
NorheimOFGjelsvikBKlemsdalTO. Norway’s new principles for primary prevention of cardiovascular disease: age differentiated risk thresholds. BMJ2011; 343: d3626–d3626.
91.
MatthysJDe MeyereMvan DrielML. Differences among international pharyngitis guidelines: not just academic. Ann Fam Med2007; 5: 436–443.
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