[Skip to Content]
[Skip to Content Landing]
Figure.  Risk Reductions in Major Coronary Events and Ischemic Stroke by Randomized Aspirin Use and Sex in Primary Prevention Trials Adapted From the 2009 ATT Meta-analysis14
Risk Reductions in Major Coronary Events and Ischemic Stroke by Randomized Aspirin Use and Sex in Primary Prevention Trials Adapted From the 2009 ATT Meta-analysis
Table 1.  Summary of the Major Aspirin Primary Prevention Trials
Summary of the Major Aspirin Primary Prevention Trials
Table 2.  Relative Risk of Aspirin vs Control in Primary Prevention Trials by Age and Study
Relative Risk of Aspirin vs Control in Primary Prevention Trials by Age and Study
Table 3.  Major Risk Factors for Gastrointestinal Bleeding and Related Complications
Major Risk Factors for Gastrointestinal Bleeding and Related Complications
1.
Mozaffarian  D, Benjamin  EJ, Go  AS,  et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee.  Heart disease and stroke statistics—2015 update: a report from the American Heart Association.  Circulation. 2015;131(4):e29-e322.PubMedGoogle ScholarCrossref
2.
Murray  CJ, Atkinson  C, Bhalla  K,  et al; U.S. Burden of Disease Collaborators.  The state of US health, 1990-2010: burden of diseases, injuries, and risk factors.  JAMA. 2013;310(6):591-608.PubMedGoogle ScholarCrossref
3.
Ford  ES, Ajani  UA, Croft  JB,  et al.  Explaining the decrease in U.S. deaths from coronary disease, 1980-2000.  N Engl J Med. 2007;356(23):2388-2398.PubMedGoogle ScholarCrossref
4.
Jack  DB.  One hundred years of aspirin.  Lancet. 1997;350(9075):437-439.PubMedGoogle ScholarCrossref
5.
Fuster  V, Sweeny  JM.  Aspirin: a historical and contemporary therapeutic overview.  Circulation. 2011;123(7):768-778.PubMedGoogle ScholarCrossref
6.
Manson  JE, Burning JE, Ridker  PM, Gaziano  JM, eds.  Clinical Trials in Cardiovascular Disease: A Companion to Braunwald's Heart Disease. 2nd ed. Philadelphia, PA: WB Saunders; 2004:333-348.
7.
Pignone  M, Anderson  GK, Binns  K, Tilson  HH, Weisman  SM.  Aspirin use among adults aged 40 and older in the United States: results of a national survey.  Am J Prev Med. 2007;32(5):403-407.PubMedGoogle ScholarCrossref
8.
Mainous  AG, Tanner  RJ, Shorr  RI, Limacher  MC.  Use of aspirin for primary and secondary cardiovascular disease prevention in the United States, 2011-2012.  J Am Heart Assoc. 2014;3(4):e000989.PubMedGoogle ScholarCrossref
9.
Whitlock  EP, Williams  SB, Burda  BU, Feightner  A, Beil  T.  Aspirin Use in Adults: Cancer, All-Cause Mortality, and Harms: A Systematic Evidence Review for the US Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality; 2015. Report No. 13-05193-EF-1.
10.
Vane  JR.  Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.  Nat New Biol. 1971;231(25):232-235.PubMedGoogle ScholarCrossref
11.
Bhatt  DL, Scheiman  J, Abraham  NS,  et al; American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents.  ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents.  J Am Coll Cardiol. 2008;52(18):1502-1517.PubMedGoogle ScholarCrossref
12.
Wallace  JL.  Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn’t the stomach digest itself?  Physiol Rev. 2008;88(4):1547-1565.PubMedGoogle ScholarCrossref
13.
Yin  MJ, Yamamoto  Y, Gaynor  RB.  The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta.  Nature. 1998;396(6706):77-80.PubMedGoogle ScholarCrossref
14.
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.PubMedGoogle ScholarCrossref
15.
 Collaborative overview of randomised trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists’ Collaboration.  BMJ. 1994;308(6921):81-106.PubMedGoogle ScholarCrossref
16.
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(7329):71-86.PubMedGoogle ScholarCrossref
17.
Siu  AL; US Preventive Services Task Force.  Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: US Preventive Services Task Force recommendation statement.  Ann Intern Med. 2016;164: Epub ahead of print. doi:10.7326/M7316-0577.Google Scholar
18.
US Preventive Services Task Force.  Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement.  Ann Intern Med. 2009;150(6):396-404.PubMedGoogle ScholarCrossref
19.
American Diabetes Association.  8. Cardiovascular disease and risk management.  Diabetes Care. 2016;39(suppl 1):S60-S71.PubMedGoogle ScholarCrossref
20.
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(suppl 2):e637S-668S.Google ScholarCrossref
21.
Perk  J, De Backer  G, Gohlke  H,  et al; European Association for Cardiovascular Prevention & Rehabilitation (EACPR); ESC Committee for Practice Guidelines (CPG).  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 Heart J. 2012;33(13):1635-1701.PubMedGoogle ScholarCrossref
22.
Mosca  L, Benjamin  EJ, Berra  K,  et al.  Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update: a guideline from the american heart association.  Circulation. 2011;123(11):1243-1262.PubMedGoogle ScholarCrossref
23.
Bell  AD, Roussin  A, Cartier  R,  et al.  The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society Guidelines Executive Summary.  Can J Cardiol. 2011;27(2):208-221.PubMedGoogle ScholarCrossref
24.
US Department of Health and Human Services. FDA. Can an aspirin a day help prevent a heart attack? http://www.fda.gov/forconsumers/consumerupdates/ucm390539.Htm. 2014. Accessed October 11, 2015.
25.
Mora  S.  Aspirin therapy in primary prevention: comment on “effect of aspirin on vascular and nonvascular outcomes.”  Arch Intern Med. 2012;172(3):217-218.PubMedGoogle ScholarCrossref
26.
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.PubMedGoogle ScholarCrossref
27.
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):129-135.PubMedGoogle ScholarCrossref
28.
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.PubMedGoogle ScholarCrossref
29.
Thrombosis prevention trial.  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):233-241.PubMedGoogle ScholarCrossref
30.
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.PubMedGoogle ScholarCrossref
31.
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.PubMedGoogle ScholarCrossref
32.
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.PubMedGoogle ScholarCrossref
33.
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.PubMedGoogle ScholarCrossref
34.
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.PubMedGoogle ScholarCrossref
35.
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(9):841-848.PubMedGoogle ScholarCrossref
36.
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.PubMedGoogle ScholarCrossref
37.
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(3):209-216.PubMedGoogle ScholarCrossref
38.
Sutcliffe  P, Connock  M, Gurung  T,  et al.  Aspirin in primary prevention of cardiovascular disease and cancer: a systematic review of the balance of evidence from reviews of randomized trials.  PLoS One. 2013;8(12):e81970.PubMedGoogle ScholarCrossref
39.
Cuzick  J, Thorat  MA, Bosetti  C,  et al.  Estimates of benefits and harms of prophylactic use of aspirin in the general population.  Ann Oncol. 2015;26(1):47-57.PubMedGoogle ScholarCrossref
40.
Raju  N, Sobieraj-Teague  M, Hirsh  J, O’Donnell  M, Eikelboom  J.  Effect of aspirin on mortality in the primary prevention of cardiovascular disease.  Am J Med. 2011;124(7):621-629.PubMedGoogle ScholarCrossref
41.
Bartolucci  AA, Tendera  M, Howard  G.  Meta-analysis of multiple primary prevention trials of cardiovascular events using aspirin.  Am J Cardiol. 2011;107(12):1796-1801.PubMedGoogle ScholarCrossref
42.
Berger  JS, Roncaglioni  MC, Avanzini  F, Pangrazzi  I, Tognoni  G, Brown  DL.  Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials.  JAMA. 2006;295(3):306-313.PubMedGoogle ScholarCrossref
43.
Becker  DM, Segal  J, Vaidya  D,  et al.  Sex differences in platelet reactivity and response to low-dose aspirin therapy.  JAMA. 2006;295(12):1420-1427.PubMedGoogle ScholarCrossref
44.
Campbell  CL, Smyth  S, Montalescot  G, Steinhubl  SR.  Aspirin dose for the prevention of cardiovascular disease: a systematic review.  JAMA. 2007;297(18):2018-2024.PubMedGoogle ScholarCrossref
45.
Wallace  JL, Vong  L.  NSAID-induced gastrointestinal damage and the design of GI-sparing NSAIDs.  Curr Opin Investig Drugs. 2008;9(11):1151-1156.PubMedGoogle Scholar
46.
Krasopoulos  G, Brister  SJ, Beattie  WS, Buchanan  MR.  Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis.  BMJ. 2008;336(7637):195-198.PubMedGoogle ScholarCrossref
47.
Grosser  T, Fries  S, Lawson  JA, Kapoor  SC, Grant  GR, FitzGerald  GA.  Drug resistance and pseudoresistance: an unintended consequence of enteric coating aspirin.  Circulation. 2013;127(3):377-385.PubMedGoogle ScholarCrossref
48.
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):224-230.PubMedGoogle ScholarCrossref
49.
Chasman  DI, Shiffman  D, Zee  RY,  et al.  Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy.  Atherosclerosis. 2009;203(2):371-376.PubMedGoogle ScholarCrossref
50.
Roden  DM.  Cardiovascular pharmacogenomics: current status and future directions.  J Hum Genet. 2016;61(1):79-85.PubMedGoogle ScholarCrossref
51.
Paynter  NP, Ridker  PM, Chasman  DI.  Are genetic tests for atherosclerosis ready for routine clinical use?  Circ Res. 2016;118(4):607-619.PubMedGoogle ScholarCrossref
52.
Rothwell  PM, Fowkes  FG, Belch  JF, Ogawa  H, Warlow  CP, Meade  TW.  Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials.  Lancet. 2011;377(9759):31-41.PubMedGoogle ScholarCrossref
53.
Bosetti  C, Rosato  V, Gallus  S, Cuzick  J, La Vecchia  C.  Aspirin and cancer risk: a quantitative review to 2011.  Ann Oncol. 2012;23(6):1403-1415.PubMedGoogle ScholarCrossref
54.
Chubak  J, Whitlock  EP, Williams  SB,  et al.  Aspirin for the prevention of cancer incidence and mortality: Systematic evidence reviews for the US Preventive Services Task Force.  Ann Intern Med. 2016; Epub ahead of print. doi:10.7326/M15-2117.PubMedGoogle Scholar
55.
Cook  NR, Lee  IM, Zhang  SM, Moorthy  MV, Buring  JE.  Alternate-day, low-dose aspirin and cancer risk: long-term observational follow-up of a randomized trial.  Ann Intern Med. 2013;159(2):77-85.PubMedGoogle ScholarCrossref
56.
Burn  J, Gerdes  AM, Macrae  F,  et al; CAPP2 Investigators.  Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial.  Lancet. 2011;378(9809):2081-2087.PubMedGoogle ScholarCrossref
57.
Chan  AT, Arber  N, Burn  J,  et al.  Aspirin in the chemoprevention of colorectal neoplasia: an overview.  Cancer Prev Res (Phila). 2012;5(2):164-178.PubMedGoogle ScholarCrossref
58.
Stone  NJ, Robinson  JG, Lichtenstein  AH,  et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  Circulation. 2014;129(25)(suppl 2):S1-S45.PubMedGoogle ScholarCrossref
59.
Goff  DC  Jr, Lloyd-Jones  DM, Bennett  G,  et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  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):S49-S73.PubMedGoogle ScholarCrossref
60.
Pearson  TA, Blair  SN, Daniels  SR,  et al; American Heart Association Science Advisory and Coordinating Committee.  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.  Circulation. 2002;106(3):388-391.PubMedGoogle ScholarCrossref
61.
Redberg  RF, Benjamin  EJ, Bittner  V,  et al; American Academy of Family Physicians; American Association of Cardiovascular and Pulmonary Rehabilitation; Preventive Cardiovascular Nurses Association.  AHA/ACCF [corrected] 2009 performance measures for primary prevention of cardiovascular disease in adults: a report of the American College of Cardiology Foundation/American Heart Association task force on performance measures (writing committee to develop performance measures for primary prevention of cardiovascular disease): developed in collaboration with the American Academy of Family Physicians; American Association of Cardiovascular and Pulmonary Rehabilitation; and Preventive Cardiovascular Nurses Association: endorsed by the American College of Preventive Medicine, American College of Sports Medicine, and Society for Women’s Health Research.  Circulation. 2009;120(13):1296-1336.PubMedGoogle ScholarCrossref
62.
Goldstein  LB, Bushnell  CD, Adams  RJ,  et al; American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Epidemiology and Prevention; Council for High Blood Pressure Research; Council on Peripheral Vascular Disease, and Interdisciplinary Council on Quality of Care and Outcomes Research.  Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.  Stroke. 2011;42(2):517-584.PubMedGoogle ScholarCrossref
63.
Abbas  AE, Brodie  B, Dixon  S,  et al.  Incidence and prognostic impact of gastrointestinal bleeding after percutaneous coronary intervention for acute myocardial infarction.  Am J Cardiol. 2005;96(2):173-176.PubMedGoogle ScholarCrossref
64.
Moukarbel  GV, Signorovitch  JE, Pfeffer  MA,  et al.  Gastrointestinal bleeding in high risk survivors of myocardial infarction: the VALIANT Trial.  Eur Heart J. 2009;30(18):2226-2232.PubMedGoogle ScholarCrossref
65.
Whitlock  EP, Burda  BU, Williams  SB, Guirguis-Blake  JM, Evans  CV.  Bleeding risks with aspirin use for primary prevention in adults: A systematic evidence review for the US Preventive Services Task Force.  Ann Intern Med. 2016; Epub ahead of print. doi:10.7326/M15-2112.PubMedGoogle Scholar
66.
Mant  J, Hobbs  FD, Fletcher  K,  et al; BAFTA investigators; Midland Research Practices Network (MidReC).  Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial.  Lancet. 2007;370(9586):493-503.PubMedGoogle ScholarCrossref
67.
Lip  GY.  Implications of the CHA(2)DS(2)-VASc and HAS-BLED Scores for thromboprophylaxis in atrial fibrillation.  Am J Med. 2011;124(2):111-114.PubMedGoogle ScholarCrossref
68.
Hernández-Díaz  S, Rodríguez  LA.  Incidence of serious upper gastrointestinal bleeding/perforation in the general population: review of epidemiologic studies.  J Clin Epidemiol. 2002;55(2):157-163.PubMedGoogle ScholarCrossref
69.
Hernández-Díaz  S, García Rodríguez  LA.  Cardioprotective aspirin users and their excess risk of upper gastrointestinal complications.  BMC Med. 2006;4:22.PubMedGoogle ScholarCrossref
70.
Talley  NJ, Evans  JM, Fleming  KC, Harmsen  WS, Zinsmeister  AR, Melton  LJ  III.  Nonsteroidal antiinflammatory drugs and dyspepsia in the elderly.  Dig Dis Sci. 1995;40(6):1345-1350.PubMedGoogle ScholarCrossref
71.
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):2286-2294.PubMedGoogle ScholarCrossref
72.
García Rodríguez  LA, Hernández-Díaz  S, de Abajo  FJ.  Association between aspirin and upper gastrointestinal complications: systematic review of epidemiologic studies.  Br J Clin Pharmacol. 2001;52(5):563-571.PubMedGoogle ScholarCrossref
73.
Tran-Duy  A, Vanmolkot  FH, Joore  MA, Hoes  AW, Stehouwer  CD.  Should patients prescribed long-term low-dose aspirin receive proton pump inhibitors? a systematic review and meta-analysis.  Int J Clin Pract. 2015;69(10):1088-1111.PubMedGoogle ScholarCrossref
74.
Lanas  A, Wu  P, Medin  J, Mills  EJ.  Low doses of acetylsalicylic acid increase risk of gastrointestinal bleeding in a meta-analysis.  Clin Gastroenterol Hepatol. 2011;9(9):762-768.e6..PubMedGoogle ScholarCrossref
75.
Laine  L, Hennekens  C.  Proton pump inhibitor and clopidogrel interaction: fact or fiction?  Am J Gastroenterol. 2010;105(1):34-41.PubMedGoogle ScholarCrossref
76.
Abraham  NS, Hlatky  MA, Antman  EM,  et al; ACCF/ACG/AHA.  ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents.  Circulation. 2010;122(24):2619-2633.PubMedGoogle ScholarCrossref
77.
Hamm  CW, Bassand  JP, Agewall  S,  et al; ESC Committee for Practice Guidelines.  ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC).  Eur Heart J. 2011;32(23):2999-3054.PubMedGoogle ScholarCrossref
78.
Gisbert  JP, Calvet  X, Cosme  A,  et al; H. pylori Study Group of the Asociación Española de Gastroenterología (Spanish Gastroenterology Association).  Long-term follow-up of 1,000 patients cured of Helicobacter pylori infection following an episode of peptic ulcer bleeding.  Am J Gastroenterol. 2012;107(8):1197-1204.PubMedGoogle ScholarCrossref
Review
August 2016

Aspirin for Primary Prevention of Atherosclerotic Cardiovascular Disease: Advances in Diagnosis and Treatment

Author Affiliations
  • 1Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
  • 2Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
  • 3Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
JAMA Intern Med. 2016;176(8):1195-1204. doi:10.1001/jamainternmed.2016.2648
Abstract

Importance  Clinical decision making regarding the appropriate use of aspirin for the primary prevention of atherosclerotic cardiovascular disease (ASCVD) events is complex, and requires an individualized benefit to risk assessment.

Objective  To review advances in the individualized assessment for ASCVD and bleeding risk, and to provide an update of the randomized clinical trial evidence that examined the use of aspirin for primary prevention (primarily for ASCVD, and secondarily for colorectal cancer). The recently released 2016 US Preventive Services Task Force recommendations are discussed, as well as the role of ASCVD risk, age, sex, and aspirin dose/formulation in clinical decision making.

Evidence Review  We performed a detailed review of peer-reviewed publications that were identified through searches of MEDLINE and the Cochrane Database through 2016 using the literature search terms “aspirin,” “primary prevention,” “cardiovascular disease,” “mortality,” “cancer.” Bibliographies from these references as well as meta-analyses of these randomized clinical trials were also reviewed.

Findings  Evidence from a total of 11 trials involving more than 118 000 patients is available to guide clinical decision making for aspirin use in the primary prevention of ASCVD. Clinicians should balance the benefit to risk ratio and the individual’s preferences, calculating the 10-year ASCVD risk and evaluating risk factors for gastrointestinal bleeding, to facilitate a safer and more personalized approach to appropriate selection of candidates for low-dose aspirin (75 to 81 mg/d) for the primary prevention of ASCVD, with secondary considerations for reducing colorectal cancer risk when taken for longer periods (>10 years). Both the net ASCVD benefit and the bleeding risk of aspirin therapy increased as the absolute ASCVD risk increased, but the net benefits generally exceeded the risks at higher baseline ASCVD risk (≥10% ASCVD 10-year risk). The Aspirin-Guide is a clinical decision making support tool (app for mobile devices) with internal risk calculators to help clinicians with this dual assessment by calculating the ASCVD risk and the bleeding risk in the individual patient, and incorporating age- and sex-specific guidance based on randomized trial results.

Conclusions and Relevance  Balancing the benefit of ASCVD reduction with the risk of bleeding from low-dose aspirin is difficult but essential for informed decision making and achieving a net clinical benefit from aspirin for primary prevention. This is facilitated by a free and readily available evidence-based clinical decision support tool.

Introduction

Cardiovascular death remains the leading cause of death in the United States, for both women and men.1 Over the past decades, death rates from cardiovascular disease (which include coronary heart disease and stroke) have declined in US men, and more recently over the past decade in US women.1,2 Approximately half of the decline in cardiovascular death rates may be accounted for by improvements in cardiovascular risk factors, including smoking cessation and lower rates of untreated cholesterol and blood pressure, while the other half may be accounted for by evidence-based therapies including aspirin, other antiplatelet medications, statins, and antihypertensives, among other advances.3

The use of aspirin in medicine dates as far back as 3500 years ago, when Assyrian and Egyptian physicians reported (on stone and papyrus, respectively) on the analgesic and antiinflammatory effects of the extract (salicin) of willow leaves.4-6 Aspirin remains one of the most widely used medications. Currently, approximately 40% of US adults older than 50 years use aspirin for the prevention of cardiovascular diseases.7-9 Aspirin irreversibly and nonselectively inactivates cyclooxygenase (COX), inhibiting both COX-1 and COX-2 enzymes.10 At the doses used for prevention of cardiovascular diseases, aspirin’s effect on COX-1 predominates,11 preventing platelets from synthesizing thromboxane A2, a potent vasoconstrictor and promoter of platelet aggregation. But inhibiting COX-1 also depletes prostaglandin production, resulting in gut injury and contributing to the main adverse effects of aspirin including gastrointestinal (GI) bleeding and ulceration.11,12 Aspirin also has other antiinflammatory and vasodilatory effects that may be important.12,13

Randomized clinical trials14,15 confirm that, in the high-risk setting of prevalent atherosclerotic cardiovascular disease (ASCVD) or acute myocardial infarction (MI), aspirin decreases ASCVD events (approximately 20% reduction in coronary events and total stroke) and, to a lesser extent, total and cardiovascular mortality, with similar results in men and women. On an absolute scale, aspirin use for secondary prevention reduced ASCVD events by about 1% to 2% per year (greater reduction for nonfatal than fatal events), at a cost of bleeding that was generally an order of magnitude less than the ASCVD benefit.14,16 However, the picture is less clear for patients without established ASCVD (primary prevention), which has resulted in inconsistent guideline recommendations from various national and international organizations (Box). In 2014, the US Food and Drug Administration advised against aspirin use by patients to lower their risk of first heart attack or stroke unless it was prescribed by a health care professional and after a careful evaluation of the risks and benefits.24 This review focuses on advances in treatment and diagnosis that relate to the use of aspirin for primary prevention of cardiovascular disease, with discussion of additional benefits that relate to colorectal cancer, and evaluates the evidence base for recent clinical recommendations, including those of the 2016 US Preventive Services Task Force (USPSTF) (Box).17

Box Section Ref ID
Box.

Summary of Guideline Recommendations on the Use of Low-Dose Aspirin for Primary Prevention of Atherosclerotic Cardiovascular Disease

  • US Preventive Services Task Force

    • 201617

      • Use aspirin for adults aged 50-59 y with 10-y ASCVD risk ≥10%, not at increased risk of bleeding, life expectancy of ≥10 y, and willing to take aspirin for ≥10 y

      • Individualize the decision for adults aged 60-69 y with 10-y ASCVD risk 10%, not at increased risk of bleeding, life expectancy of ≥10 y, and willing to take aspirin for ≥10 y

      • No recommendation for adults aged <50 y or ≥70 y

    • 200918

      • Use aspirin when potential benefit outweighs the risk of GI bleeding:

      • Men

      • Aged 45-59 y with 10-y CHD risk ≥4%

      • Aged 60-69 y with 10-y CHD risk ≥9%

      • Aged 70-79 y with 10-y CHD risk ≥12%

      • Women

      • Aged 55-59 y with 10-y stroke risk ≥3%

      • Aged 60-69 y with 10-y stroke risk ≥8%

      • Aged 70-79 y with 10-y stroke risk ≥11%

      • Not recommended for men aged <45 y, women aged < 55 y, men and women ≥80 y

  • American Diabetes Association,19 2016

    • Use aspirin 75 to 162 mg/d for individuals with diabetes who are not at increased bleeding risk and who have 10-y ASCVD risk >10% (includes most men and women ≥50 y with diabetes and with ≥1 other ASCVD risk factors)

    • Individualize for adults with diabetes, <50 y, and multiple ASCVD risk factors (10-y ASCVD risk 5%-10%)

    • Not recommended for adults with diabetes who are at low ASCVD risk (10-y risk <5%)

  • American College of Chest Physicians,20 2012

    • Suggest aspirin use for adults ≥50 y

  • European Society of Cardiology,21 2012

    • Not recommended

  • American Heart Association,22 2011

    • Can be useful in women ≥65 y if blood pressure is controlled and benefit outweighs risk

    • May be reasonable in women <65 y for prevention of ischemic stroke

    • Not recommended for women <65 y for prevention of myocardial infarction

  • Canadian Cardiovascular Society,23 2011

    • Consider only in special circumstances (CHD risk is high and bleeding risk is low)

    • Not recommended for routine use

Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CHD, coronary heart disease; GI, gastrointestinal.

Box Section Ref ID

Key Points

  • Question Which patients should be prescribed aspirin for the primary prevention of atherosclerotic cardiovascular disease?

  • Findings In this review of advances in cardiovascular and bleeding risk assessment and the randomized clinical trial results for aspirin in primary prevention, the net cardiovascular benefit and the bleeding events increased as the absolute cardiovascular risk increased, but the benefits exceeded the risks among individuals with higher cardiovascular risk (approximate 10-year risk ≥10%). The Aspirin-Guide is a clinical decision making support tool (app for mobile devices ) with internal risk calculators to help clinicians with this dual assessment, and incorporates age- and sex-specific guidance based on randomized clinical trial results and secondary considerations for colorectal cancer prevention.

  • Meaning For the primary prevention of cardiovascular disease, decisions regarding aspirin use should be individualized, balancing the benefit to risk ratio. This can be facilitated by a free and readily available evidence-based clinical decision support tool.

Methods

We identified English-language, peer-reviewed publications through searches of the electronic databases of MEDLINE and the Cochrane Database through April 2016 using the literature search terms “aspirin,” in combination with one of the following: “primary prevention,” “heart disease,” “stroke,” “cardiovascular disease,” “mortality,” “cancer,” “clinical trials.” Bibliographies from these references as well as meta-analyses of these randomized clinical trials, were also reviewed. We also reviewed the studies in the relevant systematic reviews on aspirin from the 2009 and 2016 USPSTF recommendations.

Advances in Treatment
Randomized Clinical Trials and Meta-analyses in Primary Prevention

In individuals without clinical ASCVD, the benefit to risk ratio for aspirin should be carefully weighed because the absolute ASCVD risk is lower than that associated with patients who have been diagnosed with ASCVD and the increased risk of aspirin-related bleeding (GI bleeding and, rarely, hemorrhagic stroke) is more closely matched with the potential for benefit.25 In the 2016 USPSTF systematic evidence review of the major aspirin primary prevention clinical trials (11 trials, total N = 118 445) (Table 1),17 aspirin significantly reduced nonfatal MI (22%), cardiovascular mortality (6%), and all-cause mortality (6%), with a nonsignificant reduction in nonfatal stroke (5%).9 In the 8 trials (N = 87 524) (Table 1) that examined doses of 100 mg or less daily, aspirin significantly reduced nonfatal MI (17%), nonfatal stroke (14%), with a nonsignificant reduction in all-cause mortality (5%).9 These results are consistent with the earlier 2009 Antithrombotic Trialists’ (ATT) individual-level meta-analysis (N = 6 trials, 95 456 individuals),14 that found a 12% relative risk reduction of total ASCVD events (absolute risk reduction 0.51% vs 0.57%) in primary prevention trials (compared with 20% in secondary prevention trials), as well as results from several more recent meta-analyses. Since the ATT meta-analysis, 4 additional recent randomized trials37-41 have evaluated aspirin in primary prevention on a background of contemporary statin and other preventative therapies (included in the USPSTF analysis) (Table 1).33-36 In each of these trials individually, aspirin did not significantly reduce the primary endpoints of total ASCVD (nonfatal and fatal events), raising questions about the use of aspirin for primary prevention. However, reductions in nonfatal ASCVD events were seen in some of these recent trials, although they may have been underpowered to detect significant differences in these events and had lower than expected incidence rates.

Cardiovascular Mortality

In individuals without ASCVD, there has been little or no benefit from aspirin in reducing cardiovascular mortality (Table 1). However, the smaller reduction in cardiovascular mortality in primary prevention trials has to be viewed in the context of several important points: (1) recent advances in contemporary treatments (including antiplatelet and other regimens) and interventions (eg, revascularization and thrombolysis) for both MI and stroke, which have resulted in lower ASCVD death rates; (2) cross-contamination by crossover to active aspirin among individuals in the control arms once a nonfatal ASCVD event occurs, resulting in attenuation of the relative risk reduction of aspirin vs control for fatal ASCVD events; (3) lower absolute mortality rates in primary vs secondary prevention populations, which would necessitate much longer follow-up periods than the mean follow-up in these trials (5 to 10 years); and (4) significant reductions in nonfatal ASCVD events (MI and stroke) with aspirin in primary prevention populations would be expected to result in lower cardiovascular mortality if the duration of follow-up were adequate, because individuals with prior MI or stroke are at the highest risk for cardiovascular mortality.

Baseline ASCVD Risk

There is a continuum of risk from primary to secondary prevention, and it is uncertain where along this continuum lies the threshold level of risk that warrants aspirin use in patients without clinical ASCVD (ie, when benefit exceeds risk). Importantly, the primary prevention trials reported so far have mostly enrolled subjects with low or very low estimated baseline ASCVD risk, with more than 90% of participants having an estimated risk of less than 1% per year (10-year risk <10%).14 Both the net ASCVD benefit and the bleeding events increased as the absolute ASCVD risk increased, but the net benefits exceeded the risks at higher baseline ASCVD risk (above 1% per year, or 10% ASCVD risk over 10 years).14,37 Hence, the absolute benefit vs risk of aspirin depends on baseline ASCVD risk. Specifically, among individuals with a baseline calculated 10-year ASCVD risk of at least 10%, the estimated absolute benefit of aspirin was about 1% to 2% for reducing ASCVD events over 5 years (ie, 2% to 4% over 10 years), with a corresponding absolute GI bleeding rate of 0.5% to 1% over the same period (ie, 1% to 2% over 10 years).14 The results of ongoing trials are eagerly awaited, as these have enrolled a large proportion of individuals with 10-year risk of 10% or more on a background of modern-day therapies including statins.

Age

Age is the strongest predictor of ASCVD risk.14 Although the 2009 ATT meta-analysis of primary prevention trials found similar relative risk reduction with aspirin for individuals younger or older than 65 years,14 several individual trials found differences by age (Table 2). Age was a key determinant of a woman’s cardiovascular response to aspirin and her benefit to risk ratio with treatment.32 In the 4097 participants 65 years and older in the Women’s Health Study (WHS), the only large primary prevention trial of aspirin in women (total N = 39 876), aspirin was clearly beneficial for the primary endpoint of the trial (major ASCVD, 26% reduction), including for both MI and ischemic stroke (for aspirin by age interaction, P= .05 for major ASCVD and P = .03 for MI).32 On the other hand, women aged 45 to 64 years had no reduction in ASCVD events, but experienced a similar increase in GI bleeding, which resulted in an unfavorable benefit to risk ratio. In unpublished data, the relative risk reduction for WHS women aged 70 to 79 years was similar to women aged 60 to 69 years, with a similar relative risk of GI bleeding. Age also modified (P for interaction, .02) the aspirin benefit in reducing MI in the Physicians’ Health Study,27 where aspirin did not reduce MI or ASCVD in men younger than 50 years, in contrast with relative risk reductions in men age 50 to 59 years (42%), 60 to 69 years (54%), and 70 to 84 years (51%). In the more recent Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes trial,34 aspirin significantly reduced ASCVD (by a third) only in participants 65 years and older. Prior guidelines18 concluded that the evidence was insufficient to assess the balance of benefits and harms of aspirin therapy for primary prevention in individuals 80 years and older, while the 2016 USPSTF recommendations considered the evidence insufficient for individuals 70 years or older, or for those younger than 50 years.17

Differences by Sex

Trials14 in patients with established ASCVD have found similar aspirin efficacy in men and women. However, trials in primary prevention populations have reported sex differences (Figure). In men, aspirin reduces the risk of MI but not ischemic stroke; in women, aspirin reduces the risk of ischemic stroke but not MI.32,42 It is unclear if this reflects biologic sex differences in aspirin pharmacokinetics and/or pharmacodynamics or different incidence rates in MI and stroke by sex and age (as the occurrence of stroke relative to MI is greater in younger than older women, and MI occurs on average a decade later in women than men). The former explanation of biological differences is less likely, as no substantial differences have been noted in aspirin effects on platelet reactivity43 and no sex differences were observed in secondary prevention trials. The WHS suggested a different pattern of ASCVD benefit with aspirin in women whereby aspirin significantly lowered the risk of total and ischemic stroke, but did not lower the risk of MI except in women 65 years or older.32 This contrasted with the significant reduction in MI in men 50 years and older and neutral effect on stroke observed for men in the Physicians’ Health Study27 and other primary prevention trials.42

Nonetheless, the 2009 ATT meta-analysis and the 2016 USPSTF concluded that there is no strong evidence supporting effect modification of aspirin benefit by sex, citing that the P values for interaction by sex was no longer significant after accounting for multiple testing, despite clear sex differences in effect estimates for both MI and stroke (Figure).9,14 The 2016 USPSTF recommendations for aspirin use in primary prevention do not differ by sex (Box).17 Indeed, the strongest recommendation (Grade B, the net benefit is moderate to substantial) is given for men and women aged 50 to 59 years with a 10% or greater ASCVD risk, in contrast with a Grade I (insufficient evidence) recommendation for men and women 70 years and older.17 In our opinion, the results of the 2009 ATT meta-analysis, which included trials of diverse study populations with respect to sex, age, and risk factor profiles, as well as a wide array of aspirin doses, are less relevant than the results of the WHS—the only large-scale primary prevention trial in initially healthy women—for developing primary prevention guidelines for this population. We favor the approach taken by the 2011 American Heart Association (AHA) Guidelines for Cardiovascular Prevention in Women,22 which used the age cutpoint of 65 years (evidence-based from WHS) to recommend aspirin for older women with a favorable benefit to risk ratio, and only recommended consideration of aspirin in younger women if the benefit for ischemic stroke outweighed the risk.

Aspirin Dose and Formulation

Current guidelines offer mixed recommendations regarding the aspirin dose, ranging from not mentioning the dose to considering doses up to 325 mg /d, reflecting uncertainty in the optimal dose for cardiovascular prevention. Currently available data support the use of doses between 75 and 162 mg /d, since these are as effective as higher doses for ASCVD prevention, and may have lower bleeding rates.44 Most primary prevention trials tested doses of 100 mg/d or less (Table 1).14 We agree with the pragmatic 2016 USPSTF recommendation to use a dose of 81 mg/d (or 75 to 100 mg/d outside the United States),17 because higher doses do not prevent more ASCVD events while possibly increasing the risk of bleeding. The 2016 recommendations also appropriately point out that enteric-coated or buffered formulations do not improve the safety of aspirin, because GI bleeding and ulceration is a systemic adverse effect of prostaglandin depletion by aspirin inhibiting COX-1.45 Aspirin resistance based on platelet function testing can occur in up to 28% of individuals treated with aspirin, and this has been associated with worse ASCVD outcomes in small observational studies.46 A recent study in healthy volunteers compared a dose of 325 mg immediate-release with enteric-coated aspirin and found no aspirin resistance (by platelet function testing) in subjects given immediate-release aspirin, compared with a substantial proportion of aspirin resistance (49% at 4 hours and 17% at 8 hours) with the enteric-coated aspirin.47 Aspirin dosing of 100 mg twice daily may be more effective in inhibiting platelets than 200 mg or 100 mg once daily,48 but the data are insufficient for recommending doses higher than 162 mg daily.19 For cardiovascular primary prevention, we recommend using regular (noncoated, nonbuffered) aspirin at a daily dose of 75 to 81 mg.

Genetic Profiling

There are currently no clinical indications for targeting aspirin use based on genetic testing. In the WHS study, 2 genetic variations influenced aspirin efficacy, 1 in the LPA gene encoding lipoprotein(a)50,51 and another in the COMT gene encoding catecho-O-methyltransferase.49 These promising findings await replication in other populations. Genetic variation in the genes encoding the COX enzymes has been associated with platelet function, but there is no strong evidence of association with clinical outcomes.50,51

Colorectal Cancer Incidence and Mortality

The 2016 USPSTF recommendations now incorporate the advice to take low-dose aspirin daily for at least 10 years among individuals with a life expectancy of at least 10 years (predominantly for colorectal cancer benefit), on top of the ASCVD risk cutpoints (predominantly for cardiovascular benefit).

An association between daily aspirin allocation and reduction of long-term cancer mortality has been recently reported, with a 2011 meta-analysis52 of pooled cardiovascular randomized trials of daily aspirin vs no aspirin (25 570 participants, 674 cancer deaths) finding a net reduction in cancer mortality of about 20%, which was greater with longer duration of follow-up and consistent in both sexes. In addition to the observed effect of aspirin in reducing cancer mortality, the data for aspirin’s delayed benefit for reducing GI cancer incidence, in particular colorectal cancer, are also plausible and consistent,39,53 with aspirin reducing the long-term risk of colorectal cancer incidence by approximately 20%. The 2016 USPSTF systematic review54 estimated a relative risk reduction of 40% for aspirin use of at least 10 years on colorectal cancer incidence. Although most of the data come from a follow-up of more than 10 years in randomized clinical trials of cardiovascular prevention, these results are remarkably consistent with a recent extended follow-up report55 from 1 large trial done in women (WHS), which had cancer as a prespecified primary endpoint, as well as with a trial done among individuals with a genetic predisposition for colorectal cancer.56 Aspirin may be particularly beneficial for reducing cancer incidence and cancer mortality,39,52 especially for colorectal and other GI cancers,57 with longer durations of aspirin use (>5 to 10 years) and among individuals with risk factors for colorectal cancer, including a family history of colorectal cancer, familial syndromes (familial adenomatous polyposis or Lynch syndrome), or a personal history of colorectal adenomas. Aspirin for cancer prevention may be considered for individuals in whom the risks for ASCVD and bleeding are closely balanced; those at higher risk for colorectal cancer may have net benefit even if the net cardiovascular benefit for aspirin in these individuals is less clear.

Advances in Diagnosis
Advances in Cardiovascular Risk Assessment

Estimating cardiovascular risk is central to clinical decision making to initiate and maintain preventative therapies when risks and benefits of interventions are in question, as in the case of aspirin use for primary prevention. Cardiovascular risk assessment is usually obtained from a global risk score.58,59 Until recently, separate risk scores were used to estimate the risk of coronary heart disease (CHD: MI and coronary death) and stroke. In 2013, the American College of Cardiology (ACC) and the AHA recommended using a risk score that estimates 10-year risk of ASCVD, which includes MI, ischemic stroke, and ASCVD death, providing separate equations for women, men, blacks, and whites. These sex- and race-specific risk equations quantify the 10-year risk of ASCVD events in asymptomatic women and men age 40 to 79 years, taking into account their age, systolic blood pressure, antihypertensive therapy, diabetes, smoking status, and total and HDL cholesterol.58,59 Moreover, these risk equations can also be used among individuals treated with statins. While the calibration accuracy of these equations in contemporary populations has been debated (ie, whether the estimated ASCVD risks accurately correspond to the observed 10-year ASCVD risks), the high-risk threshold for considering aspirin use in the 2016 USPSTF recommendations is a 10-year ASCVD risk of 10%, which is more conservative than the 10-year risk of 5% to 7.5% recommended for initiating a statin discussion,58 and also similar to or higher than thresholds recommended in other recent aspirin guidelines.18,60-62

Advances in Bleeding Risk Assessment

Individuals who are at highest risk for ASCVD events tend to also be at highest risk for bleeding complications.63,64 The 2016 USPSTF aspirin recommendations apply to individuals without increased risk of bleeding (eg, history of GI ulcers, recent bleeding, or use of medications that increase bleeding risk). In the 2009 ATT meta-analysis,14 extracranial and/or GI bleeding rates were low (0.7 per 1000 person-years) and hemorrhagic stroke was even lower (0.3 per 1000 person-years). Risk factors for hemorrhagic stroke include increasing age, current smoking, and hypertension.65 Older age is a strong risk factor for intracranial hemorrhage, and the risk of bleeding in elderly individuals on aspirin is comparable to the risk of bleeding on oral anticoagulation.1,66,67 Individuals with a history of atrial fibrillation are often older and have comorbidities and concomitant medications that put them at increased risk of bleeding.66,67

GI Bleeding

Gastrointestinal bleeding is a significant predictor of death, even after adjusting for comorbidities.63,64 The 2009 meta-analysis14 found no increase in the risk of fatal GI bleeding with aspirin use in the primary prevention trials. In general populations, the estimated incidence rate of upper GI complications is approximately 1 to 2 per 1000 person-years,65 with a case fatality rate of 5% to 10% of these complications.68,69 The incidence rate of upper GI complications is often more than 2% per year in high-risk individuals. The risk of GI bleeding increases with the number of risk factors. Major risk factors (Table 3) include a history of an upper GI disorder (dyspepsia, peptic ulcer, Helicobacter pylori infection, upper GI bleeding and/or perforation), age more than 60 years (doubling in risk with each decade), male sex, and concomitant or recent use of NSAIDs and other medications, ASCVD risk factors, excess alcohol, and renal or liver disease. The strongest risk factor for GI bleeding is a prior history of peptic ulcer disease, in particular if complicated by bleeding or perforation. Gastrointestinal bleeding risk increases exponentially with age, going from less than 0.1% per year in those older than 60 years to greater than 0.5% per year at age 85 years, with approximately doubling of risk per decade. Men have a 2-fold increased risk compared with women. The ues of NSAIDs, which is common among the elderly population,70 has been associated with a variable increased risk from 1.1 in a recent Italian study71 to an increased risk of 2- to 4-fold in other populations.68,69 This risk is not mitigated by using a selective NSAID (COX-2 inhibitor) as the GI ulcer and bleeding risk of a COX-2 inhibitor combined with aspirin is similar to the risk of a nonselective NSAID.11 In randomized clinical trials, the risk of GI bleeding is approximately 50% higher with aspirin than placebo,14,37 but risks may be higher in real-world situations.72

GI Prophylaxis

A 2015 meta-analysis73 of randomized clinical trials and observational studies reported that the use of a proton pump inhibitor (PPI) may reduce the aspirin-related risk of upper GI bleeding by half, because it suppresses gastric acid production and promotes healing of ulcers and erosions.74,75 Routine use of PPI is not recommended for patients at lower bleeding risk.76 Limited data suggest that PPIs may be more effective than H2 receptor antagonists.76 Proton pump inhibitor use is recommended for reducing risk of GI bleeding in individuals with multiple bleeding risk factors who require aspirin.11,76 A recent expert consensus statement recommended PPI use for individuals with 2 or more GI risk factors (≥ 60 years, current use of corticosteroids, NSAIDs, anticoagulant therapy [each counts as 1 risk factor], and dyspepsia and/or gastroesophageal reflux disease symptoms), similar to recent recommendations from the European Society of Cardiology.77 Furthermore, limited evidence suggests that patients with a history of a peptic ulcer may derive additional benefit from Helicobacter pylori eradication.78

Aspirin-Guide: A Clinical Decision Support Tool

Guidelines have relegated the individualized ASCVD and bleeding risk assessments to health care providers in discussion with patients, although there are limited support tools for these complex comparative calculations in the busy clinic setting. The Aspirin-Guide decision support tool (available for mobile devices) aids clinicians with this dual assessment for individual patients by incorporating evidence-based decision making for the use of aspirin in primary prevention. Formal assessment of the ASCVD and GI bleeding risks is provided through internal risk calculators for these dual risk scores, along with the estimated numbers needed to treat and harm. As further refinements to the 10-year ASCVD risk estimates, the decision support tool additionally uses age and sex categories (<50 or ≥50 years for men, and <65 or ≥65 years for women, based on age- and sex-specific results from the randomized trials) to further enhance ASCVD risk stratification, and also incorporates considerations for reducing colorectal cancer risk among individuals in whom the ASCVD and bleeding risks are closely balanced.

Conclusions

In the absence of contraindications, decisions regarding aspirin use for the primary prevention of ASCVD should be highly individualized, balancing the benefit to risk ratio and patient preferences regarding anticipated long-term treatment. Clinicians should consider GI bleeding risk factors and personalize the ASCVD risk assessment with 10-year ASCVD risk calculations as well as age- and sex-specific guidance based on randomized clinical trial results, with secondary considerations regarding the potential benefit of aspirin use for colorectal cancer prevention. The Aspirin-Guide is a clinical decision making support tool and mobile app with internal risk calculators to help busy clinicians make more personalized and evidence-based decisions. Aspirin should be used consistently in both sexes for the secondary prevention of ASCVD unless contraindicated.

Back to top
Article Information

Corresponding Author: Samia Mora, MD, MHS, Center for Lipid Metabolomics, Brigham and Women’s Hospital, Harvard Medical School, 900 Commonwealth Ave E, Boston, MA 02215 (smora@partners.org).

Correction: This article was corrected on July 11, 2016, to fix an error in reporting the P for interaction value in the figure. It previously said P for interaction =.05, where it should read .005.

Published Online: June 20, 2016. doi:10.1001/jamainternmed.2016.2648.

Conflict of Interest Disclosures: Dr Mora has received research support from Atherotech Diagnostics and NHLBI, served as a consultant to Quest Diagnostics, Lilly, Amgen, Pfizer, and Cerenis Therapeutics. No other disclosures are reported.

Funding/Support: Drs Manson and Mora receive support from the National Institutes of Health (HL034594, HL117861, CA138962, and HHSN268201100001C).

Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Jeffrey M. Ames, BS, MEng, computer scientist, for expert assistance in the development of Aspirin-Guide, a mobile application and clinical decision support tool that facilitates assessment of the comparative benefits and risks of aspirin for the individual patient. He was not compensated for his contribution.

References
1.
Mozaffarian  D, Benjamin  EJ, Go  AS,  et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee.  Heart disease and stroke statistics—2015 update: a report from the American Heart Association.  Circulation. 2015;131(4):e29-e322.PubMedGoogle ScholarCrossref
2.
Murray  CJ, Atkinson  C, Bhalla  K,  et al; U.S. Burden of Disease Collaborators.  The state of US health, 1990-2010: burden of diseases, injuries, and risk factors.  JAMA. 2013;310(6):591-608.PubMedGoogle ScholarCrossref
3.
Ford  ES, Ajani  UA, Croft  JB,  et al.  Explaining the decrease in U.S. deaths from coronary disease, 1980-2000.  N Engl J Med. 2007;356(23):2388-2398.PubMedGoogle ScholarCrossref
4.
Jack  DB.  One hundred years of aspirin.  Lancet. 1997;350(9075):437-439.PubMedGoogle ScholarCrossref
5.
Fuster  V, Sweeny  JM.  Aspirin: a historical and contemporary therapeutic overview.  Circulation. 2011;123(7):768-778.PubMedGoogle ScholarCrossref
6.
Manson  JE, Burning JE, Ridker  PM, Gaziano  JM, eds.  Clinical Trials in Cardiovascular Disease: A Companion to Braunwald's Heart Disease. 2nd ed. Philadelphia, PA: WB Saunders; 2004:333-348.
7.
Pignone  M, Anderson  GK, Binns  K, Tilson  HH, Weisman  SM.  Aspirin use among adults aged 40 and older in the United States: results of a national survey.  Am J Prev Med. 2007;32(5):403-407.PubMedGoogle ScholarCrossref
8.
Mainous  AG, Tanner  RJ, Shorr  RI, Limacher  MC.  Use of aspirin for primary and secondary cardiovascular disease prevention in the United States, 2011-2012.  J Am Heart Assoc. 2014;3(4):e000989.PubMedGoogle ScholarCrossref
9.
Whitlock  EP, Williams  SB, Burda  BU, Feightner  A, Beil  T.  Aspirin Use in Adults: Cancer, All-Cause Mortality, and Harms: A Systematic Evidence Review for the US Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality; 2015. Report No. 13-05193-EF-1.
10.
Vane  JR.  Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.  Nat New Biol. 1971;231(25):232-235.PubMedGoogle ScholarCrossref
11.
Bhatt  DL, Scheiman  J, Abraham  NS,  et al; American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents.  ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents.  J Am Coll Cardiol. 2008;52(18):1502-1517.PubMedGoogle ScholarCrossref
12.
Wallace  JL.  Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn’t the stomach digest itself?  Physiol Rev. 2008;88(4):1547-1565.PubMedGoogle ScholarCrossref
13.
Yin  MJ, Yamamoto  Y, Gaynor  RB.  The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta.  Nature. 1998;396(6706):77-80.PubMedGoogle ScholarCrossref
14.
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.PubMedGoogle ScholarCrossref
15.
 Collaborative overview of randomised trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists’ Collaboration.  BMJ. 1994;308(6921):81-106.PubMedGoogle ScholarCrossref
16.
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(7329):71-86.PubMedGoogle ScholarCrossref
17.
Siu  AL; US Preventive Services Task Force.  Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: US Preventive Services Task Force recommendation statement.  Ann Intern Med. 2016;164: Epub ahead of print. doi:10.7326/M7316-0577.Google Scholar
18.
US Preventive Services Task Force.  Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement.  Ann Intern Med. 2009;150(6):396-404.PubMedGoogle ScholarCrossref
19.
American Diabetes Association.  8. Cardiovascular disease and risk management.  Diabetes Care. 2016;39(suppl 1):S60-S71.PubMedGoogle ScholarCrossref
20.
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(suppl 2):e637S-668S.Google ScholarCrossref
21.
Perk  J, De Backer  G, Gohlke  H,  et al; European Association for Cardiovascular Prevention & Rehabilitation (EACPR); ESC Committee for Practice Guidelines (CPG).  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 Heart J. 2012;33(13):1635-1701.PubMedGoogle ScholarCrossref
22.
Mosca  L, Benjamin  EJ, Berra  K,  et al.  Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update: a guideline from the american heart association.  Circulation. 2011;123(11):1243-1262.PubMedGoogle ScholarCrossref
23.
Bell  AD, Roussin  A, Cartier  R,  et al.  The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society Guidelines Executive Summary.  Can J Cardiol. 2011;27(2):208-221.PubMedGoogle ScholarCrossref
24.
US Department of Health and Human Services. FDA. Can an aspirin a day help prevent a heart attack? http://www.fda.gov/forconsumers/consumerupdates/ucm390539.Htm. 2014. Accessed October 11, 2015.
25.
Mora  S.  Aspirin therapy in primary prevention: comment on “effect of aspirin on vascular and nonvascular outcomes.”  Arch Intern Med. 2012;172(3):217-218.PubMedGoogle ScholarCrossref
26.
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.PubMedGoogle ScholarCrossref
27.
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):129-135.PubMedGoogle ScholarCrossref
28.
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.PubMedGoogle ScholarCrossref
29.
Thrombosis prevention trial.  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):233-241.PubMedGoogle ScholarCrossref
30.
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.PubMedGoogle ScholarCrossref
31.
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.PubMedGoogle ScholarCrossref
32.
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.PubMedGoogle ScholarCrossref
33.
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.PubMedGoogle ScholarCrossref
34.
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.PubMedGoogle ScholarCrossref
35.
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(9):841-848.PubMedGoogle ScholarCrossref
36.
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.PubMedGoogle ScholarCrossref
37.
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(3):209-216.PubMedGoogle ScholarCrossref
38.
Sutcliffe  P, Connock  M, Gurung  T,  et al.  Aspirin in primary prevention of cardiovascular disease and cancer: a systematic review of the balance of evidence from reviews of randomized trials.  PLoS One. 2013;8(12):e81970.PubMedGoogle ScholarCrossref
39.
Cuzick  J, Thorat  MA, Bosetti  C,  et al.  Estimates of benefits and harms of prophylactic use of aspirin in the general population.  Ann Oncol. 2015;26(1):47-57.PubMedGoogle ScholarCrossref
40.
Raju  N, Sobieraj-Teague  M, Hirsh  J, O’Donnell  M, Eikelboom  J.  Effect of aspirin on mortality in the primary prevention of cardiovascular disease.  Am J Med. 2011;124(7):621-629.PubMedGoogle ScholarCrossref
41.
Bartolucci  AA, Tendera  M, Howard  G.  Meta-analysis of multiple primary prevention trials of cardiovascular events using aspirin.  Am J Cardiol. 2011;107(12):1796-1801.PubMedGoogle ScholarCrossref
42.
Berger  JS, Roncaglioni  MC, Avanzini  F, Pangrazzi  I, Tognoni  G, Brown  DL.  Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials.  JAMA. 2006;295(3):306-313.PubMedGoogle ScholarCrossref
43.
Becker  DM, Segal  J, Vaidya  D,  et al.  Sex differences in platelet reactivity and response to low-dose aspirin therapy.  JAMA. 2006;295(12):1420-1427.PubMedGoogle ScholarCrossref
44.
Campbell  CL, Smyth  S, Montalescot  G, Steinhubl  SR.  Aspirin dose for the prevention of cardiovascular disease: a systematic review.  JAMA. 2007;297(18):2018-2024.PubMedGoogle ScholarCrossref
45.
Wallace  JL, Vong  L.  NSAID-induced gastrointestinal damage and the design of GI-sparing NSAIDs.  Curr Opin Investig Drugs. 2008;9(11):1151-1156.PubMedGoogle Scholar
46.
Krasopoulos  G, Brister  SJ, Beattie  WS, Buchanan  MR.  Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis.  BMJ. 2008;336(7637):195-198.PubMedGoogle ScholarCrossref
47.
Grosser  T, Fries  S, Lawson  JA, Kapoor  SC, Grant  GR, FitzGerald  GA.  Drug resistance and pseudoresistance: an unintended consequence of enteric coating aspirin.  Circulation. 2013;127(3):377-385.PubMedGoogle ScholarCrossref
48.
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):224-230.PubMedGoogle ScholarCrossref
49.
Chasman  DI, Shiffman  D, Zee  RY,  et al.  Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy.  Atherosclerosis. 2009;203(2):371-376.PubMedGoogle ScholarCrossref
50.
Roden  DM.  Cardiovascular pharmacogenomics: current status and future directions.  J Hum Genet. 2016;61(1):79-85.PubMedGoogle ScholarCrossref
51.
Paynter  NP, Ridker  PM, Chasman  DI.  Are genetic tests for atherosclerosis ready for routine clinical use?  Circ Res. 2016;118(4):607-619.PubMedGoogle ScholarCrossref
52.
Rothwell  PM, Fowkes  FG, Belch  JF, Ogawa  H, Warlow  CP, Meade  TW.  Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials.  Lancet. 2011;377(9759):31-41.PubMedGoogle ScholarCrossref
53.
Bosetti  C, Rosato  V, Gallus  S, Cuzick  J, La Vecchia  C.  Aspirin and cancer risk: a quantitative review to 2011.  Ann Oncol. 2012;23(6):1403-1415.PubMedGoogle ScholarCrossref
54.
Chubak  J, Whitlock  EP, Williams  SB,  et al.  Aspirin for the prevention of cancer incidence and mortality: Systematic evidence reviews for the US Preventive Services Task Force.  Ann Intern Med. 2016; Epub ahead of print. doi:10.7326/M15-2117.PubMedGoogle Scholar
55.
Cook  NR, Lee  IM, Zhang  SM, Moorthy  MV, Buring  JE.  Alternate-day, low-dose aspirin and cancer risk: long-term observational follow-up of a randomized trial.  Ann Intern Med. 2013;159(2):77-85.PubMedGoogle ScholarCrossref
56.
Burn  J, Gerdes  AM, Macrae  F,  et al; CAPP2 Investigators.  Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial.  Lancet. 2011;378(9809):2081-2087.PubMedGoogle ScholarCrossref
57.
Chan  AT, Arber  N, Burn  J,  et al.  Aspirin in the chemoprevention of colorectal neoplasia: an overview.  Cancer Prev Res (Phila). 2012;5(2):164-178.PubMedGoogle ScholarCrossref
58.
Stone  NJ, Robinson  JG, Lichtenstein  AH,  et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  Circulation. 2014;129(25)(suppl 2):S1-S45.PubMedGoogle ScholarCrossref
59.
Goff  DC  Jr, Lloyd-Jones  DM, Bennett  G,  et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  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):S49-S73.PubMedGoogle ScholarCrossref
60.
Pearson  TA, Blair  SN, Daniels  SR,  et al; American Heart Association Science Advisory and Coordinating Committee.  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.  Circulation. 2002;106(3):388-391.PubMedGoogle ScholarCrossref
61.
Redberg  RF, Benjamin  EJ, Bittner  V,  et al; American Academy of Family Physicians; American Association of Cardiovascular and Pulmonary Rehabilitation; Preventive Cardiovascular Nurses Association.  AHA/ACCF [corrected] 2009 performance measures for primary prevention of cardiovascular disease in adults: a report of the American College of Cardiology Foundation/American Heart Association task force on performance measures (writing committee to develop performance measures for primary prevention of cardiovascular disease): developed in collaboration with the American Academy of Family Physicians; American Association of Cardiovascular and Pulmonary Rehabilitation; and Preventive Cardiovascular Nurses Association: endorsed by the American College of Preventive Medicine, American College of Sports Medicine, and Society for Women’s Health Research.  Circulation. 2009;120(13):1296-1336.PubMedGoogle ScholarCrossref
62.
Goldstein  LB, Bushnell  CD, Adams  RJ,  et al; American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Epidemiology and Prevention; Council for High Blood Pressure Research; Council on Peripheral Vascular Disease, and Interdisciplinary Council on Quality of Care and Outcomes Research.  Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.  Stroke. 2011;42(2):517-584.PubMedGoogle ScholarCrossref
63.
Abbas  AE, Brodie  B, Dixon  S,  et al.  Incidence and prognostic impact of gastrointestinal bleeding after percutaneous coronary intervention for acute myocardial infarction.  Am J Cardiol. 2005;96(2):173-176.PubMedGoogle ScholarCrossref
64.
Moukarbel  GV, Signorovitch  JE, Pfeffer  MA,  et al.  Gastrointestinal bleeding in high risk survivors of myocardial infarction: the VALIANT Trial.  Eur Heart J. 2009;30(18):2226-2232.PubMedGoogle ScholarCrossref
65.
Whitlock  EP, Burda  BU, Williams  SB, Guirguis-Blake  JM, Evans  CV.  Bleeding risks with aspirin use for primary prevention in adults: A systematic evidence review for the US Preventive Services Task Force.  Ann Intern Med. 2016; Epub ahead of print. doi:10.7326/M15-2112.PubMedGoogle Scholar
66.
Mant  J, Hobbs  FD, Fletcher  K,  et al; BAFTA investigators; Midland Research Practices Network (MidReC).  Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial.  Lancet. 2007;370(9586):493-503.PubMedGoogle ScholarCrossref
67.
Lip  GY.  Implications of the CHA(2)DS(2)-VASc and HAS-BLED Scores for thromboprophylaxis in atrial fibrillation.  Am J Med. 2011;124(2):111-114.PubMedGoogle ScholarCrossref
68.
Hernández-Díaz  S, Rodríguez  LA.  Incidence of serious upper gastrointestinal bleeding/perforation in the general population: review of epidemiologic studies.  J Clin Epidemiol. 2002;55(2):157-163.PubMedGoogle ScholarCrossref
69.
Hernández-Díaz  S, García Rodríguez  LA.  Cardioprotective aspirin users and their excess risk of upper gastrointestinal complications.  BMC Med. 2006;4:22.PubMedGoogle ScholarCrossref
70.
Talley  NJ, Evans  JM, Fleming  KC, Harmsen  WS, Zinsmeister  AR, Melton  LJ  III.  Nonsteroidal antiinflammatory drugs and dyspepsia in the elderly.  Dig Dis Sci. 1995;40(6):1345-1350.PubMedGoogle ScholarCrossref
71.
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):2286-2294.PubMedGoogle ScholarCrossref
72.
García Rodríguez  LA, Hernández-Díaz  S, de Abajo  FJ.  Association between aspirin and upper gastrointestinal complications: systematic review of epidemiologic studies.  Br J Clin Pharmacol. 2001;52(5):563-571.PubMedGoogle ScholarCrossref
73.
Tran-Duy  A, Vanmolkot  FH, Joore  MA, Hoes  AW, Stehouwer  CD.  Should patients prescribed long-term low-dose aspirin receive proton pump inhibitors? a systematic review and meta-analysis.  Int J Clin Pract. 2015;69(10):1088-1111.PubMedGoogle ScholarCrossref
74.
Lanas  A, Wu  P, Medin  J, Mills  EJ.  Low doses of acetylsalicylic acid increase risk of gastrointestinal bleeding in a meta-analysis.  Clin Gastroenterol Hepatol. 2011;9(9):762-768.e6..PubMedGoogle ScholarCrossref
75.
Laine  L, Hennekens  C.  Proton pump inhibitor and clopidogrel interaction: fact or fiction?  Am J Gastroenterol. 2010;105(1):34-41.PubMedGoogle ScholarCrossref
76.
Abraham  NS, Hlatky  MA, Antman  EM,  et al; ACCF/ACG/AHA.  ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents.  Circulation. 2010;122(24):2619-2633.PubMedGoogle ScholarCrossref
77.
Hamm  CW, Bassand  JP, Agewall  S,  et al; ESC Committee for Practice Guidelines.  ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC).  Eur Heart J. 2011;32(23):2999-3054.PubMedGoogle ScholarCrossref
78.
Gisbert  JP, Calvet  X, Cosme  A,  et al; H. pylori Study Group of the Asociación Española de Gastroenterología (Spanish Gastroenterology Association).  Long-term follow-up of 1,000 patients cured of Helicobacter pylori infection following an episode of peptic ulcer bleeding.  Am J Gastroenterol. 2012;107(8):1197-1204.PubMedGoogle ScholarCrossref
×