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Opinion

VIEWPOINT

Samia Mora, MD, MHS
Division of Preventive
Medicine, Department
of Medicine, Brigham
and Women’s Hospital
and Harvard Medical
School, Boston,
Massachusetts; and
Division of
Cardiovascular
Medicine, Department
of Medicine, Brigham
and Women’s Hospital
and Harvard Medical
School, Boston,
Massachusetts.
Jeffrey M. Ames, BS,
MEng
Software and Mobile
Application
Development, Boston,
Massachusetts.
JoAnn E. Manson, MD,
DrPH
Division of Preventive
Medicine, Department
of Medicine, Brigham
and Women’s Hospital
and Harvard Medical
School, Boston,
Massachusetts; and
Department of
Epidemiology, Harvard
T. H. Chan School of
Public Health, Boston,
Massachusetts.

Supplemental
content at jama.com

Related article at
jamainternal
medicine.com

Corresponding
Author: JoAnn E.
Manson, MD, DrPH,
Brigham and Women’s
Hospital, Harvard
Medical School, 900
Commonwealth Ave,
Third Floor, Boston, MA
02215 (jmanson@rics
.bwh.harvard.edu).

Low-Dose Aspirin in the Primary Prevention
of Cardiovascular Disease
Shared Decision Making in Clinical Practice
50 years and aged 70 years or older, they considered the
evidence to be insufficient (grade I).3
The USPSTF also conducted updated systematic reviews of aspirin use for primary prevention of ASCVD,4
cancer,5 all-cause mortality,5 and bleeding.6 In the updated study-wide meta-analysis of 11 primary prevention trials (N = 118 445 participants), random allocation to receiving aspirin vs control was associated with
reductions during the trials’ follow-up periods (range,
5-10 years) in nonfatal myocardial infarction (MI) (from
14.4 to 11.6 per 1000; relative risk [RR], 0.78 [95% CI,
0.71-0.87]) and all-cause mortality (from 43.0 to 41.6 per
1000; RR, 0.94 [95% CI, 0.89-0.99]) with nonsignificant reductions in nonfatal total stroke (from 13.8 to
13.3 per 1000; RR, 0.95 [95% CI, 0.851.06]) and cardiovascular mortality (from
15.0 to 14.6 per 1000; RR, 0.94 [95% CI,
Aspirin for primary prevention should
0.86-1.03]).4 In the 8 trials (N = 87 524
be highly individualized based on a
participants) that tested aspirin dose
benefit/risk ratio assessment for each
(ⱕ100 mg/d), there was a statistically
significant reduction in nonfatal total
patient and a clinician-patient
stroke (from 14.7 to 12.7 per 1000; RR,
discussion regarding potential benefits,
0.86 [95% CI, 0.76-0.98]),4 despite the
potential harms, and patient
small increase in hemorrhagic stroke
(from 2.0 to 2.5 per 1000; RR, 1.27 [95%
preferences.
CI, 0.96-1.68]) because only 15% of
patients for treatment. Inappropriate use of aspirin for strokes are hemorrhagic.6 The risk of GI bleeding with
primary prevention is common in clinical practice,2 high- aspirin use (ⱕ100 mg/d) significantly increased (from
lighting the important need for improving evidence- 4.2 to 6.7 per 1000; RR, 1.58 [95% CI, 1.29-1.95]).6
based decision making about aspirin use and for providThe following 2 cases demonstrate the challenges of
ing tools to facilitate this benefit/risk assessment.
weighing potential benefits and risks of aspirin use for priThere is general consensus across clinical guide- mary prevention of ASCVD (eFigure in the Supplement).
lines that aspirin for primary prevention should be highly
individualized based on a benefit/risk ratio assessment Patient 1
for each patient and a clinician-patient discussion re- A 57-year-old nonsmoking man with diabetes and
garding potential benefits, potential harms, and pa- treated hypertension (blood pressure, 120/75 mm Hg)
tient preferences.1 The 2016 US Preventive Services Task and no prior GI disorders or bleeding has a calculated
Force (USPSTF) gave a grade B recommendation (mod- 10-year ASCVD risk of 12.0% (calculated using the 2013
erate certainty for net benefit) for the use of low-dose American College of Cardiology and the American Heart
aspirin (75-81 mg/d) for primary prevention of ASCVD Association pooled cohorts risk equations).7 He is reand colorectal cancer in adults aged 50 to 59 years who ceptive to the concept of long-term aspirin use. The 2016
meet all of the following criteria: (1) ASCVD 10-year risk USPSTF guidelines and the 2016 American Diabetes
of at least 10%; (2) at least 10 years of life expectancy Association recommendations advise use of low-dose
and willingness to take aspirin; and (3) no increased risk aspirin for a patient with his clinical history.8
of bleeding (eg, no recent bleeding, no recent history of
The net benefit of aspirin for this patient would be
gastrointestinal [GI] ulcers, and no use of medications moderate to substantial for preventing ASCVD (specifithat increase bleeding risk such as anticoagulant or cally MI) and also for preventing colorectal cancer. The
antiplatelet agents).3 For adults aged 60 to 69 years patient, with an estimated 0.12% absolute annual risk of
meeting the above criteria, the USPSTF gave a grade C GI bleeding, is not at increased risk of bleeding (10-year
recommendation (not routinely recommended; indi- risk, 1.2%). With low-dose aspirin, the estimated bleedvidualize the decision), and for all adults younger than ing risk increases to 0.19% per year (10-year risk, 1.9%;
Clinical decision making regarding the appropriate use
of aspirin for the primary prevention of atherosclerotic
cardiovascular disease (ASCVD) events is a complex process that requires assessment of the benefits and risks
for each patient. Critically important elements of the process include evaluation of the patient’s absolute risk of
ASCVD (the primary determinant of potential benefit
from aspirin), the patient’s absolute risk of bleeding (the
primary determinant of potential risk), and the patient’s willingness to undergo long-term therapy.1 Despite numerous general guidelines on the use of aspirin
for primary prevention, there is limited formal guidance in making these parallel assessments of benefit and
risk or in using this information to identify appropriate

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decisions regarding aspirin use should be highly individualized. randomized clinical trials of aspirin therapy indicate that the RR reduction for preventing MI for men 50 years and older may be even greater than 15%.2016 . Robinson JG. Lilly. Preventive Services Task Force [published online April 12.6. et al. However.9. 2011-2012. JAMA Published online June 20. Tanner RJ. Guirguis-Blake JM. Despite a high 10-year ASCVD risk of 13. the app calculates the NNT and NNH. Mora S. Beil T. Manson JE. Lucisano G.1001/jama. 144). 8.10 Using this information. 307(21):2286-2294. Preventive Services Task Force.2%).6. 144). this patient would be a poor candidate for initiation of aspirin therapy. doi:10. García Rodríguez LA. management. which would reduce this patient’s 10-year ASCVD risk from 12. and Blood Institute. Diabetes Care. Aspirin for primary prevention of atherosclerotic cardiovascular E2 rin may further increase this risk to more than 12% (10-year NNH of 23 compared with an NNT of 50).1 2. 4. Rockville. and interpretation of the data. Circulation. Conflict of Interest Disclosures: Dr Mora reports receipt of research support from Atherotech Diagnostics and the National Heart. BMC Med. Use of a practical benefit/risk assessment approach for shared decision making (eFigure in the Supplement) and companion mobile app (Aspirin-Guide. The other authors report no disclosures. collection. and decision to submit the manuscript for publication. 2016].9 Conversely. If her prior ulcer was complicated by bleeding. This app and other tools may help clinicians and patients work together to personalize treatment decisions based on risk stratification and incorporation of patient preferences. doi:10. Role of the Funder/Sponsor: The National Institutes of Health had no role in the design and conduct of the study. Furthermore. Ann Intern Med. analysis. disease: advances in diagnosis and treatment. 155/82 mm Hg) and dyslipidemia (lowdensity lipoprotein cholesterol. Conclusions For the primary prevention of ASCVD. 2006. Lichtenstein AH. 8: Cardiovascular disease and risk management. ARTICLE INFORMATION Published Online: June 20. 6. and Harms: A Systematic Evidence Review for the U. Lung. preparation. Preventive Services Task Force recommendation statement [published online April 12. concomitant GI prophylaxis should be seriously considered. the estimated 10-year number needed to treat (NNT) to prevent 1 ASCVD event is 56 (assuming 15% RR reduction of ASCVD with low-dose aspirin. 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.2016.S. 7.7326/M15-2112. Whitlock EP.2648. 2014.39(suppl 1):S60-S71. 2015. Mainous AG.1001/jamainternmed. Even if she had a remote history of uncomplicated ulcer. Cardioprotective aspirin users and their excess risk of upper gastrointestinal complications. et al. 9. Ann Intern Med.9 and aspi- Decision Support Algorithm and App Limited guidance is available regarding how to estimate the aspirin benefit/risk ratio in clinical practice without tools for these complex comparative calculations. available for iPhone and iPad devices free of charge) could potentially help clinicians with this dual assessment and support evidence-based decision making.2%) and randomized clinical trial evidence suggests a benefit of aspirin for reducing both MI and stroke in women aged 65 years and older. Evans CV. balancing the benefit/risk ratio and patient preferences regarding anticipated long-term treatment. JAMA Intern Med. HL117861. If the patient and clinician chose to proceed with cautious use of low-dose aspirin. The patient’s peptic ulcer history and higher bleeding risk increase the complexity of decision making. Evidence Synthesis 132/AHRQ publication 13-05193-ef-1. 2016 (Reprinted) Copyright 2016 American Medical Association. Feightner A. the USPSTF would give this patient a grade C recommendation for aspirin use (individualize therapy). the proposed practical approach incorporates age and sex categories based on results from randomized clinical trials.3(4): e000989. However. CA138962.8% over 10 years. Ann Intern Med. 2016]. American College of Cardiology/American Heart Association Task Force on Practice Guidelines.7326/M15-2113. Bibbins-Domingo K. Aspirin Use in Adults: Cancer. 70 mg/dL while taking a statin) has a history of peptic ulcer disease.jamanetwork. J Am Heart Assoc. Whitlock EP. her NNT would still be higher than her NNH.4:22. 3. review. Williams SB. Burda BU. US Preventive Services Task Force. American Diabetes Association. Preventive Services Task Force [published online April 12. 2014.6. Shorr RI.8362. the guidelines would also consider her at high risk for GI bleeding (older age and prior peptic ulcer disease could increase her GI bleeding risk as much as 6-fold if an uncomplicated ulcer and as much as 10-fold if the ulcer was complicated by bleeding). O’Connor EA. De Berardis G.com . doi:10. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U. Funding/Support: Drs Manson and Mora receive support from the National Institutes of Health (HL034594. 5. Association of aspirin use with major bleeding in patients with and without diabetes. Pfizer. Even without accounting for the potential 20% to 40% relative reduction in colorectal cancer risk with 10 years of daily aspirin use. and Cerenis Therapeutics. and the clinician’s judgment remains paramount for individual decision making.129(25) (suppl 2):S1-S45. 2016. Whitlock EP.Opinion Viewpoint number needed to harm [NNH].10 Because the estimated risk of ASCVD for this patient is high (13. and HHSN268201100001C). REFERENCES 1. doi:10. As further refinements to the ASCVD risk estimates. Whitlock EP. 2012. Williams SB.7326/M16-0577. her GI bleeding risk without aspirin could be as high as 7. JAMA. D’Ettorre A. Guirguis-Blake JM. MD: Agency for Healthcare Research and Quality. All-Cause Mortality. Evans CV. 10. the performance of the suggested practical approach and the accompanying app have not been rigorously assessed or validated in clinical studies. The app has internal risk calculators that calculate both ASCVD risk7 and GI bleeding risk. Use of aspirin for primary and secondary cardiovascular disease prevention in the United States. serving as a consultant to Amgen. 2016. 56) outweighs the GI bleeding risk (10-year NNH.1 Patient 2 A 68-year-old nondiabetic nonsmoking woman with treated hypertension (blood pressure. Senger CA.S. Thus. Quest Diagnostics.S. Downloaded From: http://jama. Hernández-Díaz S. Stone NJ. Burda BU.2%. 2016].1 this patient would be a candidate for low-dose aspirin (10year NNH of 133 compared with an NNT of 50) if she did not have a history of peptic ulcer disease and her blood pressure were well controlled (systolic <150 mm Hg). or approval of the manuscript. Limacher MC.com/ by a Mahidol University User on 06/28/2016 jama. the ASCVD benefit alone (10-year NNT. Aspirin for the primary prevention of cardiovascular events: a systematic evidence review for the U.0% to 10. Bleeding risks with aspirin use for primary prevention in adults: a systematic evidence review for the U. and a patent application on the use of an NMR spectroscopy biomarker for predicting risk of colorectal cancer. doi:10. All rights reserved.S.