Opinion

VIEWPOINT

Samia Mora, MD, MHS

Division of Preventive
Medicine, Department
of Medicine, Brigham
and Womens Hospital
and Harvard Medical
School, Boston,
Massachusetts; and
Division of
Cardiovascular
Medicine, Department
of Medicine, Brigham
and Womens 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 Womens 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 Womens
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
(100 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 (100 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 patients absolute risk of
ASCVD (the primary determinant of potential benefit
from aspirin), the patients absolute risk of bleeding (the
primary determinant of potential risk), and the patients 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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E1

Opinion Viewpoint

number needed to harm [NNH], 144).6,9 Conversely, 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,
which would reduce this patients 10-year ASCVD risk from 12.0%
to 10.2%).
Even without accounting for the potential 20% to 40% relative
reduction in colorectal cancer risk with 10 years of daily aspirin use,
the ASCVD benefit alone (10-year NNT, 56) outweighs the GI bleeding risk (10-year NNH, 144). Furthermore, 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%.1

Patient 2
A 68-year-old nondiabetic nonsmoking woman with treated hypertension (blood pressure, 155/82 mm Hg) and dyslipidemia (lowdensity lipoprotein cholesterol, 70 mg/dL while taking a statin) has
a history of peptic ulcer disease. Despite a high 10-year ASCVD risk
of 13.2%, the USPSTF would give this patient a grade C recommendation for aspirin use (individualize therapy). However, 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).10
Because the estimated risk of ASCVD for this patient is high
(13.2%) and randomized clinical trial evidence suggests a benefit of
aspirin for reducing both MI and stroke in women aged 65 years and
older,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). The patients peptic ulcer history and
higher bleeding risk increase the complexity of decision making. If
her prior ulcer was complicated by bleeding, her GI bleeding risk
without aspirin could be as high as 7.8% over 10 years,6,9 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. Use of a practical benefit/risk
assessment approach for shared decision making (eFigure in the
Supplement) and companion mobile app (Aspirin-Guide, available
for iPhone and iPad devices free of charge) could potentially help
clinicians with this dual assessment and support evidence-based
decision making. The app has internal risk calculators that calculate both ASCVD risk7 and GI bleeding risk.6,9,10 Using this information, the app calculates the NNT and NNH. As further refinements
to the ASCVD risk estimates, the proposed practical approach
incorporates age and sex categories based on results from randomized clinical trials. 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. However, the performance of the suggested practical
approach and the accompanying app have not been rigorously
assessed or validated in clinical studies, and the clinicians judgment remains paramount for individual decision making.

Conclusions
For the primary prevention of ASCVD, decisions regarding aspirin use
should be highly individualized, balancing the benefit/risk ratio and
patient preferences regarding anticipated long-term treatment.

disease: advances in diagnosis and treatment.

JAMA Intern Med. doi:10.1001/jamainternmed.2016
.2648.

ARTICLE INFORMATION
Published Online: June 20, 2016.
doi:10.1001/jama.2016.8362.
Conflict of Interest Disclosures: Dr Mora reports
receipt of research support from Atherotech
Diagnostics and the National Heart, Lung, and
Blood Institute; serving as a consultant to Amgen,
Quest Diagnostics, Lilly, Pfizer, and Cerenis
Therapeutics; and a patent application on the use of
an NMR spectroscopy biomarker for predicting risk
of colorectal cancer. The other authors report no
disclosures.
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 National
Institutes of Health 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.
REFERENCES
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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). Even if she had a remote history
of uncomplicated ulcer, her NNT would still be higher than her NNH.
Thus, this patient would be a poor candidate for initiation of aspirin
therapy. If the patient and clinician chose to proceed with cautious
use of low-dose aspirin, concomitant GI prophylaxis should be
seriously considered.1

2. Mainous AG, Tanner RJ, Shorr RI, Limacher MC.

Use of aspirin for primary and secondary
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