Opinion

VIEWPOINT
Low-Dose Aspirin in the Primary Prevention
of Cardiovascular Disease
Shared Decision Making in Clinical Practice
Samia Mora, MD, MHS Clinical decision making regarding the appropriate use 50 years and aged 70 years or older, they considered the
Division of Preventive of aspirin for the primary prevention of atherosclerotic evidence to be insufficient (grade I).3
Medicine, Department cardiovascular disease (ASCVD) events is a complex pro- The USPSTF also conducted updated systematic re-
of Medicine, Brigham
cess that requires assessment of the benefits and risks views of aspirin use for primary prevention of ASCVD,4
and Women’s Hospital
and Harvard Medical for each patient. Critically important elements of the pro-cancer,5 all-cause mortality,5 and bleeding.6 In the up-
School, Boston, cess include evaluation of the patient’s absolute risk of dated study-wide meta-analysis of 11 primary preven-
Massachusetts; and ASCVD (the primary determinant of potential benefit tion trials (N = 118 445 participants), random alloca-
Division of
Cardiovascular
from aspirin), the patient’s absolute risk of bleeding (thetion to receiving aspirin vs control was associated with
Medicine, Department primary determinant of potential risk), and the pa- reductions during the trials’ follow-up periods (range,
of Medicine, Brigham tient’s willingness to undergo long-term therapy.1 De- 5-10 years) in nonfatal myocardial infarction (MI) (from
and Women’s Hospital
spite numerous general guidelines on the use of aspirin 14.4 to 11.6 per 1000; relative risk [RR], 0.78 [95% CI,
and Harvard Medical
School, Boston, for primary prevention, there is limited formal guid- 0.71-0.87]) and all-cause mortality (from 43.0 to 41.6 per
Massachusetts. ance in making these parallel assessments of benefit and 1000; RR, 0.94 [95% CI, 0.89-0.99]) with nonsignifi-
risk or in using this information to identify appropriate cant reductions in nonfatal total stroke (from 13.8 to
Jeffrey M. Ames, BS, 13.3 per 1000; RR, 0.95 [95% CI, 0.85-
MEng
1.06]) and cardiovascular mortality (from
Software and Mobile
Application Aspirin for primary prevention should 15.0 to 14.6 per 1000; RR, 0.94 [95% CI,
Development, Boston, 0.86-1.03]).4 In the 8 trials (N = 87 524
Massachusetts.
be highly individualized based on a
participants) that tested aspirin dose
benefit/risk ratio assessment for each (ⱕ100 mg/d), there was a statistically
JoAnn E. Manson, MD,
DrPH patient and a clinician-patient significant reduction in nonfatal total
Division of Preventive stroke (from 14.7 to 12.7 per 1000; RR,
Medicine, Department
discussion regarding potential benefits, 0.86 [95% CI, 0.76-0.98]),4 despite the
of Medicine, Brigham potential harms, and patient small increase in hemorrhagic stroke
and Women’s Hospital
and Harvard Medical preferences. (from 2.0 to 2.5 per 1000; RR, 1.27 [95%
School, Boston, CI, 0.96-1.68]) because only 15% of
Massachusetts; and patients for treatment. Inappropriate use of aspirin for strokes are hemorrhagic.6 The risk of GI bleeding with
Department of
primary prevention is common in clinical practice,2 high- aspirin use (ⱕ100 mg/d) significantly increased (from
Epidemiology, Harvard
T. H. Chan School of lighting the important need for improving evidence- 4.2 to 6.7 per 1000; RR, 1.58 [95% CI, 1.29-1.95]).6
Public Health, Boston, based decision making about aspirin use and for provid- The following 2 cases demonstrate the challenges of
Massachusetts. ing tools to facilitate this benefit/risk assessment. weighing potential benefits and risks of aspirin use for pri-
There 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
Supplemental
for each patient and a clinician-patient discussion re- A 57-year-old nonsmoking man with diabetes and
content at jama.com
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
Related article at Force (USPSTF) gave a grade B recommendation (mod- 10-year ASCVD risk of 12.0% (calculated using the 2013
jamainternal
erate certainty for net benefit) for the use of low-dose American College of Cardiology and the American Heart
medicine.com
aspirin (75-81 mg/d) for primary prevention of ASCVD Association pooled cohorts risk equations).7 He is re-
and 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
Corresponding and willingness to take aspirin; and (3) no increased risk aspirin for a patient with his clinical history.8
Author: JoAnn E. of bleeding (eg, no recent bleeding, no recent history of The net benefit of aspirin for this patient would be
Manson, MD, DrPH,
Brigham and Women’s
gastrointestinal [GI] ulcers, and no use of medications moderate to substantial for preventing ASCVD (specifi-
Hospital, Harvard that increase bleeding risk such as anticoagulant or cally MI) and also for preventing colorectal cancer. The
Medical School, 900 antiplatelet agents).3 For adults aged 60 to 69 years patient, with an estimated 0.12% absolute annual risk of
Commonwealth Ave,
meeting the above criteria, the USPSTF gave a grade C GI bleeding, is not at increased risk of bleeding (10-year
Third Floor, Boston, MA
02215 (jmanson@rics recommendation (not routinely recommended; indi- risk, 1.2%). With low-dose aspirin, the estimated bleed-
.bwh.harvard.edu). vidualize the decision), and for all adults younger than ing risk increases to 0.19% per year (10-year risk, 1.9%;

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 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 patient’s 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 bleed-
ing 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 hyper-
tension (blood pressure, 155/82 mm Hg) and dyslipidemia (low-
density 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 recommen-
dation for aspirin use (individualize therapy). However, the guide-
lines 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 (10-
year 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 con-
trolled (systolic <150 mm Hg). The patient’s 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-
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
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 com-
plex 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 calcu-
late both ASCVD risk7 and GI bleeding risk.6,9,10 Using this informa-
tion, 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 ran-
domized 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 prefer-
ences. However, the performance of the suggested practical
approach and the accompanying app have not been rigorously
assessed or validated in clinical studies, and the clinician’s judg-
ment 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.

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.
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