Clinical Review & Education

Review

Aspirin for Primary Prevention of Atherosclerotic

Cardiovascular Disease
Advances in Diagnosis and Treatment
Samia Mora, MD, MHS; JoAnn E. Manson, MD, DrPH

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.
Author Affiliations: Division of
CONCLUSIONS AND RELEVANCE Balancing the benefit of ASCVD reduction with the risk of Preventive Medicine, Department of
bleeding from low-dose aspirin is difficult but essential for informed decision making and Medicine, Brigham and Women’s
Hospital and Harvard Medical School,
achieving a net clinical benefit from aspirin for primary prevention. This is facilitated by a free
Boston, Massachusetts (Mora,
and readily-available evidence-based clinical decision support tool. Manson); Cardiovascular Division,
Department of Medicine, Brigham
and Women’s Hospital and Harvard
Medical School, Boston,
Massachusetts (Mora); Department
of Epidemiology, Harvard T. H. Chan
School of Public Health, Boston,
Massachusetts (Manson).
Corresponding Author: Samia Mora,
MD, MHS, Center for Lipid
Metabolomics, Brigham and
Women’s Hospital,
Harvard Medical School,
900 Commonwealth Ave E,
JAMA Intern Med. doi:10.1001/jamainternmed.2016.2648 Boston, MA 02215
Published online June 20, 2016. (smora@partners.org).

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 Clinical Review & Education Review
C
ardiovascular 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 in-
clude coronary heart disease and stroke) have declined in US men,
and more recently over the past decade in US women.1,2 Approxi-
mately half of the decline in cardiovascular death rates may be ac-
counted for by improvements in cardiovascular risk factors, includ-
ing smoking cessation and lower rates of untreated cholesterol and
blood pressure, while the other half may be accounted for by evi-
dence-based therapies including aspirin, other antiplatelet medica-
tions, 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 ef-
fects 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 car-
diovascular diseases.7-9 Aspirin irreversibly and nonselectively in-
activates cyclooxygenase (COX), inhibiting both COX-1 and COX-2
enzymes.10 At the doses used for prevention of cardiovascular dis-
eases, aspirin’s effect on COX-1 predominates,11 preventing plate-
lets from synthesizing thromboxane A2, a potent vasoconstrictor and
promoter of platelet aggregation. But inhibiting COX-1 also de-
pletes prostaglandin production, resulting in gut injury and contrib-
uting to the main adverse effects of aspirin including gastrointesti-
nal (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 simi-
lar 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 re-
sulted in inconsistent guideline recommendations from various na-
tional 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 pre-
scribed by a health care professional and after a careful evaluation
of the risks and benefits.24 This review focuses on advances in treat-
ment and diagnosis that relate to the use of aspirin for primary pre-
vention of cardiovascular disease, with discussion of additional ben-
efits 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
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,”
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Aspirin for Primary Prevention of Atherosclerotic Cardiovascular Disease
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.
“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 as-
pirin should be carefully weighed because the absolute ASCVD risk
is lower than that associated with patients who have been diag-
nosed with ASCVD and the increased risk of aspirin-related bleed-
ing (GI bleeding and, rarely, hemorrhagic stroke) is more closely
matched with the potential for benefit.25 In the 2016 USPSTF sys-
tematic evidence review of the major aspirin primary prevention clini-
cal 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 ear-
lier 2009 Antithrombotic Trialists’ (ATT) individual-level meta-
analysis (N = 6 trials, 95 456 individuals),14 that found a 12% rela-
tive 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 re-
cent randomized trials37-41 have evaluated aspirin in primary pre-
vention on a background of contemporary statin and other preven-
tative 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
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 Aspirin for Primary Prevention of Atherosclerotic Cardiovascular Disease
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 anti-
platelet and other regimens) and interventions (eg, revasculariza-
tion 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 non-
fatal 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 popu-
lations, 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 preven-
tion trials reported so far have mostly enrolled subjects with low or
very low estimated baseline ASCVD risk, with more than 90% of par-
ticipants 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 ben-
efits exceeded the risks at higher baseline ASCVD risk (above 1% per
year, or 10% ASCVD risk over 10 years).14,37 Hence, the absolute ben-
efit 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 re-
sults 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), aspi-
rin was clearly beneficial for the primary endpoint of the trial (major
ASCVD, 26% reduction), including for both MI and ischemic stroke (for
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Review Clinical Review & Education
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
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 reduc-
tion in ASCVD events, but experienced a similar increase in GI bleed-
ing, which resulted in an unfavorable benefit to risk ratio. In unpub-
lished data, the relative risk reduction for WHS women aged 70 to 79
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Clinical Review & Education Review

Table 1. Summary of the Major Aspirin Primary Prevention Trials

Aspirin Dose No. of Subjects Relative Risk (95% CI), Aspirin/Control Number of Events
(Daily, Unless Control (Aspirin/Control), Nonfatal Nonfatal Cardiovascular All-Cause
Trial (Acronym) Noted) Group Sex, Mean Age, y MI Stroke Mortality Mortality
British Doctors’ Study (BDS)26 300-500 mg No aspirin 3429/1710, M, 61 0.97 (0.67-1.41), 80/41 1.13 (0.72-1.77), 61/27 1.01 (0.74-1.37), 119/59 0.89 (0.74-1.08), 270/151
Physicians’ Health Study (PHS)27 325 mg every Placebo 11 037/11 034, M, 53 0.59 (0.47-0.74), 129/213 1.20 (0.91-1.59), 110/92 0.92 (0.66-1.28), 66/72 0.96 (0.80-1.14), 217/227
other day
Early Treatment Diabetic 650 mg Placebo 1856/1855, M/F, ~50 0.83 (P ≤ .05), 524 (combined) 1.26 (0.89-1.80), 67/53 0.89 (0.76-1.04), 244/275 0.93 (0.79-1.09), 284/305
Retinopathy Study (ETDRS)28
Thrombosis Prevention Trial 75 mg Placebo 1268/1272, M, 57 0.65 (0.45-0.92), 47/73 0.64 (0.34-1.20), 16/25 1.05 (0.69-1.61), 42/40 1.03 (0.80-1.32), 113/110
(TPT)29
Hypertension Optimal Treatment 75 mg Placebo 9399/9391, M/F, 61 0.60 (0.45-0.81), 68/113 0.99 (0.78-1.24),a 146/148 0.95 (0.75-1.20), 133/140 0.93 (0.79-1.09), 284/305
(HOT)30
Copyright 2016 American Medical Association. All rights reserved.

Primary Prevention Project 100 mg No aspirin 2226/2269, M/F, 64 0.69 (0.36-1.33), 15/22 0.84 (0.42-1.67), 15/18 0.56 (0.31-1.01), 17/31 0.81 (0.58-1.13), 62/78
(PPP)31
Women’s Health Study (WHS)32 100 mg every Placebo 19 934/19 942, F, 54 1.01 (0.83-1.24), 184/181 0.81 (0.67-0.97), 198/244 0.95 (0.74-1.22), 120/126 0.95 (0.85-1.06), 609/642
other day
Prevention of Progression 100 mg Placebo 638/638, M/F, 60 0.98 (0.69-1.40), 55/56 0.71 (0.45-1.12), 29/41 1.23 (0.80-1.89), 43/35 0.93 (0.72-1.21), 94/101
of Arterial Disease and Diabetes
(POPADAD)33
Japanese Primary Prevention 81-100 mg No aspirin 1262/1277, M/F, 65 1.35 (0.57-3.19), 12/9 1.01 (0.60-1.72), 27/27 0.10 (0.01-0.79), 1/10 0.91 (0.57-1.43), 33/38
of Atherosclerosis with Aspirin
for Diabetes (JPAD)34
Aspirin for Asymptomatic 100 mg Placebo 1675/1675, M/F, 62 0.91 (0.65-1.28), 62/68 0.97 (0.62-1.52), 37/38 1.17 (0.72-1.89), 43/35 0.95 (0.85-1.06), 609/642
Atherosclerosis (AAA)35
Japanese Primary Prevention 100 mg No aspirin 7220/7244, M/F, 70 0.53 (0.31-0.91), 20/38 1.00 (0.77-1.31), 109/109 1.02 (0.71-1.47), 58/57 0.98 (0.84-1.15), 297/303
Project (JPPP)36
b
Total All doses 118 445 0.78 (0.71-0.87) 0.95 (0.85-1.06) 0.94 (0.86-1.03) 0.94 (0.89-0.99)

Aspirin for Primary Prevention of Atherosclerotic Cardiovascular Disease

Low-dose aspirin trialsb ≤100 mg 87 524 0.83 (0.74-0.94) 0.86 (0.76-0.98) 0.97 (0.85-1.10) 0.95 (0.89-1.01)

Abbreviation: MI, myocardial infarction.

a
Total stroke.
b
From Guirguis-Blake et al, US Preventive Services Task Force 2016 Systematic Evidence Review.9
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 Aspirin for Primary Prevention of Atherosclerotic Cardiovascular Disease Review Clinical Review & Education

Table 2. Relative Risk of Aspirin vs Control in Primary Prevention Trials by Age and Study
Relative Risk, P Value
Age, Aspirin for Interaction
Source Endpoint Range, y vs Control by Age
Physicians’ Health Study (PHS)27 MI 40-49 1.12
50-59 0.58
.02
60-69 0.46
70-84 0.49
Thrombosis Prevention Trial (TPT)29 CHD 45-49 0.48
50-54 0.77
55-59 0.73 .055
60-64 0.61
65-69 1.29
Hypertension Optimal Treatment (HOT)30 CVD (MI) <65 0.79 (0.66)
NR (NR)
≥65 0.92 (0.62)
Women’s Health Study (WHS)32 CVD (MI) 45-54 1.01 (1.23)
55-64 0.98 (1.17) .05 (.03)
≥65 0.74 (0.66)
Prevention of Progression of Arterial CVD/limb <60 1.11
Disease and Diabetes (POPADAD)33 ischemia .44
≥60 0.89
Japanese Primary Prevention CVD <65 1.0
of Atherosclerosis with Aspirin .27
for Diabetes (JPAD)34 ≥65 0.68
Aspirin for Asymptomatic Atherosclerosis CVD <62 0.85
(AAA)35 NR
≥62 1.13 Abbreviations: CHD, coronary heart
Japanese Primary Prevention Project CVD <65 1.00 disease; CVD, cardiovascular disease;
(JPPP)36 NR MI, myocardial infarction; NR, not
≥65 0.92
reported.

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

Events (%/y)
RR Favors Favors
Subgroup Allocated Aspirin Allocated Control (95% CI) protection harm
Major coronary events
Men 635 (0.57%/y) 801 (0.72%/y) 0.77 (0.67-0.89)
Women 299 (0.14%/y) 314 (0.14%/y) 0.95 (0.77-1.17)
P for interaction = .03
Ischemic stroke
Men 312 (0.28%/y) 292 (0.26%/y) 1.06 (0.85-1.32)
Women 227 (0.10%/y) 301 (0.14%/y) 0.75 (0.60-0.94)
P for interaction = .05

0.50 0.75 1.0 1.25 1.50

RR (95% CI)

years was similar to women aged 60 to 69 years, with a similar rela-
tive 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 Dia-
betes 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 evi-
denceinsufficientforindividuals70yearsorolder,orforthoseyounger
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 pre-
vention 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 phar-
macokinetics 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

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 Clinical Review & Education Review
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 USP-
STF concluded that there is no strong evidence supporting effect
modification of aspirin benefit by sex, citing that the P values for in-
teraction by sex was no longer significant after accounting for mul-
tiple 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 re-
spect 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 as-
pirin 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 rec-
ommendation 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, be-
cause GI bleeding and ulceration is a systemic adverse effect of pros-
taglandin depletion by aspirin inhibiting COX-1.45 Aspirin resis-
tance 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 resis-
tance (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 effec-
tive in inhibiting platelets than 200 mg or 100 mg once daily,48 but
the data are insufficient for recommending doses higher than
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Aspirin for Primary Prevention of Atherosclerotic Cardiovascular Disease
162 mg daily.19 For cardiovascular primary prevention, we recom-
mend 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 rep-
lication in other populations. Genetic variation in the genes encod-
ing 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 colo-
rectal cancer benefit), on top of the ASCVD risk cutpoints (predomi-
nantly 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) find-
ing 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 can-
cer 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 inci-
dence. Although most of the data come from a follow-up of more
than 10 years in randomized clinical trials of cardiovascular preven-
tion, these results are remarkably consistent with a recent ex-
tended 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 co-
lorectal cancer.56 Aspirin may be particularly beneficial for reduc-
ing cancer incidence and cancer mortality,39,52 especially for colo-
rectal and other GI cancers,57 with longer durations of aspirin use
(>5 to 10 years) and among individuals with risk factors for colorec-
tal cancer, including a family history of colorectal cancer, familial syn-
dromes (familial adenomatous polyposis or Lynch syndrome), or a
personal history of colorectal adenomas. Aspirin for cancer preven-
tion may be considered for individuals in whom the risks for ASCVD
and bleeding are closely balanced; those at higher risk for colorec-
tal 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
jamainternalmedicine.com
 Aspirin for Primary Prevention of Atherosclerotic Cardiovascular Disease Review Clinical Review & Education

use for primary prevention. Cardiovascular risk assessment is usu- Table 3. Major Risk Factors for Gastrointestinal Bleeding
ally obtained from a global risk score.58,59 Until recently, separate and Related Complications
risk scores were used to estimate the risk of coronary heart dis-
Risk Factor Adjusted Relative Risk Increase
ease (CHD: MI and coronary death) and stroke. In 2013, the Ameri-
History of upper GI disorder
can College of Cardiology (ACC) and the AHA recommended using
Dyspepsia/pain 2
a risk score that estimates 10-year risk of ASCVD, which includes
Prior GI hospitalization 3
MI, ischemic stroke, and ASCVD death, providing separate equa-
Peptic ulcer (uncomplicated) 3 to 6
tions for women, men, blacks, and whites. These sex- and race-
Peptic ulcer with GI 10
specific risk equations quantify the 10-year risk of ASCVD events in bleeding/perforation
asymptomatic women and men age 40 to 79 years, taking into Age >60 y Exponential
account their age, systolic blood pressure, antihypertensive Male sex 2
therapy, diabe te s, smoking status, and total and HDL Medications Variable
cholesterol.58,59 Moreover, these risk equations can also be used
NSAID use (current or recent) 1.1 to 2
among individuals treated with statins. While the calibration accu-
Aspirin (≤325 mg/d) 1.5 to 2
racy of these equations in contemporary populations has been
Other antiplatelets/anticoagulants 1.3 to 2
debated (ie, whether the estimated ASCVD risks accurately corre-
Other Variable (generally <2)
spond to the observed 10-year ASCVD risks), the high-risk thresh-
Smoking
old for considering aspirin use in the 2016 USPSTF recommenda-
Excess alcohol
tions is a 10-year ASCVD risk of 10%, which is more conservative
Hypertension
than the 10-year risk of 5% to 7.5% recommended for initiating a
Diabetes
statin discussion,58 and also similar to or higher than thresholds
recommended in other recent aspirin guidelines.18,60-62 Increased BMI
Renal or liver disease

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 as-
pirin recommendations apply to individuals without increased risk
of bleeding (eg, history of GI ulcers, recent bleeding, or use of medi-
cations 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 fac-
tor 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 medica-
tions that put them at increased risk of bleeding.66,67
GI Bleeding
Gastrointestinal bleeding is a significant predictor of death, even af-
ter adjusting for comorbidities.63,64 The 2009 meta-analysis14 found
no increase in the risk of fatal GI bleeding with aspirin use in the pri-
mary prevention trials. In general populations, the estimated inci-
dence 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 fac-
tors (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 de-
cade), 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 per-
foration. Gastrointestinal bleeding risk increases exponentially with
age, going from less than 0.1% per year in those older than 60 years
Abbreviations: BMI, body mass index calculated as weight in kilograms divided
by height in meters squared; GI, gastrointestinal.
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 com-
pared 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 observa-
tional studies reported that the use of a proton pump inhibitor (PPI)
may reduce the aspirin-related risk of upper GI bleeding by half, be-
cause 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 in-
dividuals with multiple bleeding risk factors who require aspirin.11,76
A recent expert consensus statement recommended PPI use for in-
dividuals 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 Euro-
pean Society of Cardiology.77 Furthermore, limited evidence sug-
gests that patients with a history of a peptic ulcer may derive
additional benefit from Helicobacter pylori eradication.78

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 Clinical Review & Education Review Aspirin for Primary Prevention of Atherosclerotic Cardiovascular Disease

Aspirin-Guide: A Clinical Decision Support Tool

Guidelines have relegated the individualized ASCVD and bleeding
risk assessments to health care providers in discussion with pa-
tients, 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 cli-
nicians with this dual assessment for individual patients by incor-
porating evidence-based decision making for the use of aspirin in
primary prevention. Formal assessment of the ASCVD and GI bleed-
ing 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 fur-
ther enhance ASCVD risk stratification, and also incorporates con-
siderations 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
s exe s f o r t h e s e c o n d a r y p r e ve n t i o n o f A S C V D u n l e s s
contraindicated.

ARTICLE INFORMATION
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.
5. Fuster V, Sweeny JM. Aspirin: a historical and
contemporary therapeutic overview. Circulation.
2011;123(7):768-778.
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,
individual participant data from randomised trials.
Lancet. 2009;373(9678):1849-1860.
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.

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.
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