Aspirin For Primary Prevention of Atherosclerotic Cardiovascular Disease PDF

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 individuals 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.
JAMA Intern Med. doi:10.1001/jamainternmed.2016.2648

Published online June 20, 2016.
Author Affiliations: Division of

Preventive Medicine, Department of
Medicine, Brigham and Womens
Hospital and Harvard Medical School,
Boston, Massachusetts (Mora,
Manson); Cardiovascular Division,
Department of Medicine, Brigham
and Womens 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
Womens Hospital,
Harvard Medical School,
900 Commonwealth Ave E,
Boston, MA 02215
(smora@partners.org).
(Reprinted) E1
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Mahidol University User on 06/28/2016
Clinical Review & Education Review
Aspirin for Primary Prevention of Atherosclerotic Cardiovascular Disease
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 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, aspirins 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
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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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 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 allcause 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 metaanalysis (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
JAMA Internal Medicine Published online June 20, 2016 (Reprinted)
jamainternalmedicine.com
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 womans cardiovascular response to aspirin and
her benefit to risk ratio with treatment.32 In the 4097 participants 65
years and older in the Womens 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
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%
Women
Aged 55-59 y with 10-y stroke risk 3%
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 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
(Reprinted) JAMA Internal Medicine Published online June 20, 2016
E3
E4
26

No aspirin
Placebo
75 mg
100 mg
100 mg every
other day
100 mg
81-100 mg
100 mg
100 mg
All doses
100 mg
Hypertension Optimal Treatment

(HOT)30
Primary Prevention Project

(PPP)31
Womens Health Study (WHS)32
Prevention of Progression
of Arterial Disease and Diabetes
(POPADAD)33
Japanese Primary Prevention

of Atherosclerosis with Aspirin
for Diabetes (JPAD)34
Aspirin for Asymptomatic

Atherosclerosis (AAA)35

Project (JPPP)36
Totalb
Low-dose aspirin trialsb
Total stroke.
From Guirguis-Blake et al, US Preventive Services Task Force 2016 Systematic Evidence Review.9
87 524
118 445
7220/7244, M/F, 70
1675/1675, M/F, 62
1262/1277, M/F, 65
638/638, M/F, 60
19 934/19 942, F, 54
2226/2269, M/F, 64
9399/9391, M/F, 61
1268/1272, M, 57
No aspirin
Placebo
No aspirin
Placebo
Placebo
1856/1855, M/F, ~50
11 037/11 034, M, 53
3429/1710, M, 61
No. of Subjects
(Aspirin/Control),
Sex, Mean Age, y
Abbreviation: MI, myocardial infarction.
Placebo
75 mg
Thrombosis Prevention Trial

(TPT)29
Placebo
650 mg
Early Treatment Diabetic

Retinopathy Study (ETDRS)28
No aspirin
Placebo
325 mg every
other day
300-500 mg
Control
Group
Physicians Health Study (PHS)27
British Doctors Study (BDS)
Trial (Acronym)
Aspirin Dose
(Daily, Unless
Noted)
Table 1. Summary of the Major Aspirin Primary Prevention Trials
0.83 (0.74-0.94)
0.78 (0.71-0.87)
0.53 (0.31-0.91), 20/38
0.91 (0.65-1.28), 62/68
1.35 (0.57-3.19), 12/9
0.98 (0.69-1.40), 55/56
1.01 (0.83-1.24), 184/181
0.69 (0.36-1.33), 15/22
0.60 (0.45-0.81), 68/113
0.65 (0.45-0.92), 47/73
0.83 (P .05), 524 (combined)
0.59 (0.47-0.74), 129/213
0.97 (0.67-1.41), 80/41
Nonfatal
MI
0.86 (0.76-0.98)
0.95 (0.85-1.06)
1.00 (0.77-1.31), 109/109
0.97 (0.62-1.52), 37/38
1.01 (0.60-1.72), 27/27
0.71 (0.45-1.12), 29/41
0.81 (0.67-0.97), 198/244
0.97 (0.85-1.10)
0.94 (0.86-1.03)
1.02 (0.71-1.47), 58/57
1.17 (0.72-1.89), 43/35
0.10 (0.01-0.79), 1/10
1.23 (0.80-1.89), 43/35
0.95 (0.74-1.22), 120/126
0.56 (0.31-1.01), 17/31
0.95 (0.75-1.20), 133/140
0.99 (0.78-1.24),a 146/148

0.84 (0.42-1.67), 15/18
1.05 (0.69-1.61), 42/40
0.89 (0.76-1.04), 244/275
0.92 (0.66-1.28), 66/72
1.01 (0.74-1.37), 119/59
Cardiovascular
Mortality
0.64 (0.34-1.20), 16/25
1.26 (0.89-1.80), 67/53
1.20 (0.91-1.59), 110/92
1.13 (0.72-1.77), 61/27
Nonfatal
Stroke
Relative Risk (95% CI), Aspirin/Control Number of Events
0.95 (0.89-1.01)
0.94 (0.89-0.99)
0.98 (0.84-1.15), 297/303
0.95 (0.85-1.06), 609/642
0.91 (0.57-1.43), 33/38
0.93 (0.72-1.21), 94/101
0.95 (0.85-1.06), 609/642
0.81 (0.58-1.13), 62/78
0.93 (0.79-1.09), 284/305
1.03 (0.80-1.32), 113/110
0.93 (0.79-1.09), 284/305
0.96 (0.80-1.14), 217/227
0.89 (0.74-1.08), 270/151
All-Cause
Mortality

Table 2. Relative Risk of Aspirin vs Control in Primary Prevention Trials by Age and Study
Source
Endpoint
Physicians Health Study (PHS)27
MI
Thrombosis Prevention Trial (TPT)29
CHD
Age,
Range, y
40-49
1.12
50-59
0.58
60-69
0.46
70-84
0.49
45-49
0.48
50-54
0.77
55-59
0.73
60-64
0.61
65-69
Hypertension Optimal Treatment (HOT)30
Womens Health Study (WHS)32
CVD (MI)
CVD (MI)
Prevention of Progression of Arterial

Disease and Diabetes (POPADAD)33
CVD/limb
ischemia

of Atherosclerosis with Aspirin
for Diabetes (JPAD)34
CVD
Aspirin for Asymptomatic Atherosclerosis

(AAA)35
CVD
Japanese Primary Prevention Project

(JPPP)36
CVD
Relative Risk,
Aspirin
vs Control
P Value
for Interaction
by Age
.02
.055
1.29
<65
0.79 (0.66)
65
0.92 (0.62)
45-54
1.01 (1.23)
55-64
0.98 (1.17)
65
0.74 (0.66)
<60
1.11
60
0.89
<65
1.0
65
0.68
<62
0.85
62
1.13
<65
1.00
65
0.92
NR (NR)
.05 (.03)
.44
.27
NR
Abbreviations: CHD, coronary heart
disease; CVD, cardiovascular disease;
MI, myocardial infarction; NR, not
reported.
NR
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)
Allocated Aspirin Allocated Control
RR
(95% CI)
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)
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)
Subgroup
Favors
protection
Favors
harm
Major coronary events
P for interaction = .03

Ischemic stroke
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 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 evidenceinsufficientforindividuals70yearsorolder,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 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
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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 metaanalysis, 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 WHSthe only
large-scale primary prevention trial in initially healthy womenfor
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 immediaterelease 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
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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 aspirins 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 racespecific 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, diabe te s, 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
Table 3. Major Risk Factors for Gastrointestinal Bleeding

and Related Complications
Risk Factor
Adjusted Relative Risk Increase
History of upper GI disorder

Dyspepsia/pain
Prior GI hospitalization
Peptic ulcer (uncomplicated)
Peptic ulcer with GI
bleeding/perforation
Age >60 y
Male sex
Medications
2
3
3 to 6
10
Exponential
2
Variable
NSAID use (current or recent)
1.1 to 2
Aspirin (325 mg/d)
1.5 to 2
Other antiplatelets/anticoagulants
Other
1.3 to 2
Variable (generally <2)
Smoking
Excess alcohol
Hypertension
Diabetes
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 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 personyears) and hemorrhagic stroke was even lower (0.3 per 1000 personyears). 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
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 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 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
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
E7
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 AspirinGuide 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.
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 evidencebased 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.
5. Fuster V, Sweeny JM. Aspirin: a historical and

contemporary therapeutic overview. Circulation.
2011;123(7):768-778.
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.
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 statistics2015 update: a report from
the American Heart Association. Circulation. 2015;
131(4):e29-e322.
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.
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.
4. Jack DB. One hundred years of aspirin. Lancet.
1997;350(9075):437-439.
E8
Conclusions
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.
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.
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.
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.
12. Wallace JL. Prostaglandins, NSAIDs, and gastric
mucosal protection: why doesnt the stomach
digest itself? Physiol Rev. 2008;88(4):1547-1565.
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.
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.
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.
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.
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.
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.
19. American Diabetes Association. 8.
Cardiovascular disease and risk management.
Diabetes Care. 2016;39(suppl 1):S60-S71.
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.
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.
22. Mosca L, Benjamin EJ, Berra K, et al.
Effectiveness-based guidelines for the prevention
of cardiovascular disease in women2011 update:
a guideline from the american heart association.

Circulation. 2011;123(11):1243-1262.
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):208221.
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.
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.
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.
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.
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 Councils General Practice Research
Framework. Lancet. 1998;351(9098):233-241.
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.
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.
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.
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.
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.
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.
50. Roden DM. Cardiovascular

pharmacogenomics: current status and future
directions. J Hum Genet. 2016;61(1):79-85.
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.
51. Paynter NP, Ridker PM, Chasman DI. Are genetic

tests for atherosclerosis ready for routine clinical
use? Circ Res. 2016;118(4):607-619.
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.
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.
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.
40. Raju N, Sobieraj-Teague M, Hirsh J, ODonnell
M, Eikelboom J. Effect of aspirin on mortality in the
primary prevention of cardiovascular disease. Am J
Med. 2011;124(7):621-629.
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.
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.
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.
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.
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.
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.
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):377385.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
E9
and Pulmonary Rehabilitation; and Preventive

Cardiovascular Nurses Association: endorsed by the
American College of Preventive Medicine, American
College of Sports Medicine, and Society for
Womens Health Research. Circulation. 2009;120
(13):1296-1336.
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.
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.
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.
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.
66. Mant J, Hobbs FD, Fletcher K, et al; BAFTA
investigators; Midland Research Practices Network
(MidReC). Warfarin versus aspirin for stroke
E10
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.
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.
68. Hernndez-Daz S, Rodrguez LA. Incidence of
serious upper gastrointestinal bleeding/perforation
in the general population: review of epidemiologic
studies. J Clin Epidemiol. 2002;55(2):157-163.
69. Hernndez-Daz S, Garca Rodrguez LA.
Cardioprotective aspirin users and their excess risk
of upper gastrointestinal complications. BMC Med.
2006;4:22.
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.
71. De Berardis G, Lucisano G, DEttorre A, et al.
Association of aspirin use with major bleeding in
patients with and without diabetes. JAMA. 2012;
307(21):2286-2294.
72. Garca Rodrguez LA, Hernndez-Daz 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.
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.
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..
75. Laine L, Hennekens C. Proton pump inhibitor
and clopidogrel interaction: fact or fiction? Am J
Gastroenterol. 2010;105(1):34-41.
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.
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.
78. Gisbert JP, Calvet X, Cosme A, et al; H. pylori
Study Group of the Asociacin Espaola de
Gastroenterologa (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.

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Clinical Review & Education

Aspirin for Primary Prevention of Atherosclerotic

prevention of atherosclerotic cardiovascular disease (ASCVD) events is complex, and requires

JAMA Intern Med. doi:10.1001/jamainternmed.2016.2648

Author Affiliations: Division of

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Clinical Review & Education Review

Aspirin for Primary Prevention of Atherosclerotic Cardiovascular Disease

ardiovascular death remains the leading cause of death in

mortality, cancer, clinical trials. Bibliographies from these

JAMA Internal Medicine Published online June 20, 2016 (Reprinted)

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Aspirin for Primary Prevention of Atherosclerotic Cardiovascular Disease

of these recent trials, although they may have been underpowered

Baseline ASCVD Risk

Review Clinical Review & Education

Box. Summary of Guideline Recommendations on the Use

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Hypertension Optimal Treatment

Primary Prevention Project

Womens Health Study (WHS)32

Japanese Primary Prevention

Aspirin for Asymptomatic

Japanese Primary Prevention

Low-dose aspirin trialsb

1856/1855, M/F, ~50

Abbreviation: MI, myocardial infarction.

Thrombosis Prevention Trial

Early Treatment Diabetic

Physicians Health Study (PHS)27

British Doctors Study (BDS)

Table 1. Summary of the Major Aspirin Primary Prevention Trials

0.53 (0.31-0.91), 20/38

0.91 (0.65-1.28), 62/68

1.35 (0.57-3.19), 12/9

0.98 (0.69-1.40), 55/56

1.01 (0.83-1.24), 184/181

0.69 (0.36-1.33), 15/22

0.60 (0.45-0.81), 68/113

0.65 (0.45-0.92), 47/73

0.83 (P .05), 524 (combined)

0.59 (0.47-0.74), 129/213

0.97 (0.67-1.41), 80/41

1.00 (0.77-1.31), 109/109

0.97 (0.62-1.52), 37/38

1.01 (0.60-1.72), 27/27

0.71 (0.45-1.12), 29/41

0.81 (0.67-0.97), 198/244

1.02 (0.71-1.47), 58/57

1.17 (0.72-1.89), 43/35

0.10 (0.01-0.79), 1/10

1.23 (0.80-1.89), 43/35

0.95 (0.74-1.22), 120/126

0.56 (0.31-1.01), 17/31

0.95 (0.75-1.20), 133/140

0.99 (0.78-1.24),a 146/148

1.05 (0.69-1.61), 42/40

0.89 (0.76-1.04), 244/275

0.92 (0.66-1.28), 66/72