Aspirin for Primary Prevention of Cardiovascular

Disease in the 21st Century: A Review of the Evidence

, ,
Dominick J Angiolillo, MD,PhD,FACC,FESC,FSCAIa * #, and Davide Capodanno, MD,PhDb

Aspirin (ASA) is the most commonly prescribed antiplatelet agent. Although the evidence
for efficacy of aspirin for secondary prevention of ischemic events in patients with estab-
lished cardiovascular disease is strong, its role in primary prevention has been subject of
controversies over the past decades. In fact, historical trials have shown only modest benefit
in terms of reduction of ischemic events, mostly myocardial infarction and to a lesser extent
stroke, and only at the expense of an increased risk of bleeding. These observations have led
to divergent recommendations from professional societies on the use of ASA for primary
prevention of cardiovascular disease manifestations. However, recent results from three tri-
als of primary prevention have shown either no benefit or modest benefit on combined ische-
mic end points, without any impact on hard cardiovascular events such as myocardial
infarction or stroke, accompanied by an increased risk of bleeding. Overall, this translated
into neutral net benefit or even harm with the use of aspirin in patients with no overt cardio-
vascular disease. These results have accordingly led to a downgrade in the current recom-
mendations on the use of ASA for primary prevention. This article provides an overview on
the current evidence on the use of aspirin for primary prevention of cardiovascular dis-
ease. © 2020 Elsevier Inc. All rights reserved. (Am J Cardiol 2021;144:S15−S22)

Acetylsalicylic acid, universally known as aspirin
(ASA), is the most commonly utilized antiplatelet agent
and has long represented the cornerstone of pharmacologic
treatment for the prevention of atherothrombotic complica-
tions associated with cardiovascular disease (CVD).1
Although the benefits of aspirin in secondary prevention are
well established, its role in primary prevention is a matter
of controversy.1 Trials conducted over 2 decades ago, dur-
ing which time other primary prevention measures such as
lipid-lowering therapy were not commonly utilized,
reported that ASA could reduce myocardial infarction (MI)
and stroke at the expense of increased bleeding, with no
effect on mortality.2 These findings resulted in a widespread
use of aspirin for primary prevention. However, results of
more contemporary trials have recently become available
and overall demonstrate neutral net clinical benefit or even
evidence of harm.3−8 These observations have led to recon-
sider the value of ASA for primary prevention and for prac-
tice guidelines to provide revised recommendations. The
present manuscript provides an overview on the use of
ASA for primary prevention of CVD.
Aspirin: Key Pharmacologic Principles
Enteric-coated oral formulations of low-dose aspirin
(e.g., 75 to 100 mg) are most commonly used for chronic
a
Division of Cardiology, University of Florida College of Medicine,
Jacksonville, Florida; and bDivision of Cardiology, A.O.U. “Policlinico-
Vittorio Emanuele,” University of Catania, Catania, Italy. Manuscript
received November 21, 2020; revised manuscript received and accepted
December 11, 2020.
This article is published as part of a supplement supported by an educa-
tional grant from AstraZeneca.
#
https://orcid.org/0000-0001-8451-2131
*Corresponding author: Tel: (1) 904-244-3378; fax: (1) 904-244-3102.
E-mail address: dominick.angiolillo@jax.ufl.edu (D.J. Angiolillo).
treatment.1,9 The reason for the increased uptake of enteric-
coated formulations of ASA is because these were devel-
oped to overcome gastrointestinal toxicity associated with
uncoated formulations, although such safety benefit remain
unproven.1 Enteric-coated aspirin is absorbed by the gastro-
intestinal mucosa. Compared with uncoated formulations,
plasma peak levels after oral intake is slower with enteric-
coated (3 to 4 hours vs 15 to 20 minutes) and also associ-
ated with reduced bioavailability.1,9 The dosing regimen,
gastric pH and presence of food may modulate absorption
rate.1,9 Once in the portal circulation, platelets are exposed
to a higher levels of aspirin compared with the systemic cir-
culation, characterized by a fast renal clearance.1 The half-
life is 15 to 20 minutes, but the pharmacodynamic effects
of ASA last for the life-span of the platelet (7-10 days)
given its irreversible mechanism of action, represented by
permanent blockade of cyclooxygenase (COX)-1 enzyme
activity.1 Thus, generation of new platelets is the only way
to overcome this effect.9
Low-dose aspirin regimens (e.g., 75 to 100 mg once
daily) exceeds the minimum dose required for complete
COX-1 blockade.1,9 Moreover, aspirin may accumulate in
the bone marrow and exert COX-1 inhibitory effects on
megakaryocytes, leading to a dose-dependent inhibi-
tion.10,11 By inhibiting prostaglandin H synthases 1 and 2,
named respectively COX-1 and COX-2, aspirin can
decrease generation of thromboxane A2 (TXA2), prostacy-
clin (PGI2), and other arachidonic acid-derived prosta-
noids.9 However, these molecules are characterized by 2
opposed biological effects. The TXA2 pathway stimulates
platelet activation and aggregation, while PGI2 is critical in
protecting the gastrointestinal mucosa.12 In particular, in
the gastrointestinal tract, prostaglandins are key in epithe-
lial mucus production, microvascular mucosal perfusion,
and wound healing. Therefore, the physical disruption of
the protective gastric phospholipid barrier induced by ASA

0002-9149/© 2020 Elsevier Inc. All rights reserved. www.ajconline.org

https://doi.org/10.1016/j.amjcard.2020.12.022
S16 The American Journal of Cardiology (www.ajconline.org)
associated with impaired gastrointestinal protection facili-
tates and perpetuates direct acid injury (i.e., promoting new
mucosal lesions and worsening of existing lesions in a
dose-dependent manner).12 The presence of impaired
hemostasis induced by ASA adds to this phenomenon,
favoring the risk of bleeding complications.9 The risk of
bleeding complications is increased with the use of non-
selective nonsteroidal anti-inflammatory drugs (ns-
NSAIDs) which also compete with aspirin for its binding
site (i.e., COX-1), potentially also increasing the risk of
thrombotic events.13 These findings underscore the impor-
tance of avoiding the use of ns-NSAIDS (e.g., ibuprofen,
naproxen) in subjects concomitantly treated with ASA.
In addition to drugs interfering with the COX-1 enzyme,
other mechanisms have been identified as contributory to
impaired aspirin-induced antiplatelet effects. These include
noncompliance, medical conditions such as diabetes melli-
tus, and impaired absorption of enteric-coated formula-
tions.9,14 Indeed, avoiding interfering agents such as ns-
NSAIDs and being compliant are pivotal to ensure that
ASA is exerting its effects. Twice-daily aspirin administra-
tion for patients with diabetes mellitus, which is character-
ized by high platelet turnover rates, have been suggested to
provide more effective platelet inhibition in pharmacody-
namic studies, but its clinical implications still remain
unknown.11,15−17 The development of novel formulations
that overcome drawbacks associated with enteric-coating
are also under investigation,9 and will be addressed in this
Supplement by Dr. Bhatt. Most recently it has been sug-
gested that the efficacy of ASA can be modulated by subject
weight, with modest benefits of aspirin being attributed to
under-dosing in patients of large body size and excess dos-
ing in patients of small body size.18 The impact of twice-
daily ASA regimens in patients with diabetes mellitus (to
tackle the high platelet turnover rates) and that of different
dosing regimens of aspirin is being testing in secondary pre-
vention, but not primary prevention trials.19
Historical Trials And Meta-Analyses of Aspirin for
Primary Prevention
Multiple trials of aspirin for primary prevention of CVD
have been reported.20−35 However, only few trials
Table 1
Study design and selected clinical outcomes of aspirin (100 mg once daily) in the ARRIVE, ASCEND and ASPREE trials
ARRIVE (N=12,546)
Type of study Randomized, double-blind, placebo-con-
trolled, multicenter
Study Population Moderate risk of CVD
Primary endpoint HR 0.96; 95% CI 0.81 - 1.13; p=0.60
All-cause death HR 0.99; 95% CI 0.80 -1.24); p=0.95
CV death HR 0.97; 95% CI 0.62 − 1.52; p=0.90
GI bleeding HR 2.11; 95% CI 1.36 - 3.28; p=0.0007
ICH NA
Outcomes are reported for aspirin vs. placebo. Abbreviations: BMI = body mass index; CI = confidence interval; CVD = cardiovascular disease; GI = gas-
trointestinal; ICH = intracranial hemorrhage; HR = hazard ratio; MI = myocardial infarction; NA = not available; SD = standard deviation; RR = rate ratio;
UA = unstable angina; TIA = transient ischemic attack.
demonstrated a significant reduction in their primary effi-
cacy end points, and most studies showed an increased risk
of bleeding.22,23,30,34 Heterogeneity in the dosing regimen
and populations studied could have contributed to these
conflicting findings. In a pooled analysis from the Antith-
rombotic Trialists’ collaboration of 6 primary prevention
studies, ASA was associated with a 12% and 0.07% relative
and absolute risk reduction, respectively, in the composite
of vascular death, MI or stroke, corresponding to 1,429
patients needed to treat to prevent 1 serious vascular
event.36 A number of other meta-analyses reported similar
relative and absolute risk reductions in combined serious
vascular events, mostly driven by a reduction in MI (13%
to 22% relative reduction) and, to a lesser extent, in stroke
(5% to 14% relative reduction).37−40 All-cause mortality
was observed to be reduced only in few meta-analyses and
only very modestly (6% relative reduction).41,42 Such
reduction in ischemic benefit was largely counterbalanced
by an increase in major bleeding (55% to 69% relative
increase) and hemorrhagic stroke (33% to 43% relative
increase).41,43
Contemporary Trials of Aspirin for Primary Prevention
In 2018, 3 randomized primary prevention trials of ASA
were published and provided new insights in the contempo-
rary era on the safety and efficacy of this strategy. These tri-
als include the ARRIVE (Aspirin to reduce risk of initial
vascular events),3 ASCEND (Study of cardiovascular
events in diabetes),4 and ASPREE (Aspirin in reducing
events in the elderly) trials.5−7 Study design and key out-
comes of these 3 trials are summarized in Table 1 and
Figure 1. Most recently, in 2020, the TIPS-3 (the Interna-
tional Polycap Study 3) evaluated the role of aspirin either
alone or as part of a polypill for the primary prevention of
cardiovascular disease.44 Study design and key outcomes of
TIPS-3 are not included in Table 1 and Figure 1 given the
nature of the study design and absence of analytical assess-
ments of bleeding complications at the of writing of this
manuscript. However, a detailed description of all 4 trials is
provided below.
ARRIVE - ARRIVE was a prospective randomized,
double-blind, placebo-controlled trial. A total of 12,546
ASCEND (N=15,840) ASPREE (N=19,114)
Randomized, double-blind, placebo-con- Randomized double-blind placebo-controlled,
trolled, multicenter multicenter
Diabetes with no evident CVD 70+ years (non-minorities) or 65+ years (U.S.
minorities) with no CVD, dementia, or physi-
cal disability
RR 0.88; 95% CI 0.79-0.97; p=0.01 HR 1.01; 95% CI 0.92 - 1.11; p=0.79
NA HR 1.14; 95% CI 1.01 - 1.29; p=NA
RR 0.91; 95% CI 0.75 - 1.10; p=NA HR 0.82; 95% CI 0.62−1.08; p=NA
RR 1.36; 95% CI 1.05 - 1.75 p=NA HR 1.87; 95% CI 1.32 - 2.66; p=NA (Upper GI)
HR 1.36; 95% CI 0.96 - 1.94; p=NA (Lower GI)
RR 1.22; 95% CI 0.82 - 1.81 p=NA HR 1.50; 95% CI 1.11 - 2.02; p=NA
 Aspirin CVD Supplement/Aspirin for Primary Prevention
Figure 1. Treatment effects in ARRIVE, ASCEND and ASPREE. Efficacy outcomes are synthetized as number of patients needed to treat (NNT) to prevent
one event. Safety outcomes are synthetized as number of patients needed to harm (NNH) to provoke an event. NNT and NNH are reported for illustrative pur-
poses regardless of statistical significance. Only ASCEND significantly reduced its primary end point, with a NNT of 91. *Statistically significant increase;
y
Upper gastrointestinal bleeding
men aged ≥55 years and women aged ≥60 years at antici-
pated moderate CVD risk were recruited 3. The trial aimed
at randomizing patients at moderate CVD risk defined as a
10-year risk of coronary heart disease ranging between
10% and 20%. Diabetic patients were intentionally not
included, as they were felt to represent a cohort at high
CVD risk. In light of the lower than anticipated event rate,
the primary end point of cardiovascular death, MI, and
stroke was expanded to include unstable angina and tran-
sient ischemic attack. Moreover, the study design was mod-
ified from event-driven to duration-driven and the duration
of the trial was extended. Subjects were followed for a
median of 5 years; men represented 70% of the trial popula-
tion, and the mean age was 69 years. Compared with pla-
cebo, aspirin did not significantly reduce the primary
efficacy end point, a composite of cardiovascular death,
MI, unstable angina, stroke, or transient ischemic attack
(4.29% ASA vs 4.48% placebo, hazard ratio [HR] 0.96,
95% confidence interval [CI] 0.81 to 1.13; p = 0.60). None
of the components of the primary end point were reduced
with ASA. Similarly, all-cause death also did not differ
between groups. Aspirin treatment was associated with an
increased risk of gastrointestinal bleeding (0.97% aspirin vs
0.46% placebo, HR 2.11, 95% CI 1.36 to 3.28; p = 0.0007);
the rates of hemorrhagic stroke were similar between
groups. Despite the modifications made to the study proto-
col, cardiovascular events occurred at a lower than antici-
pated rate based on risk the score assessments used. These
observations could have affected the efficacy findings of
aspirin in ARRIVE, which ultimately was a trial conducted
in subjects at low, rather than moderate, CVD risk. Impor-
tantly, observations from this trial question the validity of
available risk scores calculators and underscore the need
for more contemporary risk assessment measures.45
ASCEND - ASCEND was specifically designed to com-
pare the safety and efficacy of ASA in patients with type 1
or 2 diabetes without established CVD.4 ASCEND had a
S17
2 £ 2 factorial design, and in addition to comparing aspirin
vs placebo, it also compared the effects of n
3 fatty acids
or placebo on vascular events.46 Because of the lower than
expected event rates, the design of ASCEND was modified
during the course of the trial by including transient ischemic
events in the primary efficacy end point, by extending the
study duration, and by expanding the sample size. A total
of 15,480 patients presented mostly with type 2 diabetes
mellitus (94%); 58% of participants were on hypoglycemic
agents and 25% were on insulin with or without hypoglyce-
mic agents. Men represented 63% of the trial population,
and the mean age was 63 years. At a mean follow up of
7.4 years, compared with placebo, ASA significantly
reduced the primary efficacy end point, a composite of vas-
cular death excluding confirmed intracranial hemorrhage,
MI, non-hemorrhagic stroke or transient ischemic attack
(8.5% aspirin vs 9.6% placebo, risk ratio [RR] 0.88, 95%
CI 0.79 to 0.97; p = 0.01). However, aspirin did not reduce
all-cause death and vascular death. Major bleeding events,
a composite of intracranial hemorrhage, sight-threatening
intra-ocular bleeding, gastrointestinal bleeding, or other
serious bleeding, were significantly increased by aspirin
(4.1% ASA vs 3.2% placebo, RR 1.29, 95% CI 1.09 to
1.52; p = 0.003), driven by a higher incidence of gastroin-
testinal bleeding. However, there was no significant
increase in fatal bleeding and hemorrhagic stroke. Finally,
there was no significant difference between ASA and pla-
cebo in the incidence of gastrointestinal tract cancer or all
cancers. Although ASCEND was a positive trial, the treat-
ment effect was overall small (1.1% absolute reduction in
the primary end point) corresponding to a number of
patients needed to treat with ASA to prevent a vascular
event of 91. However, this must be weighed against a 0.9%
absolute increase in major bleeding and the lack of any
effect on cardiovascular or all-cause mortality.
ASPREE −ASPREE was a prospective randomized,
double-blind, placebo-controlled trial designed to
S18 The American Journal of Cardiology (www.ajconline.org)
investigate the role of aspirin in elderly patients of
>70 years (>65 for Black and Hispanic study participants),
with a focus on disability-free survival and cardiovascular
outcomes.5−7 Subjects with confirmed dementia, poor cog-
nitive status, physical disability, contraindication to ASA
use, or at increased bleeding risk were excluded. A total of
19,114 participants were randomized to aspirin or placebo.
Men represented 44% of the trial population, and the
median age was 74 years. At a median follow-up of
4.7 years, there were no differences on the primary efficacy
end point, a composite of death, dementia, or persistent
physical disability (21.5 events per 1000 person-years in
the aspirin group and 21.2 per 1,000 person-years in the pla-
cebo group, HR 1.01, 95% CI, 0.92 to 1.11; p = 0.79).7
There were also no differences in cardiovascular events,
including cardiovascular death, MI and stroke.6 The risk of
major bleeding was higher with aspirin (3.8% ASA vs 2.8%
placebo, HR 1.38; 95% CI, 1.18 to 1.62; p <0.001), driven
by an increased risk of upper gastrointestinal bleeding. Of
note, any intracranial bleeding was also significantly
increased among ASA-treated subjects (HR 1.50, 95% CI
1.11 to 2.02) (Figure 1).6 Importantly, all-cause mortality
was increased among aspirin-treated subjects (12.7 events
per 1000 person-years in the ASA group and 11.1 events
per 1000 person-years in the placebo group; HR 1.14; 95%
CI 1.01 to 1.29), largely attributed to cancer.5
TIPS-3 - TIPS-3 was a double-blind, randomized, pla-
cebo-controlled trial with a 2-by-2-by-2 factorial design.44
The first randomized comparison tested the effect of treat-
ment with a daily polypill comprising 40 mg of simvastatin,
100 mg of atenolol, 25 mg of hydrochlorothiazide, and
10 mg of ramipril, as compared with placebo, on the inci-
dence of cardiovascular outcomes. The second randomized
comparison tested the effect of treatment with enteric-
coated aspirin at a dose of 75 mg per day, as compared with
placebo, on the incidence of cardiovascular outcomes (pri-
mary outcome) and the composite of cardiovascular out-
comes and cancer (secondary outcome); the effects of the
polypill plus aspirin as compared with double placebo was
also tested. The third randomized comparison tested the
effect of treatment with vitamin D at a monthly dose of
60,000 IU, as compared with placebo, on the incidence of
fractures and falls. For the polypill-alone and polypill-plus-
aspirin comparisons, the primary outcome was death from
cardiovascular causes, MI, stroke, resuscitated cardiac
arrest, heart failure, or revascularization. For the aspirin
comparison, the primary outcome was death from cardio-
vascular causes, MI, or stroke. The study enrolled men
≥50 years of age and women ≥55 years of age who did not
have known cardiovascular disease but at intermediate or
high cardiovascular risk as defined by the INTERHEART
Risk Score.
A total of 5713 participants were randomized; the mean
follow-up was 4.6 years. Men represented 47% of the trial
population, and the mean age was 64 years. Low-density
lipoprotein cholesterol level was lower by approximately
19 mg per deciliter and systolic blood pressure was lower
by approximately 5.8 mm Hg with the polypill and with
combination therapy than with placebo. The primary out-
come for the polypill comparison was of borderline statisti-
cal significance occurring in 126 participants (4.4%) in the
polypill group and in 157 (5.5%) in the placebo group (HR,
0.79; 95% CI, 0.63 to 1.00). The primary outcome for the
aspirin comparison was not significantly reduced occurring
in 116 participants (4.1%) in the aspirin group and in 134
(4.7%) in the placebo group (HR, 0.86; 95% CI, 0.67 to
1.10). Similarly, there were no differences on new cancer
which occurred in 38 participants (1.3%) in the aspirin
group and in 46 (1.6%) in the placebo group (HR, 0.83;
95% CI, 0.54 to 1.27). The primary outcome for the poly-
pill-plus-aspirin comparison occurred in 59 participants
(4.1%) in the combined-treatment group and in 83 (5.8%)
in the double-placebo group (HR, 0.69; CI, 0.50 to 0.97).
The incidence of hypotension or dizziness was higher in
groups that received the polypill than in their respective
placebo groups leading to higher rates of treatment discon-
tinuation. Although statistical comparisons have not been
reported, the incidence of major and minor bleeding were
low and similar between aspirin and placebo.
Guideline Recommendations
Prior to the release of the ARRIVE, ASCEND and
ASPREE trials, guidelines on the use of aspirin for the pri-
mary prevention of cardiovascular events broadly varied.
Most, but not all, recommendations from the European
Society of Cardiology (ESC) and affiliated working groups
recommended against initiating ASA in patients without
overt CVD.47 The American Heart Association (AHA) and
American Diabetes Association (ADA) guidelines released
in 2015 instead recommended a risk-based approach. In
particular, aspirin was recommended for primary preven-
tion in diabetes mellitus patients with a 10-year risk of
CVD events >10% who are not at increased risk of bleeding
(class IIa) and on a case-by-case basis in patients with an
intermediate 10-year risk of 5% to 10% (class IIb).48−50
Similarly, the 2016 US Preventative Services Task Force
guideline recommended ASA for patients aged 50 to
59 years with a 10% or greater 10-year CVD risk and a low
risk of bleeding, but recommended individualized decision-
making in patients aged 60 to 69 years.51 The more recent
recommendations incorporating the evidence coming from
the ARRIVE, ASCEND and ASPREE trials are included in
an updated iteration of the ACC/AHA prevention guide-
lines released in March 2019. These recommendations do
not take into consideration the results of TIPS-3 as this was
reported in November 2020. In particular, these guidelines
indicate that aspirin is contraindicated for primary preven-
tion in adults older than 70 years (class III), while it can
potentially be considered in high-risk adults aged between
40 years and 70 years (class IIb).52 Similar recommenda-
tions have also been provided by the ADA and the Euro-
pean Society of Cardiology (Table 2).53,54
Ongoing Research and Future Directions
The ongoing ACCEPT-D (Aspirin and Simvastatin
Combination for Cardiovascular Events Prevention Trial in
Diabetes) is a randomized, double-blind, event-driven trial
of low-dose aspirin (100 mg once daily) evaluating the syn-
ergy of ASA and statins on primary CVD prevention
in patients (n=5,170) with type 1 and type 2 diabetes aged
 Aspirin CVD Supplement/Aspirin for Primary Prevention S19

Table 2
Guideline recommendations for low-dose aspirin for primary prevention of stroke and myocardial infarction
Guideline, Year Recommendations Class LOE
ACC/AHA Primary CVD Prevention,2019
Aspirin (75 mg to 100 mg/day) might be considered among select adults IIb A
40−70 years of age who are at higher ASCVD risk but not at increased
bleeding risk*
Low-dose aspirin should not be administered routinely among adults III B-Ry
> 70 years of age
Low-dose aspirin should not be administered among adults of any age who III C-LDz
are at increased risk of bleeding
ADA, 2020
Aspirin (75 to 162 mg/day) may be considered for patients age 50 N/A A
−70 years of age with DM who are at increased risk for ASCVD after a
comprehensive discussion on the benefits vs increased risk of bleeding
Aspirin is not recommended for those at low risk of ASCVD (including
patients age < 50 years)
Clinical judgment should be used for patients age 50−70 years at moderate
risk of ASCVD
Aspirin should general not be used in older adults age > 70 year
ESC Guidelines on Diabetes, Prediabetes
and CVDs, 2019
Aspirin (75 mg to 100 mg/day) may be considered in patients with DM at IIb A
high/very high risk in the absence of clear contraindicationsx,{
Aspirin is not recommended for patients with DM at moderate CV risk III B
If low-dose aspirin is used, consider using a proton pump inhibitor to pre- IIa A
vent GI bleeding
AHA = American Heart Association; ACC = American College of Cardiology; ADA = American Diabetes Association; ASCVD = atherosclerotic cardio-
vascular disease; CV = cardiovascular; DM = diabetes mellitus; ESC = European Society of Cardiology; GI = gastrointestinal; N/A = not applicable
**
Is not recommended, evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful.
* history of previous gastrointestinal bleeding or peptic ulcer disease or bleeding from other sites, age > 70 years, thrombocytopenia, coagulopathy, chronic
kidney disease, and concurrent use of other medications that increase bleeding risk, such as nonsteroidal anti-inflammatory agents, steroids, oral
anticoagulants
y
Level B evidence, randomized, controlled trials.
z
Level C evidence, limited data.
x
contraindications: gastrointestinal bleeding, peptic ulceration within the previous 6 months, active hepatic disease, or history of aspirin allergy.
{
Very high risk: patients with diabetes mellitus and established cardiovascular disease, or other target organ damage, or 3 or more major risk factors, or
early onset type 1 diabetes mellitus of long duration; High risk: patients with diabetes mellitus duration of 10 years or greater without target organ damage
plus any other additional risk factor.

≥ 50 years with no clinically overt CVD and on therapy
with a starting dose of simvastatin 20 mg.55 The primary
outcome will be a composite of cardiovascular death, non-
fatal MI, non-fatal stroke, or inpatient or outpatient hospital
admission for cardiovascular causes, including acute coro-
nary syndrome, unplanned revascularization procedures
and peripheral vascular disease. This will likely be the last
of the contemporary trials evaluating the efficacy of ASA
for primary prevention of vascular events.
The observation from post-hoc assessments that aspirin
may have an impact on cancer-related complications have
prompted prospective investigations in the field. The ADD-
ASPIRIN trial is investigating the use of aspirin after stan-
dard anticancer therapy for preventing cancer recurrence in
patients with 4 different common types of nonmetastatic
solid tumors (colorectal, breast, gastro-esophageal, pros-
tate).56 Indeed, results of these investigations could modify
the current position of the benefit-risk ratio of aspirin in
patients with no overt CVD.
Other areas of investigation that may impact the role of
aspirin for primary prevention include studies of aspirin for-
mulations with reduced gastrointestinal toxicity. Whether
the use of proton pump inhibitors can have an impact on the
risk-benefit profile of aspirin in primary prevention also
represents an area poorly explored. However, a better
assessment of risk of future vascular events, using risk
scores derived from more contemporary data integrated
with imaging studies associated with prognostic value (e.g.,
calcium score) are warranted to evaluate a treatment effect
of aspirin as traditional risk scores utilized in most recent
trials have clearly overestimated vascular risk.57 The benefit
of ASA in populations at higher ischemic risk than those
enrolled in most recent trials, and perhaps younger than the
population that did not derive any benefit in the ASPREE
cohort, potentially followed for a longer period of time,
warrants further investigation.
Conclusions
In summary, the totality of the evidence supporting the
use of aspirin for primary prevention of vascular events,
particularly in light of the most recent ARRIVE, ASCEND,
and ASPREE trials, is weak. The lack of or very modest
reductions in overall combined ischemic event rates is
S20 The American Journal of Cardiology (www.ajconline.org)
offset by an increase in bleeding. The newer clinical trial
evidence is even less convincing than prior trials given that
no reductions in MI and stroke were observed. Overall,
these findings suggest that aspirin should not be routinely
prescribed to patients with no overt CVD in the modern era.
Practice guidelines have been updated to reflect these most
recent clinical trial observations.
Conflict of Interest
Dr. Angiolillo declares that he has received consulting
fees or honoraria from Abbott, Amgen, Aralez, AstraZe-
neca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-
Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemo-
netics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer,
Sanofi, and The Medicines Company and has received pay-
ments for participation in review activities from CeloNova
and St Jude Medical. D.J.A. also declares that his institution
has received research grants from Amgen, AstraZeneca,
Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-San-
kyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani
Chemical Industry Co., Merck, Novartis, Osprey Medical,
Renal Guard Solutions, and the Scott R. MacKenzie Foun-
dation. Dr. Capodanno declares that he has received con-
sulting and speaker’s fee from AstraZeneca, Bayer,
Boehringer Ingelheim, Daiichi Sankyo, outside the present
work. The authors of this Supplement gratefully acknowl-
edge the financial support of educational grant funding
from AstraZeneca Pharmaceuticals.
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