JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 73, NO.

23, 2019

ª 2019 THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION.

PUBLISHED BY ELSEVIER. ALL RIGHTS RESERVED.

ORIGINAL INVESTIGATIONS

Aspirin for Primary Prevention of

Cardiovascular Events
Hesham K. Abdelaziz, MD, PHD,a,b,* Marwan Saad, MD, PHD,b,c,* Naga Venkata K. Pothineni, MD,c
Michael Megaly, MD, MS,d,e Rahul Potluri, MD,f Mohammed Saleh, MD,g David Lai Chin Kon, MD,a
David H. Roberts, MD,a Deepak L. Bhatt, MD, MPH,h Herbert D. Aronow, MD, MPH,i J. Dawn Abbott, MD,i
Jawahar L. Mehta, MD, PHDc

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Author Disclosures: Dr. Bhatt has served on the Advisory Board of Car-
dax, Elsevier Practice Update Cardiology, Medscape Cardiology, Phase-
Bio, and Regado Biosciences; has served on the Board of Directors of
Boston VA Research Institute, Society of Cardiovascular Patient Care,
and TobeSoft; has served as Chair of the American Heart Association
Quality Oversight Committee, NCDR-ACTION Registry Steering
Committee, and VA CART Research and Publications Committee; has
served on Data Monitoring Committees for Baim Institute for Clinical
Research (formerly Harvard Clinical Research Institute, for the
PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland
Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai
School of Medicine (for the ENVISAGE trial, funded by Daiichi-
Sankyo), and Population Health Research Institute; has received
honoraria from American College of Cardiology (Senior Associate
Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC
Accreditation Committee), Baim Institute for Clinical Research
(formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical
trial steering committee funded by Boehringer Ingelheim), Belvoir
Publications (Editor-in-Chief, Harvard Heart Letter), Duke Clinical
Research Institute (clinical trial steering committees), HMP Global
(Editor-in-Chief, Journal of Invasive Cardiology), Journal of the
American College of Cardiology (Guest Editor; Associate Editor),
Population Health Research Institute (for the COMPASS operations
committee, publications committee, steering committee, and
USA national co-leader, funded by Bayer), Slack Publications (Chief
Medical Editor, Cardiology Today’s Intervention), Society of
Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME
steering committees); has served as Deputy Editor of Clinical
Cardiology; has received research funding from Abbott, Amarin,
Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers
Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood,
Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi,

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2019.03.501

2916 Abdelaziz et al. JACC VOL. 73, NO. 23, 2019

Aspirin for Primary Prevention of CVD JUNE 18, 2019:2915–29

Synaptic, and The Medicines Company; has received royalties from
Elsevier (Editor, Cardiovascular Intervention: A Companion to
Braunwald’s Heart Disease); has served as Site Co-Investigator for
Biotronik, Boston Scientific, St. Jude Medical (now Abbott), and
Svelte; has served as a Trustee of the American College of Cardiology;
and has performed unfunded research for FlowCo, Merck, Novo
Nordisk, PLx Pharma, and Takeda. Dr. Abbott has received research
grant support from Bayer, Boehringer Ingelheim, and AstraZeneca,
and the Department of Veterans Affairs, Veterans Health
Administration, Office of Research and Development, Biomedical
Laboratory Research and Development (Washington, DC, USA) (grant
No BX-000282-05).
Medium of Participation: Print (article only); online (article and quiz).

grants with no direct compensation from Sinomed, Abbott Vascular,

CME/MOC/ECME Term of Approval
Biosensors Research, Bristol-Myers Squibb, AstraZeneca, and CSL
Behring. Dr. Mehta has served as consultant to Bayer, Boehringer Issue Date: June 18, 2019
Ingelheim, AstraZeneca, MedImmmune, and Pfizer; and has received Expiration Date: June 17, 2020

From the aLancashire Cardiac Center, Blackpool Victoria Hospital, Blackpool, United Kingdom; bDepartment of Cardiovascular
Medicine, Ain Shams University, Cairo, Egypt; cDivision of Cardiovascular Medicine, University of Arkansas for Medical Sciences
and The Central Arkansas Veterans Healthcare System, Little Rock, Arkansas; dMinneapolis Heart Institute, Abbott Northwestern
Hospital, Minneapolis, Minnesota; eHennepin Healthcare, Minneapolis, Minnesota; fAston Medical School, School of Medical
Sciences, Aston University, Birmingham, United Kingdom; gDepartment of Medicine, Creighton University, Omaha, Nebraska;
h
Brigham and Women’s Hospital Heart & Vascular Center, Harvard Medical School, Boston, Massachusetts; and the iDivision of
Cardiovascular Medicine, The Warren Alpert Medical School of Brown University and Lifespan Cardiovascular Institute, Provi-
dence, Rhode Island. *Drs. Abdelaziz and Saad contributed equally to this work and are joint first authors. Dr. Bhatt has served on
the Advisory Board of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, and Regado Biosciences; has
served on the Board of Directors of Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; has served
as Chair of the American Heart Association Quality Oversight Committee, NCDR-ACTION Registry Steering Committee, and VA
CART Research and Publications Committee; has served on Data Monitoring Committees for Baim Institute for Clinical
Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott),
Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial,
funded by Daiichi-Sankyo), and Population Health Research Institute; has received honoraria from American College of
Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim
Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee
funded by Boehringer Ingelheim), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Duke Clinical Research
Institute (clinical trial steering committees), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the
American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (for the COMPASS
operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack
Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Trea-
surer), and WebMD (CME steering committees); has served as Deputy Editor of Clinical Cardiology; has received research funding
from Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest
Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi, Synaptic, and The
Medicines Company; has received royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s
Heart Disease); has served as Site Co-Investigator for Biotronik, Boston Scientific, St. Jude Medical (now Abbott), and Svelte; has
served as a Trustee of the American College of Cardiology; and has performed unfunded research for FlowCo, Merck, Novo
Nordisk, PLx Pharma, and Takeda. Dr. Abbott has received research grants with no direct compensation from Sinomed, Abbott
Vascular, Biosensors Research, Bristol-Myers Squibb, AstraZeneca, and CSL Behring. Dr. Mehta has served as consultant to Bayer,
Boehringer Ingelheim, AstraZeneca, MedImmmune, and Pfizer; and has received grant support from Bayer, Boehringer Ingel-
heim, and AstraZeneca, and the Department of Veterans Affairs, Veterans Health Administration, Office of Research and
Development, Biomedical Laboratory Research and Development (Washington, DC) (grant No BX-000282-05). All other authors
have reported that they have no relationships relevant to the contents of this paper to disclose.

Manuscript received December 5, 2018; revised manuscript received March 10, 2019, accepted March 12, 2019.
JACC VOL. 73, NO. 23, 2019 Abdelaziz et al. 2917
JUNE 18, 2019:2915–29 Aspirin for Primary Prevention of CVD

Aspirin for Primary Prevention of

Cardiovascular Events
Hesham K. Abdelaziz, MD, PHD,a,b,* Marwan Saad, MD, PHD,b,c,* Naga Venkata K. Pothineni, MD,c
Michael Megaly, MD, MS,d,e Rahul Potluri, MD,f Mohammed Saleh, MD,g David Lai Chin Kon, MD,a
David H. Roberts, MD,a Deepak L. Bhatt, MD, MPH,h Herbert D. Aronow, MD, MPH,i J. Dawn Abbott, MD,i
Jawahar L. Mehta, MD, PHDc

ABSTRACT

BACKGROUND The efficacy and safety of aspirin for primary prevention of cardiovascular disease (CVD)
remain debatable.

OBJECTIVES The purpose of this study was to examine the clinical outcomes with aspirin for primary pre-
vention of CVD after the recent publication of large trials adding >45,000 individuals to the published data.

METHODS Randomized controlled trials comparing clinical outcomes with aspirin versus control for primary
prevention with follow-up duration of $1 year were included. Efficacy outcomes included all-cause death, cardiovascular
(CV) death, myocardial infarction (MI), stroke, transient ischemic attack (TIA), and major adverse cardiovascular events.
Safety outcomes included major bleeding, intracranial bleeding, fatal bleeding, and major gastrointestinal (GI) bleeding.
Random effects DerSimonian-Laird risk ratios (RRs) for outcomes were calculated.

RESULTS A total of 15 randomized controlled trials including 165,502 participants (aspirin n ¼ 83,529, control
n ¼ 81,973) were available for analysis. Compared with control, aspirin was associated with similar all-cause death
(RR: 0.97; 95% confidence interval [CI]: 0.93 to 1.01), CV death (RR: 0.93; 95% CI: 0.86 to 1.00), and non-CV death
(RR: 0.98; 95% CI: 0.92 to 1.05), but a lower risk of nonfatal MI (RR: 0.82; 95% CI: 0.72 to 0.94), TIA (RR: 0.79; 95% CI:
0.71 to 0.89), and ischemic stroke (RR: 0.87; 95% CI: 0.79 to 0.95). Aspirin was associated with a higher risk of major
bleeding (RR: 1.5; 95% CI: 1.33 to 1.69), intracranial bleeding (RR: 1.32; 95% CI: 1.12 to 1.55), and major GI bleeding (RR:
1.52; 95% CI: 1.34 to 1.73), with similar rates of fatal bleeding (RR: 1.09; 95% CI: 0.78 to 1.55) compared with the control
subjects. Total cancer and cancer-related deaths were similar in both groups within the follow-up period of the study.

CONCLUSIONS Aspirin for primary prevention reduces nonfatal ischemic events but significantly increases
nonfatal bleeding events. (J Am Coll Cardiol 2019;73:2915–29) © 2019 the American College of Cardiology Foundation.
Published by Elsevier. All rights reserved.

T he role of aspirin for secondary prevention of

myocardial infarction (MI), stroke, or tran-
sient ischemic attack (TIA) is well established
(1–4). A serial cross-sectional study of 94,270 individ-
uals from 2007 to 2015 reported that aspirin use for
primary prevention of cardiovascular disease (CVD)
averaged 43% (5). However, the efficacy and safety
of aspirin for primary prevention varied among multi-
ple randomized controlled trials (RCTs) (6–15),
creating significant variability in societal guidelines
(4,16–18).
The recently published 10-year follow-up of the
JPAD 2 study (Japanese Primary Prevention of
Atherosclerosis With Aspirin for Diabetes) (19), as well
as 3 large RCTs, ARRIVE (Aspirin to Reduce Risk of
Initial Vascular Events) (20), ASCEND (A Study of
Cardiovascular Events in Diabetes) (21), and ASPREE
(Aspirin in Reducing Events in the Elderly) (22,23),
added more data to the existing debate. Long-term
aspirin use has also been associated with a reduction
in cancer incidence and mortality (24,25). The current
systematic review represents the most comprehensive
analysis of the available data to evaluate the efficacy
and safety of aspirin for primary prevention of CVD as
well as its effect on cancer incidence and mortality
within the period of follow-up.
METHODS
DATA SOURCES, TRIAL ELIGIBILITY, AND DATA
EXTRACTION. This study was conducted according
to PRISMA (Preferred Reporting Items for Systematic
2918 Abdelaziz et al.
Aspirin for Primary Prevention of CVD
ABBREVIATIONS reviews and Meta-Analyses) guidelines and is
AND ACRONYMS registered with the International Prospective
Register for Systematic Reviews (PROSPERO:
CVD = cardiovascular disease
CRD42018115612). A systematic search of on-
MACE = major adverse
line databases was performed until
cardiovascular events
September 2018 for RCTs. Online Figure 1 il-
MI = myocardial infarction
lustrates the search strategy.
TIA = transient ischemic attack
Trials that: 1) compared aspirin (any dose)
versus control (placebo or no aspirin) for
primary prevention of CVD; and 2) reported outcomes
of interest at minimum follow-up duration of 1 year
were included. Details of inclusion/exclusion criteria
and data extraction are provided in the Online
Appendix.
SEE PAGE 2930
RISK OF BIAS AND QUALITY ASSESSMENT. We uti-
lized the Cochrane Collaboration tool to assess the
risk of bias among included studies, and the GRADE
(Grades of Recommendation, Assessment, Develop-
ment, and Evaluation) tool to assess quality of
evidence for each outcome (26).
OUTCOMES. The main efficacy outcomes included
all-cause death, cardiovascular (CV) death, MI, stroke,
TIA, and major adverse cardiovascular events
(MACE). Safety outcomes included major bleeding,
intracranial bleeding, fatal bleeding, and major
gastrointestinal (GI) bleeding. Cancer incidence and
cancer-related death were evaluated. All outcomes
were analyzed by an intention-to-treat. The Online
Appendix provides details regarding study outcomes
and definitions.
DATA SYNTHESIS AND STATISTICAL ANALYSIS.
Categorical variables were reported as frequencies
and percentages, continuous variables as mean " SD.
The DerSimonian and Laird model was utilized to
calculate random-effects weighted incidences and
summary risk ratios (RRs) (27), using study popula-
tion size as its weight. Confidence intervals (CIs) were
calculated at the 95% level for overall effect esti-
mates. All p values were 2-tailed and were considered
statistically significant if <0.05. The Higgins I 2 sta-
tistic (28), and the Egger method (29) were used to
evaluate for heterogeneity and publication bias,
respectively. Numbers needed to treat (NNT) and
to harm (NNH) were calculated; however, these
numbers should be interpreted with caution as they
are strongly dependent on the baseline risk for CVD
in the participants of each trial. Annual risk of CV
events was calculated for each study population
(Online Appendix).
SECONDARY ANALYSES. We performed multiple
sensitivity and subgroup analyses for main efficacy
JACC VOL. 73, NO. 23, 2019
JUNE 18, 2019:2915–29
and safety outcomes. Furthermore, random-effect
meta-regression analyses were performed to eval-
uate for treatment modification effects in outcomes
with baseline characteristics. Further details on sec-
ondary analyses are provided in the Online Appendix.
All analyses were performed using STATA software
version 14 (StataCorp, College Station, Texas).
RESULTS
CHARACTERISTICS OF THE INCLUDED STUDIES. Our
search yielded 9,838 citations (Online Figure 1). A total
of 15 RCTs including 165,502 participants (aspirin
n ¼ 83,529, and control n ¼ 81,973) were included
(6–11,13–15,19–22,30,31). The estimated 10-year CV risk
was high (i.e., $7.5%) in 11 studies, and low-
intermediate in 4 trials. Three RCTs were conducted
exclusively in men (6,7,9), and 1 was exclusively in
women (11). Four RCTs enrolled only diabetic patients
(13,19,21,30), whereas 1 excluded this population (20).
The weighted mean duration of follow-up was 6.44 "
2.04 years. Table 1 reports details of included trials.
BASELINE CHARACTERISTICS OF THE INCLUDED
COHORTS. Mean age was 61.6 " 5.6 years in the
aspirin group versus 61.5 " 5.5 years in the control
group. Study populations in aspirin and control
groups were well balanced for various CV risk factors.
Baseline patient demographics are detailed in
Online Table 1.
QUALITY ASSESSMENT AND RISK OF BIAS OF THE
INCLUDED TRIALS. A total of 5 trials were deemed at
low risk and 10 at intermediate risk for bias. The body
of evidence for outcomes reached a level of high
quality (Online Tables 2 and 3). No significant risk of
bias was demonstrated by the Egger test for any of
the outcomes.
EFFICACY OUTCOMES. A l l - c a u s e , C V , a n d n o n - C V
d e a t h . Aspirin was associated with similar all-cause
death (4.75% vs. 4.82%; RR: 0.97; 95% CI: 0.93 to
1.01; p ¼ 0.13; I 2 ¼ 0%) and non-CV death (3.3% vs.
3.3%; RR: 0.98; 95% CI: 0.92 to 1.05; p ¼ 0.53;
I 2 ¼ 29%). There was a modest nonstatistically sig-
nificant reduction in CV death with aspirin compared
with the control group (1.46% vs. 1.52%; RR: 0.93;
95% CI: 0.86 to 1.00; p ¼ 0.064; I 2 ¼ 0%) (Figure 1).
C a r d i o v a s c u l a r e v e n t s . Aspirin use was associated
with lower risk of total MI (2.07% vs. 2.35%; RR: 0.85;
95% CI: 0.76 to 0.95; p ¼ 0.003; I 2 ¼ 60%), driven by a
lower risk of nonfatal MI (1.37% vs. 1.62%; RR: 0.82;
95% CI: 0.72 to 0.94; p ¼ 0.005; I 2 ¼ 58%) compared
with the control group. The risks of fatal MI (RR: 0.93;
95% CI: 0.79 to 1.11; p ¼ 0.43; I 2 ¼ 13%), angina pec-
toris (RR: 0.92; 95% CI: 0.79 to 1.08; p ¼ 0.30;
JACC VOL. 73, NO. 23, 2019
JUNE 18, 2019:2915–29
I 2 ¼ 0%), coronary revascularization (RR: 0.96;
95% CI: 0.87 to 1.05; p ¼ 0.36; I2 ¼ 0%),
and symptomatic peripheral arterial disease (5.95%
vs. 6.28%; RR: 0.88; 95% CI: 0.70 to 1.09; p ¼ 0.24;
I 2 ¼ 9%) were similar in both groups (Figure 2, Online
Figure 2).
The risk of TIA was lower in the aspirin (1.06% vs.
1.33%; RR: 0.79; 95% CI: 0.71 to 0.89; p < 0.001;
I 2 ¼ 0%) compared with the control group. Total
stroke rates (1.82% vs. 1.86%; RR: 0.97; 95% CI: 0.89
to 1.04; p ¼ 0.37; I 2 ¼ 10%), including fatal (RR: 1.03;
95% CI: 0.84 to 1.26; p ¼ 0.81), and nonfatal stroke
(RR: 0.94; 95% CI: 0.85 to 1.02; p ¼ 0.15) were similar
in the 2 groups. Further analysis revealed a lower risk
of ischemic stroke (1.29% vs. 1.49%; RR: 0.87; 95% CI:
0.79 to 0.95; p ¼ 0.002; I 2 ¼ 0%), but a trend toward a
higher risk of hemorrhagic stroke (0.29% vs. 0.23%;
RR: 1.21; 95% CI: 0.99 to 1.47; p ¼ 0.059; I 2 ¼ 0%) with
aspirin versus control (Figure 3, Online Figure 3). The
NNTs to prevent 1 event of MI, TIA, and ischemic
stroke were 357, 370, and 500, respectively.
M a j o r a d v e r s e c a r d i o v a s c u l a r e v e n t s . A compos-
ite of nonfatal MI, nonfatal stroke, TIA, or CV death
utilizing data from 6 RCTs was lower with aspirin
compared with the control group (3.86% vs. 4.24%,
RR: 0.903; 95% CI: 0.85 to 0.96; p ¼ 0.001).
SAFETY OUTCOMES. M a j o r b l e e d i n g e v e n t s . Aspirin
use for primary prevention was associated with a
significant increase in the risk of major bleeding
(1.47% vs. 1.02%; RR: 1.50; 95% CI: 1.33 to 1.69;
p < 0.001; I 2 ¼ 25%), intracranial bleeding including
hemorrhagic stroke (0.42% vs. 0.32%; RR: 1.32;
95% CI: 1.12 to 1.55; p ¼ 0.001; I 2 ¼ 0%), and major GI
bleeding (0.80% vs. 0.54%; RR: 1.52; 95% CI: 1.34 to
1.73; p < 0.001; I 2 ¼ 0%) compared with the control
group (Figure 4). Fatal bleeding was reported in 5
trials (8,10,16,17,26) and was similar in the 2 groups
(0.23% vs. 0.19%; RR: 1.09; 95% CI: 0.78 to 1.55;
p ¼ 0.6; I 2 ¼ 0%). The NNHs to cause a major bleeding
event and intracranial bleeding were 222 and
1,000, respectively.
G a s t r o i n t e s t i n a l u l c e r a t i o n . Aspirin was associ-
ated with increased risk of GI ulcers (RR: 1.37; 95% CI:
1.07 to 1.76; p ¼ 0.013; I 2 ¼ 80%) compared with the
control group.
CANCER. At a mean follow-up of 6.46 years, cancer
incidence (6.1% vs. 6.2%; RR: 0.99; 95% CI: 0.93 to
1.06; p ¼ 0.85; I 2 ¼ 24%) and cancer-related death
(1.95% vs. 1.89%; RR: 0.99; 95% CI 0.82 to 1.20;
p ¼ 0.92; I 2 ¼ 80%) were similar in both groups
(Online Figure 4).
META-REGRESSION ANALYSES. Female sex was
associated with a favorable treatment effect on total
Abdelaziz et al. 2919
Aspirin for Primary Prevention of CVD
stroke (p ¼ 0.046). Meta-regression across the year of
publication showed favorable treatment effect on
nonfatal MI in older compared with recent studies
(p ¼ 0.05). Other baseline characteristics, including
age, hypertension, diabetes, or statin use, demon-
strated no modification of any efficacy or safety out-
comes (Online Table 4).
SENSITIVITY ANALYSES. In our pre-specified sensi-
tivity analyses of: 1) populations who received
low-dose aspirin #100 mg/day; 2) populations with
estimated 10-year ASCVD risk $7.5%; and 3) outcomes
reported at follow-up $5 years, aspirin remained
associated with a lower risk of total MI, nonfatal
MI, TIA, ischemic stroke, and MACE compared with
the control group.
All-cause death was lower with aspirin only at
follow-up $5 years (RR: 0.95; 95% CI: 0.90 to 0.99;
p ¼ 0.032), likely derived by consistent effects on
non-CV death (RR: 0.95; 95% CI: 0.89 to 1.0; p ¼ 0.08)
and CV death (RR: 0.95; 95% CI: 0.87 to 1.03; p ¼ 0.3).
In populations with a high estimated 10-year ASCVD
risk, aspirin showed a trend toward lower CV death
(RR: 0.92; 95% CI: 0.84 to 1.0; p ¼ 0.06); however, all-
cause death remained similar (RR: 0.97; 95% CI: 0.91
to 1.02; p ¼ 0.26). In all other sensitivity analyses, all-
cause and CV death were similar between both
groups. Risk of major bleeding was higher with
aspirin versus control among all sensitivity analyses.
In populations who received low-dose aspirin
(#100 mg/day), there was a significant reduction in
total stroke (RR: 0.92; 95% CI: 0.85 to 0.99; p ¼ 0.04)
and nonfatal stroke (RR: 0.88; 95% CI: 0.80 to 0.96;
p ¼ 0.007), a finding that was not observed when
trials with all doses were pooled. To further explore
this effect, we performed a subgroup analysis
comparing low-dose (#100 mg/day) versus high-dose
($300 mg/day) aspirin, and observed an association
between high-dose aspirin and increased risk of
total stroke (RR: 1.19; 95% CI: 1.0 to 1.4; p ¼ 0.05), and
a 57% relative increase in the risk of hemorrhagic
stroke (RR: 1.57; 95% CI: 0.89 to 2.77) (Online
Figure 5).
SUBGROUP ANALYSES. Diabetes. The current analysis
demonstrates similar outcomes in terms of all-cause
death (RR: 0.96; 95% CI: 0.91 to 1.00 vs. RR: 0.96;
95% CI: 0.85 to 1.10), CV death (RR: 0.91; 95% CI:
0.82 to 1.00 vs. RR: 0.89; 95% CI: 0.6 to 1.3), and total
stroke (RR: 0.91; 95% CI: 0.76 to 1.1 vs. RR: 0.98;
95% CI: 0.88 to 1.1) with aspirin versus control in
patients with or without diabetes. The risk of MI was
lower with aspirin in subjects without diabetes but
not in those with diabetes (RR: 0.8; 95% CI: 0.66 to
0.98; p ¼ 0.03 vs. RR: 0.90; 95% CI: 0.75 to 1.07;
2920 Abdelaziz et al. JACC VOL. 73, NO. 23, 2019

Aspirin for Primary Prevention of CVD JUNE 18, 2019:2915–29

T A B L E 1 Baseline Characteristics of the Included Studies

Study (Year) Country Aspirin/Control, n Study Design Patient Population

ASPREE (2018) Australia and United States 9,525/9,589 Double-blinded RCT Age $70 yrs ($65 yrs among blacks and Hispanics in U.S.)
ARRIVE (2018) Europe and United States 6,270/6,276 Triple-blinded RCT Male >55 yrs þ 2–4 CV risk factors, female >60 yrs
þ3–4 CV risk factors
ASCEND (2018) United Kingdom 7,740/7,740 Quadruple-blinded, 2 $ 2 RCT, Age >40 yrs þ DM
omega-3 fatty acid
AASER (2018) Spain 50/61 Open-label RCT CKD Stage 3–4

JPAD 2 (2017) Japan 1,262/1,277 Open-label RCT Age 30–85 yrs þ DM

JPPP (2014) Japan 7,220/7,224 Open-label RCT Age 60–85 yrs þ HTN, DM, or dyslipidemia

AAA (2010) United Kingdom 1,675/1,675 Double-blinded RCT Age 50–75 yrs þ ABI <0.96

POPADAD (2008) United Kingdom 638/638 Double-blinded, 2 $ 2 RCT, antioxidant Age >40 yrs þ DMþ asymptomatic PAD with ABI #0.99

WHS (2005) United States 19,934/19,942 Double-blinded, 2 $ 2 RCT, vitamin E Female health professionals age >45 yrs

PPP (2001) Italy 2,226/2,269 Open-label 2 $ 2 RCT, vitamin E Age >50 yrs þ $1 CVD risk factor
HOT (1998) Europe, Asia, Americas 9,399/9,391 Double-blinded, 3 $ 2 RCT, hypertension Age 50–80 yrs þ HTN
treatment goals
TPT (1998) United Kingdom 1,268/1,272 Double-blinded, 2 $ 2 RCT, warfarin Male aged 45-69 yrs at the top 20% or
25% of CVD risk score
ETDRS (1992) United States 1,856/1,855 Double-blinded RCT Age 18–70 yrs þ DM þ diabetic retinopathy
PHS (1989) United States 11,037/11,034 Double-blinded RCT Healthy male doctors ages 40–84 yrs
BMD (1988) United Kingdom 3,429/1,710 Open-label RCT Healthy male doctors age #80 yrs

*Median. †Mean compliance over the follow-up years. ‡Value for the whole population. §7% of the information on vital status was obtained through census offices.
AAA ¼ Aspirin for Asymptomatic Atherosclerosis; AASER ¼ Acido Acetil Salicilico en la Enfermedad; ABI ¼ ankle brachial index; ARRIVE ¼ Aspirin to Reduce Risk of Initial Vascular Events; ASCEND ¼ A Study
of Cardiovascular Events in Diabetes; ASPREE ¼ Aspirin in Reducing Events in the Elderly; BMD ¼ British Male Doctors Trial; CHD ¼ coronary heart disease; CKD ¼ chronic kidney disease; CV ¼ cardiovascular;
CVD ¼ cardiovascular disease, DBP ¼ diastolic blood pressure, DM ¼ diabetes mellitus; ETDRS ¼ Early Treatment Diabetic Retinopathy; HOT ¼ Hypertension Optimal Treatment; HTN ¼ hypertension;
ICH ¼ intracranial hemorrhage; IHD ¼ ischemic heart disease; JPAD2 ¼ Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes; JPPP ¼ Japanese Primary Prevention Project; MI ¼ myocardial
infarction; NR ¼ not reported; PAD ¼ peripheral arterial disease; PHS ¼ Physician’s Health Study; POPADAD ¼ Prevention of Progression of Arterial Disease and Diabetes; PPP ¼ Primary Prevention Project;
RCT ¼ randomized controlled trial; TIA ¼ transient ischemic attack; UA ¼ unstable angina; WHS ¼ Woman Health Study.

Continued on the next page

p ¼ 0.23), but without a significant subgroup
interaction (p interaction ¼ 0.48).
S e x . Aspirin was associated with a lower risk of MI
than control in men, but not in women (RR: 0.69;
95% CI: 0.58 to 0.83; p < 0.001 vs. RR: 0.92; 95% CI:
0.78 to 1.1; p ¼ 0.35; pinteraction ¼ 0.03). Otherwise, sex
did not affect the outcomes of all-cause death
(RR: 0.96; 95% CI: 0.87 to 1.00 vs. RR: 0.92; 95% CI:
0.78 to 1.10), CV death (RR: 0.93; 95% CI: 0.82 to 1.00
vs. RR: 0.9; 95% CI: 0.75 to 1.10), total stroke (RR: 1.19;
95% CI: 0.96 to 1.12 vs. RR: 0.95; 95% CI: 0.81 to 1.12),
and major bleeding (RR: 1.44; 95% CI: 1.21 to 1.73 vs.
RR: 1.48; 95% CI: 1.25 to 1.75) with aspirin versus
control.
S t u d y q u a l i t y . Aspirin was associated with a lower
risk of all-cause death (RR: 0.94; 95% CI: 0.88 to 1.00;
p ¼ 0.05 vs. RR: 0.99; 95% CI: 0.91 to 1.08; p ¼ 0.88;
p interaction ¼ 0.24), total MI (RR: 0.84; 95% CI: 0.73 to
0.97; p ¼ 0.01 vs. RR: 0.85; 95% CI: 0.70 to 1.03;
p ¼ 0.1; p interaction ¼ 0.89), and nonfatal MI (RR: 0.77;
95% CI: 0.63 to 0.94; p ¼ 0.01 vs. RR: 0.87; 95% CI:
0.72 to 1.05; p ¼ 0.16; p interaction ¼ 0.37) in fair- versus
high-quality trials, but without significant p interaction .
Major bleeding remained significantly higher with
aspirin versus control regardless of study quality
(Online Figure 6).
DISCUSSION
The current meta-analysis represents the largest and
most contemporary examination of long-term out-
comes with aspirin use for primary prevention of
CVD. Our primary analysis found that: 1) aspirin is
not associated with a reduction in all-cause or
non-CV death, but is associated with a modest, non-
statistically significant relative reduction of 7% in CV
death; 2) aspirin (even #100 mg/day) is associated
with lower rates of MI (NNT ¼ 357), nonfatal MI
(NNT ¼ 400), TIA (NNT ¼ 370), and ischemic stroke
(NNT ¼ 500); 3) aspirin use is associated with a
JACC VOL. 73, NO. 23, 2019 Abdelaziz et al. 2921
JUNE 18, 2019:2915–29 Aspirin for Primary Prevention of CVD

T A B L E 1 Continued

Adherence Estimated Completed Mean

Aspirin Dose Primary Outcome to Aspirin, % 10-yr CV Risk Follow-Up, % Follow-Up, yrs

100 mg/day Composite of death, dementia, or persistent physical disability 62 8.2 98.5/98.4 4.7*
100 mg/day Composite of MI, stroke, CV death, UA, or TIA 80 6.9 96/96.3 5*

100 mg/day Composite of nonfatal MI, nonfatal stroke (excluding confirmed 70† 10.2 99.1‡ 7.4
ICH) or TIA, or death from any vascular cause.
100 mg/day Composite of CV death, ACS (nonfatal MI, coronary 92.6 31 NR 5.4*
revascularization, or UA), cerebrovascular disease, HF,
or nonfatal PAD
81–100 mg/day Composite of sudden death, CV death, nonfatal MI, nonfatal 79 7.8 62/65 10.3*
stroke, UA, TIA, or PAD
100 mg/day Composite of CV death (MI, stroke, and other CV causes), 76 5.9 89.2/89.6 5.02*
nonfatal stroke and MI
100 mg/day Composite of fatal or nonfatal coronary event or stroke or 88 9.9 NR 8.2
revascularization.
100 mg/day Composite of death from CHD or stroke, nonfatal MI or stroke, or 50 25.3 84.5/84 6.7*
above ankle amputation for critical limb ischemia
100 mg every other day Composite of nonfatal MI, nonfatal stroke, or CV death 73† 2.6 97.2 (morbidity), 10.1
99.4 (mortality) ‡
100 mg/day Composite of CV death, nonfatal MI, and nonfatal stroke 81 7.6 99.3ठ3.6
75 mg/day Composite of all (fatal and nonfatal) MI, all (fatal and nonfatal) NR 11.9 97.4‡ 3.8
strokes, and all other CV deaths
75 mg/day All IHD (coronary death and fatal and nonfatal MI) NR 15.3 NR 6.7*

650 mg/day All-cause mortality 70 40.8 80–90‡ 5

325 mg every other day CVD mortality 85 6.7 99.7‡ 5
500 mg/day or 300 mg/day CVD mortality 75 15.4 NR 6
if requested

significant increase in the risk of nonfatal major
bleeding events, regardless of dose or population
characteristics; and 4) aspirin does not affect the
incidence of cancer or risk of cancer death within a
median follow-up period of 6.46 years. Secondary
analyses revealed that: 1) aspirin may reduce all-
cause death after 5 years of follow-up; 2) the trend
toward lower risk of CV death with aspirin is only
observed in populations with high estimated 10-year
ASCVD risk; and 3) lower risk of total and nonfatal
stroke with aspirin use is observed only when low-
dose aspirin (#100 mg/day) is utilized.
ASPIRIN AND PRIMARY PREVENTION OF DEATH.
Prior meta-analyses of aspirin use for primary pre-
vention have provided conflicting evidence regarding
its effect on all-cause death (1,32–34). In the current
analysis, although aspirin did not reduce all-cause
death, a modest nonstatistically significant relative
reduction of 7% in CV death was observed. Further-
more, in populations followed for >5 years (mean 6.7
years), a potential benefit for all-cause death was
noticed. In a previous meta-analysis, a similar finding
was attributed to reduction in nonvascular rather
than vascular death (24). A uniform reduction in all-
cause death may be challenging to demonstrate in
primary prevention trials due to heterogeneity of
populations studied and the high incidence of
nonvascular death (>60% of all deaths), in particular,
nonvascular noncancer death (20% to 25% of all
deaths) (35). It remains plausible that misattribution
of cause of death occurred. Although some trials
restricted the definition of CV death to a composite of
fatal MI and fatal stroke (13,14,30), others included
other causes (e.g., sudden cardiac death, heart fail-
ure, and pulmonary embolism) (6,7,11,19,21–23).
Further evaluation of temporal distribution and
actual cause of death in participants enrolled in
recent RCTs would provide additional insight.
ASPIRIN AND PRIMARY PREVENTION OF CV
EVENTS. We observed a significant reduction in total
and nonfatal MI with aspirin. The lack of effect on
fatal MI has been previously established
(6,7,11,19–21,23). Among cerebrovascular outcomes,
we noted a benefit with aspirin use in primary pre-
vention of TIA and ischemic stroke; however, this
benefit was offset by an increase in rates of hemor-
rhagic stroke, resulting in a similar overall rate of
stroke in the 2 groups. This is in concordance with
prior meta-analyses (32–34). Only the WHS (Women’s
Health Study), a trial of aspirin 100 mg every other
2922 Abdelaziz et al. JACC VOL. 73, NO. 23, 2019

Aspirin for Primary Prevention of CVD JUNE 18, 2019:2915–29

F I G U R E 1 Summary Forest Plot of All-Cause Death and Cardiovascular Death With Aspirin Versus Control

Events, Events, %
Study Year RR (95% CI) Aspirin Control Weight

All-Cause Death
ARRIVE 2018 0.99 (0.80, 1.23) 160/6270 161/6276 3.87
ASCEND 2018 0.94 (0.86, 1.04) 748/7740 792/7740 20.07
ASPREE 2018 1.14 (1.01, 1.28) 558/9525 494/9589 13.03
JPPP 2014 0.98 (0.84, 1.15) 297/7220 303/7244 7.35
AAA 2010 0.95 (0.78, 1.15) 176/1675 186/1675 4.76
JPAD 2008 0.91 (0.57, 1.43) 34/1262 38/1277 0.87
POPADAD 2008 0.93 (0.72, 1.21) 94/638 101/638 2.70
WHS 2005 0.95 (0.85, 1.06) 609/19934 642/19942 15.16
PPP 2001 0.81 (0.58, 1.13) 62/2226 78/2269 1.67
HOT 1998 0.93 (0.79, 1.09) 284/9399 305/9391 7.13
TPT 1998 1.03 (0.80, 1.32) 113/1268 110/1272 2.87
ETDRS 1992 0.93 (0.81, 1.06) 340/1856 366/1855 10.22
PHS 1989 0.96 (0.79, 1.15) 217/11037 227/11034 5.32
BMD 1988 0.89 (0.74, 1.08) 270/3429 151/1710 4.97
Subtotal (I-squared = 0.0%, p = 0.643) 0.97 (0.93, 1.01) 3962/83479 3954/81912 100.00
.
CV Death
ARRIVE 2018 0.98 (0.62, 1.52) 38/6270 39/6276 3.04
ASCEND 2018 0.91 (0.75, 1.10) 197/7740 217/7740 16.63
ASPREE 2018 0.82 (0.62, 1.08) 91/9525 112/9589 7.95
JPAD 2 2017 0.94 (0.44, 1.99) 13/1262 14/1277 1.07
JPPP 2014 1.02 (0.71, 1.47) 58/7220 57/7244 4.54
AAA 2010 1.17 (0.72, 1.89) 35/1675 30/1675 2.58
POPADAD 2008 1.23 (0.80, 1.89) 43/638 35/638 3.22
WHS 2005 0.95 (0.74, 1.22) 120/19934 126/19942 9.69
PPP 2001 0.56 (0.31, 1.01) 17/2226 31/2269 1.74
HOT 1998 0.95 (0.75, 1.20) 133/9399 140/9391 10.85
TPT 1998 1.05 (0.69, 1.61) 42/1268 40/1272 3.32
ETDRS 1992 0.89 (0.76, 1.04) 244/1856 275/1855 23.54
PHS 1989 0.92 (0.66, 1.28) 66/11037 72/11034 5.43
BMD 1988 1.01 (0.74, 1.37) 119/3429 59/1710 6.40
Subtotal (I-squared = 0.0%, p = 0.875) 0.93 (0.86, 1.00) 1216/83479 1247/81912 100.00
NOTE: Weights are from random effects analysis

.1 1 10
<<< Favors Aspirin Favors Control >>>

The relative size of the data markers indicates the weight of the sample size from each study. AAA ¼ Aspirin for Asymptomatic Atherosclerosis; AASER ¼ Acido Acetil
Salicilico en la Enfermedad; ARRIVE ¼ Aspirin to Reduce Risk of Initial Vascular Events; ASCEND ¼ A Study of Cardiovascular Events in Diabetes; ASPREE ¼ Aspirin in
Reducing Events in the Elderly; BMD ¼ British Male Doctors Trial; CI ¼ confidence interval; ETDRS ¼ Early Treatment Diabetic Retinopathy; HOT ¼ Hypertension
Optimal Treatment; JPAD2 ¼ Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes; JPPP ¼ Japanese Primary Prevention Project;
PHS ¼ Physician’s Health Study; POPADAD ¼ Prevention of Progression of Arterial Disease and Diabetes; PPP ¼ Primary Prevention Project; RR ¼ risk ratio;
WHS ¼ Woman Health study.

day in middle-age female health professionals,
showed a significant reduction in ischemic stroke
with aspirin (11). Interestingly, a meta-regression
analysis of our study shows possible modification in
the incidence of stroke in women. It should be noted
that most of these trials were designed with power
calculation for composite endpoints, thereby making
it difficult to detect significant differences between
treatment groups for the less common, individ-
ual outcomes.
We also demonstrate a reduction in total and
nonfatal stroke in populations who received low-dose
aspirin #100 mg/day, but an increase in total stroke
driven primarily by higher incidence of hemorrhagic
stroke with aspirin $300 mg/day. A dose-related in-
crease in bleeding with aspirin is well established
JACC VOL. 73, NO. 23, 2019 Abdelaziz et al. 2923
JUNE 18, 2019:2915–29 Aspirin for Primary Prevention of CVD

F I G U R E 2 Summary Forest Plot of Total, Nonfatal and Fatal Myocardial Infarction With Aspirin Versus Control

Events, Events, %
Study Year RR (95% CI) Aspirin Control Weight

Total MI
AASER 2018 0.07 (0.00, 1.21) 0/50 8/61 0.15
ARRIVE 2018 0.85 (0.65, 1.11) 95/6270 112/6276 7.20
ASCEND 2018 0.93 (0.80, 1.09) 296/7740 317/7740 10.16
ASPREE 2018 0.94 (0.76, 1.15) 171/9525 184/9589 8.81
JPAD 2 2017 0.98 (0.58, 1.63) 28/1262 29/1277 3.40
JPPP 2014 0.58 (0.36, 0.92) 27/7220 47/7244 3.83
AAA 2010 1.05 (0.78, 1.40) 90/1675 86/1675 6.83
POPADAD 2008 1.10 (0.83, 1.45) 90/638 82/638 7.04
WHS 2005 1.03 (0.84, 1.25) 198/19934 193/19942 9.05
PPP 2001 0.69 (0.39, 1.23) 19/2226 28/2269 2.83
HOT 1998 0.65 (0.49, 0.85) 82/9399 127/9391 7.09
TPT 1998 0.78 (0.59, 1.03) 83/1268 107/1272 7.09
ETDRS 1992 0.85 (0.73, 1.00) 241/1856 283/1855 10.06
PHS 1989 0.58 (0.47, 0.72) 139/11037 239/11034 8.78
BMD 1988 0.96 (0.75, 1.23) 169/3429 88/1710 7.68
Subtotal (I-squared = 60.2%, p = 0.001) 0.85 (0.76, 0.95) 1728/83529 1930/81973 100.00
.
Nonfatal MI
AASER 2018 0.08 (0.00, 1.39) 0/50 7/61 0.22
ARRIVE 2018 0.90 (0.68, 1.20) 88/6270 98/6276 8.68
ASCEND 2018 0.98 (0.80, 1.19) 191/7740 195/7740 10.93
ASPREE 2018 0.93 (0.75, 1.15) 157/9525 170/9589 10.46
JPAD 2 2017 1.10 (0.63, 1.93) 25/1262 23/1277 4.09
JPPP 2014 0.53 (0.31, 0.91) 20/7220 38/7244 4.31
AAA 2010 0.91 (0.65, 1.28) 62/1675 68/1675 7.51
POPADAD 2008 0.98 (0.69, 1.40) 55/638 56/638 7.14
WHS 2005 1.02 (0.83, 1.25) 184/19934 181/19942 10.74
PPP 2001 0.69 (0.36, 1.34) 15/2226 22/2269 3.26
HOT 1998 0.60 (0.45, 0.81) 68/9399 113/9391 8.35
TPT 1998 0.65 (0.45, 0.92) 47/1268 73/1272 7.09
PHS 1989 0.61 (0.49, 0.75) 129/11037 213/11034 10.40
BMD 1988 0.97 (0.67, 1.41) 80/3429 41/1710 6.82
Subtotal (I-squared = 57.5%, p = 0.004) 0.82 (0.72, 0.94) 1121/81673 1298/80118 100.00
.
Fatal MI
AASER 2018 0.41 (0.02, 9.74) 0/50 1/61 0.29
ARRIVE 2018 0.50 (0.20, 1.24) 7/6270 14/6276 3.40
ASCEND 2018 0.86 (0.66, 1.12) 105/7740 122/7740 24.87
ASPREE 2018 1.01 (0.48, 2.11) 14/9525 14/9589 4.95
JPAD 2 2017 0.51 (0.13, 2.02) 3/1262 6/1277 1.51
JPPP 2014 0.78 (0.29, 2.09) 7/7220 9/7244 2.89
AAA 2010 1.56 (0.86, 2.80) 28/1675 18/1675 7.45
POPADAD 2008 1.35 (0.82, 2.21) 35/638 26/638 9.97
WHS 2005 1.17 (0.54, 2.52) 14/19934 12/19942 4.59
PPP 2001 0.68 (0.19, 2.40) 4/2226 6/2269 1.80
HOT 1998 1.00 (0.48, 2.09) 14/9399 14/9391 4.95
TPT 1998 1.06 (0.67, 1.69) 36/1268 34/1272 11.16
PHS 1989 0.38 (0.19, 0.80) 10/11037 26/11034 5.09
BMD 1988 0.94 (0.67, 1.34) 89/3429 47/1710 17.08
Subtotal (I-squared = 13.2%, p = 0.309) 0.93 (0.79, 1.11) 366/81673 349/80118 100.00
NOTE: Weights are from random effects analysis

.1 1 10
<<< Favors Aspirin Favors Control >>>

The relative size of the data markers indicates the weight of the sample size from each study. Abbreviations as in Figure 1.
2924 Abdelaziz et al. JACC VOL. 73, NO. 23, 2019

Aspirin for Primary Prevention of CVD JUNE 18, 2019:2915–29

F I G U R E 3 Summary Forest Plot of TIA and Stroke With Aspirin Versus Control

Events, Events, %
Study Year RR (95% CI) Aspirin Control Weight

TIA
ARRIVE 2018 0.93 (0.61, 1.42) 42/6270 45/6276 7.37
ASCEND 2018 0.85 (0.70, 1.05) 168/7740 197/7740 31.27
JPAD 2 2017 1.01 (0.42, 2.42) 10/1262 10/1277 1.70
JPPP 2014 0.56 (0.32, 0.98) 19/7220 34/7244 4.12
AAA 2010 0.93 (0.60, 1.43) 38/1675 41/1675 6.80
POPADAD 2008 0.70 (0.36, 1.37) 14/638 20/638 2.85
WHS 2005 0.78 (0.65, 0.95) 186/19934 238/19942 35.53
PPP 2001 0.71 (0.44, 1.15) 28/2226 40/2269 5.63
BMD 1988 0.58 (0.34, 0.97) 30/3429 26/1710 4.75
Subtotal (I-squared = 0.0%, p = 0.745) 0.80 (0.71, 0.89) 535/50394 651/48771 100.00
.
Total Stroke
AASER 2018 2.44 (0.47, 12.78) 4/50 2/61 0.21
ARRIVE 2018 1.12 (0.81, 1.55) 75/6270 67/6276 5.05
ASCEND 2018 0.91 (0.77, 1.08) 240/7740 263/7740 15.28
ASPREE 2018 0.97 (0.80, 1.17) 195/9525 203/9589 12.59
JPAD 2 2017 0.90 (0.63, 1.28) 56/1262 63/1277 4.44
JPPP 2014 1.04 (0.84, 1.29) 166/7220 160/7244 10.70
AAA 2010 0.88 (0.59, 1.31) 44/1675 50/1675 3.49
POPADAD 2008 0.74 (0.49, 1.12) 37/638 50/638 3.31
WHS 2005 0.83 (0.70, 0.99) 221/19934 266/19942 14.59
PPP 2001 0.68 (0.36, 1.28) 16/2226 24/2269 1.45
HOT 1998 0.99 (0.79, 1.24) 146/9399 148/9391 9.74
TPT 1998 0.69 (0.38, 1.26) 18/1268 26/1272 1.61
ETDRS 1992 1.18 (0.88, 1.58) 92/1856 78/1855 6.14
PHS 1989 1.21 (0.93, 1.58) 119/11037 98/11034 7.38
BMD 1988 1.16 (0.80, 1.69) 91/3429 39/1710 4.02
Subtotal (I-squared = 10.1%, p = 0.340) 0.97 (0.89, 1.04) 1520/83529 1537/81973 100.00
NOTE: Weights are from random effects analysis

.1 1 10
<<< Favors Aspirin Favors Control >>>

The relative size of the data markers indicates the weight of the sample size from each study. TIA ¼ transient ischemic attack; other
abbreviations as in Figure 1.

(36). Furthermore, prior studies have shown higher
mortality with hemorrhagic versus ischemic stroke
(1). Our results illustrate a critical association be-
tween aspirin dose and risk of total stroke, favoring
lower doses for primary prevention of stroke. The
current analysis shows that to prevent 1 MI, TIA, or
ischemic stroke event, 357, 370, and 500 persons
would require treatment, respectively.
In recent RCTs (19–21,23), the modest reduction in
CV events or lack of benefit with aspirin suggests a
role for other primary prevention strategies that are
being employed in the patient population, and is
supported by a trend toward a lower estimated
10-year ASCVD risk in these RCTs (mean 8.3%) when
compared with older studies (mean 14.4%). For
example, in the ASCEND study, the mean systolic
blood pressure in the aspirin group was 136 mm Hg,
with >75% of population receiving statins, and only
8% actively smoking (21). In the ARRIVE trial, almost
50% of patients were on statins, >65% on anti-
hypertension medications, and less than one-third
were smokers (20). Our meta-regression showing a
favorable treatment effect on nonfatal MI in older
versus recent trials supports this theory and follows
the general trend of reduction/plateauing of the
burden of CVD worldwide (37).
Primary prevention strategies in healthy adults are
multifaceted. These subjects are more likely to be
JACC VOL. 73, NO. 23, 2019 Abdelaziz et al. 2925
JUNE 18, 2019:2915–29 Aspirin for Primary Prevention of CVD

F I G U R E 4 Summary Forest Plot of Any Major Bleeding, Intracranial Bleeding, and Major GI Bleeding With Aspirin Versus Control

Events, Events, %
Study Year RR (95% CI) Aspirin Control Weight

Any Major Bleeding

ARRIVE 2018 2.72 (1.14, 6.46) 19/6270 7/6276 1.83
ASCEND 2018 1.28 (1.09, 1.51) 314/7740 245/7740 23.58
ASPREE 2018 1.37 (1.17, 1.60) 361/9525 265/9589 24.62
JPPP 2014 1.61 (1.10, 2.35) 69/7220 43/7244 8.06
AAA 2010 1.70 (0.98, 2.94) 34/1675 20/1675 4.29
WHS 2005 1.37 (1.05, 1.79) 129/19934 94/19942 13.76
PPP 2001 4.08 (1.67, 9.96) 24/2226 6/2269 1.73
HOT 1998 1.74 (1.32, 2.30) 136/9399 78/9391 12.97
TPT 1998 2.01 (0.61, 6.65) 8/1268 4/1272 0.98
PHS 1989 1.75 (1.10, 2.78) 49/11037 28/11034 5.76
BMD 1988 1.61 (0.76, 3.39) 29/3429 9/1710 2.43
Subtotal (I-squared = 24.8%, p = 0.207) 1.50 (1.33, 1.69) 1172/79723 799/78142 100.00
.
Intracranial Bleeding
ARRIVE 2018 0.73 (0.29, 1.81) 8/6270 11/6276 3.24
ASCEND 2018 1.22 (0.83, 1.81) 55/7740 45/7740 17.41
ASPREE 2018 1.50 (1.11, 2.01) 107/9525 72/9589 30.36
JPAD 2 2017 0.74 (0.34, 1.61) 11/1262 15/1277 4.48
JPPP 2014 1.66 (0.99, 2.78) 38/7220 23/7244 10.06
AAA 2010 1.57 (0.61, 4.04) 11/1675 7/1675 3.01
WHS 2005 1.24 (0.83, 1.88) 51/19934 41/19942 15.93
PPP 2001 1.36 (0.30, 6.07) 4/2226 3/2269 1.20
HOT 1998 0.93 (0.45, 1.93) 14/9399 15/9391 5.07
TPT 1998 1.50 (0.25, 8.99) 3/1268 2/1272 0.84
PHS 1989 1.92 (0.95, 3.85) 23/11037 12/11034 5.52
BMD 1988 1.08 (0.41, 2.84) 13/3429 6/1710 2.88
Subtotal (I-squared = 0.0%, p = 0.739) 1.32 (1.12, 1.55) 338/80985 252/79419 100.00
.
Major GI Bleeding
ARRIVE 2018 2.00 (0.37, 10.93) 4/6270 2/6276 0.58
ASCEND 2018 1.36 (1.05, 1.75) 137/7740 101/7740 25.58
ASPREE 2018 1.60 (1.25, 2.05) 162/9525 102/9589 27.49
AAA 2010 1.12 (0.44, 2.91) 9/1675 8/1675 1.84
WHS 2005 1.37 (1.05, 1.79) 129/19934 94/19942 23.70
PPP 2001 2.04 (0.51, 8.14) 6/2226 3/2269 0.87
HOT 1998 2.08 (1.41, 3.07) 77/9399 37/9391 10.89
TPT 1998 3.01 (0.61, 14.88) 6/1268 2/1272 0.65
PHS 1989 1.75 (1.10, 2.78) 49/11037 28/11034 7.75
BMD 1988 0.50 (0.10, 2.47) 3/3429 3/1710 0.65
Subtotal (I-squared = 0.0%, p = 0.581) 1.52 (1.34, 1.73) 582/72503 380/70898 100.00
NOTE: Weights are from random effects analysis

.1 1 10
<<< Favors Aspirin Favors Control >>>

The relative size of the data markers indicates the weight of the sample size from each study. GI ¼ gastrointestinal; other abbreviations as in Figure 1.

health-conscious, to engage in healthy lifestyle tend to have higher rates of statin intake, which have
practices such as regular exercise, and to consume a been shown to have an effect on coagulation cascade
heathy diet as well as other over-the-counter com- and inhibit thrombin production. Demonstrating an
pounds that may have antiplatelet effects, and also incremental benefit of aspirin on a background of
JACC VOL. 73, NO. 23, 2019
JUNE 18, 2019:2915–29
Prevention Trial in Diabetes) will provide important
insight into the role of aspirin on a background of
statin therapy for the primary prevention of CVD in a
diabetic population (38).
Sex differences in the efficacy of aspirin for
primary prevention remain a matter of debate
(1,32,34,39). Although our analysis demonstrates a
possible sex difference in the benefit with aspirin, the
heterogeneity in population characteristics, in
particular, the baseline risk of ASCVD, may have
contributed to the results. In another subgroup
analysis, we did not observe benefit of aspirin in
primary prevention of MI in diabetic populations.
The biological plausibility of this observation could
be based on possible aspirin resistance and increase
in platelet turnover in diabetic patients (40–43).
Although this was recently challenged by the ASCEND
trial, it is important to note that the risk of nonfatal
MI was similar between aspirin and control groups in
high-risk diabetic patients in this trial.
SAFETY OF ASPIRIN USE IN PRIMARY PREVENTION.
Our analysis shows an increased risk for major
bleeding (NNH ¼ 222) with aspirin use for primary
prevention, a finding that remains consistent even
when restricting the analysis to low-dose aspirin tri-
als. However, fatal bleeding was similar in both
groups. Aspirin (especially at higher doses) was
associated with a 32% relative increase in intracranial
bleeding risk (including hemorrhagic stroke) as well
as >50% increase in the risk of major GI bleeding.
Such findings are similar to results from prior
studies (1,33,36,44).
Although certain baseline characteristics such as
older age, male sex, history of GI ulcers, elevated
mean BP, and NSAID use, have shown to increase the
risk of aspirin-related bleeding (36,45), our meta-
regression analysis failed to demonstrate any effect
modification of major bleeding by baseline charac-
teristics. Patient-level metanalysis would be helpful
to further investigate these effects.
CANCER INCIDENCE AND MORTALITY. Our analysis
shows no reduction in the risk of cancer or cancer-related
death with aspirin use in primary prevention, even on
secondary analysis restricted to long-term follow-up
trials ($5 years). The discrepancy between our results
and prior meta-analyses that showed potential lower
risk of cancer and cancer death with aspirin (24,35,46)
can be attributed to the inconsistency of results in
recent RCTs reporting similar risk of cancer-related
outcomes in aspirin versus control and the need for
even longer follow-up to see any potential effect on
cancer (20–22).
Abdelaziz et al. 2927
Aspirin for Primary Prevention of CVD
BENEFIT VERSUS RISK PREDICTION TOOL FOR
ASPIRIN USE IN PRIMARY PREVENTION. The clinical
dilemma of identifying the population that would
benefit from aspirin in primary prevention still per-
sists. In 2016, the U.S. Preventive Service Task Force
utilized a decision-analysis model to estimate the
magnitude of net benefit with aspirin based on age,
sex, and 10-year CVD risk using the American Heart
Association/American College of Cardiology risk
calculator (47). The U.S. Preventive Service Task
Force indicated that a net benefit in life expectancy is
expected for most men and women started on aspirin
at age 40 to 59 years and 60 to 69 years if they are at
high risk for CVD. However, overestimation of CVD
risk with this calculator in real-world is a current
concern (48). In addition, the current analysis dem-
onstrates a potential reduction of net benefit with
aspirin in the contemporary era. Furthermore, a valid
prediction tool for estimating the bleeding risk with
aspirin in primary prevention is lacking, and only a
single risk prediction tool for GI complications with
aspirin is available (49). Our study calls for an upda-
ted decision-analysis model that incorporates the
new evidence and utilizes a comprehensive risk pre-
diction tool for GI bleeding. This would improve the
precision of the model to define an appropriate
ischemic versus bleeding risk threshold, based on
which an adequately validated benefit-risk prediction
tool can be calibrated to determine individuals in
whom the benefits of using aspirin for primary pre-
vention outweigh the risks.
STUDY STRENGTHS AND LIMITATIONS. The current
study aims to provide comprehensive and updated
data about efficacy and safety of aspirin in primary
prevention of CVD. Since the submission of our paper,
2 meta-analyses have been published (50,51). Our
study, however, provides further insight through
more comprehensive subgroup, sensitivity, and meta-
regression analyses. In particular, the current study
emphasizes: 1) a potential benefit with aspirin on all-
cause death on long-term follow-up >5 years; 2) a
trend toward lower CV death in population with high
ASCVD risk; 3) a favorable treatment effect with
aspirin on nonfatal MI in older compared with recent
studies; and 4) a difference in the outcome of stroke
with a low-dose (#100 mg/day) versus high-dose
($300 mg/day) aspirin. We included only RCTs to
avoid bias associated with observational studies.
However, our study has limitations. The main limita-
tions are the heterogeneity in the definition of com-
posite outcomes among trials, as well as the
heterogenous quality of studies included. To over-
come these limitations, we analyzed individual