Aspirin for Primary Prevention of Cardiovascular Events

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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2916

Abdelaziz et al.

JACC VOL. 73, NO. 23, 2019 JUNE 18, 2019:2915–29

Aspirin for Primary Prevention of CVD

Synaptic, and The Medicines Company; has received royalties from

grant support from Bayer, Boehringer Ingelheim, and AstraZeneca,

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and the Department of Veterans Affairs, Veterans Health

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Svelte; has served as a Trustee of the American College of Cardiology;

No BX-000282-05).

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,

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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, Providence, 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/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, 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 Ingelheim, 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.

Abdelaziz et al.

JACC VOL. 73, NO. 23, 2019 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 prevention 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

Cardiovascular Events in Diabetes) (21), and ASPREE

myocardial infarction (MI), stroke, or tran-

(Aspirin in Reducing Events in the Elderly) (22,23),

sient ischemic attack (TIA) is well established

added more data to the existing debate. Long-term

(1–4). A serial cross-sectional study of 94,270 individ-

aspirin use has also been associated with a reduction

uals from 2007 to 2015 reported that aspirin use for

in cancer incidence and mortality (24,25). The current

primary prevention of cardiovascular disease (CVD)

systematic review represents the most comprehensive

averaged 43% (5). However, the efficacy and safety

analysis of the available data to evaluate the efficacy

of aspirin for primary prevention varied among multi-

and safety of aspirin for primary prevention of CVD as

ple

well as its effect on cancer incidence and mortality

randomized

controlled

trials

(RCTs)

(6–15),

creating significant variability in societal guidelines

within the period of follow-up.

(4,16–18). The recently published 10-year follow-up of the

METHODS

JPAD 2 study (Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes) (19), as well

DATA SOURCES, TRIAL ELIGIBILITY, AND DATA

as 3 large RCTs, ARRIVE (Aspirin to Reduce Risk of

EXTRACTION. This study was conducted according

Initial Vascular Events) (20), ASCEND (A Study of

to PRISMA (Preferred Reporting Items for Systematic

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Aspirin for Primary Prevention of CVD

ABBREVIATIONS

reviews and Meta-Analyses) guidelines and is

and safety outcomes. Furthermore, random-effect

AND ACRONYMS

registered with the International Prospective

meta-regression analyses were performed to eval-

Register for Systematic Reviews (PROSPERO:

uate for treatment modification effects in outcomes

CRD42018115612). A systematic search of on-

with baseline characteristics. Further details on sec-

line

until

ondary analyses are provided in the Online Appendix.

September 2018 for RCTs. Online Figure 1 il-

All analyses were performed using STATA software

lustrates the search strategy.

version 14 (StataCorp, College Station, Texas).

CVD = cardiovascular disease MACE = major adverse cardiovascular events

MI = myocardial infarction TIA = transient ischemic attack

databases

was

performed

Trials that: 1) compared aspirin (any dose) versus control (placebo or no aspirin) for

RESULTS

primary prevention of CVD; and 2) reported outcomes of interest at minimum follow-up duration of 1 year

CHARACTERISTICS OF THE INCLUDED STUDIES. Our

were included. Details of inclusion/exclusion criteria

search yielded 9,838 citations (Online Figure 1). A total

and data extraction are provided in the Online

of 15 RCTs including 165,502 participants (aspirin

Appendix.

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

SEE PAGE 2930

was high (i.e., $7.5%) in 11 studies, and lowRISK OF BIAS AND QUALITY ASSESSMENT. We uti-

intermediate in 4 trials. Three RCTs were conducted

lized the Cochrane Collaboration tool to assess the

exclusively in men (6,7,9), and 1 was exclusively in

risk of bias among included studies, and the GRADE

women (11). Four RCTs enrolled only diabetic patients

(Grades of Recommendation, Assessment, Develop-

(13,19,21,30), whereas 1 excluded this population (20).

ment, and Evaluation) tool to assess quality of

The weighted mean duration of follow-up was 6.44 

evidence for each outcome (26).

2.04 years. Table 1 reports details of included trials.

OUTCOMES. The main efficacy outcomes included

BASELINE CHARACTERISTICS OF THE INCLUDED

all-cause death, cardiovascular (CV) death, MI, stroke,

COHORTS. Mean age was 61.6  5.6 years in the

TIA,

events

aspirin group versus 61.5  5.5 years in the control

(MACE). Safety outcomes included major bleeding,

group. Study populations in aspirin and control

intracranial bleeding, fatal bleeding, and major

groups were well balanced for various CV risk factors.

gastrointestinal (GI) bleeding. Cancer incidence and

Baseline

cancer-related death were evaluated. All outcomes

Online Table 1.

were analyzed by an intention-to-treat. The Online

QUALITY ASSESSMENT AND RISK OF BIAS OF THE

and

major

adverse

cardiovascular

patient

demographics

are

detailed

in

Appendix provides details regarding study outcomes

INCLUDED TRIALS. A total of 5 trials were deemed at

and definitions.

low risk and 10 at intermediate risk for bias. The body

DATA SYNTHESIS AND

ANALYSIS.

of evidence for outcomes reached a level of high

Categorical variables were reported as frequencies

STATISTICAL

quality (Online Tables 2 and 3). No significant risk of

and percentages, continuous variables as mean  SD.

bias was demonstrated by the Egger test for any of

The DerSimonian and Laird model was utilized to

the outcomes.

calculate random-effects weighted incidences and

EFFICACY OUTCOMES. A l l - c a u s e , C V , a n d n o n - C V

summary risk ratios (RRs) (27), using study popula-

d e a t h . Aspirin was associated with similar all-cause

tion size as its weight. Confidence intervals (CIs) were

death (4.75% vs. 4.82%; RR: 0.97; 95% CI: 0.93 to

calculated at the 95% level for overall effect esti-

1.01; p ¼ 0.13; I 2 ¼ 0%) and non-CV death (3.3% vs.

mates. All p values were 2-tailed and were considered

3.3%; RR: 0.98; 95% CI: 0.92 to 1.05; p ¼ 0.53;

statistically significant if <0.05. The Higgins I 2 sta-

I 2 ¼ 29%). There was a modest nonstatistically sig-

tistic (28), and the Egger method (29) were used to

nificant reduction in CV death with aspirin compared

evaluate for heterogeneity and publication bias,

with the control group (1.46% vs. 1.52%; RR: 0.93;

respectively. Numbers needed to treat (NNT) and

95% CI: 0.86 to 1.00; p ¼ 0.064; I2 ¼ 0%) (Figure 1).

to harm (NNH) were calculated; however, these

C a r d i o v a s c u l a r e v e n t s . Aspirin use was associated

numbers should be interpreted with caution as they

with lower risk of total MI (2.07% vs. 2.35%; RR: 0.85;

are strongly dependent on the baseline risk for CVD

95% CI: 0.76 to 0.95; p ¼ 0.003; I 2 ¼ 60%), driven by a

in the participants of each trial. Annual risk of CV

lower risk of nonfatal MI (1.37% vs. 1.62%; RR: 0.82;

events was calculated for each study population

95% CI: 0.72 to 0.94; p ¼ 0.005; I 2 ¼ 58%) compared

(Online Appendix).

with the control group. The risks of fatal MI (RR: 0.93; performed multiple

95% CI: 0.79 to 1.11; p ¼ 0.43; I 2 ¼ 13%), angina pec-

sensitivity and subgroup analyses for main efficacy

toris (RR: 0.92; 95% CI: 0.79 to 1.08; p ¼ 0.30;

SECONDARY

ANALYSES. We

Abdelaziz et al.

JACC VOL. 73, NO. 23, 2019 JUNE 18, 2019:2915–29

Aspirin for Primary Prevention of CVD

I 2 ¼ 0%), coronary revascularization (RR: 0.96; ¼ 0.36;

I2

stroke (p ¼ 0.046). Meta-regression across the year of

¼ 0%),

publication showed favorable treatment effect on

and symptomatic peripheral arterial disease (5.95%

nonfatal MI in older compared with recent studies

vs. 6.28%; RR: 0.88; 95% CI: 0.70 to 1.09; p ¼ 0.24;

(p ¼ 0.05). Other baseline characteristics, including

I 2 ¼ 9%) were similar in both groups (Figure 2, Online

age, hypertension, diabetes, or statin use, demon-

Figure 2).

strated no modification of any efficacy or safety out-

95%

CI:

0.87

to

1.05;

p

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

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

in the 2 groups. Further analysis revealed a lower risk

MI, TIA, ischemic stroke, and MACE compared with

of ischemic stroke (1.29% vs. 1.49%; RR: 0.87; 95% CI:

the control group.

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

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

aspirin versus control (Figure 3, Online Figure 3). The

non-CV death (RR: 0.95; 95% CI: 0.89 to 1.0; p ¼ 0.08)

NNTs to prevent 1 event of MI, TIA, and ischemic

and CV death (RR: 0.95; 95% CI: 0.87 to 1.03; p ¼ 0.3).

stroke were 357, 370, and 500, respectively.

In populations with a high estimated 10-year ASCVD

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-

risk, aspirin showed a trend toward lower CV death

ite of nonfatal MI, nonfatal stroke, TIA, or CV death

(RR: 0.92; 95% CI: 0.84 to 1.0; p ¼ 0.06); however, all-

utilizing data from 6 RCTs was lower with aspirin

cause death remained similar (RR: 0.97; 95% CI: 0.91

compared with the control group (3.86% vs. 4.24%,

to 1.02; p ¼ 0.26). In all other sensitivity analyses, all-

RR: 0.903; 95% CI: 0.85 to 0.96; p ¼ 0.001).

cause and CV death were similar between both

SAFETY OUTCOMES. M a j o r b l e e d i n g e v e n t s . Aspirin

groups. Risk of major bleeding was higher with

use for primary prevention was associated with a

aspirin versus control among all sensitivity analyses.

significant increase in the risk of major bleeding

In populations who received low-dose aspirin

(1.47% vs. 1.02%; RR: 1.50; 95% CI: 1.33 to 1.69;

(#100 mg/day), there was a significant reduction in

p < 0.001; I 2 ¼ 25%), intracranial bleeding including

total stroke (RR: 0.92; 95% CI: 0.85 to 0.99; p ¼ 0.04)

hemorrhagic stroke (0.42% vs. 0.32%; RR: 1.32;

and nonfatal stroke (RR: 0.88; 95% CI: 0.80 to 0.96;

95% CI: 1.12 to 1.55; p ¼ 0.001; I 2 ¼ 0%), and major GI

p ¼ 0.007), a finding that was not observed when

bleeding (0.80% vs. 0.54%; RR: 1.52; 95% CI: 1.34 to

trials with all doses were pooled. To further explore

1.73; p < 0.001; I 2 ¼ 0%) compared with the control

this effect, we performed a subgroup analysis

group (Figure 4). Fatal bleeding was reported in 5

comparing low-dose (#100 mg/day) versus high-dose

trials (8,10,16,17,26) and was similar in the 2 groups

($300 mg/day) aspirin, and observed an association

(0.23% vs. 0.19%; RR: 1.09; 95% CI: 0.78 to 1.55;

between high-dose aspirin and increased risk of

p ¼ 0.6; I 2 ¼ 0%). The NNHs to cause a major bleeding

total stroke (RR: 1.19; 95% CI: 1.0 to 1.4; p ¼ 0.05), and

event

a 57% relative increase in the risk of hemorrhagic

and

intracranial

bleeding

were

222

and

1,000, respectively.

stroke (RR: 1.57; 95% CI: 0.89 to 2.77) (Online

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-

Figure 5).

ated with increased risk of GI ulcers (RR: 1.37; 95% CI:

SUBGROUP ANALYSES. Diabetes. The current analysis

1.07 to 1.76; p ¼ 0.013; I 2 ¼ 80%) compared with the control group.

demonstrates similar outcomes in terms of all-cause death (RR: 0.96; 95% CI: 0.91 to 1.00 vs. RR: 0.96;

CANCER. At a mean follow-up of 6.46 years, cancer

95% CI: 0.85 to 1.10), CV death (RR: 0.91; 95% CI:

incidence (6.1% vs. 6.2%; RR: 0.99; 95% CI: 0.93 to

0.82 to 1.00 vs. RR: 0.89; 95% CI: 0.6 to 1.3), and total

1.06; p ¼ 0.85; I 2 ¼ 24%) and cancer-related death

stroke (RR: 0.91; 95% CI: 0.76 to 1.1 vs. RR: 0.98;

(1.95% vs. 1.89%; RR: 0.99; 95% CI 0.82 to 1.20;

95% CI: 0.88 to 1.1) with aspirin versus control in

p ¼ 0.92; I 2 ¼ 80%) were similar in both groups

patients with or without diabetes. The risk of MI was

(Online Figure 4).

lower with aspirin in subjects without diabetes but

META-REGRESSION

ANALYSES. Female

was

not in those with diabetes (RR: 0.8; 95% CI: 0.66 to

associated with a favorable treatment effect on total

0.98; p ¼ 0.03 vs. RR: 0.90; 95% CI: 0.75 to 1.07;

sex

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Aspirin for Primary Prevention of CVD

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, omega-3 fatty acid

Age >40 yrs þ DM

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 treatment goals

Age 50–80 yrs þ HTN

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

95% CI: 0.63 to 0.94; p ¼ 0.01 vs. RR: 0.87; 95% CI:

interaction (p interaction ¼ 0.48).

0.72 to 1.05; p ¼ 0.16; p interaction ¼ 0.37) in fair- versus

S e x . Aspirin was associated with a lower risk of MI

high-quality trials, but without significant p interaction .

than control in men, but not in women (RR: 0.69;

Major bleeding remained significantly higher with

95% CI: 0.58 to 0.83; p < 0.001 vs. RR: 0.92; 95% CI:

aspirin versus control regardless of study quality

0.78 to 1.1; p ¼ 0.35; pinteraction ¼ 0.03). Otherwise, sex

(Online Figure 6).

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:

DISCUSSION

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;

The current meta-analysis represents the largest and

95% CI: 0.96 to 1.12 vs. RR: 0.95; 95% CI: 0.81 to 1.12),

most contemporary examination of long-term out-

and major bleeding (RR: 1.44; 95% CI: 1.21 to 1.73 vs.

comes with aspirin use for primary prevention of

RR: 1.48; 95% CI: 1.25 to 1.75) with aspirin versus

CVD. Our primary analysis found that: 1) aspirin is

control.

not associated with a reduction in all-cause or

S t u d y q u a l i t y . Aspirin was associated with a lower

non-CV death, but is associated with a modest, non-

risk of all-cause death (RR: 0.94; 95% CI: 0.88 to 1.00;

statistically significant relative reduction of 7% in CV

p ¼ 0.05 vs. RR: 0.99; 95% CI: 0.91 to 1.08; p ¼ 0.88;

death; 2) aspirin (even #100 mg/day) is associated

p interaction ¼ 0.24), total MI (RR: 0.84; 95% CI: 0.73 to

with lower rates of MI (NNT ¼ 357), nonfatal MI

0.97; p ¼ 0.01 vs. RR: 0.85; 95% CI: 0.70 to 1.03;

(NNT ¼ 400), TIA (NNT ¼ 370), and ischemic stroke

p ¼ 0.1; p interaction ¼ 0.89), and nonfatal MI (RR: 0.77;

(NNT ¼ 500); 3) aspirin use is associated with a

2921

Abdelaziz et al.

JACC VOL. 73, NO. 23, 2019 JUNE 18, 2019:2915–29

Aspirin for Primary Prevention of CVD

T A B L E 1 Continued

Aspirin Dose

Adherence to Aspirin, %

Primary Outcome

Estimated 10-yr CV Risk

Completed Follow-Up, %

Mean 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 ICH) or TIA, or death from any vascular cause.

70†

10.2

99.1‡

7.4

100 mg/day

Composite of CV death, ACS (nonfatal MI, coronary revascularization, or UA), cerebrovascular disease, HF, or nonfatal PAD

92.6

31

NR

5.4*

81–100 mg/day

Composite of sudden death, CV death, nonfatal MI, nonfatal stroke, UA, TIA, or PAD

79

7.8

62/65

10.3*

100 mg/day

Composite of CV death (MI, stroke, and other CV causes), nonfatal stroke and MI

76

5.9

89.2/89.6

5.02*

100 mg/day

Composite of fatal or nonfatal coronary event or stroke or revascularization.

88

9.9

NR

8.2

100 mg/day

Composite of death from CHD or stroke, nonfatal MI or stroke, or above ankle amputation for critical limb ischemia

50

25.3

84.5/84

6.7*

100 mg every other day

Composite of nonfatal MI, nonfatal stroke, or CV death

73†

2.6

97.2 (morbidity), 99.4 (mortality) ‡

10.1

100 mg/day

Composite of CV death, nonfatal MI, and nonfatal stroke

81

7.6

99.3‡§

3.6

75 mg/day

Composite of all (fatal and nonfatal) MI, all (fatal and nonfatal) strokes, and all other CV deaths

NR

11.9

97.4‡

3.8

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 if requested

CVD mortality

75

15.4

NR

6

significant increase in the risk of nonfatal major

primary prevention trials due to heterogeneity of

bleeding events, regardless of dose or population

populations studied and the high incidence of

characteristics; and 4) aspirin does not affect the

nonvascular death (>60% of all deaths), in particular,

incidence of cancer or risk of cancer death within a

nonvascular noncancer death (20% to 25% of all

median follow-up period of 6.46 years. Secondary

deaths) (35). It remains plausible that misattribution

analyses revealed that: 1) aspirin may reduce all-

of cause of death occurred. Although some trials

cause death after 5 years of follow-up; 2) the trend

restricted the definition of CV death to a composite of

toward lower risk of CV death with aspirin is only

fatal MI and fatal stroke (13,14,30), others included

observed in populations with high estimated 10-year

other causes (e.g., sudden cardiac death, heart fail-

ASCVD risk; and 3) lower risk of total and nonfatal

ure,

stroke with aspirin use is observed only when low-

Further evaluation of temporal distribution and

dose aspirin (#100 mg/day) is utilized.

actual cause of death in participants enrolled in

and

pulmonary

embolism)

(6,7,11,19,21–23).

recent RCTs would provide additional insight. ASPIRIN AND PRIMARY PREVENTION OF DEATH.

Prior meta-analyses of aspirin use for primary pre-

ASPIRIN

vention have provided conflicting evidence regarding

EVENTS. We observed a significant reduction in total

its effect on all-cause death (1,32–34). In the current

and nonfatal MI with aspirin. The lack of effect on

analysis, although aspirin did not reduce all-cause

fatal

death, a modest nonstatistically significant relative

(6,7,11,19–21,23). Among cerebrovascular outcomes,

reduction of 7% in CV death was observed. Further-

we noted a benefit with aspirin use in primary pre-

more, in populations followed for >5 years (mean 6.7

vention of TIA and ischemic stroke; however, this

years), a potential benefit for all-cause death was

benefit was offset by an increase in rates of hemor-

noticed. In a previous meta-analysis, a similar finding

rhagic stroke, resulting in a similar overall rate of

was attributed to reduction in nonvascular rather

stroke in the 2 groups. This is in concordance with

than vascular death (24). A uniform reduction in all-

prior meta-analyses (32–34). Only the WHS (Women’s

cause death may be challenging to demonstrate in

Health Study), a trial of aspirin 100 mg every other

MI

AND

has

PRIMARY

been

PREVENTION

previously

OF

CV

established

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Abdelaziz et al.

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Aspirin for Primary Prevention of CVD

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

Study

Year

RR (95% CI)

Events, Aspirin

Events, 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

0.97 (0.93, 1.01)

3962/83479

3954/81912

100.00

Subtotal (I-squared = 0.0%, p = 0.643) . 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

0.93 (0.86, 1.00)

1216/83479

1247/81912

100.00

Subtotal (I-squared = 0.0%, p = 0.875) NOTE: Weights are from random effects analysis .1 <<< Favors Aspirin

1

10 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,

treatment groups for the less common, individ-

showed a significant reduction in ischemic stroke

ual outcomes.

with aspirin (11). Interestingly, a meta-regression

We also demonstrate a reduction in total and

analysis of our study shows possible modification in

nonfatal stroke in populations who received low-dose

the incidence of stroke in women. It should be noted

aspirin #100 mg/day, but an increase in total stroke

that most of these trials were designed with power

driven primarily by higher incidence of hemorrhagic

calculation for composite endpoints, thereby making

stroke with aspirin $300 mg/day. A dose-related in-

it difficult to detect significant differences between

crease in bleeding with aspirin is well established

Abdelaziz et al.

JACC VOL. 73, NO. 23, 2019 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

Year

RR (95% CI)

Events, Aspirin

Events, Control

% Weight

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) . Nonfatal MI

0.85 (0.76, 0.95)

1728/83529

1930/81973

100.00

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) . Fatal MI

0.82 (0.72, 0.94)

1121/81673

1298/80118

100.00

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

0.93 (0.79, 1.11)

366/81673

349/80118

100.00

Study Total MI

Subtotal (I-squared = 13.2%, p = 0.309) NOTE: Weights are from random effects analysis .1 <<< Favors Aspirin

1

10 Favors Control >>>

The relative size of the data markers indicates the weight of the sample size from each study. Abbreviations as in Figure 1.

2923

2924

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JACC VOL. 73, NO. 23, 2019 JUNE 18, 2019:2915–29

Aspirin for Primary Prevention of CVD

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

Year

RR (95% CI)

Events, Aspirin

Events, Control

% Weight

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

0.80 (0.71, 0.89)

535/50394

651/48771

100.00

Study TIA

Subtotal (I-squared = 0.0%, p = 0.745) . 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

0.97 (0.89, 1.04)

1520/83529

1537/81973

100.00

Subtotal (I-squared = 10.1%, p = 0.340) NOTE: Weights are from random effects analysis .1 <<< Favors Aspirin

1

10 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

compared with older studies (mean 14.4%). For

mortality with hemorrhagic versus ischemic stroke

example, in the ASCEND study, the mean systolic

(1). Our results illustrate a critical association be-

blood pressure in the aspirin group was 136 mm Hg,

tween aspirin dose and risk of total stroke, favoring

with >75% of population receiving statins, and only

lower doses for primary prevention of stroke. The

8% actively smoking (21). In the ARRIVE trial, almost

current analysis shows that to prevent 1 MI, TIA, or

50% of patients were on statins, >65% on anti-

ischemic stroke event, 357, 370, and 500 persons

hypertension medications, and less than one-third

would require treatment, respectively.

were smokers (20). Our meta-regression showing a

In recent RCTs (19–21,23), the modest reduction in

favorable treatment effect on nonfatal MI in older

CV events or lack of benefit with aspirin suggests a

versus recent trials supports this theory and follows

role for other primary prevention strategies that are

the general trend of reduction/plateauing of the

being employed in the patient population, and is

burden of CVD worldwide (37).

supported by a trend toward a lower estimated

Primary prevention strategies in healthy adults are

10-year ASCVD risk in these RCTs (mean 8.3%) when

multifaceted. These subjects are more likely to be

Abdelaziz et al.

JACC VOL. 73, NO. 23, 2019 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

Study

Year

RR (95% CI)

Events, Aspirin

Events, 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

1.50 (1.33, 1.69)

1172/79723

799/78142

100.00

Subtotal (I-squared = 24.8%, p = 0.207) . 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

1.32 (1.12, 1.55)

338/80985

252/79419

100.00

Subtotal (I-squared = 0.0%, p = 0.739) . 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

1.52 (1.34, 1.73)

582/72503

380/70898

100.00

Subtotal (I-squared = 0.0%, p = 0.581) NOTE: Weights are from random effects analysis .1

1

<<< Favors Aspirin

10 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

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Aspirin for Primary Prevention of CVD

C E NT R AL IL L U STR AT IO N Aspirin for Primary Prevention of Cardiovascular Events

Abdelaziz, H.K. et al. J Am Coll Cardiol. 2019;73(23):2915–29.

Relative benefit and risk of aspirin use for primary prevention of cardiovascular disease based on pooled data from 15 randomized controlled trials.

aggressive primary prevention measures is chal-

included trials hindered a comprehensive analysis

lenging and may explain the lack of a net benefit in

about its role in modification of outcomes with

this population. Furthermore, the lack of data

aspirin. The ongoing ACCEPT-D (Aspirin and Simva-

regarding percentage of statin use in many of the

statin

Combination

for

Cardiovascular

Events

Abdelaziz et al.

JACC VOL. 73, NO. 23, 2019 JUNE 18, 2019:2915–29

Aspirin for Primary Prevention of CVD

Prevention Trial in Diabetes) will provide important

BENEFIT VERSUS RISK PREDICTION TOOL FOR

insight into the role of aspirin on a background of

ASPIRIN USE IN PRIMARY PREVENTION. The clinical

statin therapy for the primary prevention of CVD in a

dilemma of identifying the population that would

diabetic population (38).

benefit from aspirin in primary prevention still per-

Sex differences in the efficacy of aspirin for

sists. In 2016, the U.S. Preventive Service Task Force

primary prevention remain a matter of debate

utilized a decision-analysis model to estimate the

(1,32,34,39). Although our analysis demonstrates a

magnitude of net benefit with aspirin based on age,

possible sex difference in the benefit with aspirin, the

sex, and 10-year CVD risk using the American Heart

heterogeneity

in

Association/American College of Cardiology risk

particular, the baseline risk of ASCVD, may have

calculator (47). The U.S. Preventive Service Task

contributed to the results. In another subgroup

Force indicated that a net benefit in life expectancy is

analysis, we did not observe benefit of aspirin in

expected for most men and women started on aspirin

primary prevention of MI in diabetic populations.

at age 40 to 59 years and 60 to 69 years if they are at

The biological plausibility of this observation could

high risk for CVD. However, overestimation of CVD

be based on possible aspirin resistance and increase

risk with this calculator in real-world is a current

in platelet turnover in diabetic patients (40–43).

concern (48). In addition, the current analysis dem-

Although this was recently challenged by the ASCEND

onstrates a potential reduction of net benefit with

trial, it is important to note that the risk of nonfatal

aspirin in the contemporary era. Furthermore, a valid

MI was similar between aspirin and control groups in

prediction tool for estimating the bleeding risk with

high-risk diabetic patients in this trial.

aspirin in primary prevention is lacking, and only a

in

population

characteristics,

single risk prediction tool for GI complications with SAFETY OF ASPIRIN USE IN PRIMARY PREVENTION.

aspirin is available (49). Our study calls for an upda-

Our analysis shows an increased risk for major

ted decision-analysis model that incorporates the

bleeding (NNH ¼ 222) with aspirin use for primary

new evidence and utilizes a comprehensive risk pre-

prevention, a finding that remains consistent even

diction tool for GI bleeding. This would improve the

when restricting the analysis to low-dose aspirin tri-

precision of the model to define an appropriate

als. However, fatal bleeding was similar in both

ischemic versus bleeding risk threshold, based on

groups. Aspirin (especially at higher doses) was

which an adequately validated benefit-risk prediction

associated with a 32% relative increase in intracranial

tool can be calibrated to determine individuals in

bleeding risk (including hemorrhagic stroke) as well

whom the benefits of using aspirin for primary pre-

as >50% increase in the risk of major GI bleeding.

vention outweigh the risks.

Such findings are similar to results from prior studies (1,33,36,44). Although certain baseline characteristics such as

STUDY STRENGTHS AND LIMITATIONS. The current

study aims to provide comprehensive and updated

older age, male sex, history of GI ulcers, elevated

data about efficacy and safety of aspirin in primary

mean BP, and NSAID use, have shown to increase the

prevention of CVD. Since the submission of our paper,

risk of aspirin-related bleeding (36,45), our meta-

2 meta-analyses have been published (50,51). Our

regression analysis failed to demonstrate any effect

study, however, provides further insight through

modification of major bleeding by baseline charac-

more comprehensive subgroup, sensitivity, and meta-

teristics. Patient-level metanalysis would be helpful

regression analyses. In particular, the current study

to further investigate these effects.

emphasizes: 1) a potential benefit with aspirin on allcause death on long-term follow-up >5 years; 2) a

CANCER INCIDENCE AND MORTALITY. Our analysis

trend toward lower CV death in population with high

shows no reduction in the risk of cancer or cancer-related

ASCVD risk; 3) a favorable treatment effect with

death with aspirin use in primary prevention, even on

aspirin on nonfatal MI in older compared with recent

secondary analysis restricted to long-term follow-up

studies; and 4) a difference in the outcome of stroke

trials ($5 years). The discrepancy between our results

with a low-dose (#100 mg/day) versus high-dose

and prior meta-analyses that showed potential lower

($300 mg/day) aspirin. We included only RCTs to

risk of cancer and cancer death with aspirin (24,35,46)

avoid bias associated with observational studies.

can be attributed to the inconsistency of results in

However, our study has limitations. The main limita-

recent RCTs reporting similar risk of cancer-related

tions are the heterogeneity in the definition of com-

outcomes in aspirin versus control and the need for

posite outcomes among trials, as well as the

even longer follow-up to see any potential effect on

heterogenous quality of studies included. To over-

cancer (20–22).

come these limitations, we analyzed individual

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Abdelaziz et al.

JACC VOL. 73, NO. 23, 2019 JUNE 18, 2019:2915–29

Aspirin for Primary Prevention of CVD

outcomes separately, and MACE was examined only from studies with a homogenous definition. We

ADDRESS FOR CORRESPONDENCE: Dr. Jawahar L.

further performed multiple secondary analyses to

Mehta, University of Arkansas for Medical Sciences,

enhance the quality of our analysis. Another limitation

4301 West Markham Street, Little Rock, Arkan-

to be acknowledged is that the use of summary esti-

sas

mates of absolute risk reduction and NNT/NNH is

@MarwanSaadMD, @DLBHATTMD, @JDawnAbbott1,

suboptimal when pooling data to perform a meta-

@herbaronowMD, @chandu991.

analysis. Hence, we performed our analysis primarily

72205.

E-mail:

[email protected].

Twitter:

PERSPECTIVES

using summary estimates of RRs. Finally, the lack of patient-level data precluded a more robust analysis.

COMPETENCY IN MEDICAL KNOWLEDGE:

CONCLUSIONS Aspirin

use

for

Aspirin reduces the risk of first nonfatal MI and stroke,

primary

prevention

but increases the risk of bleeding. The decision to use

decreased

aspirin for primary prevention should be based on a

nonfatal ischemic events and increased nonfatal

patient’s risk of CV events and bleeding and the dose

bleeding events (Central Illustration). The benefits

should not exceed 100 mg daily.

were more pronounced when estimated ASCVD risk was $7.5% over 10 years. These findings suggest that

TRANSLATIONAL OUTLOOK: Longer-term

the decision to use aspirin for primary prevention

follow-up studies are needed to better characterize

should be tailored to the individual patient based on

individuals for whom the benefit of aspirin for primary

estimated ASCVD risk and perceived bleeding risk, as

prevention outweighs the risk of bleeding, and to

well as patient preferences regarding types of events

assess potential effects on incident cancer and all-

prevented versus potential bleeding caused. When

cause mortality.

aspirin is used for primary prevention, a low dose (#100 mg/day) should be recommended.

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KEY WORDS aspirin, cardiovascular events, primary prevention

A PP END IX For an expanded Methods section as well as supplemental figures and tables, please see the online version of this paper.

Go to http://www.acc.org/ jacc-journals-cme to take the CME/MOC/ECME quiz for this article.

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