Invest Clin 64(3): 405 - 423, 2023 https://doi.org/10.54817/IC.v64n3a11

Corresponding author: Gilberto Vizcaino. Instituto de Investigaciones Clínicas “Dr. Américo Negrette”, Facultad

de Medicina, Universidad del Zulia , Maracaibo, Venezuela. E-mail: gilvizcaino@gmail.com

Aspirin in primary cardiovascular

prevention: the two faces of the coin

and the importance of the Number Needed

to Treat: a systematic review and meta-

analysis.

Gilberto Vizcaino

and Jesús Weir Medina

Instituto de Investigaciones Clínicas “Dr. Américo Negrette”, Facultad de Medicina,

Universidad del Zulia , Maracaibo, Venezuela.

Instituto Hematológico de Occidente/Banco de Sangre del Estado Zulia, Maracaibo,

Venezuela.

Keywords: aspirin; cardiovascular disease; primary prevention; bleeding risk; number

needed to treat.

Abstract. Aspirin has been an essential treatment for the primary preven-

tion of cardiovascular diseases (CVD). Several randomized controlled studies do

not support the routine use of aspirin, mainly due to its association with bleed-

ing risk. This systematic review aims to advocate aspirin prescription based on

the Number Needed to Treat (NNT) and the Number Needed to Harm (NNH).

This combination provides a good measure of the effort to avoid an unfavor-

able outcome, weighed against possible associated risks. A search of random-

ized studies on aspirin treatment was conducted in two separate periods. Four

studies from 1988-1998 and six from 2001-2018 were included in the analysis

(157,060 participants). The primary endpoint was a composite outcome of Non-

fatal Myocardial Infarction (NFMI), Non-fatal Ischemic Stroke (NFIS), and CV

mortality. Major bleeding was a safety endpoint. We calculated the Absolute Risk

Reduction (ARR%), NNT, and NNH, alongside the Relative Risk (RR) and 95%

CI of each primary endpoint. The results of all included studies (10) showed

a net benefit with aspirin treatment for NFMI (NNT= 259) and the composite

outcome (NNT=292) with a significant relative risk reduction of 20% (p=0.003;

= 0%) and 10% (p<0.001; I

= 0%), respectively. There was a relevant 60% in-

crease in the bleeding risk (p<0.0001, NNH=208; I

= 3%). The NNT and NNH

may constitute measures of efficacy and risk in clinical shared decision-making.

However, it is essential to consistently establish that patients’ benefit-risk should

be individualized and not represent a clinical guide for everyone.

406 Vizcaíno and Weir Medina

Investigación Clínica 64(3): 2023

Aspirina en prevención cardiovascular primaria. Las dos caras

de la moneda y la importancia del número necesario a tratar.

Revisión sistemática y metanálisis.

Invest Clin 2023; 64 (3): 405 – 423

Palabras clave: aspirina; enfermedad cardiovascular; prevención primaria; riesgo

hemorrágico; número necesario a tratar.

Resumen. La aspirina ha sido un tratamiento esencial para la prevención

primaria de las enfermedades cardiovasculares (ECV). Varios estudios controla-

dos aleatorizados no apoyan el uso rutinario de la aspirina principalmente debido

a su asociación con el riesgo de sangrado. Esta revisión sistemática tiene como

objetivo evaluar la prescripción de aspirina basada en el Número Necesario para

Tratar (NNT) y el Número Necesario para Dañar (NNH). Esta combinación pro-

porciona una buena medida del esfuerzo para evitar un resultado desfavorable,

sopesado frente a los posibles riesgos asociados. Se realizó una búsqueda de estu-

dios aleatorios sobre el tratamiento con aspirina en dos períodos separados. En el

análisis se incluyeron cuatro estudios de 1988 a 1998 y seis de 2001 a 2018 (157

060 participantes). El criterio principal de valoración fue un resultado compuesto

de infarto de miocardio no mortal (NFMI), accidente cerebrovascular isquémico

no mortal (NFIS) y mortalidad cardiovascular. La hemorragia mayor fue el punto

final de seguridad. Se calculó la reducción del riesgo absoluto (RAR), el NNT y el

NNH, junto con el riesgo relativo (RR) y el IC del 95% de cada criterio principal

de valoración. Los resultados de todos los estudios incluidos (10) mostraron un

beneficio neto con el tratamiento con aspirina para NFMI (NNT= 383) y el resul-

tado compuesto (NNT=445) con una reducción significativa del riesgo relativo

del 20% (p=0,003; I

= 0%) y 10% (p<0,001; I

= 0%), respectivamente. Hubo un

incremento relevante del 60% en el riesgo de sangrado (p<0,0001, NNH=208;

= 3%). El NNT y el NNH pueden constituir medidas de eficacia y riesgo en la

toma de decisiones clínicas compartidas. Sin embargo, es importante establecer

consistentemente que el riesgo-beneficio de los pacientes debe ser individualiza-

do, y no una guía clínica para todos.

Received: 25-01-2023 Accepted: 11-03-2023

INTRODUCTION

More than 30 years have passed since

the Physician´s Health Study was published.

This painstaking work demonstrated a 44%

risk reduction of myocardial infarction

(MI) with aspirin (RR: 0.56; 95 %CI, 0.45

to 0.70; p<0.0001)

. This effect was more

pronounced in the group of individuals older

than 50 years, while the presence of ulcer

and transfusion demand as secondary events

were not significant compared with the pla-

cebo group (RR: 1.22; 95%CI,0.98 to 1.53;

p = 0.08 for ulcer). The conclusion of this

work was a recommendation for the use of

aspirin in the primary prevention of a first

MI in healthy individuals. However, the US

Food and Drug Administration (FDA) did not

approve the professional labeling of aspirin

for the prevention of MI because another

Aspirin in cardiovascular prevention 407

Vol. 64(3): 405 - 423, 2023

similar trial, The British Doctor´s Trial, did

not show benefit from aspirin administration

for cardiovascular prevention

. In 2003, the

use of aspirin was updated in the primary

prevention of cardiovascular disease

. In

addition to the two mentioned trials, three

more trials were also analyzed: The Throm-

bosis Prevention Trial

, The Hypertension

Optimal Treatment Study

, and The Primary

Prevention Project

, including 55.580 ran-

domized participants (11.466 women). The

studies mentioned above revealed a 32% re-

duction in the risk of a first MI and a 15%

reduction in the risk of all important vas-

cular events following aspirin´s treatment,

demonstrating strong evidence of the use of

aspirin in the primary prevention of MI. At

that time, the US Preventive Services Task

Force (USPTF)

and the American Heart As-

sociation recommended aspirin for men and

women whose 10-year risk of a first coronary

event was 10% or greater

since the benefits

of a reduction of cardiovascular (CV) events

outweighed the risks in most of the patients

presenting this sort of cardiovascular risk.

Additionally, there are gender-specific

differences in platelet function and response

to aspirin

9,10

. Women under 65 years old

without known CVD have a minor response

to aspirin therapy in the primary prevention

of coronary artery disease

; the dose recom-

mended was 81-100 mg every other day

The net benefits for persons who have

started taking aspirin continue accumulat-

ing over time without a bleeding event. The

net benefits, however, generally become

progressively smaller with advancing age

because of an increased risk for bleeding,

and modeling data suggest that it may be

reasonable to consider stopping aspirin use

at around age 75

for primary prevention.

Despite this, there is a gap in understand-

ing the benefits and risks of giving aspirin

to patients at moderate risk of CVD. Aspirin

has been a primary preventive drug for car-

diovascular and cerebrovascular diseases for

years. What has happened recently to change

the concept and the prescription for the use

of aspirin in the primary prevention of CVD?

Today, the use of aspirin for primary preven-

tion has been a subject of debate. Based on

well-conducted studies, organizations such

as the European Society of Cardiology, Euro-

pean Association for Cardiovascular Preven-

tion & Rehabilitation, and the USPSTF, have

delivered an almost uniform verdict that

substantially changed the aspirin prescrip-

tion for primary CV prevention

13,14

The Number Needed to Treat (NNT),

calculated as the reciprocal of the absolute

risk reduction percentage, is a concise, clini-

cally useful parameter that provides quanti-

tative information on the efficacy of thera-

peutic interventions. Moreover, NNT allows

clinicians to understand how much effort is

needed to prevent a given event. The NNT

and its opposite, the Number Needed to

Harm (NNH), can be helpful in medical de-

cision-making, then the use of NNT or NNH

could be the likelihood of obtaining a ben-

efit or harm

. This systematic review aims

to study the effect of aspirin in the primary

prevention of CVD, under the scope of fun-

damental trials that have been an essential

guide in the prescription or not of aspirin

throughout decades till nowadays. Based on

this premise, we believe that using the NNT

and NNH could guide physicians in deciding

whether aspirin could be prescribed to pre-

vent primary CV events.

METHODOLOGY

Search Strategy

The present review exclusively focuses

on aspirin as a preventive drug for primary

CVD treatment. The search was divided into

two periods to differentiate the times when

the aspirin prescription was relevant (from

1988 to 1999, Table 1a) to the one where

aspirin was questioned for primary preven-

tion (from 2000 to 2018, Table 1b). The lat-

er period has been considered the modern

era of cardiovascular primary prevention

408 Vizcaíno and Weir Medina

Investigación Clínica 64(3): 2023

Table 1a.

Features of randomized controlled studies on the aspirin primary prevention

in cardiovascular diseases (1989-1999).

Study Number of

individuals/

follow-up

(years)

Intervention

design

Primary

events

Secondary

events

Outcomes in

primary events

Outcomes in

secondary events:

The British

Doctor´s Trial

(1988)

5139 (3429 vs

1710)

Aspirin 500

mg/d/ vs no

aspirin

NFMI: Not

specified

NFMI: 1.03 (0.71-1.49), p=0,96.

Stroke: 1.377

(0.72-2.60), p=0.40

Not specified

Physician´s

health study

(PHS)(1989)

22071 (11037

vs 11034)/

Aspirin 325

mg/beta-

carotene

every other

day vs

placebo

NFMI, non-

fatal stroke,

and death for

CVD

Ulcer,

hemorrhage of

any cause, and

transfusion

For non-fatal MI: 0.56 (CI:0.45-

0.70), p<0,0001. For Stroke:

1.22 (0.93-1.60), p=0.15. For

CV Mortality: 0.96 (0.60-1.54),

p=0.87

Hemorrhage of any cause:

2979 (27%) in aspirin group

vs 2248 (20,3%) RR=1.32

(1.25-1.40). p<0,0001

The Thrombosis

Prevention Trial

(TPT) (1998)

5085 (2545 vs

2540)/

Aspirin 75

mg/d vs

placebo

Ischemic

Heart Disease:

Coronary

death, fatal

and NFMI

Major,

intermediate

and minor

hemorrhage

For NFMI: 0.69 (0.53-0.89),

p<0,0049. For fatal MI: 1.13

(0.78- 1.63), p= 0,57. For

coronary death: 0.81 (0.66-0.99),

p<0,048

Hemorrhage of any cause:

1.24 (1.12-1.37), p<0.0001.

Major bleeding: 1.52

(1.01-2.28), p<0.055.

Intermediate: 2,00 (0.61-

6.65),p=0.38

The

Hypertension

Optimal

Treatment

(HOT)

Study(1998)

18790 (9399

vs 9391)/

Aspirin 75

mg/d vs

placebo

Major CV

events: fatal

and NFMI,

stroke, and

other CV

deaths

Major fatal, non-

fatal hemorrhage,

and minor

hemorrhage

Major CV events, 0·85 (0·73–

0·99), p<0.03.

Fatal and NFMI: 0·64 (0·49–0·85)

p<0,002. Stroke: 0·98 (0·78–

1·24), p=0.88

CV death: 0·95 (0·75–1·20), p=

0.65

Any type of hemorrhage:

1.74 (1.44-2.09), p<0,0001.

Major hemorrhage: 1.84

(1.38-2.46), p<0,0001

NFMI: Non-fatal Myocardial Infarction; CV: Cardiovascular; CVD: Cardiovascular disease.

Aspirin in cardiovascular prevention 409

Vol. 64(3): 405 - 423, 2023

Table 1b

Features of randomized controlled studies on the aspirin primary prevention

in cardiovascular diseases (2001-2018).

Study Number of

individuals/

follow up

(years)

Intervention

design

Primary

events

Secondary

events

Outcomes in

primary events :

Outcomes in

secondary events:

The Primary

Prevention

Project (PPP)

(2001)

4495

(2226 vs

2269)/

3.6

Aspirin 100 mg/

d/vitamin E

vs no aspirin

CV Death, NFMI,

and non-fatal stroke.

Major fatal

/non-fatal

hemorrhage

CV deaths: 0·56 (0·31–1.00),

p=0.06. All MI: 0·69 (0·38–

1·23), p=0,27. Stroke: 0·67

(0·36–1·27), p=0,29

Any type of

hemorrhage: 4.07

(1.67-9.96), p<0,0015

Major hemorrhage:

1.74 (1.32-2.30),

p<0,0001

The Primary

Prevention of

Cardiovascular

Disease in

Women (WHS)

(2005)

39876 (19934

vs 19942)

Aspirin 100mg

every other day

vs placebo

Patients; >45

year old

NFMI, non-fatal

stroke, or death from

cardiovascular causes

GI bleeding

requiring

transfusion

Major CV events: (RR, 0.91;

(0.80 to 1.03); p=0.13. Stroke:

RR;0.83; (0.69-0.99); p=0.04).

Fatal or NFMI: RR: 1.02; (0.84-

1.25); p=0.83, or death from

cardiovascular causes RR 0.95;

(0.74-1.22); p=0.68)

Major bleeding:

RR, 1.40; (1.07- 1.83);

p=0.02

The Japanese

Primary

Prevention

Project (JPPP)

(2014)

14 464 (7220

vs 7244)/

6.5

Aspirin 100mg

daily vs no

aspirin

Composite primary

outcome was death

from CV causes (MI,

stroke, and other CV

causes), non-fatal

stroke (ischemic

or hemorrhagic,

including undefined

cerebrovascular

events), and NFMI

Secondary

outcomes

included

in divide

endpoints.

Composite outcome: HR:0.94

(0.77-1.15); p= 0.54. NFMI:

HR:0.53 (0.31-0.91), p= 0.02.

TIA:HR: 0.57 (0.32-0.99);p

=0.04

Extracranial (major)

hemorrhage: HR:1.85

(1.22-2.81); p =

0.004).

410 Vizcaíno and Weir Medina

Investigación Clínica 64(3): 2023

Study Number of

individuals/

follow up

(years)

Intervention

design

Primary

events

Secondary

events

Outcomes in

primary events :

Outcomes in

secondary events:

The ASPREE

Trial

(2018)

19114 (9525

vs 9589)/

4.7

Aspirin 100mg

daily vs placebo

Endpoints included

major hemorrhage

and cardiovascular

disease (fatal

coronary heart

disease, NFMI, fatal

or non-fatal stroke,

or hospitalization for

heart failure).

Major

Hemorrhage

as secondary

endpoint

For CVD: HR: 0.95; (0.83-1.08),

p=NS. Fatal, NFMI: HR:0.93

(0.76-1.15). Stroke: HR: 0.89

(0.71-1.11)

Major Hemorrhage:

HR: 1.38; (1.18-1.62);

p<0.001

The ARRIVE

Trial (2018)

12546 (6270

vs 6276)/

5 years

Aspirin vs

placebo

Eligible patients

were aged 55

years (men)

or 60 years

(women) and

older and

had an average

cardiovascular

risk

The primary efficacy

endpoint was a

composite outcome of

cardiovascular death,

MI, unstable angina,

stroke, or TIA.

Safety

endpoints

were

hemorrhagic

events and

incidence of

other adverse

events

HR:0·96; (0·81–1·13),

p=0·6038).; NFMI: HR 0·90,

(0·67–1·20); p=0·4562

The ASCEND

Trial (2018)

15,480 (7740

vs 7740)/

7.4

Aspirin 100mg

vs placebo in

diabetic patients

The primary

efficacy outcome (MI.,

stroke or TIA, or

death from any

vascular cause,

excluding

any confirmed

intracranial

hemorrhage)

The primary

safety

outcome was

the first

major

bleeding

event

Serious vascular events: 0.88;

(0.79-0.97), p=0.01. NFMI: 0.98

(0.80–1.19). Stroke: 0.88 (0.73–

1.06)

Major bleeding

events:1.29 (1.09

-1.52); p=0.003

Table 1b.

CONTINUACIÓN

NFMI: Non-Fatal Myocardial Infarction; CV: Cardiovascular; TIA: Transient ischemic attack; HR: Hazard ratio; RR: Relative risk.

Aspirin in cardiovascular prevention 411

Vol. 64(3): 405 - 423, 2023

The bibliography search was conducted

in PUBMED by MEDLINE and Google Scholar

under the following MESH (Medical Subject

Headings) terminology: aspirin in primary

prevention, aspirin in myocardial infarction,

aspirin in stroke, aspirin in cardiovascular

death or mortality, aspirin in bleeding or hem-

orrhage; those terms were connected thru a

Boolean “and” with randomized controlled

trials (Fig. 1). Additionally, the term number

needed to treat was used for the complemen-

tary bibliography. The primary endpoint to

report was a composite of non-fatal myocar-

dial infarction (NFMI), non-fatal ischemic

stroke (NFIS), and cardiovascular mortality

(CVM). The primary bleeding outcome was

major bleeding, as stated by the studies. The

exclusion criteria were: a) studies with less

than 4000 participants, b) systematic reviews

on aspirin treatment because there are good

reviews about it

16-18

, c) a combination of an-

tiplatelet or anticoagulants treatments with

aspirin (The Thrombosis Prevention Trial

assessed warfarin and aspirin alone and in

combination but data for participants who re-

ceived warfarin were excluded from the analy-

sis), d) duplicate publications and e) those

works that do not contain the composite as

the endpoint.

Finally, four studies from 1988-1998

1,2,4,5

and six studies from 2001-2018

6,19-23

were included in the analysis (Tables 1a and

1b). This article has been assessed according

to the PRISMA 2020 statement and checklist

. The bias risk in each study was assumed ac-

cording to a systematic review published pre-

viously

, following the Cochrane risk of bias

assessment, and the Jadad scale was used to

evaluate the quality of the randomized con-

trolled studies (< 3: high risk of bias, ≥ 3:

low risk of bias)

. Ethical approval was not

required for conducting this study.

Fig. 1. Flow chart of literature search strategy according to the MESH terminology. Note: some data might

be lost in the early stages of the search.

412 Vizcaíno and Weir Medina

Investigación Clínica 64(3): 2023

Statistical approach

NNT and NNH

NNT or NNH would be the number of

patients to be treated to obtain one ben-

efit or one harm in a predefined period

26.

The number needed to treat is simply the

reciprocal of the absolute risk difference

obtained from the percentage of events in

the control group minus the percentage

of events in the experimental group (also

named as absolute difference). Depending

on the treatment, when the difference in

the two groups proportions is significant,

the NNT is small, and vice versa. NNT is a

concise, clinically helpful presentation of

the effect of an intervention. The NNT and

the NNH are calculated as the inverse of the

absolute reduction (ARR) or absolute incre-

ment of the risk (ARI). A 95% CI for NNT

can be constructed by simply inverting and

exchanging the limits of a 95% CI from the

ARR. When the result shows an ARR or ARI

with 95% CI extended from negative to posi-

tive values, it means that the zero is includ-

ed, and the NNT is infinity thus, we need

to separate two intervals using via infinity

(∞) and indicate that the treatment may be

helpful or harmful

As Altman has mentioned

, the terms

NNT and NNH may not be appropriate to

denote benefit and harm. He proposes the

abbreviations of NNTB (benefit) and NNTH

(harm). However, we maintain the conven-

tional abbreviations of NNH and NNT to re-

fer to benefit or harm, respectively. We also

constructed an arbitrary classification of

the NNT or NNH effect as follow: Net ben-

efit, Uncertain benefit (treatment could be

harmful), Uncertain harm (treatment could

be helpful), and net harm.

Because the included studies have dif-

ferent follow-up periods, we have to make

assumptions about it and make a “time ad-

justment” because if we want to be able to

compare these NNTs, it is necessary to ad-

just all of them to refer to the same track-

ing time. So it is necessary to uniform the

time of these studies to obtain the same rel-

ative interpretation of the results regarding

benefit and harm. For this purpose, we have

to use the following formula:

28,29

Rearranging the terms, we have;

In the present study,

we have adjust-

ed five years as a hypothetical time for

all the included studies to calculate NNT

and NNH. We used a computer program

for ARR, NNT, and NNH to obtain the data

and their 95% CI (https://www.graphpad.

com/quickcalcs/NNT1/). Additionally, as

an effect measure, a Relative Risk and its

95% CI were estimated using the Compre-

hensive Meta-Analysis program (Biostat,

Englewood, NJ) alongside the relative

weight and random effect. As statistical

parameters, the consistence for heteroge-

neity (I

) was determined as low (<25%),

moderate (25% to 75%,), and high (>75%)

by testing the chi-square calculation of

each meta-analysis (Cochrane Q) accord-

ing to the Higgins formula

; and statisti-

cal significance was fixed as p<0.05.

The forest plot for meta-analysis of

each primary effective endpoint and safety

was constructed under NNT and NNH pa-

rameters, with all included studies perform-

ing a logarithmic scale with infinity value in

the middle of the scale according to previ-

ous reference

, the NNT 95%CI (benefit)

values are shown to the left and NNH 95%

CI (harm) values on the right with the over-

all estimate.

RESULTS

Table 2a shows the total results of the

endpoints in the trials made in the last year

of the 20

century (four trials with a total of

51,085 participants), with a net benefit for

NFMI (NNT= 156) confirmed by a significant

relative risk reduction of 31% [RR,95%CI:

0.69(0.61-0.79); p<0,0001; I

= 10.5%].

Aspirin in cardiovascular prevention 413

Vol. 64(3): 405 - 423, 2023

Table 2a. Summarized results of the endpoints in the included studies, period 1988-1998 (n= 4).

ENDPOINTS Aspirin

events (%)

n: 26410

No Aspirin

events (%)

n:24675

RR(95%CI),

p value; I²

ARR%

(95%CI)

ARI%

(95%CI)

NNT

(95%CI)

NNH

(95%CI)*

Observations

NFMI 385 (1.46) 518 (2.10) 0.69

(0.61-0.79)

<0.0001; 10.5%

0.64

(0.41-

0.87)

156

(115 - 244)

Net benefit of

aspirin treatment

NFIS 338 (1.28) 300 (1.22) 1.02

(0.83-1.25)

0.87; 11.5%

0.06

(-0.13 to

0.26)

1667

(770 to ∞ to 390)

Uncertain harm

(aspirin could be

helpful)

CV Mortality 463 (1.75) 383 (1.55) 1.12

(0.99-1.30)

0.08 ; 0%

0.20

(-0.02 to

0.42)

500

(4986 to ∞ to 237)

Uncertain harm

(aspirin could be

helpful)

Composite

Outcome

1186 (4.49) 1201 (4.87) 0.92

(0.85-0.99)

0.046; 0%

0.38

(0.01-

0.74)

266

(135 -

10158)

Net benefit of

aspirin treatment

Major

bleeding

205 (0.78) 109 (0.44) 1.79

(1.42-2.26)

<0.0001; 0%

0.33 (0.20

-0.47)

299

(213 - 500)

Net harm of

aspirin treatment

The composite outcome shows

an NNT of 266 and an 8% relative risk

reduction [RR,95%CI: 0.92(0.85-

0.99); p=0.046; I

= 0%]. The ma-

jor bleeding revealed a 79% increase

in the relative risk [RR,95%CI;

1.79(1.42-2.26); p<0.0001; I

= 0%,

NNH=299;].

Table 2b points out the same

elements of the previous table with

105,975 participants and six trials

made in two decades of the 21

cen-

tury. The result of the studies carried

out showed a benefit with the treat-

ment for NFIS (NNT= 553) with a 12%

in relative risk reduction [RR,95%CI:

0.88 (0.80-0.98); p<0.01; I

= 0%].

The composite outcome presented

an NNT of 288 with a significant rela-

tive risk reduction of 9% [RR,95%CI:

0.91 (0.86-0.97); p<0.003; I

0%], and for major bleeding, there

was a 57% increase of the relative

risk [RR,95%CI: 1.57 (1.30-1.91);

p<0.0001; I

= 0%, NNH= 175;].

The total of the results in the

combined and separate primary end-

points of all studies are shown in Ta-

ble 2c. From a total of 157,060 par-

ticipants, there was a net benefit of

20% and 10% on the relative risk re-

duction for NFMI [RR= 0.80 (0.69 to

0.93); p=0.003; I

= 0%; NNT= 259]

and Composite outcome [RR= 0.90

(0.85 to 0.99); p<0.001; I

= 0%;

NNT= 292] respectively. Major bleed-

ing presents a 60% increase in the

relative risk [RR: 1.60 (1.38 to 1.85);

p<0.0001; I

= 3%; NNH= 208]. The

rest of the endpoints showed an un-

certain result because the aspirin

treatment could be harmful or help-

ful compared with the control.

Forest plots of the meta-analysis

of aspirin treatment in the total in-

cluded studies are shown in terms

of NNT (benefit) or NNH (harm) for

each primary endpoint.

414 Vizcaíno and Weir Medina

Investigación Clínica 64(3): 2023

The overall estimate points out that

concerning aspirin treatment revealed a

net benefit for NFMI (Fig. 2a), an uncer-

tain benefit for NFIS (Fig. 2b), and un-

certain harm for CV mortality (Fig. 2c).

As we expected, net harm was associated

with major bleeding (Fig. 2d)

DISCUSSION

The light of the results of this sys-

tematic review, we argued that aspirin

has an ambiguous place in the prescrip-

tion for primary CV prevention. NFMI

from studies of the 20th century and

NFIS in this century showed a net ben-

efit with the aspirin treatment. In some

instances, the treatment could be harm-

ful, given negative ARR 95% CI values.

The composite outcome results also

reported benefits in the two groups of

studies. Globally there was a net benefit

of aspirin treatment for NFMI and the

composite outcome but also a signifi-

cant bleeding risk. This study demon-

strates that the absolute risk reduction

for cardiovascular events and absolute

risk increase for major bleeding asso-

ciated with aspirin use were of similar

magnitude. In terms of NNT and NNH,

this represents notable data on the aspi-

rin prescription despite some evidence

that indicates the efficacy of aspirin

could be uncertain in the NNT/NNH

ratio since all of the studies and the

combined results have shown a relevant

bleeding risk. These findings have simi-

larities with a recent meta-analysis

. A

systematic review

revealed an ARR of

0.41% in the composite cardiovascular

outcome with an NNT of 241 and an ARI

of 0.47% for major bleeding risk, repre-

senting an NNH of 210. This confirmed a

possible adverse effect of aspirin due to

bleeding risk. Another systematic review

showed a reduction of 10% of MCE

(major cardiovascular events) (0.90,

95% CI 0.85-0.96, p<0.001) with an

Table 2b. Summarized results of the endpoints in the included studies, period 2001-2018 (n= 6).

ENDPOINTS

Aspirin

events (%)

n: 52915

No Aspirin

events (%)

n: 53060

(95%CI)

p value; I

ARR%

(95%CI) r

ARI%

(95%CI)

NNT

(95%CI)

NNH

(95%CI)

Observations

NFMI 669 (1.26) 718 (1.35)

0.93

(0.82-1.05)

0.21; 9.6%

0.09

(-0.05 to

0.23)

1112

(435 to ∞

to2086)

Uncertain benefit (aspirin

could be harmful)

NFIS 721 (1.36) 819 (1.54)

0.88

(0.80-0.98)

<0.01; 0%

0.18

(0.04 -0.33)

553

(303- 2500)

Net benefit of

aspirin treatment

CV Mortality 508 (0.96) 551 (1.04)

0.92

(0.82-1.04)

0.20; 0%

0.08

(-0.04 to

0.20)

1250

(505 to ∞ to

2419)

Uncertain benefit (aspirin

could be harmful)

Composite

Outcome

1898 (3.59) 2088 (3.94)

0.91

(0.86- 0.97)

0.003; 0%

0.35

(0.12 - 0.58 )

288

(174- 839)

Net benefit of

aspirin treatment

Major

bleeding

964 (1.82) 662 (1.25)

1.57

(1.30-1.91)

<0.0001; 0%

0.57

(0.43

-0.72)

175

(139- 233)

Net harm of

aspirin treatment

Aspirin in cardiovascular prevention 415

Vol. 64(3): 405 - 423, 2023

Table 2c

Summarized results of the endpoints in all included studies (n=10).

ENDPOINTS Aspirin

events (%)

n: 79325

No aspirin

events%

n:77735

RR (95%CI)

p value; I

ARR%

(95%CI)

ARI%

(95%CI)

NNT

(95%CI)

NNH

(95%CI)

Observations

NFMI 954 (1.20) 1236 (1.59) 0.80

(0.69-0.93)

0.003; 0%

0.39

(0.27-0.50)

259

(199-369)

Net benefit

of aspirin treatment

NFIS 1059 (1.34) 1119 (1.44) 0.93

(0.83-1.01)

0.09; 0%

0.10

(-0.01 to

0.22)

958

(454 to ∞ to

8910)

Uncertain benefit

(aspirin could be

harmful)

CV.

Mortality

971 (1.22) 934 (1.20) 0.96

(0.88-1.05)

0.39; 0%

0.02

(-0.09 to

0.13)

4433

(1167 to ∞

to 765)

Uncertain harm

(aspirin could be

helpful)

Composite

Outcome

3084 (3.89) 3289 (4.23) 0.90

(0.85-0.99)

<0.001; 0%

0.34

(0.15-0.54)

292

(186-676)

Net benefit of

aspirin treatment

Major

bleeding

1169 (1.47) 771(1.00) 1.60

(1.38-1.85)

<0.0001;3%

0.48

(0.37-

0.59)

208

(269-170)

Net harm of

aspirin treatment

NFMI: Non-fatal Myocardial Infarction, NFIS: Non-fatal Ischemic Stroke, CV: Cardiovascular, RR: Relative Risk, ARR: Absolute Risk Reduction, ARI: Absolute

Risk Increase, NNT: Number Needed to Treat, NNH: Number Needed to Harm, CI: Confidence Interval. Note: In the present study, each individual study was

adjusted to 5 years a hypothetical time to calculate NNT and NNH: NNT(hypothetic) = NNT(observed) X [ Time(hypothetic) / Time (observed)].

When the result shows an ARR with 95%CI positive values means a net benefit (NNT); when the result shows an ARI with 95%CI means net harm (NNH). When

the result shows an ARR or ARI with 95%CI extended from negative to positive values means that the zero is included thus we need to separate two intervals

using via infinity (∞) and indicates that the treatment may be helpful or harmful

416 Vizcaíno and Weir Medina

Investigación Clínica 64(3): 2023

Fig. 2. Forest plot of meta-analysis of the included studies calculating from ARR95%CI as effect measure the NNT

or NNH with their respective 95%CI. Non-fatal myocardial infarction (A), Non-fatal ischemic stroke (B),

Cardiovascular mortality (C), and Major bleeding (D) as endpoints. *Denotes Absolute Risk Increase (ARI).

When the ARR95%CI includes zero we need to separate two intervals using via infinity (∞) in the

middle of the scale

NNT (Benet)

Favors ASPIRIN

NNH (Harm)

Favors BLEEDING

NNT

Favors ASPIRIN

NNH

Favors BLEEDING

NNT (Benet)

Favors ASPIRIN

NNH (Harm)

Favors BLEEDING

NNT (Benet)

Favors ASPIRIN

NNH (Harm)

Favors BLEEDING

Aspirin in cardiovascular prevention 417

Vol. 64(3): 405 - 423, 2023

ARR of 0.39% (95%CI: 0.18-0.61), which cor-

respond to NNT of 253 (95%CI: 163-568) to

prevent one single MCE, and the NNH (ma-

jor bleeding) was 306. These results are sim-

ilar to our work, indicating potential harm

in aspirin use due to increased bleeding

risk. Abdelaziz et al.

showed in an illustra-

tion the NNT for MI (357), ischemic stroke

(500), TIA (370), and MACE (263) with

the NNH for major bleeding (222), hemor-

rhagic stroke (1000), and GI bleeding (385),

based on pooled data from 15 randomized

controlled trials. Therefore, it was deduced

that bleeding risk is present when calculat-

ing the NNTs over NNH with major bleeding.

These findings suggest that the decision to

use aspirin for primary prevention should be

tailored to the individual patient based on

the estimated CV risk. Another approach to

evaluate aspirin treatment in the primary

prevention of CV events is to compare bene-

fits (prevention of MI and stroke) and harms

(major GI bleeds and hemorrhagic stroke)

using relative weights in the assessment of

systematic reviews of the NNT and NNH as

the number of person-years with treatment

need to prevent one adverse event

. This ap-

proach demonstrated a net benefit for aspi-

rin; nevertheless, in the sensitivity analysis,

aspirin was harmful due to greater relative

weight for GI bleeds.

We tried to give a better scope of aspi-

rin as a primary preventive treatment for CV

events, but unfortunately, the controversy

persists. To treat or not to treat with aspirin

is the question, and this situation is under

debate. To better understand this complex

scenario, we follow the timing of the decla-

rations of the USPSTF about the statements

on aspirin prevention in CVD

7,36-38

In this contemporary period, aspirin

passed from being a good prescription for

primary prevention of CVD at any age to a

restriction for its use only in 40-59 years

old individuals, with a strong recommen-

dation against its use in older people. The

last decision came from another six stud-

ies, whose results regarding the therapy

with aspirin in primary prevention for CVD

were unfavorable for its recommendation

(Table 1b). Additionally, in an analysis of

17 RCT (164.862 participants)

, aspirin

did not show any significant reduction in

all-cause mortality compared with placebo

(RR:0.97;95%CI:0.93-1.01; p=0.13). How-

ever, when ≥ 65 years old patients were

excluded, it significantly reduced all-cause

mortality (RR 0.94; 95% CI 0.90–0.99; p =

0.01) in the aspirin group. These results

concord with the age arguments recently

expressed by the USPSTF. The European So-

ciety of Cardiology and Other Societies on

Cardiovascular Disease Prevention in Clini-

cal Practice colleagues and other system-

atic reviews share the same opinion since

its guidelines do not recommend aspirin

for the primary prevention of CVD at all

14,40

. However, those agreements can lead to

misinterpretation or confusion for patients

in whom aspirin therapy may be essential:

such as those on primary or secondary pre-

vention with an established CV risk of more

than 10%

The only explanation for this change

is attributed to the bleeding risk that in-

creases with age. However, there is a debate

about this new scenario, and doubts must be

cleared. For example, should they stop tak-

ing aspirin for people who have been using

aspirin for years and do not have evidence of

bleeding? If yes, what could we probably ex-

pect? So we could expect an increase in CV

events in this particular group unless there

is an indication of another alternative sur-

rogate for aspirin prescription.

A comment arises regarding the differ-

ent conduct over time on aspirin prescrip-

tion, during the last decades of the 20

cen-

tury and then the change of opinion in the

two decades of the 21

century. The first

studies on aspirin and prevention of cardio-

vascular risk focused mainly on the signifi-

cant relative reduction of the risk of myocar-

dial infarction (44% PHS, 31% TPT, and 36%

HOT, only the BDT showed a non-significant

3%). Perhaps this finding eluded the atten-

418 Vizcaíno and Weir Medina

Investigación Clínica 64(3): 2023

tion to the side effects of bleeding caused

by the administration of aspirin, which was

barely mentioned in those papers, but was

not given its due importance, despite the

relevant relative increase in the risk of ma-

jor bleeding (71% PHS, 52% TPT, and 84%

HOT). On the contrary, the trials that were

performed in the two decades of the 21

cen-

tury addressed with great interest the risk

of bleeding with aspirin prescription in the

prevention of CVD. For this reason, these

papers highlighted the relevance of major

hemorrhage as a contraindication to aspi-

rin intake. They concluded that serious but

no fatal bleeding

is frequent with aspirin

administration compared with the benefit

achieved in CV prevention. As a representa-

tive example, the myocardial infarction in

terms of RRR (Relative Risk Reduction for

efficacy) vs. major bleeding as RRI (Relative

Risk Increase for safety) is shown as follows:

PPP (31% vs. 74%), WHS (2% vs. 40%), JPPP

(47% vs. 85%), ASPREE (7% vs. 38%), AS-

CEND (2% vs. 29%) and the ARRIVE (10%

vs 110%), all of them favoring the bleed-

ing risk. The different points of view above

about aspirin treatment changed the opin-

ion of doctors and their patients regarding

the routine use of aspirin as a primary pre-

ventive drug in CV events.

Another point of view of this conflictive

situation is that the prescription of aspirin

is unnecessary in some instances because

it is an over-a-counter (OTC) drug that can

be freely purchased, and patients have been

buying the drug without considering the po-

tential bleeding risk

Although there are relevant evidence

and guidelines as instruments for shared

decision-making to help clinicians in the

use of aspirin in primary prevention

43-46

and

the search for a benefit versus risk predic-

tion tool, we propose the NNT and NNH as

valuable measures in the balancing benefit-

risk with aspirin in the therapy of the ef-

fective primary prevention of CV events.

Knowing or estimating NNT and NNH for

an individual patient’s risk could be a guide

for the overall or net value of a prophylactic

intervention

. This combination provides

a good measure of the effort in avoiding an

unfavorable outcome, weighed against pos-

sible associated risks. The calculation of

these measures is straightforward, and also

its interpretation so that physicians could

make an individual clinical decision based

on the results of the interventions for CV

primary prevention guided by the calcula-

tion of how many patients can be treated

to avoid one adverse event, counterbalanc-

ing with the collateral side effects of the

aspirin prescription. However, although the

calculation of the NNT is simple, we need

to consider the treatment time to ensure

its correct interpretation

. An essential

limitation of NNT and NNH is that these

metrics are limited to dichotomous (rather

than continuous) outcomes

Limitations

The present study has several limi-

tations: first, the dose of aspirin was dif-

ferent in the studies, oscillating between

75mg and 500mg with six trials using

100mg daily. Second, there were some dif-

ficulties in classifying endpoints (MI and

Stroke are sometimes not defined as non-

fatal, and several studies did not specify

major bleeding as a safety endpoint). On

the other hand, one crucial point that is

missing is the evolution of the definition

of non-fatal MI: in the “modern era”, the

use of troponin captures minor MIs which

were previously missed by ECG and/or

CPK only, and on the other hand, we did

not include total mortality as an outcome,

and this could probably be a significant

cause of bias. Third, in the studies made

in the 20

century, particularly bleeding

events were poorly reported despite the ap-

parent evidence. Fourth, the studies were

not analyzed, separating participants from

high and low cardiovascular risk. Fifth,

The NNT and NNH were calculated in hy-

pothetical results that were expressed as

five years of tracking time as a standard

Aspirin in cardiovascular prevention 419

Vol. 64(3): 405 - 423, 2023

unit for all studies and their calculations,

thus the results of this review need to be

interpreted with prudence. Sixth, the for-

est plots for meta-analysis for NNT and

NNH were constructed with a scale includ-

ing infinity (∞) and quoting to separate in

two confidence intervals when there were

negative values.

CONCLUSION

Recent studies have demonstrated

that aspirin should not be recommended in

the primary prevention of CVD, although

it has a place in the secondary prevention

of CVD

17,45,49

. The use of aspirin in primary

cardiovascular disease was associated with

a lower risk of cardiovascular events and an

increased risk of major bleeding. NNT as a

measure of effect and NNH to determine

harm could be helpful in clinical share deci-

sion-making. However, as the “two faces of

the coin” (not determined by a coin flip),

it is essential to establish consistently that

the benefit-risk for patients should be in-

dividualized and not be a clinical practice

guide for everyone.

ACKNOWLEDGMENTS

We are grateful to María Diez-Ewald,

Humberto Martínez, and Sergio Ballaz for

their helpful review of the manuscript and

English style.

Funding

The author(s) received no financial sup-

port for this article’s research, authorship,

and/or publication.

Declaration of conflicting interests

The author(s) declared no potential

conflicts of interest concerning this article’s

research, authorship, and/or publication.

ORCID Numbers

• Gilberto Vizcaíno (GV):

0000-0003-2785-1879

• Jesús Weir Medina (JWM):

0000-0003-4966-6375.

Author’s contribution

GV was responsible for the study ratio-

nale, manuscript drafting, and statistical analy-

sis. JWM performed the literature search and

made the final review of the manuscript. All

authors were involved in the conception and

the design of the study and interpretation of

the data, revised the manuscript critically for

important intellectual content, and finally ap-

proved the manuscript submitted.

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