Aspirin for primary prevention of cardiovascular disease in diabetes

Abstract

Cardiovascular disease (CVD) is a major cause of morbidity and mortality in people with diabetes. Aspirin is commonly used in the treatment and prevention of CVD, and the effectiveness of aspirin for the secondary prevention of CVD is well established in people with or without diabetes. In contrast, the role of aspirin in primary prevention is still controversial as the cardiovascular benefit of aspirin may not outweigh the risk of haemorrhage. Even though diabetes raises cardiovascular risk which would suggest that aspirin could have a greater benefit, it remains uncertain whether there is a clear net benefit of aspirin in primary prevention of CVD in people with diabetes.
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Aspirin for primary prevention of
cardiovascular disease in diabetes
Cardiovascular disease (CVD) is a major
cause of morbidity and mortality in peo-
ple with diabetes. Aspirin is commonly
used in the treatment and prevention of
CVD, and the effectiveness of aspirin for
the secondary prevention of CVD is well
established in people with or without dia-
betes. In contrast, the role of aspirin in
primary prevention is still controversial,
as the cardiovascular benefitofaspirin
might not outweigh the risk of hemor-
rhage. Even though diabetes raises car-
diovascular risk, which would suggest
that aspirin could have a greater benefit,
it remains uncertain whether there is a
clear net benefit of aspirin for the pri-
mary prevention of CVD in people with
diabetes.
A number of randomized clinical trials
have investigated the impact of aspirin
for primary prevention in healthy men
and women, in individuals with cardio-
vascular risk factors, and in individuals
with documented subclinical atheroscle-
rosis. People with diabetes were included
in some of these primary prevention tri-
als. However, the diabetes subgroups
were usually small and therefore most of
these studies did not have adequate
power to evaluate the cardiovascular
effect of aspirin in people with diabetes.
To date, just three primary prevention
trials of aspirin specifically involving peo-
ple with diabetes have been carried out
(Table 1). The Early Treatment of Dia-
betic Retinopathy Study carried out back
in the 1980s investigated the effect of
aspirin in people with diabetes and
retinopathy, and suggested that aspirin
might have cardiovascular benefits
1
.
However, that study was in fact a
combination of primary and secondary
prevention, as nearly half of the random-
ized participants had prior CVD. The
other two trials were carried out at the
turn of this century. The Japanese Pri-
mary Prevention of Atherosclerosis with
Aspirin for Diabetes showed that aspirin
did not have any significant effect on
cardiovascular outcome
2
,andasubse-
quent10-yearfollowupreportedan
increased risk for gastrointestinal hemor-
rhage. The Prevention of Progression of
Arterial Disease and Diabetes also did
not find any cardiovascular benefitof
aspirin in people with diabetes and
asymptomatic peripheral artery disease
3
.
These early prevention trials of aspirin in
people with diabetes had limited power,
and a number of meta-analyses have
been carried out over the years to evalu-
atetheuseofaspirinintheprimarypre-
vention of CVD in people with diabetes.
The latest meta-analysis combining the
data of people with diabetes from 10 ran-
domized trials of primary prevention
suggested that there was a significant
reduction in the risk of major adverse
cardiovascular events with a relative risk
of 0.90 (95% confidence interval 0.81–
0.99; P=0.03) in the aspirin-treated
group. The increase in the risk of major
or gastrointestinal bleeding events was
not statistically significant, but the esti-
mates were imprecise due to insufficient
detailed information on bleeding events
4
.
Two large randomized trials have been
designed to address this important issue
of primary prevention with aspirin in
people with diabetes: A Study of Cardio-
vascular Events in Diabetes (ASCEND)
trial and the Aspirin and Simvastatin
Combination for Cardiovascular Events
Prevention Trial in Diabetes. The
ASCEND trial has been completed and
the results have been released
5
.Table1
summarizes the salient features of all
the completed and ongoing primary
prevention trials with aspirin in people
with diabetes. ASCEND was a large, ran-
domized, placebo-controlled trial of
aspirin involving 15,480 participants with
diabetes (94% with type 2 diabetes). The
average duration of follow up was
approximately 7 years, and at the end of
the study, there was a significant 12%
reduction in the rate of serious vascular
events in the aspirin group compared
with the placebo group. This was accom-
panied by a 29% increase in the rate of
major bleeding episodes, which were pre-
dominantly gastrointestinal or extracra-
nial hemorrhage. There were no
significant differences in all-cause mortal-
ity and in the incidence of gastrointesti-
nal tract cancer or all cancers between
the two groups.
Compared with the previous preven-
tion trials of aspirin in people with dia-
betes, the ASCEND trial was a much
larger study, and had the statistical power
to identify a 15% difference in the pri-
mary cardiovascular outcome between
the aspirin and placebo group. The ear-
lier aspirin prevention trials in people
with diabetes were carried out at a time
when modifiable risk factors were treated
less aggressively. The management of
cardiovascular risk factors has since
improved, and the contemporary
approach in risk factor control might
potentially reduce the benefits of aspirin
and/or decrease the overall risk and
change the benefit-to-harm ratio. In the
ASCEND trial, cardiovascular risk factors
were managed according to the current
standard of care. A large proportion of
the participants were taking statins and
antihypertensive drugs, and only a small
proportion were current smokers. Hence,
the ASCEND trial is able to address the
balance of the benefits and risks of
aspirin within the setting of current pre-
ventive practice of CVD. The trial has
shown that aspirin is beneficial in
*Corresponding author. Kathryn Tan
Tel.: +852-2255-5859
Fax: +852-2816-2187
E-mail address: kcbtan@hku.hk
Received 27 December 2018; revised 7 January
2019; accepted 9 January 2019
ª2019 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd
J Diabetes Investig Vol. 10 No. 4 July 2019
899
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reducing cardiovascular events, but it also
adversely increases the risk of major
bleeding. Based on the results of
ASCEND, it has been estimated that the
numbers needed to treat to avoid a seri-
ous cardiovascular event and to induce a
major bleeding episode are 91 and 112,
respectively. The absolute benefits from
avoiding major cardiovascular events are
therefore mostly negated by the increased
risk of hemorrhage. Even when partici-
pants were stratified according to their
baseline cardiovascular risk, there was no
group in which the benefits of aspirin
clearly outweighed the hazards in
ASCEND.
In addition to ASCEND, the recently
published Aspirin in Reducing Events in
the Elderly trial provided further insight
into the role of aspirin in primary pre-
vention
6
.IntheAspirininReducing
Events in the Elderly trial, 19,114 elderly
participants (aged ≥70 years) free from
CVD, dementia and disability were
enrolled. A total of 11% of the partici-
pants had diabetes at baseline, and the
presence of diabetes was a pre-specified
subgroup analysis. Cardiovascular out-
come was a secondary end-point of the
study. The trial showed that in healthy
elderly participants, the use of aspirin
conferred no cardiovascular benefits, but
the risk of major bleeding was signifi-
cantly increased by 38% (P<0.001). No
differential effect of aspirin on CVD was
seen in the pre-specified diabetes sub-
group analysis.
Current recommendations on the use
of aspirin in people with diabetes are
based on data derived from other high-
risk populations and diabetes subgroup
analysis of primary prevention trials.
The United States Preventive Services
Task Force advocates initiating low-dose
aspirin for primary prevention based on
age regardless of the presence or
absence of diabetes
7
. Aspirin is recom-
mended to prevent CVD in adults aged
50–59 years with 10-year cardiovascular
risk ≥10% and not at increased risk of
bleeding. For adults aged 60–69 years
with 10-year risk ≥10% and not at
increased risk of bleeding, the decision
to use aspirin is individual-based. The
Table 1 | Primary prevention trials with aspirin in diabetes
Trial ETDRS POPADAD JPAD ASCEND ACCEPT-D
Participants Type 1 or type 2 diabetes
mellitus aged 18–70 years
with retinopathy,
n=3,711 (49% with prior CVD)
Type 1 or type 2
diabetes mellitus
aged ≥40 years, ABI ≤0.99 but no
symptomatic CVD, n=1,276
Type 2 diabetes mellitus
aged 30–85
years, no prior CVD,
n=2,539
Type 1 or type 2 diabetes
mellitus
aged ≥40, no prior CVD,
n=15,480
Type 1 or type 2
diabetes mellitus
aged ≥50, no prior CVD,
n=5,170
Mean age (years) 52% aged ≥50 60 65 63 –
Mean duration
of follow up (years)
5.0 6.7 4.4 7.4 –
Intervention 650 mg aspirin vs placebo Low dose aspirin vs placebo Low dose aspirin vs placebo Low dose aspirin vs placebo Simvastatin +low dose
aspirin vs simvastatin
Main cardiovascular
end-point
Cardiovascular death,
non-fatal MI or stroke
0.90 (95% CI 0.74–1.09)
Death from CHD or stroke,
non-fatalMIor
stroke, or above ankle
amputation
0.98 (95% CI 0.76–1.26)
Total atherosclerotic events
0.80 (95% CI 0.58–1.10)
MI,strokeorTIA,ordeathfrom
any vascular cause
0.88 (95% CI 0.79–0.97),
P=0.01
Cardiovascular death,
non-fatal MI, non-fatal
stroke, and hospital
admission for
cardiovascular causes
Bleeding risk No significant difference 0.90 (95% CI 0.53–1.52) No significant difference 1.29 (95% CI 1.09–1.52),
P=0.003
–
95% CI, 95% confidence interval; ABI, ankle brachial index; ACCEPT-D, Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes; ASCEND, A Study of Car-
diovascular Events in Diabetes; CHD, coronary heartdisease;CVD,cardiovasculardisease;ETDRS,Early Treatment Diabetic Retinopathy Study; JPAD, Japanese Primary Prevention of
Atherosclerosis with Aspirin for Diabetes; MI, myocardial infarction; POPADAD, Prevention of Progression of Arterial Disease and Diabetes; TIA, transient ischemic attack.
900
J Diabetes Investig Vol. 10 No. 4 July 2019
ª2019 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd
COMMENTARY
Xing and Tan http://wileyonlinelibrary.com/journal/jdi

2018 guidelines from the American Dia-
betes Association recommend aspirin
therapy for primary prevention in those
with diabetes and high cardiovascular
risk; that is, those aged ≥50 years who
have one additional major risk factor
(family history, hypertension, dyslipi-
demia, smoking or chronic kidney dis-
ease/albuminuria) and do not have any
susceptibility to bleeding
8
.Inlightofthe
new evidence from the recent contem-
porary aspirin trials, how should physi-
cians approach the use of aspirin for
primary prevention in people with dia-
betes? It is clear that although people
with diabetes have increased cardiovas-
cularrisk,themerepresenceofdiabetes
is insufficient to bestow a distinct
advantage for cardiovascular protection
using aspirin with respect to bleeding.
There is a fine balance between the
risks and benefits of aspirin, and the
overall magnitude of the net benefitof
aspirin in primary prevention is likely
to be small. For adults with diabetes
aged >70 years, aspirin therapy is not
indicated for primary prevention, as the
risk outweighs the benefit. Similarly, for
those aged <50 years with no major risk
factors and low cardiovascular risk,
aspirin is also not recommended, as the
benefitissmall.Forthoseaged
>50 years, an approach based on cardio-
vascular risk is still reasonable. Assess-
ment of the benefit-to-risk profile
should be made on an individual basis
in those individuals with major cardio-
vascular risk factor(s), and aspirin might
be offered as an additional risk-reducing
therapy after maximizing cardiovascular
risk control with smoking cessation, sta-
tins and blood pressure control. Shared
decision-making taking into account the
individual’s values, preferences and will-
ingness to undergo long-term aspirin
therapy is necessary.
DISCLOSURE
The authors declare no conflict of interest.
Ying Xing
1
,KathrynCBTan
2,
*
1
Department of Endocrinology and
Metabolic Disease, Xijing Hospital,
Air Force Medical University, Xi’an,
Shaanxi, China;
2
Department of
Medicine, University of Hong Kong,
Hong Kong SAR
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