JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
14, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
EDITORIAL COMMENT
A COGENT Argument for
Gastrointestinal Protection
With Low-Dose Aspirin*
Michael E. Farkouh, MD, MSC
D ual antiplatelet therapy with aspirin and
P2Y12 inhibitors, such as clopidogrel, have
become the mainstay of patients undergo-
ing percutaneous coronary intervention (PCI) either
for acute coronary syndromes or for stable coronary
artery disease. Recent evidence suggests that low-
dose aspirin defined as #100 mg daily is as effective
as high-dose aspirin in secondary cardiovascular
prevention (1). One may question why some still
continue to prescribe high-dose aspirin in the setting
of dual antiplatelet therapy (DAPT).
However, many cardiologists may not be aware of
the association of low-dose aspirin with a wide variety
of gastrointestinal (GI) side effects, including upper
and lower GI bleeding, peptic ulcers, and dyspepsia.
In 2010, the American College of Cardiology, the
American College of Gastroenterology, and the Amer-
ican Heart Association recommended that beyond the
debate of a potential interaction between proton pump
inhibitors (PPIs) and clopidogrel in patients receiving a
coronary stent, upper GI bleeding also must be taken
into account in the overall safety profile (2). They
identified that factors such as the concomitant use of
anticoagulant agents, steroids, or nonsteroidal anti-
inflammatory drugs; advanced age; and H. pylori
infection were associated with an increased risk of GI
bleeding. The association of high-dose aspirin and
upper GI bleeding is well documented, but earlier
studies have suggested that low-dose aspirin was not
associated with these risks (3). Yu et al. (4) compared
*Editorials published in the Journal of the American College of Cardiology
reflect the views of the authors and do not necessarily represent the
views of JACC or the American College of Cardiology.
From the Peter Munk Cardiac Centre and the Heart and Stroke Richard
Lewar Centre of Excellence, University of Toronto, Toronto, Ontario,
Canada. Dr. Farkouh has reported that he has no relationships relevant to
the contents of this paper to disclose.
VOL. 67, NO.
ISSN 0735-1097/$36.00
http://dx.doi.org/10.1016/j.jacc.2016.01.039
the relative safety of high- versus low-dose aspirin
after PCI in ST-segment elevation myocardial infarc-
tion from the HORIZONS (Harmonizing Outcomes
With Revascularization and Stents in Acute Myocar-
dial Infarction) trial and found that high-dose aspirin
was an independent predictor of major bleeding
with a hazard ratio of 2.8 (95% confidence interval
[CI]: 0.13 to 5.99). Similarly, the CURRENT-OASIS-7
(Clopidogrel Optimal Loading Dose Usage to Reduce
Recurrent EveNTs/Optimal Antiplatelet Strategy for
InterventionS) trial showed excess bleeding in the
group randomized to high-dose aspirin compared
with the low-dose arm (1). These findings led many
cardiologists to believe that the use of low-dose ace-
tylsalicylic acid (ASA) would be associated with
significantly reduced rates of gastrointestinal bleeding
particularly when used with DAPT strategies.
SEE PAGE 1661
For clinicians, the current analysis by the
Vaduganathan et al. and the COGENT (Clopidogrel and
the Optimization of Gastrointestinal Events Trial) in-
vestigators (5) in this issue of the Journal provides
important insights into patients treated with DAPT with
clopidogrel and aspirin. First, patients on low-dose
compared with high-dose aspirin do not have an
increased risk of cardiovascular events. Secondly, they
confirm that patients taking low-dose aspirin are at risk
for significant upper GI events including gastroduo-
denal bleeding and symptomatic gastroduodenal
ulcers. However, the low-dose aspirin group had com-
parable primary GI events to the high-dose ASA group
in the non-PPI patient population (3.08% vs. 2.61%).
There are a number of strategies to restratify
patients and reduce the risk of GI bleeding in patients
receiving DAPT. Over the years, the use of H 2 receptor
antagonists has gained popularity particularly in the
era when there was a concern about the clopidogrel–
JACC VOL. 67, NO. 14, 2016 Farkouh 1673
APRIL 12, 2016:1672–3 GI Protection for Low-Dose Aspirin

PPI interaction. A recent meta-analysis evaluated 10
randomized trials and showed that PPIs decreased the
risk of low-dose aspirin–associated upper GI bleeding
in patients treated with DAPT by 64% (odds ratio 0.36;
95% CI: 0.15 to 0.87) without any increase in the risk of
major cardiovascular events, with an odds ratio of 1.0
(95% CI: 0.76 to 1.31) (6). This study also confirmed the
superiority of PPIs over H2 receptor antagonists.
What remains concerning is the apparent lack of
enthusiasm for the use of PPIs in patients on low-dose
aspirin despite this significant GI risk. de Jong et al. (7)
reported on data from 120 Dutch primary care centers
looking at patients 18 years and older who were regu-
larly prescribed low-dose ASA. They found that 26% of
patients on low-dose aspirin (3,213 of 12,343) were
considered at increased risk of GI complications but
that the concomitant use of PPIs was only in 46% of
these patients. In the low-dose aspirin group of
the COGENT, omeprazole therapy was associated with
1.9% absolute risk reduction in primary upper GI
events at 180 days (1.2% vs. 3.1%), which was compa-
rable to the 1.7% absolute risk reduction for the high-
dose aspirin–treated patients (p for interaction 0.80).
This confirms similar findings from a recent meta-
analysis of randomized trials of PPI therapy with
low-dose aspirin (8). It is important to note that
although older patients, those who were treated
conservatively, and those outside the United States
were more likely to be prescribed low-dose aspirin,
they clearly enjoyed a benefit with concomitant PPI
therapy. When compared with other efficacious ther-
apies used in cardiovascular medicine, the number
needed to treat of about 50 to prevent an upper GI
event with the use PPIs in patients treated with DAPT
and low-dose aspirin appears quite cost-effective.
This report from the COGENT must be placed in
proper context. The median follow-up was only 110
days. Kaplan-Meier estimates in this trial are presented
as a 180-day event rates and so the long-term reduction
in bleeding risk with PPIs for low-dose aspirin–treated
patients is not definitive in this analysis. All patients
received clopidogrel in this study, but data on GI events
with other P2Y 12 inhibitors using a DAPT strategy with
low-dose aspirin are also of clinical interest and
currently lacking. The evaluation of the regional dif-
ferences and the impact on practice need to be further
documented in large-scale observational studies.
WHERE DO WE GO FROM HERE?
PPIs in patients on low-dose aspirin receiving DAPT
are underutilized, and this needs to be evaluated as a
quality metric in patients undergoing PCI with stent-
ing. The real question becomes whether all patients on
low-dose ASA should receive PPI in the long term
versus only those at high risk of upper GI bleeding. As
stated earlier, the current guidelines recommend PPI
use in those who have a prior history of GI bleeding and
in those with multiple risk factors for GI bleeding who
require antiplatelet therapy, including advanced age,
the use of nonsteroidal drugs, anticoagulant agents,
and steroids, and the documentation of H. pylori
infection. With the confirmation of the GI protective
effects of PPIs without any excess of cardiovascular
events in the COGENT, it appears that a practice
change is in order when prescribing low-dose aspirin.
The COGENT investigators should be commended for
bringing this important GI safety issue to the forefront
because it has been long overshadowed by both the
concern about a PPI–clopidogrel interaction and by the
false sense of security in the belief that low-dose
aspirin, as opposed to high-dose aspirin, does not
warrant a GI protective strategy.
REPRINT REQUEST AND CORRESPONDENCE: Dr.
Michael E. Farkouh, Peter Munk Cardiac Centre, 585
University Avenue, 4N474, Toronto, Ontario M5G
2N2, Canada. E-mail: michael.farkouh@uhn.ca.

REFERENCES

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KEY WORDS bleeding, clinical outcomes,
clinical trials, coronary artery disease