Low-Dose Acetylsalicylic Acid Use and the Risk of Upper Gastrointestinal Bleeding: A Meta-Analysis of Randomized Clinical Trials and Observational Studies
Can J Gastroenterol
Low-dose acetylsalicylic acid use and the risk of upper gastrointestinal bleeding: A meta-analysis of randomized clinical trials and observational studies
Vera E Valkhoff
Miriam CJM Sturkenboom
Sander Veldhuyzen van Zanten
Ernst J Kuipers
VE Valkhoff, MCJM Sturkenboom, C Hill, S Veldhuyzen van Zanten, EJ Kuipers. Low-dose acetylsalicylic acid use and the risk of upper gastrointestinal bleeding: A meta-analysis of randomized clinical trials and observational studies. Can J Gastroenterol 2013;27(3):159-167. BACKGround: Low-dose acetylsalicylic acid (LDA, 75 mg/day to 325 mg/day) is recommended for primary and secondary prevention of cardiovascular events, but has been linked to an increased risk of upper gastrointestinal bleeding (UGIB). o BJECtiVE: To analyze the magnitude of effect of LDA use on UGIB risk. MEtHodS: The PubMed and Embase databases were searched for randomized controlled trials (RCTs) reporting UGIB rates in individuals receiving LDA, and observational studies of LDA use in patients with UGIB. Studies were pooled for analysis of UGIB rates. rESuLtS: Eighteen studies were included. Seven RCTs reported UGIB rates in individuals randomly assigned to receive LDA (n=22,901) or placebo (n=22,923). Ten case-control studies analyzed LDA use in patients with UGIB (n=10,816) and controls without UGIB (n=30,519); one cohort study reported 207 UGIB cases treated with LDA only. All studies found LDA use to be associated with an increased risk of UGIB. The mean number of extra UGIB cases associated with LDA use in the RCTs was 1.2 per 1000 patients per year (95% CI 0.7 to 1.8). The number needed to harm was 816 (95% CI 560 to 1500) for RCTs and 819 (95% CI 617 to 1119) for observational studies. Meta-analysis of RCT data showed that LDA use was associated with a 50% increase in UGIB risk (OR 1.5 [95% CI 1.2 to 1.8]). UGIB risk was most pronounced in observational studies (OR 3.1 [95% CI 2.5 to 3.7]). ConCLuS ionS: LDA use was associated with an increased risk of UGIB.
Acetylsalicylic acid; Gastrointestinal bleeding; Gastrointestinal hemorrhage; Peptic ulcer disease; Meta-analysis
A(low-dose ASA [LDA]) is recommended for secondary
cetylsalicylic acid (ASA) at doses of 75 mg/day to 325 mg/day
tion of cardiovascular events (
) and is also commonly used for
primary prevention in patients with a markedly increased risk of
cardiovascular events. LDA use has been shown to decrease the
incidence of cardiovascular events in patients at high cardiovascular risk
); however, its use is associated with an increased risk of upper
gastrointestinal bleeding (UGIB) (
). Peptic ulcer bleeding (PUB)
accounts for most of this increased risk (
It is important to be able to assess the strength of the association
between LDA use and UGIB risk because of the widespread use of
LDA, both as a prescription and as an over-the-counter medication.
L’utilisation d’acide acétylsalicylique à faible dose et
le risque de saignement du tube digestif supérieur :
une méta-analyse d’essais aléatoires et contrôlés et
HiStoriQuE : L’acide acétylsalicylique à faible dose (AFD, 75 mg/jour
à 325 mg/jour) est recommandé pour la prévention primaire et secondaire
des événements cardiovasculaires, mais s’associe à une augmentation du
risque de saignement du tube digestif supérieur (STDS).
oBJECtiF : Analyser la magnitude de l’effet de l’utilisation d’AFD sur le
risque de STDS.
MÉtHodoLoGiE : Les chercheurs ont fouillé les bases de données de
PubMed et d’Embase pour en extraire les essais aléatoires et contrôlés
(EAC) rendant compte des taux de STDS chez les personnes qui prennent
de l’AFD, ainsi que les études d’observation sur l’utilisation d’AFD chez les
patients ayant un STDS. Ils ont regroupé les études pour analyser les taux
rÉSuLtAtS : Dix-huit études ont été incluses. Sept EAC indiquaient les
taux de STDS chez des personnes réparties au hasard pour recevoir de
l’AFD (n=22 901) ou un placebo (n=22 923). Dix études cas-témoin
portaient sur l’analyse de l’utilisation d’AFD chez des patients ayant un STDS
(n=10 816) et des sujets témoins sans STDS (n=30 519); une étude de
cohorte faisait état de 207 cas de STDS traités seulement à l’AFD. Toutes
les études ont révélé que l’utilisation d’AFD s’associe à une augmentation
du risque de STDS. Le nombre moyen de cas supplémentaires de STDS
associés à l’utilisation d’AFD dans les EAC s’élevait à 1,2 cas sur 1 000 patients par
année (95 % IC 0,7 à 1,8). Le nombre nécessaire pour nuire était de
816 (95 % IC 560 à 1 500) dans les EAC et de 819 (95 % IC 617 à 1 119),
dans les études d’observation. La méta-analyse des données des EAC a
démontré que l’utilisation d’AFD s’associait à une augmentation de 50 %
du risque de STDS (RRR 1,5 [95 % IC 1,2 à 1,8]). Le risque de STDS était
plus prononcé dans les études d’observation (RRR 3,1 95 % IC [2,5 à
ConCLuSionS : L’utilisation d’AFD s’associait à une augmentation du
risque de STDS.
The overall prevalence of LDA use among adults in the United
Kingdom in 2006 was 9.6%, with a much higher prevalence (35%) in
individuals older than 75 years of age (
). Several reviews and
metaanalyses have estimated the risk of UGIB with ASA use; however,
they have used different selection criteria or have been different types
of studies (
). Many previous reviews have not specifically
examined the risk of UGIB associated with LDA use; have not separated
UGIB from lower gastrointestinal bleeding or other gastrointestinal
complications such as perforation (
); have not specifically
examined ASA doses <325 mg/day (
); or compared the bleeding
risk associated with different doses of ASA rather than comparing the
risk of bleeding in ASA users with the risk in nonusers (
1Department of Gastroenterology & Hepatology; 2Department of Medical Informatics; 3Department of Epidemiology, Erasmus MC – University Medical
Center, Rotterdam, The Netherlands; 4Research Evaluation Unit, Oxford PharmaGenesisTM Ltd, Oxford, United Kingdom; 5Division of
Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta; 6Department of Internal Medicine, Erasmus MC – University
Medical Center, Rotterdam, The Netherlands
Correspondence: Dr Vera E Valkhoff, Erasmus MC – University Medical Center, Department of Medical Informatics, Room Ee – 2159, Dr Molewaterplein
50–60, 3015 GE Rotterdam, The Netherlands. Telephone 31-10-704-4116, fax 31-10-704-4722, e-mail
Received for publication May 11, 2012. Accepted August 18, 2012
addition, some studies limited inclusion to a single indication for ASA
such as primary cardiovascular prevention (10) or secondary
). The majority of reviews only included randomized
controlled trials (RCTs) (
). However, many of the RCTs
included in such reviews excluded patients at high risk for UGIB and,
thus, may have underestimated the risk of bleeding associated with LDA
use in real-world practice. One systematic review by García Rodríguez et
al (9) included observational epidemiological studies published from
1990 to 2001, but no RCTs. Another review (
) included only
casecontrol studies conducted before 1989.
The aim of the present study was to perform a meta-analysis of
prospective RCTs that compared LDA therapy with placebo in
different populations, regardless of indication, duration of follow-up or
duration of use, as well as observational studies that evaluated the
strength of the association between LDA use and UGIB risk
specifically. In addition, the absolute increase in the risk of UGIB with LDA
use compared with placebo was determined from RCTs.
The PubMed and Embase databases were searched (entries from 1989 to
2009) for RCTs reporting UGIB (including hematemesis and/or
melena) or PUB involving individuals receiving LDA or placebo; and
observational studies of LDA use in cases involving UGIB or PUB, or
controls. The references from previous meta-analyses and reviews were
also reviewed. Searches were limited to studies published in English,
French, German, Spanish, Italian or Japanese. Search results were
combined and duplicates were removed. Access (Microsoft Corporation,
USA) was used to screen the search results in a structured manner.
Initially, study titles were screened for relevance and identified for
further screening using the abstract/full text. Studies were excluded if
any of the following criteria applied: all studied ASA doses were
>325 mg/day; ASA doses were not reported; all patients were
undergoing gastroprotective therapy or receiving Helicobacter pylori
eradication therapy; patients were taking nonsteroidal anti-inflammatory drugs
(NSAIDs); or the absence of an appropriate control group(s). Studies
were also excluded if UGIB or PUB rates were not reported separately
from rates of lower gastrointestinal bleeding, rates of upper
gastrointestinal complications were reported as a whole rather than UGIB
specifically, or data were reported only for uncomplicated peptic ulcer disease.
Study selection was performed independently by two authors and
decisions regarding study inclusion were reached by consensus.
Data regarding study populations, treatments and end points were
independently extracted from each identified study by two authors and
any discrepancies were resolved by consensus. For each treatment arm
in the RCTs, the number of trial participants, the follow-up period and
the number of patients who developed the primary end point of PUB
or UGIB were recorded. Two of the RCT publications (
on melena and hematemesis separately. Only the hematemesis data
from these two studies were included to minimize outcome
misclassification and to avoid the possibility of double-counting UGIB events.
In a sensitivity analysis, the melena data were included instead.
For the observational studies, the matching criteria, covariates in
the model and adjusted OR with 95% CI were recorded. For all
studies, the mean age at baseline and the percentage of male participants
were assessed. For some of the studies (
), this involved referring
to other published articles investigating the same study populations
). For studies in which age was presented in categories, patient
age was inferred to be the midpoint in the range. For example, for
patients between 60 and 69 years of age, a mean age of 64.5 years was
The rate of UGIB (per 1000 individuals per year) was calculated for
each included RCT. The treatment-years weighted mean number of
extra UGIB cases associated with LDA use (per 1000 individuals per
year) was also calculated. The number needed to harm (NNH) – based
on the inverse of the risk difference in patients using LDA compared
with patients receiving placebo – was calculated for RCTs. For
observational studies, the NNH was calculated (
) using the pooled OR
provided by the meta-analyses of the observational studies, given a
UGIB event rate of 59 per 100,000 person-years in subjects not
exposed to ASA (derived from the cohort study by Sørensen et al
). The NNH represents the number of patients needed to be
exposed to LDA to cause UGIB in one patient.
The meta-analyses were based on the OR, which can be
interpreted as an estimate of the relative risk (RR). The OR is defined as
the odds of LDA exposure among patients with UGIB divided by the
odds of exposure to LDA among those without UGIB. For the
observational studies, the adjusted ORs or RRs, as reported in the original
article, were pooled if possible; in one of the 11 studies (
outcome data were used to calculate unadjusted ORs (which may be
susceptible to confounding). None of the RCTs reported an RR;
therefore, the crude OR and the corresponding 95% CI was calculated
for UGIB comparing ASA therapy with placebo for each individual
RCT (it was hypothesized that confounding was less of an issue in
RCTs than in observational studies). To include the study by Silagy et
), which had four confirmed UGIB cases in the ASA group but
no cases in the placebo group, 0.1 events were added to both groups,
resulting in 4.1 cases in the ASA group and 0.1 case in the placebo
group. This avoided an infinite OR due to null events in the placebo
group. In a sensitivity analysis, 0.5 events were added to both arms.
Given the potential diversity of study designs, stratified analyses
according to the two groups were performed: RCTs and observational
studies. Within the observational studies, a subgroup analysis of five
studies was performed investigating ASA doses ≤100 mg and four
studies investigating ASA doses 300 mg to 325 mg.
To estimate an overall pooled OR, a fixed-effects model was used for
the RCTs (inverse variance model) using Mix version 1.7 (BiostatXL,
). To be as conservative as possible, a random-effects model
was also applied. For the observational studies, a random-effects model
was used because statistical heterogeneity existed across the studies.
Publication bias was examined using funnel plot asymmetry and
quantified using the Egger regression test (
). All statistical tests were two
sided and P<0.05 was considered to be statistically significant.
Statistical heterogeneity among the studies was tested using Cochran’s
Q statistic. For this test, a two-sided P≤0.10 was considered to indicate
heterogeneity. To measure the degree of heterogeneity, an I2 value was
calculated, with I2 values <30% representing a low level, 30% to 75%
representing a moderate level and >75% representing a high level of
The PubMed and Embase database searches resulted in the
identification of 2011 unique studies. The titles of these studies were
screened for relevance and 709 studies were identified for further
screening using the abstract/full text. A total of 688 studies were
subsequently excluded for the reasons listed in Figure 1, leaving a total of
21 studies (six RCTs and 15 observational studies) eligible for
inclusion. The references from previous meta-analyses and reviews were
also examined (
) and one additional eligible RCT was identified
(22). Thus, a total of 22 studies (seven RCTs and 15 observational
studies) were eligible for inclusion (Figure 1). Of the 15 observational
studies, 14 were case-control studies and one was a cohort study.
Of the 22 studies meeting all of the inclusion criteria, three (
were suspected of reporting results from the same study populations as
those included in more recently published articles (
), and one
study (40) presented additional analyses from a sample that overlapped
with a previous study (
). Thus, the final number of studies included
in the analyses was 18: seven RCTs (
) and 11
observational studies (
The main characteristics of the 18 studies included in the
metaanalysis are summarized in Table 1 (RCTs) and Table 2 (observational
rCts: The seven RCTs reported rates of UGIB or PUB (including
hematemesis and/or melena) in 45,824 individuals randomly assigned
to receive LDA (average daily dose 50 mg to 300 mg [n=22,901]) or
placebo (n=22,923) (Table 1) (
). The mean age of
patients, weighted according to sample size, in the RCTs was 63.3 years
(range 53.8 to 79.0 years) and 70.0% were male (range 21.0% to
100%). Mean follow-up periods ranged from 35 days to seven years.
None of the RCTs tested more than one dose level of ASA; therefore,
it was not possible to assess any potential dose-response relationship.
observational studies: Eleven observational studies were identified,
of which 10 were case-control studies and one was a cohort study. Five
of the 10 case-control studies analyzed LDA use in patients presenting
with UGIB (rather than PUB specifically) and controls with no UGIB
); the other five examined LDA use in patients
presenting with PUB and controls with no PUB (Table 2) (
A total of 41,335 patients were observed in the case-control studies, of
whom 10,816 were UGIB cases and 30,519 were controls. In the
Diener et al 13 European Stroke (fatal/non-fatal), death Patients with a recent TIA
), 1997 countries (all cause), stroke and/or or completed ischemic
all-cause death (allowed stroke randomly assigned
first event to be counted for to receive ASA or placebo
survival analysis but
avoided duplicate counting).
Secondary outcomes: TIA
and other vascular events
Thrombosis prevention trial (41), 1998
Prevention trial (42), 2000
Ogawa et al
Kelly et al
≤300 mg/day, any Age
use within the (±5 years)
week before and sex
Smoking, ulcer history,
H pylori infection,
Various, any use in Center, date Clopidogrel, dipyridamole,
the 7 days before of admission indobufen, ticlopidine, and
the index date (within triflusal use, history of peptic
2 months), ulcer, diabetes mellitus,
sex and age heart failure, acute
(±5 years) myocardial infarction,
angina, stroke, transient
ischemic attack, intermittent
alcohol consumption, use of
antacids, H2RAs, PPIs,
nitrates, systemic NSAIDs,
topical NSAIDs, analgesics,
ACE inhibitors, statins,
from 100 mg/day
to >1000 mg/
day), used within
7 days before the
<325 mg/day used Sex, age
within 7 days (±5 years),
before the index region
2 weeks Age (±5 years) and sex
Age, sex, calendar semester,
ulcer history and use of
nitrates, oral anticoagulants,
Use of acetaminophen,
NSAIDs, consumption of
smoking, history of gastric or
duodenal ulcer, H pylori
status if available
Ulcer history, H pylori infection, NSAID use, alcohol consumption, smoking
Hospital patients admitted for
reasons that were unlikely to
be related to NSAID treatment
and community controls from
primary care practices (one of
each control per case)
Primary care patients with no
UGIB rate in general population Cases 49.9 68.1 NA
Male, years, Definition of
% mean LDA
*Median age, years. ACE Angiotensin-converting enzyme; ASA Acetylsalicylic acid; coxibs selective inhibitors of cyclooxygenase-2; H2RA Histamine-2 receptor
antagonist; H pylori Helicobacter pylori; NA Not applicable (cohort study); NSAID Nonsteroidal anti-inflammatory drug; PPI Proton pump inhibitor; SIR Standard
incidence ratio; SSRI Selective serotonin reuptake inhibitor; UK United Kingdom
Cases: 62.8 63.8
cohort study, there were 207 UGIB cases exposed to LDA only (
The mean age in the observational studies, weighted according to
sample size, was approximately 63.3 years (range 60.1 to 73.6 years),
and 64.0% of participants were male (range 43.7% to 74.5%).
The control groups used in the 10 case-control studies varied.
Three studies used a control group comprising hospital patients
), three studies included a control group obtained from
primary care or the general population (
), and three studies
included a combination of hospital patients and community-based
). One study used a control group of patients with
endoscopically confirmed nonulcer dyspepsia (
Four of the case-control studies examined the risks of PUB or
UGIB associated with specific doses of ASA (
), while the
other six grouped ASA doses into one or more dose ranges
). The cohort study reported the standard
incidence ratios (SIRs) of UGIB for doses of 100 mg/day and 150 mg/day,
but it was unclear whether these findings were from a group of patients
who were also being treated with other NSAIDs (
Association between LdA use and uGiB
rCts: During follow-up, 1.3% (288 of 22,901) of participants assigned
to the ASA group developed UGIB. During the same period, 0.8%
(194 of 22,923) of participants assigned to the placebo group developed
All of the RCT publications reported increased rates of UGIB or
PUB in individuals receiving LDA compared with those receiving
placebo, of which two were statistically significant (
) and five
) were not. Across the various studies, UGIB rates
were in the range of 0.6 to 328.1 per 1000 patients per year in the LDA
group, and 0 to 231.3 per 1000 patients per year in the placebo group.
Based on this analysis, the number of extra UGIB cases associated with
LDA use ranged from 0.2 to 96.8 per 1000 patients per year. The
personyears weighted average number of extra UGIB cases associated with
LDA use was 1.2 per 1000 patients per year (95% CI 0.7 to 1.8). The
NNH was 816 (95% CI 560 to 1500), meaning that if 816 individuals
received LDA, one would have developed UGIB as a result of
After pooling the results, the OR of UGIB associated with LDA
use was 1.5 (95% CI 1.2 to 1.8; P<0.0001) (Figure 2). There was no
heterogeneity (I²=0%) and, because this was not significant (P=0.50),
a fixed-effects model was applied. The result of the Egger regression
test for publication bias was not significant (intercept 0.8 [95% CI
–0.3 to 1.9]; P=0.12) and no funnel plot asymmetry was observed
(Figure 3A), indicating no evidence of publication bias. The pooled
estimate was mostly driven by the Pulmonary Embolism Prevention
), with a relative weight of 75.6%.
As mentioned previously, two of the RCTs (
) reported on
hematemesis and melena separately. When the melena data of these
studies were included instead of the hematemesis data, the association
Figure 3) Funnel plot for publication bias in seven randomized controlled
trials (A) and 11 observational studies (B). A Egger regression P=0.12
(intercept 0.8 [95% CI –0.3 to 1.9]). B Egger regression P=0.21
(intercept 1.6 [95% CI –1.1 to 4.2])
remained the same as in the primary analysis (OR 1.5 [95% CI 1.3 to
1.7]; P<0.0001; P for heterogeneity = 0.57, also using a fixed-effects
model). In addition, a sensitivity analysis was performed by adding
0.5 events instead of 0.1 events to the placebo and LDA arms of the
study by Silagy et al (32), which did not influence the result.
o bservational studies: All 11 observational studies reported a
significant increase in the rate of PUB or UGIB in individuals treated with
LDA compared with those who were not treated with LDA (Figure 4).
The pooled OR of the meta-analysis of the observational studies
examining the risk of UGIB associated with ASA use was 3.1 (95% CI
2.5 to 3.7; P<0.0001) (Figure 4). There was a high degree of
heterogeneity (I²=78%); thus, a random-effects model was applied. The
result of the Egger regression test for publication bias was not
significant (intercept 1.6 [95% CI –1.1 to 4.2]; P=0.21) and no funnel plot
asymmetry was apparent (Figure 3B), indicating no evidence of
publication bias. As mentioned in the Methods section, in the study by
Uppalapati et al (
), raw outcome data were used to calculate
unadjusted crude ORs, regardless of dose (81 mg/day or 325 mg/day).
The NNH was 819 (95% CI 617 to 1119).
Subgroup analysis within observational studies: Two observational
studies showed a trend for a greater risk of UGIB with increasing (but
still low) doses of ASA (
). Another study showed that the risk of
UGIB remained the same (44). Meta-analysis of the studies examining
the risk of UGIB associated with ASA doses ≤100 mg/day found the
pooled OR to be 2.6 (95% CI 1.9 to 3.7; P<0.001) (Figure 5). The OR
for doses of 300 mg/day to 325 mg/day was 3.6 (95% CI 1.7 to 7.3;
P=0.001) (Figure 5). A random-effects model was applied because
there was a high degree of heterogeneity (I2=76% and I2=90%,
respectively). In the cohort study, the risk was similar for users of ASA
100 mg/day (SIR 2.6 [95% CI 1.8 to 3.5]) and ASA 150 mg/day (SIR
2.6 [95% CI 2.2 to 3.0]); however, it was not clear whether ASA was
used in combination with other NSAIDs.
The present meta-analysis demonstrates that use of LDA significantly
increases the risk of UGIB compared with nonuse. The analysis
included data from well-designed RCTs and from observational studies
encompassing a broad range and large number of patients (n=87,366).
The pooled estimate of the RCTs yielded an OR of 1.5 (95% CI 1.2 to
1.8; P<0.0001) and the observational studies yielded an OR of 3.1 (95%
CI 2.5 to 3.7; P<0.0001).
Although RRs are significantly increased, the absolute increases in
UGIB risk are small. RCTs involving more than 22,000 patients
treated with LDA show that, on average, the number of extra cases of
UGIB associated with LDA use are 1.2 per 1000 patients per year. In
our analysis, the NNH for the RCTs was 816, meaning that if 816
individuals received LDA rather than placebo for one year, one would have
developed UGIB as a result of treatment. The observational studies
yielded a very similar NNH of 819.
In spite of different event and/or exposure definitions, several other
meta-analyses have examined the risk of gastrointestinal bleeding with
LDA use (
). In general, our findings are consistent with those
of others, who reported an absolute rate increase of major
gastrointestinal bleeding with LDA use of approximately one per 1000 person-years
), with a corresponding NNH of 833 (
). The RR of
gastrointestinal bleeding due to ASA use has been reported to range from
1.5 to 2.5 (
) for clinical trials, and from 2.6 (
) to 3.3 (
for observational studies. A recently published meta-analysis of RCTs
) reported a risk of major gastrointestinal bleeding (including lower
gastrointestinal bleeding) with LDA use of 1.6 (95% CI 1.3 to 1.9),
consistent with the findings from our meta-analysis of the risk of UGIB
with LDA use in RCTs. Compared with other previously published
reviews and meta-analyses, our analyses included fewer studies. This was
due to more stringent inclusion and data extraction criteria; to
harmonize the outcome definition across studies, we only included studies in
which UGIB could be clearly separated from other gastrointestinal
complications such as perforation or lower gastrointestinal bleeding. To
harmonize the exposure definition, we included only studies in which
LDA dose was clearly reported to be <325 mg/day. Our analysis has
extended previous meta-analysis data by specifically examining low
dosages of ASA only and focusing on the risk of UGIB rather than
gastrointestinal bleeding in general, especially from observational data.
A potential limitation of RCTs is that they often recruit highly
selected populations and, therefore, may not be representative of
patients seen in routine clinical practice. For example, despite some
of the RCTs included in the present analysis, which enrolled patients
with a history or a high risk of cardiovascular and cerebrovascular
events, all of the RCTs identified excluded certain groups of
individuals who would be at an increased risk of bleeding or complications
such as those with a history of peptic ulcer disease (
individuals who were also treated with NSAIDs, anticoagulants or
). The risk of bleeding found in LDA users
in these trials may, therefore, be lower than that in the general
population. In addition, the majority of RCTs included in the present
analysis were post hoc or subgroup analyses of studies in which a
cardiovascular or cerebrovascular outcome (and not UGIB) was the
original primary outcome measure. Thus, UGIB may have been
under-reported, especially after a cardiovascular event occurred. This
is supported by the finding that the risk of UGIB associated with
LDA use is higher in the observational studies than in the RCTs,
although it is possible that residual confounding played a role.
None of the RCTs identified in the present review tested more than
one dose level of LDA. However, several of the observational studies
examined the dose-response relationship between LDA and UGIB,
although the results were inconsistent. For ASA doses ≤325 mg/day, two
studies reported an increased trend for UGIB risk with higher doses of
). Another study showed the same risk (44) with increased
There is no evidence of a dose-response relationship in terms of
the cardiovascular benefit of LDA, and low doses appear to be as
effective as high doses (
). However, all doses of ASA are associated
with an increased risk of UGIB. Therefore, there does not appear to
be a ‘safe’ dose of ASA in terms of gastrointestinal risks. This suggests
that LDA should be prescribed whenever possible, not only to ensure
cardiovascular benefit, but also to reduce the risk of UGIB that is
potentially associated with high doses of ASA. This is consistent with
European and United States (US) guidelines, which recommend
maintenance treatment with ASA 75 mg/day to 100 mg/day for
patients with non-ST-segment elevation myocardial infarction
). US guidelines on reducing the gastrointestinal risks of
antiplatelet therapy recommend that ASA doses >81 mg/day should not
be used routinely (51).
Recent studies have highlighted the importance of continuing LDA
treatment, even for patients with UGIB (
). Patients prescribed
LDA for secondary prevention of cardiovascular and cerebrovascular
events have a 40% increased risk of ischemic stroke or transient
ischemic attack for up to six months after discontinuation of ASA
treatment compared with patients who continue ASA treatment (54).
US guidelines recommend concomitant gastroprotection for patients
taking LDA who are at risk for upper gastrointestinal events (eg, elderly
patients, individuals using other NSAIDs or antithrombotic agents, and
patients with a history of peptic ulcer disease) rather than treatment
with enteric-coated or buffered LDA (
). To facilitate a more accurate
estimation of the risk of UGIB, the current analysis excluded studies
that reported that all participants were treated with proton pump
inhibitors (PPIs). However, this guideline recommendation is supported by
the finding of Ibáñez et al (
) that the risk of UGIB is lower in patients
treated with LDA and a PPI than in those treated with LDA alone (
Furthermore, there is evidence from other RCTs that PPI use decreases
the incidence of peptic ulcer disease in patients treated with LDA
The present study, in contrast with previous reviews and
metaanalyses, systematically evaluated the association between LDA use
and UGIB, both in RCTs and in observational studies. Many
previously published meta-analyses have relied on high-quality evidence
from RCTs and, although observational studies have some
disadvantages, such as the potential for confounding due to the nonrandomized
nature of the patient groups, they allow a more representative sample
of real-world data to be collected than other study designs.
Despite our efforts to harmonize the outcome definition as much as
possible, potential limitations of the included studies include lack of
consistency in bleeding definition and ASA dose used, which makes it
difficult to compare findings across the studies. In addition, the risk
estimates given in the observational studies included in the analysis
are influenced by the choice of control group as, for example, in the
study by Weil et al (
), in which cases were compared with hospital
controls (OR 2.7 [95% CI 1.9 to 3.80]), community controls (OR 4.2
[95% CI 2.8 to 6.3]) or combined controls (OR 3.2 [95% CI 2.3 to
4.4]). Risk estimates in the observational studies are also dependent on
the methods used to analyze the estimates of risk (eg, variations in
matching and adjustment in multivariate analyses).
A potential limitation of the search strategy was the exclusion of
studies published before 1989. However, some of the studies published
before 1989 that were included in previous reviews would have been
excluded from our study owing to other exclusion criteria, such as not
separating UGIB from gastrointestinal bleeding as a whole (
) or not
reporting on ASA doses <325 mg/day (
). In addition, there were
many more case-control studies than cohort studies included in our
review; only one cohort study was eligible for inclusion in our analysis
). To our knowledge, the only other published systematic review of
epidemiological studies of upper gastrointestinal complications and
ASA use in this time period also included more case-control studies
than cohort studies (
). This may have led to an underestimation of
some of the results. However, it does ensure that the focus remains on
recent data and that the results are likely to be as representative as
possible of current clinical practice.
Another potential limitation is that it was not possible to assess
precisely how many individuals in the included studies were being
treated with gastroprotective medication. This may have resulted in
the incidence of UGIB being underestimated.
All of the observational studies and RCTs included in these analyses
show that LDA use is associated with an increased risk of UGIB.
Gastroprotective prophylaxis should be considered in patients receiving
long-term LDA therapy, particularly in those who have additional risk
factors such as concomitant NSAID use or a history of peptic ulcer
diSCLoSurE: The preparation of the manuscript was funded, in part,
by AstraZeneca R&D, Mölndal, Sweden.
ACKnoWLEd GEMEntS: Writing support was provided by Dr
Rowan Pearce, from Oxford PharmaGenesis™ Ltd, Oxford, United
Kingdom, and was funded by AstraZeneca R&D, Mölndal, Sweden.
ConFLiCt oF intErESt: Vera Valkhoff, as employee of the
Erasmus MC, has conducted research for AstraZeneca. Miriam Sturkenboom
is head of a unit that conducts research for pharmaceutical companies
(Pfizer, Lilly, AstraZeneca, and Altana). She has also acted as a consultant
for Pfizer and Lundbeck. Catherine Hill is an employee of Oxford
PharmaGenesis™ Ltd, which has received project funding from
AstraZeneca. Sander Veldhuyzen van Zanten has received research support
or speaker honoraria from, and/or served on advisory boards for, Abbott,
AstraZeneca, Janssen-Ortho, Nycomed, Pfizer, and Takeda. He is a
member of a data safety monitoring board of Novartis. Ernst Kuipers has served
as a consultant and advisory board member for AstraZeneca.
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1. Anderson JL , Adams CD , Antman EM , et al. 2011 ACCF/AHA Focused Update Incorporated Into the ACC/AHA 2007 Guidelines for the management of patients with unstable angina/non-STelevation myocardial infarction: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines . Circulation 2011 ; 123 : 2022 - 60 .
2. Baigent C , Sudlow C , Collins R , et al. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients . BMJ 2002 ; 324 : 71 - 86 .
3. Björklund L , Wallander MA , Johansson S , et al. Aspirin in cardiology - benefits and risks . Int J Clin Pract 2009 ; 63 : 468 - 77 .
4. Cea Soriano L , García Rodríguez LA . Risk of upper gastrointestinal bleeding in a cohort of new users of low-dose ASA for secondary prevention of cardiovascular outcomes . Front Pharmacol 2010 ; 1 : 126 - 35 .
5. Lanas A , Scheiman J . Low-dose aspirin and upper gastrointestinal damage: Epidemiology, prevention and treatment . Curr Med Res Opin 2007 ; 23 : 163 - 73 .
6. Slattery J , Warlow CP , Shorrock CJ , et al. Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin - analysis of gastrointestinal bleeding during the UK-TIA trial . Gut 1995 ; 37 : 509 - 11 .
7. Sprigg ER , Fleming KM , Logan RFA . Is low dose aspirin use associated with iron deficiency anaemia? An analysis of data from the Health Survey for England 2006 . Gut 2009 ; 58 ( Suppl II ): A91 .
8. Derry S , Loke YK . Risk of gastrointestinal haemorrhage with long term use of aspirin: Meta-analysis . BMJ 2000 ; 321 : 1183 - 7 .
9. García Rodríguez LA , Hernández-Díaz S , de Abajo FJ. Association between aspirin and upper gastrointestinal complications: Systematic review of epidemiologic studies . Br J Clin Pharmacol 2001 ; 52 : 563 - 71 .
10. Hayden M , Pignone M , Phillips C , et al. Aspirin for the primary prevention of cardiovascular events: A summary of the evidence for the U.S. Preventive Services Task Force . Ann Intern Med 2002 ; 136 : 161 - 72 .
11. McQuaid KR , Laine L. Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials . Am J Med 2006 ; 119 : 624 - 38 .
12. Roderick PJ , Wilkes HC , Meade TW . The gastrointestinal toxicity of aspirin: An overview of randomised controlled trials . Br J Clin Pharmacol 1993 ; 35 : 219 - 26 .
13. Serebruany VL , Steinhubl SR , Berger PB , et al. Analysis of risk of bleeding complications after different doses of aspirin in 192,036 patients enrolled in 31 randomized controlled trials . Am J Cardiol 2005 ; 95 : 1218 - 22 .
14. Stalnikowicz-Darvasi R . Gastrointestinal bleeding during low-dose aspirin administration for prevention of arterial occlusive events. A critical analysis . J Clin Gastroenterol 1995 ; 21 : 13 - 6 .
15. Weisman SM , Graham DY . Evaluation of the benefits and risks of low-dose aspirin in the secondary prevention of cardiovascular and cerebrovascular events . Arch Intern Med 2002 ; 162 : 2197 - 202 .
16. Hawkey CJ . Non-steroidal anti-inflammatory drugs and peptic ulcers . BMJ 1990 ; 300 : 278 - 84 .
17. Dickinson JP , Prentice CR . Aspirin: Benefit and risk in thromboprophylaxis . QJM 1998 ; 91 : 523 - 38 .
18. Cappelleri JC , Lau J , Kupelnick B , et al. Efficacy and safety of different aspirin dosages on vascular diseases in high-risk patients. A metaregression analysis . Online J Curr Clin Trials 1995 ; Doc No 174.
19. Sudlow C . Cardiovascular disorders: Primary prevention. Clinical evidence. American College of Physicians-American Society of Internal Medicine, 5th edn . London: BMJ Publishing Group, 2001 .
20. Lanas A , Wu P , Medin J , et al. Low doses of acetylsalicylic acid increase risk of gastrointestinal bleeding in a meta-analysis . Clin Gastroenterol Hepatol 2011 ; 9 : 762 - 8 .
21. Final report on the aspirin component of the ongoing Physicians' Health Study . Steering Committee of the Physicians' Health Study Research Group. N Engl J Med 1989 ; 321 : 129 - 35 .
22. Diener HC , Forbes C , Riekkinen PJ , et al. European stroke prevention study 2: Efficacy and safety data . J Neurol Sci 1997 ; 151 : S41 - S51 .
23. Weil J , Colin-Jones D , Langman M , et al. Prophylactic aspirin and risk of peptic ulcer bleeding . BMJ 1995 ; 310 : 827 - 30 .
24. Ibáñez L , Vidal X , Vendrell L , et al. Upper gastrointestinal bleeding associated with antiplatelet drugs . Aliment Pharmacol Ther 2006 ; 23 : 235 - 42 .
25. Diener HC , Cunha L , Forbes C , et al. European Stroke Prevention Study . 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke . J Neurol Sci 1996 ; 143 : 1 - 13 .
26. Langman MJ , Weil J , Wainwright P , et al. Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs . Lancet 1994 ; 343 : 1075 - 8 .
27. Laporte JR , Ibáñez L , Vidal X , et al. Upper gastrointestinal bleeding associated with the use of NSAIDs: Newer versus older agents . Drug Saf 2004 ; 27 : 411 - 20 .
28. Farrell B , Godwin J , Richards S , et al. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: Final results . J Neurol Neurosurg Psychiatry 1991 ; 54 : 1044 - 54 .
29. Bjerre LM , LeLorier J. Expressing the magnitude of adverse effects in case-control studies: The number of patients needed to be treated for one additional patient to be harmed . BMJ 2000 ; 320 : 503 - 6 .
30. Sørensen HT , Mellemkjaer L , Blot WJ , et al. Risk of upper gastrointestinal bleeding associated with use of low-dose aspirin . Am J Gastroenterol 2000 ; 95 : 2218 - 24 .
31. Uppalapati SS , Boylan JD , Stoltzfus J . Risk factors involved in patients with bleeding peptic ulcers: A case-control study . Dig Dis Sci 2009 ; 54 : 593 - 8 .
32. Silagy CA , McNeil JJ , Donnan GA , et al. Adverse effects of low-dose aspirin in a healthy elderly population . Clin Pharmacol Ther 1993 ; 54 : 84 - 9 .
33. Bax L , Yu LM , Ikeda N , et al. Development and validation of MIX: Comprehensive free software for meta-analysis of causal research data . BMC Med Res Methodol 2006 ; 6 : 50 .
34. Egger M , Davey Smith G , Schneider M , et al. Bias in meta-analysis detected by a simple, graphical test . BMJ 1997 ; 315 : 629 - 34 .
35. Lanas A , Bajador E , Serrano P , et al. Effects of nitrate and prophylactic aspirin on upper gastrointestinal bleeding: A retrospective case-control study . J Int Med Res 1998 ; 26 : 120 - 8 .
36. Santolaria S , Lanas A , Benito R , et al. Helicobacter pylori infection is a protective factor for bleeding gastric ulcers but not for bleeding duodenal ulcers in NSAID users . Aliment Pharmacol Ther 1999 ; 13 : 1511 - 8 .
37. Kaufman DW , Kelly JP , Sheehan JE , et al. Nonsteroidal antiinflammatory drug use in relation to major upper gastrointestinal bleeding . Clin Pharmacol Ther 1993 ; 53 : 485 - 94 .
38. Lanas A , Bajador E , Serrano P , et al. Nitrovasodilators, low-dose aspirin, other nonsteroidal anti-inflammatory drugs, and the risk of upper gastrointestinal bleeding . N Engl J Med 2000 ; 343 : 834 - 9 .
39. Kelly JP , Kaufman DW , Jurgelon JM , et al. Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product . Lancet 1996 ; 348 : 1413 - 6 .
40. Kaufman DW , Kelly JP , Wiholm BE , et al. The risk of acute major upper gastrointestinal bleeding among users of aspirin and ibuprofen at various levels of alcohol consumption . Am J Gastroenterol 1999 ; 94 : 3189 - 96 .
41. The Medical Research Council's General Practice Research Framework . Thrombosis prevention trial: Randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk . Lancet 1998 ; 351 : 233 - 41 .
42. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial . Lancet 2000 ; 355 : 1295 - 302 .
43. Ogawa H , Nakayama M , Morimoto T , et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: A randomized controlled trial . JAMA 2008 ; 300 : 2134 - 41 .
44. de Abajo FJ , García Rodríguez LA . Risk of upper gastrointestinal bleeding and perforation associated with low-dose aspirin as plain and enteric-coated formulations . BMC Clin Pharmacol 2001 ; 1 : 1 .
45. Stack WA , Atherton JC , Hawkey GM , et al. Interactions between Helicobacter pylori and other risk factors for peptic ulcer bleeding . Aliment Pharmacol Ther 2002 ; 16 : 497 - 506 .
46. Lanas A , García Rodríguez LA , Arroyo MT , et al. Risk of upper gastrointestinal ulcer bleeding associated with selective cyclooxygenase-2 inhibitors, traditional non-aspirin non-steroidal antiinflammatory drugs, aspirin and combinations . Gut 2006 ; 55 : 1731 - 8 .
47. Sakamoto C , Sugano K , Ota S , et al. Case-control study on the association of upper gastrointestinal bleeding and nonsteroidal antiinflammatory drugs in Japan . Eur J Clin Pharmacol 2006 ; 62 : 765 - 72 .
48. Udd M , Miettinen P , Palmu A , et al. Analysis of the risk factors and their combinations in acute gastroduodenal ulcer bleeding: A case-control study . Scand J Gastroenterol 2007 ; 42 : 1395 - 403 .
49. Becker RC , Meade TW , Berger PB , et al. The primary and secondary prevention of coronary artery disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 8th edn . Chest 2008 ; 133 : 776S - 814S .
50. Hamm CW , Bassand JP , Agewall S , et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC) . Eur Heart J 2011 ; 32 : 2999 - 3054 .
51. Bhatt DL , Scheiman J , Abraham NS , et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents . Circulation 2008 ; 118 : 1894 - 909 .
52. Sung JJ , Lau JY , Ching JY et al. Continuation of low-dose aspirin therapy in peptic ulcer bleeding: A randomized trial . Ann Intern Med 2010 ; 152 : 1 - 9 .
53. García Rodríguez LA , Cea Soriano L , Johansson S. Increased risk of stroke after discontinuation of low-dose acetylsalicylic acid therapy: A UK primary care study . Cerebrovasc Dis 2010 ; 29 Suppl 2 : 79 .
54. García Rodríguez LA , Cea Soriano L , Hill C , et al. Increased risk of stroke after discontinuation of acetylsalicylic acid: A UK primary care study . Neurology 2011 ; 76 : 740 - 6 .
55. Yeomans N , Lanas A , Labenz J , et al. Efficacy of esomeprazole (20 mg once daily) for reducing the risk of gastroduodenal ulcers associated with continuous use of low-dose aspirin . Am J Gastroenterol 2008 ; 103 : 2465 - 73 .
56. Scheiman J , Herlitz J , Agewall S , et al. Peptic ulcer prevention by esomeprazole 20 mg and 40 mg once daily in patients taking lowdose acetylsalicylic acid for secondary cardiovascular prevention . Gut 2010 ; 59 : A53 .
57. Lewis HD Jr. Unstable angina: Status of aspirin and other forms of therapy . Circulation 1985 ; 72 : V155 - 60 .
58. Peto R , Gray R , Collins R , et al. Randomised trial of prophylactic daily aspirin in British male doctors . BMJ (Clin Res Ed) 1988 ; 296 : 313 - 16 .
59. Levy M. Aspirin use in patients with major upper gastrointestinal bleeding and peptic-ulcer disease . A report from the Boston Collaborative Drug Surveillance Program , Boston University Medical Center. N Engl J Med 1974 ; 290 : 1158 - 62 .
60. Levy M , Miller DR , Kaufman DW , et al. Major upper gastrointestinal tract bleeding. Relation to the use of aspirin and other nonnarcotic analgesics . Arch Intern Med 1988 ; 148 : 281 - 5 .
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