Association between aspirin and upper gastrointestinal complications:
`Systematic review of epidemiologic studies
`
`Luis A. Garcı´a Rodrı´guez,1 Sonia Herna´ndez-Dı´az2 & Francisco J. de Abajo3
`1Centro Espan˜ol de Investigacio´n Farmacoepidemiolo´gica, Madrid, Spain, 2Department of Epidemiology, Harvard School of Public Health, Boston,
`USA and 3Divisio´n de Farmacoepidemiologı´a y Farmacovigilancia, Agencia Espan˜ola del Medicamento, Madrid, Spain
`
`Aims Because of the widespread use of aspirin for prevention of cardiovascular
`diseases, side-effects associated with thromboprophylactic doses are of interest. This
`study summarizes
`the relative risk (RR)
`for
`serious upper gastrointestinal
`complications (UGIC) associated with aspirin exposure in general and with specific
`aspirin doses and formulations in particular.
`Methods After a systematic review, 17 original epidemiologic studies published
`between 1990 and 2001 were selected according to predefined criteria. Heterogeneity
`of effects was explored. Pooled estimates were calculated according to different study
`characteristics and patterns of aspirin use.
`Results The overall relative risk of UGIC associated with aspirin use was 2.2 (95%
`confidence interval (CI): 2.1, 2.4) for cohort studies and nested case-control studies
`and 3.1 (95% CI: 2.8, 3.3) for non-nested case-control studies. Original studies found
`a dose–response relationship between UGIC and aspirin, although the risk was still
`elevated for doses lower or up to 300 mg dayx1. The summary RR was 2.6 (95%
`CI: 2.3, 2.9) for plain, 5.3 (95% CI: 3.0, 9.2) for buffered, and 2.4 (95% CI: 1.9, 2.9)
`for enteric-coated aspirin formulations.
`Conclusions Aspirin was associated with UGIC even when used at low doses or in
`buffered or enteric-coated formulations. The latter findings may be partially explained
`by channeling of susceptible patients to these formulations.
`
`Keywords: aspirin, complications, epidemiology, meta-analysis
`
`Introduction
`
`Safety data from randomized, controlled, trials showed that
`aspirin use increases about two-fold the risk of severe
`gastrointestinal events and suggested a lower, but persis-
`tent, risk associated with low doses [1–5]. Based on the
`general population, early observational
`studies have
`reported risks of upper gastrointestinal complications
`(UGIC) from 1 to 10 times higher among aspirin users,
`with an estimated pooled relative risk between 2 and 3
`[6, 8], Nonetheless, the fact that aspirin is widely available
`over-the-counter without prescription complicates the
`assessment of its effects in observational studies.
`During the last years, aspirin has been increasingly
`used in a long-term fashion for primary and secondary
`
`Correspondence: Dr Luis Alberto Garcı´a Rodrı´guez, CEIFE, Almirante, 28–2,
`28004 Madrid – Spain. Tel.: +34-91-5313404; Fax: +34-91-5312871; E-mail:
`lagarcia@ceife.es
`
`Received 24 November 2000, accepted 17 June 2001.
`
`prevention of cardiovascular diseases. Since the dose
`required for thromboprophylaxis (j300 mg dayx1) is
`lower than that needed for analgesic or anti-inflammatory
`indications [2], the assessment of side-effects associated
`with low doses is particularly important. Moreover, to
`diminish gastric damage, enteric-coated and buffered
`aspirin formulations have been suggested as alternatives
`to plain aspirin. Endoscopic studies showed a reduction
`in gastric and duodenal injury with the use of enteric-
`coated aspirin, but not with buffering [9–12]; whether
`these preparations are associated with lower risks of
`UGIC than plain aspirin outside an experimental setting
`is still unclear.
`Our objective was to systematically review the literature
`on serious gastrointestinal complications associated with
`aspirin use and to evaluate the influence of dose and
`formulation of aspirin as well as the effect of study design.
`Since studies published before 1990 were included in
`previous reviews [6–8], this paper summarizes the main
`results from observational epidemiologic studies published
`from 1990 to 2001.
`
`f 2001 Blackwell Science Ltd Br J Clin Pharmacol, 52, 563–571
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`L. A. Garcı´a Rodrı´guez et al.
`
`Methods
`
`To be considered, a publication had to meet predefined
`inclusion criteria: Articles had to be case-control or
`cohort studies on aspirin use and UGIC (defined as
`bleeding, perforation, or other serious upper gastro-
`intestinal event resulting in hospitalization or visit to
`specialist), and the articles had to provide valid relative
`risk estimates or enough data for us to estimate a relative
`risk comparing aspirin users with nonusers.
`We conducted a MEDLINE search from 1990 to
`February 2001 searching for the terms: ‘anti-inflammatory
`nonsteroidal agents’ (both overall and aspirin), ‘adverse
`effects’, and ‘toxicity’ combined with ‘peptic ulcer’,
`‘stomach ulcer’,
`‘duodenal ulcer’, or
`‘gastrointestinal
`diseases’ (including haemorrhage and perforation). The
`search was restricted to human studies on adults.
`We identified 2477 entries and examined their abstracts.
`Studies on any nonsteroidal anti-inflammatory drug
`were considered in this first screening to avoid missing
`those in which aspirin was one among other drugs. When
`the abstract had no clear reason for exclusion, the full
`article was obtained. We also examined the references
`of previous
`reviews.
`Inclusion criteria were applied
`independently by two of us and decisions regarding
`inclusion of studies were reached by consensus. When
`two articles reported results from the same study popula-
`tion,
`the most recent version was chosen. However,
`if the earliest version provided additional subanalyses,
`they were considered.
`A total of 46 original research articles were examined,
`but 20 of them did not provide specific data on aspirin
`[13–32]. Among the remaining 26 studies,
`four were
`rejected for the following reasons: inappropriate reference
`group for this particular analysis [33], the outcome was
`identification of gastrointestinal bleeding with endoscopy
`rather
`than the presence of
`serious gastrointestinal
`complications [34], the outcome combined upper and
`lower gastrointestinal bleeding [35], or methodological
`concerns regarding both the design (i.e. patients with
`ulcer history excluded only from cases) and the analysis
`(i.e. unclear
`interpretation of discordant pairs
`for
`McNemar’s test) [36]. From the 22 published epidemi-
`ologic studies
`fulfilling all
`the inclusion criteria, one
`reported the same results in a different language [37, 38],
`three reported results from the same study population
`as more recently published articles
`[39–41], and one
`presented additional analyses from a sample that over-
`lapped with a previous article [42]. Hence,
`the final
`number of analysed studies was 17 [38, 43–58].
`A standardized data extraction form was designed
`to collect
`information on study methodology and
`objective quality-related characteristics. The
`list of
`characteristics was based on literature about the methods
`
`in general and on previous
`of epidemiologic studies
`meta-analyses on anti-inflammatory drugs and UGIC
`[6, 7, 59]. Data from articles was abstracted in duplicate
`and entered into a database.
`To determine whether it was appropriate to pool the
`individual results into one common summary measure,
`the heterogeneity in effects between studies was analysed
`using the DerSimonian & Laird’s test statistic for hetero-
`geneity (Q) [60]. We calculated a summary relative risk
`(RR) and 95% confidence interval (CI), weighting study
`estimates by the inverse of the variance and estimating
`linear predictors for the log effect measure [61, 62]. In
`addition to these fixed effects estimates, we also calculated
`the corresponding random effects models. The odds ratio
`from case-control studies was assumed to provide a valid
`estimate of the relative risk [63]. We explored potential
`publication bias qualitatively using a ‘funnel plot’ [64].
`
`Results
`
`The relative risks of UGIC associated with aspirin use
`reported in the original studies are shown in Table 1 and
`Figure 1. The pooled RR was 2.6 (95 CI: 2.4, 2.7).
`However,
`the individual RR estimates were hetero-
`geneous (P<0.01) and varied from 1.4 to 11.2. We
`explored sources of variability among results and estimated
`specific RRs.
`
`Methodological factors
`
`The main study characteristics are summarized in Table 2.
`Among the 16 studies considered, three were cohorts and
`14 were case-control studies. Nonetheless, three case-
`control studies were nested in a well-defined cohort [54,
`55, 58]. Ten case-control studies used matched designs.
`The nested case-control studies obtained their control
`subjects from registries; the other case-control studies
`ascertained controls from hospitals (n=7), communities
`(n=1), or both (n=3). Study years ranged from 1982 to
`1998. Three studies restricted their sample to elderly
`populations. Seven studies used computerized records
`as
`the source of exposure and outcome information
`(all cohort and nested case-control
`studies and one
`hospital-based case-control study); the rest were based
`on interviews. Nine studies specifically excluded oesoph-
`ageal lesions and only considered lesions located in the
`stomach or duodenum. Studies often had the following
`exclusion criteria: cancer (n=10), oesophageal varices
`(n=10), Mallory-Weiss disease
`(n=10),
`alcoholism
`(n=7),
`liver disease (n=7) or/and coag-
`chronic
`ulopathies (n=6). Aspirin exposure was defined as use
`during the last week in nine studies, use in the last month
`in three studies, and use reaching the index date or
`prescriptions that would cover the index date in the other
`
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`Table 1 Pooled and individual relative risk (RR) and 95% confidence intervals (CIs) of UGIC associated with aspirin use. Studies published from
`1990 to 2001.
`
`Review of aspirin and UGIC epidemiologic studies
`
`Study
`
`Cases (n)
`
`Controls (n)
`
`Laporte et al. [43]
`Holvoet et al. [44]
`Nobili et al. [38]
`Keating J, [45]{
`Henry et al. [46]
`Savage et al. [47]{
`Weil et al. [48]
`Hallas et al. [49]
`Kelly et al. [51]{
`Matikainen et al. [50]{
`Pe´rez Gutthann et al. [54]
`McMahon et al. [52]
`Wilcox et al. [53]
`Garcı´a Rodrı´guez et al. [55]
`Lanas et al. [56]
`Sorensen et al. [57]
`De Abajo et al. [58]
`Pooled RR: Fixed effects
`Random effects
`P value test for heterogeneity:<0.001
`
`875
`161
`441
`77
`644
`494
`1121
`183
`550
`48
`1377
`172
`461
`1505
`1122
`804
`2105
`
`*Relative risk estimate and 95% CIs provided in the publication.
`n: number of cases or controls. NA: not applicable, cohort study.
`{Estimated from raw data provided in the publication.
`
`2682
`161
`1323
`77
`1268
`972
`2115
`NA
`1202
`156
`10 000
`NA
`1895
`20 000
`2231
`NA
`11 500
`
`RR*
`
`7.2
`2.2
`11.2
`2.6
`2.4
`2.1
`3.0
`1.9
`2.4
`1.5
`1.4
`2.3
`3.0
`2.3
`2.4
`2.6
`2.0
`2.6
`2.7
`
`95% CI
`
`5.4, 9.6
`1.3, 4.0
`7.8, 16.9
`1.0, 7.3
`1.9, 3.0
`1.5, 3.0
`2.5, 3.7
`1.2, 2.9
`2.0, 3.0
`0.6, 3.4
`1.0, 1.8
`1.4, 3.8
`2.4, 3.7
`1.7, 3.2
`1.8, 3.3
`2.2, 2.9
`1.7, 2.3
`2.4, 2.7
`2.2, 3.2
`
`3.1
`
`2.2
`
`Case/control
`Laporte [43]
`Holvoet [44]
`Nobili [38]
`Keating [45]
`Henry [46]
`Savage [47]
`Weil [48]
`Kelly [51]
`Matikainen [52]
`Wilcox [53]
`Lanas [56]
`Cohorts
`Hallas [49]
`McMahon [52]
`Pérez Gutthan [54]
`García Rodríguez [55]
`Sorensen [57]
`De Abajo [58]
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10 11 12
`
`13 14 15
`
`Figure 1 Relative risks and 95% confidence interval reported in original publications on aspirin use and UGIC during 1990 –2001,
`stratified by study design.
`
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`L. A. Garcı´a Rodrı´guez et al.
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`Table 2 Description of studies on UGIC and aspirin use published from 1990 to 2001.
`
`Study
`
`Design
`
`Period
`
`Location
`
`Exposure assessment
`
`Exposure window
`
`Outcome
`
`Laporte et al. [43]
`Holvoet et al. [44]
`Nobili et al. [38]
`Keating [45]
`Henry et al. [46]
`Savage et al. [47]
`Weil et al. [48]
`Hallas et al. [49]
`Kelly et al. [51]
`Matikainen et al. [52]
`Pe´rez Gutthann et al. [54]
`
`McMahon et al. [52]
`Wilcox et al. [53]
`Garcı´a Rodrı´guez et al. [55]
`
`Lanas et al. [56]
`Sorensen et al. [57]
`De Abajo et al. [58]
`
`Case-control
`Case-control
`Case-control
`Case-control
`Case-control
`Case-control
`Case-control
`Cohort
`Case-control
`Case-control
`Nested
`Case-control
`Cohort
`Case-control
`Nested
`Case-control
`Case-control
`Cohort
`Nested
`Case-control
`
`87–88
`87–89
`87–88
`87–91
`85–89
`86–90
`87–91
`91–92
`87–94
`92–93
`82–86
`
`89–92
`91–93
`91–95
`
`95–98
`91–95
`93–98
`
`Spain
`Belgium
`Italy
`New Zealand
`Australia
`New Zealand
`UK
`Denmark
`US
`Finland
`Canada
`
`UK
`US
`Italy
`
`Spain
`Denmark
`UK
`
`Interview
`Interview
`Interview
`Records
`Interview
`Interview
`Interview
`Records
`Interview
`Interview
`Records
`
`Records
`Interview
`Records
`
`Interview
`Records
`Records
`
`Last week
`Last week
`Last week
`Index day
`Last week
`Last week
`Last month
`Prescription coverage
`Last week
`Last week
`Prescription last month
`
`Hospitalization for gastric or duodenal bleeding
`Hospitalization for upper GI tract bleeding
`Hospitalization for upper GI tract bleeding+
`Hospitalization for upper GI tract bleeding or perforation
`Hospitalization for upper GI tract bleeding or perforation
`Hospitalization for gastric or duodenal bleeding or perforation
`Hospitalization for gastric or duodenal bleeding
`Hospitalization for gastric or duodenal bleeding
`Hospitalization for gastric or duodenal bleeding
`Hospitalization for upper GI tract bleeding
`Hospitalization for gastric or duodenal bleeding or perforation
`
`Prescription coverage
`Last week
`Prescription coverage
`
`Hospitalization for upper GI tract bleeding or perforation
`Hospitalization for upper GI tract bleeding
`Hospitalization for gastric or duodenal bleeding or perforation
`
`Last week
`Prescription coverage
`Last month
`
`Hospitalization for upper GI tract bleeding
`Hospitalization for upper GI tract bleeding
`Hospitalization for gastric or duodenal bleeding or perforation
`
`566
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`five studies. Aspirin use was the main exposure of interest
`in four studies, was one among other anti-inflammatory
`drugs in 10, and was only considered as a potential
`confounder for other main associations in three studies.
`Study design was associated with differences in RRs.
`Cohort studies and nested case-control studies (n=6) had
`a significantly lower summary estimate (RR=2.2, 95%
`CI: 2.1, 2.4)
`than non-nested case-control
`studies
`(RR=3.1, 95% CI: 2.8, 3.3). All nested case-control
`and cohort
`studies used computerized records as
`the
`source of exposure and outcome information, vs only
`one non-nested case-control study [45]. Exposure was
`defined as prescriptions that would cover the month
`before the index date or the index date itself in the six
`cohort studies or nested case-control studies. Once design
`was accounted, the other methodological characteristics
`mentioned in the paragraph above did not significantly
`affect the summary estimate of aspirin.
`Heterogeneity of
`results within study design was
`mainly due to two non-nested case-control
`studies
`with high RR estimates (Figure 1) [38, 43]. Yet, even
`excluding these ‘outliers’, non-nested case-control studies
`had still a significantly higher average RR (RR=2.6, 95%
`CI: 2.4, 2.9).
`In addition, since aspirin has been widely used for
`cardioprotection (i.e. at lower doses) only in recent years,
`we estimated summary RRs for studies conducted only
`before and studies conducted at least in part after 1991.
`The pooled RR was 2.9 (95% CI: 2.6, 3.3) for earlier
`studies and 2.4 (95% CI: 2.2, 2.6) for later ones.
`Regarding quality-related characteristics, all the studies
`had adequate definitions of exposure and outcome,
`five had slightly different
`inclusion criteria for cases
`and controls, and one had dissimilar ascertainment of
`compared groups. Thirteen studies verified the outcome
`with endoscopies, and the 6 studies using computerized
`records verified the information by chart review. All but
`two studies attempted to control for potential confound-
`ers. The most
`frequent confounders considered were
`age (n=15), sex (n=15), prior ulcer history (n=9), and
`concomitant medication (n=9). Among the 10 matched
`case-control studies, five utilized statistical analysis for
`matched data, three considered the matching factors in
`the multivariate model and two did not consider the
`matching factors during the analysis. Restricting the
`analysis to those publications with best quality did not
`substantially change the results.
`
`Aspirin use factors
`
`Five studies addressed the effect of different daily doses
`of aspirin in their analyses [46–48, 51, 58]; all of them
`found greater risks of UGIC for aspirin doses above
`300 mg dayx1 than for lower doses. However, the risk
`
`f 2001 Blackwell Science Ltd Br J Clin Pharmacol, 52, 563–571
`
`Review of aspirin and UGIC epidemiologic studies
`
`was still elevated for doses up to 300 mg dayx1. Studies
`reported a significantly increased risk of UGIC with daily
`doses below 300 mg, [47, 56] 150 mg [46, 57], and even
`as low as 75 mg [48, 58] (Table 3).
`Only four studies reported data on aspirin formulation
`[48, 51, 57, 58]. The pooled RRs were 2.4 (95% CI: 1.9,
`2.9) for coated and 2.6 (95% CI: 2.3, 2.9) for plain
`preparations. Two studies found buffered aspirin not to
`be associated with a lower UGIC risk than regular aspirin;
`the pooled RRs were 4.1 (95% CI: 3.2, 5.1) for plain
`and 5.3 (95% CI: 3.0, 9.2) for buffered aspirin in those
`two studies (Table 4).
`When frequency of exposure was investigated, the RR
`was higher for patients using aspirin regularly (RR=3.2;
`95% CI: 2.6, 3.9)
`than for patients using aspirin
`occasionally (RR=2.1; 95% CI: 1.7, 2.6) [48, 51]. The
`risk of UGIC associated with aspirin was higher during
`the first month of use (RR=4.4; 95% CI: 3.2, 6.1) than
`in the subsequent months of treatment (RR=2.6; 95%
`CI: 2.1, 3.1) [46, 48, 58].
`
`Other factors
`
`The relative risk associated with aspirin use was not
`significantly different in women than in men [43, 44, 46,
`57]; nor for patients below or above 60 years of age
`[38, 43, 44, 46, 57].
`
`Table 3 Original relative risks (RR) and 95% confidence interval (CI)
`of UGIC comparing aspirin users with nonusers according to aspirin
`dose, 1990 –2001 studies.
`
`Articles
`
`Cutoff points
`
`RR
`
`95% CI
`
`Henry et al. [46]
`
`Savage et al. [47]
`
`Weil et al. [48]
`
`Kelly et al. [51]
`
`Lanas et al. [56]
`Sorensen et al. [57]
`
`De Abajo et al. [58]
`
`j150 mg dayx1
`>150 mg dayx1
`
`j300 mg dayx1
`>300 mg dayx1
`
`75 mg dayx1
`150 mg dayx1
`300 mg dayx1
`
`j325 mg dayx1
`>325 mg dayx1
`j300 mg dayx1
`
`100 mg dayx1
`150 mg dayx1
`
`75 mg dayx1
`150 mg dayx1
`300 mg dayx1
`>600 mg dayx1
`
`1.4
`2.7
`
`1.3
`3.1
`
`2.3
`3.2
`3.9
`
`2.1
`4.3
`2.4
`
`2.6
`2.6
`
`1.9
`2.1
`1.9
`4.0
`
`1.0, 2.1
`2.0, 3.5
`
`0.8, 1.9
`3.1, 5.1
`
`1.2, 4.4
`1.7, 6.5
`2.5, 6.3
`
`1.5, 2.9
`3.1, 6.0
`1.8, 3.3
`
`1.8, 3.5
`2.2, 3.0
`
`1.6, 2.4
`1.6, 2.7
`1.3, 2.7
`1.4, 11.5
`
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`L. A. Garcı´a Rodrı´guez et al.
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`Table 4 Specific pooled relative risks (RR) and 95% confidence
`interval (CI) of UGIC comparing aspirin users with nonusers according
`to patterns of use and other factors, 1990 –2001 studies.
`
`Factors
`
`Number of studies
`
`P value*
`
`RR
`
`95% CI
`
`Formulation
`Plain
`Coated
`Buffered
`Frequency
`Occasional use
`Regular use
`Duration of use
`<1 month
`>1 month
`Site of the lesion
`Gastric
`Duodenal
`Type of lesion
`Bleeding
`Perforation
`Gender
`Women
`Men
`Age
`<60 years
`>60 years
`
`4
`4
`2
`
`2
`2
`
`3
`3
`
`8
`8
`
`2
`2
`
`4
`4
`
`4
`4
`
`<0.001
`0.515
`0.572
`
`0.047
`0.389
`
`0.859
`0.152
`
`<0.001
`<0.001
`
`0.256
`0.737
`
`<0.001
`<0.001
`
`<0.001
`<0.001
`
`2.6
`2.4
`5.3
`
`2.1
`3.2
`
`4.4
`2.6
`
`2.9
`2.6
`
`2.1
`1.7
`
`3.0
`3.0
`
`5.0
`4.0
`
`2.3, 2.9
`1.9, 2.9
`3.0, 9.2
`
`1.7, 2.6
`2.6, 3.9
`
`3.2, 6.1
`2.1, 3.1
`
`2.5, 3.2
`2.2, 2.9
`
`1.8, 2.5
`1.1, 2.5
`
`2.6, 3.6
`2.7, 3.4
`
`4.1, 6.1
`3.3, 4.8
`
`*P value test for heterogeneity.
`
`Studies that looked at different sites of bleeding found
`similar relative risks for gastric (RR=2.9; 95% CI: 2.5,
`3.2) and duodenal lesions (RR=2.6; 95% CI: 2.2, 2.9)
`[43, 44, 46, 48, 50, 51, 53, 58]. Estimates of RR were
`not much different between bleeding (RR=2.1; 95%
`CI: 1.8, 2.5) and perforation (RR=1.7; 95% CI: 1.1,
`2.5) [46, 58].
`Results were practically unchanged when we used
`random effect models. Publication bias is unlikely in this
`meta-analysis, the plot of standard error vs effect size does
`not quite look as a pyramid but does not suggest a lack of
`publication of small studies with results closer to the null
`(Figure 2). Finally, notice that pooled RRs were often
`different
`in subanalyses
`than the overall pooled RR
`because the former were based on restricted small samples
`of articles that reported the required data.
`
`Discussion
`
`This systematic review confirms that aspirin, as used in
`the general population,
`increases
`the risk of upper
`gastrointestinal complications. A greater risk is suggested
`for analgesic/anti-inflammatory (greater
`than 300 mg
`daily) doses than for cardioprotective (up to 300 mg)
`doses. Still, users of low dose of aspirin present a twofold
`increased risk with no clear dose–response observed
`
`under 300 mg daily. Formulation of aspirin has only
`a minor impact, if any, on serious UGIC. These findings
`are consistent with a recent meta-analysis of randomized
`clinical
`trials
`that
`shows an increased incidence of
`gastrointestinal haemorrhage associated with long-term
`aspirin, even at
`low doses or with modified release
`formulations [5].
`Aspirin might induce gastrointestinal damage through
`several proposed mechanisms:
`local
`topical
`irritation,
`complete and irreversible impairment of platelet aggre-
`gation trough inactivation of the enzyme cyclo-oxygenase
`(COX-1), and inhibition of COX-1 in the gastroduodenal
`mucosa [65, 66]. Endoscopic studies found that enteric-
`coated aspirin, which is designed to reduce local damage,
`produces
`fewer gastroduodenal erosions
`than regular
`aspirin despite similar serum levels,
`similar inhibition
`of gastric mucosal prostaglandin synthesis, and similar
`suppression of serum thromboxane A2. These findings
`initially suggested that topical effects of aspirin could be of
`greater importance than systemic effects [9–12]. A local
`action would also explain the lesser degree of endoscopic
`mucosal erosion in the duodenum, which has a more
`alkaline environment [9, 10, 12]. However, in epidemi-
`ologic studies, the similar UGIC risk associated with plain,
`coated tablets and buffered agents is more supportive of
`a systemic effect [51, 57, 58]. Another line of evidence
`supporting a systemic rather than a topical action for
`serious upper gastrointestinal complications is the similar
`relative risk showed for duodenal and gastric lesions.
`Moreover, the elevated risk found with low doses would
`make biologic sense, since daily doses of aspirin as low as
`30/50 mg are sufficient to inactivate platelet thromboxane
`A2 synthesis, one of
`the mechanisms
`implied in the
`causation of UGIC [66, 67]. Perhaps, coated aspirin is
`able to reduce the incidence of minor lesions in the
`upper GI tract, but may not be able to prevent the more
`serious gastrointestinal events resulting to a large extent
`from a systemic effect. Channeling of susceptible patients
`to enteric-coated aspirin may also explain the results,
`although original
`studies controlled for prior gastro-
`intestinal history [51, 57, 58]. Regarding buffered
`preparations, the data from epidemiologic studies suggest
`that
`they do not only reduce the risk of upper
`gastrointestinal complications but appear
`to be asso-
`ciated with a more elevated risk than plain aspirin. The
`fact that a number of buffered formulations of aspirin
`(i.e. Alka-Seltzer1) have ‘heartburn’, ‘acid indigestion’ or
`‘upset stomach’ as accepted indications in most countries
`may help to explain such results [68].
`the overall
`Residual confounding might also bias
`association. Recent studies have suggested that patients
`with heart failure or other cardiovascular diseases, the most
`common indication for low dose aspirin, might be at
`higher
`independent
`risk for gastrointestinal bleeding
`
`568
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`
`Page 6 of 9
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`CFAD v. Pozen
`IPR2015-01718
`
`

`
`Review of aspirin and UGIC epidemiologic studies
`
`Figure 2 Funnel plot. The RR from
`each study is plotted on the horizontal
`axis and an estimate of its precision (in
`this case the standard error) on the
`vertical axis.
`
`Std
`0
`
`1
`
`2
`
`3
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`RR
`
`[32, 56]. Although individual studies did not specifically
`report the effect of controlling for cardiovascular diseases,
`we have calculated the RR with and without adjust-
`ment
`for cardiovascular diseases using our data and
`found no major difference: RRs were 1.8 and 2.0,
`respectively.
`The data from observational studies are rather support-
`ive of a duration response with the highest risk con-
`centrated during the first weeks of treatment. Clinical
`trials had also suggested a greater aspirin-related UGIC
`risk early in treatment [4, 46, 48, 58]. Such pattern may
`be explained by a gastric adaptation phenomena [69].
`However,
`the self-exclusion of patients developing
`minor gastrointestinal symptoms associated with aspirin
`throughout their treatment periods could be an alternative
`explanation.
`computed from observational
`Summary estimates
`studies with heterogeneous results have been criticized
`[61, 70]. Heterogeneity among publications may arise
`from differences in the study design, disease definition,
`variation in aspirin dose used by the population, occasional
`vs regular use, etc. In the present analysis, studies with
`automated databases as the source of
`information on
`exposure and outcome provided lower RR estimates than
`those based on personal interviews. Underestimation of
`aspirin use, particularly if obtained over-the-counter
`(OTC), and misclassification of exposed days due to
`noncompliance is probably greater when computerized
`prescriptions are used. We did a sensitivity analysis to
`quantify the impact of nonrecorded aspirin use [71]. With
`false negative probabilities beyond 50%, the net impact
`of nondifferential under-recorded use of OTC aspirin
`with respect to case status would have been a small
`underestimation of
`the RR. Moreover,
`although
`misclassification of exposures collected prospectively
`is usually close to nondifferential between cases and
`controls, we also examined the effects of differential
`
`and
`misclassification. Only extreme (50% or over)
`unrealistically differential under-recording were able to
`cancel the elevated risk of UGIC found for aspirin. The
`limited impact of missing OTC anti-inflammatory drugs
`use has been previously reported [72, 73]. Conversely, the
`assessment of exposure in non-nested case-control studies
`was collected retrospectively through interviews not
`always blinded to the case status; this may have introduced
`a differential misclassification of exposure resulting in an
`overestimation of the RR.
`Studies that collected data in the eighties reported
`a greater risk than studies with data collected in the
`nineties. This could be an indirect reflection of the higher
`doses of aspirin used in those days for indications other
`than cardioprotection. This is especially true in the two
`studies performed in Spain and Italy at a time when
`prophylactic use with low dose aspirin was materially
`nonexistent.
`that
`suggest
`In conclusion, epidemiologic studies
`aspirin even at daily doses lower or up to 300 mg is still
`associated with a twofold increased risk of upper gastro-
`intestinal complications and that neither buffered nor
`enteric-coated formulations appear to materially reduce
`such a risk.
`
`The study was supported in part by a research grant from Pharmacia.
`
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