Q J Med "2011; 104:133-139
`doi:10.1093/gjmed/hcG169 Advance Access Publication 25 September 2010
`
`Preeraler~ce and independ~n~ factors f or gastr~aduadenal
`ulcers/ero$ions in asymptomatic patients taking low-dose
`aspiran and ga~troprotective agents: the OITA-GF study
`
`A. TAMURA~, I<. MURAI<AM12, )..KADOTA' and OITA-GF STUDY INVESTIGATORS*
`
`From the'Internal Medicine 2 and ZGeneral Medicine, Oita University, Yufu, Japan
`
`Address correspondence to A. Tamura, Internal Medicine 2, Oita University, Idaigaoka 1-1, Hasama-machi,
`Yufu 879-5593, Japan. email: akira«oita-u.ac.jp
`*The members of the OITA-GF Study Investigators are provided in the Appendix 1.
`
`Received 27 July 2010 and in revised form 23 August 2010
`
`0F
`
`3
`
`ulcers/erosions [odds ratio (OR) 0.35, 95% confi-
`dence interval (95`%, CI} 0.17-0.75, P=0.007]. A
`multivariate logistic regression analysis selected
`PPI use as the only independent factor for gastro-
`du~denal ulcers/erosions (OR 0.35, 95% CI
`0.14-0.86, P= 0.02). Nore of the 53 patients with
`PPI use had any gastroduodenal ulcers, and 11 with
`standard-dose PPI use tended to have a lower preva-
`lence of gastroduodenal erosions than 42 with
`low-dose PPI use (~% vs. 28.6%, P=0.052).
`Conclusions: Gastroduodenal ulcers/erosions were
`observed in about one-third of asymptomatic pa-
`tients taking low-dose aspirin and gastroprotective
`agents, and PPI use was a negative independent
`factor for gastroduodenal ulcers/erosions in those
`patients. In addition, standard-dose PPI therapy
`might be more effective in the prevention of
`aspirin-induced gastroduodenal mucosal injury
`than low-dose PPI therapy.
`
`Summary
`
`Background: Although it is well known that aspirin
`causes gastroduodenal mucosal injury and that
`aspirin-induced gastroduodenal mucosal injury is
`often asymptomatic, the prevalence and independ-
`ent fa~:it~rs fo. r gasfi~oduodenal mucosal injury have' ~.
`not been clarified in asymptomatic patients taking
`low-dose aspirin and gastroprotective agents.
`Aim: "fn clarify the prevalence and independent fac-
`tors for gastroduodenal ulcers/erosions in asymp-
`tomatic patients taking low-dose aspirin and
`gastro~~rotective agents.
`Design: Prospective observational study.
`Methods: We performed endoscopy in 150 asymp-
`tomatic patients taking low-dose. aspirin and gastro-
`protective agents for at least 3 months.
`Results: Gastroduodenal ulcers/erosions were
`observed in 373% [ulcers (4.0%); erosions
`(34.0`%)1. Univariate logistic regression analyses
`showed ti~at proton-pump inhibitor (PPI) use was
`with
`gastroduodenal
`associated
`negatively
`
`Introduction
`Low-dose aspirin (75-325 mg/day) is widely used for
`primary and secondary prevention of cardiovascular
`events and prevention of coronary stmt throm-
`bosis.'--' "the use of low-dose aspirin is associated
`with a 2- to 4-fold increased risk of upper gastro-
`intestinal complications such as gastroduodenal
`
`ulcers and gastrointestinal bleeding.~~' There are
`only a few endoscopic studies investigating the
`exact prevalence of gastroduoden~l i7iucosal injury
`in patients taking low-dose aspirin'-10 (Table 1).
`Yeomans et al.~ performed endoscopy in 1B7 pa-
`ticnts tal<ing low-dose aspirin and no gastroprotec-
`tive agents and found gastroduodenal ulcers in
`10.7% end gastroduodenal erosions in 63.1 %.
`
`~c The Author 2010. Published by Oxford University Press on behalf of the Association of Physicians.
`All rights reserved. For Permissions, please email: journals.permissions~~oxfordjournals.orb
`Page 1 of 8
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`134
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`A. Tamura et al.
`
`Table 1 The prevalences of gastroduodenal ulcers/erosions in patients taking low-dose aspirin among previous studies and
`the present study
`
`References
`
`n
`
`Mean
`age (years)
`
`Definition of Gastroduodenal Hz bl~ckers PPis
`Male Upper
`(%)
`ulcers/erosions (%)
`(%) gastrointestial ulcers (size)
`(%)
`(mm)
`symptoms
`
`Yeomans et aL"
`
`47.II —
`68.4 +/—
`
`1 B7 49.9 (Edmonton) 64.2 +/—
`61.0 (Melbourne)
`63.9 (Nottingham)
`61.3 (Sydney)
`67.6 (Zaragoza)
`Niv et x1.10 46 70
`190 69J (BA)
`Nema ct aL`'
`68.8 (ECA)
`The present study 150 71.6
`
`68
`
`—
`
`>3
`
`>3
`?5
`
`>3
`
`Ulcers 1 UJ
`Erosions 63.1
`
`U
`
`0
`
`47.5
`48.4
`
`37.3
`
`10.9
`30
`
`36.7
`
`13.0
`4.7
`
`35.3
`
`BA: bufferin, ECA: Bayaspirin. The study by Yeomans et al. was performed at five centers. The study by Nema et al. consisted
`of 89 patients taking 6A, 101 taking ECA and 46 controls not taking aspirin.
`
`0F
`
`3 0
`
`who were taking low-dose aspirin and gastroprotec-
`tive agents for the preceding >3 months were regis-
`tered in this study. Inclusion criteria were as follows:
`age >20 years; no upper gastrointestinal symptoms
`(epigastric pain, burning or discomfort, heartburn,
`pain, acid regurgitation, nausea and bloating); no
`changes of gastroprotective agents within the pre-
`ceding 3 months; no history of operations for the
`esophagus, stomach and duodenum; neither acute
`coronary syndrome nor stroke within the preceding
`3 months; severe chronic heart failure (New York
`Heart Association functional Class IV); and no ma-
`lignantdiseases. Finally, 150 patients (102 men and
`48 women, mean age of 71.6 ~ 10.0 years) were
`enrolled in this study and underwent esophagogas-
`troduodenal endoscopy.
`
`Demographic data
`The following demographic clad were collected:
`age, gender, body mass index, coronary risk factors,
`alcohol consumption, histories of cardiovascular
`ulcers and eradication of
`disease, peptic
`Helicobacter pylori, and current medications.
`Patients who reported that they drank alcohol every-
`day were considered as regular alcohol drinkers.
`Standard-dose proton-pump inhibitors (PPIs) were
`defined as lansoprazole of 30 mg/day, omeprazole
`of 20 mg/day and raveprazole of 7.0 mg/day, and
`low-dose PPis were defined as lansoprazole of
`15 mg/day, omeprazole of 10 mg/day and ravepra-
`zole of 10 mg/day.
`
`Helicobacter pylori infection status
`Helicobacter pylori infection was examined using
`a urine-based enzyme-linked immunosorbent
`assay (Otsuka Pharmaceutical, Tol<yo, Japan).
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`Nema et al.~ performed endoscopy in 190 patients
`tal<ing low-dose aspirin and found gastroducdenal
`ulcers/erosions in 48.4%. These studies included pa-
`tients with and without upper gastrointestinal symp-
`toms. Because it is well I<no~vn that aspirin-induced
`gastroduodenal mucosal injury is often asymptom-
`atic,f;," it would be expectedthat some of asymp-
`tomatic patients taking low-dose aspirin may have
`gastroduodenal erosions/ulcers. Niv et aL10 investi-
`gated the prevalence of gastroduodenal ulcers/ero-
`sions in 46 asymptcxnatic patients taking low-dose
`aspirin ar~d found gastroduodenal erosions/ulcers in
`47.£3%~. In their study, only 24% of patients were
`taking a gastroprotective agent. Therefore, the
`prevalence and independent factors for gastroduo-
`denal ulcers/erosions have not been clarified in
`asymptomatic patients taking low-dose aspirin and
`gastroprotectiv~ agents. In the present. study, we
`examined these points.
`
`Methods
`The present study was conducted between January
`2008 and December 2008 ~t three centers (Oita
`University Hospital, Oita Nakamura Hospital and
`I<osciren Tsurumi Hospital), in accordance with
`the Declaration of Helsinki and its amendments.
`The study protocol was approved by the ethics com-
`mittee at Oita University Hospital, and written in-
`formcd consents were obtained from all patients
`betore enrollment.
`
`Patients
`Eligible patients who were hospitalized to cardi-
`ology department of the three hospitals or attending
`cardiology outpatient clinics of these hospitals and
`Page 2 of 8
`
`

`
`S
`
`3 0
`
`135
`
`71.6 ~ 1 U.0
`102 (6II.0)
`24.0 f 3.3
`125 (II3.3)
`56 (37.3)
`16 (10.7)
`51 (34.0)
`17.8 (£35.3)
`14 (9.3)
`113 (75.3)
`Z7 (7II.0)
`45 (30.0)
`1U (6.7)
`68 (45.3)
`
`5 (3.3)
`143 (95.3)
`2 (1.3)
`
`145 (96.7)
`5 (3.3)
`53 (35.3)
`55 (36.7)
`53 (35.3)
`37 (24.7)
`8 (5.3)
`0 (0)
`71 (47.3)
`86 (57.3)
`24 (16.0)
`84 (56.0)
`
`Table 2 Patient characteristics
`
`Age (years)
`Male
`body mass index (I<g/mz)
`Hypertension
`Diabetes mellitus
`Current smoker
`Regular alcohol drinker
`Coronary heart disease
`Stroke
`PCI
`Atrial fibrillation
`History of peptic ulcer
`History of eradication of hl. pylori
`Positive urinary H. pylori antibody
`Dose of aspirin
`8.1 mg/day
`100 m;/day
`200 mg/day
`Type of aspirin
`Enteric.-coated formulation
`Buffered formulation
`PPis
`Ha Mockers
`Mucoprotective agents
`Warfarin
`NSAIDs
`Steroids
`Nitrates
`Calcium antagonists
`ncris
`APBs
`
`~
`
`Data are presented as mean f SD or number (%). PCI:
`percutaneous coronary intervention; PPI: proton-pump
`inhibitor; NSAID: nonsteroidal anti-inflammatory drug;
`AC[L angiotensin-converting enzyme inhibitor; ARB:
`angiotensin receptor Mocker. Another abbreviation is as
`Table I.
`
`q Duodenal D Gastric D Gasd•odnoJenal
`
`ui~~~•ti
`
`c~•as~~„s~
`
`0% 5% 70% t5% 20% 25% 30% 35%
`
`Fibure 1. The prevalence of gastroduodenal ulcers/
`erosions.
`
`Table ~ shows results of univariate and multivari-
`ate logistic regression analyses to determine factors
`for gastroduodenal ulcers/erosions. Univariate logis-
`tic regression analyses shoved that PPI use was
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`OITA-GF study
`
`The sensitivity, specificity and accuracy of this assay
`has been shown to be almost equivalent to
`serum-based enzyme-linked immunosorbent assays
`for identifying patients with 1-1, pylori infection.12~'~
`
`Endoscopic examinations
`Esophagogastroduodenal endoscopy was performed
`without cessation of aspirin because cessation of as-
`pirin may affect gastroduodenal mucosal status. An
`ulcer was defines as a mucosal defect having signifi-
`cant depth, measuring at least 3 mm over its longest
`diameter. An erosion was defined as a mucosal
`defect <3 mm. The evaluation was performed by
`experienced endoscopists who were blinded to all
`clinical data.
`
`Statistical analysis
`Continuous data are exp,essed as mean ~ SD or
`median (first-third quartiles), and categorical data
`are expressed as n (°i~>). Univariate and multivariate
`logistic regression analyses were performed to deter-
`mine factors for gastroduodenal ulcers/erosions.
`A multivariate logistic regression analysis was per-
`formed using explanatory variables that showed
`P<0.3 in univariate logistic regression analyses.
`A I'-value -; 0.05 was considered to be statistically
`significant. fill analyses were performed using SS
`12.OJ for Windows (SPSS Inc, "fol<yo, Japan).
`
`R.eSUI~~S
`Patient characteristics are shown in Tak~le 2. The
`doses of aspirin were 81 mg/day in five patients
`(3.3%), 100 r7~b/day in 143 patients (95.3`%) and
`200 m~;/day in two patients (1.3°/~). The enteric
`coated and buffered formulations were being taken
`in 145 patients (96J%) and five patients (3.3%j,
`respectively. PPIs [lansoprazole (n=31), omepra-
`zole (n=15) and ravepra$ole (n = 7)], Hz blod<ers
`[famotidine (n=37), ranitidine (n-14) and nizati-
`dine (n=4)~ and mucoprotective agents [rebamipide
`(n=15), cetraxate (n.=14), teprenone (n=12), azu-
`lenesulfonate (n=6), plaunotol (n=2), isoglandin
`(n = Z), ~cebet (n =1) and sofalcone (n =1)] were.
`being taken in 53 patients (35.3%), 55 patients
`(36.7%~) and 53 patients (35.3`%0, respectively.
`Gastroduadenal ulcers/erosions were observed in
`56 patients (37.3`%): ulcers in six (4.0%); erosions in
`51 (34.0`%0 (Figure 1). One patient had a gastric
`ulcer and gastric erosions. Table 3 shows detailed
`data of six patients with a gastric or duodenal ulcer.
`Three of six patients with a gastric or duodenal ulcer
`had a positive H. pylori urinary test.
`Page 3 of 8
`
`

`
`136
`
`A. Tamura et al.
`
`Table 3 Detailed data of patients with a gastric or duodenal ulcer
`
`Age (years)
`
`Sex
`
`Location
`
`History hf ulcers
`
`Urinary 1l. pylori
`antibody
`
`Gastroprotective
`agent
`
`0
`
`F35
`71
`71
`84
`83
`71
`
`Male
`Female
`Female
`Female
`Iviale
`Male
`
`Stomach
`Stomach
`Stomach
`Stomach
`Stomach
`Duodenum
`
`Gastric ulcer
`-
`Duodenal ulcer
`-
`-
`-
`
`-
`-
`+
`+
`-
`+
`
`Ranitidine
`Cetraxate
`Isogladine
`Rebamipide
`Nizatidine
`Rebamipide
`
`Table 4 Univariate and multivariate logistic regression analyses to determine variables for gastroduodenal ulcers/erosions
`
`Univariate
`
`Multivariate
`
`OR (95% CI)
`
`P
`
`OR (95% CI)
`
`P
`
`Age (years)
`Male
`Hypertension
`Diabetes mellitus
`Current smoKer
`Regular alcohol drinker
`Positive urinary H. pylori antibody
`History of eradication of H. pylori
`History of peptic ulcer
`PPIs
`I-I1 blod<ers
`Mucoprotective agents
`Warfarin
`NSAIDs
`Calcium antagonists
`Nitrates
`
`0.99 (0.96-1.02)
`0.£39 (0.43-1.II1)
`OJZ (U.30-1.7"I)
`0.79 (0.40-1.5II)
`OJ4 (D.24-2.25)
`1.01 (0.50-2.05)
`0.85 (0.44-1.66)
`0.40 (O.OB-1.95)
`0.78 (0.38-7.63)
`0.35 (0.17-0.75)
`1 .52 (0.77-3.01)
`1.32 (0.66-2.62)
`1.61 (0.76-3.43)
`1 .73 (0.42-7.21)
`0.62 (0.32-1.21)
`0.72 (0.34-1.30)
`
`0.58
`0.89
`0.45
`0.51
`0.60
`0.9f3
`O.IIS
`0.26
`OJE3
`0.007
`0.23
`0.44
`0.2"I
`0.45
`0.16
`0.24
`
`F
`
`3
`
`0.42 (0.08-2.24)
`
`035 (0.14-O.IIb)
`O.t33 (0.36--1 .90)
`
`1.47 (0.65-3.32)
`
`OJ3 (036-1 .50)
`0.71 (0.35-1.45)
`
`0.31
`
`0.02
`O.h6
`
`0.36
`
`0.39
`0.34
`
`Other abbreviations are as Tables 1 and 2.
`OR: odds ratio, CL• confidence interval.
`
`significantly associated with gastroduodenal ulcers/
`erosions [odds ratio (OR) 0.35, 95`%o confidence
`interval X95°/~ CI) 0.17-0.75, P=0.007]. The follow-
`ing explanatory variables were entered into a multi-
`variate logistic regression analysis: a history of
`eradication of H. pylori, PPI use, H1 blocker use,
`warfarin use, calcium antagonist use and nitrate
`use. Tl~e multivariate logistic regression analysis
`showed - that PPI use was the only independent
`factor for gastroduodenal ulcers/erosions (OR 0.35,
`95%, CI 0."14-0.86, P= 0.02).
`None of 53 patients with PPI use had any gastro-
`duodenal ulcers. Figure 2 shows the prevalence of
`gastroduodenal erosions in 11 patients with
`standard-dose PPI use (lansoprazole of 30 mg/day
`in seven patients, omeprazole of 20mg/day in
`three patients and raveprazole of 20 mg/day in one
`patient) and 42 patients with low-dose PPI use
`Page 4 of 8
`
`(lansoprazole of 75mg/day in 24 patients, omepra-
`zole of 10 mg/day in 12 patients and raveprazole of
`10 mg/day in six patients). The former tended to
`have a lower prevalence of gastroduodenal erosions
`than the latter (~% vs. Z8.6%, P= 0.052).
`
`Discussion
`Thc: major findings of the present study are as fol-
`lows: (i) gastroduodenal ulcers/erosions were
`observed in 37.3%> [ulcers (~.0%); erosions
`(34.0%)] of 150 asymptoma[ic patients taking
`low-dose aspirin and gastroprotective agents;
`(ii) PPI use was the only independent factor for ~as-
`troduodenal ulcers/erosions; (iii) none of patients
`with PPI use had any gastroduodenal ulcers; and
`(iv) patients with standard-dose PPI use tended to
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`
`DITA-GF study
`
`137
`
`3o~a
`
`25%
`
`20%
`
`IS ~/o
`
`io~io
`
`s%
`o% -_
`
`~ = a.os2
`
`~'
`
`low-dose PPI
`
`standard-close PPI
`
`Figure 2. Comparisons of the prevalence af gastroduode-
`nal erosions between patients with I~w-dose PPI use and
`those with standard-dose PPI use.
`
`have a lower prevalence of gastroduodenal erosions
`than those evi[h low-dose PPI use.
`Low-close aspirin causes gastrointestinal mucosal
`injury tl~ro~;gh topical injury to the; mucosa and sys-
`temic effect> by prostaglandin depletion.'a,is
`Aspirin is non-ionized by the acid environment of
`the stomach and accumulates in gastric mucosal
`cells. Then, it alters the permeability of the cell
`membrane due to iron trapping and hack-diffuses
`H+ irons from the gastrointestinal lumen, leading
`to cellullr toxicity. Inhibition of cyclo-oxygenase-1
`pathway decreases production of prostaglandins
`that have protective effects on the stomach through
`the following mechanisms: an increase in mucosal
`blood flow, stimulation of the synthesis and secre-
`tion of mucus and bicarbonate, and promotion of
`epithelial proliferation. Depletion of prostaglandins
`males a gastric environment more susceptible to
`topical attacks by endogenous factors including
`acid, pepsin and bile salts. In addition, low-dose
`aspirin pram<~tes gastrointestinal bleeding through
`its antiplatelet effect.
`It is well known that aspirin-induced gastroduo-
`denal mucosal injury is often asymptomaticf;~" be-
`cause of an aspirin induced increase in a sensory
`threshold.' Niv et al.10 investigated the prevalence
`of gastroduodenal ulcers/erosions in 46 asymptom-
`atic patients taking low-dose aspirin and found these
`lesions in 47.8`%. In their study, only 24`% of patients
`were taking a gastroprotectiye agent. Therefore, the
`prevalence and independent factor for gastroduode-
`nal ulcers/erosions have not been clarified in asymp-
`tornatic .patients taking low-dose aspirin and
`gastroprotective agents. In addition, no information
`is avzilable on the prevalence of gastroduodenal
`ulcers/erosions in asymptomatic patients tal<ing
`low-dose aspirin and a PPI, which has been shown
`to be effective in the prevention of aspirin-induced
`gastroduodenal ulcers.' Therefore, it would be clin-
`ically importan( to examine these points. In the
`Page 5 of 8
`
`present study, gastroduodenal ulcers/erosions were
`observed in 37.3% of 150 asymptomatic patients
`taking low-dose aspirin and gastroprotective
`agents. The prevalence of gastroduodenal ulcers/
`erosions was relatively lower in the present study
`compared to the prevalences in previous studies. -10
`This is thought to be because the present study con-
`sisted of asymptomatic patients taking gastroprotec-
`tive agents together with love-dose aspirin. In the
`present study, none of 53 patients with PPI use
`had any gastroduodenal ulcers, and PPI use was
`the only negative independent factor for gastroduo-
`dena) ulcers/erosions, suggesting an efficacy of PPis
`in the prevention of aspirin-induced gastroduodenal
`ulcers/erosions. It has been already shown that PPI
`therapy prevents upper gastrointestinal bleeding~ H~~~
`and gastroduodenal ulcers'Fs in patients taking
`low-dose aspirin. Because gastric acid more easily
`injures gastroduodenal mucosae under the environ-
`ment of prostaglandin depletion, it would be
`can
`protect
`that
`PPI
`therapy
`expected
`aspirin-induced gastroduodenal mucosal injury
`through its strongly suppressive effect on gastric
`acid. Of interest, in the present study, patients with
`standard-dose PPI use had no gastroduodenal ero-
`sions and tended to have a lower prevalence of gas-
`troduodenal erosions than those with low-dose PPI
`use. These suggest that standard-dose PPI therapy
`may be more effective in the prevention of
`aspirin-induced gastroduodenal mucosal injury
`than low-dose PPI therapy. No information is so
`far available with regard to the association between
`the dose of PPIs and the preventive effects on
`aspirin-induced gastrodi.iodenal mucosal injury.
`Future studies are required to clarify whether
`standard-dose PPI therapy is more effective in the
`prevention of aspirin-induced gastroduodenal mu-
`cosal injury than low-dose PPI therapy.
`In the present study, Hz blocl<er use was not a
`negative independent factor for gastroduodenal
`ulcers/erosions. This might Inc because the majority
`(89%) of patients with H1 blocl<er use was taking a
`low-dose Hz blocl<er (famotidine of <20 mg/day,
`ranitidine of <150mg/day or nizatidine of
`<150 mg/day): It was recently demonstrated that
`standard-dose famotidine (40 mg/day) is effective in
`the prevention of gastroduodenal ulcers in patients
`taking lo~v-dose aspirin.20 The association between
`the dose of Hl blockers and aspirin-induced gastro-
`duodenal mucosal injury remains to be further
`investigated.
`The present study has a few limitations. First, we
`did not evaluate the exact administration duration
`and compliance of gastroprotective agents, which
`would affect gastroduodenal mucosal status.
`Second, the prevalcnces of PPI use and Hz blocker
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`138
`
`A. Tamura et al.
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`pylori: a collaborative study in nine medical institutions in
`Japan. I lelicobacter 2000; 5:109-19.
`14. Hawthorne A6, Mahida YR, Cole nT, Hawl<cy CJ.
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`
`Patent Owner Ex. 2012
`CFAD v. Pozen
`IPR2015-01718
`
`use were relatively higher in the present study com-
`pared to those in previous studies.~'~'~10 A kind of
`gastroprotective agents being used would naturally
`affect the prevalence of gastroduodena) ulcers/ero-
`sions in patients taking low-dose aspirin. We did not
`investigate the reason why the gastroprotective
`agent was selected in each patient, but the relatively
`higher prevalences of PPI use and I-Iz bloc)<er use
`might he partly because 30% of patients had a his-
`tory of a peptic ulcer. In addition, the increasing use
`of PPIs inpatients tal<ing low-dose aspirin in Japan is
`likely to have contributed to the relatively higher
`prevalence of PPI use. in the present study. Thirds,
`because the present study included only asymptom-
`atic patients, the associations between gastroprotec-
`tive agents and gastroduodenal ulcers/erosions
`indicated by the present study Tray not be general-
`izecl in the whole of patients taking low-dose
`aspirin.
`In conclusion, gastroduodenal ulcers/erosions
`were observed in about one-third of asymptomatic
`patients taking low-dose aspirin and gastroprotective
`agents, and PPI use was a negative independent
`factor for ~;astroduodenal ulcers/erosions in those
`patients. !n addition, standard-dose PPI therapy
`might be .more eft'ective in the prevention of
`aspirin-induced gastroduodenal mucosal injury
`than low-dose PPI therapy.
`
`t:'onflict of interest: None declared.
`
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`139
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`Rensburg C, RScz I, et a/. Efficacy of esomeprazole (20 mg
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`
`Appendix 1: OITA-GF study
`investigators
`Y. Goto, P~iD, Y. Kawano, MD, S. Naono, MD,
`T. Sato, MD, M. Kotol<u, MD, Internal Medicine 2,
`
`Oita University; T. Abe, MD, M. Watada, MD,
`Tanahashi, MD, PhD,
`J. Anan, MD, J.
`K. Mizukami, MD, S. Yasal<a, MD, T. Okimoto,
`MD, PhD, M. Kodama, MD, PhD, General
`Medicine, 'Oita University; I<. Miyamoto, MD,
`N. Aso, MD, T. Watanabe, MD, Division of
`Nakamura
`Oita
`Medicine,
`Cardiovascular
`Ilospital; M. Hino, MD, K. Shinozaki, MD,
`I-I. Laizen, N1 D, Division of Cardiovascular
`I-lospital;
`Tsurumi
`I<oseiren
`Medicine,
`A. Hisamatsu, MD, W. Soma, MD, Y. Nakagawa,
`MD, H. Nal<ashima, MD, H. Okawara, MD,
`i. Nagai, MD, PhD, Division of Gastroenterology,
`i<oseiren Tsurumi Hospital.
`
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