CLINICAL STUDIES
`Nonsteroidal Anti-Inflammat~►ry Drug-Associated
`Gr~stropathy: Incidence and Risk Factor Models
`JAMES F. FRIE5,'M.D., CATHERINE A. WILLtAMS, M.A., DANIEL A. BI.00M. Ph.p.,
`BEAT A. MICHEL, M.p., Stantord, California
`
`PURPC)SE: The moat prevalent serious drug tng-
`icity in the United States ua inareat~ingly reco~-
`nized ea gastrointaetinal (GI) pathology as~oei-
`atRd with the use of aondteroidal
`anti-infl~mmatary drubs (NSAIDsy. The inci-
`dencae of serious GI events (hoapitaalirati~n or
`death) associated with NSAID use was therefore
`prospectively analyred in patients with rheuma-
`taid arGhrit3e (RA) and patients with
`osteoaQrthritis.
`oes, Atvn s~wsuL~s; The study
`en~rrrq, n
`consisted of 2,747 patients with RA and 1.,091 pa-
`bents with ostecwrthritia. The Yearly haspital-
`ization incidence during N9AIll treatment way
`1.68% in RA patients amd was similtrr in all 15ve
`populations studied. The hazard ratio of patients
`taking N~AiDs to those not rplung NSAIT)s ~cvaA
`5.2. The incidence in aeteoarthrtt~s may be less.
`The rlsk of GI-relaked death in RA padenta vas
`0.19% per year with N9AIDe. Multivariate ausl-
`yses wing risk faotor~ for a~riouts GI event
`were performed in the 1,694 (9$ with as event)
`R.A, patients taking NSAID~ at the pradietive
`visit, 'The main r3~k Pastors were higher age, use
`of pradnieone, previous N9AID GI aide effects,
`prior GI hospitalization, level nf. ttisability, and
`NSAID dose. A rule i~ presented that allows ~ti-
`rnation of the risk far the inc~ividixal t}atient vaith
`RA.
`corroLvstoly: Knowledge r►f the risk factors far
`NSAIIi-asxociated gastropathy and their inter-
`rel~tionelup~ provides a tool for identification of
`the patient at h9gh risk and for initiation of ap-
`prapriate theraPaatic action,
`
`From the Division of Immunology and Rheumatoingy, Department of
`Medicine, Stanford University School 01 Medicine, Stanfortl, California.
`this work was supported by a grant from the National Institutes of
`Health (AR21393) to ARAMIS (the Arthritis, Rheumatism, and Aging
`Medical Information System) and in part by a grant irom Searle
`Laboratories.
`Requests for repnMs should be addressed to Jamas F. Fries, M.D„
`100(1 Welch Road. Suite 203, Palo Alto, California 94304.
`Manuscript submitted November 30, 1990, and accepted in revised
`form March t8. 1991.
`
`astxointeatinel (GI) pathology associated with
`the use of nansteroidsl anti-inflammatory
`drugs (NSAIDa} is increasingly recognized as the
`mast prevalent serious drug toaiaity in the United
`5tatea, resulting in an estimated 2,604 depths and
`24,OOQ hospitalizations annually in patients with
`rheumatoid arthritis (RA) alone [1,2]. The predom-
`inant syndrome consists of antral prepyloric ulcers,
`whech may eventuate in GT hemarxhage or perfnra-
`tion, although evenCs in the duodenum, small bow-
`el, and the large bowel are also seen. Ulcerations
`visible nn endoscapy have a paint prevalence of 10%
`to 26%, tend severe erosions aze seen in additional
`patients (3-5]. The risk of GI hospitelizatian hse
`'been estimated. at 1% to l.5°k per year in persons
`taking NSAIbs [1), and the risk of death is approai-
`rnately 0.13% per year in iridividraals treated with
`NSAIDs [1,6,7j. The importance of the syndrome
`hss been empk~asized by gastroenterologists [3,$,9],
`rheumatolagista [2,5,1OJ, and the Food and Drug
`Administration (FDA) Cliff.
`Impost information required for estimation of
`the magnitude of the problem and for development
`of strategies for resolution, however, has been lack-
`ing. For example, the prevalence of complicatiaz~e in
`conditions other than RA, such as osteourChritis,
`has not been established. Generalizability of the
`observations to different practice sites has not been
`presented. Quantitation of likely risk factors such
`as prior bleeding has not been reported, and the
`frequency of deaths lase not been confirmed by pro-
`speetive study. Moat importantly, while individual
`risk factors have been suggested by a number of
`iixvestigatars [x,12,13], no multivariate risk factor
`mode! that permits estimation of risk in the individ-
`ual patient has been presented.
`'Phis report addresses these iseaes in two steps:
`(t) with descriptive analyses of 2,747 patients with
`RA Followed prospectively far an average of 4 years
`at eve ARAMIS (Arthritis, Rheumatism, and Aging
`Medical Information System) data bank centers
`[14,15] and 1,091 patient; with osteoarthritis, and
`(2) with risk factor analyses based on the 1,694 of
`these RA patients taking NSAIDs at the predictive
`V1$l~.
`
`September 1991 The Americas Journal of Medicine Volume 91 Z13
`
`Page 1 of 10
`
`Patent Owner Ex. 2010
`CFAD v. Pozen
`PR201 5-01 71 8
`
`

`

`NSAIDASSOCIATED GASTRQPA7HY / FRIES ET Al
`
`TABLE t
`Rheumatad Arttx~itis Gastroirttestlnal {Gp Hospitalization by Center
`
`-_-~'
`
`Number of patients
`Person-yearsaf observation
`Person-years takingNSAiDs
`
`GI hospitalizations
`Numberotpatients
`Rate perperson•year(%)
`NombertakingNSA1Ds
`Rate per year whileWkingNSAIDs(%)
`Number of years of observation aflei ist
`huspitalizafion
`NumberofadditionalGlhospitalizations
`while takingNSAIDs
`Rate foratleastonemweGllaspItalia•
`tian per year while taking NSAIDs (! )
`Number of patientswith upper GI taspi•
`talizations
`Rate of upper GI hospitalkzations per year
`while taking NSAIDs (%)
`NumAerof patients with IowerGi haspi~
`ta~aations
`Rate of lower GI hospitalizations per year
`while taking NSAIDs (°b)
`
`Al!
`Ceotea
`
`2,1A7
`9,525
`6,74]
`
`]16
`1.22
`107
`1.58
`201
`
`l0
`
`4.98
`
`95
`
`1.A1
`
`12
`
`0.18
`
`Center
`
`Santa
`Clata
`
`Saskatoon
`
`Phoenix
`
`Star~ord
`
`Wichita
`
`302 ~ 679
`2,458
`1,632
`1,712
`1,122
`
`3D7
`1,016
`720
`
`379
`1,318
`903
`
`1,090
`3,091
`2,284
`
`13
`0.80
`13
`1.16
`24
`
`2
`
`8.33
`
`13
`
`1.16
`
`0
`
`0
`
`3Q
`1.38
`30
`1.75
`73
`
`4
`
`5.48
`
`27
`
`1.59
`
`3
`
`0.18
`
`14
`t.38
`13
`L8t
`22
`
`Q
`
`0.00
`
`I 1
`
`1.53
`
`2
`
`0.3D
`
`16
`L21
`l5
`1.6G
`27.5
`
`2
`
`7.27
`
`13
`
`1,44
`
`2
`
`0.22
`
`39
`1.26
`36
`1.55
`54.5
`
`2
`
`3.66
`
`31
`
`1,36
`
`5
`
`022
`
`PATIENTS ANp MEl'HObS
`Two thousand seven hunrired and forty-6even
`patients with RA consecutively enrolled and fol-
`lawed at eve ARAMIS centers, for a total of 9,525
`gears of abaervatton, were available for study (Te~-
`ble I). The Santa Clara County population of 302
`patients represents a community population re-
`cruited by advertisement. The other populations
`were formed by consecutive patie~at accrual at the
`site. The 679 Saskatoon patients are believed to
`makeup the great majority of patients in Northern
`Saskatchewan province, the 307 Phcenig patient
`were drawn £rom a rheumatology private practice,
`as were the 1,080 Wichita patients, and the 379
`Stanford patients were enrolled from a tertiary Dare
`referral center. Data are coAected in two modes.
`F'inat, all routine clinical data including diagaa,osia,
`symptoms, signs, demographics, past history, labo-
`ratory tests, and treatment ere entered for each
`pnCient encounter and hospitalization. Second, pa-
`tients complete the Health Assessment Question-
`naire (HAQ) [1,16-18J at6-month intervals, pravid-
`ing validated self-report of disability, discomfort,
`drug tonicity, and economic impact. All hospitaliza-
`tions and deaths are audited by abstrsction of dis-
`oharge summaries and NSAID usage at time of
`evert confirmed. I?eaths are reviewed by death oer-
`tificate discharge summary and recent clinical
`notes, The system, procedures, and vatida~ion teeh-
`niques hive been previously described [2>14-i8J.
`The dependent variable in this study was "GI
`event,"consisting of an event auf~ciently serious es
`
`to result in hospitslization or death. Events ere
`counted only when they are the primary basie for
`hospitalization ordeath, not if they occurred during
`a hospitalization ox as part of a terminal illneea
`sequence. Patients ere considered to be taking
`NSAIDa if they report on the HA(a immediately
`prior to the event that they are taking any one oP the
`follawin~; drugs: aspirin, napro~an, ibuprofen, pir-
`oaicam, indomethaoin, sulindac, mec]ofenamaCe,
`tolm~tin> fenaprofen, ketoprofen, »onacetylated sa-
`licyletea, ealsalate, diflunisal, or diclofenac.
`For risk factor delineation, items considered were
`those available at the HAQ prior to the event-the
`predictive visit. Patients had had from one to Z3 6-
`month periods of observation. Obviously, patients
`analyzed for risk factors for NSAII? gaetxopathy
`were xequired to be taking an N$AID atthe predic-
`tivevisit. Amangthe 130 patients with GI events, 32
`patients were not included in the analysis because
`they were not taking NSAIDs at the predictive visit,
`or did not have HAQ data within 9 months prior to
`the event. 'I'herePore, 98 patients with GI events
`were available far comparison with patients with-
`out GI events (controls). Similarly, of the 2,617
`(2,747 minus 130) patients eligible as controls,1,021
`were excluded because thsy did not meet one or
`more of the above criteria. By definition, the non-
`event group could not have a GT event; however,
`control patiet►ts' records were randomly truncated
`to match the number of 6-month periods in whioh
`events occurred in patients with GI events. For ex-
`ample, 5% of the GT events €~ccurzed at the seventh
`
`21A
`
`September 1991 The American Jaurnat of ModtcEne Volume 91
`
`Page 2 of 10
`
`Patent Owner Ex. 2010
`CFAD v. Pozen
`PR201 5-01 71 8
`
`

`

`N9AID~A5SQCIATED GASTROPATNY / FRIES E1" AL
`
`TABLE II
`Variables Associated with Gastrointestinal t61}Hospitalization prDeath at Predictive Visit
`
`GI Events (n = 98i
`Mean
`Numher
`(SE)
`Defined
`
`No GI Events (n = 1,596
`Mean
`Number
`Defined
`fSE)
`
`Contlnoous va~i2bles
`98
`Age (yezrs)
`95
`Education level (years)
`98
`Disease duration (yearst
`9B
`Disabilityi~dexi0-3)
`75
`Smoking(picks/day)
`92
`Akofrol (drinh~/day)
`98
`Specialrycare
`93
`NSAIDdose(seetexU
`93
`NumberofnMARRs
`74
`Number ofHz-antagonists
`Number ofantacidsorHrantagonists 93
`
`65.47 il.o5)
`11.9A 10.25)
`18.75 (1.20)
`1.69(0,09)
`01G{0.041
`0.2C (0.08}
`0.53(O.OA)
`1.03(0.06)
`0.45f0.06)
`028(0.05)
`0.53(0.07)
`
`Categorical variables (%positive)
`Femaiesex
`White race
`Smoker
`Alcohpl
`NSAIpGlsideeffeclever
`Prednisone
`Antacids
`Hz-antagonists
`Anta~idsor Hz antaKonists
`
`98
`95
`75
`92
`93
`93
`74
`74
`43
`
`76.5
`98.9
`IOJ
`13.0
`32.3
`51.6
`20.3
`28A
`40.9
`
`1,596
`1,525
`1,5$3
`1,596
`1,287
`1,529
`1,558
`1,582
`1,583
`1314
`1,563
`
`1,596
`1,545
`1.287
`1,529
`1,583
`1,583
`1,312
`1,314
`1,583
`
`58.65 (0.33)
`12.50 (0,07)
`16.86 (0.28)
`1,38(0.02)
`0.2710.01)
`O.d4 (0.12)
`0.59(0.01)
`0.91 (0.01)
`0.5610.OU
`0.0910.01)
`0.2210A1)
`
`76.1
`94,5
`17.2
`18.2
`18.6
`31A
`10.1
`9.1
`19.2
`
`pValue
`
`<O.00I
`0.06
`0.11
`c0,001
`0,08
`0.09
`0,15
`<QA5
`O.D7
`<0.001
`<0.001
`
`0.97
`0.06
`0.14
`0.21
`<0.001
`<0.001
`<0.01
`<O~OOt
`<0.001
`
`6•month observation period and, therefore, predic-
`tion a~ae made using information at the sloth obser-
`vntion period; similarly, tt random 5% of tho control
`subjects were analyzed at the sixth ahaervation pe-
`rzad eu~ predictive of an "event" at the seventh ob-
`servation period. T'hia method was applied to each
`of the 13 possible 6-month observation periods to
`adjust for differences that would otherwise have
`bean present zn the amount of data available for
`prediction in cases and controls. The mean time
`interval between the predictive data at the HAQ
`prior to the event and the HA(a associated with the
`event was 8,2 months.
`Univ~riate analyses warp pozforcYzed using s t-test
`for 11 continuous variables and by using a chi-square
`test nn 2 X 2 tables far nine binary variables. The p
`values are those comgutecl for each individual com-
`parison and may be adjusted for multiple campari-
`sona by the Bon£erroni adjustment. All variables ata-
`tiatictilly significant as predictors at the 0.~5 level
`(twro-tailed) sod asverat additional variables cansid-
`ered as potentially important were furttYer analyzed
`by multivariate aiaalyses. Stepwitse multiple lagi~tic
`xegxeseion and recursive partitioning (classification
`and regression tree} anAlyses were employed [19J.
`~~su~rs
`Incidence
`Of the 2,747 RA patients available faz study, 130
`had GT events suf~ciQntly serious to result in hospi-
`talizetion ar death. When hoapitaliz~tiona were
`tabulated in these 130 patients, 11G patients had
`
`128 hospitalizations (10 patients had two hoapital-
`izatiorns and ane patient had three) and 1.7 had GI-
`retutad deaths. Among the 17 GI death~t, three pu-
`tients had had prier GI hospitalizations. Data
`presented in Table 7 desorik~e the 116 ho~pitaliza-
`tion evente (the last event among patients with
`multiple haspitalizationa). Deter subsequently pre-
`sented inTables II through VT result from analysis
`df the last GI event (death or hospitalization). Four-
`teen patients had previous GT events (three pa-
`
`TABLE III
`Odds Ratios for Selected Variables with Respect to Gastrointestinal (GI)
`Nospitalizatkn err Death
`
`4ariable
`
`Odds
`Rath
`
`95%Confidence
`Interval
`
`~Femalesex
`White race
`Smoker
`A(cand
`PriorGicomplaint
`Prednisone
`Antacid
`HZ-antagonist
`Antacid orHz~antagonist
`NSAID dose > 1.0 (see tezU
`ass
`>45years
`>5Qyears
`>60year's
`>65years
`> 70 years
`:> 75 years
`D!5ability index (Q-3)
`> 1
`,2
`
`1.0
`5.5
`Q.6
`0.7
`2.1
`Z.4
`2.3
`3.9
`2,9
`1.4
`
`7.0
`4.4
`2J
`2.4
`2.0
`2.2
`
`1.8
`1.9
`
`0.61-1.60
`0.75-39.73
`0.27-1.22
`0.36-1.25
`1.32-3.27
`1.56-3.62
`1.25-4,12
`2.36-6.76
`1,89-k.48
`0.81-2.11
`
`2.2t-22.35
`2.~1-9.52
`tJ0-4.30
`L56-3.55
`1.30-3.08
`1.28-3.85
`
`1.13-2.95
`123-2.91
`
`September 1991 The American Journal ai Medicine Volume 81 218
`
`Page 3 of 10
`
`Patent Owner Ex. 2010
`CFAD v. Pozen
`IPR2015-01718
`
`

`

`NSAID~A550CIATED GASTR4PATNY I FRIES ET AL
`
`TABLE iV
`Risk Factors for Gastrointestinal (G1) Campllcations Relaked to Nospitalizatfon or Death: Stepwise Logistic Regrexsion
`
`Step
`Number
`
`1
`2
`3
`4
`5
`
`Variable
`
`Age (years)
`Prednisone
`Previous NSAID G{ side effect
`NSAIO dose
`Uisabilityindex(0-3)
`
`Coefficient (SE)
`
`0.047 (0.01)
`0.35 (01U
`0,39 (0.121
`0.29 (0.18)
`0,19(4.141
`
`Improvement
`p Value
`
`<p.0001
`<0.0001
`O.OD1
`0.07
`O.1B
`
`Odds Ratio
`
`1.05:1 per year
`1.42:1 yes/no
`1.48:1 yeslnu
`1.34:1 per unit
`121;lperunit
`
`95'h Co~idence Interval
`for pd~s Ratios
`
`1.03-1.07
`1.75-l.76
`1.1$-t.8b
`0.95-L90
`092--1.59
`
`tient~ wfth GI-related deaths Fvho had previous GI
`hospitalizations, and 11 patients with multiple GI
`hospitalizations).
`Qf the 116 last hospitalizations, 107 occurred
`while patients were taking N$AIDs. Ninety-£ive of
`these were noted ~s upper GI problems on discharge
`summaries, and 82 of these were gastric in location.
`Twelve were localised to the lower GI tract. The
`Uverall rate of GI hospitalizations pgiryear of obser-
`vationwas 1.2%.During periods when NSAIDe were
`
`being taken, the overall frequency was 1.58%n per
`year. When the analysis wt~ limited to upper GI
`hospitalizations, the rate during treatment with
`NSAIDs was 1.4% per year.
`Table I breaks down these hoapitalizstions by
`data bank center to evaluate the genezalixsbiiity of
`the observations. The percentage of GT hoapitaliza-
`tions per year during NSAID treatment ranged
`from 1.2% in Santa Clara Coeznty to 1.8°/o in Seska-
`toon and in Phoenix. Upper GI hoapitalizationg
`
`TABLE V
`Characteristics of Classification Tree Subgroups with Respect to Gastrointes!inaf (GI) Nospitaliution pr peath
`R GI Evert Rate pet
`YearTaking NSAIDs
`Percent of Patients
`(%1
`with GI Event
`
`Num6erofPatients
`GI/NoGi Eveni
`
`Subgroup
`Number
`
`Characteristics
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`Age 76 years or older, rro pred•
`nisone
`
`AgeA8yearsorolder,takingpied-
`nisone, disease duration > 3.7
`years, disabiliTy~ index ~ 1.7
`
`Age 48 ro 63 years, previous
`NSAID sideeHec's, disability
`index > 1.3
`
`GI event group: 10 seeond events
`vut of 96 (102°/ )
`
`Age A$ years or older, takingpied-
`nisnne. disease duration '~ 3.7
`years, disabliity index 0.3 to
`1.7
`
`Age 63 to 76 years, no prednisone
`
`lie <47 yeas
`
`Age 47 to 63 years, eo pred-
`nisone, never NSpID side e~•
`fects
`
`Age 47 to 63 years, prev'ous
`NSAIp side effects, disability
`index < 1,3, no prednisone
`
`Age 47 years orolder, taking pretl•
`nisone, disease duratin~ ~ 3.7
`years
`
`Age 4lyearswoider,takiogpred•
`nisone, disease d~uatlon > 3J
`years, disability index <0,3
`
`12179
`
`33/199
`
`i73G
`
`131148
`
`2i/369
`
`:+1 42
`
`~l390
`
`0137
`
`13.2
`
`142
`
`163
`
`8.1
`
`6.8
`
`0.9
`
`0.9
`
`0
`
`4.2
`
`3.9
`
`3.4
`
`3.1
`
`2.2
`
`1.9
`
`0.3
`
`0.3
`
`0
`
`Ql2A ~ 0 ~ 0
`
`0122
`
`d
`
`0
`
`216 September 1991 The Amerlean Journal of Medicine Volume 41
`
`Page 4 of 10
`
`Patent Owner Ex. 2010
`CFAD v. Pozen
`IPR201 5-01 71 8
`
`

`

`NSAIp~ASSOCIATED GASTRQPATHY / FRIE5 ET AL
`
`TA9LE VI
`bescnption of Selected 4adabies Within Subgroups of Tree (Figure 1)*
`
`',
`
`'~
`
`Number ofpa;ients
`Variables
`Agaiyears)
`
`Disease duration (Years)
`
`Disabilityind~(~-3)
`
`previous NSAIp-related
`GI side e;fects (%)
`NSAID dose (see tex8
`
`Use ofptednlsone
`Use of antacids or
`Nz antagonists (11
`Tim~e taking NSAIDs
`(months)
`L._-
`~Valus n~c mrarr, fSE 1
`
`~
`
`All
`
`1
`
`2
`
`9
`
`5utr~roup Number (GI Event Group)
`7
`6
`5
`4
`
`$
`
`9
`
`10
`
`71
`
`1,694
`
`91
`
`232
`
`G3
`
`98
`
`16l
`
`396
`
`345
`
`343
`
`37v 24 22~
`
`79
`59
`(0.3)
`(0.31
`18
`ll
`(0.3)
`11.21
`1.7
`1.4
`(0.02) (O.0
`13
`20
`
`65
`(0.6)
`21
`{0.7)
`2.3
`(0.Q2)
`2d
`
`57
`i0J}
`16
`(1.5)
`1.9
`(O.D71
`lOD
`
`65
`(1.1'
`19
`(L2'-
`i.l
`I0.1`
`32
`
`53
`(0.61
`19
`(0.91
`1.2
`(O,Q3)
`14
`
`LO
`0.8
`0.9
`(0.0$)
`(09ll (0.1)
`0 1Q0
`30
`35
`20
`20
`
`1.0
`(0.1!
`6
`26
`
`I.0
`(O.l
`52
`w1
`
`d.9
`(O.OA)
`100
`28
`
`4l
`(0.51
`
`43
`38
`(22) f1.3)
`
`51
`(3.3)
`
`40
`(2.1i
`
`A3
`(1.61
`
`69
`(021
`20
`(0.71
`l.5
`(0.041
`20
`
`0.9
`10.03}
`0
`21 ~
`
`a3
`(1.1)
`
`39
`(0.3)
`l2
`(0.4)
`1.1
`(0.041
`24
`
`0.9
`(0.03{
`29
`Z5
`
`38
`(1,_I)
`
`56
`(0.2)
`11
`i0.5)
`1.2
`(O.Q4)
`0
`
`57
`106)
`15
`(0,U
`0.1
`(O.0
`100
`
`66
`(1.8)
`2
`(0.2}
`1,5
`(021
`8
`
`64
`11.7)
`15
`(0.02)
`0.t
`10.02)
`23
`
`1.0
`10.03)
`0
`11
`
`Al
`p.2}
`
`1.3
`1.0
`(Q2}
`(0.11
`0 100
`2t
`24
`
`0.8
`iO.0
`100
`27
`
`45
`f3.2)
`
`16
`(1.2?
`
`35
`(4.0)
`
`ranged from 12% per year with NSAID treat~aent
`in Santa Clara Cpunty patients to 1.6% in Saska-
`toon. Results st all eenters were similar, without
`statistically signi~eant differences.
`Table I also lists patients taking NSAIDs who
`were hospitalized more than once. Qne subject waa
`hospitalized three times. After the first hospitaliza-
`tion, the 10 additional hospiLalizstians occurred in
`only 241 years of observation, for a rate of 5% for at
`lea$t one more GI hospitalization per yeax during
`treatment with NSAIDs. This rate varied from 0%
`in Phcenia to 8.3% in Santa Clara County, This
`overall rake of rehospitalization is approufmately
`four times the rate of first hospitalization,
`There were 17 GI-related deathe occurring dur-
`ing these 9,625 years of observation. Thirteexl of
`these deaths occurred in patients who were reliably
`known to be tmkittg NSAIDs at the time of death;
`each of the others might have been 'Phis gives ~n
`overall GI death rate of 0.18°/o per year grid a GI
`death rate during known treatment with NSAIDa of
`0.19% per yeaz.
`
`Risk Factor Analyses
`Table II lists continuous variables analyzed uni-
`variately fprtheir aseocationwith serious GI events
`(hospitalization or death} for patients having taken.
`NSAIDa at the predictive visit. Thy zyumber pf pub-
`jecte reflects the inclusion criteria previously de-
`ecribecl. The meat significant differences were ab-
`tained for age, HAQ disability indez, NSAID dose,
`and use of antacids or Ha-antagonists. The ai£Per-
`ence in HAQ disability scares of 0.31 is clinically
`significant, representing the equivalent of 4 years of
`disease progresainn in RA. NSAID dose was enlcu-
`
`lated by setting a value of 1.00 for the manufactur-
`er'$ highest recommended dcase an the package in-
`sert and narrnalizing ttre dc~e of each patient to this
`standard. Thus, the value 1.03 means that patients
`with events, on average, were taking 103% of the
`manufacturer's highest recommended dose.
`"DMARDs" refers to prior use of "diseaee-mndify-
`ing antirheumatic dxuga." The variable "specialty
`Dare" refers to the proportion of all doctor visits
`that were made to rheumatologista.
`The seeand pari; of Table IT presents univariate
`comparisons of potentially predictive categorical
`variables dichotomized as present or absent (pre-
`sented as percent positive). The statistically most
`significant differences were seen for having previ-
`ouelyreported GI symptoms attributed try use of an
`NSALU (nausea, heartburn, loss of appetite, vomit-
`ipg, or upper abdominal pain), ues of prednisone
`(average dosage 7 mg/day) in the previous 6
`months, and use of antacids or H?-antagoniatg with-
`in 9 months of the event. Female sag was not predic-
`tive. Race was not predictive, nor was cigarette
`smoking or alcohol use, although these analyses
`were limited in power because of small numbers of
`nonwhites, smokers, and heavy drinkers. Eight of
`the XO statistically significant (p G0.05) differences
`reruain sigzxi~cant after adjudtuzent for Llie 2p mul-
`tipl~ com~~ri~gns pf T&b18 II,
`Odds ratios far selected variables with respect to
`GT events along with 95°k confidence intervals are
`shown in Table TII. For example, the odds ratio for
`females was obtained as follows: the propnrtian of
`females with GI events was 75 of 98 = 76.5%; thus,
`the odds are 76.5/(100 - 76.b) = 3.26. Similarly, the
`proportion of females without GrI events was 1,224
`
`September 1491 The American Journal of Medicine Volume 9Y
`
`217
`
`Page 5 of 10
`
`Patent Owner Ex. 2010
`CFAD v. Pozen
`IPR2015-01718
`
`

`

`N5RIt~A5Sf1C1ATED GA5TROPA7HY ! FRIES ET AL
`
`Figure 1. Classification tree for GI
`hospitalization or death (GI evenly.
`The value within the circles and
`boxes is the percentage of patients
`with GI events par year during
`treatment with NSAIOs. Numbers
`below the boxes are subgroup iden-
`titication numbers of final sub-
`groups. N 5A10 dose - 1.0 corre-
`sponds to the manufacturer's high-
`est recommended dose.
`
`of 1,586 = 76.7%; thus, the odds are 76.7/(100 —
`76,7) = 3.29. Therefore, the odds iataio fir females
`with GI events to females without UI events is
`1.Q. For the values considered, age
`3.2B/3.29
`showed the highest odds ratio when dichotamizeci
`at age 45 (only two events occurred below that age).
`Odds ratios are significant at p GO.dS if 9~i% cone
`dance limits do not include the value of 1.
`Table N summRri7.~ the results of stepwise logir~tic
`re~ea~ian analysis using most of the variables of Table
`II. Three variables had improvement p values ~ese Char►
`0,05: age, use of pzeclx~iacsne, and previous NSATD GI
`side effects. NSAID dose and disability index were the
`nest two variables stepped into the model. `Phe odds
`ratio is the estimated multiplicative effect of a 1•unit
`increase in that variable on the odds of having a GI
`event, holding all other covariat,~a constant.
`Figure 1 summarizes the results of the clae~~ca-
`tion tree analysis (recursiae partitioning). E~.ch node
`o£ the tree (represented by round and square boxes)
`contains the risk per year during NSAID treatment
`for patients in that nozle, in percent. With this meth-
`oci, each ngde of tAe tree is recursively partitioned
`into two subgroups, one containing ewes with v~ri-
`able valuealess then some cutoff point acid the other
`containing cases with values greater than this cutoff.
`
`The "best" variable along with its splitting vaiae
`(cutoff point) is AelecCed with the use of a "goodnesa-
`of-split" criterion. The program (CA1~T) cross-vali•
`dates the results to present a stable tree structure
`(19], The same vruiable may appear twice in succes-
`sion in the tree at different cutpointa; this occurred
`with both ago c►nd dieAbility.
`The tree apli~ ~r~t on age, yielding ovary-low-risk
`group (~.3% events per year during NSAID thera-
`py) below age 47. The tree split nest on prednisone
`use, az►d then an age and disease duration. Disabili-
`ty index and pxevio~s NSAID GI side effects ap-
`peared atlower levels of the tree, The tree displayed
`in Figure 1 conta%ns 10 claesifyitrg subgroups (rep-
`resented by square boxes), Eleven groups are num-
`bered and ranked in order of risk, from a high of
`4.2% per yefxr while taking NSAID~ in individuals
`over the ago of ?6 snd not taking prednieone at the
`predictive visit to near zero: far example, in the
`groups with young individuel~ ~xd with individuals
`between 48 and 63 years of age nat taking pretlni-
`sanQ at the predrative visit and without previoug~y
`having had an NSAIll GI side effect.
`T&ble V provides descriptive data fpr ~"igure 1,
`and Table VI describes the average values of the
`ma,~or risk variables in esah group of Figure 1; the
`
`218 September 1891 The American Journal of Madlclna Volume 9F
`
`Page 6 of 10
`
`Patent Owner Ex. 2010
`CFAD v. Pozen
`IPR2015-01718
`
`

`

`very different patient characteriaticg are ap-
`parent.
`
`COMMENTS
`Results reported here confirm prospectively the
`high xelstive risk of haapetalizatian or death in RA
`patients taking NSATDe. The rate of GI hoapitxlizn-
`tions per year in patients taking NSAIDe is 1.58°{0,
`oompared weth a hoapitatization rate of 0.3% (nine
`of 2,7$4) in patients not treated with NSATDe, for a
`hazazd ratio of 5.2. A~ previously reported [1], use of
`PtSAIDe in RA does not appear to represent a sever-
`itymarker for RA, and mean HAQ disability scores,
`pain scores, age, disease duration, and use of pred-
`nisane are closely similar in patients taking
`NSAIDs and in those not taking NSAIDs. Without
`a randomized controlled trial of NSAID versus no
`NSAID use, one cannot absolutely attribute caus~l-
`ity to the use of NSAIDs, but this use does not
`appear likely to be a marker of disease severity.
`Our results were cpnaiatent across all five popula-
`tions studied. It appears likely from preliminary
`data that the rate of hospitalizations in patient,
`with osteoarthritia may be half ar less of that ob-
`aerved in patients with RA, Previous GI hospital-
`ization is zdenti~ed as a major risk factor.
`We performed a preliminary evaluation of pa-
`tientswith asteottrthritie, with a smaller number of
`years of observation available. Patients with. osteo-
`arthriti$ were drawn from the Wichita population
`(590 patients, 893 years of observation) and from a
`national pool of osteoarthritze patients who had
`taken the Arthritis Setf-Management Course
`[20,21) offered by the Arthxitia Foundation (501 pa-
`tients, 261 patient-years of nbservatinn). Only three
`GI hospitalizations occurred in these patients with
`oateoarthritis. A.11 of these ceees were gastric in Ioca-
`tiaa and all were in patients taking NSATb~. Thus,
`the rate of upper GI hnepitali2atiane per year dur-
`ing NSAID treatu~ent was 1.4% in RA r►nd only 0.4%
`in o~teoarthritie. There were no GI-related deaths
`duri ng this period ot" observation. This suggests the
`possibility of s higher hospitalization rate for FtA
`patients, but the namkrera of patients with osteoar-
`thritis were too small to achieve etatietical
`significance.
`Other studies have addressed the question of in-
`cidence of serious GI events, and generally yield
`estimates conaietent with those here. Thus, Carson
`et al (22,23] found hospitalization rates of 4.5%per
`year for bleeding ulcer in NSAID us~ra foz all indi-
`cations, end FDA estunates of "serious" problems
`are from 2% to 4%per year [241.Other estimates are
`somewhat lower [25-27], but ucidexaecertainment
`appears to be present in some of these studies. (Jar
`
`NSAID~AS50CIATEU GA5TROPATNY /FRIES ET AL
`
`data by study protocol do not allow for averaecer-
`tainment. indeed, even the data presented here are
`subject to Borne undera~oertainment, since if our
`patients did not report a hospitalization, we did not
`routinely seek discharge summaries, and addition-
`eliy we failed to obtain dischaxge summaries about
`.5% of the time. In general, Y•he literature data ere
`consistent with the highest incidences in R.A pa-
`tients,who have the highest levels of NSAID intake,
`and lower incidences for more occasional NSAID
`ussrs [1,12,22-27].
`Twa recent major publications further reinforce
`the results reported here. Tn a Heated case-control
`study of Teauressee Medicaid (}I hoepitalizixtiaiid,
`Griffin et al [28] found a relative risk of 4.1 for
`NSAiD users versus nonusers regardless of disease
`indication, rising to a relative risk of 8.0 for current
`users at high NSAID dosage. Excess risk was found
`to be 17.4 events per 1,000 patient-years, as com-
`pared with 16.8 per 1,000 patient•,yeazs as reported
`here. Dpsage way found important, end no role for
`confounding by current smoking or current heavy
`alcohol use could be identified. Sall et al [29] pro-
`vide a careful review of published data on NSAID-
`associated ulcers, with a full discussion of relative
`risk, mechanisms, and approaches to prevention.
`Previous studies Gave suggested that ons half to
`two thirds of GI deaChs in RA patients taking
`NSAIDs are "eacese," while the zemainder repre-
`sent "background" events [6,7]. Thee, these data
`are similar to the 0.13R'o per year egress GI death
`rate previously estimated j1].
`The individual clinical variables appearing to be
`predictive of serious GI events included age, die-
`ability, NSAID dose, previaua GI haspitslizatinn,
`prior GI eomplaintf+ with NSAIDs, aixd use of pred-
`nisone, antacids, or H2-antagonists. Inadequate
`data were available for analysis of prior sucralfate
`use. Female sea was not predictive, in contrast to
`the preponderance of female admiserons re~rorted
`in a series of GI hospitalizations [9]. These ~ndinge
`axe not contar~dictory, since the prevalence of
`NSATD use ie much higher in females than in males
`[1.3]. A variable termed "specialty cure" was not
`predictive, suggesting that hospitalization az~c~
`death rates are not related to the experience or ex-
`pertise of the particular provider.
`The at~pwiae lagisti~ regression model identified
`eve variables that appear predictive (improvement
`p value <0.20), and these are, in the main, intuitive.
`The univariate ~ndin¢ that prior use of GI protec-
`tive agents (antacids ar H2•ant~goniste) was a
`strong predictive factor (p <0.001) was somewhat
`surprising. Moat NSAID GI ulcers are "silent" (3,$J,
`but a substantial number of patients had prior
`
`September 1991 The American Journal of Medlclne 4olume 91 219
`
`Page 7 of 10
`
`Patent Owner Ex. 2010
`CFAD v. Pozen
`IPR2015-01718
`
`

`

`NSAIO•ASSCCIATEO GASYROPATHY / fR1ES ET Ai.
`
`GI-EVENT 5CORE TABLE FOR RA
`
`AGE (years)
`
`HISTORY OF PREVIQUS N5A1D GI SIpE EFFECT
`
`D15AE31LITY IPlDEX {0-3) qR (ARA CLASS -1)
`
`x Z =
`
`50
`
`x 10
`
`NSA1D DOSH (fraction of maximum recommended) x 15 =
`
`CURRENT PREDNtSQNE 11S~
`
`40 =
`
`TOTAL SCORE
`
`GI-EVENT RISK PAR YEAR (~2l1 NSAIDS IN RA
`
`RISK - (SCARE • 100} /4Ci
`
`Figure 2. GI event score table for
`RA. Derived from logistic regres-
`sion results, a simplified schema is
`presented here: the sum of (1) pa-
`tient age X 2, (2) 50 points if theta
`is a prior history pf NSAID dyspep-
`sia, (3) Q points for American Rheu-
`matism Association (ARA) functlon-
`al class 1 (normal), 10 for class 2
`{adequate), 20 for class 3 (limited),
`or 30 for class 4 (unable), (4) 15
`times the fraction patient NSAID
`dose/manufacturer's highest rec-
`ommended dose, and (5) 40 points
`for current prednisone use. When
`100 is subtracted from this sum
`and the result divided by 40, the
`risk 4i GI hospitalization or death
`over the next 12 months, in per-
`Cent, i5 obtained,
`
`symptom~tology that might hive led to the uae of practice: fret, by treating dyspeptic ~ymptnma and
`"protective" agents. These agents are not believed removing premonitory warning signs, and second,
`to tae effective in prevention of NSAID uleera by reassuring the physzaian that pzeventivs mea-
`[4,5,10,30-33], and this is supported by the experi- aure~ had been taken. I-Towever, "protective" agents
`ence reported here. `Phere are two passible mc~nha- are probably given to patients already canaidered to
`nisma by which these agenty might prove harmful in be at higher risk, thus expressing the higher rick
`
`5.0
`
`4.5
`
`4.0
`
`3.5
`
`3.0
`
`Y
`~ 2.5
`~
`
`2.0
`,.~
`
`'1.0
`
`0.5 ~
`
`~
`
`o a
`
`p •
`
`r ~
`
`a
`
`O Actual Values
`r
`O •Values from
`RISKc SCORE- i00
`40
`
`~ ~
`1q0
`
`140
`
`2Z0
`180
`sca~~
`
`260
`
`300
`
`220 September 1981 The American Journal of Medicine Yalume 91
`
`figure ~. Risk for GI hospitalization
`or death per year during treatment
`with NSAIDs. Comparison of risk
`scores for individual patients (Fig-
`ure 'L) with actual measured risk
`(GI events/years at risk) for pa-
`tients grouped by 2D-unit score
`categories, demonstrating a strong
`correlation between results pre-
`dicted by the simplified scoring rule
`and actual experience.
`
`Page 8 of 10
`
`Patent Owner Ex. 2010
`CFAD v. Pozen
`IPR201 5-01 71 8
`
`

`

`GASTROPRTHY / FBIE5 ET AL
`
`mended dose, and contributes relatively little for
`most patients. Other factors are readily ascertained
`by hisCnry. Figure 2 presents a simple scoring table.
`In these data sets, the estimated risk for serious
`GI events over the next year is well approximated
`by suk~tracting 100 from the score And dividing by
`4b. F` Bare 3 d