CLINICAL STUDIES
`
`Nonsteroidal Anti-Inflammatory Drug-Associated
`Gastropathy: Incidence and Risk Factor Models
`JAMES F. FRIES, M.D., CATHERINE A. WILLIAMS. M.A., DANIEL A. BLOCH. Ph.D.,
`BEAT A. MICHEL, M.D., Stanford, California
`
`maroon- The most prevalent serious drug tox-
`icity in the United States is increasingly recog-
`nized as gastrointestinal (GI) pathology succi-
`ated with the use of nonstemidal
`anti-inflammatory drugs (NSAIDI). The inci-
`dence of serious GI events (hospimliution or
`death) associated with NSAID use was therefore
`prospectively analyzed in patients with rheum-
`toid arthritfi (RA) and patients with
`osteoarthritis
`PATIENTS. mops, AND mums: The study
`consisted of 2,747 patients with RA and 1,091 pa-
`tients with osteoarthritis. The yearly hospital-
`imtion incidence during NSAID treatment was
`1.58% inRApatientsandwassimiIu-inallflve
`populations studied. The hamrd ratio of patients
`takingNSAIDstothosenottahincNSAlewas
`5.2.Theincidenceinostooarthritismsybelem
`The risk of (ll-related death in RA patients was
`0.19% per year with NSAIDs. Multivariate anal-
`yses amassing risk factors for serious Gl events
`were performed in the 1.694 (98 with an event)
`RA patienm mkin‘ NSAle at the predictive
`vidtfismhrbkfactorswemhigheragame
`of predn'lone, previous NSAID GI side effects,
`prior GI hospitalimtion. level of d'nability, and
`NSAID dose. A rule is pruented that allows esti-
`mation of the rhlr for the individual patient with
`RA.
`CONCLUSION: Knowledge of the risk factors for
`NSAm-sssoeiated gastropathy and their inter-
`relationships provides a tool for identification of
`the patient at high risk and for initiation of ap-
`propriate therapeutic action.
`
`From the DMSiOn of Immunology and Rheumatology. Department or
`Medicine. Stardom University School 0! Medlclns. Staniord, Calliomla.
`This work was supported by a grant from the National Institutes at
`Health (M21393) to ARAMiS (the Arthritls, Rheumatism, and Aging
`Medical
`Iniormatlon System) and in part by a grant from Searls
`Laboratories.
`Requests ior reprints should be adtessed to James F‘ Frias, no,
`1000 Welch Road. Suite 203. Palo Alto. Cslilornis 94304.
`Manuscnpl swmltted November 30. 1990. and accepted In revised
`
`form March 18, 1991.
`
`astrointestinal (GI) pathology associated with
`the use of nonsteroidal anti-inflammatory
`drugs (NSAIDs) is increasingly recognized as the
`most prevalent serious drug toxicity in the United
`States, resulting in an estimated 2,600 deaths and
`24,000 hospitalizations annually in patients with
`rheumatoid arthritis (RA) alone [1,2]. The predom-
`inant syndrome consists of antral oreovloric ulcers.
`which may eventuate in GI hemorrhage or perfora-
`tion, although events in the duodenum, small bow-
`el, and the large bowel are also seen. Ulcerations
`visible on endoscopy have a point prevalence of 10%
`to 25%, and severe erosions are seen in additional
`patients [3—5]. The risk of GI hospitalization has
`been estimated at 1% to 1.5% per year in persons
`taking NSAIDs [1], and the risk of death is approxi-
`mately 0.13% per year in individuals treated with
`NSAIDs [1,6,7]. The importance of the syndrome
`has been emphasized by gastroenterologists [3,8,9],
`rheumatelogists [2,5,10]. and the Food and Drug
`Administration (FDA) [11].
`important 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 complications in
`conditions other than RA, such as oswoarthritis,
`has not been established. Generaliaability 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 has not been confirmed by pro-
`spective study. Most importantly, while individual
`risk factors have been suggested by a number of
`investigators [1,12,13]. no multivariate risk factor
`model that permits estimation ofrisk in the individ-
`ual patient has been presented.
`This report addresses these issues in two steps:
`( 1) with descriptive analyses of 2,747 patients with
`RA followed prospectively for an average of 4 years
`at five ARAMIS (Arthritis, Rheumatism, and Aging
`Medical Information System) data bank centers
`[14,15] and 1,091 patients with osteoarthritis, and
`(2) with risk factor analyses based on the 1,694 of
`these RA patients taking NSAIDs at the predictive
`visit.
`
`Sommher 1991 the American Joumsl oi Medicine Volume 91
`
`213
`
`Page 1 of 10
`
`Patent Owner Ex. 2003
`
`DRL v. Horizon
`
`lPR2018-01341
`
`Patent Owner Ex. 2003
`DRL v. Horizon
`IPR2018-01341
`
`Page 1 of 10
`
`

`

`"SAID-ASSOCIATED GASTROI’M'IIY / FRIES ET Al
`
`TABLE I
`
`mm ArthriisWWI (GI) "WWW by Carter
`
`(mill ,
`Saskatoon M
`307
`1.016
`720
`
`11
`
`14
`1.38
`13
`1.81
`22
`
`0 0
`
`.00
`
`Numberot patients
`Personyears of observation
`Peron—years taking NSNDs
`or hosu'lalizations
`Number at patients
`Rate per personyser (56)
`Number taking NSAI D5
`Rae in year while taking NSAIDS (1:)
`Number of years of observation after is!
`hospitsization
`Number of ”coronal GI hospitalizations
`while hiking Wills
`Rate lor at least one more GI
`’taliza-
`lion per yearwhile taking M ID: (‘3‘)
`Number ofpatienls with upper GI impi-
`idizaliuns
`Rate of inner GI hospitalizations per year
`while taking Hams (7.)
`Number of patients with lower GI hasn-
`idizatirins
`Rate at lower GI ncsptal'rzrtions per year
`while taking NSAIDs 1%)
`
`PATIENTS AND METHODS
`
`Two thousand seven hundred and forty—seven
`patients with RA consecutively enrolled and fol-
`lowed at five ARAMIS centers, for a total of 9,525
`years of observation, were available for study (Ta-
`ble 1). The Santa Clara County population of 302
`patients represents a community population re-
`cruited by advertisement. The other populations
`were formed by consecutive patient accrual at the
`site. The 679 Saskatoon patients are believed to
`make up the great majority of patients in Northern
`Saskatchewan province. the 307 Phoenix patients
`were drawn from a rheumatology private practice,
`as were the 1,080 Wichita patients, and the 379
`Stanford patients were enrolled from a tertiary care
`referral center. Data are collected in two modes.
`First. all routine clinical data including diagnosis,
`symptoms, signs, demographics, past history, labo-
`ratory tests, and treatment are entered for each
`patient encounter and hospitalization. Second. pa-
`tients complete the Health Assessment Question-
`naire (HAQ) [1,16-18] at 6—month intervals, provid-
`ing validated self-report of disability, discomfort,
`drug toxicity, and economic impact. All hospitaliza-
`tions and deaths are audited by abstraction of dis-
`charge summaries and NSAID usage at time of
`event confirmed. Deaths are reviewed by death cer-
`tificate discharge summary and recent clinical
`notes. The system. procedures, and validation tech-
`niques have been previously described [2,14—18].
`The dependent variable in this study was “GI
`event,” consisting of an event sufficiently serious as
`
`to result in hospitalization or death. Events are
`counted only when they are the primary basis for
`hospitalization or death, not if they occurred during
`a hospitalization or as part of a terminal illneu
`sequence. Patients are considered to be taking
`NSAle if they report on the HAQ immediately
`prior to the event that they are taking any one of the
`following drugs: aspirin, naproxen, ibuprofen, pir-
`oxicam,
`indomethacin, sulindac, meclofenamate,
`tolmetin, fenoprofen, ketcprofen, nonacctylated sa-
`licylates, salsalate. 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 13 6-
`month periods of observation. Obviously, patients
`analyzed for risk factors for NSAID gastropathy
`were required to be taking an NSAID at the predic-
`tive visit. Among the 130 patients with GI events, 32
`patients were not included in the analysis because
`they were nottaking NSAle at the predictive visit,
`or did not have HAQ data within 9 months prior to
`the event Therefore, 98 patients with GI events
`were available for comparison with patients with-
`out GI events (controls). Similarly, of the 2,617
`(2.747 minus 130) patients eligible ascontrols. 1,021
`were excluded because they did not meet one or
`more of the above criteria. By definition, the non-
`event group could not have a GI event; however,
`control patients‘ records were randomly truncated
`to match the number of 6-month periods in which
`events occurred in patients with G1 events. For ex-
`ample, 5% of the GI events occurred at the seventh
`
`214
`
`September I”! The Random Jot-rad of lsdlclne Volunt- 91
`
`Page 2 of 10
`
`Patent Owner Ex. 2003
`
`DRL v. Horizon
`
`lPR2018-01341
`
`Patent Owner Ex. 2003
`DRL v. Horizon
`IPR2018-01341
`
`Page 2 of 10
`
`

`

`NSAID-ISSOCIA‘I’ED GASTRWATHY / FRIES ET Al.
`
`
`TABLE II
`Verifies Associated with Gaimirtestinal (GI) Hospiflifion or Death at Predictive Visit
`
`GI Events (I = 98?
`Number
`Mm
`Deflied
`(SE)
`
`NoGI Events“! = 1.596)
`Nutrient
`Mun
`Defined
`(SE)
`
`p Value
`
`98
`95
`98
`98
`75
`92
`98
`93
`93
`74
`93
`
`65.47 (1.05)
`11.94 (0.25)
`l8.75 (1.20)
`1.69 (0.08)
`0.10 (0.04)
`0.20 (0(5)
`0.53 (0.04)
`1.03 (0.06)
`0.45 (0.06)
`0.28 (0.05)
`0.53 (0.07)
`
`1.596
`1.525
`1,583
`1,596
`1.287
`[.529
`1,558
`1.582
`1,583
`1.314
`1.583
`
`58.65 (0.33)
`12.50 (0.07)
`16.86 (028)
`1.38 (0.02)
`0.17 (0.01)
`0.44 (0.12)
`0.59 (0.01)
`0.91 (0.01)
`0.56 (0.01)
`0.09 (0.01)
`0.22 (0.0))
`
`< 0.001
`0.06
`0.11
`< 0.001
`0.08
`0.09
`0.15
`< 0.05
`0.07
`< 0.001
`< 0.001
`
`(hummus variables
`A: (years)
`Eduealion level (yeas)
`Disease duration (years)
`Disability index (04)
`Smoking (melts/day)
`Alcohol (drinks/day)
`Smelly care
`NSAID dose (see text)
`Number of DMARD:
`Number of Hz-antatonisis
`Number of antacids or strmgonists
`Categoricalvariabies (% positive)
`0.97
`76.7
`1.596
`76.5
`98
`Female sex
`0.06
`94.5
`1.545
`98.9
`95
`What not
`0.14
`17.?
`1.237
`1117
`75
`Smnlier
`0.21
`18.2
`1.529
`13.0
`92
`Alcohol
`< 0.001
`18.6
`1.583
`32.3
`93
`NSAID G) Side eiieci ever
`<0.001
`31.0
`1,583
`51.6
`93
`Prednisme
`< 0.01
`10.1
`1.312
`20.3
`74
`Antacids
`< 0.001
`9.1
`1.314
`28.4
`74
`Hz-anlagmisis
`Antacids or Hz-anmonists < 0.001 93 40.9 1.583 19.2
`
`
`
`
`
`
`6-month observation period and, therefore, predic-
`tion was made using information at the sixth obser-
`vation period; similarly, a random 5% of the control
`subjects were analyzed at the sixth observation pe-
`riod as predictive of an “even ” at the seventh ob-
`servation period. This method was applied to each
`of the 13 possible 6-month observation periods to
`adjust for differences that would otherwise have
`been present in the mount 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 HAQ associated with the
`event was 6.1 months.
`Univariate analyses were performed using a t—test
`for 11 continuous variables and by using a chi-square
`teston2 x 2tablee for nine binary variables.Thep
`values are those computed for each individual oom-
`pariwn and may be adjusted for multiple oompari-
`sons by the Bonferroni adjustment. All variables sta-
`tistically significant as predictors at the 0.05 level
`(two-tailed) and several additional variables oonsid-
`ered as potentially important were further analyzed
`by multivariate analyses Stepwise multiple logistic
`”gram“ and Ni“ partitioning (classification
`and regression tree) analyses were employed [19].
`RESULTS
`Incidence
`Of the 2,747 RA patients available for study. 130
`had GI events sufficiently serious to result in hospi-
`talization or death. When hospitalizations were
`tabulated in these 130 patients, 116 patients had
`
`128 hospitalizations (10 patients had two hospital-
`izations and one patient had three) and 17 had GI-
`related deaths. Among the 17 G1 deaths, three pa—
`tients had had prior GI hospitalizations. Data
`presented in Table I describe the 116 hospitaliza-
`tion events (the last event among patients with
`multiple hospitalizations). Data subsequently pre-
`sented in Tables [I through VI result from analysis
`ofthe last GI event (death or hospitalization). Four-
`teen patients had previous GI events (three pa-
`
`‘IABLE lll
`oars Ratiosinr Selected Variables with Raped in Grumman” (GI)
`Hospitalization or Death
`
`>2
`
`VIM
`gmm‘
`5mm,
`33%| oanpiaim
`Prednisone
`kfifikm
`Antacidoer aniagsnist
`gm“ >1~° (”9‘9“)
`3333:
`33%:
`> 7Dyears
`> 75 years
`Disability ildex (0—3)
`> 1
`
`g-g
`0:5
`g;
`2:4
`33
`2:9
`1'4
`iii
`3.;2.0
`2.2
`
`.8
`.9
`
`._.._.
`
`September 1991 The American Journal of Medlclrie Volume 91
`
`215
`
`Page 3 of 10
`
`Patent Owner Ex. 2003
`
`DRL v. Horizon
`
`lPR2018-01341
`
`Patent Owner Ex. 2003
`DRL v. Horizon
`IPR2018-01341
`
`Page 3 of 10
`
`

`

`NSAD-ASSOCMTED GASIROPMDIY / FRI‘ ET AL
`
`
`TABLE IV
`Risk Factors for Gastoiniesfinal (GI) Complication: Related to mention or Death: Stepwise Logistic Regression
`
` (0.0001
`
`Step
`umber
`
`Variable
`
`P69 (793's)
`Prod
`msone
`Prevhis NSNDGIsideeflect
`NSAD dose
`Disability index 10-31
`
`Coefideni (SE)
`
`0.047 (0.011
`035(011)
`0.39 (0.12)
`0.29 (0.18)
`019(014)
`
`95% Cum marvel
`Improvement
`
`moods Ratiosp Value
`1.03-1.07
`1.15-1.76
`1.18-1.86
`0.95—1.90
`0.92—1.59
`
`<0.0001
`0.00]
`0.07
`0.18
`
`being taken, the overall frequency was 1.58% per
`tients with GI-related deaths who had previous GI
`year. When the analysis was limited to upper GI
`hospitalizations, and 11 patients with multiple GI
`hospitalizations).
`hospitalizations, the rate during treatment with
`NSAIDs was 1.4% per year.
`0f the 116 last hospitalizations, 107 occurred
`Table I breaks down these hospitalizations by
`while patients were taking NSAIDs. Ninety-five of
`data bank center to evaluate the generalizability of
`these were noted as upper GI problems on discharge
`summaries. and 82 of these ware gastric in location.
`the observations. The percentage of G] hospitaliza-
`Welve were localized to the lower GI tract. The
`tions per year during NSAID treatment ranged
`from 1.2% in Santa Clara County to 1.8% in Saska-
`overall rate of G1 hospitalizations per year of obser-
`toon and in Phoenix. Upper GI hospitalizations
`vation was 1.2%. During periods when NSAIDs were
`
`
`TABLE V
`
`Characteristics at Classificalim Tree Subgroups with Respect to Gastrointestilai (GI) Hospitalintion or Death
`
`Subgroup
`Nunaer
`
`Characteristics
`
`Nurrberoi Patients
`Gl/NoGl Even!
`
`Percent oi Patients
`with GI Even
`
`GI Even! Rate
`Veal Taki- N
`(it
`
`IDs
`
`3
`
`7/36
`
`16.3
`
`3.8
`
`
`
`msme
`1
`Age 76 yearsorolder. neared
`12/79
`13.2
`4.2
`
`2
`Age 48 yearsorolder. taking pred-
`32/199
`14.2
`3.9
`
`[15009. disease duration > 3.7
`years. disability inder > 1.7
`
`Age 48 10 63 years, previous
`NSAID side effects, d‘sability
`meet > 1.3
`
`4
`GI event group: 10 second events
`3.1
` oul of 98110290
`
`5
`Age 48 yearsorolder, taking pred-
`13/148
`8.1
`2.2
`
`nisone. disease duration > 3.7
`years, disability index 0.3 to
`1.7
`
`6
`7
`
`Age 6310 76 years, no predmsone
`Age < 47 years
`
`27/369
`3/342
`
`6.8
`0.9
`
`1.9
`0.3
`
`
`
`
`
`
`
`
`3
`Age 6710 63 years, nopred-
`3/340
`0.9
`name. new NSAID side ef-
`facts
`
`
`9
`
`10
`
`Age ~17 to 63 years, previous
`MAID side eflects, usability
`idex 51.3. no prednisone
`
`Age 47 years molder, [along pred-
`msone. onseaseduralion s 37
`years
`
`[/37
`
`[/24
`
`[/22
`
`0
`
`0
`
`0
`
`0.3
`
`0
`
`0
`
`
`
`
`
`
`
`0
`11
`Age 47 yearsorolder,1a|ungpred-
`n'sone. dim duration >37
`
`
`years, disability ”rider $0.3
`
`
`216
`
`September 1991 m American Jownel of Medicine
`
`Volume 91
`
`Page 4 of 10
`
`Patent Owner Ex. 2003
`
`DRL v. Horizon
`
`lPR2018-01341
`
`Patent Owner Ex. 2003
`DRL v. Horizon
`IPR2018-01341
`
`Page 4 of 10
`
`

`

`TABLE VI
`Descriptiostelectsd Vzrlahkthhh Singular: a free (rm 1r
`
`
`
`NSAID-ISSOCIATED “SWAT!" / FRIES ET AL
`
`Subgroup Number (GI Event Group)
`4
`5
`6
`7
`
`98
`
`65
`(1.1
`19
`(1.2
`1.7
`(0.1.
`32
`10
`(01‘
`52
`(1
`
`161
`
`396
`
`345
`
`53
`(0.6)
`19
`(0.9)
`1.2
`(0.03)
`14
`0.9
`(0.04)
`100
`28
`
`69
`(0.2)
`20
`(0.7)
`1.5
`(0.04)
`20
`0.9
`(003)
`0
`21
`
`39
`(0.3)
`12
`(0.4)
`1.1
`(0.04)
`24
`0.9
`(0.03)
`29
`15
`
`Number 01 natienls
`Variables
`Age (years)
`D'seasedural‘on (years)
`
`D'sabilityindexiO—B)
`Previous NSAD-related
`GI side effects (2)
`NSAID dose (seetert)
`
`All
`
`1,694
`
`59
`(0.3)
`17
`(0.3)
`1.4
`(0.02)
`20
`0.9
`(001)
`30
`20
`
`1
`
`91
`
`79
`(0.3)
`18
`(1.2)
`1.7
`(0.1)
`13
`0.8
`(0.1)
`0
`20
`
`2
`
`232
`
`65
`(0.6)
`21
`(0.7)
`2,3
`(0.02)
`20
`1.0
`(0 03)
`100
`35
`
`3
`
`43
`
`57
`(0.7)
`16
`(1.5)
`1.9
`(0.07)
`100
`1.0
`(0.1)
`0
`26
`
`
`
`
`
`
`
`Usedmdmsone
`Usedantzcidsor
`
`Hzraniagonsts ()2)
`40
`51
`43
`38
`41
`Timetsking NSNDS
`(2 1‘
`(3.3)
`(13)
`(2.2)
`(0 5)
`(months)
` Wilma: (run: 65),
`
`8
`
`343
`
`56
`(0.2)
`17
`(0.5)
`1.2
`(0.04)
`0
`1.0
`(0.03)
`0
`11
`
`9
`
`37
`
`57
`(0.6)
`15
`(0.1)
`0.7
`(0.1)
`100
`1.0
`(011
`0
`24
`
`m
`
`24
`
`66
`(1.8)
`2
`(0.2)
`1.5
`(0.2)
`5
`1.3
`(0.2)
`100
`21
`
`43
`(1.6)
`
`16
`45
`41
`38
`43
`
`(1.1)
`(1.1)
`(1.2)
`(32)
`(1.2)
`
`ranged from 1.2% per year with NSAID treatment
`in Santa Clara County patients to 1.6% in Saska-
`toon. Results at all centers were similar, without
`statistically significant differences.
`Table I also lists patients taking NSAIDs who
`were hospitalized more than once. One subject was
`hospitalized three times. After the first hospitaliza-
`tion, the 10 additional hospitalizations occurred in
`only 201 years of observation, for a rats of 5% for at
`least one more GI hospitalization per year during
`treatment with NSAIDs. This rate varied from 0%
`in Phoenix to 8.3% in Santa Clara County. This
`overall rate of rehospitalimtion is approximately
`four times the rate of first hospitalization.
`_
`There were 17 GI-related deaths occurring dur-
`ing these 9,525 years of observation. Thirteen of
`these deaths occurred in patients who were reliably
`known to be taking NSAIDs at the time of death;
`each of the others might have been. This gives an
`overall GI death rate of 0.18% per year and a GI
`death rate during known treatment with NSAIDs of
`0.19% per year.
`
`Risk Factor Analyses
`Table II lists continuous variables analyzed uni-
`variately for their association with serious GI events
`(hospitalization or death) for patients having taken
`NSAIDs at the predictive visit. The number ofsub-
`jects reflects the inclusion criteria previously de-
`scribed. The most significant differences were ob-
`tained for age. HAQ disability index, NSAID dose.
`and use of antacids or fig-antagonists. The differ-
`ence in HAQ disability scores of 0.31 is clinically
`significant. representing the equivalent of 4 years of
`disease progression in RA. NSAID dose was calcu-
`
`lated by setting a value of 1.00 for the manufactur-
`er’s highest recommended dose on the package in-
`sert and normalizing the dose 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 “disease-modify-
`ing antirheumatic drugs.” The variable “specialty
`care” refers to the proportion of all doctor visits
`that were made to rheumatologists.
`The second part of Table 11 presents univariate
`comparisons of potentially predictive categorical
`variables dichotomizsd as present or absent (pre-
`sented as percent positive). The statistically most
`significant differences were seen for having previ-
`ously reported GI symptoms attributed to use of an
`NSAID (nausea, heartburn, loss of appetite, vomit-
`ing. or upper abdominal pain), use of prednisone
`(average dosage 7 mg/day) in the previous 6
`months, and use of antacids or lib-antagonists with-
`in 9 months of the event. Female sex 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 10 statistically significant (p <0.05) differences
`remain significant after adjustment for the 20 mul-
`tiple comparisons of Table II.
`Odds ratios for selected variables with respect to
`GI events along with 95% confidence intervals are
`shown in Table III. For example. the odds ratio for
`females was obtained as follows: the proportion of
`females with GI events was 75 of 98 = 76.5%; thus,
`the odds are 76.5/(100 — 76.5) - 3.26. Similarly, the
`proportion of females without GI events was 1,224
`
`Santanber 1991 The Americm Journd of Hedlclns Volume 91
`
`217
`
`Page 5 of 10
`
`Patent Owner Ex. 2003
`
`DRL v. Horizon
`
`lPR2018-01341
`
`Patent Owner Ex. 2003
`DRL v. Horizon
`IPR2018-01341
`
`Page 5 of 10
`
`

`

`HMO-ASSOCIATED WAT," / FRIES El’ Al
`
`
` Flzura 1, Classitiration tree for GI
`
`
`hospitalization or death (GI event).
`The value within the circles and
`boxes :5 the percentage of patients
`with GI events per year during
`treatment with NSAIDs. Numbers
`below the boxes are subgroup iden-
`tification numbers of final sub-
`groups. NSAID dose - 1.0 corre-
`sponds to the manufacturer's high~
`est reccn'mended dose.
`
`of 1,596 = 76.7%; thus, the odds are 76.7/(100 -
`76.7) = 3.29. Therefore, the odds ratio for females
`with G1 events to females without GI events is
`326/329 - 1.0. For the values considered, age
`showed the highest odds ratio when dichotcmized
`at age 45 (only two events occurred below that age).
`Odds ratioe are significant at p <0.05 if 95% confi-
`dence limits do not include the value of 1.
`Table IV summarizes the results of stepwise logistic
`regressim analysis using most of the variables of Table
`H.1‘hreevafiableshadimpmvementpvaluesleasthan
`0.06: age, we of predn'none, and previous NSAJD GI
`sideeflectsNSAIDdoseand disabilityindexwerethe
`next two variables stepped into the model. The odds
`ratio is the estimated multiplicative effect of a 1-unit
`increaseinthatvariableontheoddsofhsvingaGI
`event, holding all other eovar‘nta constant
`Figure 1 summarizes the results of the classifies?
`tion tree analysis (recursive partitioning). Each node
`of the tree (represented by round and square boxes)
`contains the risk per year during NSAID treatment
`for patients in that node, in percent. With this meth-
`od. each node of the tree is recursively partitioned
`into two subgroups, one containing cases with vari—
`able values less than some cutoff point and the other
`containing cases with values greater than this cutoff.
`
`The “best" variable along with its splitting value
`(cutoff point) is selected with the use of a “goodness-
`of-split" criterion The program (CART) cross-vali-
`dates the results to present a stable tree structure
`[19]. The same variable may appear twice in succes-
`sion in the tree at different cutpoints; this occurred
`with both age and disability.
`The tree split first on age, yielding a very-low-risk
`group (0.3% events per year during NSAID thera-
`DY) below age 47. The tree split next on prednisone
`use, and then on age and disease duration. Disabili-
`ty index and previous NSAID GI side effects ap-
`peared at lower levels of the tree. The tree displayed
`in Figure 1 contains 10 classifying subgroups (rep-
`resented by square boxes). Eleven groups are num-
`bered and ranked in order of risk, from a high of
`4.2% per year while taking NSAIDs in individuals
`over the age of 75 and not taking prednisono at the
`predictive visit to near zero: for example, in the
`groups with young individuals and with individuals
`between 48 and 63 years of age not taking predni-
`sone at the predictive visit and without previously
`having had an NSAID GI side effect.
`Table V provides descriptive data for Figure 1.
`and Table VI describes the average values of the
`major risk variables in each group of Figure l; the
`
`218
`
`September 1991 the American Journal ct Medicine Volume 91
`
`Page 6 of 10
`
`Patent Owner Ex. 2003
`
`DRL v. Horizon
`
`lPR2018-01341
`
`Patent Owner Ex. 2003
`DRL v. Horizon
`IPR2018-01341
`
`Page 6 of 10
`
`

`

`very different patient characteristics are ap-
`parent.
`
`COMMENTS
`Results reported here confirm prospectively the
`high relative risk of hospitalization or death in RA
`patients taking NSAIDs. The rate of GI hospitaliza-
`tions per year in patients taking NSAIDs is 1.58%,
`compared with a hospitalization rate of 0.3% (nine
`of 2,784) in patients not treated with NSAle, for a
`hazard ratio of5.2. As previously reported [1], use of
`NSAle in RA does not appear to represent a sever-
`ity marker for RA. and mean HAQ disability scores.
`pain scores, age, disease duration, and use of pred-
`nisone 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 causal-
`ity to the use of NSAIDs, but this use does not
`appear likely to be a marker of disease severity.
`Our results were consistent across all five popula-
`tions studied. It appears likely from preliminary
`data that the rate of hospitalizations in patients
`with osteoarthritis may be half or less of that ob-
`served in patients with RA. Previous GI hospital-
`ization is identified as a major risk factor.
`We performed a preliminary evaluation of pa-
`tients with osteoarthritis. with a smaller number of
`years of observation available. Patients with osteo—
`arthritis were drawn from the Wichita population
`(690 patients, 893 years of observation) and from a
`national pool of osteoarthritis patients who had
`taken the Arthritis Self-Management Course
`[20,21] offered by the Arthritis Fondation (501 pa-
`tients, 251 patient-years of observation). Only three
`GI hospitalizations occurred in these patients with
`osteoarthritis. All of these cases were gastric in loca-
`tion and all were in patients taking NSAIDs. Thus,
`the rate of upper GI hospitalizations per year dur-
`ing NSAID treatment was 1.4% in RA and only 0.4%
`in osteoarthritis. There were no GI-related deaths
`during this period of observation. This suggests the
`possibility of a higher hospitalization rate for RA
`patients, but the numbers of patients with osteoar-
`thritis were too small to achieve statistical
`significance.
`Other studies have addressed the question of in-
`cidence of serious GI events, and generally yield
`estimates consistent with those here. Thus, Carson
`et al [22,23] found hospitalization rates of 0.5% per
`year for bleeding ulcer in NSAID users for all indi-
`cations, and FDA estimates of “serious” problems
`srefrom 2%to 4% perysar [24]. Other estimates are
`somewhat lower [25—27], but underascertainment
`appears to be present in some of these studies. Our
`
`NSIID-ISSOCIA‘IED GASTROPATHY / FRIES El II.
`
`data by study protocol do not allow for overascer-
`tainment. Indeed. even the data presented here are
`subject to some underascertainment, since if our
`patients did not report a hospitalization, we did not
`routinely seek discharge summaries, and addition-
`ally we failed to obtain discharge summaries about
`5% of the time. In general, the literature data are
`consistent with the highest incidences in RA pa-
`tients, who have the highest levels of NSAID intake,
`and lower incidences for more occasional NSAID
`users [1,12,22—27].
`Two recent major publications further reinforce
`the results reported here. In a nested case-control
`study of Tennessee Medicaid GI hospitalizations,
`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 15.8 per 1,000 patient-years as reported
`here. Dosage was found important, and no role for
`confounding by current smoking or current heavy
`alcohol use could be identified. 8011 et a! [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 have suggested that one half to
`two thirds of GI deaths in RA patients taking
`NSAle are “excess,” while the remainder repre-
`sent “background” events [6,7]. Thus, these data
`are similar to the 0.13% per year excess GI death
`rate previously estimated [1].
`The individual clinical variables appearing to be
`predictive of serious GI events included age, dis-
`ability. NSAID dose. previous GI hospitalization,
`prior GI complaints with NSAIDs, and use of pred-
`nisone, antacids, or Hg-antagonists. Inadequate
`data were available for analysis of prior sucralfate
`use. Female sex was not predictive, in contrast to
`the preponderance of female admissions reported
`in a series of GI hospitalizations [9]. These findings
`are not contradictory, since the prevalence of
`NSAID use is much higher in females than in males
`[13]. A variable termed “specialty care” was not
`predictive, suggesting that hospitalization and
`death rates are not related to the experience or ex-
`pertise of the particular provider.
`The stepwise logistic regression model identified
`five variables that appear predictive (improvement
`p value (0.20), and these are, in the main. intuitive.
`The univariate finding that prior use of GI protec-
`tive agents (antacids or Hz-antagonists) was a
`strong predictive factor (p <0.001) was somewhat
`surprising. Most NSAID GI ulcers are “silent” [3,8],
`but a substantial number of patients had prior
`
`Sewn-her 1991 The American Journal at Medicine Volume 91
`
`219
`
`Page 7 of 10
`
`Patent Owner Ex. 2003
`
`DRL v. Horizon
`
`lPR2018-01341
`
`Patent Owner Ex. 2003
`DRL v. Horizon
`IPR2018-01341
`
`Page 7 of 10
`
`

`

`RISK = (SCORE - 100) I40
`
`TOTAL SCORE
`
`E
`
`—n
`HISTORY OF PREVIOUS NSAID GI SIDE EFFECT E
`Figure 2. GI event score table for
`RA. Derived from logistic regres-
`X10:
`DISABILITY INDEX (0-3) OR (ARA CLASS - 1)
`sion results, a simplified scheme is
`X15:
`NSAID DOSE (traction oi maximum recommended)
`presented here:
`the sum 0! (l) pa-
`tient age X 2. (2) 50 po‘l'lts it there
`CURRENT PREDNISONE USE
`is a prior history at NSAID dyspep-
`sia. (3) 0 points tor American Rheu-
`matism Association (ARA)
`lunction—
`al class 1
`(normal). 10 tor class 2
`(adequate). 20 for class 3 (limited).
`or 30 tor class 4 (unable). (4) 15
`times the traction patient NSAID
`don/manufacturer's highest rec-
`ommended dose. and (5) 40 points
`tor current prednisone use. When
`100 is subtracted from this sum
`and the result divided by 40. the
`risk 01 GI hospitalization or death
`over the next 12 months,
`in per-
`cent. is obtained.
`
`MAID-ASSOCIATED GASTROPATHY / FRIES ET AL
`
`Gl-EVENT SCORE TABLE FOR RA
`
`(SI-EVENT RISK PER YEAR 0N NSAIDS IN RA
`
`symptomatology that might have led to the use of
`“protective” agents. These agents are not believed
`to be effective in prevention of NSAID ulcers
`[4,5,10,30—33], and this is supported by the experi-
`ence reported here. There are two possible mecha-
`nisms by which these agents might prove harmful in
`
`practice: first, by treating dyspeptic symptoms and
`removing premonitory warning signs, and second,
`by reassuring the physician that preventive mea-
`sures hnd been taken. However, “protective” agents
`are probably given to patients already considered to
`be at higher risk, thus expressing the higher risk
`
`SCORE
`
`140
`
`1 80
`
`220
`
`0 Actual Values
`0 Values from
`RISK: SCORE - 100
`40
`
`Figure 3. Risk for GI hospitalization
`or death per year during treatment
`with NSAIDs. Comparison of risk
`scores for individual patients (Fig-
`UN: 2) WIIh actual measured risk
`(GI events/years at risk) for pa-
`tients grouped by 20-unit score
`categories. demonstrating a strong
`correlation between results pre-
`dicted by the simplified scoring rule
`and actual experience.
`
`220
`
`September 1991 The America Journal of Medicine Volume 91
`
`Page 8 of 10
`
`Patent Owner Ex. 2003
`
`DRL v. Horizon
`
`lPR2018-01341
`
`Patent Owner Ex. 2003
`DRL v. Horizon
`IPR2018-01341
`
`Page 8 of 10
`
`

`

`NSMD-ASSOCIATED GASTROFATNY / FRIES ET AI.
`
`mended dose, and contributes relatively little for
`most patients Other factors are readily ascertained
`by history. 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 subtracting 100 from the score and dividing by
`40. Figure 3 displays the relationship between risk
`as estimated by the scoring rule and actual inci-
`dence of events per year during NSAID therapy in
`subjects grouped into 20-unit score categories. It is
`apparent that the scoring rule accurately models
`actual experience of events per year during NSAID
`therapy in these RA patients.
`These major risk factors are modifiable in part,
`since prednisone use and NSAID dose may be
`changed. It is likely, but not yet proven, that sub—
`stantial differences between NSAIDs, not analyzed
`here, may allow choice of less hazardous agents for
`some patients. Prophylaxis with exogenous prosta-
`glsndins greatly reduces the rate of endoscopic ul-
`cerations in similar patients, and current evidence
`suggests consideration of use of these agents in
`high-risk groups [l,8,l3,25,28,29]. Increased under-
`standing of the role of clinical and demographic
`factors in determining the risk of NSAID gastro-
`pathy will provide an important means to reduce
`the magnitude of this serious national problem.
`
`ACKNOWLEDGMENT
`We thank Nong Sm ror statistical suppon and Llsa (tenders: tor typing or the
`manuscript We also thank [‘n Fred Wolle, Dan Mitchell, John Sihley and
`Sanlord Roth for pernissron to study their ARAMIS populations.
`
`level of those patie