fIQO?!1"? 70/91 J8GO~t~0161
`'~;IF ,~nll: itlC'AN .I~l]li\'At.()I' ~i A.ti'f R(74!Y7'I!II()l.!)(; 1'
`CnVY~ight'-ti9 1991 by Am. Coll. of q.~s~rocntcrologY
`
`Veil. R6. No. F, 1991
`Prinicd in U.S~1.
`
`~~per C~a~~~°o~~~~~~i~aal .~,~~~~~s z~ Ia~~le~°~~ F~~~~~~~ti~ ~~~~~n~~~~
`
`a. V. iiella~•Y, M.I2.C.P., P. I~. "l`, Isaacs, A'I:[>., ~►ul ~'.1. I.ec, F'.R.C.3?., i+'.A.C.G.
`l~eparinae~rl ~J~C;crslr~<xrr~Ic~rologn, Victoria IFospila(, L3/rrch~~ool, I.arrcasl~ire, L7rg/<u~d
`
`'i'he occ~~rrencc of upper kasfroint44tina~l <1iy~a4e at~d
`tEye relev~l~ce ~f nfinsteroid.~l sinkiinfln~r~anatory drag
`(1~~~l.[I)) ~is<~gc were cloc~l~me~~Ced in 5l 1 consecutive
`.patients (321 women, 1J4 men) over 7Q yr Cold, referred
`(o, ul~per~ ~;<Gstrointesti~ta~l cndoscop)~ in a district genera?(
`hospital. T`lie finitinR were bet~igi~ ~sopliagc~~~tl di9e;ts~
`(q:~~%), normal (]5"l0), ~;1siT~ic ulcer (] 1.5%), ,tnd duc~-
`den.al ulcer ~1 1X70), fx7stric ulcers were mare common
`in ~i°omen taltin~; NSAIlls (2S'Io) tlia~i in iVSAfI) .~b-
`ist~ir~scs (7%) p < (1.01?1 xnd ix~~lc NSt1Ill users (5~~,)
`;~~ ~ O.Qf)I.. I;soph~rgitds .end esn7~fr<rgcal stt~ictxrr~ ~r~ere
`'not f~i#lueraced by NSrAID usug~, but ~;nstric e~rasi~~s
`rse7•o ~rnore cotnrnt>n (IQ°/q vs. 3%a) p ~ 0.01, Of ~(4M
`~tztients recci~~ing NSAID~, 4l zIo presc►ited with hear
`orrha~e, compered ~t~ith 20.5% of IV:SAII) .~bsTxineJ•s (p
`~ O.O01), F~emnrrhage ~v;is srs comitaoti in as~>iri~~ t:el<eNs
``(7.5 of 33, 45%) as ixz standx~•c1-di~se NANSAlf3 takers
`'~(43 of li}9, 39°In), ever th~u~l~ 86% 1~~cre takiirg 3Qb
`m~ oP .is,pirin pe~~_ (lay ter ,less. In cldarly p:i~icnts,
`~esopl~ageF~l dise;~so is coix~~tton. NSAID use, even ]prv-
`dose aspirin, is associated ~r~itir sat incx~cascd risk of
`iieYtio►~k9»~~, In f'e~nsiles, :NS~Ati) ~sa~c is ~ssnciatod
`~sitli ~;;~stric ulcer.
`
`INTRC~DCJCT'lON
`
`Up~~er gastroirttesfinal endoscopy is a safe <iud va~lu-
`~al~e rr~eth~d of evFiluatin~ up,~cr gast~•onitesCinal symE~-
`to~ns; in the vLderly, fhei~E is ti IiighcT~ difl~nc~stic yield
`than i,i1 younger E~atients (J, 2), An aissociatior7 bet~vee~l
`N;i/~ID risage and up~~er gastrointestinal. dise~~9e leas
`been reported, notably, in elderly f'em<ilc,s (3, 4.). A~/c
`1~1~~e attempted to ~~sse<,s these problems as seen in a
`dist~rir:C gastr'oi~~iestina( enc~oscopy service try ~a prospec-
`tive evaluation in coz~scctttive rcierred elderly patients.
`
`iv1E'i"HODS
`
`Palier~ts
`Blitckpool V_ictoi~ia F[osprtal is a ~~i5tricE general hos-
`pital scrviztb ~i ~~opulation of 320,000, o(~wlxom ap~arox~
`iniat~;ly 46,50 are more: tt~~~n 70 yr old (30,000 I~,
`
`Ru<~i~Prl,Tr[IY.~O, 19x0; revise~l~L9ar, ~C, 1J91; acctr/~ledrlpr. 22,
`~a~~.
`
`1 fi,St)0 M). All ~~ltients over 70 yr t>(' age r•efe~~i~e~i Eon•
`iiWper gastroi~testin~t( ctidoscopy over ail H-month
`pe~•iod wei~c essessect pz'os(~eeti~ely.
`
`1'roce~l~itrc:s
`l~etrtils of drugs t~iken withil~ the prcviorrs 3 ~i~outl7s
`were obkai7ied from Ilic; patiEnts and from hcrspita[
`recorr3s, acid ge~ieral practitiot~crs were c<~ntacted for
`details of prescik~ti.ons issued ire ibis period. Cn tl~c
`description q~f pt3tient's drug usage, patients t~ik:ing nox~-
`SCeroi~al ~tr~tiirrflainr7i~~tory drugs, including aspirin,
`wero e1l~ractez•ized as NSAID takers. ~'atiei~its taking
`aspirin and its deriv:~Yives ~vcre categoci7~d as ASA
`as~i•s, aric9 ~ationts taking nonsteroicial ~ntii~~l7~tmn1~~-
`tary clrt~gs, bui not ~aspicin ~a~ its deriv~rtives, were
`cat~egocire<i as NAN:SAID users.
`In ttssessm~:nt of peptic lesio~~s, g~st~ic ~nci duodenal
`ulcer we~'e diabn~>sed whu~7 tY7ei~ was a br•~ak in mucosnl
`continuity greater tk~an 3 mn~ iai di~cmeter, with ort~ter
`fori~~<iti~>n. Gastric erosions were ❑otrd whc~1 n~t~cosal
`conCir~riity was t~rokeu, but wittl no depth tc~ the intlam-
`ii~~to~y process. CasYzitis was ~~e~~'esented by rc:d~~ess,
`rntic~sal hyperiK~upt7y, ar7ci exudate. Duodtnitis ~vais not
`ine{uded iii tl~e encic7sco~aie assessment.
`Statistical analysis was perfr~rrncd by calculating x~'~;
`~~ < O.Q5 was coasiduG~ed si.~nificanL
`
`RE~SUI..; I'S
`
`During <t~i 8-rrtonfil~ pet•iod, 2190 g~stroscopies were:
`C~7et~Yormcd in Cl~~ U~~~~u•tmcnt. Q£ these, S89 exazziin~l-
`tio~ls ~i~ere e1r~'ied~oiit in 511 patients 7f) yr old ~ncl
`ever (321 F, f 9C) M); 29U (S7 %) were ii5~7ati~r~ts. I'a-
`tier~ls were referred by ~eticra) pkiysicians (S7%n), ~eri~t-
`t~~aitjns {22%), gezleral p.rtietitioners (5%), aud, ocher
`f~ospitat cansi~lCants (16%).
`Ti~iiicatioiis for referz•~il az~d NSAJI~usage itt tbcse
`paeiEnis are shown in 'Table I . NSAtlls h~td been pre-
`scrsb~:d foe ostcoarthritis (67°l0), ccretx•al transient is-
`cl~en~ic attacks (~'TA) (21 0), ~ia~isculotike:lefal paiif
`([0%), and rheumatoid arChrititi (2%), O[' I42 p~Itieilts
`on NSAiIJs, 58 (~l f %r) ~~>rusentecl cvitl~ upper gastK•oin-
`tcstinal~kzE:mot~rhage, cotlip~~red wiilz 76 (20.5°a) of the
`369 NS~II_~ absf.iJzze~~s (~~ ~~ 0.O01), OI~ the 14 c3ifTerent
`
`Page 1 of 4
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`Patent Owner Ex. 2015
`CFAD v. Pozen
`IPR2015-01718
`
`

`
`x162
`
`k1LL1.~ARY el r~l.
`
`NSAIDs pz~escz~ibed, ~tspix~in was the ci~ost corzirnox~
`(23%), Followed 17y ibuprofeiz (16%), indomcdlaci~~
`(l~l%), ttnd ~ir•oxican~ (1 U%). 'C'hcre wet~c ix~suE73cie~~t
`numbers taking many of the NSAIDs to permit any
`coriciusioiis to he clrakvn about the specific risk bk'
`}iemo~•rl~~~ge. '['lie dur~tio~~ of tce~ttmenl with NAN-
`SA~tT~s va~•ied fi~om~ 2 ~vk to t0 yz~, ~m ~veragc a~f 16
`months. Porty~tive patients ~~~erc on NANSAlE>s for
`more th~ul 1 year, and 26 we~•e taking them on an
`intermittent basis, The consumption of other suppos-
`edly gastra-toxic drubs (potassium, potassicixT~-coiit<iin-
`ing diuretics, oral corkicoste,roids,, thec~~hy~a~nes, di:
`goxiv, allopuxinol, and dnxycy~c(ine) wris canxparable
`ixi NSAID tf~kers (33%} and abst~tiilers (28%), As~ixin
`liad be~i~ prescribed For 33 }r<ttients (i+ga range, 70-9 i.
`yr) iti 30 of ~rhom tlac inclicatir~n was a Supposed 1't,A.
`7'he naeail dose w~1s 336 mg/day evith a ciucxtio~~ to the
`finxe ok'pz~csct9tation ~~xryirtg fi•~>r~1 2 ~vk to 3 yr. F~'iftecrr
`of 33 (45%p) of llYe ri5pirii~i t<ikcrs presented wii~h gas-
`t~•ointc~tinxl l~etnorrhrtge, cocri~~~u~ed with 43 ofth~ lf)~
`(391,} of ttae nonaspia•i~a, nonstcruidal, ~ntiin(larnma-
`torydrug {I~IANSAID) takers,
`Endosco~ic findings are shown in Table 2. In the S 11
`patients, besiigr~ esoE'~l~~age~~( diselse ~m.as mast ec~mu~on
`(43°l0), followed by i~~rmal endoseopy (15%), gastric
`ulcer (11,5%) and duodenal ulcer (11%); other diseases
`rvex'e ~<tstric e~trciiioXr~~i (6%), gastritis/ero5icans (5%),
`esophageal carci~~o~na (3%)gastric ~7o1~1>s (3%v), v~rices
`(1,5`/0}, and ~aetroduodenal arigiodvspiasia (1%u), 7'1~c
`~revalanc~ of gastric ulcer w~is iti.creased iri ~vou~eai who
`were taking N'SAIDs, com~>ared with those who were
`NSAID absCai~7ers (p t. Q.001}, ztnd in f'cnlal~ NSATb
`takers coz~~p~i•~d with male NSAII) t~akci~s (p E 0.001).
`The prevalence ~f gastric ulcer ii1 males did not appear
`to be it~t7u~nc~d ~,~ N~SAI[~ usage. 1'n l~oi:h sexes, tkie
`~7revatez~ce o,f g<~stric erosions was significanSly hi~iier
`in~NSAID takers (l0°lo compered with 3°~) (p ~ 0.O1)•
`There r~~as ~ tcr~deney+ far duodenal ulcaratioi~ to bc~
`coanrrot~er in NSATD tz~kers, althcangt~ this difference
`►•e~chcd statistical signific~x~ec Duly when figures for
`rna!e and f'crnale takes vrct~c coznE~iiicd (cO,02). 'Che
`prevalence of esoph~gitis anci stricture was not. i[iflu-
`exzceti ~y NS~7I~ ingest~un in eitlae~~ sex.
`
`r~oL S'i7, No. 8, t 9<J1
`'T'11e pi•evtticnce of g~sfi•ic ulcer was similar ire ~~sp~r~i~
`t~l[rers and NANSAID t~itcers (18% cf' 22%, respectivePy}
`(Table 3), In the I1~Srl~TD talcer~s ~rese~nCiug with hcm_
`ot~rltagc, the prevale~ic~ of gast~~ic t~lecr in females tivas
`24%, cormpared with 5% in tkie NSA'li~ ~ibstair7~:~~s (1~
`0,01), ~3lceding was Zs freq~ienk in ~spiri~~ takers (1 fi out
`of 33, 45%) rls irz ~IANS.~TD takers (43 of It)~), 3410),
`A hig(~ 4~roportion (8G%) of tl~e zispirin takccs were ors
`a law cios~ (300 ~~rgfd<~y or less}, wli~i•eas thasc in the
`NANSnTD group were taking tine aquiwileut of>~,2 ~
`of sispirin per city. In flte NSAill grota~~, there ~v~r~
`seven ~aCicnts (5 1~, 2 M) who had both gastric ~~i~~
`duade~~~l ulcers. Trvo of tl~cse k~aCients presented e~~itla
`~icute I~eznorrh~gt;, lint ~aonc of the NSAID abst<~i~iecs
`4aad both types of tilecr, At t~hc time of patient discl~<irge,
`frorii hospital, the overall morC~ill.ty 1'or those presei7ting
`wit} bask~•arnfie;;tiaial henaori~h~ige was 8%, and Pnr those
`F~~~csenting with bleeding peptic ulcer (Sa patients), inor_
`t~lity was 20`0 {7 F, 4 M}, Thcr~ was n~~ mortttlily due
`to g~i~trointesti~l~il deeding ti~om ca~ises other thou ~~~ep-
`tic tilccr, No miles w7dec~4venl suz~ge~~y, ~vhcreas six
`I~maics hack operations, three oi' whom died. HigEier
`moz~t~ifity (l4% vs 4%) was abscr•vett iii patients iii tltc
`ovtr~-ft0 age ~r~up; nip none of tlle~n were oper[tt~ions
`performed.
`
`llISCUSSION
`
`"['lris study showed a l~i~l1 prevalence (85%) of ab-
`noxmality in elderly patients x•e~e~•re~i fog• upper ~;<ist~~oin-
`testiu~l cndos~opy, a~~d these elderly patients snore
`Crec~uet~tly t~i7d serious disease. Endoseopy should he
`considered in ~riy p~itie~al having significant tiip~~e~~ ~~s-
`[rnintestin~tl symptoms, and ready access to endosco~y
`in this gro~rp should lie available (5, 6). In this sh.idY,
`elderly ~~rtients liavc shown a high prcvaleucc of esc~ph-
`ageatdisease (43 % oP cei`erz~ed patients, 24% of bleeding
`lesi~us). The lligl~ prcvalen,ce of~ esop}i~igeat disease i~r
`tk~e eldez~ly may be related to deteridx~ating motor fu~ic-
`tiorti (7). It was not. rented to NSACD usage. However,
`~~s obcerv~d previously (R), the situation with regard to
`gastric ulcer vas dif~T~crcY~t. Gastric uiccr }gas ~ high
`prevalel~ce (2(5% ~f bleeding lesions) a~ci is associated
`with NSAID usrig~, `Chore a~lsa was ~ s~igni~ic:rx~t tend-
`
`GI bleed
`L)yspcpsin
`Refiux
`Dysphugiti
`A~~emin
`
`"p G O.00I,
`
`Page 2 of 4
`
`'Cni+i.r
`L~rlicar(on.s /br G'I~P~'~• Gnstrornresrintr! (i~idasco~~v
`
`~
`'Total
`[n = 51 I (19f1 M)l
`
`Not ou NSATDs
`f)n TdS~TDs
`(n = 1a7. (3(i N1}] (n - 3fi9 (l54 fvl)]
`
`134 (<48 M}
`I S7 (57 N1)
`54 (22 M)
`7b (30 ~Yt}
`90 (33 M)
`
`58* 119 Nl)
`36 (9 Yt)
`21 (3 b4)
`9 (3 M)
`lR (2 1)
`
`~
`
`74" (29 Nl)
`l21 (4R JAI)
`33 (19 M)
`fi7 (27 M)
`72 (3~ A.4)
`
`Patent Owner Ex. 215
`CFAD v. Pozen
`IPR2015-01718
`
`

`
`,4rr~~rsl 19>I
`
`UGI I.,I SIONS 1t~~ CITI:i 1;i7.T1I Tt[.Y: R~I,E"VANC:'L3 CAF nl,~+Ali? U,f?
`
`9(i3
`
`'cnnt.r. 2
`l~rrtorco(~ir L.esia~s: aVSAlt) Takers rsAb.r«rlrrer,r
`
`W~~men
`
`Endosco}aic
`1^'ntdi ngs
`
`Nlen
`NSAID tibstuiners NSAID tnl<ers NSAID aibstain~rs NSAlD takers
`NS~\iC7 takers
`(n = Id2)
`(n = 215)
`(n = IOG)
`(u = ISA)
`(rt = 36)
`$4 (38%)
`!OS (~19%)
`;S9 (~?Y;)
`63 (41':x}
`IS (A2°l)
`Etioph~tgitiy/stricture
`14 (IU%n)
`7 (5~;)* 9 (8°i)* 5 (2%,)*
`S (14;'~a)'~
`f.~tisirilis/erosions
`30 (21 °/a)
`I S (7t%)~
`27 (?.5%)1'~
`13 (8~)
`3 (8°/r~)9~
`C~ustric ulcer
`2a (1'7%)Q
`19 (990)
`1 ~) (l8%)
`12 ($'%)
`5 (1 G7o)
`UuOdCni11 Ulcer•
`6 (~i%)
`37 (17%)
`2 (?°io)
`32 (21 ~~)
`4 (I 1 "/o)
`C)thcr diset~scs
`14 O0%,)
`34 (Ib°/n)
`10 (9io}
`27 (ISIo)
`4 (I t%)
`Nonnt~l
`* DiFlerencc in occurrence of g,istril~is/erosions in men and women NS.AID takers and tibstainers, p ~ tl.pl
`~' DifTerenc~ in occurrenrc of o~tstric ulcer between men end women NSAIL) hikers, p < 0.001.
`f Diil'creaoc in occurrence of g~~stric ulcer i~~ NSAID-ttiking a~~d -~bsuakiulg women, p < O.ODI .
`a J~ift~~~en~e in accurrcuee oFciuoclennl ulcer bcttivicen total NSAID tnkers Find abstainers, to <0,02.
`
`,I trial
`
`NS~UC) ;abctainrrs
`(n == 369)
`—._.
`1(K (49~I)
`f2 (346)
`28 (8%)
`11 (8%)~
`G9 l 19`.'/0)
`GI (1(i~%)
`
`Tne~.i ~
`Gn~lo.rcnpir, 1.,<~aion.c in Anlienls nor N.S'i(lD.e~ Aspiri~~ and NANS'flll)s C'ariprn'2d
`
`1>ndoscgpic
`
`1~'Atiunlx on NSAII.)s
`(n — (42)
`
`1'alicnts r>n Aspirin
`(t~ - 33)
`
`I'atienls u~i NANSAIDs
`(n = 1D9)
`
`GII~*
`
`Toll
`CtllI* TOtill
`~(~ (37%)
`G
`14 (q2%a)
`16
`I1 ~Ip`~)
`3
`:3 {9~,)
`$
`2~4 (22%)
`3
`6 (lR~i"~,)
`l5
`19 (17%)
`2
`S (15%)
`12
`3(J~7)~
`2
`3(<)%){
`2
`6 2 (G%) 12 (I t%)
`
`CR~I*
`ID
`S
`l7_
`10
`
`G
`
`'1'olai
`54 (3$%)
`]?soplt8~itis/SifiClu[G
`1~4 (104u)
`Brnsinits/gnsU~itis
`30 (Z] ru)
`Oastric ulcer
`24 (170
`lluod~nf~l ulcer
`G(d"1o)
`Olhctrs
`Normal IA (10`;6)
`'" I'irscnting with gestionttestinnl her»orrhngc (Cilti).
`t fVl three were ulezrated antral pniyr>s.
`Onn gasu•ie caireinoma, rnic csnphageai c.ircinoina, vna polyp, '('here were. three patienix, e.iciz witty <t single esopha~scal ulcer, ~vhy tivere on
`aspirin. These lesions wart not seen on Ni1NSA1D takers.
`er~ey fox these gastric ulecrs Co be in fem~iles, as was
`observed also in Nottingham (8, 9) but not in the
`1Jiutcci BCafea (10), 2~~ additio~~, when the numbex•s for
`'males anti t~eNnales ~vuz•e eambirzed, clu~den<ii ulce~•ation
`was eo~v.~noncr in patients taking NSAIDs. This wF~s
`true ~~~so in one othea; study (1 1},
`It has been noted in other studies that NSAIns
`increase the risk of peptic ulce~•atio77 by a factor of
`approximately 4, 'bleedittg by ~t factor of approximately
`2,5, acid deatia by approximately 7.6 (3}. This inere~ised
`incicfenec is of particulHr relevance in ~Iderly patients
`((2), Other studies 'have shown that elderly pakients
`~yi~i~; of ~~aptie ulcer are Chroe tines snore likely ths~n
`coi~tG•ols to leave beEn taking N5AI1:)s (13), and 6U°la of
`p~~ti~;~~ts dying of peK~tic Meer at any ale would }~.ave
`l~ce~7 a~ NSAZlls (14).
`}despite the widely held belief ttz~t low-dose aspir~xi
`is enfc, in this study Che risk c?f ~e~~tic ulcer appesns ~a
`~re~tt f~>r those air lo~v-dose aspirin as for NflNSA7i7
`takers. Acute $astzointestina) hcmorril~i~e was tx coi77-
`morl feature of aspiri►~ take~~s, corr7p~red with absfaincxs
`(42°b vs 151). Low-doscas~ii•in is gastratoxic (1S) nncl
`'can produce more mucosal b1eedin~; than warf'ar.in (16).
`Thy LJ1C TIA study group (l7) C~~u~~cl high-<lase aspirin
`
`iT~orc gastra-toxic tkaan 30U ix~g/day, aild irx other sim-
`iLaraspirin Criais (18, 19), the side efEccts vary From 9%n
`to l~%, Law-ctc~se aspirin has been a m~ich-proposed
`therapy €or vascular' disease, but most studies relate io
`younger patiaxits, ar~d iu thy; elderly this indication has
`not been valiciatecl, In addition, many of our pati~iits
`had a diagnosis of TIA wliicfs was poorly subst<intiaCed,
`e,g~,, a single c~frzy spell, or they v~~ere self-medicating,
`believing that as~iz•in ~~+quid ~~revent vascular disease,
`The increased risk o1' blecditig su~;~ests that moc'e cau-
`tion is n~edecl in pr~esci•ibing. vastric iiloei~atinn iii
`elderly patients is rnorc likely to be parr less (20) and,
`therefore, snore )ikcly to pz'eser~t with an unex~ccted
`complication. Iia another study {2l), the frequency of
`gastric and ~luoder~al lesions ita patie~ai's «n chronic
`~s~zzin ~~tad NANSATll therapy wlio lead no uppe~~
`gastrointestinal sy~~lpton~s was 76% and 27%, rest~ec-
`tively. T or eldea•ly patie~xis needing an a~i~ilgesic, p~ira-
`cetarnot array be safer (9), (nit when the antiinfl~tmma-
`tory EFf~ct of au i'VSAIL7 is rcc~uired, Yliere is iao agr~e-
`ment over whether Borne agents are less gastro-toxic
`than others f'or equivalent antiinflammato~y effect. (22).
`In cldecly pata~Ylts in.capacitatcd by muscril~skElctal
`~liseasc,~ NSAID usage is invahiGible f<>r relieving pazn
`
`Page 3 of 4
`
`Patent Owner Ex. 2015
`CFAD v. Pozen
`IPR2015-1718
`
`

`
`X164
`
`~ I3EL,LARY cat ~rl.
`
`and i;~a~roving ~T~obility. It is probat~le tf~at oi7ly by
`~~r~esceiE~itt~ NSA.1Ds less ofter7 wi11 tlae cotzside~•ablc
`arltitir~l death rate ~ot~ NSAID-attcit~~itable ulcers tie t•e~
`duced New sipper gastrointestinal symptoitl, i1t elclei•ly
`pu~tients merit early endosco~~y,~ as they. ~'eflect a high
`incicic~~c~e of p~ithology, much of ~wl~ic]Z, ~7Gu-~iciilRrly
`~sophagitis, can be ~f#cetively tre~ited. If they are on
`~a~pirin, ~rre9~eative a~ dfls~, or NANS~IDs, tR~ivi~tl
`sy~r~~~ptorris sll~uld be i~~vesligated.
`
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`
`Page 4 of 4
`
`Patent Owner Ex. 2015
`CFAD v. Pozen
`IPR201 5-01 71 8