TIIE AMERICAN JOLRNAL or GASTROENTEROLooY
`Copyright (0 l‘)‘)8 by Am. Coll. of Gastroenterology
`Published by Elsevier Science Inc.
`
`Vol. 93, No. 11, 1998
`ISSN anemone/98319.00
`r11 50002-9270(98)004o9-9
`
`A Guideline for the Treatment and Prevention of
`
`NSAID-Induced Ulcers
`
`Frank L. Lanza, M.D., F.A.C.G.
`Baylor College ofMedicine, Houston, Texas
`
`and the Members of the Ad Hoc Committee on Practice Parameters of the American College of Gastroenterology”
`
`PREAMBLE
`
`INTRODUCTION
`
`Guidelines for clinical practice are intended to indicate pre-
`ferred approaches to medical problems as established by sci-
`entifically valid research. Double-blind, placebo-controlled
`studies are preferable, but compassionate use reports and ex-
`pert review articles are used in a thorough review of the
`literature conducted through Medline with the National Library
`of Medicine. When only data, that will not withstand objective
`scrutiny are available, a recommendation is identified as a
`consensus of experts. Guidelines are applicable to all physi-
`cians who address the subject Without regard to specialty train-
`ing or interests and are intended to indicate the preferable, but
`not necessarily the only, acceptable approach to a specific
`problem. Guidelines are intended to be flexible and must be
`distinguished from standards of care, which are inflexible and
`rarely violated. Given the wide range of specifics in any health
`care problem, the physician must always choose the course best
`suited to the individual patient and the variables in existence at
`the moment of decision.
`
`Guidelines are developed under the auspices of the Ameri—
`can College of Gastroenterology and its Practice Parameters
`Committee and approved by the Board of Trustees. Each has
`been intensely reviewed and revised by the Committee, other
`experts in the field, physicians who will use them, and spe-
`cialists in the science of decision analysis. The recommenda-
`tions of each guideline are therefore considered valid at the
`time of their production based on the data available. New
`developments in medical research and practice pertinent to
`each guideline will be reviewed at a time established and
`indicated at publication to assure continued validity.
`
`* J. Patrick W'aring, NH), Atlanta, GA; James J_. Alchord, M.D.,
`Jackson, MS; Todd H. Baron, M.D., Birmingham, AL; Eugene M. Bozym—
`ski, M.D., Chapel Hill, NC; Patrick G. Brady, M.D., Tampa, FL; W. Scott
`Brooks. Jr., M.D., Atlanta, GA; William D. Carey, M.D., Cleveland. OH:
`Kenneth R. DeVault, M.D., Jacksonville, FL: Norman D. Grace, M.D.,
`Boston, MA: John 1. Hughes, M.D., Ilouston, TX; Simon K. Lo, M.D.,
`Torrance, CA; Jack A. DiPalma, M.D., Schenectady, NY; George W.
`Meyer, M.D., Atlanta, GA; Jolm F. Reinus, M.D., Bronx, NY; Marvin M.
`Schuster, M.D., Baltimore, MD; Douglas M. Simon, M.D., New Rochelle.
`NY; Robert H. Squires, Jr., M.D., Dallas, TX; Rosalind U. Van Stolk.
`M.D., Cleveland, OH; John Wo, M.D., Atlanta, GA; and Gregory Zuccaro.
`J11, M.D., Cleveland, OH.
`Received June 24, 1998; accepted Aug. 12, 1998.
`
`The relationship between nonsteroidal anti-inflammatory
`drugs (NSAle) and gastroduodenal
`injury is now well
`established (l, 2). Patients with rheumatoid arthritis (RA)
`and osteoarthritis (OA) taking NSAle have an ulcer inci—
`dence of approximately 15—20% (3, 4). Complications of
`ulcer disease,
`i.e., hemorrhage and perforation, occur far
`more often in patients taking these agents than in compa-
`rable control groups (577). The overall risk for serious
`adverse gastrointestinal
`(GI) events in patients taking
`NSAJDs is about three times greater than that of controls. In
`elderly patients (>60 yr), this risk rises to more than five
`times that of controls, whereas the risk for younger patients
`is only slightly more than one—and—one—half times (6)111
`elderly patients taking NSAJDs the relative risk of GI sur-
`gery is ten times, and for GI cause of death, about four-
`and-one-half times greater than in control groups (6). Ap-
`proximately 20 million patients in the US take NSAIDs on
`a regular basis; the risk for hospitalization for serious Gl
`adverse effects is l—2%, resulting in approximately 200,000
`to 400,000 hospitalizations per year at an average cost of
`$4,000 per patient, or 0.8—1.6 billion dollars annually (8, 9).
`The economic impact of this problem is increased by mul—
`tiple other factors, including lost wages, postop care, etc.
`Two major issues confront clinicians using these agents:
`1) the prevention of NSAlD-induced ulcers, especially in
`high risk groups, and 2) their treatment, often when under—
`lying disease mandates continued NSAID use. A third prob—
`lem is the recent recognition of small bowel and colon
`NSAlD-related mucosa] injury. The purpose of this guide-
`line is to make recommendations based on the pertinent
`medical literature addressing these problems.
`
`PREVENTION OF NSAlD-INDUCED ULCERS
`
`Recommendation
`
`Patients at high risk for hemorrhage and perforation
`from aspirin and other NSAID-induceo’ ulcers should be
`consideredfor prophylaxis with misoprostol. Proton pump
`inhibitors are an acceptable alternative for prevention of
`NSAID—related complications. H2 receptor antagonists
`have been shown to prevent only duodenal ulcer, and there-
`
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`203 8
`
`LANZA et al.
`
`4.4
`12.7
`
`TABLE 1
`Factors Related to Increased Rislr ofNSAID Induced GI Complications
`95% CIRelative RiskRisk Factor Ref #
`
`
`
`2.74
`25472.97
`Overall
`6
`Age (>60)
`5.52
`4.63460
`6
`Prior GI event
`4.76
`4.057559
`6
`High dosage (>2 X
`10.1
`467220
`43
`normal)
`Concurrent corticosteroids
`Concurrent anticoagulants
`
`2079.7
`637257
`
`44
`45
`
`fore cannot be recommended for prophylaxis. Factors that
`have been identified as placingpatients at increased riskfor
`NSAID—relaled GI complications include the following:
`
`1. Prior history ofgastrointestinal event (ulcer, hem—
`orrhage)
`
`2. Age >60 yr
`
`3. High dosage
`
`4. Concurrent use of corticosteroids
`
`5. Concurrent use of anticoagulants
`
`Although a direct link has not been established between
`NSAID-induced ulcers and gastrointestinal hemorrhage and
`perforation,
`these complications occur significantly more
`often in patients taking NSAIDs when compared with con—
`trol groups. As noted above, these serious adverse events
`also tend to occur more often in high risk groups which
`include patients with a prior history of a GI event, advanced
`age (>60 yr), high NSAID dosage, and concomitant use of
`corticosteroids or anticoagulants (Table 1). Several random—
`ized controlled trials (RCTs) have been published attempt-
`ing to show that various therapeutic maneuvers can prevent
`the development of gastric ulcer (GU) and duodenal ulcer
`(DU) in patients taking NSAIDs. However, only one study
`has been published linking any cotherapy with prevention of
`the complications of ulcer disease, i.e., bleeding and perfo-
`ration (10). It is not unreasonable, however, to assume that
`prevention of NSAID—induced ulcer should be associated
`with a similar prevention of the complications of ulcer
`disease.
`Numerous RCTs have been carried out, both in normal
`volunteers and in patients with altln'itic disorders, to eval—
`uate the efficacy of coadministration of various agents for
`the prevention ofhoth NSAID-related, nonulcer gastropathy
`and GU and DU (1 1—28). Generally, these have shown that
`concomitant administration of the prostaglandin E1 analog
`misoprostol along with various NSAIDs can prevent both
`GU and DU ( 1 1—23); that the proton pump inhibitor (PPI)
`(24 —26) omeprazole reduces GU and prevents DU; and that
`H2 receptor antagonists are effective in preventing DU but
`not GU (27, 28).
`Prophylaxis with prostaglandins or PPIs for all patients
`taking NSAIDs is unnecessary and cost—prohibitive. Studies
`
`AJG — Vol. 93, No. II, 1998
`
`with misoprostol have shown that in high risk groups, pro—
`phylaxis may be cost-effective (7). The numerous factors
`involved in these analyses,
`i.e., the time lost from work,
`expense of hospitalization with or without surgery, varying
`costs of prophylactic and therapeutic drugs, and quality of
`life issues make it very difficult to determine the cost
`effectiveness of prophylactic therapy for NSAID-related
`ulcer disease and its complications.
`
`Risk Factors
`
`All patients taking NSAIDs do not require prophylaxis.
`These drugs are used extensively as treatment for limited
`illnesses. Anti—inflammatory doses of numerous NSAIDs
`have been administered for short periods of time (up to 7
`days) to large numbers of young, healthy volunteers without
`any reports of significant GI bleeding or other serious event
`(29). Many patients of all ages, however, take anti-inflam-
`matory NSAID doses for longer periods, and many case—
`eontrol studies have shown that, in these patients, significant
`GI bleeding and other severe adverse events occur more
`commonly than in matched control patients (30—37). An
`increased risk of GI bleeding has even been noted in patients
`taking low dose aspirin therapy for cardiovascular proph 7—
`laxis (38—41). Obviously, as all patients taking NSAIDs do
`not develop serious complications, risk factors must exist in
`some patients that increase the incidence of GI bleeding,
`perforation, stu‘gery, and even death.
`A series of nested case—controlled studies based on hos—
`
`pitalization for GI hemorrhage of Medicaid recipients aged
`>65 yr in the state of Tennessee showed an increased
`bleeding risk for patients >65 yr (odds ratio 4.7), increased
`dose (odds ratio 8.0), concomitant corticosteroid (odds ratio
`4.4), or anticoagulant therapy (odds ratio l2.7), and short
`term onset of use (<1 month) (7.2) (42—45). A large au-
`topsy series on patients with a history of NSAID use showed
`that gastric and duodenal lesions were more common in
`patients who took NSAIDs for <3 months, whereas patients
`with a longer duration of therapy tended to have more
`lesions in the small bowel and colon (46).
`A large retrospective cohon study, also based on data
`from Medicaid patients, confirmed the overall increased risk
`for GI bleeding in patients taking NSAIDs, especially over
`the aged >60 yr (47). Similar data have been obtained from
`other large cohort studies (40, 48, 49). In a large prospec-
`tive, multicenter study in patients with RA (N = 2747) and
`CA (N : 1091), the principal risk factors for hospitalization
`for serious GI events were age, prior NSAID GI side effect,
`prior Gl hospitalization, corticosteroid use, and debility
`expressed as a level of disability. The overall risk in this
`study for hospitalization during NSAID therapy in patients
`with RA was 1.58% (5).
`A large meta-analysis of these and other studies showed
`an overall odds ratio for GI bleeding of 2.74 in all patients
`taking NSAIDs. Patients with a prior gastrointestinal event
`had an odds ratio of 4.76. Age ( >60 yr), concurrent corti—
`costeroids, and shorter duration (>3 months) of NSAID
`
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`AJG — November 1998
`
`NSAID-INDUCED ULCER TREATMENT AND PREVENTION
`
`2039
`
`16
`
`17
`19
`
`323
`
`465
`
`25
`
`47
`
`7.7
`
`10.3
`
`TABLE 2
`NSAID Protection Studies Wit/7 Afimprosm/fnr Gastric Ulcer
`
`Misoprostol
`Placebo
`Ref.
`
`Dose
`N
`Ulcers
`“/6
`N
`Ulcers
`%
`p
`100 pg q.i.d.
`143
`8
`5.6
`138
`30
`21.7
`0.001
`200 pg girl.
`139
`2
`1.9
`0.001
`200 pg girl.
`320
`6
`1.9
`0.001
`200 pg hid.
`465
`27
`5.8
`0.05
`200 pg Lid.
`474
`15
`3.2
`0.01
`200 pg girl.
`229
`7
`3.1
`0.01
`21
`200 pg Lid. or q.i.d.
`2
`4
`12.5
`38
`11
`28.9
`0.05
`
`Sucralfate 1 qm girl.
`18
`200 pg girl.
`122
`2
`1.6
`131
`21
`16.0
`0.001
`
`Ranitidine 150 mg t.i.cl.
`22 0.01 200 pg q.i.cI. 180 1 0.5 194 11 5.7
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`consumption were all associated with an increased relative
`risk ratio for serious adverse GI events (Table 1). Gender,
`smoking, and alcohol were not found to be independent risk
`factors (6).
`A large, double blind, randomized, controlled treatment
`prevention trial in >8000 patients with RA also identified a
`history of cardiovascular disease as a risk factor for UGI
`complications ofNSAID use (odds ratio 1.84). In this same
`trial, age >75 yr (odds ratio 2.48), prior peptic ulcer (odds
`ratio 2.29), and prior GI bleeding (odds ratio 2.56) were
`again associated with increased risk (10).
`There appears to be some difference between the various
`NSAIDs with reference to the incidence of significant GI
`bleeding and other adverse events. Four large cohort studies
`have been published comparing the risk of these complica—
`tions associated with the various NSAIDs. Overall, these
`studies show an increased toxicity for ketorolac and piroxi-
`cam, and intermediate toxicity for naproxen, indomefliacin,
`ketoprofen, and diclofenac. Ibuprofen in all studies was less
`toxic than the other agents, but this is probably related to the
`generally lower doses employed with this agent, which is
`available over the counter (50—54).
`No good prospective controlled data for GI bleeding and
`other ulcer complications is available for the recently intro—
`duced, newer NSAle purported to be less toxic to the
`upper GI mucosa (nabumetone, etodolac, oxaproxin). Sev-
`eral large postmarketing, open label studies involving thou-
`sands of patients in Europe suggest that bleeding rates with
`these agents are in the range of 0.5% (55759). These studies
`have recently been reviewed in the American literature (60).
`Of these agents, nabumetone has been the most extensively
`studied. A 12-wk endoscopic study compared nabumetone
`(1000 mg q.d.), ibuprofen (600 mg q.i.cl), and the same dose
`of ibuprofen plus misoprostol
`in 171 patients with OA.
`There was no difference in the number of ulcers found in the
`
`nabumetone and nabumetone/misoprostol groups (one and
`zero, respectively), which were significantly less (p < 0.01)
`than the eight ulcers found in the ibuprofen group (61).
`Another endoscopic study compared nabumetone 1000 mg
`
`(1.11. with naproxen 500 mg bid. in RA patients for 4 wk.
`One ulcer was found in the 22 patients taking nabumetone
`and eight in the 30 patients treated with naproxen (p = 0.01)
`(62). In a third study, 27 patients with either RA or ()A were
`followed for 5 yr taking either naproxen 250 mg bid. or
`nabumetone 1000 mg q.a’. Ulcers were found in eight of 12
`patients taking naproxen and in one of 15 taking nabum-
`etone (p = 0.02). No bleeding was found in either group
`(63).
`The combination of advanced age with any of the other
`noted risk factors has also been noted to further increase the
`
`probability of ulcer complications in NSAID users, espe-
`cially in the first month of therapy. The relative risk of
`requiring GI surgery or GI cause of death increases dramat-
`ically in patients >60 yr (6). Although a 15725% incidence
`of gastric and/or duodenal ulcer has been demonstrated in all
`patients taking NSAIDs (3, 4), the bleeding rate is estimated
`by most experts at only 2—4%. In a meta-analysis of 100
`trials of NSAID therapy, bleeding occurred in 24 of 1157
`patients taking active drug (2%), compared with only eight
`of 1103 taking placebo (0.6%) (64). It can be derived from
`these data that about only one in 10 NSAID-induced ulcer
`bleeds. A recent large, multicenter, double-blind RCT in
`>800 arthritic patients taking NSAIDs showed that the
`incidence of perforation, outlet obstruction, and hemorrhage
`was reduced by 40% in those subjects taking misoprostol
`compared with placebo. In this study, these complications
`were seen in 22 of 4404 patients on misoprostol compared
`with 42 of 4439 taking placebo (p : 0.049) (10).
`
`Prostaglandins
`C Lnrently, the only available prostaglandin is misopros-
`tol, a synthetic prostaglandin E1 analog. A series of RCTs in
`normal volunteers have shown that this agent can prevent
`acute NSAID-related erosion and ulceration (1 1—15). Sub-
`sequent RCTs in patients with GA and RA have demon-
`strated that misoprostol was significantly better than pla—
`cebo,
`sucralfate, and ranitidine for
`the prevention of
`NSAID—related GU (Table 2). Misoprostol was also signif—
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`2040
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`LANZA et a].
`
`AJG — Vol. 93, No. II, 1998
`
`TABLE 3
`NSAID Protection Studies Witli il/[iroprortol for Duodenal Ulcer
`
`Misoprostol
`Placebo
`Ref
`
`Dose
`N
`Ulcers
`"/0
`N
`Ulcers
`%
`p
`200 ptg q.i.d.
`320
`2
`0.6
`323
`15
`4.6
`0.002
`200 Mg bid.
`465
`10
`2.2
`0.05
`200 [.Lg t.i.d.
`474
`12
`2.5
`0.05
`200 ptg gin].
`229
`2
`0.9
`0.01
`
`Ranitidjne 150 mg [Lip].
`2
`1.1
`
`26
`
`5.7
`
`465
`
`185
`
`NS
`
`17
`19
`
`22
`
`200 Mg girl.
`
`181
`
`2
`
`1.1
`
`TABLE 4
`NSAID Protection Studies With Oineprozole
`
`24
`
`O 20 4.11.
`Placebo
`
`
`Ulcers (%)
`Rel:
`Regimen
`
`GU
`DU
`p*
`2/85 (2.4)
`2/85 (2.4)
`>0.005 vs placebo
`6/90 (6.6)
`15/90 (16.7)
`GU
`DU
`35/274 (12.0)
`7/274 (3)
`31/296 (9.5)
`30/296 (10)
`50/155 (30.3)
`19/155 (12)
`11/210 (52)
`1/210 (05)
`35/215 (16.3)
`7/215 (4.2)
`
`25
`
`O 20 (1.1!.
`M 200 bid.
`Placebo
`O 20 qr].
`R 150 bid.
`* All ulcers combined (G1: and D1.)
`0 : omeprazole (in mg); M : misoprostol (in jig); R : ranitidine (in mg).
`
`26
`
`O .001 vs M and placebo
`
`0.004 vs R
`2/215 (0.9)
`
`icantly better than placebo for the prevention of duodenal
`ulcer. Ranitidine and mi soprostol were equally effective in
`preventing DU (Table 3). Lower doses of misoprostol were
`also effective in preventing GU and DU with a side effect
`profile indistinguishable from that of placebo (16719, 21,
`22). I11 another double blind RCT, two groups of arthritic
`patients requiring chronic NSAID therapy with either endo-
`scopically normal (N = 223) or nonulcer-injured gastrodu-
`odenal mucosa (N = 778) were treated with NSAIDs for 2
`wk with concurrently administered misoprostol (4007800
`jug/day) or placebo. The incidence of severe mucosal dain—
`age, including ulcer, was significantly reduced by misopros-
`tol in the previously endoscopically normal subjects and
`also in the group with preexisting nonulcer damage (p <
`0.001) (20). A recent large meta—analysis of RCTs of pre—
`vention of NSAID-induced gastric mucosal injury by miso-
`prostol or H2 receptor antagonists, published between 1970
`and 1994, showed that misoprostol (but not H2 receptor
`antagonists) was beneficial in the prevention of NSAID—
`induced GUS. It was also found that the number of patients
`to be treated to prevent one GU with short and long term
`NSAID therapy is 11 and 15, respectively (23).
`
`Proton pump inhibitors
`Omeprazole,
`the most extensively studied PPI, has a
`protective effect against N SAID-related mucosal injury. Not
`unexpectedly, because of its potent acid—inhibiting propelty,
`it prevents DU in patients taking NSAIDs. There is evidence
`that omeprazole also protects against GU. In a crossover,
`
`double—blind RCT, 20 normal volunteers were given aspirin
`650 mg q.i.d, with either placebo or omeprazole 40 mg/day
`for 14 days, with endoscopy before and after each treatment
`period. Omeprazole significantly decreased aspirin-induced
`gastric mucosal injury (1) < 0.01) by protecting 85% of the
`subjects from extensive erosions or ulcer, whereas 70% of
`the subjects developed severe injury (rate 3 or 4 on 0—4
`scale) on aspirin and placebo. No duodenal injury was seen
`in any grade or any subject on omeprazole, whereas 50% on
`placebo developed erosions and 15% had DU (p < 0.001)
`(65).
`Three large RCTs have been carried out in patients with
`OA and RA comparing omeprazole with placebo, misopros-
`tol, and ranitidine for the prevention of GU and DU (Table
`4) (24—26). Overall, omeprazole significantly reduced the
`total number of NSAID-related ulcers when compared with
`placebo and ranitidine (26). It was more effective than
`misoprostol in preventing DU, and equally so in reducing
`GU (25). It should be noted that the lowest effective dose of
`misoprostol was used in this study, and that most of the
`overall prevention in NSAID-related ulcer in the placebo-
`controlled studies was due to a reduction in the numbers of
`duodenal ulcers.
`
`H2 receptor antagonists
`Although commonly coadministered with N SAle, H2
`receptor antagonists (HZRAs) have not been shown to pre—
`vent gastric ulcer, the most common NSAID—related lesion,
`but do prevent DU. Ranitidine has been the most extensively
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`AJG — November 1998
`
`N SAID-1N DU CED ULCER TREATMENT AND PREVENTION
`
`2041
`
`studied HZRA. In two large, multicenter RCTs, ranitidine
`(150 mg, bid.) or matching placebo was given to patients
`with CA and RA in conjunction with various N SAle. In
`both studies there was no difference in the occurrence of
`
`gastric ulcer between the two groups; however. the inci—
`dence of duodenal ulcer was significantly reduced in both
`studies in the ranitidine group (27, 28). Nizatidine (150 mg
`b. id), in an RCT of 496 patients W’lfl’l 0A, did not lower the
`overall incidence of NSAID—related ulcers. However, a sep—
`arate analysis of high risk groups (patients with ulcer hist01y
`and patients >65 yr of age) showed statistically less GU and
`DU in patients receiving nizatidine (p = 0.035 and p =
`0.042, respectively) (66). In a nonplacebo—controlled RCT
`of 221 arthritic patients with recently healed NSAID—related
`ulcers, cumulative relapse rates for nizatidine 150 mg HS
`and 150 mg bid. were 5.5% and 1.8%, respectively (67). A
`double-blind RCT of famotidine for the prevention of gas-
`tric and duodenal ulcers caused by NSAIDs was performed
`in arthritic patients receiving placebo, famotidine 20 mg
`bid, and famotidine 40 mg bid, concurrently with the
`usual N SAID. The cumulative incidence of GU was 20% in
`
`the placebo group (n = 93), 13% in the patients receiving
`famotidine 20 mg bid, (NS), and 8% in the group receiv—
`ing famotidine 40 mg bid, (p = 0.03 vs placebo) (68). This
`study, however, has been criticized because of the small
`minimum ulcer size of 0.3 cm. In a similar study from the
`same group of investigators, patients with RA or DA with
`GU or DU were treated with famotidine 40 mg bid. The
`subjects with healed ulcers were then randomized to 6
`months of therapy with famotidine 40 mg bid. or placebo.
`Ulcer recurrence was seen in 26% of the subjects on famo-
`tidine, compared with 54% with placebo (p : 0.01). Despite
`the superiority over placebo, the recurTence rate of ulcer in
`patients on famotidine was unacceptably high (69). High
`dose ranitidine (300 mg bid.) was found to be ineffective
`for the prevention of gastric ulcers, but was protective
`against duodenal ulcer. Patients with rheumatoid arthritis
`and a past history of peptic ulcer disease were followed for
`1 yr on NSAIDs with either high dose (300 mg bid.)
`ranitidine (n = 10) or placebo (11 = 10). Four patients in the
`placebo group had recurrent DU and none in the ranitidine
`group (p = 0.04). Six recurrent GUs were found in the
`placebo group and three in the ranitidine group (p = 0.18)
`(70). Recurrence of DU in patients taking N SAle is more
`likely when there is a past history of that disease.
`
`Other agents
`Sucralfate has not been shown to be effective in prevent-
`ing NSAID-related ulcers (13, 18, 71). In a recent study
`from two sites in Europe, 107 arthritic patients were ran—
`domly allocated to receive diclofenac 200 mg/day or
`naproxen 1 g/day, plus sucralfate gel 1 g b.i.d. (n = 53) or
`identical placebo (n = 54) for 14 days in an RCT. Although
`there was an unexplained difference in the incidence of ulcer
`between the two centers, there was an overall decrease in the
`occun‘ence of ulcer between patients receiving sucralfate
`
`(8%) compared with placebo (28%) (p < 0.05). Both GU
`and DU were analyzed together in this study. and the proven
`efficacy of sucralfate for DU may account for these results
`(72). Studies have shown that antacids and buffered tablets
`do not protect against NSAID injury (73775). Enteric coat—
`ing may be helpful in reducing aspirin-related gastric and
`duodenal ulcer (74, 75). but does not reduce the risk of
`NSAID-related ulcer complications (76).
`Several new compounds have shown promise in both
`animal studies and patients. In a double—blind RCT, sulgly—
`cotide 200 mg t.i.d. or placebo was coadministered with an
`NSAID to patients with rheumatoid arthritis. Gastric or
`duodenal ulcer was seen in six of 42 (18%) in the sulgly—
`cotide group and in 15 of 44 (34%) in the placebo group
`(p = 0.02) (77). Another new agent under study is zinc
`acexonite (ZAC). Either ZAC 300 mg/day or placebo was
`randomly assigned in a double blind manner to 276 arthritic
`patients receiving NSAIDs. Of 141 patients receiving ZAC,
`no GU and only one DU (0.9%) was found, whereas 12 of
`135 subjects (6.0%) on placebo developed an ulcer. Unfor-
`tunately, this study suffers from a high withdrawal and loss
`to follow up rate (67/276) (78). Because of lack of confir-
`matory studies, no recommendations can be made at this
`time concerning either of these agents.
`More promising is the development of new, purp01tedly
`nontoxic. NSAIDs. These fall
`into two groups: COX-2-
`selective
`inhibitors,
`and nitric
`oxide
`(NO)—releasing
`NSAIDs. Studies of these agents are very limited. Meloxi—
`cam (15 mg/day), a weak COX-2 inhibitor (COX 1: COX-2
`ratio 0.33), has been studied in an uncontrolled manner in
`357 patients with rheumatoid arthritis. Severe side effects
`(bleeding, perforation, and ulcer) were seen in only three
`patients (0.8%) (79). The GI effects of more potent COX—2
`inhibitors have thus far only been studied in normal volun-
`teers. These studies have shown a lesser degree of overall
`erosive injury and ulcer when compared with other NSAIDs
`(80, 81). At this time,
`there are no published RCTs of
`NO-NSAIDs in patients or human volunteers.
`
`TREATMENT OF NSAID-TNDUCED ULCERS
`
`Recommendation
`
`NSAID—induced ulcer disease may be treated with any
`approved therapy for ulcer disease. It is preferable to stop
`NSAID therapy when ulcer disease occurs. A proton pump
`inhibitor is the agent of choice when NSAIDs must be
`continued in the presence of ulcer disease and for large
`ulcers. Treatmentvfor H. pylori is recommendedfor patients
`taking NSAIDS who have ulcers and are infected with this
`organism.
`NSAID—related ulcers may be treated effectively with any
`approved therapy for peptic ulcer disease. Healing generally
`is more rapid when the N SAID is discontinued and com-
`pares favorably with healing rates for peptic ulcer disease
`not associated with NSAID intake. Several recent RCTs
`
`provide what are probably the best data on the healing rates
`
`Page 5 of 10
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`Patent Owner Ex. 2064
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`Mylan v. Pozen
`lPR2017-01995
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`Page 5 of 10
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`Mylan v. Pozen
`IPR2017-01995
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`

`2042
`
`LANZA et a].
`
`AJG — Vol. 93, N0. 11, 1998
`
`TABLE 5
`Treatment afNS'AID-Re/afed Ulcers
`"/o Healed
`Regimen — p
`Ref
`Based on Treated
`4 wk
`8 wk
`
`
`25
`
`26
`
`84
`
`82
`
`All ulcers
`NSAIDS con’t
`
`All Ulcers
`NSAIDS con’t
`
`GU only
`NSAIDS con’t
`
`O 20 (1.11.
`0 4O qr].
`R 150 bid.
`O 20 (1.11.
`O 40 (1.5!.
`M 200 bid.
`020 (1d.
`0 40 £1.51.
`R 150 hid.
`
`GU
`
`DU
`
`83
`
`R 150 [Ll-11.
`NSAle DC’d
`NSAIDS Con’t
`NSAIDs DC‘d
`NSAIDs eon’t
`
`
`8 wk
`95
`63
`100
`84
`
`R 150 bid.
`
`65
`63
`52
`56
`60
`56
`61
`81
`332
`
`
`12 wk
`100
`79
`100
`92
`
`80
`79
`63
`75
`75
`71
`82
`75
`63
`
`((0.001 vs R 150 hid.
`<0.001 vs R 150 [MIL].
`
`NS vs 0 40 and M 200
`NS vs 0 20 and M 200
`NS vs 0 20 and O 40
`<0.001 vs R 150 bid.
`<0.03 vs R 150 bald.
`
`
`12 wk
`70.004
`
`8 wk
`
`0.001
`DC’d vs eon’t NSAIDS
`0.006
`DC’d vs eon’t NSAIDS
`
`4 Wk
`
`NSAIDS Con’t
`NSAIDs DC‘d
`Placebo
`NSAIDs DC’d
`R 150 hid.
`NSAIDs Con’t
`NSAIDS DC’d
`Placebo
`
`NSAIDs DC’d 42
`
`NS vs placebo
`NS vs placebo
`
`NS vs placebo
`0.02 vs Placebo
`
`GU
`
`DU
`
`67
`68
`
`47
`
`61
`81
`
`0 : omeprazole (in mg); M : misoprosLol (in pig); R : raniLidine (in mg).
`
`of NSAID-related ulcers treated with H2 RAs or PPI’s
`
`(Table 5). These studies showed that good healing rates
`could be obtained at both 4 and 8 wk with all of the agents
`employed. Generally, healing rates were better for all treat-
`ments when NSAIDs were discontinued, but satisfactory
`healing still occurred with prolonged therapy when it was
`necessary to continue NSAID treatment. Healing rates in
`patients taking omeprazole were significantly better than
`those in patients taking ranitidine when NSAle were con-
`tinued (25, 26, 82— 84). In an uncontrolled study, famotidine
`40 mg/day was given to 71 patients with endoscopically—
`proven GU for 8 wk. The healing rate for patients with
`NSAID-related ulcers was compared with that for idiopathic
`ulcer. It was found that healing occurred in 46 of 48 (96%)
`of patients with NSAID—related ulcer, which was signifi—
`cantly greater than the 17 of 23 (74%) seen for idiopathic
`ulcer (p = 0.01) (85). In a nonplacebo-controlled study,
`three doses ofnizatidine (150 mg HS, 150 mg b.i.d., 300 mg
`b. 110'.) were given to patients with active GU or DU while
`they continued their original NSAID. After 8 wk of therapy,
`>90% of the ulcers of all three groups were healed. There
`was a tendency to higher healing rates for GU after four
`weeks in the high dose (300 mg b. i. d.) nizatidine group (67).
`In another RCT, substitution of enteric—coated aspirin in
`patients with ASA—related ulcers did not increase healing
`rates in patients treated with cimetidine (400 mg/day) and
`
`in fact, seven patients given enteric-coated
`antacids and,
`aspirin failed to heal their ulcers, whereas 15 of 16 healed
`after aspirin was discontinued in all forms (86).
`Helicobacter pylori infection has been strongly associ-
`ated with peptic ulcer disease, especially duodenal ulcer.
`However,
`this association has not been demonstrated in
`patients with NSAID—related ulcer (87—90). In one study,
`however, gastropathy was more severe in I]. pylori-positive
`patients (88). Some recent studies have shown that the
`incidence of DU is increased in H. pylori-positive patients
`taking NSAIDs (91, 92). However,
`in another study H
`pylori eradication did not increase the healing of GU and
`DU associated with long-term NSAID use (93). It has been
`recently reported that eradication ofH. pylori before NSAID
`therapy strikingly reduces the incidence of ulcer disease in
`patients being treated with naproxen (750 mg/day). Standard
`triple therapy (bismuth subcitrate 120 mg q.i.d., tetracycline
`500 mg q. i.d., and metronidazole 400 mg q. id) was given to
`45 H. pylori-positive patients before 8 wk of naproxen
`therapy. Naproxen alone was given to 47 patients over the
`same period. In the triple therapy group, only three patients
`(7%) developed ulcer, two of whom were found to have
`failed H. pylori eradication. 1n the naproxen group, 12
`patients (26%) had ulcers, one of which bled (94). Another
`recent case—control study of ulcer bleeding in 487 elderly
`patients revealed that NSAID usage (odds ratio 4.93) and H.
`
`Page 6 of 10
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`MYL-EN000041042
`
`Patent Owner Ex. 2064
`
`Mylan v. Pozen
`lPR2017-01995
`
`Page 6 of 10
`
`Patent Owner Ex. 2064
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`AJG — November 1998
`
`NSAID-1N DUCED ULCER TREATMENT AND PREVENTION
`
`2043
`
`pylori status (odds ratio 2.80) increased risk substantially,
`but there was no evidence of interaction (95). In View of the
`conflicting data, screening for H. pylori infection cannot be
`recommended for all patients receiving NSAIDs. There is
`some recent evidence that H pylori—negative patients heal
`more slowly than those who are positive for this organism
`(26). However, experts still agree that H. pylori-positive
`patients with a past or current history of ulcer requiring
`NSAID therapy should be treated for the infection, as it
`cannot be determined whether the prior ulcer was due to
`NSAID therapy or to II. pylori infection.
`
`NSAID INJURY TO THE SMALL BOWEL
`AND COLON
`
`Recommendations
`
`NSAID-related injury to both the small and large bowel
`has includes occult and flank bleeding, perforation, ob-
`struction, an acute colitis, anal exacerbation of existing
`colon disease. Physicians prescribing NSAIDs should be
`aware of these potential complications
`NSAID-related injury to the small bowel and colon has
`only recently been described and has been documented
`primarily by anecdotal case reports. However,
`these are
`numerous and constitute a significant body of literature. The
`overall incidence of NSAID-related injury to the gastroin-
`testinal tract distal to the duodenum is much less than that
`
`seen in the stomach and proximal duodenum. Nevertheless,
`it occurs frequently enough to warrant serious consideration
`by physicians treating patients with NSAIDs.
`
`Small bowel injury
`Injury to the small intestine can be manifested by perfo—
`ration, ulceration and stricture, or by an NSAID-induced
`enteropathy (31, 46, 96 —9 8). Perforation of the small bowel,
`although a rare complication of NSAID use, was found in
`one retrospective review to be significantly more common
`among patients taking NS