`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The New England Journal of Medicine
`
`COMPARISON OF UPPER GASTROINTESTINAL TOXICITY OF ROFECOXIB
`AND NAPROXEN IN PATIENTS WITH RHEUMATOID ARTHRITIS
`
`R
`UBEN
`
`.P.H.,
`, D
` S
`, M.D., D
` R
`, M.D., A
` L
`, M.D., L
` B
`C
`R
`HAPIRO
`EBORAH
`EICIN
`LISE
`AINE
`OREN
`OMBARDIER
`LAIRE
`-V
`, M.D., B
` D
`, M.D., P
`.D., R
` D
`, M.D., M
` B
` F
`, M.D., P
` B
`ERRAZ
`H
`ARRY
`ARGAS
`URGOS
`AVIS
`ICHARD
`AY
`ARCOS
`OSI
`H
`C
` J. H
`, M.D., M
` C. H
`, M.D., T
` K. K
`, M.D.,
`HRISTOPHER
`AWKEY
`ARC
`OCHBERG
`ORE
`VIEN
` T
` J. S
`, M.D., P
`.D.,
`
` VIGOR S
` G
`AND
`HOMAS
`CHNITZER
`H
`FOR
`THE
`TUDY
`ROUP
`
`.D.,
`
`A
`BSTRACT
`Background
`Each year, clinical upper gastrointes-
`tinal events occur in 2 to 4 percent of patients who
`are taking nonselective nonsteroidal antiinflammatory
`drugs (NSAIDs). We assessed whether rofecoxib, a
`selective inhibitor of cyclooxygenase-2, would be as-
`sociated with a lower incidence of clinically important
`upper gastrointestinal events than is the nonselective
`NSAID naproxen among patients with rheumatoid
`arthritis.
`Methods
`We randomly assigned 8076 patients who
`were at least 50 years of age (or at least 40 years of
`age and receiving long-term glucocorticoid therapy)
`and who had rheumatoid arthritis to receive either
`50 mg of rofecoxib daily or 500 mg of naproxen twice
`daily. The primary end point was confirmed clinical
`upper gastrointestinal events (gastroduodenal perfo-
`ration or obstruction, upper gastrointestinal bleeding,
`and symptomatic gastroduodenal ulcers).
`Results
`Rofecoxib and naproxen had similar effica-
`cy against rheumatoid arthritis. During a median fol-
`low-up of 9.0 months, 2.1 confirmed gastrointestinal
`events per 100 patient-years occurred with rofecoxib,
`as compared with 4.5 per 100 patient-years with na-
`proxen (relative risk, 0.5; 95 percent confidence inter-
`val, 0.3 to 0.6; P<0.001). The respective rates of com-
`plicated confirmed events (perforation, obstruction,
`and severe upper gastrointestinal bleeding) were 0.6
`per 100 patient-years and 1.4 per 100 patient-years
`(relative risk, 0.4; 95 percent confidence interval, 0.2
`to 0.8; P=0.005). The incidence of myocardial infarc-
`tion was lower among patients in the naproxen group
`than among those in the rofecoxib group (0.1 percent
`vs. 0.4 percent; relative risk, 0.2; 95 percent confidence
`interval, 0.1 to 0.7); the overall mortality rate and the
`rate of death from cardiovascular causes were simi-
`lar in the two groups.
`Conclusions
`In patients with rheumatoid arthritis,
`treatment with rofecoxib, a selective inhibitor of cy-
`clooxygenase-2, is associated with significantly fewer
`clinically important upper gastrointestinal events than
`treatment with naproxen, a nonselective inhibitor.
`(N Engl J Med 2000;343:1520-8.)
`©2000, Massachusetts Medical Society.
`
`1520
`
`·
`
`November 23, 2000
`
`N
`
`ONSTEROIDAL antiinflammatory drugs
`(NSAIDs) are among the most common-
`ly used medications in the world.
` A major
`1
`factor limiting their use is gastrointesti-
`nal toxicity. Although endoscopic studies reveal that
`gastric or duodenal ulcers develop in 15 to 30 percent
` the chief con-
`of patients who regularly take NSAIDs,
`2
`cern is clinically important gastrointestinal problems,
`such as bleeding. It has been estimated that more than
`100,000 patients are hospitalized and 16,500 die each
`year in the United States as a result of NSAID-asso-
`ciated gastrointestinal events.
`3,4
`Most NSAIDs inhibit both cyclooxygenase-1 and
`cyclooxygenase-2, isoenzymes involved in the synthe-
`sis of prostaglandins.
` Cyclooxygenase-1 is constitu-
`5
`tively expressed and generates prostanoids involved in
`the maintenance of the integrity of gastrointestinal
`mucosa and platelet aggregation,
` whereas at sites of
`6
`inflammation, cyclooxygenase-2 is induced to generate
`prostaglandins that mediate inflammation and pain.
`7
`The antiinflammatory effects of nonselective NSAIDs
`(those that inhibit both cyclooxygenase-1 and cyclo-
`oxygenase-2) therefore appear to be mediated through
`the inhibition of cyclooxygenase-2,
` whereas their
`8
`harmful effects in the gastrointestinal tract as well as
`their antiplatelet effects are believed to occur primar-
`ily through the inhibition of cyclooxygenase-1.
`5
`Agents that selectively inhibit cyclooxygenase-2 have
`antiinflammatory and analgesic effects that are simi-
`
`From the Institute for Work and Health, Mount Sinai Hospital, and the
`University Health Network, Toronto (C.B.); the Gastrointestinal Division,
`Department of Medicine, University of Southern California School of
`Medicine, Los Angeles (L.L.); Merck, Rahway, N.J. (A.R., D.S.); the Fac-
`ulty of Medicine and Research Division, Universidad Nacional Autonoma
`de Mexico, and Hospital General de Mexico, Mexico City, Mexico (R.B.-V.);
`University of Texas–Houston School of Public Health, Houston (B.D.); the
`Department of Clinical Pharmacology, University of New South Wales
`and St. Vincent’s Hospital, Sydney, Australia (R.D.); the Division of Rheu-
`matology, Department of Medicine, Escola Paulista de Medicina, Univer-
`sidade Federal de São Paulo, São Paulo, Brazil (M.B.F.); the Division of
`Gastroenterology, School of Medical and Surgical Sciences, University Hos-
`pital, Nottingham, United Kingdom (C.J.H.); the Division of Rheumatol-
`ogy and Clinical Immunology, University of Maryland, Baltimore (M.C.H.);
`Oslo City Department of Rheumatology, and Diakonhjemmet Hospital, Oslo,
`Norway (T.K.K.); and the Office of Clinical Research and Training, North-
`western University School of Medicine, Chicago (T.J.S.). Address reprint re-
`quests to Dr. Bombardier at the Institute for Work and Health, 250 Bloor
`St. E., Suite 702, Toronto, ON M4W 1E6, Canada, or at claire.bombardier@
`utoronto.ca.
`Arthur Weaver, M.D., Arthritis Center of Nebraska, Lincoln, was another
`author.
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on March 19, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`Page 1 of 9
`
`Patent Owner Ex. 2045
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`UPPER GASTROINTESTINAL TOXICITY OF ROFECOXIB AND NAPROXEN IN PATIENTS WITH RHEUMATOID ARTHRITIS
`
` but they in-
`lar to those of nonselective NSAIDs,
`9-12
`duced significantly fewer ulcers in endoscopic tri-
` Whether such a decrease in the number of
`als.
`12-15
`ulcers translates into a similar decrease in the number
`of clinical gastrointestinal events is a matter of con-
`troversy. We performed a prospective, randomized,
`double-blind comparison of rofecoxib and naproxen
`in more than 8000 patients with rheumatoid arthritis.
`
`METHODS
`
`Study Population
`Patients with rheumatoid arthritis who were at least 50 years
`old (or at least 40 years old and receiving long-term glucocorticoid
`therapy) and who were expected to require NSAIDs for at least
`one year were eligible. Patients were excluded if they had a history
`of another type of inflammatory arthritis, upper gastrointestinal
`surgery, or inflammatory bowel disease; an estimated creatinine
`clearance of 30 ml or less per minute; a positive test for fecal occult
`blood (this test was performed at base line in all patients); an un-
`stable medical condition; a history of cancer or alcohol or drug
`abuse in the five years before the study; a history of cerebrovas-
`cular events in the two years before the study; or a history of my-
`ocardial infarction or coronary bypass in the year before the study.
`Patients with morbid obesity and those who required or who had
`been receiving treatment with aspirin, ticlopidine, anticoagulants,
`cyclosporine, misoprostol, sucralfate, or proton-pump inhibitors or
`treatment with histamine H
`–receptor antagonists in prescription-
`2
`strength doses were also excluded from the study. Patients enrolled
`in the study were not thought to require the use of these agents
`by their treating physicians.
`
`Study Design
`The study was conducted at 301 centers in 22 countries. Three
`to 14 days after discontinuing NSAIDs, eligible patients were ran-
`domly assigned to receive either 50 mg of rofecoxib (Vioxx, Merck,
`Whitehouse Station, N.J.) once daily or 500 mg of naproxen (No-
`vopharm Biotech, Toronto) twice daily. The groups were stratified
`according to the presence or absence of a history of gastroduode-
`nal ulcer, upper gastrointestinal bleeding, and gastroduodenal per-
`foration. Blinding was achieved through the use of a matching pla-
`cebo for each study medication.
`Patients were permitted to take acetaminophen, non-NSAID
`analgesic medications, glucocorticoids, and disease-modifying drugs
`(e.g., methotrexate) to control their rheumatoid arthritis. Patients
`were also allowed to take antacids and H
`-receptor antagonists in
`2
`the following maximal doses: ranitidine, 150 mg daily; famotidine,
`20 mg daily; cimetidine, 400 mg daily; and nizatidine, 150 mg
`daily. Nonstudy NSAIDs were not allowed. After randomization,
`the patients returned to the clinic at six weeks and at four months
`and every four months thereafter until the end of the study. Patients
`were contacted by telephone at week 10 and every four months
`thereafter. Compliance was assessed by pill counts at clinic visits
`and by questioning of patients during the scheduled telephone calls.
` test-
`Serum was obtained from all patients for
`Helicobacter pylori
`ing (HM-CAP, Enteric Products, Stonybrook, N.Y.). Investigators
`were not informed of the results of these tests during the study.
`The institutional review board or ethics review committee at
`each center approved the protocol, and all patients gave written in-
`formed consent. A steering committee oversaw the study design,
`conduct of the trial, analyses of data, and drafting of this report. This
`committee was composed of 14 members, 2 of whom were employ-
`ees of the sponsoring pharmaceutical company. An independent data
`and safety monitoring board monitored the patients’ safety. An in-
`dependent, external (end-point) committee whose members were
`unaware of the patients’ treatment assignments reviewed the data
`to determine which patients had reached the study end points. Be-
`cause highly selective cyclooxygenase-2 inhibitors do not inhibit
`
`platelet aggregation, which is mediated by cyclooxygenase-1, there
`was a possibility that the incidence of thrombotic cardiovascular
`events would be lower among patients treated with nonselective
`cyclooxygenase inhibitors than among those treated with cyclooxy-
`genase-2–selective inhibitors. Therefore, cardiovascular events were
`also assessed for a future meta-analysis by independent committees
`whose members were unaware of the patients’ treatment assign-
`ments. A separate analysis of these events, however, was not spec-
`ified in the study design.
`
`Study End Points
`
`Patients who had potential clinical upper gastrointestinal events
`were evaluated and treated according to the standard practice of
`the physicians who were caring for them. Patients who stopped
`taking the study medication before the study ended were followed
`until the end of the study to determine whether an upper gastro-
`intestinal event had occurred. Only events that were confirmed by
`the end-point committee according to prespecified criteria (Table 1)
`and that occurred during treatment or within 14 days after the dis-
`continuation of treatment were included in the primary analysis.
`In addition, the protocol called for the analysis of all episodes
`of gastrointestinal bleeding, including confirmed and unconfirmed
`episodes of upper gastrointestinal bleeding, and bleeding from a
`site beyond the duodenum that resulted in hospitalization, dis-
`continuation of treatment, or a decrease in the hemoglobin level
`of at least 2 g per deciliter.
`
`Assessment of Efficacy
`
`For each patient both the investigator and the patient answered
`a Global Assessment of Disease Activity question at base line (af-
`ter the discontinuation of prestudy NSAIDs), 6 weeks, 4 months,
`and 12 months and at the end of the study or when treatment was
`discontinued. The score can range from 0 (“very well”) to 4 (“very
`poor”), and higher scores indicate more disease activity. The Mod-
`ified Health Assessment questionnaire was administered only to
`patients enrolled at centers in the United States at base line, at six
`weeks, and at the end of the study or when treatment was discon-
`tinued. This questionnaire evaluates the extent of functional dis-
`ability in eight types of tasks performed on a daily basis. The level
`of effort required to perform each task is assessed on a 4-point
`scale on which a score of 0 indicates no difficulty in performing the
`task and a score of 3 indicates an inability to perform the task.
`16
`Higher scores indicate more severe disability.
`
`Statistical Analysis
`
`The primary hypothesis was that the risk of confirmed upper
`gastrointestinal events (gastroduodenal perforation or obstruction,
`upper gastrointestinal bleeding, and symptomatic gastroduodenal
`ulcers) would be lower among patients who were taking rofecoxib
`than among those who were taking naproxen. Secondary hypoth-
`eses were that the risk of confirmed complicated events (perforation,
`obstruction, and severe upper gastrointestinal bleeding) and the
`risk of both confirmed and unconfirmed upper gastrointestinal
`events would be lower among patients who were taking rofecoxib.
`Cox proportional-hazards analysis was used to compare the ef-
`fect of treatment; the presence or absence of a history of gastro-
`intestinal events was a stratification factor in the analysis.
` The
`17,18
`scores for the Global Assessment of Disease Activity question and
`Modified Health Assessment questionnaire were analyzed in terms
`of the mean change from base line during the treatment period.
`The primary population for analysis comprised all randomized pa-
`tients. Subgroup analyses were conducted with use of Cox regres-
` Interactions between treatments and subgroups
`sion analysis.
`17,18
`were assessed to determine whether the effect of rofecoxib as com-
`pared with that of naproxen was consistent in the subgroups. We
`assessed data on general safety by evaluating 95 percent confidence
`intervals of the differences in the proportions of the treatment
` All statistical tests were two-sided.
`groups with each adverse event.
`19
`
`Volume 343 Number 21
`
`·
`
`1521
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on March 19, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`Page 2 of 9
`
`Patent Owner Ex. 2045
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The New England Journal of Medicine
`
`T
`
`ABLE
`
` 1.
`
` C
`
`RITERIA
`
`
`
`FOR
`
` G
`
`ASTROINTESTINAL
`
` E
`
`VENTS
`
`.
`
`E
`VENT
`
`C
`RITERIA
`
` R
`EQUIRED
`
`
`
`FOR
`
` C
`ONFIRMATION
`
`
`
`OF
`
` E
`VENT
`
`Perforation due to nonmalignant
`gastric or duodenal ulcer
`Obstruction due to gastric or
`duodenal ulcer
`
`Upper gastrointestinal bleeding
`
`Gastric or duodenal ulcer
`
`Evidence of perforation on endoscopy, at surgery, on radiography (evidence of
`free intraabdominal air or extravasation of contrast medium), or at autopsy
`Occurrence of nausea and vomiting »24 hours postprandially and evidence of
`narrowing of distal portion of stomach or duodenum as a result of a nonmalig-
`nant ulcer on endoscopy, at surgery, on radiography, or at autopsy
`Episode of hematemesis or aspiration of bloody gastric fluid witnessed by health
`care provider; episode of melena witnessed by health care provider; evidence of
`active bleeding on endoscopy, at surgery, or on angiography; positive test for
`fecal occult blood with documented upper gastrointestinal lesion judged to be
`the source and associated with either clinically significant bleeding or decrease
`in volume* or evidence of visible vessel, clot, or pigmented spot on ulcer at
`endoscopy; or episode of hematemesis or melena reported by patient with up-
`per gastrointestinal lesion judged to be the source and associated with either
`clinically significant bleeding or decrease in volume* or evidence of visible ves-
`sel, clot, or pigmented spot on ulcer at endoscopy
`Evidence of gastric or duodenal ulcer on endoscopy, at surgery, on contrast-
`enhanced radiography of the upper gastrointestinal tract, or at autopsy
`
`*A decrease in volume was defined by the finding of a decrease in hemoglobin of at least 2 g per deciliter; by the
`finding of an orthostatically induced change in pulse of more than 20, change in systolic blood pressure of more than
`20 mm Hg, or change in diastolic blood pressure of more than 10 mm Hg; by the finding of other evidence of a clinically
`significant reduction in circulatory volume (e.g., clinically significant hypotension that is corrected by volume replace-
`ment); or by the need for blood transfusion.
`
`RESULTS
`Characteristics of the Patients
`Between January 1999 and July 1999, we screened
`9539 patients and enrolled 8076; 4047 were ran-
`domly assigned to receive rofecoxib, and 4029 to re-
`ceive naproxen. The major reasons for exclusion were
`a contraindication to prolonged NSAID therapy (in
`the case of 246 patients), a positive test for fecal oc-
`cult blood (203 patients), and a failure to meet in-
`clusion criteria (355 patients). The median follow-
`up was 9.0 months in both treatment groups (range,
`0.5 to 13). A total of 5742 patients (71.1 percent)
`continued to take their assigned medication until
`the end of the study. Rates of discontinuation were
`similar in the two groups: 29.3 percent in the rofe-
`coxib group (16.4 percent because of adverse events,
`6.3 percent because of a lack of efficacy, and 6.6 per-
`cent for other reasons) and 28.5 percent in the naprox-
`en group (16.1 percent because of adverse events,
`6.5 percent because of a lack of efficacy, and 5.9 per-
`cent for other reasons). Ninety-nine percent of the
`patients in both groups took their medication on at
`least 75 percent of the study days. The base-line char-
`acteristics were similar in the two groups (Table 2).
`
`Efficacy
`Rofecoxib and naproxen had similar efficacy against
`rheumatoid arthritis (Table 3). In addition, the rates
`of discontinuation of treatment owing to a lack of
`efficacy were low in both groups (6.3 percent in the
`rofecoxib group and 6.5 percent in the naproxen
`group).
`
`1522
`
`·
`
`November 23, 2000
`
`Adverse Gastrointestinal Events
`Confirmed upper gastrointestinal events occurred
`in 177 patients. In 53 of these patients the event was
`complicated. An additional 13 patients had events that
`were reported by investigators but that were judged
`by the end-point committee to be unconfirmed.
`The time to the development of a confirmed up-
`per gastrointestinal event is shown in Figure 1. The
`rates per 100 patient-years and incidences of the pre-
`specified clinical events are shown in Tables 4 and 5,
`respectively. The relative risk of confirmed upper
`gastrointestinal events for patients in the rofecoxib
`group as compared with those in the naproxen group
`was 0.5 (95 percent confidence interval, 0.3 to 0.6;
`P<0.001), whereas the relative risk of complicated
`confirmed upper gastrointestinal events was 0.4 (95
`percent confidence interval, 0.2 to 0.8; P=0.005).
`The relative risk of complicated upper gastrointesti-
`nal bleeding for patients in the rofecoxib group as
`compared with those in the naproxen group was 0.4
`(95 percent confidence interval, 0.2 to 0.7; P=
`0.004), whereas the relative risk of bleeding beyond
`the duodenum was 0.5 (95 percent confidence in-
`terval, 0.2 to 0.9; P=0.03).
`A per-protocol analysis of the 7925 patients with-
`out substantial protocol violations demonstrated rel-
`ative risks of confirmed upper gastrointestinal events
`and complicated confirmed events of 0.4 (95 per-
`cent confidence interval, 0.3 to 0.6; P<0.001) and
`0.4 (95 percent confidence interval, 0.2 to 0.7; P=
`0.003), respectively. The results of an intention-to-
`treat analysis of all confirmed upper gastrointestinal
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on March 19, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`Page 3 of 9
`
`Patent Owner Ex. 2045
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`UPPER GASTROINTESTINAL TOXICITY OF ROFECOXIB AND NAPROXEN IN PATIENTS WITH RHEUMATOID ARTHRITIS
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`tients with glucocorticoid therapy at base line (rela-
`tive risk, 0.4; 95 percent confidence interval, 0.2 to
`0.6). The relative risks in these subgroups and the oth-
`er prespecified subgroups (defined according to sex,
`race or ethnic group, and location of study center)
`were not significantly different, indicating that there
`was no significant interaction between the treatments
`and the subgroups.
`Treatment with rofecoxib was associated with a
`significantly lower incidence of clinical gastrointestinal
`events regardless of the results of serologic tests for
`
`H. pylori. However, the relative risks of clinical events
`
`
`
`
`among H. pylori–negative patients and H. pylori–pos-
`itive patients were significantly different (P=0.04, data
`not shown). Finally, the relative risk of gastrointesti-
`nal events remained significantly lower (0.1; 95 per-
`cent confidence interval, 0.02 to 1.0) in the rofecoxib
`group than in the naproxen group even in a subgroup
`at very low risk (i.e., patients who were younger than
`65 years, who were negative for
`
`H. pylori, who had
`no history of a clinical gastrointestinal event, and who
`were not taking glucocorticoids at base line).
`
`General Safety
`The safety of both rofecoxib and naproxen was
` The
`similar to that reported in previous studies.
`20,21
`mortality rate was 0.5 percent in the rofecoxib group
`and 0.4 percent in the naproxen group. The rate of
`death from cardiovascular causes was 0.2 percent in
`both groups. Ischemic cerebrovascular events occurred
`in 0.2 percent of the patients in each group. Myo-
`cardial infarctions were less common in the naproxen
`group than in the rofecoxib group (0.1 percent vs.
`0.4 percent; 95 percent confidence interval for the
`difference, 0.1 to 0.6 percent; relative risk, 0.2; 95
`percent confidence interval, 0.1 to 0.7). Four percent
`of the study subjects met the criteria of the Food and
`Drug Administration (FDA) for the use of aspirin for
`secondary cardiovascular prophylaxis (presence of a
`history of myocardial infarction, angina, cerebrovas-
`cular accident, transient ischemic attack, angioplasty,
` but were not taking low-dose
`or coronary bypass)
`22
`aspirin therapy. These patients accounted for 38 per-
`cent of the patients in the study who had myocardial
`infarctions. In the other patients the difference in the
`rate of myocardial infarction between groups was not
`significant (0.2 percent in the rofecoxib group and
`0.1 percent in the naproxen group). When the data
`showing a reduction in the rate of myocardial infarc-
`tion in the naproxen group became available after the
`completion of this trial, Merck, the manufacturer of
`rofecoxib, notified all investigators in ongoing studies
`of a change in the exclusion criteria to allow patients
`to use low-dose aspirin. There was no association be-
`tween hypertension and myocardial infarction; only
`a single patient (in the rofecoxib group) had both
`hypertension and a myocardial infarction as adverse
`events.
`
`Volume 343 Number 21
`
`·
`
`1523
`
`T
`
`ABLE
`
` 2.
`
` B
`
`ASE
`
`-L
`
`INE
`
` C
`
`HARACTERISTICS
`
`
`
`OF
`
`
`
`THE
`
` P
`
`ATIENTS
`
`.*
`
`R
`OFECOXIB
`G
`ROUP
`(N=4047)
`
`N
`APROXEN
`G
`ROUP
`(N=4029)
`
`58±10
`58±9
`3223 (79.6) 3215 (79.8)
`
`2761 (68.2)
`207 (5.1)
`101 (2.5)
`501 (12.4)
`477 (11.8)
`
`2750 (68.3)
`202 (5.0)
`85 (2.1)
`516 (12.8)
`476 (11.8)
`
`3 (0.1)
`6 (0.1)
`430 (10.6)
`455 (11.3)
`1991 (49.2)
`1996 (49.5)
`1623 (40.1)
`1572 (39.0)
`2946 (72.8) 2967 (73.6)
`
`3321 (82.1) 3331 (82.7)
`
`2260 (55.8)
`2263 (55.9)
`1847 (45.6)
`365 (9.0)
`
`2263 (56.2)
`2269 (56.3)
`1826 (45.3)
`335 (8.3)
`
`314 (7.7)
`
`316 (7.8)
`
`2.0±0.9
`1.9±0.8
`
`2.0±0.9
`1.9±0.8
`
`881 (21.8)
`2160 (53.4)
`928 (22.9)
`78 (1.9)
`
`830 (20.6)
`2199 (54.6)
`932 (23.1)
`68 (1.7)
`
`C
`HARACTERISTIC
`
`Age — yr
`Female sex — no. (%)
`Race or ethnic group — no. (%)
`White
`Black
`Asian
`Hispanic
`Other
`Duration of disease — no. (%)
`Unknown
`<2 yr
`2–10 yr
`>10 yr
`Positive test for rheumatoid
`factor — no. (%)
`Prior use of NSAIDs — no. (%)
`Treatment for rheumatoid arthritis — no. (%)
`Glucocorticoids
`Methotrexate
`Other disease-modifying drugs
`-receptor antagonists
`Low-dose H
`2
`— no. (%)†
`History of clinical gastrointestinal events
`Global Disease Activity score‡
`Patient’s assessment
`Investigator’s assessment
`American College of Rheumatology
`functional class — no. (%)§
`
`II
`
`I
`III
`IV
`
`*Plus–minus values are means ±SD. NSAIDs denotes nonselective non-
`steroidal antiinflammatory drugs.
`†A low dose was defined as a maximal daily dose of 150 mg of ranitidine,
`20 mg of famotidine, 400 mg of cimetidine, and 150 mg of nizatidine.
`‡Scores can range from 0 (“very well”) to 4 (“very poor”). Higher
`scores indicate more disease activity.
`§According to the American College of Rheumatology’s system of clas-
`sification, functional class I indicates complete ability to perform usual ac-
`tivities of daily living, and class IV indicates limited ability to perform usual
`activities of daily living.
`
`events throughout the study, including those that oc-
`curred at any time after the discontinuation of treat-
`ment, were similar and remained statistically signifi-
`cant (data not shown).
`Subgroup analyses showed the following relative
`risks of clinical gastrointestinal events among the
`patients in the rofecoxib group as compared with
`those in the naproxen group: patients with no prior
`gastrointestinal events (relative risk, 0.5; 95 percent
`confidence interval, 0.3 to 0.7), patients with prior
`gastrointestinal events (relative risk, 0.4; 95 percent
`confidence interval, 0.2 to 0.8), patients with no
`glucocorticoid therapy at base line (relative risk, 0.7;
`95 percent confidence interval, 0.4 to 1.2), and pa-
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on March 19, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`Page 4 of 9
`
`Patent Owner Ex. 2045
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The New England Journal of Medicine
`
`T
`
`ABLE
`
` 3.
`
`E
`
`FFECTIVENESS
`
`
`
`OF
`
` R
`
`OFECOXIB
`
`
`
`AND
`
` N
`
`APROXEN
`
`
`
`FOR
`
` R
`
`HEUMATOID
`
` A
`
`RTHRITIS
`
`.*
`
`
`
`IN
`
` S
`CORE
`
`
`
`DURING
`
`V
`ARIABLE
`
`B
`ASE
`
`-L
`INE
`
` S
`CORE
`
`C
`HANGE
`
`ROFECOXIB
`GROUP
`
`NAPROXEN
`GROUP
`
`
`
`ROFECOXIB
`GROUP
`
`NAPROXEN
`GROUP
`
` T
`REATMENT
`-SQUARES MEAN
`LEAST
`DIFFERENCE BETWEEN
`GROUPS (95% CI)†
`
`Global Disease Activity score‡
`Patient’s assessment
`Investigator’s assessment
`Modified Health Assessment
`score§
`
`1.96±0.93
`1.85±0.80
`0.59±0.49
`
`1.99±0.94
`1.87±0.78
`0.59±0.49
`
`¡0.53±0.94
`¡0.51±0.93
`¡0.52±0.85
`¡0.49±0.84
`¡0.11±0.37 ¡0.12±0.36
`
`0.00 (¡0.03 to 0.03)
`0.01 (¡0.02 to 0.04)
`0.01 (¡0.01 to 0.04)
`
`*Plus–minus values are means ±SD.
`†The values were calculated by analysis of variance in a model that included treatment assignment and presence or
`absence of a history of gastrointestinal events and the base-line value as covariates. CI denotes confidence interval.
`‡Scores can range from 0 (“very well”) to 4 (“very poor”). Higher scores indicate more disease activity.
`§Scores can range from 0 (no difficulty in performing a task) to 3 (unable to perform the task). Higher scores indicate
`more severe disability. The questionnaire was administered only to patients enrolled at centers in the United States (1735
`in the rofecoxib group and 1732 in the naproxen group).
`
`Naproxen
`
`Rofecoxib
`
`0
`
`2
`
`8
`6
`4
`Months of Follow-up
`
`10
`
`12
`
`5.0
`
`4.5
`
`4.0
`
`3.5
`
`3.0
`
`2.5
`
`2.0
`
`1.5
`
`1.0
`
`0.5
`
`0.0
`
`Cumulative Incidence (%)
`
`NO. AT RISK
`RofecoxibF
`Naproxen
`
`4047F
`4029
`
`3641F
`3644
`
`3402F
`3389
`
`3180F
`3163
`
`2806F
`2796
`
`1073F
`1071
`
`533F
`513
`
`Figure 1. Cumulative Incidence of the Primary End Point of a Confirmed Upper Gastrointestinal Event
`among All Randomized Patients.
`
`The most common adverse events leading to dis-
`continuation of treatment, excluding the gastroin-
`testinal end points, were dyspepsia, abdominal pain,
`epigastric discomfort, nausea, and heartburn. In the
`rofecoxib group, significantly fewer patients discon-
`tinued treatment as a result of any one of these five
`upper gastrointestinal symptoms than in the naprox-
`
`en group (3.5 percent vs. 4.9 percent). The rates of
`discontinuation for any gastrointestinal events, includ-
`ing gastrointestinal end points, were also significant-
`ly lower in the rofecoxib group than in the naproxen
`group (7.8 percent vs. 10.6 percent). The incidence of
`adverse effects related to renal function was low and
`was similar in the two groups (1.2 percent in the ro-
`
`1524
`
`·
`
`November 23, 2000
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on March 19, 2015. For personal use only. No other uses without permission.
`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`Page 5 of 9
`
`Patent Owner Ex. 2045
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`UPPER GASTROINTESTINAL TOXICITY OF ROFECOXIB AND NAPROXEN IN PATIENTS WITH RHEUMATOID ARTHRITIS
`
`TABLE 4. INCIDENCE OF GASTROINTESTINAL EVENTS IN THE TREATMENT GROUPS.
`
`TYPE OF EVENT
`
`ROFECOXIB
`GROUP
`(N=4047)
`
`NAPROXEN
`GROUP
`(N=4029)
`
`ROFECOXIB
`GROUP
`(N=4047)
`
`NAPROXEN
`GROUP
`(N=4029)
`
`RELATIVE RISK
`(95% CI)*
`
`P
`VALUE
`
`no. with event
`
`rate/100 patient-yr
`
`Confirmed upper gastrointestinal events
`Complicated confirmed upper gastrointes-
`tinal events
`Confirmed and unconfirmed upper
`gastrointestinal events†
`Complicated confirmed and unconfirmed
`upper gastrointestinal events‡
`All episodes of gastrointestinal bleeding
`
`56
`16
`
`58
`
`17
`
`31
`
`121
`37
`
`132
`
`42
`
`82
`
`2.1
`0.6
`
`2.2
`
`0.6
`
`1.1
`
`4.5
`1.4
`
`4.9
`
`1.6
`
`0.5 (0.3–0.6) <0.001
`0.4 (0.2–0.8)
`0.005
`
`0.4 (0.3–0.6) <0.001
`
`0.4 (0.2–0.7)
`
`0.002
`
`3.0
`
`0.4 (0.3–0.6) <0.001
`
`*CI denotes confidence interval.
`†The analysis includes 13 events that were reported by investigators but were considered to be unconfirmed by the
`end-point committee.
`‡The analysis includes six events that were reported by investigators but that were considered to be unconfirmed by
`the end-point committee.
`
`TABLE 5. INCIDENCE OF CONFIRMED UPPER GASTROINTESTINAL EVENTS.*
`
`TYPE OF UPPER
`GASTROINTESTINAL EVENT
`
`Perforations†
`Gastric ulcer
`Duodenal ulcer
`Obstruction†
`Bleeding
`Total
`
`ALL CONFIRMED UPPER
`GASTROINTESTINAL EVENTS
`ROFECOXIB
`NAPROXEN
`GROUP
`GROUP
`(N=4047)
`(N=4029)
`
`ALL COMPLICATED CONFIRMED
`UPPER GASTROINTESTINAL
`EVENTS
`ROFECOXIB
`GROUP
`(N=4047)
`
`NAPROXEN
`GROUP
`(N=4029)
`
`3 (0.1)‡
`28 (0.7)
`27 (0.7)
`1 (<0.1)
`14 (0.3)
`56 (1.4)
`
`number (percent)
`
`4 (0.1)
`81 (2.0)
`39 (1.0)
`0
`35 (0.9)
`121 (3.0)
`
`3 (0.1)
`1 (<0.1)
`3 (0.1)
`1 (<0.1)
`12 (0.3)§
`16 (0.4)
`
`4 (0.1)
`6 (0.1)
`5 (0.1)
`0
`32 (0.8)¶
`37 (0.9)
`
`*Patients may have been included in more than one column, but each is counted only once in the
`total.
`†Perforations and obstructions are complicated events by definition.
`‡Two confirmed upper gastrointestinal events occurred after only one dose of rofecoxib and most
`likely resulted from prior use of nonselective nonsteroidal antiinflammatory drugs.
`§The cause or source of bleeding was gastric ulcers in five patients, duodenal ulcers in five, and
`other upper gastrointestinal source in three. One patient in the rofecoxib group had both a gastric
`and a duodenal ulcer.
`¶The cause or source of bleeding was gastric ulcers in 16 patients, duodenal ulcers in 9, and other
`upper gastrointestinal sources in 7.
`
`fecoxib group and 0.9 percent in the naproxen group);
`only 0.2 percent of patients in each group discon-
`tinued treatment because of these adverse effects.
`
`DISCUSSION
`We found that, in patients with rheumatoid arthri-
`tis, treatment with rofecoxib at twice the maximal dose
`approved by the FDA for long-term use resulted in sig-
`
`nificantly lower rates of clinically important upper gas-
`trointestinal events and complicated upper gastrointes-
`tinal events than did treatment with a standard dose
`(1000 mg per day) of naproxen. We also found that
`the incidence of complicated upper gastrointestinal
`bleeding and bleeding from beyond the duodenum
`was significantly lower among patients who received
`rofecoxib. Only 41 patients would need to be treated
`
`Volume 343 Number 21
`
`· 1525
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on March 19, 2015.