Significantly improved upper gastrointestinal (UGI) telerability with celecoxib, a COX-2 specific inhibitor, compared with conventional NSAIDs. The SUCCESS I trial

1000 mg/d (n =914) and diclofenac100 mg/d (n = 3510) with regardto UGI safety. Investigators were required to report all potential clinically significant UGI events and were a[[owud/ requested to follow local standards of care with regard to work-up and treatment of events. Events data were collected prospectively.An independentGastrointestinal Events Committee (GEC)reviewedall datain a blindedfashion. Eventswere categorizedas UGI ulcer complications (perforations, gastric outlet obstruction, bleeding)or symptomatic UGI ulcerations(predetined as in CLASS). A total of 144 cases were reviewed and adjudicated by the GEC. Results: See table. Conclusions: These data confirm CLASS results that celecoxib is associatedwith significantly fewer ulcer complications and symptomatic UGI ulcerations than conventional NSAIDs. The differences in event rates betweenSUCCESSand CLASS may relate to regional differences in surveillance or clinical practice. Sponsored by Pharmacia Corporation and Pfizer, Inc.

552 Stratilyiog the Risk of Clinical Upper Gt Events in NSAID Users: Results from a Double-Blind OutcomesStudy Loren Laine, U S C Sch of Medicine, Los Angeles, CA; Christopher J. Hawkey, Univ of Nottingham, Nottingham United Kingdom; Claire Bombardier, Univ of Toronto, Toronto Canada; Deborah Shapiro, Alise Re/c/n, Merck & Co, Inc, Rahway, NJ Studies rarely provide the rates of GI events in NSAID users stratified by different risk factors. This study determines the independentbaseline risk factors for clinical upper GI events with a multivariate analysis of a large outcomes study and provides rates of events for patients with these risk factors. METHODS:8076 rheumatoid arthritis (RA) patients -> 50 yrs (or --40 yrs and on steroids) were randomly assignedto rofecoxib 50 mg qd or naproxen500 mg bid, and followed for a median of 9 mos (range, 0.5 - 13 mos). The primary endpoint was clinical upper GI events (perforation, obstruction, bleeding, symptomatic ulcers), adjudicated by an independentcommittee using predetinedcriteria. Backwardstepwise regressionanalysis including factors from a univariateanalysiswith p -< 0.20 was performed. RESULTS:Independent risk factors included age -> 65 yrs, history of upper GI events, severe RA (ARA class 4), RA -> 25 yrs, baselinesteroid use, no baselineNSAID use, baselineH2-receptorantagonist use, and history of UGI symptoms. The annuaUzedincidences(rates of events per 100 patientyears) for the non-selective NSAID naproxenfor patients with these factors were: age -> 65 yrs, 8.6%; history of uncomplicated upper GI event, 13.5%; history of complicated upper GI event, 18.8%; severe RA, 14.3%; RA >- 25 yrs, 9.3%; baselinesteroid use, 5.7%; no baseline NSAID use, 7.6%; baselineH2-receptorantagonist use, 8.8%; history of upper GI symptoms, 8.8%; age >- 65 yrs plus baseline steroid use, 12.4%; age >- 65 plus history of upper GI event, 28.8%. A lower incidence of upper GI events was observed with rofecoxib than with naproxen in subgroups with and without each of these risk factors (range of relative risks = 0.31 - 0.68). The rates in a very low-risk group (age < 65, no steroid use, no prior upper GI events, plus no H. pylori infection) were 0.2% for rofecoxib and 1.9% for naproxen(relative risk = 0.12 (0.02 - 0.96)). CONCLUSIONS:Clinical upper GI events occurred at annualized incidences of > 12% in users of a nonselectiveNSAIDwith a past history of upper GI events, severe rheumatoid arthritis, or age - 65 plus steroid use. Older age plus a prior upper GI event increasedthe rate to > 28%. In contrast, the annualizedincidence of upper GI events in patients without standard risk factors for NSAID use (older age, past upper GI event, and steroid use) and without H. pylori infection was 1.9% with naproxen and only 0.2% with rofecoxib.

Exposure(pt.yr) UlcercomplicaUons (annualizedrate) Ulcer complications ÷ symptomaticulcers (annualizedrate)

Celecoxib

NSAlDs

2031 2/2031 (0.1%) 18/2031 (0.0%)

10t4 7/1014 (0.7%)* 2311014 (2.0%)*

Odds RaUo

95%oCI

7.02

1.34-69.27

2.23

1.12-4.48

*p=O.O03vs celecoxib 555 Significantly Improved Upper Gastrointestinal (UGI) Tolerability with Celecoxib, a COX-2 Specific Inhibitor, Comparedwith Conventional NSAIDs. The SUCCESS I Trial Jay L. Goldstein, Univ of Illinois at Chicago, Chicago, IL; NaurangAgrawal, Duke Univ Medical Ctr, Durham, NC; Glenn M. E/sen, Vanderbilt Univ Medical Ctr, Nashville, TN; William Stenson, Washington Univ Sch of Medicine, St Louis, UO; AI E. Bello, Pharmacia, Skokie, IL; John G. Fort, Susan P. Boots, Pharmacia, Peapack,NJ Background:The CelecoxibLong-termArthritis SafetyStudy (CLASS),a prospectiveoutcomes study conductedin North America, demonstrateda significant reduction in UGI ulcer complications and improved tolerability. To extend our understanding of the UGI safety advantages of celecoxib over conventional nonsteroidal anti-inflammatory drugs (NSAIDs), in day to day practice, a naturalistic study was conducted worldwide. Method: SUCCESS I, a large, 12week, multinational, double-blind, randomized trial in 13,274 osteoarthritis patients, was conducted in 39 countries. There were 6547 patients from Europe/Africa, 2756 from North America, 2889 from Latin America, and 1082 from Asia/Pacific.Celecoxib200 mg/d (n = 4421) and 400 mg/d (n = 4429) was compared with naproxen 1000 mg/d (n-~ 914) and diclofenac 100 mg/d (n=3510) with regard to GI tolerability. Results: The frequency of all reported GI adverse events (AEs), the 3 most frequently reported UGI AEs, and withdrawals due to GI AEs are shown in the table. Conclusions: UGI symptoms, more commonly associated with NSAID use, were consistently and significantly lower with celecoxib. The percent reduction ranged from 18.6% to 29.4%. Thesedata confirm the superior GI tolerability of celecoxibvs conventional NSAIDs and establish that this difference is clinically meaningful in terms of discontinuation of therapy for such symptoms. Sponsored by Pharmacia Corporation and Pfizer, Inc.

553 Lack of Correspondenceof Risk Factors and Clinical GI Outcomesfor Patients on Nonsteroidal AofHnflammatory Drugs (NSAIDs): Analysis From the Celecoxib Longterm Arthritis Safety Study (CLASS). Glenn M. E/sen, Vanderbilt Univ Medical Ctr, Nashville, TN; On Behalf Of The Class Investigators, Clin Researchand Development,Pharmacia Inc, Skokie, IL Objective: ConventionalNSAIDs are associatedwith the developmentof symptomatic ulcers and ulcer complications. Such serious gastrointestinal (GI) toxicity may occur more frequently in individuals with identifiable risk factors as noted in the MUCOSAtrial. Datafrom the CLASS study were analyzedto identity patientsat risk for NSAID-relatedserious GI toxicity. Methods: Univariate and multivariate analysis of a number of potential risk factors for symptomatic ulcers and ulcer complications was performed in patients receiving conventional NSAIDs. Results: Univariate analysis identified the following as significant risk factors (p-75 y (3.7), history of ulcer disease(2.7), history of GI bleeding(3.4), aspirin use (2.3), cardiovascular disease (1.6), and Helicobacter pylori seropositivity (2.0). The following were not significant risk factors: arthritis type, arthritis duration, patient global assessment of arthritis, alcohol use, tobacco use, corticosteroid use, anticoagulant use, and gender. Multivariate analysis identified age ->75 y, history of ulcer disease, and aspirin use as the most important dsk factors (relative risk of 3.3, 2.6, and 2.1, respectively). Risk of serious GI toxicity rose in a nonadditive fashion with the number of risk factors. Patients with B, 1, and 2 or more risk factors had crude rates of symptomatic ulcers and ulcer complications of 0.6%, 1.4%, and 4.1% on NSAIDs. Although the risk of an event increased with the number of risk factors, most events occurred in patients with 0 or 1 risk factor (65% of aft events). Patients on celecoxib were most at risk if they were on concurrent low-dose aspirin (relative risk of 3.7 by univariate analysis), which, as an NSAID, was associated with the risk factors above. Conclusions: This study confirms the NSAID risk factor analysis results of the MUCOSAtrial and that risk increases nonadditivelywith the number of risk factors. However, most events in patients treated with conventional NSAIDs occur in patients at low or no risk. Sponsored by Pharmacia Corporation and Pfizer, Inc.

NSAlDs (n--4394)

Celecoxib (n=8800)

% Reduction

p Value

All GI AES UGI AEs Abdominalpain Dyspepsia Nausea

21.0% 15.6% 6.2% 5.9% 3.4%

16.7% 11.9% 4.8% 4.8% 2.4%

20.4% 23.7% 22.5% 18.6% 29.4%

<0.00t <0.001 <0.001 <0.008 <0.001

W'dhdrawals dueto GI AE

6.8%

5.2%

23.5%

<0.001

561 Specific Targeting of Tumor Vasculofure by DT-VEGF Fusion Protein Reduces Angiogenests and Growth of Pancreatic Cancer Hubert G. Hotz, Gactrointestinal Surg, UCLA Sch of Medicine, Los Angeles, CA; Parkash S. Gill, Rizwan Uasood, Dept of Medicine and Pathology, USC Sch of Medicine, Los Angeles, CA; Birgit Hotz, Gastrointestinal Surg, UCLA Sch of Medicine, Los Angeles, CA; Heinz J. Buhr, Thomas Foitzik, Dept of Surg, UK Benjamin Franklin, Berlin Germany; Oscar J. Hines, Gastrointestinal Surg, UCLA Sch of Medicine, Los Angeles, CA; Howard A. Reber, Gastrointestinal Surg, Los Angeles, CA

554 Significant Reduction in Serious Upper Gastrointestinal (UGI) Eventswith Celecoxib, a COX-2 Specific Inhibitor, Compared with Conventional NSAIDs. The SUCCESSI Trial Jay L. Goldstein, Univ of Illinois at Chicago, Chicago, IL; Glenn M. E/sen, Vanderbilt Univ Medical Ctr, Nashville, TN; William Stenson, Washington Univ Sch of Medicine, St Louis, MO; Naurang Agrawal, Duke Univ Medical Ctr, Durham, NC; AI E. Bello, Pharmacia, Skokie, IL; John G. Fort, Susan P. Boots, Pharmacia, Peapack,NJ

Anti-angiogenesisis a noveltreatment strategyfor pancreaticcancer(PaCa).Activatedendothelial cells of the tumor vasculatureabundantlyexpress receptorsfor vascularendothelialgrowth factor (VEGF),a key mediator of angiogenesis.The aim of the study was to specificallytarget and damagethe vasculature of PaCa by fusing the VEGFisoform VEGF~ to diphtheria toxin (DT), which inhibits the protein synthesis of target cells. Methods: VEGFlesfusion protein containing the enzymaticand translocation domains of DT was produced with GST in vector pGEX-KG and expressed in E. col/SG12036. In vitro: Two human PaCacell lines (AsPC-1, poorly differentiated; HPAF-2,moderatelydifferentiated) and human endothelialcells (HUVEC) were exposedto increasing concentrations (1 - 10000 ng/ml) of DT-VEGF.Cell proliferation was assessed after 3 days by cell count and Ul-r-assay. In vivo: 1 mm~ fragments of sc. PaCadonor tumors were implanted into the pancreasof nude mice which receivedeither OTVEGF (200 pg/kg, every other day) or vehicle (Con) ip. for 14 weeks. Volume of primary tumor (TU-Vol), metastaticspread(Met-Score),and animal weight were determinedat autopsy. Microvessel density (MVD) was analyzed in CD31-stainedtumor sections. Results: In vitro:

Background: The Celecoxib Long-term Arthritis Safety Study (CLASS), a North American prospectiveoutcomes study, demonstrateda significant reduction in UGI ulcer complications and improved tolerability. To extend our understanding of the UGI safety advantages of celecoxibover conventional NSAIDs,a naturalistic study was conducted worldwide. Methods: SUCCESS I, a large, 12-week, multinational, prospective, double-blind randomized trial in 13,274 osteoarthritis patients, was conducted in 39 countries. There were 6547 patients from Europe/Africa, 2756 1rum North America, 2889 from Latin America, and 1082 from Asia/ Pacific. Celecoxib200 mg/d (n = 4421) and 400 mg/d (n = 4429) was comparedwith naproxen

A-105