gastrointestinal ulcers and ulcer complications 2 (COX2) enzyme might reduce this burden. 8 To date, two groups of investigators have attempted to

Transcription

1 Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial Thomas J Schnitzer, Gerd R Burmester, Eduardo Mysler, Marc C Hochberg, Michael Doherty, Elena Ehrsam, Xavier Gitton, Gerhard Krammer, Bernhard Mellein, Patrice Matchaba, Alberto Gimona, Christopher J Hawkey, on behalf of the TARGET Study Group* Summary Background Cyclo-oxygenase 2 (COX2)-selective inhibitors should reduce ulcer complications compared with nonselective non-steroidal anti-inflammatory drugs, but evidence is limited, and the possibility that these inhibitors increase cardiovascular events has been raised. The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) aimed to assess gastrointestinal and cardiovascular safety of the COX2 inhibitor lumiracoxib compared with two non-steroidal anti-inflammatory drugs, naproxen and ibuprofen. Methods patients age 50 years or older with osteoarthritis were randomised to lumiracoxib 400 mg once daily (n=9156), naproxen 500 mg twice daily (4754), or ibuprofen 800 mg three times daily (4415) for 52 weeks, in two substudies of identical design (lumiracoxib vs ibuprofen or naproxen). Randomisation was stratified for low-dose aspirin use and age. The primary endpoint was the difference in time-to-event distribution of upper gastrointestinal ulcer complications (bleeding, perforation, or obstruction); analysis was by modified intention to treat. The principle measure of adverse cardiovascular events was the Antiplatelet Trialists Collaboration endpoint (myocardial infarction, stroke, or cardiovascular death); this analysis was intention to treat. Findings 81 (0 44%) patients did not start treatment and 7120 (39%) did not complete the study. In patients not taking aspirin, the cumulative 1-year incidence of ulcer complications was 1 09% (95% CI ) with nonsteroidal anti-inflammatory drugs (64 events) versus 0 25% (95% CI ) with lumiracoxib (14 events; hazard ratio 0 21 [95% CI ], p<0 0001). Reductions in ulcer complications were also significant in the overall population (0 34 [ ], p<0 0001) but not in those taking aspirin (0 79 [ ], p=0 4876). In the overall population, 0 55% (50/9127) of those on non-steroidal anti-inflammatory drugs and 0 65% (59/9117) of those on lumiracoxib reached the cardiovascular endpoint (1 14 [ ], p=0 5074). Interpretation Lumiracoxib showed a three to four-fold reduction in ulcer complications compared with nonsteroidal anti-inflammatory drugs without an increase in the rate of serious cardiovascular events, suggesting that lumiracoxib is an appropriate treatment for patients with osteoarthritis. Introduction studies were of similar size (about 8000 patients) but Non-selective non-steroidal anti-inflammatory drugs are differed in several ways eg, the endpoints. 11 The widely used by patients with acute or chronic pain due to osteoarthritis and rheumatoid arthritis. 1 3 Unfortunately, people taking these drugs are at increased risk for incurring clinically important damage to the mucosa of the gastrointestinal tract. 4 Estimates suggest that nonsteroidal anti-inflammatory drugs lead to admission for ulcer complications (bleeding and perforation) in % of users per year 5,6 and result in at least 7000 deaths annually in the USA 6 and 1000 deaths every year in the UK. 7 Therefore, development of drugs that reduce or abolish these gastrointestinal side-effects is Celecoxib Long-term Arthritis Safety Study (CLASS) 9,12 compared celecoxib with either ibuprofen or diclofenac in patients with osteoarthritis or rheumatoid arthritis and failed to show a significant benefit for celecoxib for the primary endpoint of upper gastrointestinal ulcer complications for the full duration of the study. The Vioxx GI Outcomes Research (VIGOR) study 10 compared rofecoxib with naproxen in patients with rheumatoid arthritis and showed a significant benefit for rofecoxib for the broader primary endpoint of clinical upper gastrointestinal events (defined as symptomatic upper important. Selective inhibitors of the inducible cyclooxygenase gastrointestinal ulcers and ulcer complications 2 (COX2) enzyme might reduce this burden. 8 To date, two groups of investigators have attempted to [perforations, ulcers, and bleeds]). Patients receiving low-dose aspirin were excluded show a reduction in serious gastrointestinal outcomes from VIGOR, 10 so the effect of concomitant low-dose with COX2-selective inhibitors compared with nonselective non-steroidal anti-inflammatory drugs. 9,10 Both aspirin and rofecoxib on gastrointestinal outcomes could not be ascertained. Nevertheless, findings of a 12-week Lancet 2004; 364: See Comment Office of Clinical Research and Training, Northwestern University Feinberg School of Medicine, Chicago, IL, USA (Prof T J Schnitzer MD); Department of Rheumatology and Clinical Immunology, Charité University Medicine Berlin, Humboldt University of Berlin, Berlin, Germany (Prof G R Burmester MD); Department of Rheumatology, Organization Médica de Investigation, Buenos Aires, Argentina (Prof E Mysler MD); Division of Rheumatology and Clinical Immunology, University of Maryland School of Medicine, Baltimore, MD, USA (Prof M C Hochberg MD); Academic Rheumatology, University of Nottingham, City Hospital, Nottingham, UK (Prof M Doherty FRCP); Novartis Pharma, Basel, Switzerland (E Ehrsam MD, X Gitton PhD, G Krammer MSc, B Mellein PhD, A Gimona MD); Novartis Pharmaceuticals, East Hanover, NJ, USA (P Matchaba FCOG); and Institute of Clinical Research Trials Unit, Wolfson Digestive Diseases Centre, University Hospital, Nottingham NG7 2UH, UK (Prof C J Hawkey FRCP) Correspondence to: Prof Christopher J Hawkey cj.hawkey@nottingham.ac.uk *Members listed in webappendix ( thelancet.com/extras/04art6482 webappendix.pdf) Vol 364 August 21,

2 endoscopy study showed that the incidence of gastroduodenal ulcers in individuals taking low-dose aspirin and rofecoxib was similar to that in patients taking ibuprofen (800 mg three times daily) alone. 13 The exclusion of low-dose aspirin use in the VIGOR study 10 could have contributed to a much higher rate of cardiovascular thrombotic events, particularly myocardial infarctions, in patients taking rofecoxib compared with those taking naproxen. Unanswered is whether the increase in thrombotic events happened by chance; whether it represented a beneficial (antithrombotic) effect of naproxen, a harmful effect of rofecoxib, or a combination of all three; and whether the differences were specific to rofecoxib or related to comparisons between naproxen and COX2 inhibitors as a class of drugs. 14 These issues remain unresolved. Lumiracoxib is a novel COX2-selective inhibitor that differs structurally from other drugs in the class. 15,16 The other inhibitors contain a tricyclic ring and a sulfone or sulfonamide group, 17 whereas lumiracoxib is a phenyl acetic acid derivative with a pka of It has the highest selectivity and a fairly short plasma half-life (3 6 h) compared with other COX2-selective inhibitors. 18 The effectiveness of lumiracoxib is superior to placebo in patients with osteoarthritis at doses of 100 mg and 200 mg once daily. 19,20 In endoscopic studies, this drug has been associated with a rate of acute gastric injury and chronic ulcer formation that does not differ from placebo 21 and is significantly lower than with the nonselective non-steroidal anti-inflammatory ibuprofen. 22,23 To establish the gastrointestinal safety of lumiracoxib, the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) was planned to test the hypothesis that patients with osteoarthritis, randomised to lumiracoxib at two or four times the recommended dose for osteoarthritis, had significantly fewer complicated ulcers than patients randomised to either ibuprofen or naproxen at the therapeutic dose. To address the issues raised as a result of previous studies, TARGET was, by design, much larger than the CLASS and VIGOR outcome trials. Patients and methods Details of the methodology and implementation of the TARGET study have been published elsewhere 24 and are summarised briefly here. Study design TARGET was a 52-week, international, multicentre, randomised investigation using parallel group methodology and a double-dummy technique to ensure doubleblind status with respect to lumiracoxib and the active control drugs naproxen and ibuprofen. To avoid the need for patients to take many placebos, TARGET was undertaken as two similarly sized substudies with identical design. One study compared lumiracoxib 400 mg daily with ibuprofen 800 mg three times daily and the other compared lumiracoxib 400 mg daily with naproxen 500 mg twice daily. The study was undertaken in accordance with International Conference on Harmonization guidelines and the Declaration of Helsinki and was approved by the ethics committees of all participating institutions. All patients gave their informed consent at the time of enrolment. Patients We enrolled men and women aged 50 years or older with a clinical diagnosis of osteoarthritis of the hip, knee, or hand who fulfilled American College of Rheumatology preliminary classification criteria or osteoarthritis of the cervical or lumbar spine (confirmed by radiography, with absence of radicular symptoms). Patients were stratified into one of six strata before randomisation by low-dose aspirin use ( mg daily) and by age (50 64, 65 74, 75 years). Patients with primary osteoarthritis could enter the study if they had at least moderate pain (3 on a 5-point Likert scale) at baseline in a specified target joint and were anticipated to need treatment for 52 weeks or longer. We excluded individuals taking gastroprotective drugs including proton-pump inhibitors, misoprostol, and full dose H2-antagonists and those with an active upper gastrointestinal ulceration in the previous 30 days, upper gastrointestinal bleeding in the past year, or any history of gastroduodenal perforation or obstruction. Patients with a history of myocardial infarction, stroke, coronary-artery bypass graft, invasive coronary revascularisation, or new-onset angina within the previous 6 months or electrocardiogram evidence of recent silent myocardial ischaemia were excluded from enrolment, as were those with severe congestive heart failure (New York Heart Association class III IV). Individuals needing secondary prevention of coronary heart disease and those with a high risk of coronary heart disease, assessed with Framingham risk assessment equations, 28 were eligible for enrolment provided they had taken low-dose aspirin for at least 3 months. Those taking low-dose aspirin without such risk factors were also allowed to enter the study. Antiplatelet treatment (other than low-dose aspirin) and anticoagulant use were not permitted. Patients were excluded from the study if they had evidence of serious hepatic, renal, or blood coagulation disorders or severe anaemia. Procedures We randomly allocated patients treatment with lumiracoxib 400 mg once daily (two or four times the recommended chronic dose for osteoarthritis), naproxen 500 mg twice daily (maximum therapeutic dose), or ibuprofen 800 mg three times daily (maximum therapeutic dose) for 52 weeks. For logistical and masking reasons, TARGET was divided into two substudies, one with naproxen as the comparator and Vol 364 August 21, 2004

3 the other with ibuprofen. Within each substudy randomisation was stratified by age and low-dose aspirin use. The sponsor prepared a computer-generated randomisation list with appropriate blocks. The study was centrally randomised according to strata with an interactive voice response system in all countries to ensure age and low-dose aspirin stratification. Allocation of treatment was done via the interactive system and all information was verified by this system before allocation of the patient to a treatment and assignment of the drug packs. To ensure allocation concealment all treatment packs were identically designed and all study drugs were supplied as tablets with matching placebo. We prespecified that data from the two substudies would be pooled for analysis. Patients made routine visits to the study clinic at baseline and after 4, 13, 20 (additional visit, protocol amendment), 26, 39, and 52 weeks or until withdrawal, with a follow-up visit (phone contact) 4 weeks after exit from the study. We assessed compliance by counting returned treatment and rescue medication tablets. A patient was defined as compliant if they consumed the full daily dose of study medication on at least 75% of study days. We obtained clinical tolerability and laboratory data at every visit, and in keeping with the real-life nature of TARGET, endoscopic investigation was at the discretion of the investigator, reflecting local best practice. Three safety adjudication committees independent from each other and the sponsor were established before enrolment of patients to assess and categorise (under masked conditions) gastrointestinal, cardiovascular and cerebrovascular, and hepatobiliary events. Investigators were required to report all suspected occurrences of a series of gastrointestinal, cardiovascular, and hepatobiliary events, which were then forwarded to the safety committees for adjudication. Every member of the gastrointestinal safety committee independently adjudicated and categorised the reported clinical event, its likelihood (ie, definite, probable, possible, or non-event or insufficient evidence), the likely underlying cause, and whether serious clinical ulcer bleeding had taken place. Assessment was guided by extensive criteria, summarised in detail elsewhere. 24 Briefly, to have a definite or probable upper gastrointestinal ulcer complication, patients had to present with haematemesis or melaena, perforation, obstruction, or a 2 g/l or greater drop in haemoglobin and 6 point or more fall in haematocrit (packed cell volume), and to have an ulcer or erosion in the oesophagus, stomach, or duodenum that the committee were confident was the cause. Consensus was achieved on any differences at telephone conferences held at least monthly. The gastrointestinal safety committee also evaluated all reports of uncomplicated ulcers or erosions. The cardiovascular safety committee worked similarly to adjudicate cardiovascular and cerebrovascular endpoints, including those contributing to the Antiplatelet Trialists Collaboration composite endpoint (confirmed silent myocardial infarction and confirmed or probable clinical myocardial infarction, ischaemic or haemorrhagic stroke, and cardiovascular deaths). 29 The liver safety committee reviewed all increases of alanine or aspartate transaminase more than three times the upper limit of normal, or total bilirubin value more than 51 3 mol/l, to adjudicate these events as hepatocellular, mixed, cholestatic, not possible to assess, and whether the event was probably, possibly, or not related to the study drug. The primary endpoint of TARGET was difference in time-to-event distribution of definite or probable upper gastrointestinal ulcer complications (clinically significant bleeding, perforation, or obstruction from erosive or ulcer disease). As a secondary endpoint, we compared the incidence of all ulcers, combining definite or probable ulcer complications (as defined above) and uncomplicated symptomatic ulcers (ulcers discovered when endoscopy was done for dyspepsia), in an endpoint similar to that reported elsewhere as perforations, ulcers, and bleeding. 9,10 Here, we also report comparisons of acute and chronic anaemia attributed to bleeding. More detailed analyses of upper and lower gastrointestinal events and their relation to non-drug risk factors will be reported elsewhere. We used the Antiplatelet Trialists Collaboration composite endpoint as the main method of comparing cardiovascular effects of the trial drugs. Other cardiovascular endpoints were the individual events contributing to this composite endpoint and transient ischaemic attack, cardiac arrest, unstable angina, deep venous thrombosis, and pulmonary embolism. More detailed analyses of cardiovascular events are reported elsewhere in this issue. 30 A predefined combined gastrointestinal and cardiovascular safety endpoint consisted of all definite or probable upper gastrointestinal ulcer complications and all confirmed or probable occurrences of the composite cardiovascular endpoints. Additional important safety endpoints included: liver safety (as detailed above); major renal events (doubling of serum creatinine from baseline, or proteinuria 3 g/l); time to discontinuation for any reason, owing to adverse events or gastrointestinal adverse events; and incidence of prespecified gastrointestinal adverse events, serious adverse events, and deaths. We assessed efficacy at weeks 13, 26, 39, and 52 by pain intensity in the target joint, patient s global assessment of disease activity, and doctor s global assessment of disease activity, all assessed on a 5-point Likert scale. The number of paracetamol tablets taken as rescue medication was also compared. See Articles page Vol 364 August 21,

4 39 did not start treatment 9156 lumiracoxib 9117 started treatment as allocated (safety population) 3431 (38%) withdrawn 1408 (15%) adverse events 81 (1%) abnormal lab values 24 (<1%) abnormal test procedure results 754 (8%) unsatisfactory therapeutic effect 26 (<1%) condition no longer requires study drug 376 (4%) protocol violation 660 (7%) consent withdrawn 60 (1%) administrative problems 19 (<1%) lost to follow-up 23 (<1%) death Figure 1: Trial profile Percentages refer to safety population patients screened 3462 excluded patients randomised 24 did not start treatment 4754 naproxen 4415 ibuprofen 4730 started treatment as allocated (safety population) 1766 (37%) withdrawn 845 (18%) adverse events 35 (1%) abnormal lab values 6 (<1%) abnormal test procedure results 303 (6%) unsatisfactory therapeutic effect 18 (<1%) condition no longer requires study drug 167 (4%) protocol violation 344 (7%) consent withdrawn 33 (1%) administrative problems 4 (<1%) lost to follow-up 11 (<1%) death 18 did not start treatment 4397 started treatment as allocated (safety population) 1923 (44%) withdrawn 789 (18%) adverse events 33 (1%) abnormal lab values 13 (<1%) abnormal test procedure results 429 (10%) unsatisfactory therapeutic effect 16 (<1%) condition no longer requires study drug 192 (4%) protocol violation 402 (9%) consent withdrawn 21 (<1%) administrative problems 17 (<1%) lost to follow-up 11 (<1%) death 5686 (62%) completed trial 2964 (63%) completed trial 2474 (56%) completed trial Statistical analysis We did statistical analyses on the safety population, consisting of all patients randomised who received at least one dose of study drug. Since previous treatment can continue to affect the incidence of ulcer complications after cessation, the primary analysis of the primary endpoint excluded events arising within the first 48 h (modified intent-to-treat analysis) of the treatment period. The primary endpoint was analysed with a closed test procedure applying a hierarchical testing process. In the first step, this endpoint was tested in the population of patients not taking low-dose aspirin. If this test was positive the second step was to analyse the endpoint in the overall population. If this test was positive the third and final step was to do the analysis in the population of patients taking low-dose aspirin. Hypotheses were tested at a one-sided 2 5% level of significance, using the logrank test stratified by substudy and low-dose aspirin use, as appropriate. 31 Cox proportional-hazards models (with substudy, age, and low-dose aspirin as covariates) were also used to assess differences in the time-to-event distribution between treatment groups. 32 We used the Kaplan-Meier approach to generate estimates of the cumulative probability of events happening up to a particular timepoint. We averaged efficacy endpoints across visits, using a last observation carried forward-approach for missing post-baseline assessments, and did an analysis of covariance (ANCOVA) with baseline value (if missing, the median of the baseline assessments in the safety population was used), substudy, and low-dose aspirin use as factors. A post-hoc ANCOVA was done on postbaseline blood pressure assessments, averaged across visits, with baseline value and substudy as covariates. As detailed elsewhere, we anticipated an incidence of ulcer complications of 1 3% in the NSAID-treated group not taking aspirin and 2 5% in the NSAID-treated group taking low-dose aspirin. 24 To obtain 90% power to detect a 50% reduction in definite or probable upper gastrointestinal ulcer complications in patients not taking lowdose aspirin (resulting in a 44% reduction in the overall Both substudies Lumiracoxib vs ibuprofen substudy Lumiracoxib vs naproxen substudy Lumiracoxib (n=9117) NSAIDs (n=9127) Lumiracoxib Ibuprofen Lumiracoxib Naproxen (n=4376) (n=4397) (n=4741) (n=4730) Age years* 5137 (56%) 5168 (57%) 2527 (58%) 2536 (58%) 2610 (55%) 2632 (56%) years 3005 (33%) 2969 (33%) 1385 (32%) 1389 (32%) 1620 (34%) 1580 (33%) 75 years 975 (11%) 990 (11%) 464 (11%) 472 (11%) 511 (11%) 518 (11%) Mean (SD) 63 5 (8 37) 63 4 (8 35) 63 4 (8 45) 63 3 (8 38) 63 6 (8 29) 63 6 (8 31) Women 6963 (76%) 6970 (76%) 3298 (75%) 3345 (76%) 3665 (77%) 3625 (77%) Body-mass index (kg/m 2 ) Number of patients Mean (SD) 29 6 (5 70) 29 5 (5 64) 30 0 (5 91) 29 7 (5 88) 29 3 (5 48) 29 2 (5 39) High cardiovascular risk 1141 (13%) 1066 (12%) 484 (11%) 423 (10%) 657 (14%) 643 (14%) Low-dose aspirin use 2167 (24%) 2159 (24%) 975 (22%) 966 (22%) 1192 (25%) 1193 (25%) Impaired renal function 180 (2%) 171 (2%) 85 (2%) 71 (2%) 95 (2%) 100 (2%) H pylori positive 4029 (44%) 4028 (44%) 1788 (41%) 1809 (41%) 2241 (47%) 2219 (47%) Data are number of patients (%) or mean (SD). NSAIDs=non-steroidal anti-inflammatory drugs. *Includes 20 patients (ten each in the lumiracoxib and NSAIDs group) of age 49 or younger. Defined as patients with high cardiovascular risk based on Framingham equations and patients with a cardiovascular history. Defined as serum creatinine greater than the upper limit of normal or urine protein 1000 mg/l at baseline. Assessed at study end; status not available in 2106 patients (12%). Table 1: Patients characteristics (safety population) Vol 364 August 21, 2004

5 Both substudies Lumiracoxib vs ibuprofen substudy Lumiracoxib vs naproxen substudy Lumiracoxib (n=9156) NSAIDs (n=9169) Lumiracoxib Ibuprofen Lumiracoxib Naproxen (n=4399) (n=4415) (n=4757) (n=4754) Discontinued 3470 (38%) 3731 (41%) 1751 (40%) 1941 (44%) 1719 (36%) 1790 (38%) Reason for discontinuation Adverse events 1409 (15%) 1635 (18%) 699 (16%) 789 (18%) 710 (15%) 846 (18%) Abnormal laboratory values 82 (1%) 69 (1%) 42 (1%) 33 (1%) 40 (1%) 36 (1%) Abnormal test procedure 24 (<1%) 19 (<1%) 11 (<1%) 13 (<1%) 13 (<1%) 6 (<1%) results Unsatisfactory therapeutic 754 (8%) 732 (8%) 393 (9%) 429 (10%) 361 (8%) 303 (6%) effect Patient's condition no longer 26 (<1%) 34 (<1%) 11 (<1%) 16 (<1%) 15 (<1%) 18 (<1%) requires study drug Protocol violation 380 (4%) 361 (4%) 187 (4%) 192 (4%) 193 (4%) 169 (4%) Patient withdrew consent 692 (8%) 783 (9%) 363 (8%) 419 (9%) 329 (7%) 364 (8%) Administrative problems 61 (1%) 55 (1%) 21 (<1%) 22 (1%) 40 (1%) 33 (1%) Lost to follow-up 19 (<1%) 21 (<1%) 15 (<1%) 17 (<1%) 4 (<1%) 4 (<1%) Death 23 (<1%) 22 (<1%) 9 (<1%) 11 (<1%) 14 (<1%) 11 (<1%) Data are number of patients (%). NSAIDs=non-steroidal anti-inflammatory drugs. Table 2: Summary of reasons for discontinuation (randomised population) population with a power of 95%), we calculated that patients would need to be enrolled and that 156 patients would develop definite or probable ulcer complications. Role of the funding source The study was designed interactively between an advisory board and the sponsor. The sponsor managed the data and did all final analyses. Authors had full access to all data and were involved in data interpretation and wrote the first draft of the report, which was further developed in collaboration with the sponsor. Results Figure 1 and tables 1 and 2 show the disposition of patients included in the study. All demographic variables were comparable across the treatment groups and within the two substudies, with two notable differences. The substudy that compared naproxen with lumiracoxib included more patients with cardiovascular risk factors and evidence of Helicobacter pylori infection by positive serology than did the substudy that compared ibuprofen with lumiracoxib. Compliance was similar between lumiracoxib (6965, 76%) and non-steroidal anti-inflammatory drugs (6915, 76%) and within substudies (3189 [73%] ibuprofen vs 3213 [73%] lumiracoxib and 3726 [79%] naproxen vs 3752 [79%] lumiracoxib). Patients were significantly less likely to discontinue lumiracoxib for any reason compared with non-steroidal anti-inflammatory drugs (hazard ratio 0 90 [95% CI ], p<0 0001), ibuprofen (0 86 [ ], p<0 0001), and naproxen (0 93 [ ], p=0 0437; figure 1, table 2). 114 ulcer complications arose in total, two within 48 h of randomisation one event in the lumiracoxib group 1 0 Lumiracoxib Non-steroidal anti-inflammatory drugs p< p< p= Cumulative incidence (%) Non-steroidal anti-inflammatory drugs Lumiracoxib Logrank p< Crude incidence (%) Number at risk Lumiracoxib Non-steroidal anti-inflammatory drugs Study day Overall population Non-aspirin population Aspirin population Figure 2: Definite or probable upper gastrointestinal ulcer complications in the non-aspirin population Figure 3: Definite or probable upper gastrointestinal ulcer complications in all study populations Vol 364 August 21,

6 Number of patients with Hazard ratio p* events/number at risk (%) (95% CI) Overall population Both substudies Lumiracoxib29/9117 (0 32%) 0 34 ( ) < Non-steroidal anti-inflammatory drugs 83/9127 (0 91%) Lumiracoxib vs ibuprofen substudy Lumiracoxib10/4376 (0 23%) 0 29 ( ) Ibuprofen 33/4397 (0 75%) Lumiracoxib vs naproxen substudy Lumiracoxib19/4741 (0 40%) 0 37 ( ) Naproxen 50/4730 (1 06%) Non-aspirin population Both substudies Lumiracoxib14/6950 (0 20%) 0 21 ( ) < Non-steroidal anti-inflammatory drugs 64/6968 (0 92%) Lumiracoxib vs ibuprofen substudy Lumiracoxib5/3401 (0 15%) 0 17 ( ) Ibuprofen 28/3431 (0 82%) Lumiracoxib vs naproxen substudy Lumiracoxib9/3549 (0 25%) 0 24 ( ) Naproxen 36/3537 (1 02%) Aspirin population Both substudies Lumiracoxib15/2167 (0 69%) 0 79 ( ) Non-steroidal anti-inflammatory drugs 19/2159 (0 88%) Lumiracoxib vs ibuprofen substudy Lumiracoxib5/975 (0 51%) 0 92 ( ) Ibuprofen 5/966 (0 52%) Lumiracoxib vs naproxen substudy Lumiracoxib10/1192 (0 84%) 0 73 ( ) Naproxen 14/1193 (1 17%) *Based on Wald 2 statistic for treatment group comparison. Cox proportional-hazards models include, in addition to treatment group, the factors: substudy, low-dose aspirin, and age; low-dose aspirin and age; substudy and age; and age. Table 3: Incidence of upper gastrointestinal ulcer complications (definite or probable), by substudy and aspirin use (modified intention-to-treat analysis) of the ibuprofen substudy and one in the naproxen group of the naproxen substudy, which were excluded from analysis of the primary endpoint (modified intention to treat). In patients not taking low-dose aspirin, a four-fold reduction in the incidence of definite or probable ulcer complications was seen in patients taking lumiracoxib compared with non-steroidal antiinflammatory drugs (figures 2 and 3, table 3). 1-year Kaplan-Meier estimates were 0 25% in the lumiracoxib group and 1 09% in the non-steroidal anti-inflammatory group (figure 2). When the overall (aspirin and nonaspirin) population was considered, ulcer complications were significantly reduced by about three-fold on lumiracoxib compared with ibuprofen or naproxen (table 3). A significant reduction was also seen in patients both positive and negative for H pylori (status ascertained in about 90% of patients at study end; data not shown). In those taking low-dose aspirin, fewer cases of definite or probable ulcer complications were recorded with lumiracoxib than with non-steroidal antiinflammatory drugs (15 vs 19 events) but differences were not significant (table 3, figure 3). Most of the definite or probable ulcer complications presented as melaena or haematochezia (table 4). In the overall population the risk of acute or chronic anaemia (combined) was reduced with lumiracoxib by 52% versus non-steroidal anti-inflammatory drugs (p<0 0001), 60% versus ibuprofen (p<0 0001), and 40% versus naproxen (p=0 0137). Fewer symptomatic uncomplicated ulcers arose with lumiracoxib (58 [0 64%]) than with non-steroidal anti-inflammatory drugs (103 [1 13%]; hazard ratio 0 55 [95% CI ], p=0 0003). As a result, the incidence of the combined endpoint of complicated or symptomatic ulcers in patients not taking low-dose aspirin was significantly reduced for lumiracoxib versus non-steroidal anti-inflammatory drugs (0 38 [ ], p<0 0001) and compared with ibuprofen (0 36 [ ], p<0 0001) or naproxen (0 39 [ ], p<0 0001) separately. In the overall population, occurrence of this combined endpoint was significantly lower for lumiracoxib versus non-steroidal anti-inflammatory drugs (0 46 [95% CI ], p<0 0001). In patients taking low-dose aspirin, fewer cases of complicated and symptomatic ulcers arose with lumiracoxib compared with non-steroidal antiinflammatory drugs (33 vs 45 events), but the differences were not significant (0 73 [ ], p=0 1706). No significant differences were recorded in the composite cardiovascular endpoint (confirmed silent myocardial infarction and confirmed or probable clinical myocardial infarction, ischaemic or haemorrhagic stroke, and cardiovascular deaths) for lumiracoxib Both substudies Lumiracoxib vs ibuprofen substudy Lumiracoxib vs naproxen substudy Lumiracoxib (n=9117) NSAIDs (n=9127) Lumiracoxib Ibuprofen Lumiracoxib Naproxen (n=4376) (n=4397) (n=4741) (n=4730) Patients with definite or 29 (0 32%) 83 (0 91%) 10 (0 23%) 33 (0 75%) 19 (0 40%) 50 (1 06%) probable upper gastrointestinal complications Gastrointestinal perforation 1 (0 01%) 2 (0 02%) 0 1 (0 02%) 1 (0 02%) 1 (0 02%) Gastric outlet obstruction 0 1 (0 01%) 0 1 (0 02%) 0 0 Haematemesis 6 (0 07%) 8 (0 09%) (0 13%) 8 (0 17%) Haematochezia or melaena 16 (0 18%) 44 (0 48%) 8 (0 18%) 17 (0 39%) 8 (0 17%) 27 (0 57%) Laboratory evidence of bleeding 6 (0 07%) 28 (0 31%) 2 (0 05%) 14 (0 32%) 4 (0 08%) 14 (0 30%) NSAIDs=non-steroidal anti-inflammatory drugs. Table 4: Frequency of causes of definite or probable upper gastrointestinal ulcer complications (modified intention-to-treat analysis) Vol 364 August 21, 2004

7 versus non-steroidal anti-inflammatory drugs in all population groups (table 5). Additionally, the incidence of myocardial infarction (clinical and silent) did not differ in the overall population between lumiracoxib (23 [0 25%]) and non-steroidal anti-inflammatory drugs (17 [0 19%]; 1 31 [ ], p=0 4012). However, the incidence of myocardial infarction fell with naproxen (ten [0 21%]) compared with lumiracoxib (18 [0 38%]; 1 77 [ ], p=0 1471) and rose with ibuprofen (seven [0 16%]) when compared with lumiracoxib (five [0 11%]; 0 66 [ ], p=0 4833). The cardiovascular data from the TARGET study are reported in full elsewhere in this issue. 30 In the overall population, when the adjudicated gastrointestinal and cardiovascular endpoints were combined, incidence of this composite endpoint fell by 35% in patients on lumiracoxib versus non-steroidal anti-inflammatory drugs (table 6); in the naproxen substudy, this reduction was not significant. The incidence of serious liver abnormalities was 0 07% (six events) on lumiracoxib and 0 03% (three) on nonsteroidal anti-inflammatory drugs (hazard ratio 1 92 [95% CI ], p=0 3550). The proportion of patients with transaminase concentrations more than three times the upper limit of normal differed significantly between lumiracoxib (2 57% [n=230]) and non-steroidal anti-inflammatory drugs (0 63% [56]; 3 97 [ ], p<0 0001). In total, nine cases were adjudicated as probable or possible drug-induced clinical hepatitis. Six (0 07%) arose in patients randomised to lumiracoxib, two (0 05%) in those allocated ibuprofen, and one (0 02%) in a patient randomised to naproxen. Abnormalities resolved on cessation of treatment and no cases of liver failure, transplantation, or death attributable to drug-induced hepatitis were reported. The predefined endpoint of major renal events did not differ between patients randomised to lumiracoxib (46 events [0 51%]) and non-steroidal anti-inflammatory drugs (33 events [0 37%]; hazard ratio 1 34 [95% CI ], p=0 1971). Blood pressure measurements were recorded during all study visits, which was after drug intake in the morning. For systolic blood pressure, least squares mean change from baseline was +0 4 mm Hg for lumiracoxib and +2 1 mm Hg for non-steroidal antiinflammatory drugs (p<0 0001). For diastolic blood pressure, least squares mean change from baseline was 0 1 mm Hg for lumiracoxib and 0 5 mm Hg for nonsteroidal anti-inflammatory drugs (p<0 0001). Additional substudy analyses are reported elsewhere in this issue. 30 Discontinuations due to serious adverse events (hazard ratio 0 88 [95% CI ], p=0 1669) and deaths (0 92 [ ], p=0 7334) did not differ between treatments (table 7). Significantly more patients discontinued treatment because of adverse events on non-steroidal anti-inflammatory drugs (1635 [17 8%]) compared with lumiracoxib (1409 [15 4%]), based on the population randomised. The most usual adverse events were gastrointestinal, including dyspepsia and upper abdominal pain. Upper abdominal pain was reported less frequently with lumiracoxib (915 [10 0%]) than with non-steroidal anti-inflammatory drugs (1147 [12 6%]). Analgesic efficacy as measured by patient s and doctor s global assessment of disease activity and patient s target joint pain assessment with the 5-point Likert scale showed that lumiracoxib and non-steroidal anti-inflammatory drugs were similar in the intention-to-treat population (patient s global assessment, p=0 0153; doctor s global assessment, p=0 0234; patient s target joint pain assessment, p=0 1070). However, no differences were clinically significant. 33 Paracetamol was used by a similar proportion of patients in all treatment groups (data not shown). Number of patients Hazard ratio p* with events (%) (95% CI) Overall population Lumiracoxib59 (0 65%) 1 14 ( ) Non-steroidal anti-inflammatory drugs 50 (0 55%) Non-aspirin population Lumiracoxib35 (0 50%) 1 22 ( ) Non-steroidal anti-inflammatory drugs 27 (0 39%) Aspirin population Lumiracoxib24 (1 11%) 1 04 ( ) Non-steroidal anti-inflammatory drugs 23 (1 07%) *Based on Wald 2 statistic for treatment group comparison Cox proportional-hazards models include, in addition to treatment group, the factors: substudy, low-dose aspirin, and age; and substudy and age. Discussion The results of the TARGET study show a 79% reduction in ulcer complications in patients taking lumiracoxib compared with two frequently used anti-inflammatory drugs in a non-aspirin population. Similar reductions were noted when lumiracoxib was compared individually with ibuprofen (83% reduction) or naproxen (76% reduction). These overall three to fourfold proportional differences are very similar to findings of endoscopic studies. 22,23 Results of epidemiological studies suggest non-steroidal antiinflammatory drug use is associated with a four-fold increase in ulcer complications in old patients compared with those not taking these drugs. 5,34 The yearly incidence of ulcer complications on lumiracoxib was very low (0 26 events per 100 patient-years) and similar to that already reported from combined analysis of phase III trials. 35 Whether these values would differ from those in patients not using anti-inflammatory drugs would need direct placebo comparison for assessment. Results from outcome studies generally provide definitive information about clinically important endpoints in real-life settings. However, outcome study See Articles page 675 Table 5: Incidence of cardiovascular composite endpoint by aspirin use (safety population) See Articles page Vol 364 August 21,

8 Number of patients with Hazard ratio p* events/number at risk (%) (95% CI) Both substudies Lumiracoxib89/9117 (0 98%) 0 65 ( ) Non-steroidal anti-inflammatory drugs 133/9127 (1 46%) Lumiracoxib vs ibuprofen substudy Lumiracoxib30/4376 (0 69%) 0 50 ( ) Ibuprofen 56/4397 (1 27%) Lumiracoxib vs naproxen substudy Lumiracoxib59/4741 (1 24%) 0 75 ( ) Naproxen 77/4730 (1 63%) *Based on Wald 2 statistic for treatment group comparison. Cox proportional-hazards models include, in addition to treatment group, the factors sub-study, low-dose aspirin, and age; and low-dose aspirin and age. Table 6: Combined incidence of gastrointestinal and cardiovascular events, by substudy (safety population) assessments of COX2-selective inhibitors so far have generated more questions than answers We specifically designed TARGET to provide definitive answers both to the questions that motivated previous outcome studies and to the issues they raised. In particular, we wanted TARGET to address as its primary goal the clinically important endpoint of ulcer complications, rather than a broader variable of perforations, ulcers, and bleeding, and to provide answers across more than one non-steroidal antiinflammatory drug in patients in whom use of low-dose aspirin was prevalent. To achieve this aim we made TARGET a large and carefully controlled study. The 6882 patient-years on lumiracoxib and 6624 patientyears on non-steroidal anti-inflammatory drugs represent a five-fold increase in exposure compared with CLASS and three-fold increase compared with VIGOR. Other measures helped TARGET to achieve its objectives. Use of low-dose aspirin was allowed and its effect controlled for by stratification at randomisation. Power was maintained by enrolling all patients for a uniform period of 1 year, which was longer than the average in CLASS and VIGOR, and by maintaining high levels of patient retention. The size of TARGET allowed other relevant safety endpoints, particularly cardiovascular, to be studied meaningfully and the question of whether naproxen differs from ibuprofen when compared with lumiracoxib with respect to effects on cardiovascular disease to be addressed. The reductions in ulcer complications in TARGET seem larger than those reported in CLASS or VIGOR. This finding could indicate differences in the study design, populations, endpoints studied, or in the COX2 gastroprotective effect of different drugs. We did not see a difference in ulcer complications between treatments in patients taking low-dose aspirin for cardiovascular prophylaxis, although incidence of events with lumiracoxib was lower than with non-steroidal anti-inflammatory drugs. Thus, it is unlikely that lumiracoxib is associated with enhanced risk compared with nonsteroidal anti-inflammatory drugs when combined with low-dose aspirin. Overall, the incidences of cardiac events and myocardial infarction did not differ between lumiracoxib and non-steroidal anti-inflammatory drugs. When gastrointestinal and cardiovascular adjudicated adverse events were combined, lumiracoxib was associated with a 35% fall in incidence of these events compared with both non-steroidal anti-inflammatory drugs. Both substudies Lumiracoxib vs ibuprofen substudy Lumiracoxib vs naproxen substudy Lumiracoxib (n=9117) NSAIDs (n=9127) Lumiracoxib Ibuprofen Lumiracoxib Naproxen (n=4376) (n=4397) (n=4741) (n=4730) Total deaths 29 (<1%) 30 (<1%) 13 (<1%) 15 (<1%) 16 (<1%) 15 (<1%) Total number of patients with 7233 (79%) 7276 (80%) 3586 (82%) 3559 (81%) 3647 (77%) 3717 (79%) adverse events Total number of patients with 588 (6%) 566 (6%) 297 (7%) 272 (6%) 291 (6%) 294 (6%) serious adverse events Total number of patients with adverse events requiring discontinuation Any adverse event 1441 (16%) 1657 (18%) 718 (16%) 802 (18%) 723 (15 %) 855 (18%) (including serious adverse events) Serious adverse events 206 (2%) 225 (3%) 93 (2%) 110 (3%) 113 (2%) 115 (2%) Prespecified gastrointestinal 729 (8%) 1023 (11%) 365 (8%) 475 (11%) 364 (8%) 548 (12%) adverse events Prespecified gastrointestinal 3640 (40%) 3839 (42%) 1855 (42%) 1851 (42%) 1785 (38%) 1988 (42%) events Dyspepsia 2267 (25%) 2324 (26%) 1230 (28%) 1205 (27%) 1037 (22%) 1119 (24%) Abdominal pain upper 915 (10%) 1147 (13%) 380 (9%) 452 (10%) 535 (11%) 695 (15%) Diarrhoea 558 (6%) 442 (5%) 285 (7%) 247 (6%) 273 (6%) 195 (4%) Nausea 465 (5%) 525 (6%) 244 (6%) 261 (6%) 221 (5%) 264 (6%) Abdominal pain 328 (4%) 340 (4%) 147 (3%) 153 (4%) 181 (4%) 187 (4%) Vomiting 183 (2%) 182 (2%) 91 (2%) 93 (2%) 92 (2%) 89 (2%) Loose stools 71 (1%) 37 (<1%) 35 (1%) 19 (<1%) 36 (1%) 18 (<1%) Abdominal pain lower 16 (<1%) 32 (<1%) 7 (<1%) 15 (<1%) 9 (<1%) 17 (<1%) Diarrhoea (haemorrhagic) 0 2 (<1%) 0 1 (<1%) 0 1 (<1%) NSAIDs=non-steroidal anti-inflammatory drugs. Table 7: Incidence of adverse events and deaths (safety population) Vol 364 August 21, 2004

9 Abnormalities of liver function tests are recognised to arise with most non-steroidal anti-inflammatory drugs and COX2-selective inhibitors, 13,39 although rates vary between different drugs. Rises in transaminase of more than three times the upper limit of normal have been reported in 4% of patients treated for 2 6 months with diclofenac, 40 the most commonly prescribed nonsteroidal anti-inflammatory drug worldwide for treatment of osteoarthritis. 41,42 In TARGET, such an increase happened in 2 6% of patients on lumiracoxib, which was more than both non-steroidal antiinflammatory drugs (0 6%), but it was reversible on drug discontinuation. Since TARGET used a supratherapeutic dose of lumiracoxib (two or four times the chronic osteoarthritis dose), our findings could represent an overestimate of the incidence of such laboratory (and any other) abnormalities, both in absolute terms and when compared with therapeutic doses of ibuprofen and naproxen. Clinical drug-induced hepatitis, a well-known adverse event detected through post-marketing surveillance of both COX2-selective inhibitors and non-steroidal anti-inflammatory drugs, 13,39,43 was too uncommon for any statistics to be applied, although more cases were reported on lumiracoxib than non-steroidal anti-inflammatory drugs (six vs three). No difference was seen in the incidence of renal adverse events, serious adverse events, or deaths between lumiracoxib and non-steroidal antiinflammatory drugs. Similar to VIGOR and CLASS, which compared supratherapeutic doses of COX2-selective inhibitors, TARGET compared a supratherapeutic dose of lumiracoxib with standard doses of non-steroidal antiinflammatory drugs. At this dose, several efficacy measures show a significant difference in favour of lumiracoxib. We must stress that these differences in efficacy are too small to be of overall clinical significance. Nevertheless, efficacy data do show that the reduced incidence of upper gastrointestinal ulcer complications is not accounted for by use of a subtherapeutic dose of lumiracoxib. The chosen doses of comparator nonsteroidal anti-inflammatory drugs were within their recommended dose range. They are also similar to those used in previous trials. We regarded comparison of lumiracoxib with non-steroidal anti-inflammatory drugs as ethical despite the increased gastrotoxic effects of these drugs, because findings of previous outcomes studies had shown no differences in overall morbidity or mortality in favour of COX2 inhibitors. We did not use proton-pump inhibitors in our study because of differing findings that have led to recommendations not to use these drugs in patients infected with H pylori 44,45 and conversely to suggestions that they are not efficacious in H pylori-negative patients. 46,47 The morbidity and mortality associated with nonsteroidal anti-inflammatory drug-induced ulcer complications 7 results in an important health economic burden. The results of TARGET provide evidence that use of lumiracoxib, instead of ibuprofen or naproxen, could reduce the incidence of ulcer complications by up to 80%. Contributors The paper has been read and approved by all authors. Every author contributed to the drafting and reviewing of the paper. Further, C J Hawkey, X Gitton, A Gimona, and E Ehrsam contributed to development of the study protocol. T J Schnitzer was the lead investigator; B Mellein was trial statistician. G Krammer was clinical trial leader. C J Hawkey was Chairman of the independent gastrointestinal safety committee. Conflict of interest statement TJS has acted as a consultant for AAI Pharma, GlaxoSmithKline, McNeil Consumer Healthcare, Merck, Novartis, Pfizer, and Winston; has received clinical research support from AAI Pharma, Merck, Novartis, Pfizer, and Winston; and is a member of the speakers bureau for Merck and Ortho-McNeil. CJH has received research funding or honoraria from AstraZeneca, GlaxoSmithKline, Merck, Nitromed, Novartis, Pfizer, Takeda, and Wyeth. GRB has done clinical trials, acted as a scientific consultant, and is member of the speakers bureau for Novartis, Pfizer, Merck Sharp and Dohme, and Merckle. EM has received consultancy fees from Novartis. MCH has acted as a consultant for Amgen, Arakis, AstraZeneca, Aventis Pharmaceutical, Bristol Myers Squibb, Genzyme, GlaxoSmithKline, Laboratories NEGMA, Merck, Novartis, Proctor and Gamble Pharmaceutical, Purdue Pharma, Roche, Scios, and Takeda Pharmaceuticals North America; and has received clinical research support from Merck and GlaxoSmithKline. MD has received genetic research funding from GlaxoSmithKline and AstraZeneca and has received honoraria for attending advisory boards related to osteoarthritis products from Novartis, Aventis, Genzyme, Bristol Myers Squibb, Johnson and Johnson, and Merck. EE, XG, GK, BM, and PM are employees of Novartis, manufacturer of lumiracoxib. AG was an employee of Novartis until March, Acknowledgments This work was supported by Novartis Pharma AG, Basel, Switzerland. Marie-Christine Domec acted as clinical trial leader until November, References 1 American College of Rheumatology. 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Helicobacter pylori and nonsteroidal anti-inflammatory drugs: interaction with proton pump inhibitor therapy for prevention of nonsteroidal anti-inflammatory drug ulcers and ulcer complications future research needs. Am J Med 2001; 110: 58S-61S Vol 364 August 21, 2004