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Background:The cardiovascular (CV) safety of non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 inhibitors has been the subject of considerable debate.Objective:The objective of this study was to determine the risk of CV events with lumiracoxib by meta-analysis of all completed, randomized controlled trials (RCTs) of >/=1 week and up to 1 year in duration of patients with osteoarthritis and rheumatoid arthritis.Methods:The Novartis Lumiracoxib Clinical Trial Database, which includes all clinical studies conducted to date with lumiracoxib, was reviewed. Data were extracted from RCTs of >/=1 week and up to 1 year in duration, the maximum study duration; 34,668 patients were included in standard and cumulative meta-analyses. Twenty-two RCTs of lumiracoxib 100 to 1200 mg daily were identified; 22,781 patients were included in 1-year trials. Mean age of the patients was 61.5 years and 74% were female. More than 50% of the patients in these studies had hypertension at baseline and 6% had diabetes. Parameters analyzed were the Antiplatelet Trialists' Collaboration (APTC) composite CV end point of myocardial infarction (MI), stroke (ischemic and hemorrhagic), and CV death; MI alone; and stroke alone. Twenty-one of the 22 RCTs have been published.Results:For all 3 parameters, relative risk (RR) was calculated versus non-naproxen NSAIDs, naproxen, and placebo. The results were as follows: for the APTC end point versus non-naproxen NSAIDs: RR 0.83, 95% CI, 0.46-1.51; versus naproxen: RR 1.49, 95% CI, 0.94-2.36; versus placebo: RR 1.08, 95% CI, 0.41-2.86; for MI alone versus non-naproxen NSAIDs: RR 0.80, 95% CI, 0.28-2.25; versus naproxen: RR 1.69, 95% CI, 0.82-3.48; versus placebo: RR 1.27, 95% CI, 0.25-6.56; and for stroke alone versus non-naproxen NSAIDs: RR 0.91, 95% CI, 0.35-2.35; versus naproxen: RR 1.42, 95% CI, 0.70-2.91; versus placebo: RR 0.59, 95% CI, 0.13-2.74. Cumulative meta-analyses of lumiracoxib versus all comparators (placebo, diclofenac, ibuprofen, celecoxib, rofecoxib, and naproxen) did not find any significant differences in APTC, MI alone, or stroke alone.Conclusion:This meta-analysis of 34,668 patients receiving >/=1 week and up to 1 year of treatment found no evidence that lumiracoxib was associated with a significant increase in CV risk compared with naproxen, placebo, or all comparators (placebo, diclofenac, ibuprofen, celecoxib, rofecoxib, and naproxen). [ABSTRACT FROM AUTHOR]

Abstract Background Canakinumab is a fully human anti-interleukin IL-1beta monoclonal antibody, being investigated for the treatment of rheumatoid arthritis (RA). This multicenter, phase II, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study investigated the efficacy and safety of canakinumab in patients with active RA despite ongoing therapy at stable doses of methotrexate. Methods Patients were randomized to receive one of four regimens, in addition to methotrexate, for 12 weeks: canakinumab 150 mg subcutaneously (SC) every 4 weeks (q4wk), canakinumab 300 mg SC (2 injections of 150 mg SC) every 2 weeks, a 600 mg intravenous loading dose of canakinumab followed by 300 mg SC every 2 weeks', or placebo SC every 2 weeks. Results Among 274 patients with evaluable efficacy data, the percentage of responders according to American College of Rheumatology 50 criteria (the primary endpoint, based on a 28-joint count) was significantly higher with canakinumab 150 mg SC q4wk than with placebo (26.5% vs. 11.4%, respectively; p = 0.028). Compared to placebo, this dosage of canakinumab was also associated with significantly more favorable responses at week 12 with respect to secondary endpoints including the Disease Activity Score 28, scores on the Health Assessment Questionnaire and Functional Assessment of Chronic Illness Therapy-Fatigue, swollen 28-joint count, and patient's and physician's global assessments of disease activity. No safety concerns were raised with canakinumab therapy, particularly with regard to infections. Few injection-site reactions occurred. Conclusion The addition of canakinumab 150 mg SC q4wk improves therapeutic responses among patients who have active RA despite stable treatment with methotrexate. Trial Registration (ClinicalTrials.gov identifier: NCT00784628)

Background: The potential for cyclo-oxygenase 2 (COX2)-selective inhibitors to increase the risk for myocardial infarction is controversial. 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: 18325 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) in two substudies of identical design. Randomisation was stratified for low-dose aspirin use and age. The primary cardiovascular endpoint was the Antiplatelet Trialists' Collaboration endpoint of non-fatal and silent myocardial infarction, stroke, or cardiovascular death. Analysis was by intention to treat.Findings: 81 (0.44%) patients did not start treatment and 7120 (39%) did not complete the study. At 1-year follow-up, incidence of the primary endpoint was low, both with lumiracoxib (59 events [0.65%]) and the non-steroidal anti-inflammatory drugs (50 events [0.55%]; hazard ratio 1.14 [95% CI 0.78-1.66], p=0.5074). Incidence of myocardial infarction (clinical and silent) in the overall population in the individual substudies was 0.38% with lumiracoxib (18 events) versus 0.21% with naproxen (ten) and 0.11% with lumiracoxib (five) versus 0.16% with ibuprofen (seven). In the naproxen substudy, rates of myocardial infarction (clinical and silent) did not differ significantly compared with lumiracoxib in the population not taking low-dose aspirin (hazard ratio 2.37 [95% CI 0.74-7.55], p=0.1454), overall (1.77 [0.82-3.84], p=0.1471), and in patients taking aspirin (1.36 [0.47-3.93], p=0.5658). In the ibuprofen substudy, these rates did not differ between lumiracoxib and ibuprofen in the population not taking low-dose aspirin (0.75 [0.20-2.79], p=0.6669), overall (0.66 [0.21-2.09], p=0.4833), and in patients taking aspirin (0.47 [0.04-5.14], p=0.5328).Interpretation: The primary endpoint, including incidence of myocardial infarction, did not differ between lumiracoxib and either ibuprofen or naproxen, irrespective of aspirin use. This finding suggests that lumiracoxib is an appropriate treatment for patients with osteoarthritis, who are often at high cardiovascular risk and taking low-dose aspirin. [ABSTRACT FROM AUTHOR]

Background: Cyclo-oxygenase 2 (COX2)-selective inhibitors should reduce ulcer complications compared with non-selective 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: 18325 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 0.82-1.36) with non-steroidal anti-inflammatory drugs (64 events) versus 0.25% (95% CI 0.12-0.39) with lumiracoxib (14 events; hazard ratio 0.21 [95% CI 0.12-0.37], p<0.0001). Reductions in ulcer complications were also significant in the overall population (0.34 [0.22-0.52], p<0.0001) but not in those taking aspirin (0.79 [0.40-1.55], 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 [0.78-1.66], p=0.5074).Interpretation: Lumiracoxib showed a three to four-fold reduction in ulcer complications compared with non-steroidal anti-inflammatory drugs without an increase in the rate of serious cardiovascular events, suggesting that lumiracoxib is an appropriate treatment for patients with osteoarthritis. [ABSTRACT FROM AUTHOR]

A blood test identifying patients at increased risk of pulmonary hypertension (PH) could streamline the investigative pathway. The prospective, multicenter CIPHER study aimed to develop a microRNA-based signature for detecting PH in breathless patients and enrolled adults with a high suspicion of PH who had undergone right heart catheterization (RHC). The CIPHER-MRI study was added to assess the performance of this CIPHER signature in a population with low probability of having PH who underwent cardiac magnetic resonance imaging (cMRI) instead of RHC. The microRNA signature was developed using a penalized linear regression (LASSO) model. Data were modeled both with and without N-terminal pro-brain natriuretic peptide (NT-proBNP). Signature performance was assessed against predefined thresholds (lower 98.7% CI bound of ≥0.73 for sensitivity and ≥0.53 for specificity, based on a meta-analysis of echocardiographic data), using RHC as the true diagnosis. Overall, 926 CIPHER participants were screened and 888 were included in the analysis. Of 688 RHC-confirmed PH cases, approximately 40% were already receiving PH treatment. Fifty microRNA (from 311 investigated) were algorithmically selected to be included in the signature. Sensitivity [97.5% CI] of the signature was 0.85 [0.80-0.89] for microRNA-alone and 0.90 [0.86-0.93] for microRNA+NT-proBNP, and the corresponding specificities were 0.33 [0.24-0.44] and 0.28 [0.20-0.39]. Of 80 CIPHER-MRI participants with evaluable data, 7 were considered PH-positive by cMRI whereas 52 were considered PH-positive by the microRNA signature. Due to low specificity, the CIPHER miRNA-based signature for PH (either with or without NT-proBNP in model) did not meet the prespecified diagnostic threshold for the primary analysis., Competing Interests: Luke Howard has served as a member of the CIPHER steering committee for Janssen pharmaceutical companies of Johnson & Johnson, Gossamer Bio, and Lung Biotechnology; has received consulting fees from Altavant; has received research grants from Janssen pharmaceutical companies of Johnson & Johnson; has received speaker fees from Bayer PLC, Janssen pharmaceutical companies of Johnson & Johnson, and Merck; has received support for attending meetings and/or travel from Janssen pharmaceutical companies of Johnson & Johnson; has been a member of an advisory board for Acceleron, Janssen pharmaceutical companies of Johnson & Johnson, and Merck; and is a shareholder in iOWNA and Circular. David G. Kiely has served as a member of the CIPHER steering committee for Janssen pharmaceutical companies of Johnson & Johnson and his institution has received support from the National Institute of Health Research Sheffield Biomedical Research Centre as part of the support for the present manuscript. He has received consulting fees and honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen pharmaceutical companies of Johnson & Johnson, Ferrer, Altavant, MSD, United Therapeutics, Gossamer, and Liquidia; has received support for attending meetings and/or travel from Janssen pharmaceutical companies of Johnson & Johnson, Ferrer, MSD and United Therapeutics; has participated on a Data Safety Monitoring Board of Advisory Board for Janssen pharmaceutical companies of Johnson & Johnson and MSD; is a member of the Clinical Reference Group for Specialized Respiratory Medicine (NHS England, unpaid); and is the lead of the UK National Audit of Pulmonary Hypertension (paid). David G. Kiely's institution has received grants or contracts from Janssen pharmaceutical companies of Johnson & Johnson, National Institute of Health Research Sheffield Biomedical Research Centre and Ferrer. Allan Lawrie has served has received payment for serving as a steering committee member for Janssen pharmaceutical companies of Johnson & Johnson (as part of the support for the present manuscript), has received support for attending meetings and/or travel from Janssen pharmaceutical companies of Johnson & Johnson. He receives funding from the British Heart Foundation through a Senior Basic Science Research Fellowship (FS/18/52/33808), the Imperial British Heart Foundation Imperial Centre for Research Excellence (RE/18/4/34215), Alexion Pharmaceuticals, and Apple Inc (Investigator Awards). Bradley A. Maron has served as a member of the CIPHER steering committee for Janssen pharmaceutical companies of Johnson & Johnson; and has received consultancy fees from Actelion Pharmaceuticals, Tenax, and Regeneron and grants from Deerfield, Boston Biomedical Innovation Center and the Cardiovascular Medical Research Education Foundation, He has two patents pending and one patent issued relevant to the submitted work. He has served as PI or co‐PI on various projects: 5R01HL139613‐03: PI on NIH R01 award focusing on molecular mechanisms that regulate vascular fibrosis in PAH ($1,748,134); NIH R01HL163960: Co‐PI on NIH R01 award using network medicine to prognosticate patients with PH ($286,861); U54HL119145 and Boston Biomedical Innovation Center (BBIC): PI on NIH‐funded project to develop an antibody therapeutic for CTEPH ($341,589); Brigham IGNITE award: PI on project to develop an antibody therapeutic for CTEPH ($50,000); NIH R01HL153502: PI on NIH‐funded project to clarify the mechanisms regulating NEDD9‐SMAD3 interactions in thrombotic vascular disease ($864,664); NIH R01HL155096‐01: PI on NIH‐funded project to clarify individualize the pathophenotype of patients with PH ($809,353). Ioana R. Preston has served as a member of the CIPHER steering committee for Janssen pharmaceutical companies of Johnson & Johnson, Merck, Liquidia; she has received consulting fees and honoraria for lectures, presentations, manuscript writing or educational events from Janssen pharmaceutical companies of Johnson & Johnson, Altavant, Gossamer, and United Therapeutics; has received support for attending meetings and/or travel from Janssen pharmaceutical companies of Johnson & Johnson, Merck, and United Therapeutics; Ioana Preston's institution has received grants or contracts from Janssen pharmaceutical companies of Johnson & Johnson, Merck, United Therapeutics, Respira, Bellerophon. Stephan Rosenkranz has served as a steering committee member for Janssen pharmaceutical companies of Johnson & Johnson (as part of the support for the present manuscript), has received remunerations for lectures and/or consultancy from Abbott, Acceleron, Actelion, Aerovate, Altavant, AOP, AstraZeneca, Bayer, Boehringer‐Ingelheim, Edwards, Ferrer, Gossamer, Janssen, Lilly, MSD, United Therapeutics, Vifor. His institution has received research grants from Actelion, AstraZeneca, Bayer, Janssen pharmaceutical companies of Johnson & Johnson, and Lempo. Mark Toshner has served as a steering committee member for Janssen pharmaceutical companies of Johnson & Johnson (as part of the support for the present manuscript), has received support for attending meetings and/or travel from Janssen pharmaceutical companies of Johnson & Johnson & GSK and has been a member of an advisory board for MorphogenIX. Martin R Wilkins has served as a member of the CIPHER steering committee for Janssen pharmaceutical companies of Johnson & Johnson and his institution received clinical research facility and Biomedical Research Centre infrastructure support from the National Institute of Health Research Sheffield Biomedical Research Centre as part of the support for the present manuscript. Martin R. Wilkins has received consulting fees from MorphogenIX, VIVUS, Janssen pharmaceutical companies of Johnson & Johnson, Kindaset, Chiesi, Aerami and BenevolentAI and has patents planned, issued and/or pending with Imperial Innovations (patent submitted for prognostic protein model and diagnostic miRNA model and patent for ZIP12 as a drug target); has participated in an adjudication committee for three clinical trials for Acceleron and in a study safety committee for GSK. Martin R. Wilkins institute has received grants or contracts from the British Heart Foundation (RE/18/4/34215 center support). Yiu‐Lian Fong was an employee of Janssen Pharmaceuticals Inc. at the time of study, and owns shares of stock/stock options in Johnson & Johnson. Cynthia Gargano is an employee of Janssen Pharmaceuticals Inc. and owns shares of stock/stock options in Johnson & Johnson. Debbie Quinn, Dimitri Stamatiadis, and Xavier Gitton are employees of Actelion Pharmaceuticals Ltd, a Janssen pharmaceutical company of Johnson & Johnson, and own shares of stock/stock options in Johnson & Johnson. Kelly M Chin has received payment for work on steering, advisory, or adjudication committee work with Arena, Bayer, Gossamer Bio, Janssen Pharmaceuticals of Johnson & Johnson, and Merck, payment for consulting work with Altavant, and her institution has received research support for clinical studies overseen by her from Altavant, Gossamer Bio, Janssen pharmaceutical companies of Johnson & Johnson, Merck, Pfizer, and United Therapeutics. Cheng He, Li Zhou, and Lihan Zhou are employees of MiRXES Lab and received support from Janssen Pharmaceuticals of Johnson & Johnson during the conduct of this study., (© 2024 The Author(s). Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Background: Pulmonary hypertension (PH) is life-threatening, and often diagnosed late in its course. We aimed to evaluate if a deep learning approach using electrocardiogram (ECG) data alone can detect PH and clinically important subtypes. We asked: does an automated deep learning approach to ECG interpretation detect PH and its clinically important subtypes?, Methods and Results: Adults with right heart catheterization or an echocardiogram within 90 days of an ECG at the University of California, San Francisco (2012-2019) were retrospectively identified as PH or non-PH. A deep convolutional neural network was trained on patients' 12-lead ECG voltage data. Patients were divided into training, development, and test sets in a ratio of 7:1:2. Overall, 5016 PH and 19,454 patients without PH were used in the study. The mean age at the time of ECG was 62.29 ± 17.58 years and 49.88% were female. The mean interval between ECG and right heart catheterization or echocardiogram was 3.66 and 2.23 days for patients with PH and patients without PH, respectively. In the test dataset, the model achieved an area under the receiver operating characteristic curve, sensitivity, and specificity, respectively of 0.89, 0.79, and 0.84 to detect PH; 0.91, 0.83, and 0.84 to detect precapillary PH; 0.88, 0.81, and 0.81 to detect pulmonary arterial hypertension, and 0.80, 0.73, and 0.76 to detect group 3 PH. We additionally applied the trained model on ECGs from participants in the test dataset that were obtained from up to 2 years before diagnosis of PH; the area under the receiver operating characteristic curve was 0.79 or greater., Conclusions: A deep learning ECG algorithm can detect PH and PH subtypes around the time of diagnosis and can detect PH using ECGs that were done up to 2 years before right heart catheterization/echocardiogram diagnosis. This approach has the potential to decrease diagnostic delays in PH., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The cryopyrin-associated periodic syndrome (CAPS) is a rare inherited inflammatory disease associated with overproduction of interleukin-1. Canakinumab is a human anti-interleukin-1beta monoclonal antibody., Methods: We performed a three-part, 48-week, double-blind, placebo-controlled, randomized withdrawal study of canakinumab in patients with CAPS. In part 1, 35 patients received 150 mg of canakinumab subcutaneously. Those with a complete response to treatment entered part 2 and were randomly assigned to receive either 150 mg of canakinumab or placebo every 8 weeks for up to 24 weeks. After the completion of part 2 or at the time of relapse, whichever occurred first, patients proceeded to part 3 and received at least two more doses of canakinumab. We evaluated therapeutic responses using disease-activity scores and analysis of levels of C-reactive protein (CRP) and serum amyloid A protein (SAA)., Results: In part 1 of the study, 34 of the 35 patients (97%) had a complete response to canakinumab. Of these patients, 31 entered part 2, and all 15 patients receiving canakinumab remained in remission. Disease flares occurred in 13 of the 16 patients (81%) receiving placebo (P<0.001). At the end of part 2, median CRP and SAA values were normal (<10 mg per liter for both measures) in patients receiving canakinumab but were elevated in those receiving placebo (P<0.001 and P=0.002, respectively). Of the 31 patients, 28 (90%) completed part 3 in remission. In part 2, the incidence of suspected infections was greater in the canakinumab group than in the placebo group (P=0.03). Two serious adverse events occurred during treatment with canakinumab: one case of urosepsis and an episode of vertigo., Conclusions: Treatment with subcutaneous canakinumab once every 8 weeks was associated with a rapid remission of symptoms in most patients with CAPS. (ClinicalTrials.gov number, NCT00465985.), (2009 Massachusetts Medical Society)

The 52-week Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) investigated the gastrointestinal and cardiovascular safety profile of lumiracoxib 400 mg once daily compared with 2 traditional nonsteroidal anti-inflammatory drugs (NSAIDs): ibuprofen 800 mg 3 times daily and naproxen 500 mg twice daily. Data from TARGET were analyzed to examine the effect of lumiracoxib compared with ibuprofen and naproxen on blood pressure (BP), incidence of de novo and aggravated hypertension, prespecified edema events, and congestive heart failure. Lumiracoxib resulted in smaller changes in BP as early as week 4. Least-squares mean change from baseline at week 4 for systolic BP was +0.57 mm Hg with lumiracoxib compared with +3.14 mm Hg with ibuprofen (P<.0001) and +0.43 with lumiracoxib compared with +1.80 mm Hg with naproxen (P<.0001). In conclusion, the use of lumiracoxib and traditional NSAIDs results in differing BP changes; these might be of clinical relevance.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are established as treatment for managing pain associated with primary dysmenorrhea. However, the efficacy and tolerability of lumiracoxib 200 mg once daily (q.d.) has not previously been examined in primary dysmenorrhea., Methods: Two randomized, multicenter, double-blind, placebo-controlled, crossover studies of similar design have assessed the efficacy and tolerability of two regimens of lumiracoxib compared with placebo (Study 1) or naproxen and placebo (Study 2) in women (aged 18-45 years) with moderate to severe primary dysmenorrhea. In Study 1 (n = 132), patients received lumiracoxib 200 mg q.d., lumiracoxib 200 mg with a 200 mg redose (p.r.n.) on day 1, or placebo. In Study 2 (n = 144), patients received lumiracoxib 200 mg q.d., lumiracoxib 200 mg with a 200 mg redose p.r.n. on day 1, naproxen 500 mg twice daily (b.i.d.), or placebo. Patients recorded study medication use, efficacy assessments, and rescue medication use., Results: The primary efficacy variable, summed (time-weighted) pain intensity difference (categorical scale) over the first 8 hours (SPID-8), was similar between all active treatments (e.g., p = 0.939 for naproxen 500 mg b.i.d. vs. lumiracoxib 200 mg q.d. in Study 2), and all active treatments were superior to placebo (p < 0.001). Median time-to-onset of analgesia was similar between lumiracoxib 200 mg q.d. and naproxen 500 mg b.i.d. Similar trends were observed for all other secondary efficacy variables. All treatments were well tolerated., Conclusions: Short-term administration of lumiracoxib 200 mg q.d. is effective and well tolerated and provides an alternative treatment option for the management of moderate to severe pain associated with primary dysmenorrhea.

Background & Aims: Selective cyclooxygenase-2 inhibitors were developed to reduce the gastrointestinal risk associated with nonsteroidal anti-inflammatory drugs (NSAIDs). The Therapeutic Arthritis Research and Gastrointestinal Event Trial was the largest study to evaluate primarily the gastrointestinal safety outcomes of selective cyclooxygenase-2 inhibitors. Data from the Therapeutic Arthritis Research and Gastrointestinal Event Trial were used to identify risk factors and investigate the safety of lumiracoxib in subgroups., Methods: Patients with osteoarthritis (age, >or=50 y) were randomized to receive lumiracoxib 400 mg once daily, naproxen 500 mg twice daily, or ibuprofen 800 mg 3 times daily for 12 months. Events were categorized by a blinded adjudication committee. The primary end point was all definite or probable ulcer complications., Results: For patients taking NSAIDs, factors associated with an increased risk of ulcer complications were age 65 years or older (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.48-3.59), previous history of gastrointestinal bleed or ulcer (HR, 3.61; 95% CI, 1.86-7.00), non-Caucasian racial origin (HR, 2.10; 95% CI, 1.35-3.27), and male sex (HR, 1.70; 95% CI, 1.08-2.68). With lumiracoxib, significant risk factors were age 65 years or older (HR, 3.18; 95% CI, 1.40-7.20), male sex (HR, 2.60; 95% CI, 1.25-5.40), non-Caucasian racial origin (HR, 2.16; 95% CI, 1.02-4.59), and concomitant aspirin use (HR, 2.89; 95% CI, 1.40-5.97). Increased risks in patients age 65 years and older were increased further if other risk factors were present. Lumiracoxib maintained an advantage over NSAIDs across all subgroups except aspirin use., Conclusions: Lumiracoxib was associated with a reduced risk of ulcer complications compared with NSAIDs in all significant subgroups except aspirin users.

Unlabelled: Patient Acceptable Symptom State (PASS) is an absolute threshold proposed for symptomatic variables in osteoarthritis (OA) to determine the point beyond which patients consider themselves well and, as such, are satisfied with treatment. Two large previously reported studies of knee OA have shown that both lumiracoxib and celecoxib were superior to placebo in terms of conventional outcome measures. To assess the clinical relevance of these results from the patient's perspective, the same data pooled from these two studies were analysed with respect to the PASS. In total, 3,235 patients were included in two multicentre, randomised, double-blind studies of identical design. Patients were randomly assigned to receive lumiracoxib 100 mg once daily (n = 811), lumiracoxib 100 mg once daily with an initial dose of lumiracoxib 200 mg once daily for the first 2 weeks (100 mg once daily with initial dose [n = 805]), celecoxib 200 mg once daily (n = 813), or placebo (n = 806) for 13 weeks. Treatments were compared with respect to the PASS criteria (for OA pain, patient's global assessment of disease activity, and the Western Ontario and McMaster Universities Osteoarthritis Index Likert version 3.1 [WOMAC LK 3.1] Function [difficulty in performing daily activities] subscale score). At week 13, 43.3%, 45.3%, and 42.2% of patients in the lumiracoxib 100 mg once daily, lumiracoxib 100 mg once daily with initial dose, and the celecoxib 200 mg once daily groups, respectively, considered their current states as satisfactory versus 35.5% in the placebo group. Similar results were observed for patient's global assessment of disease activity and WOMAC LK 3.1 Function subscale score. This post hoc analysis suggests that the statistical significance of the results observed with lumiracoxib or celecoxib compared with placebo using conventional outcome variables is complemented by clinical relevance to the patient., Trial Registration Numbers: NCT00366938 and NCT00367315.

Background & Aims: The aim of this study was to evaluate the gastrointestinal safety of lumiracoxib, a novel selective cyclooxygenase-2 inhibitor., Methods: Results from 15 Phase II and III randomized studies of lumiracoxib in osteoarthritis and rheumatoid arthritis were pooled. Patients received lumiracoxib (200/400 mg/day), celecoxib (200/400 mg/day), rofecoxib (25 mg once daily), diclofenac (75 mg twice daily), ibuprofen (800 mg 3 times daily), naproxen (500 mg twice daily), or placebo. Outcome measures included the incidence of definite or probable ulcer complications (perforations, obstructions, or bleedings as confirmed by an adjudication committee) and symptomatic upper gastrointestinal ulcers, the incidence of prespecified gastrointestinal adverse events, and the discontinuation rate caused by adverse events. All suspected ulcer complications in these 15 studies were adjudicated prospectively. Data from 2 endoscopic studies were pooled separately to assess the cumulative incidence of gastroduodenal ulcers >or=3 mm in diameter., Results: Symptomatic upper gastrointestinal ulcers and ulcer complications were reduced nearly 10-fold with lumiracoxib (1.7 events per 100 patient-years [95% confidence interval, 1.09-2.39]) compared with nonselective nonsteroidal anti-inflammatory drugs (13.7 events per 100 patient-years [95% confidence interval, 9.47-18.82]). Symptomatic ulcer frequency was markedly lower with lumiracoxib (0.4%) than with nonselective nonsteroidal anti-inflammatory drugs (2.5%). Discontinuation rates due to gastrointestinal adverse events were higher for nonselective nonsteroidal anti-inflammatory drugs (8.4%) than for lumiracoxib (3.3%). In the endoscopy analysis, the cumulative frequency of ulcers >or=3 mm in diameter was reduced by >70% for lumiracoxib versus ibuprofen., Conclusions: Lumiracoxib exhibited a gastrointestinal safety profile superior to nonselective nonsteroidal anti-inflammatory drugs.

Objectives: Overview of three dose-response studies demonstrating the efficacy of lumiracoxib, a novel COX-2 selective inhibitor, for chronic pain associated with osteoarthritis (0A), or rheumatoid arthritis (RA) and acute pain following dental extraction., Methods: OA and RA: 4-week, randomized, placebo- and active-controlled studies of similar design. Patients (OA, n = 583; RA, n = 571) received lumiracoxib 50 mg, 100 mg or 200 mg twice daily (bid), lumiracoxib 400 mg once daily (od), diclofenac 75 mg bid or placebo. Dental: 12-h, single-center, randomized, placebo- and active-controlled study. Patients (n = 202) received single oral doses of lumiracoxib 100 mg or 400 mg, ibuprofen 400 mg or placebo., Main Outcome Measures: OA: pain intensity (PI) in the target joint (visual analogue scale [VAS]) and WOMAC score at Week 4; RA: overall PI (VAS) and ACR20 response at Week 4; Dental: difference (PID, categorical and VAS) score over 12h post dose, time to onset of analgesia., Results: Throughout the OA study, all lumiracoxib doses provided superior reductions in PI versus placebo and at Week 4, all lumiracoxib doses provided efficacy similar to each other and to diclofenac. In the RA study, lumiracoxib 100 mg bid, 200 mg bid and 400mg od were significantly better than placebo in PI at Weeks 1 and 2 (all p < 0.05) but demonstrated borderline significance at Week 4 (lumiracoxib 400 mg od, p = 0.06). In pain following dental surgery, PID scores for both lumiracoxib doses were superior to placebo from 1.5 h onwards and always comparable, or superior, to ibuprofen. Lumiracoxib 400 mg had the fastest onset of analgesia, measured as median time to confirmed first perceptible pain relief using the two-stopwatch method (37.4 min, superiority versus placebo, p < 0.001). Lumiracoxib was well tolerated in all studies., Conclusions: These studies provide initial evidence that lumiracoxib is an effective, well-tolerated agent for the treatment of chronic and acute pain.

Objective: To compare the incidence of gastroduodenal ulcers in patients with osteoarthritis (OA) treated with therapeutic doses of the novel COX-2 selective inhibitor, lumiracoxib (COX189, Prexige), and the standard nonsteroidal antiinflammatory drug (NSAID) ibuprofen. The COX-2 selective inhibitor celecoxib was included as an active control., Methods: In this randomized, multicenter, double-blind, parallel-group study, eligible patients were randomized to receive lumiracoxib 200 mg (n = 264) or 400 mg (n = 260) once daily (qd), ibuprofen 800 mg (n = 260) 3 times daily (tid), or celecoxib 200 mg qd (n = 258) for 13 weeks. The incidence of gastroduodenal ulcers and erosions was determined by endoscopy prior to randomization, and after 4 weeks and 13 weeks of treatment (end of study). Frequencies of adverse events were also recorded., Results: The cumulative incidence of gastroduodenal ulcers >/= 3 mm in diameter was significantly lower in the lumiracoxib groups (200 mg: 4.3%; 400 mg: 4.0%) than in the ibuprofen group (15.7%; p < 0.001) and similar to the celecoxib group (3.2%). In the ibuprofen group, a significantly greater number of patients (6.0%) had > 10 gastroduodenal erosions compared with lumiracoxib 200 mg (1.2%; p < 0.01), lumiracoxib 400 mg (1.6%; p < 0.05), and celecoxib (2.4%; p < 0.05). A greater number of patients in the ibuprofen group discontinued treatment due to an adverse event compared with both lumiracoxib groups and the celecoxib group., Conclusion: In patients with OA, lumiracoxib 200 mg or 400 mg qd was associated with a significantly lower risk of gastroduodenal ulceration than ibuprofen 800 mg tid, and was similar to celecoxib 200 mg qd.

Background: The potential for cyclo-oxygenase 2 (COX2)-selective inhibitors to increase the risk for myocardial infarction is controversial. 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: 18325 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) in two substudies of identical design. Randomisation was stratified for low-dose aspirin use and age. The primary cardiovascular endpoint was the Antiplatelet Trialists' Collaboration endpoint of non-fatal and silent myocardial infarction, stroke, or cardiovascular death. Analysis was by intention to treat., Findings: 81 (0.44%) patients did not start treatment and 7120 (39%) did not complete the study. At 1-year follow-up, incidence of the primary endpoint was low, both with lumiracoxib (59 events [0.65%]) and the non-steroidal anti-inflammatory drugs (50 events [0.55%]; hazard ratio 1.14 [95% CI 0.78-1.66], p=0.5074). Incidence of myocardial infarction (clinical and silent) in the overall population in the individual substudies was 0.38% with lumiracoxib (18 events) versus 0.21% with naproxen (ten) and 0.11% with lumiracoxib (five) versus 0.16% with ibuprofen (seven). In the naproxen substudy, rates of myocardial infarction (clinical and silent) did not differ significantly compared with lumiracoxib in the population not taking low-dose aspirin (hazard ratio 2.37 [95% CI 0.74-7.55], p=0.1454), overall (1.77 [0.82-3.84], p=0.1471), and in patients taking aspirin (1.36 [0.47-3.93], p=0.5658). In the ibuprofen substudy, these rates did not differ between lumiracoxib and ibuprofen in the population not taking low-dose aspirin (0.75 [0.20-2.79], p=0.6669), overall (0.66 [0.21-2.09], p=0.4833), and in patients taking aspirin (0.47 [0.04-5.14], p=0.5328)., Interpretation: The primary endpoint, including incidence of myocardial infarction, did not differ between lumiracoxib and either ibuprofen or naproxen, irrespective of aspirin use. This finding suggests that lumiracoxib is an appropriate treatment for patients with osteoarthritis, who are often at high cardiovascular risk and taking low-dose aspirin.

Seven strains of Leptospira interrogans belonging to seven different serogroups, and one strain of Leptospira biflexa were analysed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) with gradient gels and immunoblotting with hyperimmune rabbit sera raised against each strain. The molecular masses of the proteins were calculated with a polynomial regression model. The SDS-PAGE patterns of the L. interrogans strains were similar and characterized by 24 common bands. This profile was not found for L. biflexa. The immunoblots obtained either with the seven anti-L. interrogans sera or the anti-L. biflexa serum allowed a clear distinction between the two species. Taken as a whole, the L. interrogans strain patterns revealed by the seven anti-L. interrogans sera were similar, sharing eight common major bands. A serovar- or serogroup-specific antigenic zone, ranging from 21 to 26 kDa, was also identified.