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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, ≥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. [Copyright &y& Elsevier]

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]

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 18 325 patients age 50 years or older with osteoarthritis were randomised to lumiracoxib 400 mg once daily (n=9156), naproxen 500mg 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. [Copyright &y& Elsevier]

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 18 325 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. [Copyright &y& Elsevier]

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]

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: Corticosteroids used in addition to antituberculous therapy have been reported to benefit people with tuberculous pleurisy. However, research findings are inconsistent, raising doubt as to whether such treatment is worthwhile. Concern also exists regarding the potential adverse effects of corticosteroids, especially in HIV-positive people., Objectives: To evaluate the effects of adding corticosteroids to drug regimens for tuberculous pleural effusion., Search Strategy: In May 2007, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2007, Issue 2), MEDLINE, EMBASE, LILACS, Current Controlled Trials, and reference lists of articles., Selection Criteria: Randomized and quasi-randomized controlled trials comparing any corticosteroid with no treatment, placebo, or other active treatment (both groups should receive the same antituberculous drug regimen) in people diagnosed with tuberculous pleurisy., Data Collection and Analysis: Two authors independently assessed trial methodological quality and extracted data. Data were analysed using relative risks (RR) and weighted mean difference (WMD) with 95% confidence intervals (CI). The fixed-effect model was applied in the absence of statistically significant heterogeneity., Main Results: Six trials with 633 participants met the inclusion criteria; one trial included only HIV-positive people. Compared to control, corticosteroid use was associated with less residual pleural fluid at four weeks (RR 0.76, 95% CI 0.62 to 0.94; 394 participants, 3 trials) and reduced pleural thickening (RR 0.69, 95% CI 0.51 to 0.94; 309 participants, 4 trials). We found no evidence of an effect of corticosteroids on death from any cause (194 participants, 1 trial), respiratory function (191 participants, 2 trials), residual pleural fluid at eight weeks (399 participants, 4 trials), or pleural adhesions (123 participants, 2 trials). Although discontinuation of treatment due to adverse events was more frequent in participants receiving corticosteroids than placebo (RR 2.80, 95% CI 1.12 to 6.98; 586 participants, 6 trials), the effects were generally mild. The risk of Kaposi sarcoma may be increased in HIV-positive people receiving corticosteroids (RR 13.00, 95% CI 0.74 to 227.63; 194 participants, 1 trial)., Authors' Conclusions: There are insufficient data to support evidence-based recommendations regarding the use of adjunctive corticosteroids in people with tuberculous pleurisy. Randomized controlled trials that are sufficiently powered to evaluate the effects of corticosteroids on both morbidity and mortality are needed. The effects of corticosteroids on HIV-related complications, such as Kaposi sarcoma, should be assessed in people co-infected with HIV.

Background: Hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome is a severe form of pre-eclampsia. Pre-eclampsia is a multi-system disease of pregnancy associated with an increase in blood pressure and increased perinatal and maternal morbidity and mortality. Eighty per cent of women with HELLP syndrome present before term. There are suggestions from observational studies that steroid treatment in HELLP syndrome may improve disordered maternal hematological and biochemical features and perhaps perinatal mortality and morbidity., Objectives: To summarise the evidence on the effects of corticosteroids on maternal and neonatal mortality and morbidity in women with HELLP syndrome., Search Strategy: We searched the Cochrane Pregnancy and Childbirth Group trials register (October 2003). We scanned lists of references from review articles and primary studies., Selection Criteria: Randomised and quasi-randomised trials evaluating the effects of adjunctive corticosteroids in patients diagnosed with HELLP syndrome were sought., Data Collection and Analysis: The two authors independently applied inclusion criteria, assessed trial quality and extracted relevant data., Main Results: Of the five studies reviewed (n = 170), three were conducted antepartum and two postpartum. Four of the studies randomised participants to standard therapy or dexamethasone. One study compared dexamethasone with betamethasone. DEXAMETHASONE VERSUS CONTROL: There were no significant differences in the primary outcomes of maternal mortality and morbidity due to placental abruption, pulmonary oedema and liver hematoma or rupture. Of the secondary maternal outcomes, there was a tendency to a greater platelet count increase over 48 hours, statistically significantly less mean number of hospital stay days (weighted mean difference (WMD) -4.50, 95% confidence interval (CI) -7.13 to -1.87), mean interval (hours) to delivery (41 +/- 15) versus (15 +/- 4.5) (p = 0.0068) in favour of women allocated to dexamethasone. There were no significant differences in perinatal mortality or morbidity due to respiratory distress syndrome, need for ventilatory support, intracerebral hemorrhage, necrotizing enterocolitis and a five minute Apgar less than seven. The mean birthweight was significantly greater in the group allocated to dexamethasone (WMD 247.00, 95% CI 65.41 to 428.59). DEXAMETHASONE VERSUS BETAMETHASONE: There were no significant differences in all the maternal and perinatal mortality and in primary morbidity outcomes. Women randomised to dexamethasone fared significantly better for: oliguria, mean arterial pressure, mean increase in platelet count, mean increase in urinary output and liver enzyme elevations., Reviewer's Conclusions: There is insufficient evidence to determine whether adjunctive steroid use in HELLP syndrome decreases maternal and perinatal mortality, major maternal and perinatal morbidity.

Background: TB of the pleura is associated with inflammation and fibrosis. Steroids could reduce the effects of the inflammation, but the immunosuppression could make patients vunerable., Objectives: This review aims to summarise the evidence about the effects of corticosteroids in patients with TB of the pleura, and explores if HIV status is associated with differences in effect estimates., Search Strategy: We searched the Cochrane Infectious Diseases Group trials register, the Cochrane Library, MEDLINE, and EMBASE. Lists of references from review articles and primary studies were scanned and experts in the field of tuberculosis were contacted., Selection Criteria: Randomised and quasi-randomised trials evaluating the effects of adjunctive corticosteroids in patients diagnosed with TB pleurisy were sought. Both beneficial and adverse effects were noted., Data Collection and Analysis: Two authors independently applied inclusion criteria, assessed trial quality and extracted the relevant data., Main Results: Three small trials met the inclusion criteria( total participants n=236), conducted in only HIV negative patients, and with insufficient power to examine death as an outcome. There was no difference in residual lung function between steroid and control groups at completion of treatment. The point estimates for secondary outcomes tended towards benefit with steroids rather than harm, but none were significant; number with pleural fluid (RR 0.28, 95% CI 0.06 to 1.34), number with pleural thickening (RR 0.76, 95% 0.48 to 1.21), and number with pleural adhesions (RR 0.30, 95% CI 0.03 to 2.66). Adverse effects were few and did not result in treatment being discontinued., Reviewer's Conclusions: There is insufficient evidence to know whether steroids are effective in tuberculous pleural effusion.