Objective: Data on osteoarthritis patients from the PRECISION trial were used to evaluate the cost-effectiveness of celecoxib (100 mg twice daily) versus ibuprofen (600– 800 mg three times daily) and naproxen (375– 500 mg twice daily). The perspective was that of the United Arab Emirates (UAE) healthcare system. Methods: Discrete-state Markov model with monthly cycles, 30-month horizon, and 3% discount rate was constructed to assess incremental costs per quality adjusted life year (QALYs) gained from reduced incidence of three safety domains examined in PRECISION: renal, serious gastrointestinal (GI), and major adverse cardiovascular events (MACE). Costs for managing these toxicities were derived from Dubai Administrative Billing Claims (2018). Median monthly drug costs were derived from UAE Ministry of Health and Prevention's published prices ($26.98 celecoxib; $20.25 ibuprofen; $20.50 naproxen). Health utility and excess mortality associated with toxicities were sourced from the literature. The willingness-to-pay thresholds used were 1 and 3 GDP per capita ($40,000–$120,000). Results: The total average cost per patient was $812.88 for celecoxib, $775.26 for ibuprofen, and $731.17 for naproxen while cost components attributed to toxicities were lowest with celecoxib ($360.26, $438.31, and $388.60, respectively). Patients on celecoxib had more QALYs (1.339), compared with ibuprofen (1.335) and naproxen (1.337), resulting in an incremental cost-effectiveness ratio of $11,502/QALY gained for celecoxib versus ibuprofen and $39,779 for celecoxib versus naproxen. Probabilistic sensitivity analyses demonstrated celecoxib to be 81% cost-effective versus ibuprofen and 50% versus naproxen at $40,000/QALY. The most influential model parameters were MACE relative safety and drug costs. Conclusion: From UAE third payer perspective, celecoxib is a long-term cost-effective treatment for osteoarthritis patients when compared with ibuprofen, and equally likely as naproxen to be cost-effective. With the expected increasing burden of chronic diseases in the Gulf region, study findings can inform decisions regarding the cost-effective pain management of osteoarthritis in UAE. Clinicaltrials.gov Registration Number: NCT00346216. Keywords: Markov, NSAIDs, comparative effectiveness, safety, Gulf region, AfME, MENA
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used drugs, both prescribed and over the counter. The long-term cardiovascular safety of NSAIDs in patients with arthritis has engendered controversy. Concerns remain regarding the relative incidence and severity of adverse cardiorenal effects, particularly in arthritis patients with established cardiovascular (CV) disease or risk factors for disease as illustrated by the PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen) trial participants (NCT00346216).We further investigated whether the selective COX-2 Inhibitor celecoxib has a superior cardiorenal safety profile compared with ibuprofen or naproxen in the PRECISION population.Twenty-four thousand eighty-one patients who required NSAIDs for osteoarthritis or rheumatoid arthritis (RA) and had increased CV risk randomly received celecoxib, ibuprofen, or naproxen. The current pre-specified secondary analysis assessed the incidence, severity, and NSAID-related risk of the pre-specified composite cardiorenal outcome (adjudicated renal event, hospitalization for congestive heart failure, or hospitalization for hypertension) in the intention-to-treat (ITT) population. An on-treatment analysis assessed safety in those taking the study medication. Following a mean treatment duration of 20.3 ± 16.0 months and a mean follow-up of 34.1 ± 13.4 months, the primary cardiorenal composite outcome occurred in 423 patients (1.76%) in the ITT population. Of these 423 patients, 118 (28%) were in the celecoxib, 166 (39%) in the ibuprofen, and 139 (33%) in the naproxen group. In a multivariable Cox regression model adjusted for independent clinical variables, celecoxib showed a significantly lower risk compared with ibuprofen [hazard ratio (HR) 0.67, confidence interval (CI) 0.53-0.85, P = 0.001) and a trend to lower risk compared with naproxen (HR 0.79, CI 0.61-1.00, P = 0.058). In the ITT analysis, clinically significant renal events occurred in 220 patients with events rates of 0.71%, 1.14%, and 0.89% for celecoxib, ibuprofen, and naproxen, respectively (P = 0.052), while in the on-treatment analysis the rates were 0.52%, 0.91%, and 0.78% (P < 0.001).In the current era, long-term NSAID use was associated with few cardiorenal events in arthritis patients. At the doses studied, celecoxib displayed fewer renal events and hence more favourable cardiovascular safety compared with ibuprofen or naproxen. These results have considerable clinical implications for practitioners managing individuals with chronic arthritis pain and high risk of impaired renal function and/or heart failure.Clinical Trial Registration: NCT00346216.
Objective To compare the efficacy and safety of two different doses of celecoxib and diclofenac in the treatment of Norwegian patients with ankylosing spondylitis. Methods In this 12-week, double-blind, non-inferiority trial patients were randomized to 200 mg once daily (qd) celecoxib, 400 mg qd celecoxib, or 50 mg three times daily (tid) diclofenac. The primary objective compared patients’ assessments of Global Pain Intensity, measured on a visual analogue scale. Results A total of 330 patients were randomized (200 mg celecoxib, n = 107; 400 mg celecoxib, n = 108; diclofenac, n = 115). Least squares mean changes in Global Pain Intensity at 12 weeks were −25.8 mm, −30.6 mm and −28.2 mm, respectively. Both celecoxib treatment groups were non-inferior to diclofenac. More patients in the 400 mg celecoxib group met the Assessments in Ankylosing Spondylitis 20 responder criteria at Week 12 (60.2%) than in the celecoxib 200 mg (51.4%) and the diclofenac 50 mg (57.4%) groups. Adverse events were mild-to-moderate in severity, with dyspepsia and diarrhoea the most commonly reported. Conclusions Celecoxib and diclofenac both provided pain reduction, in addition to improvements in disease activity and functional capacity, in patients with ankylosing spondylitis.
The TNFα receptor is a major therapeutic target since over production of TNFα plays a key role in the development of septic shock following bacterial infection and has been implicated in the pathogenesis of many inflammatory disorders such as rheumatoid arthritis. To screen our NATCHEMTM Libraries for novel natural product inhibitors of this target we have developed a sensitive immobilised TNFα receptor binding assay based on a commercially available recombinant soluble TNFα receptor (p55) and [125I]-TNFα.
Summary Aim To evaluate GI safety of celecoxib compared with 2 nonselective (ns) NSAID s, as a secondary objective of a large trial examining multiorgan safety. Methods This randomised, double‐blind controlled trial analysed 24 081 patients. Osteoarthritis or rheumatoid arthritis patients, needing ongoing NSAID treatment, were randomised to receive celecoxib 100‐200 mg b.d., ibuprofen 600‐800 mg t.d.s. or naproxen 375‐500 mg b.d. plus esomeprazole, and low‐dose aspirin or corticosteroids if already prescribed. Clinically significant GI events ( CSGIE —bleeding, obstruction, perforation events from stomach downwards or symptomatic ulcers) and iron deficiency anaemia ( IDA ) were adjudicated blindly. Results Mean treatment and follow‐up durations were 20.3 and 34.1 months. While on treatment or 30 days after, CSGIE occurred in 0.34%, 0.74% and 0.66% taking celecoxib, ibuprofen and naproxen. Hazard ratios ( HR ) were 0.43 (95% CI 0.27‐0.68, P = 0.0003) celecoxib vs ibuprofen and 0.51 (0.32‐0.81, P = 0.004) vs naproxen. There was also less IDA on celecoxib: HR 0.43 (0.27‐0.68, P = 0.0003) vs ibuprofen; 0.40 (0.25‐0.62, P < 0.0001) vs naproxen. Even taken with low‐dose aspirin, fewer CSGIE occurred on celecoxib than ibuprofen ( HR 0.52 [0.29‐0.94], P = 0.03), and less IDA vs naproxen (0.42 [0.23‐0.77, P = 0.005]). Corticosteroid use increased total GI events and CSGIE . H. pylori serological status had no influence. Conclusions Arthritis patients taking NSAID s plus esomeprazole have infrequent clinically significant gastrointestinal events. Co‐prescribed with esomeprazole, celecoxib has better overall GI safety than ibuprofen or naproxen at these doses, despite treatment with low‐dose aspirin or corticosteroids.
Globally, osteoarthritis (OA) is the most prevalent arthritic condition in those aged over 60 years. OA has a high impact on patient disability and is associated with a significant economic burden. Pain is the most common first sign of disease and the leading cause of disability. Data demonstrating the increasing global prevalence of OA, together with a greater understanding of the burden of the disease, have led to a reassessment of the seriousness of OA and calls for the designation of OA as a serious disease in line with the diseases impact on comorbidity, disability, and mortality.While OA was traditionally seen as a prototypical 'wear and tear' disease, it is now more accurately thought of as a disease of the whole joint involving cartilage together with subchondral bone and synovium. As more has become known of the pathophysiology of OA, it has become increasingly common for it to be described using a number of overlapping phenotypes. Patients with OA will likely experience multiple phenotypes during their disease. This review focuses on what we feel are three key phenotypes: post-trauma, metabolic, and aging. A greater understanding of OA phenotypes, particularly at the early stages of disease, may be necessary to improve treatment outcomes. In the future, non-pharmacological and pharmacological treatments could be tailored to patients based on the key features of their phenotype and disease pathway.
This paper outlines a step-wise framework for monitoring foods and beverages provided or sold in publicly funded institutions. The focus is on foods in schools, but the framework can also be applied to foods provided or sold in other publicly funded institutions. Data collection and evaluation within this monitoring framework will consist of two components. In component I, information on existing food or nutrition policies and/or programmes within settings would be compiled. Currently, nutrition standards and voluntary guidelines associated with such policies/programmes vary widely globally. This paper, which provides a comprehensive review of such standards and guidelines, will facilitate institutional learnings for those jurisdictions that have not yet established them or are undergoing review of existing ones. In component II, the quality of foods provided or sold in public sector settings is evaluated relative to existing national or sub-national nutrition standards or voluntary guidelines. Where there are no (or only poor) standards or guidelines available, the nutritional quality of foods can be evaluated relative to standards of a similar jurisdiction or other appropriate standards. Measurement indicators are proposed (within ‘minimal’, ‘expanded’ and ‘optimal’ approaches) that can be used to monitor progress over time in meeting policy objectives, and facilitate comparisons between countries.
Abstract BACKGROUND Targeting programmed cell death protein 1 (PD‐1) and indoleamine 2,3‐dioxygenase (IDO1) pathways is an appealing option for cancer treatment. METHODS The open‐label, phase 1/2 ECHO‐203 study evaluated the safety, tolerability, and efficacy of the IDO1 inhibitor epacadostat in combination with durvalumab, a human anti–PD‐L1 monoclonal antibody in adult patients with advanced solid tumors. RESULTS The most common treatment‐related adverse events were fatigue (30.7%), nausea (21.0%), decreased appetite (13.1%), pruritus (12.5%), maculopapular rash (10.8%), and diarrhea (10.2%). Objective response rate (ORR) in the overall phase 2 population was 12.0%. Higher ORR was observed in immune checkpoint inhibitor (CPI)‐naïve patients (16.1%) compared with patients who had received previous CPI (4.1%). Epacadostat pharmacodynamics were evaluated by comparing baseline kynurenine levels with those on therapy at various time points. Only the 300‐mg epacadostat dose showed evidence of kynurenine modulation, albeit unsustained. CONCLUSIONS Epacadostat plus durvalumab was generally well tolerated in patients with advanced solid tumors. ORR was low, and evaluation of kynurenine concentration from baseline to cycle 2, day 1, and cycle 5, day 1, suggested >300 mg epacadostat twice daily is needed to ensure sufficient drug effect. Clinical trial information A study of epacadostat (INCB024360) in combination with durvalumab (MEDI4736) in subjects with selected advanced solid tumors (ECHO‐203) (NCT02318277).
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