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      Randomized trial of switching from prescribed non-selective non-steroidal anti-inflammatory drugs to prescribed celecoxib: the Standard care vs. Celecoxib Outcome Trial (SCOT)

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          Abstract

          Background

          Selective cyclooxygenase-2 inhibitors and conventional non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs) have been associated with adverse cardiovascular (CV) effects. We compared the CV safety of switching to celecoxib vs. continuing nsNSAID therapy in a European setting.

          Method

          Patients aged 60 years and over with osteoarthritis or rheumatoid arthritis, free from established CV disease and taking chronic prescribed nsNSAIDs, were randomized to switch to celecoxib or to continue their previous nsNSAID. The primary endpoint was hospitalization for non-fatal myocardial infarction or other biomarker positive acute coronary syndrome, non-fatal stroke or CV death analysed using a Cox model with a pre-specified non-inferiority limit of 1.4 for the hazard ratio (HR).

          Results

          In total, 7297 participants were randomized. During a median 3-year follow-up, fewer subjects than expected developed an on-treatment (OT) primary CV event and the rate was similar for celecoxib, 0.95 per 100 patient-years, and nsNSAIDs, 0.86 per 100 patient-years (HR = 1.12, 95% confidence interval, 0.81–1.55; P = 0.50). Comparable intention-to-treat (ITT) rates were 1.14 per 100 patient-years with celecoxib and 1.10 per 100 patient-years with nsNSAIDs (HR = 1.04; 95% confidence interval, 0.81–1.33; P = 0.75). Pre-specified non-inferiority was achieved in the ITT analysis. The upper bound of the 95% confidence limit for the absolute increase in OT risk associated with celecoxib treatment was two primary events per 1000 patient-years exposure. There were only 15 adjudicated secondary upper gastrointestinal complication endpoints (0.078/100 patient-years on celecoxib vs. 0.053 on nsNSAIDs OT, 0.078 vs. 0.053 ITT). More gastrointestinal serious adverse reactions and haematological adverse reactions were reported on nsNSAIDs than celecoxib, but more patients withdrew from celecoxib than nsNSAIDs (50.9% patients vs. 30.2%; P < 0.0001).

          Interpretation

          In subjects 60 years and over, free from CV disease and taking prescribed chronic nsNSAIDs, CV events were infrequent and similar on celecoxib and nsNSAIDs. There was no advantage of a strategy of switching prescribed nsNSAIDs to prescribed celecoxib. This study excluded an increased risk of the primary endpoint of more than two events per 1000 patient-years associated with switching to prescribed celecoxib.

          Clinical Trial Registration

          https://clinicaltrials.gov/show/NCT00447759; Unique identifier: NCT00447759.

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          Most cited references 18

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          Risk of cardiovascular events associated with selective COX-2 inhibitors.

          Atherosclerosis is a process with inflammatory features and selective cyclooxygenase 2 (COX-2) inhibitors may potentially have antiatherogenic effects by virtue of inhibiting inflammation. However, by decreasing vasodilatory and antiaggregatory prostacyclin production, COX-2 antagonists may lead to increased prothrombotic activity. To define the cardiovascular effects of COX-2 inhibitors when used for arthritis and musculoskeletal pain in patients without coronary artery disease, we performed a MEDLINE search to identify all English-language articles on use of COX-2 inhibitors published between 1998 and February 2001. We also reviewed relevant submissions to the US Food and Drug Administration by pharmaceutical companies. Our search yielded 2 major randomized trials, the Vioxx Gastrointestinal Outcomes Research Study (VIGOR; 8076 patients) and the Celecoxib Long-term Arthritis Safety Study (CLASS; 8059 patients), as well as 2 smaller trials with approximately 1000 patients each. The results from VIGOR showed that the relative risk of developing a confirmed adjudicated thrombotic cardiovascular event (myocardial infarction, unstable angina, cardiac thrombus, resuscitated cardiac arrest, sudden or unexplained death, ischemic stroke, and transient ischemic attacks) with rofecoxib treatment compared with naproxen was 2.38 (95% confidence interval, 1.39-4.00; P =.002). There was no significant difference in cardiovascular event (myocardial infarction, stroke, and death) rates between celecoxib and nonsteroidal anti-inflammatory agents in CLASS. The annualized myocardial infarction rates for COX-2 inhibitors in both VIGOR and CLASS were significantly higher than that in the placebo group of a recent meta-analysis of 23 407 patients in primary prevention trials (0.52%): 0.74% with rofecoxib (P =.04 compared with the placebo group of the meta-analysis) and 0.80% with celecoxib (P =.02 compared with the placebo group of the meta-analysis). The available data raise a cautionary flag about the risk of cardiovascular events with COX-2 inhibitors. Further prospective trial evaluation may characterize and determine the magnitude of the risk.
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            Prospective randomized open blinded end-point (PROBE) study. A novel design for intervention trials. Prospective Randomized Open Blinded End-Point.

            A novel design for intervention studies is presented, the so called PROBE study (Prospective Randomized Open, Blinded End-point). This design is compared to the classical double-blind design. Among the advantages of the PROBE design are lower cost and greater similarity to standard clinical practice, which should make the results more easily applicable in routine medical care. Since end-points are evaluated by a blinded end-point committee it is obvious that there should be no difference between the two types of trials in this regard.
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              Tolerability and adverse events in clinical trials of celecoxib in osteoarthritis and rheumatoid arthritis: systematic review and meta-analysis of information from company clinical trial reports

              The objective was to improve understanding of adverse events occurring with celecoxib in the treatment of osteoarthritis and rheumatoid arthritis. Data were extracted from company clinical trial reports of randomised trials of celecoxib in osteoarthritis or rheumatoid arthritis lasting 2 weeks or more. Outcomes were discontinuations (all cause, lack of efficacy, adverse event, gastrointestinal adverse event), endoscopically detected ulcers, gastrointestinal or cardio-renal events, and major changes in haematological parameters. The main comparisons were celecoxib (all doses) versus placebo, paracetamol (acetaminophen) 4,000 mg daily, rofecoxib 25 mg daily, or nonsteroidal anti-inflammatory drugs (NSAIDs) (naproxen, diclofenac, ibuprofen, and loxoprofen). For NSAIDs, celecoxib was compared both at all doses and at licensed doses (200 to 400 mg daily). Thirty-one trials included 39,605 randomised patients. Most patients had osteoarthritis and were women of average age 60 years or above. Most trials lasted 12 weeks or more. Doses of celecoxib were 50 to 800 mg/day. Compared with placebo, celecoxib had fewer discontinuations for any cause or for lack of efficacy, fewer serious adverse events, and less nausea. It had more patients with dyspepsia, diarrhoea, oedema, more adverse events that were gastrointestinal or treatment related, and more patients experiencing an adverse event. There were no differences for hypertension, gastrointestinal tolerability, or discontinuations for adverse events. Compared with paracetamol, celecoxib had fewer discontinuations for any cause, for lack of efficacy, or diarrhoea, but no other differences. Compared with rofecoxib, celecoxib had fewer patients with abdominal pain and oedema, but no other differences. Compared with NSAIDs, celecoxib had fewer symptomatic ulcers and bleeds, endoscopically detected ulcers, and discontinuations for adverse events or gastrointestinal adverse events. Fewer patients had any, or a gastrointestinal, or a treatment-related adverse event, or vomiting, abdominal pain, dyspepsia, or reduced haemoglobin or haematocrit. Discontinuations for lack of efficacy were higher. No differences were found for all-cause discontinuations, serious adverse events, hypertension, diarrhoea, nausea, oedema, myocardial infarction, cardiac failure, or raised creatinine. Company clinical trial reports present much more information than published papers. Adverse event information is clearly presented in company clinical trial reports, which are an ideal source of information for systematic review and meta-analysis.
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                Author and article information

                Journal
                Eur Heart J
                Eur. Heart J
                eurheartj
                European Heart Journal
                Oxford University Press
                0195-668X
                1522-9645
                14 June 2017
                04 October 2016
                04 October 2016
                : 38
                : 23 , Focus Issue on Prevention
                : 1843-1850
                Affiliations
                [1 ]Medicines Monitoring Unit (MEMO), Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital & Medical School Dundee, Dundee DD1 9SY, UK
                [2 ]Faculty of Medicine & Health Sciences, University of Nottingham, Queen’s Medical Centre Nottingham, Nottingham NG7 2UH, UK
                [3 ]Robertson Centre for Biostatistics, University of Glasgow, Glasgow G12 8QQ, UK
                [4 ]British Heart Foundation Cardiovascular Research Centre, University of Glasgow,126 University Place, GlasgowG12 8TA, UK
                [5 ]Division of Gastroenterology, University of Michigan Medical School, 1500 E Medical Center Drive, Ann Arbor, MI 48109, USA
                [6 ]Department of Public Health, Clinical Pharmacology, University of Southern Denmark, J. B. Winsløws Vej 19, 2.5000 Odense, Denmark
                [7 ]Julius Center for Health Sciences and Primary Care and Julius Clinical Academic Research Organization, Utrecht, The Netherlands
                [8 ]Nuffield Department of Primary Care Health Sciences, University of Oxford, Radcliffe Primary Care Building, Radcliffe Observatory Quarter, Woodstock Road, Oxford OX2 6GG, UK
                [9 ]Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital Edinburgh, Edinburgh EH4 2XU, UK
                [10 ]School of Medicine & Dentistry, University of Aberdeen, Aberdeen AB25 2ZD, UK
                [11 ]Department of Cardiology, University Heart Center, Rämistrasse 100, 8091Zürich, Switzerland
                [12 ]Centre of Academic Primary Care, School of Medicine and Dentistry, University of Aberdeen, AberdeenAB25 2ZD, UK
                [13 ]RTI Health Solutions, Trav. Gracia 56, Atico 1, Barcelona 08006, Spain
                [14 ]Department of Practice and Policy, University College London, London WC1H 9JP, UK
                Author notes
                [* ]Corresponding author. Tel: +44 (01382) 383119, Fax: +44 (01382) 740209, Email: t.m.macdonald@ 123456dundee.ac.uk
                This paper was guest edited by Marc Pfeffer.

                See page 1851 for the editorial comment on this article (doi: [Related article:]10.1093/eurheartj/ehw507)

                Article
                ehw387
                10.1093/eurheartj/ehw387
                5837371
                27705888
                © The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                Page count
                Pages: 9
                Product
                Funding
                Funded by: National Institutes of Health 10.13039/100000002
                Funded by: NIHR School for Primary Care Research, NIHR CLAHRC Oxford, NIHR Oxford BRC and Harris Manchester College, Oxford
                Categories
                Clinical Research
                Prevention and Epidemiology
                Editor's Choice

                Cardiovascular Medicine

                nsaids, celecoxib, cardiovascular, arthritis

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