Open Access Protocol BMJ Open: first published as 10.1136/bmjopen-2012-002295 on 29 January 2013. Downloaded from Methodology of a large prospective, randomised, open, blinded endpoint streamlined safety study of celecoxib versus traditional non-steroidal anti- inflammatory drugs in patients with osteoarthritis or rheumatoid arthritis: protocol of the standard care versus celecoxib outcome trial (SCOT) Thomas M MacDonald,1 Isla S Mackenzie,1 Li Wei,2 Christopher J Hawkey,3 Ian Ford,4 SCOT study group collaborators To cite: MacDonald TM, ABSTRACT et al ARTICLE SUMMARY Mackenzie IS, Wei L, . Introduction: Cyclooxygenase 2 (COX-2) inhibitors Methodology of a large prospective, randomised, have less upper gastrointestinal toxicity than traditional Article focus open, blinded endpoint non-steroidal anti-inflammatory drugs (NSAIDs). ▪ The Standard care versus Celecoxib Outcome Trial streamlined safety study of However, both COX-2 inhibitors and traditional NSAIDs (SCOT) compares the cardiovascular and gastro- celecoxib versus traditional may be associated with adverse cardiovascular side intestinal safety of a strategy of celecoxib therapy non-steroidal anti- effects. Data from randomised and observational studies and a strategy of traditional non-steroidal anti- inflammatory drugs in patients suggest that celecoxib has similar cardiovascular with osteoarthritis or inflammatory drug (NSAID) therapy in patients with http://bmjopen.bmj.com/ rheumatoid arthritis: protocol toxicity to traditional NSAIDs. The overall safety balance osteoarthritis or rheumatoid arthritis aged over of the standard care versus of a strategy of celecoxib therapy versus traditional 60 years without a history of cardiovascular disease. celecoxib outcome trial NSAID therapy is unknown. The European Medicines (SCOT). BMJ Open 2013;3: Agency requested studies of the cardiovascular safety Key messages e002295. doi:10.1136/ of celecoxib within Europe. The Standard care versus ▪ SCOT is a prospective randomised trial compar- bmjopen-2012-002295 Celecoxib Outcome Trial (SCOT) compares the ing celecoxib with traditional NSAIDs in patients ▸ Prepublication history for cardiovascular safety of celecoxib with traditional NSAID with arthritis without a history of cardiovascular this paper are available therapy in the setting of the European Union healthcare disease. online. To view these files ▪ The cardiovascular safety of NSAIDs is an system. on October 1, 2021 by guest. Protected copyright. please visit the journal online Methods and analysis: SCOT is a large streamlined important issue where more evidence is required (http://dx.doi.org/10.1136/ to guide practice. bmjopen-2012-002295). safety study conducted in Scotland, England, Denmark and the Netherlands using the Prospective Randomised ▪ SCOT uses electronic record-linkage to collect Received 1 November 2012 Open Blinded Endpoint design. Patients aged over data on endpoints. Revised 7 January 2013 60 years with osteoarthritis or rheumatoid arthritis, free Accepted 8 January 2013 from established cardiovascular disease and requiring chronic NSAID therapy, are randomised to celecoxib or This final article is available for use under the terms of their previous traditional NSAID. They are then followed hospitalised upper gastrointestinal ulcer complications the Creative Commons up for events by record-linkage within their normal or APTC endpoint; (3) first hospitalisation for heart Attribution Non-Commercial healthcare setting. The hypothesis is non-inferiority with failure; (4) first hospitalisation for APTC endpoint plus 2.0 Licence; see a confidence limit of 1.4. The primary endpoint is the heart failure; (5) all-cause mortality and (6) first http://bmjopen.bmj.com first occurrence of hospitalisation or death for the Anti- hospitalisation for new or worsening renal failure. For numbered affiliations see Platelet Trialists’ Collaboration (APTC) cardiovascular Ethics and dissemination: SCOT has been approved end of article. endpoint of non-fatal myocardial infarction, non-fatal by the relevant ethics committees. The trial results will stroke or cardiovascular death. Secondary endpoints are be published in a peer-reviewed scientific journal. Correspondence to (1) first hospitalisation or death for upper Clinical trials registration number: Clinicaltrials. Professor Thomas M gastrointestinal ulcer complications (bleeding, gov (NCT00447759). MacDonald; perforation or obstruction); (2) first occurrence of [email protected] MacDonald TM, Mackenzie IS, Wei L, et al. BMJ Open 2013;3:e002295. doi:10.1136/bmjopen-2012-002295 1 Standard care versus Celecoxib Outcome Trial (SCOT) protocol BMJ Open: first published as 10.1136/bmjopen-2012-002295 on 29 January 2013. Downloaded from therefore be interpreted with caution. In a later ARTICLE SUMMARY meta-analysis of six randomised double-blind placebo Strengths and limitations of this study controlled trials of celecoxib in non-arthritis conditions, ▪ SCOT is a prospective randomised trial in a population of which included analysis of the APC, PreSAP and ADAPT patients who take NSAIDs in the long term and are, therefore, studies and three other smaller studies (MA27, The representative of patients who might be at risk from NSAID Diabetic Macular Edema Trial and the Celecoxib/ therapy. SCOT is a streamlined safety trial with good external Selenium Trial), there was no evidence of increased car- validity as it is conducted in the normal care setting. The limita- diovascular risk with celecoxib in low-risk patients but tions of the study include the need to extrapolate from the there was a dose-dependent increase in cardiovascular results to guide therapy in younger patients and in patients risk in high-risk patients.8 without a history of using NSAIDS and the lack of traditional In the Multinational Etoricoxib and Diclofenac study follow-up visits, although it has been shown that Arthritis Long-term programme, which compared car- record-linkage can be used effectively in trial follow-up to diovascular outcomes with etoricoxib 60 or 90 mg daily detect events. and diclofenac 150 mg daily in patients with osteoarth- ritis or rheumatoid arthritis, the rates of thrombotic car- diovascular events were similar in patients randomised INTRODUCTION to either drug.9 Non-steroidal anti-inflammatory drug (NSAID)-induced In trials of celecoxib versus traditional NSAIDs, no evi- gastrointestinal toxicity is one of the most common dence of increased cardiovascular toxicity has been 1 serious drug adverse events requiring hospitalisation. seen.10 In large observational studies, celecoxib has not Upper gastrointestinal complications result in consider- been found to be associated with increased cardiovascu- able morbidity and mortality. The cyclooxygenase 2 lar risk versus other NSAIDs11 or non-use.12 13 At (COX-2) selective NSAIDs gained popularity based on present, much of the available data comes from observa- evidence that they are associated with a lower incidence tional studies and while it seems clear that rofecoxib of ulcer-related upper gastrointestinal tract complica- increased cardiovascular risk, many traditional NSAIDs – tions compared with traditional non-selective NSAID may also pose considerable risk.3111416 2 therapy. However, the withdrawal of rofecoxib due to The recent Celecoxib versus Omeprazole and cardiovascular toxicity and the suggestion that most Diclofenac in patients with Osteoarthritis and Rheumatoid NSAIDs are probably associated with increased cardiovas- arthritis study found that celecoxib was associated with a 3 cular adverse events when compared with placebo have lower incidence of clinically significant upper or lower led to the need for further prospective studies on the gastrointestinal events than the combination of diclofenac safety of other COX-2 inhibitors and traditional NSAIDs. and omeprazole, adding further evidence to the improved The cardiovascular safety profile of COX-2 inhibitors gastrointestinal safety of COX-2 inhibitors compared with http://bmjopen.bmj.com/ was brought into question following the results of two non-selective NSAIDs.17 placebo-controlled studies designed to test the hypoth- Against this background of conflicting data, the overall esis that the COX-2 inhibitors rofecoxib and celecoxib risk-benefit balance of celecoxib versus traditional NSAIDs might prevent colorectal adenomas and colorectal needs to be better clarified in a prospective trial design. tumours. The Adenomatous Polyp Prevention on Vioxx This paper describes the design and rationale for The Trial randomised patients with a history of colorectal Standard care versus Celecoxib Outcome Trial (SCOT), adenomas to rofecoxib 25 mg or placebo and reported which is a prospective trial randomising patients without a an excess of cardiovascular thrombotic events in the history of cardiovascular disease to celecoxib or traditional on October 1, 2021 by guest. Protected copyright. 4 group treated with rofecoxib. The Prevention of NSAID and measuring cardiovascular outcomes that is Sporadic Colorectal Adenomas with Celecoxib (APC) expected to report in 2014. This trial, which started Trial randomised patients with previous colorectal aden- recruiting in 2008, is a large streamlined safety study of cel- omas to celecoxib 400 mg twice daily, celecoxib 200 mg ecoxib versus traditional NSAIDs in patients with osteo- twice daily or placebo and reported a dose-related arthritis or rheumatoid arthritis that aims to address the increase in the risk of cardiovascular events in the cele-