Abstract
BackgroundMost reported outcome measures in rheumatoid arthritis (RA) trials are composite, whose components comprise single measures that are combined into one outcome. The aims of this review were to assess the range of missing data rates in primary composite outcomes and to document the current practice for handling and reporting missing data in published RA trials compared to the Consolidated Standards of Reporting Trials (CONSORT) recommendations.MethodsA systematic search for randomised controlled trials was conducted for RA trials published between 2008 and 2013 in four rheumatology and four high impact general medical journals.ResultsA total of 51 trials with a composite primary outcome were identified, of which 38 (75 %) used the binary American College of Rheumatology responder index and 13 (25 %) used the Disease Activity Score for 28 joints (DAS28). Forty-four trials (86 %) reported on an intention-to-treat analysis population, while 7 trials (14 %) analysed according to a modified intention-to-treat population. Missing data rates for the primary composite outcome ranged from 2–53 % and were above 30 % in 9 trials, 20–30 % in 11 trials, 10–20 % in 18 trials and below 10 % in 13 trials. Thirty-eight trials (75 %) used non-responder imputation and 10 (20 %) used last observation carried forward to impute missing composite outcome data at the primary time point. The rate of dropout was on average 61 % times higher in the placebo group compared to the treatment group in the 34 placebo controlled trials (relative rate 1.61, 95 % CI: 1.29, 2.02). Thirty-seven trials (73 %) did not report the use of sensitivity analyses to assess the handling of missing data in the primary analysis as recommended by CONSORT guidelines.ConclusionsThis review highlights an improvement in rheumatology trial practice since the revision of CONSORT guidelines, in terms of power calculation and participant’s flow diagram. However, there is a need to improve the handling and reporting of missing composite outcome data and their components in RA trials. In particular, sensitivity analyses need to be more widely used in RA trials because imputation is widespread and generally uses single imputation methods, and in this area the missing data rates are commonly differentially higher in the placebo group.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1402-5) contains supplementary material, which is available to authorized users.
Highlights
Most reported outcome measures in rheumatoid arthritis (RA) trials are composite, whose components comprise single measures that are combined into one outcome
Selection of studies Studies were included in the review if they met the inclusion criteria: phase 3; double blinded randomised controlled trial (RCT) conducted in adults with RA; English language papers published between January 2008 and December 2013; published in four rheumatology journals (Annals of the Rheumatic Diseases, Arthritis & Rheumatism, Arthritis Research & Therapy and Rheumatology); and four high impact factor general medical journals (Lancet, New England Journal of Medicine, Journal of the American Medical Association and the British Medical Journal); and a composite outcome measure was reported as the primary outcome
Data extraction Data extracted from the papers included the following: year of publication, journal, source of funding, primary and secondary outcomes, trial design; sample size calculation and whether this calculation included a dropout rate; amount of missing information; method of dealing with missing primary outcome data; analysis population (intention-to-treat (ITT), modified ITT, per protocol, complete or available cases); statistical method used to analyse the primary outcome; sensitivity analyses; participant flow diagram and study follow-up time
Summary
Most reported outcome measures in rheumatoid arthritis (RA) trials are composite, whose components comprise single measures that are combined into one outcome. In RA, most reported outcome measures are composites, with the Disease Activity Score for 28 joints (DAS28), a continuous measure of current status of disease activity, and the American College of Rheumatology (ACR) response criteria, a binary indicator of disease activity change over time, being the most commonly used. The use of composite endpoints has been discussed extensively in the trial literature; for example, they are used as time-to-event endpoints in cardiovascular, cancer, diabetic and HIV studies [6, 7], where the composite might involve binary variables which combine mortality with non-fatal endpoints such as hospitalisation and cardiac arrest in chronic heart patients [8]. An article by Senn and Julious criticised the use of composite response measures, as they argued that their use should be carefully thought through and accompanied by consideration of their components [10]
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