Does flare trial design affect the effect size of non-steroidal anti-inflammatory drugs in symptomatic osteoarthritis? A systematic review and meta-analysis.

Abstract

It is thought that the clinical trial benefits of oral non-steroidal anti-inflammatory drugs (NSAIDs) may relate to flare designs. The aim of this study was to examine the difference in NSAID (including cyclooxygenase-2 (COX-2) inhibitors) response in osteoarthritis (OA) trials based on different designs. Systematic review was undertaken of the databases MEDLINE, EMBASE, AMED, CINAHL and the Cochrane library till February 2015. Randomised controlled trials assessing pain, function and/or stiffness following commencement of NSAIDs in flare and non-flare designs were eligible. Trials were assessed using the Cochrane Risk of Bias tool. Meta-analyses were conducted to assess the effect sizes (ES) of NSAIDs for OA with flare versus non-flare trial designs. Fifty-seven studies including 33 263 participants assessing 26 NSAIDs were included. Twenty-two (39%) were flare design, 24 (42%) were non-flare designs, 11 (19%) were possible flare designs. On meta-analysis, there was no statistically significant difference in ES of NSAIDs versus placebo between flare and non-flare trial designs for absolute pain and function or stiffness at immediate-term (1 week), short-term (2-4 week) or longer-term (12-13 week) follow-up periods (p>0.05). However there was a lower ES for mean change in pain in flare and possible flare trials compared with non-flare trials at short-term follow-up (0.36 vs 0.69; p=0.05). Contrary to previous understanding, flare trial designs do not result in an increased treatment effect for NSAIDs in people with OA compared with non-flare design. Whether flare design influences other outcomes such as joint effusion remains unknown.