Comparative Effectiveness of Pharmacologic Interventions for Knee Osteoarthritis A Systematic Review and Network Meta-analysis Raveendhara R. Bannuru, MD; Christopher H. Schmid, PhD; David M. Kent, MD; Elizaveta E. Vaysbrot, MD; John B. Wong, MD; and Timothy E. McAlindon, MD Background: The relative efficacy of available treatments of knee osteoarthritis (OA) must be determined for rational treat- ment algorithms to be formulated. Purpose: To examine the efficacy of treatments of primary knee OA using a network meta-analysis design, which estimates rela- tive effects of all treatments against each other. Data Sources: MEDLINE, EMBASE, Web of Science, Google Scholar, Cochrane Central Register of Controlled Trials from in- ception through 15 August 2014, and unpublished data. Study Selection: Randomized trials of adults with knee OA comparing 2 or more of the following: acetaminophen, diclofe- nac, ibuprofen, naproxen, celecoxib, intra-articular (IA) cortico- steroids, IA hyaluronic acid, oral placebo, and IA placebo. Data Extraction: Two reviewers independently abstracted study data and assessed study quality. Standardized mean differ- ences were calculated for pain, function, and stiffness at 3-month follow-up. Data Synthesis: Network meta-analysis was performed using a Bayesian random-effects model; 137 studies comprising 33 243 participants were identified. For pain, all interventions signifi- cantly outperformed oral placebo, with effect sizes from 0.63 (95% credible interval [CrI], 0.39 to 0.88) for the most efficacious treatment (hyaluronic acid) to 0.18 (CrI, 0.04 to 0.33) for the least efficacious treatment (acetaminophen). For function, all interven- tions except IA corticosteroids were significantly superior to oral placebo. For stiffness, most of the treatments did not significantly differ from one another. Limitation: Lack of long-term data, inadequate reporting of safety data, possible publication bias, and few head-to-head comparisons. Conclusion: This method allowed comparison of common treatments of knee OA according to their relative efficacy. Intra-articular treatments were superior to nonsteroidal anti- inflammatory drugs, possibly because of the integrated IA pla- cebo effect. Small but robust differences were observed be- tween active treatments. All treatments except acetaminophen showed clinically significant improvement from baseline pain. This information, along with the safety profiles and relative costs of included treatments, will be helpful for individualized patient care decisions. Primary Funding Source: Agency for Healthcare Research and Quality. Ann Intern Med. 2015;162:46-54. doi:10.7326/M14-1231 www.annals.org For author affiliations, see end of text. K nee osteoarthritis (OA) is a common and progres- sive joint disease affecting more than 250 million people worldwide (1). It has significant effects on func- tion (2) and considerable societal costs in terms of work loss (3), early retirement, and joint replacement (4). Os- teoarthritis is a leading indication for use of prescrip- tion drugs, which costs about $3000 per year per pa- tient (5). In the absence of effective disease-modifying medical treatments, a range of symptomatic treatments is available. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequently prescribed medicines for OA yet have significant toxicity, especially among the demographic groups in which the disorder is most prevalent (6). Intra-articular (IA) treatments are widely used, although their efficacy and safety remain in ques- tion. More knowledge about the comparative efficacy and toxicity of these compounds, which would be help- ful for patients, physicians, payers, and policymakers, is needed to formulate rational treatment algorithms for OA. The relative effectiveness of OA treatments is diffi- cult to discern from the literature, in part because few head-to-head comparison studies are available and tra- ditional pairwise meta-analysis cannot integrate all of the evidence from several comparators. Therefore, our goal was to comprehensively review the literature and determine the relative efficacy of the primary knee OA treatments using a network meta-analysis design. METHODS Data Sources and Searches We searched MEDLINE, EMBASE, Web of Science, Google Scholar, and the Cochrane Central Register of Controlled Trials from inception to 15 August 2014 (Supplement Table 1, available at www.annals.org). All searches were limited to randomized, controlled trials in humans. No limits were applied for language, publi- cation date, or publication status, and foreign-language papers were translated. We also hand-searched the ref- erence lists of all retrieved studies and conference pro- ceedings of the American Association of Orthopedic See also: Editorial comment .......................... 71 Web-Only Supplement CME quiz REVIEW Annals of Internal Medicine 46 © 2015 American College of Physicians Downloaded From: http://annals.org/ by a Novartis Pharma AG User on 03/17/2015