Anne W.S. Rutjes, PhD; Peter Jüni, MD; Bruno R. da Costa, MSc; Sven Trelle, MD; Eveline Nüesch, PhD; Stephan Reichenbach, MD, MSc
Acknowledgment: The authors thank Malcolm Sturdy for database support; Paolo Barbaro, Dr. Aijing Shang, and Aysel Güler for the translation of the Japanese, Chinese, and Turkish reports; and Drs. Gluud, Russell, Petrella, Navarro-Sarabia, and Coronel for providing additional information about outcome data. They also thank Dr. Aggarwal, who replied to our queries and attempted to locate files but could not provide additional outcome data.
Grant Support: This study is funded by a grant from the Arco Foundation. Dr. Rutjes and Mr. da Costa are supported by the Arco Foundation, and Drs. Jüni and Reichenbach are supported by the Swiss National Science Foundation and Arco Foundation.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-3078.
Requests for Single Reprints: Peter Jüni, MD, Institute of Social and Preventive Medicine, University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Rutjes, Jüni, da Costa, Nüesch, and Reichenbach: Institute of Social and Preventive Medicine, University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland.
Dr. Trelle: Clinical Trials Unit Bern, Inselspital, and University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland.
Author Contributions: Conception and design: A.W.S. Rutjes, P. Jüni, S. Reichenbach.
Analysis and interpretation of the data: A.W.S. Rutjes, P. Jüni, B.R. da Costa, S. Trelle, E. Nüesch, S. Reichenbach.
Drafting of the article: A.W.S. Rutjes, P. Jüni, S. Reichenbach.
Critical revision of the article for important intellectual content: A.W.S. Rutjes, P. Jüni, B.R. da Costa, S. Trelle, E. Nüesch, S. Reichenbach.
Final approval of the article: A.W.S. Rutjes, P. Jüni, B.R. da Costa, S. Trelle, E. Nüesch, S. Reichenbach.
Statistical expertise: A.W.S. Rutjes, P. Jüni, S. Trelle, E. Nüesch, S. Reichenbach.
Obtaining of funding: A.W.S. Rutjes, P. Jüni, B.R. da Costa, S. Reichenbach.
Administrative, technical, or logistical support: P. Jüni.
Collection and assembly of data: A.W.S. Rutjes, B.R. da Costa, S. Reichenbach.
Rutjes AW, Jüni P, da Costa BR, Trelle S, Nüesch E, Reichenbach S. Viscosupplementation for Osteoarthritis of the Knee: A Systematic Review and Meta-analysis. Ann Intern Med. 2012;157:180-191. doi: 10.7326/0003-4819-157-3-201208070-00473
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Published: Ann Intern Med. 2012;157(3):180-191.
Viscosupplementation, the intra-articular injection of hyaluronic acid, is widely used for symptomatic knee osteoarthritis.
To assess the benefits and risks of viscosupplementation for adults with symptomatic knee osteoarthritis.
MEDLINE (1966 to January 2012), EMBASE (1980 to January 2012), the Cochrane Central Register of Controlled Trials (1970 to January 2012), and other sources.
Randomized trials in any language that compared viscosupplementation with sham or nonintervention control in adults with knee osteoarthritis.
Primary outcomes were pain intensity and flare-ups. Secondary outcomes included function and serious adverse events. Reviewers used duplicate abstractions, assessed study quality, pooled data by using a random-effects model, examined funnel plots, and explored heterogeneity by using meta-regression.
Eighty-nine trials involving 12 667 adults met inclusion criteria. Sixty-eight had a sham control, 40 had a follow-up duration greater than 3 months, and 22 used cross-linked forms of hyaluronic acid. Overall, 71 trials (9617 patients) showed that viscosupplementation moderately reduced pain (effect size, −0.37 [95% CI, −0.46 to −0.28]). There was important between-trial heterogeneity and an asymmetrical funnel plot: Trial size, blinded outcome assessment, and publication status were associated with effect size. Five unpublished trials (1149 patients) showed an effect size of −0.03 (CI, −0.14 to 0.09). Eighteen large trials with blinded outcome assessment (5094 patients) showed a clinically irrelevant effect size of −0.11 (CI, −0.18 to −0.04). Six trials (811 patients) showed that viscosupplementation increased, although not statistically significantly, the risk for flare-ups (relative risk, 1.51 [CI, 0.84 to 2.72]). Fourteen trials (3667 patients) showed that viscosupplementation increased the risk for serious adverse events (relative risk, 1.41 [CI, 1.02 to 1.97]).
Trial quality was generally low. Safety data were often not reported.
In patients with knee osteoarthritis, viscosupplementation is associated with a small and clinically irrelevant benefit and an increased risk for serious adverse events.
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