The full report is titled “Viscosupplementation for Osteoarthritis of the Knee. A Systematic Review and Meta-analysis.” It is in the 7 August 2012 issue of Annals of Internal Medicine (volume 157, pages 180-191). The authors are A.W.S. Rutjes, P. Jüni, B.R. da Costa, S. Trelle, E. Nüesch, and S. Reichenbach.
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Suresh Aravind, MD, MBA, Brad Bisson, MPH
DePuy Mitek, a Johnson & Johnson Company
August 16, 2012
Conflict of Interest:
DePuy Mitek, Distributor of Orthovisc
Viscosupplementation for Osteoarthritis of the Knee – Rutjes, et al - Comments
Dear Editors,The data and conclusions of the recent meta-analysis (August 7th, 2012) by Rutjes et al on the treatment of Osteoarthritis with viscosupplementations, raise several questions. From the efficacy standpoint, we expected the authors' summary of efficacy analyses across 71 studies to provide evidence of the efficacy of HA across patient populations. In particular, out of 69 studies with reported effect sizes, 60 (87%) showed an effect < 0 (favoring HA), and 49 (71%) showed an effect size < -0.176 (equivalent to a difference of 0.44 cm, with an assumed SD of 2.5 cm). In addition, the authors used a clinically importance difference between the treated group and the control groups of 0.9 cm on a 10 cm scale to assesses the efficacy of viscosupplementation. This cutoff is very strict given the difference between placebo and various proven first and second line treatments for osteoarthritis ranged from 0.44 cm to a 0.65 cm. These values represent the incremental and meaningful benefit of a therapy after subtracting the placebo and other non-specific effects . From the safety standpoint, the Serious Adverse Events (SAEs) listed as concerns, involve disparate body systems, unique patho-physiologies and appear unrelated to each other mechanistically. It is unclear how local intra-articular injections of HAs can be attributed to such a diverse set of SAEs (such as cancer, GI, Cardiovascular) linked to different body systems. While an increase in reported adverse events is apparent, statistically, in the absence of a plausible biological mechanism that could generate these events, some form of biased ascertainment in reporting cannot be ruled out. Moreover, communication with Dr. Baraf (author of the study in Supplement 14 SAE review which contributed 4 of the 6 cancers cases referenced in the meta-analysis), indicate that of the 4 subjects with cancers (breast, prostate, squamous and melanoma) discovered within just 16-74 days post treatment, none were judged by investigators to be related to study treatment. Post marketing safety surveillance data from over 5 million injections of ORTHOVISC® worldwide in patients with osteoarthritis has shown no signals or trends suggestive of such treatment related serious adverse events. We believe that this meta-analysis evidence citing concerns over safety and efficacy from the use of viscosupplementations, does not address the causality or mechanisms of the SAEs, does not reflect the findings from other Level 1 meta-analyses, and has methodological challenges that could affect the conclusions and current treatment paradigm.References1. Dworkin RH, Turk DC, McDermott MP, Peirce-Sandner S, Burke LB, Cowan P et al. Interpreting the clinical importance of group differences in chronic pain clinical trials: IMMPACT recommendations. Pain. 2009;146:238-44.
Viscosupplementation for Knee Osteoarthritis. Ann Intern Med. 2012;157:I-36. doi: 10.7326/0003-4819-157-3-201208070-00474
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Published: Ann Intern Med. 2012;157(3):I-36.
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