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To the Editors:

I thank Reichenbach et al for their success in distilling and interpreting complicated information for their article published in a recent issue of Arthritis Care & Research (1), which helps to clarify the much-debated issue of selecting a hyaluronic acid (HA) in the treatment of knee osteoarthritis (OA). Their meta-analysis of 13 randomized trials with a total of 2,085 patients represents the largest analysis to date thoughtfully comparing HA treatments. The study concludes that hylan (Synvisc, Genzyme, Cambridge, MA) and the other forms of HA analyzed (notably, Euflexxa, Ferring Pharmaceuticals, Inc., Parsippany, NJ, Hyalgan, Sanofi-Aventis, Bridgewater, NJ, Orthovisc, Anika Therapeutics, Bedford, MA, Artzal, AstraZeneca, Wilmington, DE, Healon, Advanced Medical Optics, Santa Ana, CA, and Ostenil, Garvinci International, St-Eustache, Quebec, Canada) have equal efficacy, although there is an ∼2-fold increased risk of adverse events and symptom flares associated with hylan. This study provides clinically relevant guidance since efficacy and safety, as well as the burden of health care costs, should factor into modern-day treatment decisions (1).

Relative to data/information extracted by Reichenbach et al from the article authored by Kirchner and Marshall, we want to clarify 3 matters. First, Euflexxa (Ferring Pharmaceuticals, Inc.) should be considered a straight-chain, high molecular weight preparation by virtue of the absence of any chemical process to effect cross-linking and its 2,400–3,600 kD molecular weight (2).

Second, the article states that the report by Jüni et al is the only study using an intent-to-treat (ITT) population (3). However, the article by Kirchner and Marshall presents an ITT analysis; i.e., all patients randomized to treatment who received at least 1 injection. All ITT data are presented as the last observation carried forward, although the authors also present a per protocol analysis in the Results section of the article (2).

Lastly, the article establishes 2 specific criteria for a double-blind study: “Therapist blinding was considered adequate if preparations were explicitly described as indistinguishable or a double-dummy technique was used” (1). In the study by Kirchner and Marshall, the preparations of HA provided to the investigational sites were indistinguishable in coded, blister-packed, unmarked boxes, although this point was not explicitly stated in the article. To allay any potential concern regarding bias, however, the individual injecting the HA was separate and distinct from the physician who performed the evaluations. This resulted in a blinded patient and a blinded evaluator, therefore meeting the criteria for a true double-blind trial.

We applaud the assessment and evaluation of these clinical data and the robust evidence presented by the authors for their meaningful analysis of the literature, which helps to define the efficacy and differing safety profiles of these agents. We trust that the clarifications to our study are considered in support of the conclusions by Reichenbach et al and will help physicians make more informed choices among the available treatment options for OA of the knee.

Dennis C. Marshall RN, MS, PhD*, * Ferring Pharmaceuticals, Inc., Parsippany, NJ.