The Impact of Excluding Patients with End-Stage Knee Disease in Intra-Articular Hyaluronic Acid Trials: A Systematic Review and Meta-Analysis

• Published in: Advances in therapy Vol. 36; no. 1; pp. 147 - 161
• Main Authors: Nicholls, Mathew, Shaw, Peter, Niazi, Faizan, Bhandari, Mohit, Bedi, Asheesh
• Format: Journal Article
• Language: English
• Published: Cheshire Springer Healthcare 01-01-2019
• Subjects: Cardiology; Endocrinology; Female; Health technology assessment; Humans; Hyaluronic Acid - therapeutic use; Injections, Intra-Articular; Internal Medicine; Knee Joint - physiopathology; Male; Medicine; Medicine & Public Health; Oncology; Original Research; Osteoarthritis, Knee - drug therapy; Pain - drug therapy; Pain Management; Pharmacology/Toxicology; Randomized Controlled Trials as Topic; Rheumatology; Treatment Outcome; Viscosupplements - therapeutic use; Knee; Intra-articular hyaluronic acid; Osteoarthritis; Rheumatology
• ISSN: 0741-238X; 1865-8652
• DOI: 10.1007/s12325-018-0847-1

Introduction
The Kellgren–Lawrence (K–L) grade is the most commonly used measure of radiographic disease severity in knee osteoarthritis (OA). Studies suggest that intra-articular hyaluronic acid (IA-HA) should only be considered in cases of early stage knee OA. The purpose of this review was to determine if trials administering IA-HA in early-moderate knee OA patients demonstrated greater pain relief than studies that also included patients with end-stage disease.
Methods
We conducted a systematic search of the literature to identify randomized controlled trials (RCT) comparing IA-HA with saline injections and that diagnosed disease severity using the K–L grade criteria. The primary outcome was mean change in pain from baseline at 4–13 weeks and 22–27 weeks. Safety was evaluated on the total number of participants experiencing a treatment-related adverse event (AE).
Results
Twenty RCTs were included. In the early-moderate OA subgroup, the mean change in pain scores was statistically significant favoring IA-HA from baseline to 4–13 weeks [SMD = − 0.30, 95% CI − 0.44 to − 0.15,
p
 < 0.0001] and within 22–27 weeks [SMD = − 0.27, 95% CI − 0.39 to − 0.16,
p
 < 0.00001]. No significant differences were observed in the late OA subgroup. IA-HA was associated with a significantly greater risk of treatment-related AEs relative to saline in the late OA subgroup [RR = 1.76, 95% CI 1.16–2.67,
p
 = 0.008].
Conclusion
IA-HA provides significant pain relief compared to saline for patients with early-moderate knee OA, compared to cohorts including patients with end-stage OA (KL grade 4), with no increase in the risk of treatment-related AEs, up to 6 months. Patients with end-stage disease had lower levels of pain relief and may be diluting study results if included in the treatment cohort.
Funding
Ferring Pharmaceuticals.