Technology Assessment Systematic Review
Newberry et al4 conducted a systematic review for effectiveness of HYALURonic acid in the treatment of severe degenerative joint disease (DJD) of the knee. The Coverage and Analysis Group at the Centers for Medicare and Medicaid Services (CMS) requested from The Technology Assessment Program (TAP) at the Agency for Healthcare Research and Quality (AHRQ), a review of the evidence that intraarticular injections of HYALURonic acid (HA) in individuals with degenerative joint disease (osteoarthritis [OA]) of the knee improve function and quality of life (QoL) and that they delay or prevent the need for total knee replacement (TKR), specifically for individuals age 65 and over. The results of the systematic review were as follows: Only one randomized controlled trial (RCT) reported on delay or avoidance of TKR as a pre-specified outcome of interest and found a non-statistically significantly longer delay of TKR compared with placebo; two RCTs reported TKR only as a secondary outcome; and 13 published observational studies reported on TKR as an outcome in HA-treated participants.
Eighteen RCTs that enrolled participants of average age 65 or older reported on functional outcomes of intra-articular HA injection: pooled analysis of ten sham-injection placebo-controlled, assessor-blinded trials showed a standardized mean difference of -0.23 (95% CI -0.34, -0.02) significantly favoring HA at 6 months’ follow-up. Durability of effect could not be assessed because of the short duration of most studies. Too few head-to-head trials were available to assess superiority of one product over another. Three RCTs that compared changes in QoL/Health-Related (HR) QoL between HA- and placebo-treated participants reported no differences between active treatment and placebo. Two recent large, good quality systematic reviews that conducted meta-analysis of the effects of HA on pain and function (pooling 71 and 52 RCTs for the outcome of pain, respectively) showed a significant and clinically important effect of HA on both outcomes among adults of all ages, but a subgroup analysis that included only the largest double-blind placebo-controlled studies reduced the average effect of HA to less than the prespecified minimum clinically important difference. Studies of intra-articular HA reported few serious adverse events, with no statistically significant difference in the rates of serious or non-serious adverse events between HA- and placebo-treated groups.
The authors concluded that trials enrolling older participants show a small, statistically significant effect of HA on function and relatively few serious adverse events; however, no studies limited participation to those 65 years or older. No conclusions can be drawn from the available literature on delay or avoidance of TKR using HA. Studies that can compare large numbers of treated and untreated individuals, preferably with a randomized design, are needed to answer this question.
The Department of Veterans Affairs (VA) and The Department of Defense (DoD) Evidence Based Clinical Practice Guideline for Non-surgical Management of the Hip and Knee Osteoarthritis Guideline Summary5 states there is insufficient evidence to recommend for or against the use of intra-articular HYALURonate/hylan injection in patients with osteoarthritis of the knee; however, it may be considered for patients who have not responded adequately to nonpharmacologic measures and who have an inadequate response, intolerable adverse events, or contraindications to other pharmacologic therapies.
The National Institute for Health and Care Excellence (NICE) Clinical Guideline Osteoarthritis: care and management6 recommendations include: do not offer intra-articular HYALURonan injections for the management of osteoarthritis.
The American Academy of Orthopaedic Surgeons (AAOS) Treatment of Osteoarthritis of the Knee: Evidence-Based Guideline, 2nd Edition7, is based on a systematic review of the current scientific and clinical research. This guideline contains 15 recommendations, replaces the 2008 AAOS clinical practice guideline, and was reevaluated earlier than the 5-year recommendation of the National Guideline Clearinghouse because of methodologic concerns regarding the evidence used in the first guideline. The current guideline does not support the use of viscosupplementation for the treatment of osteoarthritis of the knee. In addition, the work group highlighted the need for better research in the treatment of knee osteoarthritis.
Hochberg et al8 (American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee) conditionally recommended for the initial management of patients with knee OA included acetaminophen, oral and topical NSAIDs, tramadol, and intraarticular corticosteroid injections. Intraarticular HYALURonate injections, duloxetine, and opioids were conditionally recommended in patients who had an inadequate response to initial therapy.
Filardo et al9 conducted a double-blind randomized controlled trial to evaluate the effects, in terms of pain control and functional recovery, provided by a single HA injection performed at the end of arthroscopic meniscectomy. The results showed no major adverse events were reported using HA postoperatively. A statistically significant increase in all the clinical scores was reported in both treatment groups, but no significant intergroup difference was documented at any follow-up evaluation. No difference was observed also in the objective measurements. The mean time to return to full sports activity was not different between groups, and a comparable satisfaction rate was recorded in both treatment groups. The authors concluded that early postoperative viscosupplementation did not provide significant clinical benefits after arthroscopic meniscectomy. Despite the lack of major adverse events, the administration of a single HA injection at the end of the surgical procedure is not a successful strategy to provide either faster functional recovery or symptomatic improvement after meniscectomy.
DiMartino et al10 conducted a double-blind, randomized controlled trial to evaluate pain control and functional recovery provided by a single injection of HA performed the day after anterior cruciate ligament (ACL) reconstruction. The results showed no severe adverse events were documented after early viscosupplementation. A significant improvement was documented in both treatment groups. Significant differences were documented in the transpatellar circumference at 60 days and in active range of motion (ROM) at 30 days postoperatively; patients who received HA had better values compared with the placebo group (P equal to .022 and .027, respectively). No statistically relevant intergroup differences were found in the clinical scores. The authors concluded that the study documented no adverse events and had some positive findings in terms of active ROM recovery and transpatellar circumference reduction. However, the early postoperative application of viscosupplementation did not lead to significant improvement in clinical scores after ACL reconstruction.
Berkoff et al11 conducted a review to determine the effect of ultrasound guidance on the accuracy of needle placement, clinical outcomes, and cost-effectiveness in comparison with anatomical landmark-guided intra-articular large joint injections, with particular emphasis on the knee. A total of 13 relevant studies were identified; five studied the knee, seven studied the shoulder, one used both the knee and shoulder, and none studied the hip. Ultrasound was used in seven studies; the remaining studies utilized air arthrography, fluoroscopy, magnetic resonance arthrography, or magnetic resonance imaging. Across all studies (using all imaging modalities and all joints), needle placement accuracy ranged from 63% to 100% with ultrasound and from 39% to 100% with conventional anatomical guidance. Imaging guidance improved the accuracy of intra-articular injections of the knee (96.7% versus 81.0%, P less than 0.001) and shoulder (97.3% versus 65.4%, P less than 0.001). In particular, ultrasound guidance of knee injections resulted in better accuracy than anatomical guidance (95.8% versus 77.8%, P less than 0.001), yielding an odds ratio of 6.4 (95% confidence interval 2.9-14). Ultrasound guidance notably improves injection accuracy in the target intra-articular joint space of large joints including the knee. The enhanced injection accuracy achieved with ultrasound needle guidance directly improves patient-reported clinical outcomes and cost-effectiveness.