Knee OA is a chronic inflammatory joint disorder with an estimated prevalence of 250 million people worldwide.
Intra-articular injections of hyaluronic
acid (HA) used
in a 2–4 injection treatment regimen provided the greatest benefit when
compared to IA-Saline with respect to pain improvement in patients with knee osteoarthritis
(OA), and was generally deemed safe with few or no
treatment-related adverse events (AEs)
reported across studies.
Knee OA is a chronic inflammatory joint disorder with an estimated prevalence of 250 million people worldwide. It is characterized by joint pain, cartilage degeneration, and inflammation at the joints. Various treatments such as physical regimens, non-operative therapy (non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen) and intra-articular (IA) medicines such as corticosteroids and hyaluronic acid (HA) are available for the treatment of knee OA. Intra-articular HA is approved by Food and Drug Administration (FDA) and is being used since 1997 in the United States for knee OA.
In 2013, the American Academy of Orthopaedic Surgeons (AAOS)
recommended against the use of IA-HA for knee OA. However, physician-specialty
societies have recommended the IA-HA for the treatment of knee OA. For the
patients who had the inadequate response to initial therapy, the American
College of Rheumatology (ACR) recommended IA-HA for knee OA. The American
Medical Society for Sports Medicine (AMSSM) also recommended HA for knee OA
treatment. The OA Research Society International (OARSI) has an uncertain
recommendation for the use of IA-HA in treating knee OA. Despite the
availability of the number of evidence recommending the use of IA-HA in
treating knee OA, the optimal treatment regimen and patient selection criteria is
yet to be determined.
Therefore, Andrew Concof et al. conducted this
systematic to evaluate the efficacy of IA-HA vs IA-Saline in patients with knee
OA.
Rationale behind the research:
Although the number of clinical considerations recommended
the use of IA-HA in treating knee OA, the optimal treatment regimen and patient
selection criteria is yet to be determined.
Therefore, the present study was conducted to determine the
efficacy of IA-HA vs. IA-Saline in patients with knee OA.
Objective:
To determine the efficacy of IA-HA, with subgroup analyses
to explore the differences in knee pain and adverse events (AEs) across
different dosing regimens.
Study outcome measures:
Time period: 13 weeks and 26 weeks
Study Outcomes:
Most of the included studies were conducted in Europe (63.3%), followed
by North America (23.3%), Asia (10.0%) and Australia (3.3%). we included 26
double-blinded RCTs (86.7%) and four single-blinded RCTs (13.3%). A total of
5848 patients were included in this analysis. Of which four studies consisted 1196
patients who had single injections of IA-HA and sixteen studies consist of 2865
patients who had 2–4 injections, and about 1847 patients from eleven studies took
≥5 injections. One study (N = 63) reported administering 1–11 injections of
IA-HA and was included in both the 2–4 injections subgroup and ≥5 injections
subgroup. Mostly the low molecular weight HA was used (47%), followed by high
molecular weight HA (43%) and moderate weight HA (10%).
Single injection was comprised of only one estimable study (Standard mean difference [SMD] = −0.03; −0.29 to 0.23). 2–4 injections of IA-HA vs. IA-Saline produced the largest effect size of the subgroups (SMD = −0.76; −0.98 to −0.53, 95% CI, p<0.00001). IA-HA injections ≥5 vs. IA-Saline produced a non-significant effect size estimate of −0.20 (−0.43 to 0.03, 95% CI, P=0.09). Test for subgroup differences were significant (p<0.00001). Heterogeneity was only observed for studies in the 2–4 injections subgroup (I2=19%) (Figure 1).
Single injection studies yielded a non-significant treatment effect (SMD=−0.04; −0.20 to 0.13, 95% CI, P=0.67). IA-HA injections (2–4) vs. IA-Saline produced the largest significant effect size (SMD=−0.36; −0.63 to −0.09 95% CI, P=<0.00001). Studies with ≥5 injections of IA-HA vs. IA-Saline produced a significant effect size estimate of −0.18 (−0.35 to 0.01, 95% CI, P=0.04). Heterogeneity was observed for studies in the 2–4 injections subgroup (I2 = 82%) and ≥5 injections subgroup (I2 = 74%) (Figure 2).
Figure 2: Efficacy of IA-HA injections closest to 6-months
No significant subgroup difference was observed when studies were analyzed by total dose of IA-HA administered (P=0.90) (Figure 3).
Figure 3: Total number of participants experiencing a treatment-related serious adverse event
There were no statistically significant differences in the total number of treatment-related AEs compared to saline injection for single injection of IA-HA vs IA-Saline (Risk ratio [RR] = 1.11; 0.93 to 1.32 95% CI, p = 0.26) or 2–4 injections of IA-HA vs IA-Saline (RR = 0.98; 0.87 to 1.09 95% CI, p = 0.67 (Figure 4).
F
Four single-blinded studies were removed from the sensitivity analysis.
The pooled effect size remained statistically significant with little change in
total effect size when these single-blind studies were removed from the
analysis (SMD=−0.19 [−0.25, −0.13], p<0.001).
In studies with a follow-up closest to 6 months (26 weeks), removing one study
in the ≥5 injections subgroup changed the subgroup results from significant to
non-significant.
Included studies demonstrated minimal bias with respect to categories of selection bias, detection bias, performance bias, attrition bias and reporting bias. Few studies failed to report methods of randomization and methods of blinding (Figure 6).
Figure 6: Risk of bias summary
At both 3 and 6 months follow-up, it was demonstrated that
the IA-HA was more useful in the treatment of knee OA pain compared to
IA-Saline. Single injections of IA-HA were not significantly effective than
saline at 3-month or 6- month follow-ups. The subgroup with ≥5 injections
showed significant improvement in pain at 6 months only. The group with 2-4
injection demonstrated consistent results at both 3 and 6 months follow-up when
compared to IA-Saline. The overall results showed most significant improvement
at 3 months, as compared to 6 months follow-up. Bannuru and colleagues also
showed the similar type of results. The present analysis demonstrated not only
the overall pooled estimate for HA as a class benefitial for pain relief, but
there also seem to be differences in effect as a result of the injection
regimen provided.
The results of this study for evaluating the efficacy for 1 injection, 2–4 injections and ≥5 injections of IA-HA matched with a recently published RCT suggesting that the dosing regimen of IA-HA should help for the development of future guidelines on knee OA management. Zoboli et al. issued a RCT assessing whether a single 6 mL administration of HA has the same effectiveness as the three-weekly 2 mL dose. Recent evidence suggests products with a higher molecular weight (HMW) approximately ≥3000 kDa to provide more effictive outcomes than the lower molecular weight (LMW) products. This may be attributed to HMWs increased residency time off within the synovial fluid causing prolonged anti-inflammatory response within the joint. This study revealed that while molecular weight is an essential factor in the efficacy of HA products, the number of injections provided also plays a significant role in optimizing the efficacy in knee OA patients. This is particularly clear given that, although all single injection HA products were of a HMW, they did not demonstrate a reduction in pain comparable to the 2–4 injections subgroup, which included several studies of LMW HA products.
This study showed
that administration of 3 injection regimen of a HA might be more effective than
a single injection HMW product. Significantly more treatment-related AEs were
observed in participants receiving ≥5 injections vs IA-Saline.
This study meta-analysis detected very few treatment-related severe AEs, with little or no events reported for all injection regimens. A study conducted by Miller and Block also showed the similar type of results as that of our research. A search of the grey literature or unpublished literature was not performed; however, authors scanned references in articles that met the inclusion criteria for literature not captured in the search. This report showed the differences between injection regimens of IA-HA for knee pain in OA. Future studies should directly compare different injection regimens of IA-HA in head-to-head RCTs.
In conclusion, the patients administered with
2–4 and ≥5 IA-HA injection regimens provided more pain relief over IA-Saline.
More research is needed to investigate the effects of other parameters, such as
product molecular weight, in the comparison of IA-HA injection treatment
regimens.
It was revealed from this study that 2-4 or more than 5 injections of HA
can be recommended for the treatment of pain associated with knee OA.
BMC Musculoskelet Disord. 2017 Dec 21;18(1):542.
The efficacy of multiple versus single hyaluronic acid injections: a systematic review and meta-analysis
Andrew Concoff et al.
Comments (0)