Exploring reasons for the observed inconsistent trial reports on intra-articular injections with hyaluronic acid in the treatment of osteoarthritis: Meta-regression analyses of randomized trials

Mette Johansen; Henriette Bahrt; Roy D Altman; Else M Bartels; Carsten B Juhl; Henning Bliddal; Hans Lund; Robin Christensen

doi:10.1016/j.semarthrit.2016.02.010

Exploring reasons for the observed inconsistent trial reports on intra-articular injections with hyaluronic acid in the treatment of osteoarthritis: Meta-regression analyses of randomized trials

Mette Johansen, Henriette Bahrt, Roy D Altman, Else M Bartels, Carsten B Juhl, Henning Bliddal, Hans Lund, Robin Christensen

Department of Clinical Medicine

13 Citations (Scopus)

Abstract

Objective The aim was to identify factors explaining inconsistent observations concerning the efficacy of intra-articular hyaluronic acid compared to intra-articular sham/control, or non-intervention control, in patients with symptomatic osteoarthritis, based on randomized clinical trials (RCTs). Methods A systematic review and meta-regression analyses of available randomized trials were conducted. The outcome, pain, was assessed according to a pre-specified hierarchy of potentially available outcomes. Hedges׳s standardized mean difference [SMD (95% CI)] served as effect size. REstricted Maximum Likelihood (REML) mixed-effects models were used to combine study results, and heterogeneity was calculated and interpreted as Tau-squared and I-squared, respectively. Results Overall, 99 studies (14,804 patients) met the inclusion criteria: Of these, only 71 studies (72%), including 85 comparisons (11,216 patients), had adequate data available for inclusion in the primary meta-analysis. Overall, compared with placebo, intra-articular hyaluronic acid reduced pain with an effect size of −0.39 [−0.47 to −0.31; P < 0.001], combining very heterogeneous trial findings (I² = 73%). The three most important covariates in reducing heterogeneity were overall risk of bias, blinding of personnel and trial size, reducing heterogeneity with 26%, 26%, and 25%, respectively (Interaction: P ≤ 0.001). Adjusting for publication/selective outcome reporting bias (by imputing “null effects”) in 24 of the comparisons with no data available reduced the combined estimate to −0.30 [−0.36 to −0.23; P < 0.001] still in favor of hyaluronic acid. Conclusion Based on available trial data, intra-articular hyaluronic acid showed a better effect than intra-articular saline on pain reduction in osteoarthritis. Publication bias and the risk of selective outcome reporting suggest only small clinical effect compared to saline.

Original language	English
Journal	Seminars in Arthritis and Rheumatism
Volume	46
Issue number	1
Pages (from-to)	34-48
Number of pages	15
ISSN	0049-0172
DOIs	https://doi.org/10.1016/j.semarthrit.2016.02.010
Publication status	Published - 1 Aug 2016

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Journal Article
Review

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10.1016/j.semarthrit.2016.02.010

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Johansen, M., Bahrt, H., Altman, R. D., Bartels, E. M., Juhl, C. B., Bliddal, H., Lund, H., & Christensen, R. (2016). Exploring reasons for the observed inconsistent trial reports on intra-articular injections with hyaluronic acid in the treatment of osteoarthritis: Meta-regression analyses of randomized trials. Seminars in Arthritis and Rheumatism, 46(1), 34-48. https://doi.org/10.1016/j.semarthrit.2016.02.010

Exploring reasons for the observed inconsistent trial reports on intra-articular injections with hyaluronic acid in the treatment of osteoarthritis : Meta-regression analyses of randomized trials. / Johansen, Mette; Bahrt, Henriette; Altman, Roy D et al.

In: Seminars in Arthritis and Rheumatism, Vol. 46, No. 1, 01.08.2016, p. 34-48.

Research output: Contribution to journal › Review › peer-review

Johansen, M, Bahrt, H, Altman, RD, Bartels, EM, Juhl, CB, Bliddal, H, Lund, H & Christensen, R 2016, 'Exploring reasons for the observed inconsistent trial reports on intra-articular injections with hyaluronic acid in the treatment of osteoarthritis: Meta-regression analyses of randomized trials', Seminars in Arthritis and Rheumatism, vol. 46, no. 1, pp. 34-48. https://doi.org/10.1016/j.semarthrit.2016.02.010

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abstract = "Objective The aim was to identify factors explaining inconsistent observations concerning the efficacy of intra-articular hyaluronic acid compared to intra-articular sham/control, or non-intervention control, in patients with symptomatic osteoarthritis, based on randomized clinical trials (RCTs). Methods A systematic review and meta-regression analyses of available randomized trials were conducted. The outcome, pain, was assessed according to a pre-specified hierarchy of potentially available outcomes. Hedges׳s standardized mean difference [SMD (95% CI)] served as effect size. REstricted Maximum Likelihood (REML) mixed-effects models were used to combine study results, and heterogeneity was calculated and interpreted as Tau-squared and I-squared, respectively. Results Overall, 99 studies (14,804 patients) met the inclusion criteria: Of these, only 71 studies (72%), including 85 comparisons (11,216 patients), had adequate data available for inclusion in the primary meta-analysis. Overall, compared with placebo, intra-articular hyaluronic acid reduced pain with an effect size of −0.39 [−0.47 to −0.31; P < 0.001], combining very heterogeneous trial findings (I2 = 73%). The three most important covariates in reducing heterogeneity were overall risk of bias, blinding of personnel and trial size, reducing heterogeneity with 26%, 26%, and 25%, respectively (Interaction: P ≤ 0.001). Adjusting for publication/selective outcome reporting bias (by imputing “null effects”) in 24 of the comparisons with no data available reduced the combined estimate to −0.30 [−0.36 to −0.23; P < 0.001] still in favor of hyaluronic acid. Conclusion Based on available trial data, intra-articular hyaluronic acid showed a better effect than intra-articular saline on pain reduction in osteoarthritis. Publication bias and the risk of selective outcome reporting suggest only small clinical effect compared to saline.",

keywords = "Journal Article, Review",

author = "Mette Johansen and Henriette Bahrt and Altman, {Roy D} and Bartels, {Else M} and Juhl, {Carsten B} and Henning Bliddal and Hans Lund and Robin Christensen",

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doi = "10.1016/j.semarthrit.2016.02.010",

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T1 - Exploring reasons for the observed inconsistent trial reports on intra-articular injections with hyaluronic acid in the treatment of osteoarthritis

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AU - Johansen, Mette

AU - Bahrt, Henriette

AU - Altman, Roy D

AU - Bartels, Else M

AU - Juhl, Carsten B

AU - Bliddal, Henning

AU - Lund, Hans

AU - Christensen, Robin

PY - 2016/8/1

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N2 - Objective The aim was to identify factors explaining inconsistent observations concerning the efficacy of intra-articular hyaluronic acid compared to intra-articular sham/control, or non-intervention control, in patients with symptomatic osteoarthritis, based on randomized clinical trials (RCTs). Methods A systematic review and meta-regression analyses of available randomized trials were conducted. The outcome, pain, was assessed according to a pre-specified hierarchy of potentially available outcomes. Hedges׳s standardized mean difference [SMD (95% CI)] served as effect size. REstricted Maximum Likelihood (REML) mixed-effects models were used to combine study results, and heterogeneity was calculated and interpreted as Tau-squared and I-squared, respectively. Results Overall, 99 studies (14,804 patients) met the inclusion criteria: Of these, only 71 studies (72%), including 85 comparisons (11,216 patients), had adequate data available for inclusion in the primary meta-analysis. Overall, compared with placebo, intra-articular hyaluronic acid reduced pain with an effect size of −0.39 [−0.47 to −0.31; P < 0.001], combining very heterogeneous trial findings (I2 = 73%). The three most important covariates in reducing heterogeneity were overall risk of bias, blinding of personnel and trial size, reducing heterogeneity with 26%, 26%, and 25%, respectively (Interaction: P ≤ 0.001). Adjusting for publication/selective outcome reporting bias (by imputing “null effects”) in 24 of the comparisons with no data available reduced the combined estimate to −0.30 [−0.36 to −0.23; P < 0.001] still in favor of hyaluronic acid. Conclusion Based on available trial data, intra-articular hyaluronic acid showed a better effect than intra-articular saline on pain reduction in osteoarthritis. Publication bias and the risk of selective outcome reporting suggest only small clinical effect compared to saline.

AB - Objective The aim was to identify factors explaining inconsistent observations concerning the efficacy of intra-articular hyaluronic acid compared to intra-articular sham/control, or non-intervention control, in patients with symptomatic osteoarthritis, based on randomized clinical trials (RCTs). Methods A systematic review and meta-regression analyses of available randomized trials were conducted. The outcome, pain, was assessed according to a pre-specified hierarchy of potentially available outcomes. Hedges׳s standardized mean difference [SMD (95% CI)] served as effect size. REstricted Maximum Likelihood (REML) mixed-effects models were used to combine study results, and heterogeneity was calculated and interpreted as Tau-squared and I-squared, respectively. Results Overall, 99 studies (14,804 patients) met the inclusion criteria: Of these, only 71 studies (72%), including 85 comparisons (11,216 patients), had adequate data available for inclusion in the primary meta-analysis. Overall, compared with placebo, intra-articular hyaluronic acid reduced pain with an effect size of −0.39 [−0.47 to −0.31; P < 0.001], combining very heterogeneous trial findings (I2 = 73%). The three most important covariates in reducing heterogeneity were overall risk of bias, blinding of personnel and trial size, reducing heterogeneity with 26%, 26%, and 25%, respectively (Interaction: P ≤ 0.001). Adjusting for publication/selective outcome reporting bias (by imputing “null effects”) in 24 of the comparisons with no data available reduced the combined estimate to −0.30 [−0.36 to −0.23; P < 0.001] still in favor of hyaluronic acid. Conclusion Based on available trial data, intra-articular hyaluronic acid showed a better effect than intra-articular saline on pain reduction in osteoarthritis. Publication bias and the risk of selective outcome reporting suggest only small clinical effect compared to saline.

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KW - Review

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DO - 10.1016/j.semarthrit.2016.02.010

M3 - Review

C2 - 27139169

SN - 0049-0172

VL - 46

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EP - 48

JO - Seminars in Arthritis and Rheumatism

JF - Seminars in Arthritis and Rheumatism

IS - 1

ER -

Exploring reasons for the observed inconsistent trial reports on intra-articular injections with hyaluronic acid in the treatment of osteoarthritis: Meta-regression analyses of randomized trials

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