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Safety of intra-articular hyaluronic acid injections in osteoarthritis: Outcomes of a systematic review and meta-analysis

Safety of intra-articular hyaluronic acid injections in osteoarthritis: Outcomes of a systematic review and meta-analysis
Safety of intra-articular hyaluronic acid injections in osteoarthritis: Outcomes of a systematic review and meta-analysis

Background: Some controversy exists regarding the safety of intra-articular hyaluronic acid (IAHA) in the management of osteoarthritis (OA). Objective: The objective of this study was to re-assess the safety profile of IAHA in patients with OA, through a comprehensive meta-analysis of randomized, placebo-controlled trials. Methods: A comprehensive literature search was undertaken in the databases MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus. Randomized, double-blind, placebo-controlled, parallel-group trials that assessed adverse events (AEs) with IAHA in patients with OA were eligible for inclusion. Authors and/or study sponsors were contacted to obtain the full report of AEs. The primary outcomes were overall severe and serious AEs, as well as the following MedDRA System Organ Class (SOC)-related AEs: gastrointestinal, cardiac, vascular, respiratory, nervous system, skin and subcutaneous tissue disorders, musculoskeletal, renal and urinary disorders, infections and infestations, and hypersensitivity reaction. Results: Database searches initially identified 1481 records. After exclusions according to the selection criteria, 22 studies were included in the qualitative synthesis, and nine studies having adequate data were ultimately included in the meta-analysis. From the studies excluded according to the pre-specified selection criteria, 21 with other pharmacological OA treatments permitted during the trials were a posteriori included in a parallel qualitative synthesis, from which eight studies with adequate data were finally included in a parallel meta-analysis. Since this meta-analysis was designed to assess safety, the exclusion criterion on concomitant anti-OA medication was crucial. However, due to the high number of studies that allowed mainly concomitant oral non-steroidal anti-inflammatory drugs (NSAIDs), we decided to include them in a post hoc parallel analysis in order to compare the results from the two analyses. No statistically significant difference in odds was found between IAHA and placebo for all types of SOC-related disorders, except for infections and infestations, for which significantly lower odds were found with IAHA compared with placebo, both overall (odds ratio [OR] = 0.61, 95% confidence interval [CI] 0.40–0.93; I 2 = 0%) and in studies without concomitant anti-OA medication (OR = 0.49, 95% CI 0.27–0.89). There were significant increased odds of reporting serious AEs with IAHA compared with placebo, both overall (OR = 1.78, 95% CI 1.21–2.63; I 2 = 0%) and in studies with concomitant anti-OA medication (OR = 1.78, 95% CI 1.10–2.89), but not in studies without concomitant anti-OA medication (OR = 1.78, 95% CI 0.92–3.47). Conclusions: Using the available data on studies without any concomitant anti-OA medication permitted during clinical trials, IAHA seems not to be associated with any safety issue in the management of OA. However, this evidence was associated with only a “low” to “moderate” certainty. A possible association with increased risk of serious AEs, particularly when used with concomitant OA medications, requires further investigation.

1170-229X
101-127
Honvo, Germain
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Reginster, Jean Yves
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Rannou, Francois
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Rygaert, Xavier
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Geerinck, Anton
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Rabenda, Véronique
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McAlindon, Tim
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Charles, Alexia
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Fuggle, Nicholas
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Cooper, Cyrus
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Curtis, Elizabeth
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Arden, Nigel
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Avouac, Bernard
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Bruyère, Olivier
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Honvo, Germain
b028bd1a-b0a7-444f-bde5-32b5b611b9af
Reginster, Jean Yves
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Rannou, Francois
2b61556e-9368-4b92-8f27-25e6697230dc
Rygaert, Xavier
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Geerinck, Anton
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Rabenda, Véronique
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McAlindon, Tim
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Charles, Alexia
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Fuggle, Nicholas
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Cooper, Cyrus
e05f5612-b493-4273-9b71-9e0ce32bdad6
Curtis, Elizabeth
12aba0c3-1e9e-49ef-a7e9-3247e649cdd6
Arden, Nigel
23af958d-835c-4d79-be54-4bbe4c68077f
Avouac, Bernard
bb50a1a0-f315-4ff1-a311-61744a4e1088
Bruyère, Olivier
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Honvo, Germain, Reginster, Jean Yves, Rannou, Francois, Rygaert, Xavier, Geerinck, Anton, Rabenda, Véronique, McAlindon, Tim, Charles, Alexia, Fuggle, Nicholas, Cooper, Cyrus, Curtis, Elizabeth, Arden, Nigel, Avouac, Bernard and Bruyère, Olivier (2019) Safety of intra-articular hyaluronic acid injections in osteoarthritis: Outcomes of a systematic review and meta-analysis. Drugs and Aging, 36 (Supplement 1), 101-127. (doi:10.1007/s40266-019-00657-w).

Record type: Review

Abstract

Background: Some controversy exists regarding the safety of intra-articular hyaluronic acid (IAHA) in the management of osteoarthritis (OA). Objective: The objective of this study was to re-assess the safety profile of IAHA in patients with OA, through a comprehensive meta-analysis of randomized, placebo-controlled trials. Methods: A comprehensive literature search was undertaken in the databases MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus. Randomized, double-blind, placebo-controlled, parallel-group trials that assessed adverse events (AEs) with IAHA in patients with OA were eligible for inclusion. Authors and/or study sponsors were contacted to obtain the full report of AEs. The primary outcomes were overall severe and serious AEs, as well as the following MedDRA System Organ Class (SOC)-related AEs: gastrointestinal, cardiac, vascular, respiratory, nervous system, skin and subcutaneous tissue disorders, musculoskeletal, renal and urinary disorders, infections and infestations, and hypersensitivity reaction. Results: Database searches initially identified 1481 records. After exclusions according to the selection criteria, 22 studies were included in the qualitative synthesis, and nine studies having adequate data were ultimately included in the meta-analysis. From the studies excluded according to the pre-specified selection criteria, 21 with other pharmacological OA treatments permitted during the trials were a posteriori included in a parallel qualitative synthesis, from which eight studies with adequate data were finally included in a parallel meta-analysis. Since this meta-analysis was designed to assess safety, the exclusion criterion on concomitant anti-OA medication was crucial. However, due to the high number of studies that allowed mainly concomitant oral non-steroidal anti-inflammatory drugs (NSAIDs), we decided to include them in a post hoc parallel analysis in order to compare the results from the two analyses. No statistically significant difference in odds was found between IAHA and placebo for all types of SOC-related disorders, except for infections and infestations, for which significantly lower odds were found with IAHA compared with placebo, both overall (odds ratio [OR] = 0.61, 95% confidence interval [CI] 0.40–0.93; I 2 = 0%) and in studies without concomitant anti-OA medication (OR = 0.49, 95% CI 0.27–0.89). There were significant increased odds of reporting serious AEs with IAHA compared with placebo, both overall (OR = 1.78, 95% CI 1.21–2.63; I 2 = 0%) and in studies with concomitant anti-OA medication (OR = 1.78, 95% CI 1.10–2.89), but not in studies without concomitant anti-OA medication (OR = 1.78, 95% CI 0.92–3.47). Conclusions: Using the available data on studies without any concomitant anti-OA medication permitted during clinical trials, IAHA seems not to be associated with any safety issue in the management of OA. However, this evidence was associated with only a “low” to “moderate” certainty. A possible association with increased risk of serious AEs, particularly when used with concomitant OA medications, requires further investigation.

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e-pub ahead of print date: 9 May 2019

Identifiers

Local EPrints ID: 431441
URI: http://eprints.soton.ac.uk/id/eprint/431441
ISSN: 1170-229X
PURE UUID: b1c9a291-59e6-40e9-bdcf-47b725dbac55
ORCID for Cyrus Cooper: ORCID iD orcid.org/0000-0003-3510-0709
ORCID for Elizabeth Curtis: ORCID iD orcid.org/0000-0002-5147-0550

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Date deposited: 03 Jun 2019 16:30
Last modified: 26 Nov 2021 03:09

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Contributors

Author: Germain Honvo
Author: Jean Yves Reginster
Author: Francois Rannou
Author: Xavier Rygaert
Author: Anton Geerinck
Author: Véronique Rabenda
Author: Tim McAlindon
Author: Alexia Charles
Author: Nicholas Fuggle
Author: Cyrus Cooper ORCID iD
Author: Nigel Arden
Author: Bernard Avouac
Author: Olivier Bruyère

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