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Viscosupplementation for Osteoarthritis of the Knee: A Systematic Review and Meta-analysis

Anne W.S. Rutjes, PhD; Peter Jüni, MD; Bruno R. da Costa, MSc; Sven Trelle, MD; Eveline Nüesch, PhD; and Stephan Reichenbach, MD, MSc
[+] Article and Author Information

From the Institute of Social and Preventive Medicine, University of Bern, Clinical Trials Unit Bern, Bern University Hospital, Bern, Switzerland; Centre for Aging Sciences (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy; and London School of Hygiene and Tropical Medicine, London, United Kingdom.

Acknowledgment: The authors thank Malcolm Sturdy for database support; Paolo Barbaro, Dr. Aijing Shang, and Aysel Güler for the translation of the Japanese, Chinese, and Turkish reports; and Drs. Gluud, Russell, Petrella, Navarro-Sarabia, and Coronel for providing additional information about outcome data. They also thank Dr. Aggarwal, who replied to our queries and attempted to locate files but could not provide additional outcome data.

Grant Support: This study is funded by a grant from the Arco Foundation. Dr. Rutjes and Mr. da Costa are supported by the Arco Foundation, and Drs. Jüni and Reichenbach are supported by the Swiss National Science Foundation and Arco Foundation.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-3078.

Requests for Single Reprints: Peter Jüni, MD, Institute of Social and Preventive Medicine, University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland; e-mail, juni@ispm.unibe.ch.

Current Author Addresses: Drs. Rutjes, Jüni, da Costa, Nüesch, and Reichenbach: Institute of Social and Preventive Medicine, University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland.

Dr. Trelle: Clinical Trials Unit Bern, Inselspital, and University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland.

Author Contributions: Conception and design: A.W.S. Rutjes, P. Jüni, S. Reichenbach.

Analysis and interpretation of the data: A.W.S. Rutjes, P. Jüni, B.R. da Costa, S. Trelle, E. Nüesch, S. Reichenbach.

Drafting of the article: A.W.S. Rutjes, P. Jüni, S. Reichenbach.

Critical revision of the article for important intellectual content: A.W.S. Rutjes, P. Jüni, B.R. da Costa, S. Trelle, E. Nüesch, S. Reichenbach.

Final approval of the article: A.W.S. Rutjes, P. Jüni, B.R. da Costa, S. Trelle, E. Nüesch, S. Reichenbach.

Statistical expertise: A.W.S. Rutjes, P. Jüni, S. Trelle, E. Nüesch, S. Reichenbach.

Obtaining of funding: A.W.S. Rutjes, P. Jüni, B.R. da Costa, S. Reichenbach.

Administrative, technical, or logistical support: P. Jüni.

Collection and assembly of data: A.W.S. Rutjes, B.R. da Costa, S. Reichenbach.


Ann Intern Med. 2012;157(3):180-191. doi:10.7326/0003-4819-157-3-201208070-00473
Text Size: A A A

Background: Viscosupplementation, the intra-articular injection of hyaluronic acid, is widely used for symptomatic knee osteoarthritis.

Purpose: To assess the benefits and risks of viscosupplementation for adults with symptomatic knee osteoarthritis.

Data Sources: MEDLINE (1966 to January 2012), EMBASE (1980 to January 2012), the Cochrane Central Register of Controlled Trials (1970 to January 2012), and other sources.

Study Selection: Randomized trials in any language that compared viscosupplementation with sham or nonintervention control in adults with knee osteoarthritis.

Data Extraction: Primary outcomes were pain intensity and flare-ups. Secondary outcomes included function and serious adverse events. Reviewers used duplicate abstractions, assessed study quality, pooled data by using a random-effects model, examined funnel plots, and explored heterogeneity by using meta-regression.

Data Synthesis: Eighty-nine trials involving 12 667 adults met inclusion criteria. Sixty-eight had a sham control, 40 had a follow-up duration greater than 3 months, and 22 used cross-linked forms of hyaluronic acid. Overall, 71 trials (9617 patients) showed that viscosupplementation moderately reduced pain (effect size, −0.37 [95% CI, −0.46 to −0.28]). There was important between-trial heterogeneity and an asymmetrical funnel plot: Trial size, blinded outcome assessment, and publication status were associated with effect size. Five unpublished trials (1149 patients) showed an effect size of −0.03 (CI, −0.14 to 0.09). Eighteen large trials with blinded outcome assessment (5094 patients) showed a clinically irrelevant effect size of −0.11 (CI, −0.18 to −0.04). Six trials (811 patients) showed that viscosupplementation increased, although not statistically significantly, the risk for flare-ups (relative risk, 1.51 [CI, 0.84 to 2.72]). Fourteen trials (3667 patients) showed that viscosupplementation increased the risk for serious adverse events (relative risk, 1.41 [CI, 1.02 to 1.97]).

Limitations: Trial quality was generally low. Safety data were often not reported.

Conclusion: In patients with knee osteoarthritis, viscosupplementation is associated with a small and clinically irrelevant benefit and an increased risk for serious adverse events.

Primary Funding Source: Arco Foundation.

Figures

Grahic Jump Location
Figure 1.

Forest plot of differences in pain intensity expressed as effect size comparing the effects of any type of viscosupplementation and control (sham or no intervention) on knee pain in 71 trials.

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Figure 1—

Continued

Shading represents area of clinical equivalence smaller than minimal clinically important difference. Weights are from random-effects analysis.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Contour-enhanced funnel plot for effects on knee pain.

Includes prediction lines with 95% confidence lines from univariable meta-regression models with SE as explanatory variable (dashed and dotted lines). Contour areas to display areas of significance at P ≤ 0.05 (green) and nonsignificance (white). Lines for predicted effects should be interpreted independently of contours delineated by shaded areas.

Grahic Jump Location
Grahic Jump Location
Figure 3.

Results of stratified analyses of pain outcomes.

Shading represents the area of clinical equivalence smaller than minimal clinically important difference.

* P values from test for trend.

Grahic Jump Location
Grahic Jump Location
Figure 4.

Results from meta-analyses of all safety outcomes based on an analysis of all trials (green squares) and of large trials with blinded outcome assessment (black squares).

Note that comparisons with 0 events in both groups did not contribute to the analysis: 19 trials (1349 patients) for flare-ups, 24 trials (1947 patients) for serious adverse events, 19 trials (1659 patients) for dropouts because of adverse events, 10 trials (579 patients) for any adverse events, 15 trials (1109 patients) for effusions, 8 trials (1191 patients) for local adverse events, and 7 trials (427 patients) for withdrawals.

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To the Editor
Posted on July 10, 2012
Luca Maria Sconfienza, Pietro Randelli, Francesco Sardanelli
IRCCS Policlinico San Donato
Conflict of Interest: None Declared

We read with great interest the paper by Rutjes et al. (1) entitled “Viscosupplementation for Osteoarthritis of the Knee: a Systematic Review and Meta-analysis” published on www.annals.org on 12 June 2012. The topic is relevant, as witnessed by the large number of studies included in the review and by the general interest on the use of hyaluronic acid (HA) in degenerative conditions of other joints (2,3). We offer a few considerations on that work (1). Authors did not evaluate whether injections were performed using imaging guidance. This seems important, as HA must be injected directly into joint space to achieve its potential therapeutic benefit (2,4). In fact, knee injections performed without imaging guidance do not reach the target in 9-29% of cases on the first attempt, depending on the knee accession portal (4). Thus, the use or non-use of imaging guidance may have relevantly affected the results of primary studies included in the meta-analysis.

Authors decided to take into consideration Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score only and not visual analogue scale (VAS) when both available. Although VAS is less comprehensive than WOMAC, the former provides information about subjective response to HA treatment, that is not negligible when dealing with osteoarthritis. Authors state that a major limitation of their meta-analysis “is the poor methodological quality and reporting quality of many of the included trials” (1), which is agreeable. Also for this reason, we think that they should be careful to conclude that viscosupplementation in knee osteoarthritis should be discouraged due to “minimal or nonexistent” benefits (1). A similar caution should be also taken when analyzing the rate of serious adverse events. There is a very small absolute difference in the number of adverse events (26 in treatment group vs. 21 in control group) and most of them seems not to be related to viscosupplementation (e.g., gastrointestinal disorders, more likely related to oral anti-inflammatory drugs abuse). Similarly, it is unrealistic that cancer can be related to HA injections, especially if not related to the injected joint.Finally, HA injection in knee osteoarthritis has been previously shown (5) to delay total knee replacement. Although still largely debated, this outcome measure should be considered when evaluating HA efficacy.To summarize, we think that the use of viscosupplementation in knee osteoarthritis remains an open issue, still deserving high-quality well designed randomized clinical trials, using state-of-the art procedures. 

References

1. Rutjes AW, Jüni P, da Costa BR, Trelle S, Nüesch E, Reichenbach S. Viscosupplementation for Osteoarthritis of the Knee: A Systematic Review and Meta-analysis. Ann Intern Med. 2012;157.

2. Tagliafico A, Serafini G, Sconfienza LM, Lacelli F, Perrone N, Succio G, et al. Ultrasound-guided viscosupplementation of subacromial space in elderly patients with cuff tear arthropathy using a high weight hyaluronic acid: prospective open-label non-randomized trial. Eur Radiol. 2011;21:182-7.

3. Migliore A, Massafra U, Bizzi E, Vacca F, Martin-Martin S, Granata M, et al. Comparative, double-blind, controlled study of intra-articular hyaluronic acid (Hyalubrix) injections versus local anesthetic in osteoarthritis of the hip. Arthritis Res Ther. 2009;11:R183

4. Jackson DW, Evans NA, Thomas BM. Accuracy of needle placement into the intra-articular space of the knee. J Bone Joint Surg Am. 2002;84-A:1522-7.

5. Waddell DD, Bricker DC. Total knee replacement delayed with Hylan G-F 20 use in patients with grade IV osteoarthritis. J Manag Care Pharm. 2007;13:113-21.

Viscosupplementation for Osteoarthritis of the knee
Posted on October 11, 2012
F. Navarro-Sarabia MD, G. Herrero-Beaumont MD
Rheumatology Dpt. Hospital Universitario Virgen Macarena, Sevilla (Spain); Rheumatology Dpt. Fundación Jiménez Díaz, Madrid (Spain)
Conflict of Interest: Dr Navarro-Sarabia and Dr Herrero-Beaumont were authors of AMELIA Project (reference 2) and received research funds from Tedec Meiji Farma SA as study investigators.

We refer to the paper by Rutjes et al (1), where the therapeutic effect of intraarticular injections of hyaluronic acid is analyzed.First of all, in the table summarizing the methodological characteristics of the studies considered in this meta-analysis, we were surprised about the evaluation made with regards to our paper (2). It is said, for instance, that there is no evidence of the number randomized/analyzed patients (figure 2 of our publication: patients disposition, page 1959); not adequate allocation concealment (“a computer generated randomised list was used to provide balanced blocks of four patients each. Allocation to treatment as well as efficacy and safety evaluation was performed by a blinded physician”, page 1958) and blinding of patients unclear (“both treatments were packaged identically in order to maintain the blinding conditions”, page 1958). Besides, the intention-to treat-analysis (described as NA in the mentioned table) was performed and described “all randomly assigned patients with at least one efficacy assessment after randomization” (page 1959). This paper was recently published in the journal with the highest impact factor amongst those of Rheumatic diseases. The study characteristics are easily accessible and we do not understand why it has not been included. We do not know if this situation could apply to other studies evaluated in this meta-analysis, and being this the case, the results of this paper should be questioned. Moreover, we would like to make a series of methodological observations which we deem to be of interest.Pain intensity was pre-specified as primary effectiveness outcome and physical function only as secondary based on recommendations made years ago. In fact, the most recent recommendations (OARSI-FDA (3) EMA (4) consider function as co-primary endpoint. In this sense, OARSI responder criteria is recommended to evaluate improvement in osteoarthritis clinical trials (4), so it would have been convenient to consider also studies that use this particular index. The authors considered as relevant an improvement in pain of only -0.37, although smaller reductions are clinically relevant from our daily experience. This could have been significantly questionable due to the fact that the estimator value of -0.37 coincides exactly with the limit set to the lower bound of efficacy previously used by them. In addition, Rutjes et al. use “differences in mean values or differences in mean changes or used approximation”. This approach could affect the magnitude of overall efficacy biasing the results. In this type of studies demographic characteristics such as age, gender, severity, disease duration and physical activity (5) should have been considered as explanatory factors of the effect size detected.Finally, for further meta-analysis we suggest including adequately designed clinical trials, carefully reviewed, published in relevant journals and analysed using endpoints according to recent international recommendations.

References:

1.Rutjes AW, Juni P, da Costa BR, Trelle S, Nuesch E, Reichenbach S. Viscosupplementation for Osteoarthritis of the Knee: A Systematic Review and Meta-analysis. Ann Intern Med. 2012 Aug 7; 157(3): 180.191.

2.Navarro-Sarabia F, Coronel P. Collantes E, Navarro FJ, de la Serna AR, Naranjo A, Gimeno M, Herrero-Beaumont G; AMELIA study group. A 40-month multicentre, randomised placebo-controlled study to assess the efficacy and carry-over effect of repeated intra-articular injections of hyaluronic acid in knee osteoarthritis: the AMELIA project. Ann Rheum Dis. 2011 Nov; 70(11): 1957-62. Epub 2011 Aug 17

3.OARSI-FDA OA initiative. Available at http://www.oarsi.org/index2.cfm?section=OARSI_Initiative&content=FDA_OA_Initiative.

4.CPMP/EWP/784/97 Rev 1. Guideline on clinical investigation of medicinal products used in the treatment of osteoarthritis. EMA, London, 20 January 2010. http://www.ema.europa.eu/docs/en_GB/document library/Scientific_guideline/2009/09/WC500003440.pdf

5.Herrero-Beaumont G, Roman-Blas JA, Castañeda S, Jimenez SA. Primary osteoarthritis no longer primary: three subsets with distinct etiological, clinical, and therapeutic characteristics. Semin Arthritis Rheum. 2009 Oct; 39(2):71-80

Viscosupplementation for Osteoarthritis of the knee
Posted on November 7, 2012
F. Navarro-Sarabia, MD G. Herrero-Beaumont, MD
Dr. Navarro-Sarabia: Rheumatology Dpt. Hospital Universitario Virgen Macarena41011 Sevilla (Spain). Dr. Herrero-Beaumont: Rheumatology Dpt. Fundación Jiménez Díaz, Madrid (Spain)
Conflict of Interest: Potential conflict of interests: Dr Navarro-Sarabia and Dr Herrero-Beaumont were authors of AMELIA Project (reference 2) and received research funds from Tedec Meiji Farma SA as study investigators.

To the editor:We refer to the paper by Rutjes et al (1), where the therapeutic effect of intraarticular injections of hyaluronic acid is analyzed.

First of all, in the table summarizing the methodological characteristics of the studies considered in this meta-analysis, we were surprised about the evaluation made with regards to our paper (2). It is said, for instance, that there is no evidence of the number randomized/analyzed patients (figure 2 of our publication: patients disposition, page 1959); not adequate allocation concealment (“a computer generated randomised list was used to provide balanced blocks of four patients each. Allocation to treatment as well as efficacy and safety evaluation was performed by a blinded physician”, page 1958) and blinding of patients unclear (“both treatments were packaged identically in order to maintain the blinding conditions”, page 1958). Besides, the intention-to treat-analysis (described as NA in the mentioned table) was performed and described “all randomly assigned patients with at least one efficacy assessment after randomization” (page 1959). This paper was recently published in the journal with the highest impact factor amongst those of Rheumatic diseases. The study characteristics are easily accessible and we do not understand why it has not been included. We do not know if this situation could apply to other studies evaluated in this meta-analysis, and being this the case, the results of this paper should be questioned.

Moreover, we would like to make a series of methodological observations which we deem to be of interest.

Pain intensity was pre-specified as primary effectiveness outcome and physical function only as secondary based on recommendations made years ago. In fact, the most recent recommendations (OARSI-FDA (3) EMA (4) consider function as co-primary endpoint. In this sense, OARSI responder criteria is recommended to evaluate improvement in osteoarthritis clinical trials (4), so it would have been convenient to consider also studies that use this particular index. The authors considered as relevant an improvement in pain of only -0.37, although smaller reductions are clinically relevant from our daily experience. This could have been significantly questionable due to the fact that the estimator value of -0.37 coincides exactly with the limit set to the lower bound of efficacy previously used by them. In addition, Rutjes et al. use “differences in mean values or differences in mean changes or used approximation”. This approach could affect the magnitude of overall efficacy biasing the results.

In this type of studies demographic characteristics such as age, gender, severity, disease duration and physical activity (5) should have been considered as explanatory factors of the effect size detected.

Finally, for further meta-analysis we suggest including adequately designed clinical trials, carefully reviewed, published in relevant journals and analysed using endpoints according to recent international recommendations.

F. Navarro-Sarabia, MD, Rheumatology Dpt. Hospital Universitario Virgen Macarena 41011 Sevilla (Spain).

G. Herrero-Beaumont, MD, Rheumatology Dpt. Fundación Jiménez DíazMadrid (Spain)

References:

1. Rutjes AW, Juni P, da Costa BR, Trelle S, Nuesch E, Reichenbach S. Viscosupplementation for Osteoarthritis of the Knee: A Systematic Review and Meta-analysis. Ann Intern Med. 2012 Aug 7; 157(3): 180.191.

2. Navarro-Sarabia F, Coronel P. Collantes E, Navarro FJ, de la Serna AR, Naranjo A, Gimeno M, Herrero-Beaumont G; AMELIA study group. A 40-month multicentre, randomised placebo-controlled study to assess the efficacy and carry-over effect of repeated intra-articular injections of hyaluronic acid in knee osteoarthritis: the AMELIA project. Ann Rheum Dis. 2011 Nov; 70(11): 1957-62. Epub 2011 Aug 17

3. OARSI-FDA OA initiative. Available at http://www.oarsi.org/index2.cfm?section=OARSI_Initiative&content=FDA_OA_Initiative.

4. CPMP/EWP/784/97 Rev 1. Guideline on clinical investigation of medicinal products used in the treatment of osteoarthritis. EMA, London, 20 January 2010. http://www.ema.europa.eu/docs/en_GB/document library/Scientific_guideline/2009/09/WC500003440.pdf

5. Herrero-Beaumont G, Roman-Blas JA, Castañeda S, Jimenez SA. Primary osteoarthritis no longer primary: three subsets with distinct etiological, clinical, and therapeutic characteristics. Semin Arthritis Rheum. 2009 Oct; 39(2):71-80

Author's Response
Posted on November 7, 2012
Peter Jüni, MD Anne W.S. Rutjes, PhD, Bruno R. da Costa, PhD, Reichenbach, MD, MSc
Institute of Social and Preventive Medicine, University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland
Conflict of Interest: None Declared

In response:

Dr Navarro-Sarabia and Dr Herrero-Beaumont raised a number of concerns with respect to our systematic review on viscosupplementation for knee osteoarthritis (1), which we address as follows: The number of patients randomized per group was indeed unclear in their trial (2). They referred to 306 patients who were randomized, but failed to report how many of these 306 patients were allocated to hyaluronic acid (HA) and placebo. They merely describe that 149 versus 152 patients received HA and placebo, respectively, after the exclusion of 5 randomized patients for whom they had no post-randomization efficacy data. As to concealment of allocation, we still do not understand the mechanism and its adequacy. Did the authors use coded drug packs, central randomization or sequentially numbered, sealed opaque envelopes for concealment (3)? As to blinding of patients, we cannot determine whether the syringes containing HA and placebo were identical in appearance, since the authors only referred to the packages. As already implied above, the trial (2) was not analysed according to the intention-to-treat principle since 5 patients were excluded after randomisation. The primary outcome and the minimal clinically important difference of this and previous meta-analyses (4) were pre-specified before the OARSI recommendations became available. However, function was reported in detail as a secondary outcome. In addition, we recently showed that differences in pain intensity between groups can be directly converted into odds ratios of treatment response and corresponding numbers needed to treat (5). Among large trials with blinded outcome assessment, there were no differences in estimated treatment effects between the two trials that required approximations for the calculation of effect sizes and the 16 trials that did not (difference in effect size=0.05, 95%-CI -0.21 to 0.31, p for interaction=0.67). Analyses by patient characteristics, such as average age or gender, should not be performed based on aggregate-level data, as suggested by Navarro-Sarabia and Herrero-Beaumont, because of the ecological fallacy (6).

Peter Jüni, MD, Anne W.S. Rutjes, PhD, Bruno R. da Costa, PhD, Reichenbach, MD, MSc

Institute of Social and Preventive Medicine, University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland

References:

1. Rutjes AW, Juni P, da Costa BR, Trelle S, Nuesch E, Reichenbach S. Viscosupplementation for Osteoarthritis of the Knee: A Systematic Review and Meta-analysis. Ann Intern Med. 2012 Aug 7; 157(3): 180.191.

2. Navarro-Sarabia F, Coronel P. Collantes E, Navarro FJ, de la Serna AR, Naranjo A, Gimeno M, Herrero-Beaumont G; AMELIA study group. A 40-month multicentre, randomised placebo-controlled study to assess the efficacy and carry-over effect of repeated intra-articular injections of hyaluronic acid in knee osteoarthritis: the AMELIA project. Ann Rheum Dis. 2011 Nov; 70(11): 1957-62. Epub 2011 Aug 17.

3. Jüni P, Altman DG, Egger M. Systematic reviews in health care: Assessing the quality of controlled clinical trials. BMJ. 2001 Jul 7;323(7303):42-6.

4. Wandel S, Jüni P, Tendal B, Nüesch E, Villiger PM, Welton NJ, Reichenbach S, Trelle S. Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis. BMJ. 2010 Sep 16;341:c4675. doi: 10.1136/bmj.c4675

5. da Costa BR, Rutjes AW, Johnston BC, Reichenbach S, Nüesch E, Tonia T, Gemperli A, Guyatt GH, Jüni P. Methods to convert continuous outcomes into odds ratios of treatment response and numbers needed to treat: meta-epidemiological study. Int J Epidemiol. 2012 Oct;41(5):1445-1459.

6. Berlin JA, Santanna J, Schmid CH, Szczech LA, Feldman HI, Anti-Lymphocyte Antibody Induction Therapy Study Group. Individual patient- versus group-level data meta-regressions for the investigation of treatment effect modifiers: ecological bias rears its ugly head. Stat Med. 2002 Feb 15;21(3): 371-87.

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