Relative Efficacy of Intra-articular Injections in the Treatment of Knee Osteoarthritis: A Systematic Review and Network Meta-analysis

Background: In younger patients and those without severe degenerative changes, the efficacy of intra-articular (IA) injections as a nonoperative modality for treating symptomatic knee osteoarthritis (OA)–related pain while maintaining function has become a subject of increasing interest. Purpose: To assess and compare the efficacy of different IA injections used for the treatment of knee OA, including hyaluronic acid (HA), corticosteroids (CS), platelet-rich plasma (PRP), and plasma rich in growth factors (PRGF), with a minimum 6-month patient follow-up. Study Design: Meta-analysis of randomized controlled trials; Level of evidence, 1. Methods: A systematic review was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines using the following databases: PubMed/MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Google Scholar. Mean or mean change from baseline and standard deviation for outcome scores regarding pain and function were recorded at the 6-month follow-up and converted to either a 0 to 100 visual analog scale score for pain or a 0 to 100 Western Ontario and McMaster Universities Osteoarthritis Index score for function. A frequentist network meta-analysis model was developed to compare the effects of HA, CS, PRP, PRGF, and placebo on patient-reported outcomes. Results: All IA treatments except CS were found to result in a statistically significant improvement in outcomes when compared with placebo. PRP demonstrated a clinically meaningful difference in function-related improvement when compared with CS and placebo due to large effect sizes. Studies evaluating outcomes of PRGF reported significant improvement when compared with placebo due to large effect sizes, whereas a potential clinically significant difference was detected in the same comparison parameters in pain evaluation. With regard to improvements in pain, function, and both combined, PRP was found to possess the highest probability of efficacy, followed by PRGF, HA, CS, and placebo. Conclusion: PRP yielded improved outcomes when compared with PRGF, HA, CS, and placebo for the treatment of symptomatic knee OA at a minimum 6-month follow-up. Further investigations evaluating different IA and other nonoperative treatment options for patients with knee OA are warranted to better understand the true clinical efficacy and long-term outcomes of nonsurgical OA management.

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Safety of Intra-Articular Hyaluronic Acid for Knee Osteoarthritis: Systematic Review and Meta-Analysis of Randomized Trials Involving More than 8,000 Patients

Cartilage ◽

10.1177/1947603519888783 ◽

2019 ◽

pp. 194760351988878

Author(s):

Larry E. Miller ◽

Samir Bhattacharyya ◽

William R. Parrish ◽

Michael Fredericson ◽

Brad Bisson ◽

...

Keyword(s):

Systematic Review ◽

Hyaluronic Acid ◽

Adverse Events ◽

Knee Osteoarthritis ◽

Randomized Controlled Trials ◽

Meta Analysis ◽

Controlled Trials ◽

Knee Oa ◽

Randomized Controlled ◽

Symptomatic Knee

Objective The objective of this systematic review and meta-analysis was to report the safety of intra-articular hyaluronic acid (IAHA) in patients with symptomatic knee osteoarthritis (OA). Methods We identified randomized controlled trials reporting the safety of IAHA versus IA saline in adults with symptomatic knee OA. Main safety outcomes were adverse events (AEs), local AEs, serious adverse events (SAEs), study withdrawals, and AE-related study withdrawals. Results A total of 35 randomized controlled trials with 38 group comparisons comprising 8,078 unique patients (IAHA: 4,295, IA saline: 3,783) were included in the meta-analysis. Comparing IAHA with IA saline over a median of 6 months follow-up, there were no differences in the risk of AEs (42.4% vs. 39.7%, risk ratio [RR] = 1.01, 95% CI = 0.96-1.07, P = 0.61), SAEs (1.8% vs. 1.2%, RR = 1.44, 95% CI = 0.91-2.26, P=0.12), study withdrawals (12.3% vs. 12.7%, RR = 0.99, 95% CI = 0.87-1.12, P = 0.83), or AE-related study withdrawals (2.7% vs. 2.1%, RR = 1.37, 95% CI = 0.97-1.93, P = 0.08). Local AEs, all of which were nonserious, were more common with IAHA vs. IA saline (14.5% vs. 11.7%, RR = 1.21, 95% CI = 1.07-1.36, P = 0.003) and typically resolved within days. Conclusion IAHA was shown to be safe for use in patients with symptomatic knee OA. Compared with IA saline, IAHA is associated with an increased risk of nonserious, transient local reactions. There was no evidence to suggest any additional safety risks of IAHA.

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What’s the rate of knee osteoarthritis 10 years after anterior cruciate ligament injury? An updated systematic review

British Journal of Sports Medicine ◽

10.1136/bjsports-2018-099751 ◽

2019 ◽

Vol 53 (18) ◽

pp. 1162-1167 ◽

Cited By ~ 21

Author(s):

Marthe Mehus Lie ◽

May Arna Risberg ◽

Kjersti Storheim ◽

Lars Engebretsen ◽

Britt Elin Øiestad

Keyword(s):

Systematic Review ◽

Anterior Cruciate Ligament ◽

Knee Osteoarthritis ◽

Methodological Quality ◽

Cruciate Ligament ◽

Acl Tear ◽

Knee Oa ◽

Symptomatic Knee ◽

Anterior Cruciate

BackgroundThis updated systematic review reports data from 2009 on the prevalence, and risk factors, for knee osteoarthritis (OA) more than 10 years after anterior cruciate ligament (ACL) tear.MethodsWe systematically searched five databases (PubMed, EMBASE, AMED, Cinahl and SPORTDiscus) for prospective and retrospective studies published after 1 August 2008. Studies were included if they investigated participants with ACL tear (isolated or in combination with medial collateral ligament and/or meniscal injuries) and reported symptomatic and/or radiographic OA at a minimum of 10 years postinjury. We used a modified version of the Downs and Black checklist for methodological quality assessment and narrative synthesis to report results. The study protocol was registered in PROSPERO.ResultsForty-one studies were included. Low methodological quality was revealed in over half of the studies. At inclusion, age ranged from 23 to 38 years, and at follow-up from 31 to 51 years. Sample sizes ranged from 18 to 780 participants. The reported radiographic OA prevalence varied between 0% and 100% >10 years after injury, regardless of follow-up time. The studies with low and high methodological quality reported a prevalence of radiographic OA between 0%–100% and 1%–80%, respectively. One study reported symptomatic knee OA for the tibiofemoral (TF) joint (35%), and one study reported symptomatic knee OA for the patellofemoral (PF) joint (15%). Meniscectomy was the only consistent risk factor determined from the data synthesis.ConclusionRadiographic knee OA varied between 0% and 100% in line with our previous systematic review from 2009. Symptomatic and radiographic knee OA was differentiated in two studies only, with a reported symptomatic OA prevalence of 35% for the TF joint and 15% for PF joint. Future cohort studies need to include measurement of symptomatic knee OA in this patient group.PROSPERO registration numberCRD42016042693.

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US-Approved Intra-Articular Hyaluronic Acid Injections are Safe and Effective in Patients with Knee Osteoarthritis: Systematic Review and Meta-Analysis of Randomized, Saline-Controlled Trials

Clinical Medicine Insights Arthritis and Musculoskeletal Disorders ◽

10.4137/cmamd.s12743 ◽

2013 ◽

Vol 6 ◽

pp. CMAMD.S12743 ◽

Cited By ~ 91

Author(s):

Larry E. Miller ◽

Jon E. Block

Keyword(s):

Systematic Review ◽

Hyaluronic Acid ◽

Knee Osteoarthritis ◽

Knee Pain ◽

Meta Analysis ◽

Controlled Trials ◽

Serious Adverse Events ◽

Safety Outcome ◽

Symptomatic Knee Osteoarthritis ◽

Symptomatic Knee

We conducted a systematic review and meta-analysis of randomized saline-controlled trials to determine the safety and efficacy of US-approved intra-articular hyaluronic acid (IAHA) injections for symptomatic knee osteoarthritis. A total of 29 studies representing 4,866 unique subjects (IAHA: 2,673, saline: 2,193) were included. IAHA injection resulted in very large treatment effects between 4 and 26 weeks for knee pain and function compared to pre-injection values, with standardized mean difference (SMD) values ranging from 1.07–1.37 (all P < 0.001). Compared to saline controls, SMDs with IAHA ranged from 0.38–0.43 for knee pain and 0.32–0.34 for knee function (all P < 0.001). There were no statistically significant differences between IAHA and saline controls for any safety outcome, including serious adverse events (SAEs) ( P = 0.12), treatment-related SAEs ( P = 1.0), study withdrawal ( P = 1.0), and AE-related study withdrawal ( P = 0.46). We conclude that intra-articular injection of US-approved HA products is safe and efficacious in patients with symptomatic knee osteoarthritis.

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Hypertonic dextrose injections (prolotherapy) in the treatment of symptomatic knee osteoarthritis: A systematic review and meta-analysis

Scientific Reports ◽

10.1038/srep25247 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 29

Author(s):

Regina WS Sit ◽

Vincent CH Chung ◽

Kenneth D. Reeves ◽

David Rabago ◽

Keith KW Chan ◽

...

Keyword(s):

Systematic Review ◽

Knee Osteoarthritis ◽

Primary Outcome ◽

Meta Analysis ◽

Knee Oa ◽

Composite Scale ◽

Symptomatic Knee Osteoarthritis ◽

Symptomatic Knee ◽

Pain Subscale ◽

Hypertonic Dextrose

Abstract Hypertonic dextrose injections (prolotherapy) is an emerging treatment for symptomatic knee osteoarthritis (OA) but its efficacy is uncertain. We conducted a systematic review with meta-analysis to synthesize clinical evidence on the effect of prolotherapy for knee OA. Fifteen electronic databases were searched from their inception to September 2015. The primary outcome of interest was score change on the Western Ontario and McMaster Universities Arthritis Index (WOMAC). Three randomized controlled trials (RCTs) of moderate risk of bias and one quasi–randomized trial were included, with data from a total of 258 patients. In the meta-analysis of two eligible studies, prolotherapy is superior to exercise alone by a standardized mean difference (SMD) of 0.81 (95% CI: 0.18 to 1.45, p = 0.012), 0.78 (95% CI: 0.25 to 1.30, p = 0.001) and 0.62 (95% CI: 0.04 to 1.20, p = 0.035) on the WOMAC composite scale; and WOMAC function and pain subscale scores respectively. Moderate heterogeneity exists in all cases. Overall, prolotherapy conferred a positive and significant beneficial effect in the treatment of knee OA. Adequately powered, longer-term trials with uniform end points are needed to better elucidate the efficacy of prolotherapy.

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Psychological interventions for coronary heart disease: Cochrane systematic review and meta-analysis

European Journal of Preventive Cardiology ◽

10.1177/2047487317739978 ◽

2017 ◽

Vol 25 (3) ◽

pp. 247-259 ◽

Cited By ~ 53

Author(s):

Suzanne H Richards ◽

Lindsey Anderson ◽

Caroline E Jenkinson ◽

Ben Whalley ◽

Karen Rees ◽

...

Keyword(s):

Myocardial Infarction ◽

Systematic Review ◽

Coronary Heart Disease ◽

Heart Disease ◽

Meta Analysis ◽

Psychological Interventions ◽

Controlled Trials ◽

Cochrane Central Register ◽

Considerable Uncertainty

Background Although psychological interventions are recommended for the management of coronary heart disease (CHD), there remains considerable uncertainty regarding their effectiveness. Design Systematic review and meta-analysis of randomised controlled trials (RCTs) of psychological interventions for CHD. Methods The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL and PsycINFO were searched to April 2016. Retrieved papers, systematic reviews and trial registries were hand-searched. We included RCTs with at least 6 months of follow-up, comparing the direct effects of psychological interventions to usual care for patients following myocardial infarction or revascularisation or with a diagnosis of angina pectoris or CHD defined by angiography. Two authors screened titles for inclusion, extracted data and assessed risk of bias. Studies were pooled using random effects meta-analysis and meta-regression was used to explore study-level predictors. Results Thirty-five studies with 10,703 participants (median follow-up 12 months) were included. Psychological interventions led to a reduction in cardiovascular mortality (rfcelative risk 0.79, 95% confidence interval [CI] 0.63 to 0.98), although no effects were observed for total mortality, myocardial infarction or revascularisation. Psychological interventions improved depressive symptoms (standardised mean difference [SMD] –0.27, 95% CI –0.39 to –0.15), anxiety (SMD –0.24, 95% CI –0.38 to –0.09) and stress (SMD –0.56, 95% CI –0.88 to –0.24) compared with controls. Conclusions We found that psychological intervention improved psychological symptoms and reduced cardiac mortality for people with CHD. However, there remains considerable uncertainty regarding the magnitude of these effects and the specific techniques most likely to benefit people with different presentations of CHD.

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POS1099 EFFICACY OF INTRA-ARTICULAR CORTICOSTEROID INJECTIONS IN KNEE OSTEOARTHRITIS: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.3291 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 829.2-830

Author(s):

A. Najm ◽

A. Alunno ◽

C. Weill ◽

J. Gwinnutt ◽

F. Berenbaum

Keyword(s):

Knee Osteoarthritis ◽

Meta Analysis ◽

Controlled Trials ◽

Medium Term ◽

Short Term ◽

Knee Oa ◽

Randomized Controlled ◽

And Function

Background:Knee osteoarthritis (OA) is a frequent degenerative disease representing an important health and economic burden. Symptomatic medical treatments available include intra-articular (IA) injections of corticosteroids (GC) but their efficacy is debated. In addition, safety signals regarding cartilage damage with IA GC have been highlighted in a few studies.Objectives:To perform a meta-analysis of studies assessing IA GC efficacy and safety in knee OA.Methods:A systematic literature review and a meta-analysis of randomized controlled trials (RCTs) assessing the effect of GC IA injections versus other interventions (IA Hyaluronic Acid, IA placebo, IA NSAID, oral NSAID or physiotherapy) in knee OA was performed. The effect of the interventions on pain and function were extracted from the single studies and pooled and are presented as short term (<6weeks), medium term (6-24 weeks) and long term (>24 weeks) follow-up period. Standardized mean differences (SMD) are reported.Results:Of 520 studies screened, 23 were included in the SLR and 14 subsequently included in the MA. While IA GC showed a superior effect compared to control on both pain (SMD -0.61 (95% CI -1,25, 0.03)) and function (SMD -1.02 (95% CI -2.14, 0.10)) in short term follow-up; long term follow-up analysis favored controls (IA HA, IA NSAID, physiotherapy) for both pain (SMD 0.68 (95% CI -0.11, 1.47)) and function (SMD 0.88 (95% CI -0.36, 2.12) outcomes (Figure 1). No difference was found between interventions in the medium term. Safety data were reported in 18/23 studies (n= 1936/2314 patients); and side effects were reported as follows: arthralgia (69 IA GC patients, 146 IA HA patients, and 20 saline patients); site injection pain (7 in the IA GC group, 2 in the IA saline group, 14 in the IA HA group); 16 post injection knee swelling without signs of septic arthritis in the IA GC group and 24 in the IA HA group. In one study assessing cartilage effects of GCs, the rate of cartilage loss was greater in the GC group with a reduction of cartilage thickness at 2 year compared to placebo group. No difference was observed in the progression of cartilage denudation or bone marrow lesion. On the contrary, another study showed no effect of injections on the cartilage structure.Conclusion:We demonstrate in this work that IA GC injections reduce pain and improve function in the early phase (≤6 weeks) of treatment. In the long term (≥24 weeks), other intervention such as IA HA injections or physiotherapy seem to be more efficient, but this effect was largely driven by single studies with large effect sizes and the comparators were heterogeneous.Figure 1.Knee pain outcome at short term (≤6weeks) (A), medium term (>6 & <24 weeks) (B), and long term (≥24 weeks) (C) follow up.Disclosure of Interests:None declared.

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Comparison of Efficacy among Three Radiofrequency Ablation Techniques for Treating Knee Osteoarthritis: A Systematic Review and Meta-Analysis

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18147424 ◽

2021 ◽

Vol 18 (14) ◽

pp. 7424

Author(s):

Shih-Hsiang Chou ◽

Po-Chih Shen ◽

Cheng-Chang Lu ◽

Zi-Miao Liu ◽

Yin-Chun Tien ◽

...

Keyword(s):

Systematic Review ◽

Radiofrequency Ablation ◽

Knee Osteoarthritis ◽

Baseline Level ◽

Meta Analysis ◽

Cochrane Library ◽

Invasive Treatment ◽

Knee Oa ◽

Before And After

Radiofrequency ablation (RFA) was first introduced for treating knee osteoarthritis (OA) in 2010 and has emerged as a minimally invasive treatment option. Three RFA techniques have been adopted for treating knee OA, including conventional, pulsed, and cooled RFA. However, the efficacy among different RFA techniques in the treatment of knee OA is still unclear. Three electronic databases were systematically searched for relevant articles, including PubMed, Embase, and Cochrane Library. A meta-analysis of articles that investigated the use of RFA techniques in the treatment of knee OA was conducted to pool the effect size in pain before and after treatment. A total of 20 eligible articles (including 605 patients) were included for our meta-analysis. After treatment, the patients had significant improvements in pain for all three RFA techniques when compared with the baseline level for the 1, 3-, and 6-month follow-ups (p < 0.00001). However, there were no significant differences in the efficacy among the three RFA techniques for all follow-up visits (p > 0.05). The three RFA techniques demonstrated a significant improvement in pain for up to 6 months after treatment. Comparing the efficacy of the three RFA techniques in the treatment of knee OA, our results showed that no significant differences in pain relief among the three RFA techniques were observed at the 1-, 3-, 6, and 12-month follow-up visits.

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Buteyko method for people with asthma: a protocol for a systematic review and meta-analysis

BMJ Open ◽

10.1136/bmjopen-2021-049213 ◽

2021 ◽

Vol 11 (10) ◽

pp. e049213

Author(s):

Karla Morganna Pereira Pinto de Mendonça ◽

Sean Collins ◽

Tácito ZM Santos ◽

Gabriela Chaves ◽

Sarah Leite ◽

...

Keyword(s):

Systematic Review ◽

Systematic Reviews ◽

Meta Analysis ◽

Secondary Data ◽

Controlled Trials ◽

Cochrane Central Register ◽

Plain Language ◽

Randomised Controlled ◽

Meta Analyses

IntroductionButeyko method is recommended as a non-pharmacological treatment for people with asthma. Although the worldwide interest in the Buteyko method, there is a paucity of studies gathering evidence to support its use. Therefore, we aim to conduct a systematic review and meta-analysis to assess the effects of the Buteyko method in children and adults with asthma.Methods and analysisWe will search on Cochrane Central Register of Controlled Trials, MEDLINE, Embase, US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov and WHO International Clinical Trials Registry Platform for studies focusing on the Buteyko method for children and adults with asthma. The searches will be carried out in September 2021 from database’s inception to the present. We will include randomised controlled trials comparing Buteyko method alone with asthma education or inactive control intervention. There will be no restriction on language. Primary outcomes include quality of life, asthma symptoms and adverse events/side effects. Two review authors will independently screen the studies for inclusion and extract data. We will assess the quality of the included studies using the ‘Risk of Bias’ tool. The certainty of the evidence will be assessed using the GRADE approach. Data synthesis will be conducted using Review Manager software. Reporting of the review will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance and the Cochrane Handbook for Systematic Reviews of Interventions.Ethics and disseminationThis study will assess and provide evidence for the use of the Buteyko method in people with asthma. We will analyse secondary data and this does not require ethics approval. The findings will be published in peer-reviewed journals, at relevant conferences and will be shared in plain language in social media. Moreover, the findings of this review could guide the direction of healthcare practice and research.PROSPERO registration numberCRD42020193132.

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Supervised Machine Learning for Aiding Diagnosis of Knee Osteoarthritis: A Systematic Review and Meta-Analysis

10.36227/techrxiv.13132931.v1 ◽

2020 ◽

Author(s):

Luca Parisi ◽

Narrendar RaviChandran ◽

Matteo Lanzillotta

Keyword(s):

Machine Learning ◽

Systematic Review ◽

Knee Osteoarthritis ◽

Gait Analysis ◽

Meta Analysis ◽

Supervised Machine Learning ◽

Gait Patterns ◽

Kinematic Data ◽

Knee Oa ◽

Symptomatic Knee

Background Knee osteoarthritis (OA) remains a leading aetiology of disability worldwide. Clinical assessment of such knee-related conditions has improved with recent advances in gait analysis. Despite being a gold standard method, gait data acquired by motion capture (mocap) technology are highly non-linear and dimensional, which make traditional gait analysis challenging. Thus, extrinsic algorithms need to be used to make sense of gait data. Supervised Machine Learning (ML)-based classifiers outperform conventional statistical methods in revealing intrinsic patterns that can discern gait abnormalities when using mocap data, making them a suitable tool for aiding diagnosis of knee OA. Research question Studies have demonstrated the accuracy of supervised ML-based classifiers in gait analysis. However, these techniques have not gained wide acceptance amongst biomechanists for two reasons: the reliability of such methods has not been assessed and there is no consensus on which classifier or group of classifiers to select. Specifically, it is not clear whether classifiers that leverage optimal separating hyperplanes (OSH) or artificial neural networks (ANN) are more accurate and reliable. Methods A systematic review and meta-analysis were conducted to assess the capability of such algorithms to predict pathological kinematic and kinetic gait patterns as indicators of knee OA. With 153 eligible studies, 6 studies met the inclusion criteria for a subsequent meta-analysis, accounting for <a>273 healthy subjects and 313 patients </a>with symptomatic knee OA. The classification performance of supervised ML classifiers (OSH- or ANN-based) used in these studies was quantitatively assessed and compared across four following performance metrics: classification accuracy on the test set (ACC), sensitivity (SN), specificity (SP), and area under the receiver operating characteristic curve (AUC). Results There was no statistically significant discrepancy in the ACC between OSH- and ANN-based classifiers when dealing with kinetic and kinematic data concurrently, as well as when considering only kinematic data. However, there was a statistically significant difference in their SN and SP, with the ANN-based classifiers having higher SN and SP than OSH-based algorithms. As only one of the eligible studies reported AUC, this metric could not be assessed statistically across studies. Significance This study supports the use of ANN-based algorithms for classifying knee OA-related gait patterns as having a higher sensitivity and specificity than OSH-based classifiers. Considering their higher reliability, leveraging supervised ANN-based methods can aid biomechanists to diagnose knee OA objectively.

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Acupuncture for constipation in patients with stroke: protocol of a systematic review and meta-analysis

BMJ Open ◽

10.1136/bmjopen-2017-020400 ◽

2018 ◽

Vol 8 (3) ◽

pp. e020400 ◽

Cited By ~ 4

Author(s):

Jingbo Zhai ◽

Wei Mu ◽

Jinhua Si ◽

Yan Li ◽

Chen Zhao ◽

...

Keyword(s):

Systematic Review ◽

Systematic Reviews ◽

Meta Analysis ◽

Scientific Journal ◽

Primary Outcome Measure ◽

Integrated System ◽

Primary Data ◽

Controlled Trials ◽

Cochrane Central Register ◽

Medical Database

IntroductionConstipation is one of the most common complications in patients with stroke. Acupuncture has gained increased popularity for the management of constipation. However, there is a lack of supportive evidence on the efficacy of acupuncture for poststroke constipation. This systematic review aims to collect and critically appraise all the available evidence about the efficacy and safety of the acupuncture for constipation in poststroke patients.Methods and analysisA comprehensive search of Pubmed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, four Chinese databases (National Knowledge Infrastructure (CNKI), Chinese Biomedical Literatures database (CBM), Wanfang Digital Periodicals (WANFANG) and Chinese Science and Technology Periodicals (VIP) database), one Japanese medical database (National Institute of Informatics, CiNii) and one Korean medical database (Oriental Medicine Advanced Searching Integrated System, OASIS) will be conducted to identify randomised controlled trials of acupuncture for constipation in poststroke patients. There is no restriction on language or publication status. The primary outcome measure will be frequency of bowel movement. The risk of bias will be assessed using the approach recommended by Cochrane Handbook for Systematic Reviews of Interventions. We will conduct the meta-analysis to synthesise the evidence for each outcome, if possible. The heterogeneity will be statistically assessed using a χ2test and I2statistic. This protocol is developed following the guideline of Preferred Reporting Items for Systematic Reviews and Meta-analyses Protocols 2015.Ethics and disseminationThe ethical approval is not required because no primary data are collected. The findings will be presented at scientific conferences or a peer-reviewed scientific journal.PROSPERO registration numberCRD42017076880.

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