Evidence Based Report Autologous Blood Injections for Musculoskeletal Disorders

Transcription

1 Evidence Based Report Autologous Blood Injections for Musculoskeletal Disorders Reviewer Mark Ayson Date Report Completed September 2014 Important Note: The purpose of this brief report is to summarise the best evidence for the use of autologous blood injections (including platelet-rich plasma) for musculoskeletal disorders with a special focus on tendinopathies. It is not intended to replace clinical judgement, or be used as a clinical protocol. A reasonable attempt has been made to find and review papers relevant to the focus of this report, however it does not claim to be exhaustive. The document has been prepared by the staff of the Research Team, ACC. The content does not necessarily represent the official view of ACC or represent ACC policy. This report is based upon information supplied up to July 2013 Accident Compensation Corporation

2 Contents 1. Background Investigation... 3 Levels of evidence Findings... 4 Systematic reviews... 4 Table 1: Summary of included RCTs in Sheth (2012) Randomised Controlled Trials Lateral Epicondylosis/Epicondylitis or elbow tendinopathy Table 2: Summary of RCTs for elbow tendinopathies, lateral epicondylosis/epicondylitis Achilles tendinopathy Table 3: Summary of RCTs for Achilles tendinopathy Rotator cuff disease Patellar tendinopathy Plantar fasciitis Table 42: Summary of RCTs for plantar fasciitis Safety Evidence statements for tendinopathies Elbow tendinopathies, Lateral epicondylosis/epicondylitis Achilles tendinopathy Rotator cuff disease Patellar tendinopathy Plantar fasciitis Discussion External peer review comments Conclusions Appendix 1: Evidence Tables (in alphabetical order) Appendix 2: Excluded studies References Accident Compensation Corporation Page 2

3 1. Background ACC Research was asked to review the evidence about the efficacy of autologous blood products in the treatment of musculoskeletal disorders, with a focus on their use in the treatment of tendinopathies. "Tendinopathy'" describes a range of conditions that affect tendons, causing pain, stiffness, and weakness. Sites commonly involved are the elbow extensor ('tennis elbow'), Achilles, and patellar tendons. Other names used include tendonitis and tendinosis. Conservative treatments for tendinopathies known to be effective include eccentric exercise and some physiotherapy protocols. Other treatments including rest, analgesics, anti-inflammatory medication and orthotic devices may reduce pain but do not change the disease,. Other treatments such as corticosteroid injections are contraindicated and extracorporeal shockwave therapy do not work. Autologous blood products are another therapy that have been claimed to promote healing through the action of various growth factors on the affected tendon. There are various terms for autologous blood products including autologous whole blood (ABI), platelet-rich plasma (PRP), autologous platelet concentrate, autologous conditioned plasma, osteoinductive gel, platelet-leukocyte gel, autologous platelet-derived growth factor, or platelet gel. The focus of this report will be on autologous whole blood and platelet-rich plasma injections with 'autologous blood products' used as the generic term. Autologous whole blood injections involve withdrawing the person's own blood by standard venesection and injecting it into or around the affected tendon 1. Platelet-rich plasma, on the other hand, is derived from centrifuging the person s own whole blood and separating part of the centrifuged blood which has a higher concentration of platelets than seen in whole blood 2. About 2-3 mls of the whole blood or platelet-rich plasma is injected into or around the tendon, sometimes with ultrasound guidance and local anaesthetic is often used. "Dry needling" (repeatedly passing the needle through the tendon) may be performed before injection of the blood. Moreover, a "peppering" technique is sometimes used which involves inserting the needle into the tendon, injecting some blood, withdrawing without emerging from the skin, then slightly redirecting and reinserting into tendon and injecting again; this may be repeated many times 1. The mechanism of action of these injections is proposed to be a healing response in the damaged tendons that is triggered by the growth factors in the blood. These growth factors are proposed to trigger stem-cell recruitment, increase local vascularity and directly stimulate the production of collagen 1. These therapies whilst appearing to be biologically plausable have not had a significant amount of research including safety studies performed. There are commercially available systems for preparing PRP but there is no universally accepted protocol for PRP preparation. This is due to the wide variety of variables that in themselves have not been explored and the significant variation in the characterisation of the PRP delivered by the various commercial systems (3) 2. Investigation A search was conducted on 3 May 2013 in the following databases: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) 1946 to Present, and EMBASE 1988 to Present. The references of review articles and included studies were also investigated, as was the Worldwide Web. Only articles published in English were included. A repeat search was conducted on the 1 July Search terms used included: autologous blood injection, platelet-rich plasma, tendinopathy, tendinosis, tendonitis, tenosynovitis, tendon injuries, and musculoskeletal disorders. Inclusion criteria: systematic reviews or randomised controlled trials of PRP or ABI for musculoskeletal disorders reporting clinical outcomes like pain or function. Exclusion criteria: Animal or laboratory study, narrative review, or editorial; case-control, cohort, crosssectional or case series/reports; non-english studies; application of PRP or a similar substance during surgical procedure. Accident Compensation Corporation Page 3

4 This resulted in identifying 360 articles of which 28 (9 systematic reviews, one technology brief, one consensus paper, a rapid review, and 16 RCTs) were used in this report. In the first instance the systematic reviews were appraised and summarised and then the RCTs for tendinopathies were appraised separately, as this was the focus of the review. Evidence tables were created for each paper and they can be found in Appendix 1. A table of the excluded studies can be found in Appendix 2. Any relevant papers were assessed for their methodological quality using the following SIGN* criteria: Levels of evidence 1++ High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias 1+ Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias 1- Meta-analyses, systematic reviews, or RCTs with a high risk of bias High quality systematic reviews of case control or cohort or studies 2++ High quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal 2+ Well-conducted case control or cohort studies with a low risk of confounding or bias and a 2- moderate probability that the relationship is causal Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal 3 Non-analytic studies, e.g. case reports, case series 4 Expert opinion 3. Findings Systematic reviews Of the 9 systematic reviews, Sheth (2012) 3 looked at 'orthopaedic conditions', de Vos (2010a) 4, Hoksrud (2011) 5, and Martin (2011) 6 at tendinopathies, Sadoghi (2013) 7 at Achilles tendon disorders, and Krogh (2012) 8 and Rabago (2009) 9 at lateral epicondylosis. Finally, Taylor (2011) 10 looked at ligament and tendon injuries, and Hamilton (2011) 11 at muscle strain injuries. Also included are three more papers deemed relevant: a rapid review from NICE 1 in the UK, a technology brief from Australia 12 about soft tissue injuries, and a consensus paper from the International Olympic Committee on the use of PRP in sports medicine 13. The best quality, and probably most extensive, systematic review is by Sheth (2012) 3 which investigated the use of autologous blood products (including PRP) for a range of orthopaedic indications (including Achilles tendinopathy and rupture, spinal fusion, anterior cruciate ligament (ACL) reconstruction, total knee arthroplasty, lateral epicondylitis, rotator cuff repair, plantar fasciitis, and patellar tendinopathy). A total of 23 randomised controlled trials (RCTs) with 1,416 subjects and 10 prospective cohort studies (PCS) with 570 subjects were included in the review. Among these studies there was considerable heterogeneity in sample size (range n=10 to 165), length of follow-up (range 5 days to 2 years), outcome measures (27 different functional measures used), and indications. An activating agent (autologous thrombin or calcium chloride) was used in 79% (26/33) of the studies, more than one application was used in two studies, and the final volume of autologous blood product ranged from 2 to 70 mls. The three studies for plantar fasciitis were the only studies that used autologous whole blood injections. * Scottish Intercollegiate Guidelines Network tennis elbow. Recent literature has iterated that based on histological evidence epicondylosis is the appropriate term for this condition rather than epicondylitis. However please note that some studies still refer to epicondylosis as epicondylitis and for the purpose of this report will be referred to as either term. Accident Compensation Corporation Page 4

5 Overall, six of the RCTs showed a significant functional benefit for PRP, 15 showed no difference between PRP and control, and 1 demonstrated a significant clinical benefit for the control. Table 1 below summarises these studies. Table 1: Summary of included RCTs in Sheth (2012) 3 Study Condition Comparison Follow-up Functional outcome Schepull 2011 de Vos 2010 Cervellin 2011 Achilles tendon rupture Achilles tendinopathy ACL reconstruction PRP vs. none 1 yr No difference PRP vs. saline 2 yr No difference PRP gel vs. none 12 mo Favours treatment Nin 2009 ACL reconstruction platelet gel added to graft vs. no platelet gel 2 yr No difference Orrego 2008 ACL reconstruction platelet concentrate or bone plug with concentrate added to graft vs. bone plug added to graft or no platelet concentrate 6 mo No difference Vogrin 2010 ACL reconstruction platelet-leukocyte gel added to graft vs. graft alone 6 mo No difference Peerbooms 2010 Calori 2008 Lateral epicondylitis Long-bone nonunion PRP vs. steroid injection 1 yr Favours treatment PRP vs. rhbmp-7 9 mo Favours control Everts 2008 Open subacromial decompression platelet-leukocyte gel injection vs. none 6 wk Favours treatment Kiter 2006 Plantar fasciitis ABI vs. steroid injection 6 mo No difference Lee 2007 Plantar fasciitis ABI vs. steroid injection 6 mo No difference Casticini 2011 Randelli 2011 Rotator cuff repair platelet-rich fibrin matrix vs. none 16 mo No difference Rotator cuff repair PRP vs. none 1 yr Favours treatment Feiz-Erfan 2007 Spinal fusion cervical allograft with platelet concentrate vs. no platelet concentrate 2 yr N/A Sys 2011 Spinal fusion PRP vs. none 2 yr No difference Tsai 2009 Spinal fusion platelet glue added to graft vs. graft alone 2 yr No difference Dallari 2007 Tibial osteotomy lyophilized bone chips with platelet 1 yr No Accident Compensation Corporation Page 5

6 Study Condition Comparison Follow-up Functional outcome gel vs. lyophilized bone chips alone D'Elia 2010 Tibial osteotomy PRP added to iliac bone graft vs. no PRP difference 6 mo No difference Savarino 2006 Tibial osteotomy lyophilized bone chips with platelet gel vs. lyophilized bone chips alone 6 wk No difference Thomas 2009 Total hip arthroplasty osteoinductive gel vs. none 1 yr Favours treatment Horstmann 2010 Total knee arthroplasty autologous platelet gel vs. none immediate postoperative blood loss No difference Peerbooms 2009 Zavadil 2007 Total knee arthroplasty Total shoulder arthroplasty autologous platelet gel vs. none 3 mo No difference autologous platelet gel vs. none 6 wk Favours treatment N/A = not applicable; yr = year; mo = month; wk = week A meta-analysis was conducted using the most common outcome measure: a visual analogue scale (VAS) for pain. This was based on the assumption that the VAS was a consistent and general measure of pain assessed in the same way across any indication. The authors found no significant difference in pooled VAS scores between PRP and control groups across the six included RCTs (SMD = 0.34 (95%CI : 0.75 to 0.06); p=0.10) or the 3 included PCSs (SMD = 0.20 (95%CI: 0.64 to 0.23); p=0.36) **. There was also a moderate to high degree of statistical heterogeneity in the RCTs, indicating a wide variation (inconsistency) in their results. With regard to ABI for the treatment of plantar fasciitis, there was no statistically significant difference in VAS scores between ABI and control groups across the three included RCTs (SMD = 0.41 (95%CI: 0.01 to 0.83); p=0.33). In addition to this meta-analysis, the authors used the GRADE criteria to assess the overall quality of evidence (see Tables 2 & 3 below for a summary). This was judged to be 'very low' for thirteen of the fourteen indications for which PRP was used, and 'very low' for the use of ABI in plantar fasciitis. The quality of evidence was assessed as being 'moderate' only for the use of PRP in rotator cuff repairs. This is based on two RCTs with 141 participants. The general poor grading of the evidence was due to the presence of serious methodological limitations, variability in platelet separation techniques, lack of standardisation in outcome measures, and uncertainty around the precision of results. Taking all this into account, it appears reasonable to support the authors' conclusion i.e. that the current evidence is insufficient to conclude that any autologous blood product provides a clinical benefit in the treatment of orthopaedic conditions 3. standardised mean difference confidence interval ** the forest plot can be seen in the evidence table in Appendix 1 Grading of Recommendations Assessment, Development and Evaluation Accident Compensation Corporation Page 6

7 Table 2: GRADE quality assessment of evidence for platelet-rich plasma (source: Sheth ) Indication Study Design* No. of Studies (Participants) Methodological Limitations Consistency Directness Precision# Quality of the Evidence ACL reconstruction RCT 4 (298) Serious limitations (-2) Unexplained heterogeneity (-1) Indirect (-1) Uncertain (-1) + Very low PCS 3 (140) Serious limitations (-1) Unexplained heterogeneity (-1) Indirect (-1) Uncertain (-1) + Very low Spinal fusion RCT 3 (157) Serious limitations (-1) No important inconsistency Indirect (-1) Uncertain (-1) + Very low PCS 2 (72) Serious limitations (-1) No important inconsistency Direct Uncertain (-1) + Very low Tibial osteotomy RCT 3 (68) Serious limitations (-1) No important inconsistency Indirect (-1) Uncertain (-1) + Very low Total knee arthroplasty RCT 2 (142) Serious limitations (-1) No important inconsistency Indirect (-1) Uncertain (-1) + Very low PCS 1 (165) Serious limitations (-1) N/A N/A N/A + Very low Rotator cuff repair RCT 2 (141) Minimal limitations Unexplained heterogeneity (-1) Direct Certain +++ Moderate PCS 1 (42) Minimal limitations N/A N/A N/A + Very low Achilles tendon rupture RCT 1 (30) Minimal limitations N/A N/A N/A + Very low Achilles tendinopathy RCT 1 (54) Minimal limitations N/A N/A N/A + Very low Lateral epicondylitis RCT 1 (100) Serious limitations (-2) N/A N/A N/A + Very low Total shoulder arthroplasty RCT 1 (40) Minimal limitations N/A N/A N/A + Very low Total hip arthroplasty RCT 1 (120) Serious limitations (-2) N/A N/A N/A + Very low Long-bone non-unions RCT 1 (120) Serious limitations (-2) N/A N/A N/A + Very low Open subacromial decompression RCT 1 (40) Minimal limitations N/A N/A N/A + Very low Chronic elbow tendinosis PCS 1 (20) Serious limitations (-2) N/A N/A N/A + Very low Chronic refractory patellar tendinopathy PCS 1 (31) Serious limitations (-2) N/A N/A N/A + Very low Accident Compensation Corporation

8 Table 3: GRADE quality assessment of evidence for autologous blood injections (source: Sheth ) Indication Study Design* No. of Studies (Participants) Methodological Limitations Consistency Directness Precision# Quality of the Evidence Plantar fasciitis RCT 2 (106) Serious limitations (-2) Unexplained heterogeneity (-1) Direct Uncertain (-1) + Very low PCS 1 (100) Minimal limitations N/A N/A N/A + Very low *RCT = randomized controlled trial, and PCS = prospective cohort study. Randomized controlled trials are assumed to be of high quality and are downgraded accordingly (-1 or -2), while prospective cohort studies are assumed to be of low quality and are upgraded (+1 or +2) or downgraded accordingly (-1 or -2). Limitations that result in downgrading include lack of blinding with subjective outcomes, lack of concealment, failure to use intention-to-treat analysis, a large loss to follow-up, or early cessation of the study. The quality of evidence is diminished when studies with vastly differing estimates of treatment effect are unexplained. When heterogeneity exists, the quality rating of the studies is downgraded (-1). This is not applicable (N/A) for subgroups with only one study available for analysis. The population, intervention, comparison, and outcomes measured should be similar between studies in order to directly apply the results. If a discrepancy exists between studies, then the quality rating is downgraded (-1 or -2). #When there is a lack of patients and events, the results are uninformative and therefore deemed to be imprecise. Data are also imprecise if the confidence intervals are not reported or they are so wide that the estimate is consistent with conflicting recommendations. If imprecise data are detected, then the quality rating is downgraded (-1). This is not applicable (N/A) for subgroups with only one study available for analysis. **Randomized controlled trials (RCT) are deemed to be of high quality (++++), a downgraded RCT or an upgraded prospective cohort study (PCS) is considered to be of moderate quality (+++), a well-done PCS is considered to be of low quality (++), and a downgraded RCT or PCS is considered to be of very low quality (+). Note that the quality of evidence was evaluated only for full publications (not abstracts). All results classified as not applicable (N/A) received a reduction in the quality rating (-1). Accident Compensation Corporation Page 8

9 Another systematic review 10 about the use of PRP in ligament and tendon injuries located 13 relevant studies. Of the four RCTs included: one found that PRP was superior to steroid injection for chronic lateral epicondylitis in terms of pain and function at 1 year post-intervention, however this RCT did not take into account that the long-term detrimental effects which can be seen with corticosteroid injections could make PRP appear more superior than it truly is 14. Another found no difference between PRP and saline injection in a group of people with chronic Achilles tendinopathy treated with eccentric exercise at the six month follow-up 15 ; one found no clear benefit on healing of adding PRP to a hamstring graft for ACL reconstruction 16 ; and the last one found no improvement in function or MRI appearance in patellar tendon allograft for ACL reconstruction 17. The authors were cautious in their conclusions, warning that the uses of PRP in soft tissue applications were only weakly supported by the evidence and that, despite some benefits demonstrated to date, any inferences regarding potential benefits and safety of this therapy must consider the low number of studies, low sample numbers, and the lack of RCTs. The other well conducted systematic review 4 looked at autologous growth factor injections for the treatment of chronic tendinopathies. It included 11 studies, only three of which were RCTs. Kiter (2006) 18 compared up to three ABIs with steroid injections or dry needling for plantar fasciitis (n=45) and found no significant differences with regards pain and function between any of the groups at the six month follow-up. Lee (2007) 19 also found no differences at six months between the ABI group (n=32) and steroid injection group (n=32) in terms of pain improvement for plantar fasciitis. The third study, by Kalaci (2009) 20, found no differences between the ABI and local anaesthetic injection (+ dry needling) groups for plantar fasciitis. In contrast, the steroid injection arms (± dry needling) were significantly better in terms of pain improvement compared to ABI at the six month follow-up. This study was reported to be randomised but, in fact, it was not, so the results are at considerable risk of being influenced by bias. In summary, this systematic review concluded that there was strong evidence that ABI does not improve pain and/or function compared with other treatments and that there is limited evidence that PRP injections are beneficial 4. The other review considering chronic tendinopathy is by Hoksrud (2011) 5 who investigated the efficacy of sclerosing, PRP, and ABI injectable therapies. A total of 25 studies were included, however, there were only three RCTs that used PRP or ABI. These primary studies give conflicting results and will be considered separately later in the report. The authors conclude that although most studies investigating the effect of PRP on tendinopathy have shown promising results, the two RCTs available appear to show conflicting results. They add that there is limited evidence from one RCT to assess the efficacy of ABI in the treatment of tendinopathy and state,"although these therapies seem to have received clinical acceptance in managing tendon disorders, it seems that their widespread use has superseded the available scientific evidence." 5 The other two smaller 'best evidence' reviews 1 6 on tendinopathy supported these conclusions. The first, a rapid review of literature by the National Institute for Clinical Excellence (NICE) of autologous blood injections (ABI) for tendinopathy reported on eight relevant studies (five RCT's and three case series) 1. They concluded that the "evidence on efficacy remains inadequate, with few studies available that use appropriate comparators. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research." 1 The other small review 6 found four studies that met their inclusion criteria and concluded that there was "some low quality and low level evidence on the efficacy of PRP in treating tendinopathies." When the review was re-written in 2010, a high quality RCT was located which found that among patients with chronic Achilles tendinopathy treated with eccentric exercises, a PRP injection did not result in any significant improvement in pain and activity compared to saline injection at 24 weeks follow-up 15. This study will be discussed later in this report. A more specific systematic review 7 looked at the role of platelets (including PRP) in Achilles tendon injuries and found no evidence for a beneficial effect of platelets in Achilles tendinopathy. This conclusion was based on only four human studies: two for achilles tendinopathy (same study but different follow-up times) and two for achilles repair. They also concluded that there was evidence of a statistically significant effect of platelet concentrates in Achilles tendon repair, however, this conclusion was based on a meta-analysis of animal studies only and was measuring biomechanical outcomes, not patient-centred outcomes. It is difficult to extrapolate these findings to clinical outcomes in the human population. There were also two systematic reviews 8 9 that assessed the evidence for various injection therapies, including ABIs, for elbow tendinopathies. Robago (2009) 9 included three small case series using ABI and one using PRP, all of which reported an improvement in pain and/or function. Krogh (2012) 8 located four RCTs using ABI or PRP, all published another term for autologous blood products like ABI and PRP Accident Compensation Corporation

10 since Rabago (2009) 9. Their conclusion was that there was a paucity of evidence from unbiased trials on which to base treatment recommendations regarding injection therapies for lateral epicondylosis. This is similar to the findings of a 2011 systematic review 11 which investigated the efficacy of PRP in the treatment of muscle strain injuries and found only three human studies (all with serious methodological limitations) and concluded that no conclusions can be made about the efficacy of PRP for muscle strain injuries as no robust clinical studies with relevant comparators were located. Closer to home, a 2012 technology brief 12 from Australia by HealthPACT included five studies with a total of 1,416 participants that investigated ABI for the treatment of soft tissue injuries. Three studies looked at ABI efficacy as a treatment for elbow tendinopathy/lateral epicondylitis. When compared to corticosteroid injection, ABI significantly improved pain at 8 weeks in one study 22, and at 12 weeks and 6 months in another 24. The third, smaller, study 25 compared saline injection, steroid injection, and ABI and found no significant differences in pain at 6 months between the three groups. The only other RCT in this review found no difference between ABI and steroid injection in the treatment of plantar fasciitis at 6 months 19. The last study in this review was a case series of 44 people with patellar tendinosis treated with ABI which found that subjective knee function scores improved at follow-up, however since there is no comparison, definitive conclusions cannot be reached from this. In their summary of findings 12, the authors comment on the fact that the comparator chosen in these studies, steroid injections, may be inappropriate, as other options, including rest, NSAIDs, physiotherapy, and eccentric exercise may better reflect current practice. They, therefore, state that conclusions regarding the comparative effectiveness of ABIs to these more conventional and accepted treatments cannot be made. Finally, the International Olympic Committee (IOC) consensus paper 13 on the use of PRP in sports medicine was published in An expert group was assembled to critically review the clinical effectiveness of PRP and their recommendations were as follows: 1. There was a limited amount of basic science research on the influence of PRP on the inflammation and repair of connective tissue and skeletal muscle. 2. There was an even greater paucity of well-conducted clinical studies on the use of PRP to manage sport injuries. 3. Firm recommendations on the effectiveness of PRP in the clinical setting to support the healing processes of muscle, tendon, ligament and cartilage injuries cannot be given. 4. Results of studies on PRP are difficult to interpret, as the methodological quality of published investigations varies substantially. 5. The final recommendation of this consensus group was to proceed with caution in the use of PRP in athletic sporting injuries. Randomised Controlled Trials Lateral Epicondylosis/Epicondylitis or elbow tendinopathy Nine RCTs are included here that investigate PRP or ABI for the treatment of lateral epicondylosis/epicondylitis or elbow tendinopathy. The most recent by Krogh (2013) 27 randomised 60 subjects into three groups: PRP, corticosteroid, or saline injection. All participants had had LE for at least 3 months and were referred from their GP or other rheumatological or orthopaedic hospital departments. They found at three months no significant difference in terms of pain or functional improvement between the groups. Results from 6 and 12 months were not reported because large numbers of participants dropped out (73% overall at 12 months) of the study due to an unsatisfactory effect. Whether the proportions dropping out from each group was significantly different was not reported. No serious adverse events were reported, although PRP injection caused the most additional pain compared to saline or steroid injection. Health Policy Advisory Committee on Technology Accident Compensation Corporation Page 10

11 Dojode (2012) 24 compared ABI to steroid injection in 60 patients with LE. They found that the steroid group demonstrated a significantly better pain relief at 1 and 4 weeks follow-up. However, at 12 weeks and 6 months, there was significantly better pain reduction in the ABI group than in the steroid group. Interestingly, there was a greater recurrence rate in the steroid group compared to the ABI group (37% vs. 0%). In addition, there were more subjects with increased pain after the ABI injection (n=18) than in the steroid group (n=8). A smaller RCT by Omar (2012) 28 of 30 participants randomised to either ABI or steroid injection found no difference in pain reduction at 6 weeks. Creaney (2011) 21 conducted a study of 150 people comparing ABI to PRP for the treatment of lateral epicondylosis. The participants had all previously failed to respond to a more 'conservative' treatment like stretching and eccentric exercise. Using the criteria of an improvement of 25 points on the patient-related tennis elbow evaluation score (PRTEE) as indicating 'success', there was no significant difference in the success rate between either group (PRP 66% vs. ABI 72%; p=0.59). However, more participants in the ABI group progressed to surgery (20%) compared to the PRP group (10%). Whether this difference was statistically significant was not reported. Another RCT by Gosens *** (2011) 26 comparing PRP to corticosteroid injection found that at 2 years follow-up the PRP group had better pain reduction and restoration of function (using the DASH score). Like Creaney (2011) 21, Thanasas (2011) 29 compared ABI with PRP in a small number of subjects (n=28) and found no difference in pain reduction or functional improvement (using the Liverpool elbow score) at 6 months follow-up. There was a significantly better improvement in pain at 6 weeks in the PRP group [p<0.05] but this was not sustained by 3 months post-injection. Of note, all participants underwent a programme of eccentric exercises and stretching during the study period as well. Wolf (2011) 25 was the other RCT that compared an autologous blood product injection with saline injection and corticosteroid injection. They found no difference in pain or function between the three interventions at 6 months, except for the functional scores on the patient-rated forearm evaluation (PRFE) questionnaire which were significantly better for saline compared to ABI at 6 months. These results should be interpreted cautiously as the number of participants was small (n=28). The last two RCTs used corticosteroid injection as a comparator. Kazemi (2010) 22 found at 8 weeks post-injection that ABI appeared to be more efficacious on all outcomes (including pain and function) than steroid injection [all p-values <0.001]. However, there is a high risk of bias because of inadequate randomisation method, only assessors being blind to treatment allocation, and no mention of allocation concealment, so these results must be interpreted in this light. Ozturan (2010) 23 compared the efficacy of ABI, extracorporeal shockwave treatment (ESWT), and steroid injections in 60 participants. They found that at 1 year post-treatment there were higher percentages of 'success' in both the ABI and ESWT groups with respect to improved pain compared to the steroid injection group. "Success' here was defined as a 50% decrease in the Thomsen provocation test VAS value (a measure of pain). The ABI and ESWT groups also demonstrated better functional improvement compared to steroid at 1 year, and the ESWT group had significantly better improvement in maximal grip strength compared to the other groups at 1 year follow-up. Table 2: Summary of RCTs for elbow tendinopathies, lateral epicondylosis/epicondylitis Study Sample size Level of evidence Comparison Follow-up Functional outcome Comments Krogh PRP vs. steroid vs. saline 12 months No difference (at 3 months follow-up) 73% drop-out rate at 12 months; standard tennis elbow stretching *** this study is a 2 year follow-up of Peerbooms Disabilities of the Arm, Shoulder & Hand outcome score visual analogue scale Accident Compensation Corporation Page 11

12 Study Sample size Level of evidence Comparison Follow-up Functional outcome Comments & training programme Dojode ABI vs. steroid 6 months Favours ABI 37% recurrence rate in steroid group Omar ABI vs. steroid 6 weeks No difference small numbers; short follow-up period Creaney 2011 Gosens 2011 Thanasas PRP vs. ABI 6 months No difference failed previous treatment PRP vs. steroid 2 years Favours PRP 2 yr follow-up of Peerbooms PRP vs. ABI 6 months No difference programme of stretching and eccentric exercise (2x daily for 5 weeks) Wolf ABI vs. steroid vs. saline 6 months No difference small numbers; subjects given a standard sheet of stretching exercises Kazemi ABI vs. steroid 8 weeks Favours ABI short follow-up period Ozturan ABI vs. steroid vs. ESWT 1 year Favours both ABI & ESWT subjects offered 2nd 6 wks Achilles tendinopathy There were 3 RCTs located that investigated to use of autologous blood product injections for the treatment of Achilles tendinopathy. Bell (2013) 30 compared two unguided ABIs with 'dry needling' in 53 people with mid-portion Achilles tendinopathy of duration of at least 3 months. All participants also engaged in an eccentric exercise program for at least 12 weeks. At 6 months post-injection, there were no significant differences in terms of symptoms and function (measured by the VISA- A **** score), perceived rehabilitation status or level of return to sport. The authors concluded that the addition of two peritendinous ABIs a month apart to a standardised eccentric exercise programme provides no extra benefit in the treatment of mid-portion Achilles tendinopathy. Pearson (2012) 32, in a similar population as above, compared eccentric exercise alone with ABI plus eccentric exercise in 40 people. At 12 weeks, the mean change in the VISA-A score for ABI group was 18.9 (95%CI: 11.5 to 26.3) and 9.4 (95%CI: 0.4 to 18.4) for the eccentric exercise alone group. The authors used magnitude-based clinical inference to analyse findings and judged that a "slight increase" in effect was likely when comparing the two groups and concluded: "There is some evidence for small short-term symptomatic improvements with the addition of ABI to standard treatment for Achilles tendinopathy." However, a more traditional interpretation of the results would be that as the confidence intervals overlap there is not a statistically significant difference between the groups at the 5% level. Considering this in addition to the high risk of bias present in the study (due to the lack of allocation concealment and any blinding, a 30% drop-out rate, and a variable number of injections given) it seems unlikely that there is any significant benefit of adding an ABI to eccentric exercise for the treatment of mid-portion Achilles tendinopathy. where a needle is passed through the tendon repeatedly but no substance is injected into or around the tendon **** Victoria Institute of Sport Assessment Achilles score Accident Compensation Corporation Page 12

13 In their one year follow-up of the de Vos (2010) 15 study, de Jonge (2011) 31 found that the addition of a PRP injection to an eccentric exercise programme did not result in added clinical benefit in people with chronic mid-portion Achilles tendiopathy. The adjusted between-group difference was 5.5 (95%CI: -4.9 to 15.8). In addition, return to desired sports activity at pre-injury level was not significantly different (PRP 57% vs. saline 42%) and satisfaction levels were the same in each group. Table 3: Summary of RCTs for Achilles tendinopathy Study Sample size Level of evidence Comparison Follow-up Functional outcome Comments Bell ABI vs. dry needling 6 mo No difference All subjects engaged in eccentric exercise programme Pearson 2012 de Jonge ABI + eccentric exercise vs. eccentric exercise PRP vs. saline injection 12 weeks No difference 30% drop-out rate 1 yr No difference 1 yr follow-up of de Vos (2010); eccentric exercise programme Rotator cuff disease One RCT by Rha (2012) 33 investigated the efficacy of two guided PRP injections a month apart compared to dry needling in rotator cuff disease (defined here as: tendinosis or a partial tear of <1 cm) in 39 subjects. A self-exercise protocol was provided to all participants during the study. At 24 weeks post-intervention there was a significantly better improvement in pain and function (as measured by the Shoulder Pain & Disability Index) for the PRP group compared to the dry needling group [p<0.05]. There was no difference in the range of motion improvement between both groups. Study Sample size Level of evidence Comparison Follow-up Functional outcome Comments Rha PRP vs. dry needling 6 mo Favours PRP for pain but no difference for range of movement Small sample; 23% drop-out rate; mixed tendinosis and small partial tears Patellar tendinopathy Ventrano (2013) 34 compared two guided PRP injections (a week apart) with extracorporeal shockwave therapy (ESWT) in 46 people with chronic patellar tendinopathy ('jumper's knee'). All of the participants were involved in athletic activities with the majority (78%) being elite athletes. In addition, all participants were given a standardised stretching and strengthening protocol. At 12 months follow-up, the PRP group had significantly better resting and load-induced pain improvement compared to the ESWT group. Study Sample size Level of evidence Comparison Follow-up Functional outcome Comments Ventrano PRP vs. ESWT 12 mo Favours PRP Athletes Accident Compensation Corporation Page 13

14 Plantar fasciitis Three RCTs investigated the efficacy of autologous blood product injections in the treatment of plantar fasciitis The most recent, Omar (2012) 28, compared intralesional PRP injection with steroid injection in 30 people. Both pain and function were improved significantly more in the PRP group than the steroid group [p=0.001 & <0.001 respectively] at 6 weeks follow-up. All participants were women. Lee (2007) 19 compared intralesional ABI with corticosteroid injection in 64 people with chronic proximal plantar fasciitis. At 6 months post-intervention, there was no significant difference between the two groups in terms of pain [p=0.094], however steroid injection had significantly lower pain scores at 6 weeks and 3 months [p=0.011 & respectively]. Tenderness threshold was significantly higher for the steroid group at all time points. Three participants in the ABI group and two in the steroid group had repeat injections at 3 months after the first injection. Kiter (2006) 18 randomised 64 people to either receive an ABI, corticosteroid injection, or dry needling. The participants were people with plantar heel pain where conservative treatment for at least 6 months had failed, although what these treatments were was not reported. There was no difference at 6 months follow-up between any of the groups in terms of pain or functional improvement. In addition, more subjects in the dry needling and ABI groups received a third injection (7 & 10 respectively) compared to steroid injection (none). Table 42: Summary of RCTs for plantar fasciitis Study Sample size Level of evidence Comparison Follow-up Functional outcome Comments Omar PRP vs. steroid injection Lee ABI vs. steroid injection Kiter ABI vs. steroid injection vs. dry needling 6 wks Favours PRP Short follow-up 6 mo No difference 6 mo No difference Small sample (n=15 in each group) Safety Only half (n=6) of the systematic and related reviews discussed safety. NICE (2013) found that the evidence on ABI for tendinopathy raises no major safety concerns 1. Taylor (2011) found that, to date, no adverse events or deleterious effects on recovery or functional outcome had been documented 10, and Krogh (2012) found that no patients dropped out because of an adverse event 8. The commonest side-effect reported was transient post-injection pain for all the injection therapies evaluated in Krogh (2012) 8, and more complained of increased pain after ABI compared to steroid injection (60% vs. 26%; p=0.009) in one study 24 that was in the HealthPACT (2012) review 12. Local skin atrophy in two subjects after steroid injection was reported but none in the ABI group (p>0.05) 12. Two other authors were more conservative in their discussion of safety issues 11 13, stating that there is limited evidence supporting autologous blood products' safety 13. This is not to say that autologous blood injections are not safe but that there are few, if any, studies that document any adverse or serious adverse events, and there are no studies at all looking at long-term effects 13. In fact, to date, only minor adverse events, such as a mild pain reaction and effusion after the injections, have been reported 13. Safety was not reported in six of the reviews nor in seven (44%) of the RCTs called in the paper "peppering technique" Accident Compensation Corporation Page 14

15 Of the remaining RCTs, no serious adverse events (requiring hospitalisation) were reported 27 and no other side-effects were reported by the study participants in three studies The commonest side-effect recorded was additional pain where any injection was administered in up to a fifth of the participants 32. Increased pain after injection was more frequently seen after the ABI (up to 60%) than after the steroid injection (up to 26%) [p=0.009] in two studies and PRP caused the most additional pain compared with saline or steroid in another 27. One study reported modest pain lasted longer after dry needling than PRP injection but the difference was less than one day 33. To summarise, it appears that ABI and PRP injections are not associated with any serious adverse events but the evidence is limited with no long-term follow-up studies. The commonest side-effect is additional pain at the site of the autologous blood product injection of a few days duration. No infections or tendon ruptures were reported. 4. Evidence statements for tendinopathies Elbow tendinopathies, Lateral epicondylosis/epicondylitis There is conflicting evidence from two RCTs that corticosteroid injections: platelet-rich plasma injections are more efficacious than one good quality (1++) RCT 26 found PRP improved pain and function significantly more than corticosteroid injection at 2 years follow-up one small fair quality (1+) RCT 27 found no difference in terms of pain and functional improvement compared to corticosteroid injection and saline injection at 3 months follow-up There is conflicting evidence from five RCTs that corticosteroid injections: autologous blood injections are more efficacious than one fair quality (1+) RCT 25 found no difference in terms of pain and functional improvement compared to corticosteroid injection and saline injection at 6 months follow-up one poor quality (1-) RCT 28 found no difference in terms of pain and functional improvement compared to corticosteroid injection at 6 weeks follow-up two poor quality (1-) RCTs found that autologous blood injections improved pain and function significantly more than corticosteroid injection one poor quality (1-) RCT 23 found that autologous blood injection and extracorporeal shockwave treatment improved pain and function significantly more than corticosteroid injection at 1 yr follow-up. There is moderate evidence from two fair quality (1+) RCTs that autologous blood injections are no more efficacious than platelet-rich plasma for the treatment of elbow tendinopathies or lateral epicondylosis/epicondylitis.. Achilles tendinopathy There is moderate evidence from two RCTs (one good quality and the other poor quality) that the addition of autologous blood injections to a programme of eccentric exercise did not result in additional benefit in people with midportion Achilles tendinopathy when compared to dry needling and an eccentric exercise programme. There is limited evidence from one fair quality RCT 31 that the addition of platelet-rich plasma injection to a programme of eccentric exercise or combination of a saline injection and eccentric exercise did not result in additional benefit in people with mid-portion Achilles tendinopathy.. Accident Compensation Corporation Page 15

16 Rotator cuff disease There is limited evidence from one fair quality (1+) RCT 33 that platelet-rich plasma may improve pain (but not range of movement) more in rotator cuff disease compared to dry needling at 6 months follow-up. Patellar tendinopathy There is limited evidence from one fair quality (1+) RCT 34 that platelet-rich plasma may improve pain and function better than extracorporeal shockwave treatment in athletes at 1 year follow-up. Plantar fasciitis There is limited evidence from one poor quality (1-) RCT 28 that platelet-rich plasma injection may improve pain and function better than corticosteroid injection at 6 weeks follow-up. There is moderate evidence from two fair quality (1+) RCTs that there is no difference in terms of pain and functional improvement when comparing autologous blood injection with corticosteroid injection for plantar fasciitis at 6 months follow-up. There is limited evidence from one fair quality (1+) RCT 18 that no difference in terms of pain and functional improvement when comparing autologous blood injection with dry needling for plantar fasciitis at 6 months follow-up. 5. Discussion The major limitation of the evidence for autologous blood products for treatment of musculoskeletal disorders is the paucity of methodologically good RCTs. In addition, the use of corticosteroid injections as an active control in many of the studies complicates the ability to make conclusive statements about efficacy. There is some evidence to show that even though there is short-term benefit (pain relief) in using corticosteroid injections for tendinopathies there is long-term harm from increased recurrence Recurrence rates of about 70% have been reported after steroid injection for lateral epicondylosis in one study 35 compared to about 10% for 'wait-and-see' or physiotherapy treatment. Another earlier study 36 demonstrated a 92% success rate for steroid injections at six weeks, this drops to 69% for steroid injection at one year. Physiotherapy and 'wait-and-see' success rates were 47% and 32% respectively at six weeks, and 58% and 83% at one year. Therefore a positive result in favour of an autologous blood product injection when compared to steroid injection may reflect the steroid injection's detrimental effect in the long-term rather than the autologous blood product's superiority. When autologous blood products are compared to saline injections or 'dry needling' almost all studies (5 out of 6) found no difference in efficacy. When compared to extracorporeal shockwave treatment the results were conflicting (only two studies). Six studies added the autologous blood product injection to a standard programme of stretching and/or eccentric exercise; three for lateral epicondylosis and three for Achilles tendinopathy All of these studies found no significant additional benefit of the addition of the autologous blood product injection, however, only one study 30 tested the participants' compliance to any exercise programme. This evidence of no additional benefit is stronger for Achilles tendinopathy. Two other important limitations of the studies included in this report are the lack of consistent approaches to the preparation of any autologous blood product resulting in variation in the concentration of the putative active factors in the prepared blood; and the heterogeneity of the participants, number of injections given, injection technique (i.e. ± local anaesthetic and/or "peppering"), outcome measures used, follow-up times which make any comparisons between studies more difficult. Accident Compensation Corporation Page 16

17 External peer review comments It was highlighted by the external peer reviewer throughout this report that the detrimental long term effects of corticosteroid injections are not always discussed in the included RCTs. The impact of this is that although ABI and PRP products may appear superior to corticosteroid injections, this is not proof of their efficacy in that these products have less detrimental effects than a corticosteroid injection. 6. Conclusions Conclusive statements of the efficacy of autologous blood products for musculoskeletal conditions are difficult to make due to several reasons: 1. the paucity of comparative research with appropriate controls 2. the significant heterogeneity of populations studied, number of injections given, outcome measures used, and followup times, and 3. the general poor quality of any research study methodology. This can be seen clearly in the conclusions made by authors of the systematic reviews included in this report which generally find that no firm recommendations can be made. The best evidence, arguably, comes from Sheth (2012) 3 who concluded, in their good quality systematic review that: "[the] current evidence is insufficient to discern whether autologous blood concentrates provide a clinical benefit in the treatment of orthopaedic conditions." However, based on the RCTs for tendinopathy disorders, some general statements could be made: 1. The evidence for the efficacy of autologous blood injection or platelet-rich plasma injection for the treatment of elbow tendinopathies is conflicting 2. There is some evidence that autologous blood injection or platelet-rich plasma injection do not add any extra benefit to an eccentric exercise programme in terms of pain/functional improvement compared to steroid injection or saline for Achilles tendinopathy in the medium to long term 3. There is some evidence that autologous blood injection is likely not any more efficacious in terms of pain/functional improvement than steroid injection or dry needling for plantar fasciitis in the medium term 4. There are no significant safety concerns reported in the literature Accident Compensation Corporation Page 17

18 7. Appendix 1: Evidence Tables (in alphabetical order) Reference and study design Bell, (2013). "Impact of autologous blood injections in treatment of mid-portion Achilles tendinopathy: double blind randomised controlled trial." BMJ 346: f2310. Australia/New Zealand Level of evidence: 1++ Participants Intervention/comparison Outcome measure Results/effect size Conclusions Number of patients: n=53 (n= 26 ABI vs. n=27 dry needling) Inclusion criteria: >18 yrs old, 1st episode of mid-portion Achilles tendinopathy with symptoms lasting 3 months; ultrasound confirmed diagnosis Exclusion criteria: bilateral Achilles tendon symptoms; alternative diagnoses e.g. insertional Achilles tendinopathy; previous Achilles surgery or rupture or other treatments e.g. any kind of injection, ESWT or glyceryl trinitrate patches Intervention: Autologous blood injection Length of treatment: Two peri-tendinous injections (peppering technique) at baseline and 1 month later Comparison: Dry needling Co-interventions: Eccentric exercise programme (180 eccentric heel drops over a step each day for at least 12 weeks on injured leg only Mean change (95%CI) in Victorian Institute of Sports Assessment- Achilles (VISA-A) Perceived 6 months (ABI vs. control) Month 1: 2.6 (-3.4 to 8.6) Month 2: 3.4 (-3.8 to 11.0) Month 3: 0.3 (-6.9 to 7.5) Month 6: -1.2 (-10.0 to 7.9) Overall effect of treatment was not significant [p=0.689] Completely recovered: 40% vs. 36% Much better: 52% vs. 52% A little better: 8% vs. 12% Unchanged/Much worse: 0% vs. 0% Authors' conclusion: "The administration of two unguided peritendinous autologous blood injections one month apart, in addition to a standardised eccentric training programme, provides no additional benefit in the treatment of mid-portion Achilles tendinopathy." Dropouts: 3 (6%) at 6 months Follow-up: 6 months Relevant characteristics: (ABI b=vs. control) Mean age: 51.2 vs yrs Age range: 27 to 76 yrs Men: 16 (62%) vs. 12 (44%) European: 24 (92%) vs. 24 (89%) Left side affected: 20 (77%) vs. 13 (48%) Mean duration: 22.9 vs months Mean duration in those duration 100 months: 14.8 vs months Participates in sport/physical activity: 22 (85%) vs. 27 (100%) Physical activity: no change- 12 (46%) vs. 9 (33%) reduced- 9 (35%) vs. 7 (26%) ceased- 5 (19%) vs. 11 (41%) Changes on U/S: severe- 5 (19%) vs. 1 (4%) Accident Compensation Corporation Level of return to 6 months Complications or adverse events [p=0.881] Not normally active in sport: 7 (28%) vs. 1 (4%) No return to sport: 1 (4%) vs. 1 (4%) Returned to sport but not desired sport: 1 (4%) vs. 4 (16%) Returned to desired sport but not to pre-injury level: 3 (12%) vs. 10 (40%) Returned to pre-injury level in desired sport: 13 (52%) vs. 9 (36%) [p=0.679] None reported

19 moderate- 16 (62%) vs. 17 (63%) mild- 5 (19%) vs. 9 (33%) Mean VISA-A score: 58.1 vs Study type: RCT Setting: specialist multidisciplinary sports medicine clinic Comments: Adequate randomisation and allocation concealment. Participants and assessors 'blind' to treatment allocation. Blinding analysis. Power calculation done. 95% participation rate. 6% drop-out rate. Intention-to-treat analysis. Mean compliance with eccentric exercise = 65% vs. 62% [p=0.612]. No significant difference between predictions of treatment allocation between either group [p=0.564] 95%CI = 95% confidence interval Accident Compensation Corporation Page 19

20 Reference and study design Creaney, (2011). "Growth factor-based therapies provide additional benefit beyond physical therapy in resistant elbow tendinopathy: a prospective, double-blind, randomised trial of autologous blood injections versus plateletrich plasma injections." British Journal of Sports Medicine 45(12): UK Level of evidence: 1+ Participants Intervention/comparison Outcome measure Results/effect size Conclusions Number of patients: n=150 (n=80 PRP vs. n=70 ABI) Inclusion criteria: patients with lateral epicondylitis (LE) who had failed previous 'conservative' treatment* and symptoms present for at least 6 months *including physical therapy exercises e.g. stretches & eccentric loading Exclusion criteria: previous treatment with local steroid injections, dry needling or blood injections Dropouts: 20 (13%) n=10 (12%) PRP, n=10 (14%) ABI Follow-up: 6 months Relevant characteristics: Mean age 48 vs. 53 yrs (ABI vs. PRP) Male 56% vs.; 57% Mean PRTEE overall 48.8 (95%CI: ) PRP 45.8 (95%CI: ) ABI 52.5 (95%CI: ) Intervention: Platelet-rich plasma (PRP) injection Length of treatment: two injections, one at baseline & one at I month Comparison: Autologous blood injection (ABI) Co-interventions: local anaesthetic given prior to blood injection (PRP or ABI); panadol as required for pain after injection NB: blood injections were ultrasound-guided Patient-related tennis elbow evaluation (PRTEE) score success = improvement of 25 points at final analysis failure = improvement <25 points or progression to surgery Success rate: PRP 66% (95%CI: 55-77%) ABI 72% (95%CI: 61-83%) p=0.59 Failure rate: PRP 24% vs. ABI 8% p-value not reported Progression to surgery: PRP 10% vs. ABI 20% p-value not reported Composite failure rate: PRP 34% vs. ABI 28% p-value not reported Authors' conclusion: "In patients who are resistant to first-line physical therapy such as eccentric loading, ABI or PRP injections are useful second-line therapies to improve clinical outcomes. In this study, up to seven out of 10 additional patients in this difficult to treat cohort benefit from a surgery-sparing intervention." Reviewer's conclusion: The 'success' (i.e. improvement of 25 points on the PRTEE scale) rate of PRP and ABI are not statistically significantly different at 6 months follow-up. More subjects in the ABI group progressed to surgery than in the PRP group. Setting: Unclear Study type: RCT Comments: Adequate method of randomisation. Allocation concealment OK. Patients & assessors were 'blinded' to treatment allocation. Limited information about how similar the treatment & comparison groups are for both conditions. Power calculation. On-treatment analysis PRP = platelet-rich plasma; ABI = autologous blood injection; 95%CI = 95% confidence interval; PRTEE score (0-100) clinically significant improvement = 25 points Accident Compensation Corporation Page 20

21 Reference and study design de Jonge, (2011). "One-year follow-up of platelet-rich plasma treatment in chronic Achilles tendinopathy: a double-blind randomized placebo-controlled trial." American Journal of Sports Medicine 39(8): Netherlands 1 year follow-up of de Vos Level of evidence: 1+ Study type: RCT Participants Intervention/comparison Outcome measure Results/effect size Conclusions Number of patients: n= 54 (n=27 PRP vs. n=27 saline) Inclusion criteria: clinical diagnosis* of mid-portion Achilles tendinopathy for at least 2 months; aged yrs *painful thickened tendon 2 to 7 cm from calcaneal insertion Exclusion criteria: other musculoskeletal injuries e.g. insertion disorder or tendon rupture; inflammatory or systemic disease; drugs associated with tendon disorders e.g. fluoroquinolones; previous completion of eccentric exercise programme or inability to perform them; previous PRP injection Dropouts: 0% Follow-up: 1 year Relevant characteristics: (PRP vs. saline) Mean age: 49 vs. 50 yrs Male: 13 vs. 13 Median duration: 36 vs. 26 weeks Active in sports: 22 vs. 24 Recreational sports: 16 vs. 21 Sports activity at baseline: ceased 12 vs. 10 reduced 8 vs. 5 unchanged 2 vs. 9 BMI: 26.8 vs Mean VISA-A: 46.7 vs Setting: Secondary care Intervention: Platelet-rich plasma (PRP) injection Length of treatment: One injection of either PRP or saline Comparison: Saline injection Co-interventions: Eccentric exercise programme for 12 weeks (avoid sports activity for 4 weeks after injection; stretching programme in week 2) ; local anaesthetic administered to skin prior to other injection At 24 weeks, 4 participants in the PRP group decided to have another treatment (n=1 orthotics, n=3 ESWT, n=1 glyceryl trinitrate patches); one person in the control group received glyceryl trinitrate patches Mean change VISA-A (at 1 yr) PRP: 31.6 (95%CI: ) Saline: 25.0 (95%CI: ) Adjusted between-group difference at 1 year follow-up: 5.5 (95%CI: ) Satisfaction PRP: 59.3% (16/27) Saline: 59.3% (16/27) Not significantly different Return to sports activity 56.5% (PRP) vs. 41.7% (saline) returned to desired sport at preinjury level Not significantly different Ultrasound changes No statistically significant differences in the change of % echo type I & II, maximum anteriorposterior tendon diameter, or mean neovascularistion scores Authors' conclusion: "A PRP injection in addition to eccentric exercises did not result in clinical improvement and/or improved structural reorganization on ultrasound after 1 year in chronic midportion Achilles tendinopathy, compared with a placebo injection." Comments: Randomisation & allocation concealment methods good. Treating physician, researcher & participants 'blind' to treatment allocation. Participation rate = 55% (54/99). Power calculation done. No drop-outs. VISA-A = Victorian Institue of Sports Assessment-Achilles; BMI = body mass index; ESWT = extra-corporeal shockwave therapy Reference and study Studies Intervention/comparison Results/effect size Conclusions Accident Compensation Corporation Page 21

22 design de Vos, (2010a). "Autologous growth factor injections in chronic tendinopathy: a systematic review." British Medical Bulletin 95: Netherlands Included studies: Connell 2006, Edwards 2003, Filardo 2009, James 2007, Kalachi 2009, Kiter 2006, Kon 2009, Lee 2007, Mishra 2006, Suresh 2006, Ul Gani 2007 Level of evidence: 1++ Number of studies: N = 11 (7 case series, 3 RCTs, one case-control) Total number of patients: n = Inclusion criteria: clinical diagnosis of chronic tendinopathy; well-described intervention in the form of an injection with either autologous whole blood, or platelet-rich plasma; outcome reported in terms of pain and/or function; randomised controlled trial, nonrandomised clinical trial, or prospective case series Exclusion criteria: non- English and animal studies Databases used: PubMed, MEDLINE, EMBASE, CINAHL, Cochrane Library Description of the methodological assessment of studies: PEDro Fixed or random effects: not relevant Heterogeneity: not reported Intervention studied: Autologous growth factors including autologous whole blood (ABI), & platelet-rich plasma (PRP) Length of follow-up (range): 6 to 26 months Description of comparison: local anaesthetic injection, exercise therapy, corticosteroid injection Co-interventions: local anaesthetic in 6 studies ABI: N=8 Chronic elbow tendinopathy Edwards 2003 case series (n=28); one to three ABIs; 79% (22/28) were pain free at 9.5 months; both mean pain & Nirschl score improved by 71% & 69% respectively Connell 2006 case series (n=35); two to three ABIs; significant improvement in both Nirschl and VAS scores at 6 months Suresh 2006 case series (n=20); two to three ABIs; significant improvement in both Nirschl and VAS scores at 10 months Ul Gani 2007 case series (n=26); one to two ABIs; significant improvement in both Nirschl and pain scores at 8 months Chronic plantar fasciitis Kiter 2006 RCT (n=54); ABI + LA vs. LA vs. steroid + LA; no significant difference on mean VAS & AOFAS score Kalaci 2009 RCT* multicentre; ABI (n=25) vs. LA + peppering (n=25) vs. steroid (n=25) vs. steroid + peppering (n=25); significant improvement in VAS score in favour of steroid & steroid + peppering groups compared to ABI group; no significant difference in VAS score between ABI & LA + peppering groups Lee 2007 RCT; ABI (n=32) vs. steroid injection (n=32); no significant difference in VAS score at 6 months [NB: at 6 wks & 3 months, VAS score was significantly lower in steroid group] *NB: not actually randomised Chronic patellar tendinopathy James 2007 case series (n=47); two ABIs with dry needling; VISA-P score improved by 57% at 15 months PRP: N=3 Authors' conclusion: "There is strong evidence that ABIs do not improve pain and/or function compared to other treatments. There is only limited evidence that PRP injections are beneficial. All three high quality studies [Kiter 2006, Lee 2007, Kalaci 2009] on the use of autologous growth factor injections in the management of chronic tendinopathy showed no benefit." Reviewer's conclusion: There is evidence from three good quality RCTs that ABI is not more efficacious than steroid injections in terms of pain reduction and/or function for the treatment of plantar fasciitis. There is limited evidence from one small case-control study that PRP improves activity but not pain in people with patellar tendinopathy when compared to exercise. The remaining studies are all case series and all suggest that ABI or PRP may be beneficial in treating elbow or patellar tendinopathy, however no definitive conclusions can be made. Chronic patellar tendinopathy Filardo 2009 case-control; PRP (n=15 failed previous treatments) vs. exercise (n=16 previous exercise treatment alone); subjects all men; baseline differences in duration (longer in PRP group) and previous treatments (more in PRP group); no significant difference between groups on EQ-VAS; significantly greater improvement on Tegner score for PRP group Kon 2009 case series (n=20 men); 3 PRP injections; significant improvement in all parameters of SF-36, Tegner score, and EQ-VAS Chronic elbow tendinopathy Mishra 2006 case series (n=15)*; PRP (n=10) vs. local Accident Compensation Corporation Page 22

23 anaesthetic (n=5); PRP showed better improvement in pain, Mayo score than control at 4 & 8 weeks Study type: Systematic review *NB: planned as a case-control but ended up as a case series due to drop-outs in control group (3/5 dropped out at 8 weeks) Comments: Only 3 RCTs and one case-control study located. Generally well-conducted systematic review with a narrative evidence synthesis. CCT, non-randomised clinical trial; RCT, randomised controlled trial; ABI, autologous blood injection; PRP, platelet-rich plasma; VAS, visual analogue scale; AOFAS, American Orthopedics Foot and Ankle (rearfoot score); VISA-P, Victorian Institute of Sports Assessment-Patella; LA = local anaesthetic Accident Compensation Corporation Page 23

24 Reference and study design Dojode, (2012). "A randomised control trial to evaluate the efficacy of autologous blood injection versus local corticosteroid injection for treatment of lateral epicondylitis." Bone & Joint Research 1(8): India Level of evidence: 1- Participants Intervention/comparison Outcome measure Results/effect size Conclusions Number of patients: n=60 (30 ABI vs. 30 steroid) Inclusion criteria: a diagnosis of lateral epicondylitis (LE), age >15 yrs Exclusion criteria: steroid injection in the three months prior to the study treatment; history of substantial trauma; previous surgery for LE; presence of other causes of elbow pain* Dropouts: none reported Follow-up: 6 months Relevant characteristics: (ABI vs. steroid) Mean age: 42.9 vs yrs [p=0.828] Male / female: 13 / 17 vs. 12 / 18 [p=1] Mean duration: 9.5 vs. 7.7 months [p=0.828] Right / left side: 23 / 7 vs. 23 / 7 [p=1] Dominant side involved: 25 vs. 26 [p=1] Employment: manual 13 vs. 9 Intervention/comparison Intervention: autologous blood injection (ABI) Length of treatment: one injection of either ABI or steroid Comparison: Steroid injection Co-interventions: both injections had LA added (bupivacaine) Mean VAS (ABI vs. steroid) Pre-injection: 7.7 vs. 7.5 [p=0.5395] 1 week: 7.2 vs. 4.5 [p<0.0001] 4 weeks: 3.2 vs. 1.5 [p=0.0022] 12 weeks: 0.6 vs. 1.5 [p=0.0127] 6 months: 0.5 vs. 1.8 [p=0.0058] Mean Nirschl stage (ABI vs. steroid) Pre-injection: 5.4 vs. 5.2 [p=0.4918] 1 week: 5.1 vs. 3.1 [p<0.0001] 4 weeks: 2.2 vs. 1.0 [p=0.003] 12 weeks: 0.43 vs. 1.0 [p=0.0184] 6 months: 0.36 vs. 1.2 [p=0.0064] Recurrence rate: ABI: 0% Steroid: 36.8% Authors' conclusion: "Autologous blood injection is efficient compared with corticosteroid injection, with less side-effects and minimum recurrence rate." " autologous blood injection demonstrated statistically significant lower pain compared with corticosteroid injection group at longterm follow-up (six months), with 90% of patients in this group having complete relief of pain. Corticosteroid injection group showed early decrease in pain compared to autologous blood injection group but the short-term benefits of corticosteroid injection were followed by high rates of recurrence." Reviewer's conclusion: Steroid injection demonstrates a statistically greater pain relief 1 and 4 weeks after injection compared to ABI. However, at 12 weeks and 6 months, there was a statistically Accident Compensation Corporation Page 24

25 [p=0.3] non-manual 17 vs. 21 [p=0.3] Comorbidities: 20 participants (33%) reported as having diabetes mellitus no other information given Setting: Secondary care (recruited from people referred to outpatient department) Safety: Increased pain after injection ABI: 18 (60%) Steroid: 8 (26%) [p=0.009] Skin atrophy: 2 (6.6%) in steroid group; none in ABI group [p=0.150] No reports of elbow stiffness, infection, reflex sympathetic dystrophy, postinjection flare, facial flushing, neurovascular damage or tendon rupture or other untoward complications. significant greater pain reduction in the ABI group than those treated with steroid. There was also a greater recurrence rate in the steroid group compared to ABI (37% vs. 0%) Study type: RCT Comments: Unclear randomisation method. Allocation concealment and blinding not reported. The two groups are similar in age, gender-mix, duration of symptoms and employment demands. No cormorbidities reported except diabetes and don't know the % in each group. No power calculation. Therefore very likely some sort of bias present. *e.g. osteochondritis dessicans of capitellum, epiphyseal plate injuries, lateral compartment arthrosis, varus instability, radial head arthritis, posterior interosseous nerve syndrome, cervical disc syndrome, synovitis of radiohumeral joint, cervical radiculopathy, fibromyalgia, osteoarthritis of elbow, or carpal tunnel syndrome. NB: all patients were assessed by history and clinical examination; some had radiological and investigations to confirm diagnosis or identify exclusion criteria ABI = autologous blood injection; LA = local anaesthetic; LE = lateral epicondylitis Accident Compensation Corporation Page 25

26 Reference and study design Gosens, (2011). "Ongoing positive effect of platelet-rich plasma versus corticosteroid injection in lateral epicondylitis: a doubleblind randomized controlled trial with 2- year follow-up." American Journal of Sports Medicine 39(6): The Netherlands NB: 2 year follow-up of Peerbooms 2010 Level of evidence: 1++ Study type: RCT Participants Intervention/comparison Outcome measure Results/effect size Conclusions Number of patients: n=100 (51 PRP vs. 49 steroid) Inclusion criteria: Consecutive patients with lateral epicondylitis (LE) scheduled for injection therapy; LE duration of >6 months & pain of at least 50 on VAS (0=no pain; 100=max pain possible) Exclusion criteria: <18 yrs old, pregnancy, history of carpal tunnel syndrome or cervical radiculopathy, & systemic conditions like diabetes, rheumatoid arthritis, & hepatitis; surgery or steroid injection for LE in the past 6 months Dropouts: none at 2 yrs Follow-up: 2 yrs Relevant characteristics: Age 47.3 (steroid) vs (PRP) Gender 44% vs. 48% men Stage of disease duration of >6 months Right side 62% vs. 63% Dominant hand involved 76% vs. 75% Co-morbidity not reported Setting: secondary care (2 teaching hospitals) Intervention: platelet-rich plasma injection prepared using the Recover system (Bionet Biologics) using a peppering technique Length of treatment: one injection of either PRP or steroid Comparison: Corticosteroid injection using a peppering technique Co-interventions: local anaesthetic & adrenaline in both the PRP & steroid injection VAS pain (steroid vs. PRP) Baseline: 66.2 vs [p=0.340] 4 weeks: 44.3 vs [p=0.023] 8 weeks: 43.4 vs [p=0.411] 12 weeks: 45.5 vs [p=0.319] 26 weeks: 55.8 vs [p<0.001] 52 weeks: 48.8 vs [p<0.001] 104 weeks: 42.4 vs [p<0.001] DASH Baseline: 43.3 vs [p=0.002] 4 weeks: 31.2 vs [p=0.005] 8 weeks: 28.3 vs [p=0.060] 12 weeks: 32.3 vs [p=0.813] 26 weeks: 37.6 vs [p=0.37] 52 weeks: 36.8 vs [p<0.001] 104 weeks: 36.5 vs [p<0.001] Authors' conclusion: Treatment of patients with chronic lateral epicondylitis with PRP reduces pain and increases function significantly, exceeding the effect of corticosteroid injection even after a follow-up of 2 years. Future decisions for application of PRP for lateral epicondylitis should be confirmed by further follow-up from this trial and should take into account possible costs and harms as well as benefits. Reviewer's conclusion: A well conducted RCT comparing PRP with steroid injection for the treatment of painful chronic LE found that the PRP group reported significantly more pain than steroid injection at 4 weeks after injection while the opposite (where the PRP group reported significantly less pain) was found at 26, 52, & 104 weeks. A similar pattern was reported for function (DASH score). Comments: Adequate randomisation and allocation concealment methods. Subjects & investigators 'blind' to allocation. Baseline DASH score was significantly higher in the PRP group compared to the steroid group [p<0.0001]. Intention-to-treat analysis. Subjects were people with chronic LE (i.e. duration >6 months) & reported pain to be at least 50 on a VAS (0=no pain; 100 maximum pain possible). Unsure whether VAS=50 is representative of population of people with chronic LE. PRP = platelet-rich plasma; LE = lateral epicondylitis; VAS = visual analogue scale; DASH = Disabilities of the Arm, Shoulder & Hand outcome score Accident Compensation Corporation Page 26

27 Reference and study design Hamilton, (2011). "Platelet-enriched plasma and muscle strain injuries: challenges imposed by the burden of proof." Clinical Journal of Sport Medicine 21(1): USA/Qatar Included studies: Wright- Carpenter 2004 (casecontrol), Sanchez 2005 (case-control), Loo 2009 (case report) Level of evidence: 1- Studies Intervention/comparison Results/effect size Conclusions Number of studies: N = 0 clinical studies Inclusion criteria: unclear Exclusion criteria: reviews Databases used: MEDLINE & Embase (up to March 2010) Description of the methodological assessment of studies: Judet [sic] criteria Fixed or random effects: N/A Heterogeneity: not reported Intervention studied: Autologous platelet-rich plasma for muscle strain injuries Wright-Carpenter 2004: using autologous conditioned serum (ACS) to treat various muscle strains in 18 professional athletes; compared with 11 professional athletes with anatomically similar injuries; reported a significant reduction in return-to-play time (16 vs. 22 days) Sanchez 2005: 20 professional athletes with muscle injuries treated with plasma rich in growth factors (PRGF) compared to 25 age- & sex-matched controls; all underwent physiotherapy; author's concluded that PRGF reduced pain and swelling, with functional recovery in "half of the expected recovery time". Loo 2009: 35 yr old professional bodybuilder with right adductor longus strain injury; one week after final injection of PRGF the person returned to training Note on quality of studies: all have significant methodological limitations e.g. non-blinded, atypical controls, variable injury site, short follow-up period, poor reporting. No conclusions can be made regarding the efficacy of PRP for muscle strain injuries as no robust clinical studies with relevant comparators were located. Author's conclusions: Despite a high public profile, the use of autologous plasma injections in the management of acute muscle strain injuries has no clinical evidence base. Although basic science and the use of recombinant GFs in animal models support the concept, it is unclear if this evidence can be directly transposed to reflect outcomes from PEP. There remain a large number of unanswered questions, including the principle questions regarding safety and efficacy, which require appropriate scientific investigation. Study type: Systematic review Comments: Only 3 human studies located and all of low methodological quality. N/A = not applicable; PRP = platelet-rich plasma; PRGF = plasma rich in growth factors Accident Compensation Corporation Page 27

28 Reference and study design HealthPACT (2012). "Autologous blood injection for soft tissue injury." Technology Brief; November 2012 Canada Included studies: RCTs Dojode 2010, Kazemi 2010, Wolf 2011, Lee 2007 Case series James 2007 Level of evidence: unclear Studies Intervention/comparison Results/effect size Conclusions Number of studies: N = 5 (4 RCTs, one case series) Total number of patients: n = 1416 (1416 RCT, 570 prospective cohort study) Inclusion criteria: not reported Exclusion criteria: not reported Databases used: not reported Description of the methodological assessment of studies: NHMRC levels of evidence Fixed or random effects: not applicable Heterogeneity: not tested Intervention studied: Autologous blood injection (ABI) Length of follow-up (range): 6 months for one RCT others unclear Description of comparison: corticosteroid Co-interventions: none stated Dojode 2012: ABI (n=30) vs. steroid injection (n=30) for lateral epicondylitis Mean VAS in steroid 1 & 4 weeks significantly less than in ABI group, then mean VAS for ABI group significantly less than steroid group at 12 weeks and 6 months Same pattern for Nirschl staging * p<0.05 Safety: More complained of increased pain after ABI compared to steroid injection (60% vs. 26%; p=0.009); local skin atrophy in 2 subjects after steroid injection and none in ABI group (p>0.05) Kazemi 2012: ABI (n=30) vs. steroid injection (n=30) for lateral epicondylitis All outcomes except limb function, grip strength & Nirschl score showed significant improvements for the ABI group at 4 weeks; at 8 weeks, all outcomes were significantly in favour of the ABI group The two studies comparing ABI to steroid injections in lateral epicondylitis found significantly better improvement in the ABI group, particularly at >1 month follow-up. No significant differences were observed between treatment groups in the study comparing ABI to steroid to saline injections. In addition, no significant differences were observed for ABI compared to steroid injection for chronic plantar fasciitis in one RCT. No conclusions can be drawn regarding the comparative effectiveness of ABI in patellar tendinosis as no comparative data was available. Moreover, no conclusions regarding the comparative effectiveness of ABI compared to other treatments including rest, NSAIDs, and physiotherapy can be made. Safety: No reported side-effects for either group Wolf 2011: ABI (n=10) vs. steroid (n=9) vs. saline injection (n=9) for lateral epicondylitis No significant differences between groups in DASH, PRFE pain, and VAS scores. Significantly better PRFE function score at 6 months in the saline injection group compared to the ABI group [p=0.048] Safety: not reported in this study Other studies: Accident Compensation Corporation Page 28 Lee 2007 RCT of ABI (n=30) vs. steroid injection (n=31) for

29 plantar fasciitis; no significant difference between the groups at 6 months; more people in the ABI group complained of pain post-injection (53% vs. 13%) James 2007 case series of 44 people with patellar tendinosis treated with ABI; subjective knee function scores significantly improved at follow-up Study type: Technology brief Comments: Limited number of studies reported. Likely selection bias. Limited search to ABI, lateral epicondylitis and plantar fasciitis alone. Important to note that steroid injection may not be the most appropriate comparator. ABI = autologous blood injection; NHMRC = National Health and Medical Research Council; VAS = visual analogue scale (for pain); PRFE = patient-related forearm evaluation; DASH = Disabilities of the Arm, Shoulder & Hand scale; NSAIDs = non-steroidal anti-inflammatory drugs Accident Compensation Corporation Page 29

30 Reference and study design Hoksrud, (2011). "Injectable agents derived from or targeting vascularity: has clinical acceptance in managing tendon disorders superseded scientific evidence?" Journal of Musculoskeletal Neuronal Interactions 11(2): Norway Included studies: PRP Peerbooms 2010, de Vos 2010, Filardo 2010, Gaweda 2010, Kon 2009, Mishra 2006 ABI Kazemi 2010, James 2007, Suresh 2006, Connell 2006, Edwards 2003 Sclerosing injections Sterkenburg 2010, Knobloch 2008, Zeisig 2008, Clementson 2008, Willberg 2008, Alfredson 2007, Hokrud 2006, Alfredson 2006,Lind 2006, Zeisig 2006, Alfredson 2005, Alfredson 2005, Ohberg 2003, Ohberg 2002 Level of evidence: 1+ Studies Intervention/comparison Results/effect size Conclusions Number of studies: N = 25 (6 PRP, 5 ABI, 14 sclerosing injections) Total number of patients: n = (n=143 for PRP; Inclusion criteria: Clinical trials of treatment of tendinopathies using sclerosing, PRP or ABI injections published in English Exclusion criteria: Animal studies, case reports Databases used: PubMed Description of the methodological assessment of studies: Coleman Methodology Score (originally developed for grading quality of clinical studies in patellar and Achilles tendinopathies) modified to include 9 items Fixed or random effects: not applicable Heterogeneity: in tendon affected, comparitor, follow-up duration, study quality and study design Intervention studied: PRP, ABI or sclerosing injections Length of follow-up (mean): 12 months (PRP); 8.5 months (ABI) Description of comparison:. steroid injection in two studies and saline injection in the other Co-interventions: eccentric exercise in one study Platelet-Rich Plasma (2 RCTs, 2 case-control, 2 case series) Peerbooms 2010: RCT of PRP (n=51) vs. steroid injection (n=49) in lateral epicondylitis 73% success rate (PRP) vs. 49% (steroid) at 12 months [significantly different] Coleman score (quality) 73/90 de Vos 2010: RCT of PRP (n=27) vs. saline injection (n=27) in Achilles tendinopathy; co-intervention of eccentric exercise in both groups both groups reported improvement in VISA-A score but no between-group differences at 24 weeks Coleman score 68/90 Filardo 2010: case-control study of PRP + physiotherapy (n=15) vs. physiotherapy alone (n=16) in patellar tendinopathy no group differences in EQ VAS or pain level; greater improvement in Tegner score in PRP group at 6 months Coleman score 47/90 Mishra 2006: case-control study of PRP (n=15) vs. local anaesthetic + adrenaline (n=5) for lateral epicondylitis significantly better outcomes in PRP group at 8 weeks on VAS & Mayo elbow score; further improvements in VAS & Mayo elbow scores at 6 & 25 months in PRP group [3 of 5 in control group dropped out] Coleman score 57/90 Gaweda 2010: case series of 14 people with Achilles tendinopathy significant improvement in both VISA-A & AOFAS scores at 18 months Coleman score 48/90 Authors' conclusions: PRP: " although most studies investigating the effect of PRP injection therapy on patients with tendinopathy have shown promising results, the two randomized controlled trials available appear to show conflicting results." ABI: " there is limited evidence available to assess the efficacy of autologous blood injection in tendinopathy." i.e. one RCT comparing ABI to steroid injection with only assessors blinded and limited follow-up of 8 weeks " although these therapies [ABI, PRP, or sclerosing injections]* seem to have received clinical acceptance in managing tendon disorders, it seems that their widespread use has superseded the available scientific evidence." Kon 2009: case series of 20 people with patellar tendinopathy treated with PRP injection significant improvement in both Tegnar & EQ VAS scores at 6 months Coleman score 47/90 Autologous blood injection (1 RCT, 4 case series) Accident Compensation Corporation Page 30 Kazemi 2010: single-blind RCT of ABI (n=30) vs. steroid injection (n=30)

31 for lateral epicondylitis all outcomes (VAS, Nirschl, grip strength & tenderness) significantly improved in ABI group compared to steroid group at 8 weeks Coleman score 68/90 James 2007: case series of 44 people with patellar tendinopathy treated with ABI VISA-P increased at ~15 months Coleman score 55/90 Suresh 2006: case series of 20 people with medial epicondylitis treated with ABI significant improvement in VAS & Nirschl scores at 10 months Coleman score 50/90 Connell 2006: case series of 35 people with lateral epicondylitis treated with ABI significant improvement in median VAS & Nirschl scores at 6 months Coleman score 62/90 Edwards 2003: case series of 28 people with lateral epicondylitis treated with ABI improvement in VAS & Nirschl scores at 9.5 months Coleman score 57/90 See full paper for details of sclerosing injection studies Study type: Systematic review with narrative synthesis Comments: Fair systematic review with likely selection bias (only used PubMed to search) of studies; clinical question not that clear; study quality was assessed but the validity of the score used is not known (and some commentators consider allocating a number as not very useful or valid). Narrative synthesis which is appropriate. Valid conclusions. Accident Compensation Corporation Page 31

32 Reference and study design Kazemi, (2010). "Autologous blood versus corticosteroid local injection in the short-term treatment of lateral elbow tendinopathy: a randomized clinical trial of efficacy." American Journal of Physical Medicine & Rehabilitation 89(8): Iran Level of evidence: 1- Study type: RCT Participants Intervention/comparison Outcome measure Results/effect size (ABI vs. steroid) Number of patients: n=60 Intervention: Autologous (n=30 ABI vs. n=30 steroid) blood injection (ABI) Pain severity within last 24 hrs 4 weeks: 2.7 vs. 4.5 [p=0.001] Inclusion criteria: patients with new episode of lateral elbow tendinopathy within a year before recruitment Exclusion criteria: Active or history of arthritis or related disease, previous operation or any steroid injection during the last 3 months Dropouts: none Follow-up: 8 weeks Relevant characteristics: Mean age: 47 yrs Gender: 18% male Duration: 1 month: 2 (ABI) vs. 0 (steroid) 1-2 months: 3 vs. 4 >2 months: 25 vs. 26 Dominant elbow: 19 vs. 17 Pain severity within last 24 hrs: 6.5 vs. 6.7 Limb function within last 24 hrs: 6.1 vs. 5.6 Pain in maximum grip: 7 vs. 7 Pressure pain threshold: 8.8 vs. 9.4 Maximum grip strength: 27.1 vs Modified Nirschl: 2.8 vs. 3.1 Quick DASH: 51.6 vs Setting: Secondary care Length of treatment: single injection of either intervention Comparison: Steroid injection Co-interventions: Both injections also contained lidocaine Limb function within last 24 hrs Pain in maximum grip Pressure pain threshold Maximum grip strength Modified Nirschl Quick DASH 8 weeks: 1.5 vs. 4 [p<0.001] 4 weeks: 3 vs. 3.4 [p=0.351] 8 weeks: 1.5 vs. 3.4 [p<0.001] 4 weeks: 3 vs. 4.7 [p=0.002] 8 weeks: 1.4 vs. 4.2 [p<0.001] 4 weeks: 14.4 vs [p=0.031] 8 weeks: 20.7 vs [p<0.001] 4 weeks: 41.2 vs [p=0.072] 8 weeks: 47.8 vs [p<0.001] 4 weeks: 1.5 vs. 1.9 [p=0.090] 8 weeks: 0.7 vs. 1.8 [p<0.001] 4 weeks: 21 vs [p=0.004] 8 weeks: 6.9 vs [p<0.001] Conclusions Authors' conclusion: "Autologous blood was more effective in short term than the corticosteroid injection." Reviewer's conclusion: At 8 weeks ABI appears more efficacious in terms of all outcomes compared to steroid injection. However, this study has a high risk of bias due to an inadequate randomisation method, no allocation concealment reported, and only the assessors being 'blind' to treatment allocation, so these results must be regarded cautiously. Comments: Randomisation technique poor. Allocation concealment not reported. Only assessors were 'blind'. No drop-outs, however 29% (23/83) refused to participate. ABI = autologous blood injection; DASH = Disabilities of the Arm, Shoulder & Hand outcome score Accident Compensation Corporation Page 32

33 Reference and study design Kiter, (2006). "Comparison of injection modalities in the treatment of plantar heel pain: a randomized controlled trial." Journal of the American Podiatric Medical Association 96(4): Turkey Level of evidence: 1+ Study type: RCT Participants Intervention/comparison Outcome measure Results/effect size (ABI vs. steroid vs. peppering) Number of patients: n=64 Mean VAS (pain) at 6 (n=15 ABI vs. n=15 steroid months: 2.4 vs vs. 2.0 vs. n=15 peppering technique) % improvement: 68 vs. 65 vs. 68% Inclusion criteria: adults with plantar heel pain where conservative treatment for at least 6 months had failed Exclusion criteria: steroid injection for heel pain in last year; inflammatory or severe metabolic disease; morbid obesity; lower limb deformity or functional deficit Dropouts: 6.7% (1/15) at 3 months from steroid group Follow-up: 6 months Relevant characteristics: Mean age: 50.7 (range yrs) Women: n=31 Mean duration symptoms: 19.3 months Previous treatment: only heel pads or NSAIDs Setting: Secondary care Interventions: 1. Autologous blood injection (ABI) 2. steroid injection 3. peppering technique (10 15 times through the tendon) Length of treatment: one injection of either ABI, steroid or dry needling (peppering technique) Co-interventions: local anaesthetic administered with either intervention; No significant difference Rearfoot score 80.9 vs vs No significant difference Repeat injection NB: steroid injections repeated at 1-month intervals Conclusions Author's conclusion: "In light of these considerations, we conclude that the peppering technique and autologous blood injection seem to be good alternatives to corticosteroid injection for the treatment of plantar heel pain, although the mechanism of cure is not completely understood." Reviewer's conclusion: Small RCT with three active treatment arms showing no significant difference between the groups in terms of pain & rearfoot score at 6 months. This may be a type II error and/or due to threats to internal validity i.e. no allocation concealment, only assessor 'blinded', different number of injections in each group Comments: Adequate randomisation method. Allocation concealment method not reported. Assessor 'blind' to treatment allocation. 7% (n=1) drop-out rate from steroid group. Per-protocol analysis. Chronic plantar fasciitis. No power calculation. Different numbers of injections given. VAS = visual analogue scale Accident Compensation Corporation Page 33

34 Reference and study design Krogh, (2012). "Comparative Effectiveness of Injection Therapies in Lateral Epicondylitis: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials." The American Journal of Sports Medicine. Denmark Included studies: Akermark 1995, Creaney 2011, Dogramaci 2009, Espandar 2010, Kazemi 2010, Lin 2010, Lindenhovius 2008, Newcomer 2001, Ozturan 2010, Peerbooms 2010, Petrella 2010, Plazek 2001, Price 1991a, Price 1991b, Scarpone 2008, Wong 2005, Zeisig 2008 Studies Intervention/comparison Outcome measure Results/effect size Conclusions Number of studies: N = 17 RCTs (4 for ABI or PRP) Total number of patients: n = 350 for the 4 ABI/PRP studies Inclusion criteria: RCTs of peri- or intra-tendinous injection therapies (in any dosage, volume, number of injections) compared to either placebo injection(s) or other active injection therapies for lateral epicondylitis in adults (> 18 yrs) in any language Exclusion criteria: Participants with a history of trauma or systematic inflammatory conditions Databases used: MEDLINE via PubMed, EMBASE via OVID, CINAHL via EBSCO, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic reviews (all up to June 2011) Intervention studied: any injection therapy for lateral epicondylitis Length of follow-up: Range 8-52 wks (ABI/PRP studies) Description of comparison: another autologous blood product or steroid (ABI/PRP studies) Co-interventions: not reported Pain intensity (change in pain score, pooled SD) NB: only ABI or PRP reported here see full paper for other injection therapies Creaney 2011 ABI vs. PRP vs (18.66) n= wks F/U Kazemi 2010 ABI vs. methylprednisolone vs (1.95) n=60 8 wks F/U Ozturan 2010 ABI vs. methylpredisolone vs (13.52) n=40 52 wks F/U Peerbooms 2010 PRP vs. triamcinolone vs (25.74) n= wks F/U NB: Only Peerbooms 2010 was assessed as having a low risk of bias Authors' conclusion: This systematic review and network meta-analysis of randomized controlled trials found a paucity of evidence from unbiased trials on which to base treatment recommendations regarding injection therapies for lateral epicondylitis. Level of evidence: 1+ Description of the methodological assessment of studies: Cochrane Collaboration's tool for assessing risk of bias Network meta-analysis (SMD, 95%CI) [see forest plot below] ABI n= (-2.15 to -0.71) PRP n= (-1.77 to -0.49) Fixed or random effects: not relevant Heterogeneity: not formally assessed Study type: Systematic review with network meta-analysis Comments: Network meta-analyses are a relatively new type of meta-analysis and certain methodological aspects are still poorly understood Small number of studies indentified for ABI/PRP. No RCTs of ABI/PRP vs. placebo. Only one RCT for ABI/PRP [Peerbooms 2010] was considered to be of low risk of bias. ABI, autologous blood injection; PRP, platelet-rich plasma; SD = standard deviation; CI = confidence interval; SMD = standardised mean difference; RCT = randomised controlled trial; F/U = followup Reference and study design Participants Intervention/comparison Outcome measure Results/effect size Conclusions Accident Compensation Corporation Page 34

35 Krogh, (2013). "Treatment of lateral epicondylitis [LE] with plateletrich plasma, glucocorticoid, or saline: a randomized, doubleblind, placebo-controlled trial." American Journal of Sports Medicine 41(3): Denmark Level of evidence: 1+ Number of patients: n=60 (20 PRP vs. 20 steroid vs. 20 saline injection) Inclusion criteria: LE* symptoms >3 months; definite sign of tendinopathy at common tendon origin on ultrasound with colour Doppler flow grade baseline; referrals from GPs or other rheumatology/orthopaedic departments *LE is defined as pain on lateral side of elbow & pain at lateral epicondyle on palpation and resisted dorsiflexion of wrist Exclusion criteria: age <18 yrs, steroid injection within last 3 months, previous tennis elbow surgery, inflammatory diseases (e.g. rheumatoid arthritis, inflammatory bowel disease), neck pain, ipsilateral shoulder pain, chronic widespread pain syndromes Dropouts: 34/60 (57%) at 6 months (50% PRP, 65% saline, 45% steroid), 44/60 (73%) at 12 months (60% PRP, 75% saline, 85% steroid) - all drop-outs were due to unsatisfactory effect Follow-up: 12 months Relevant characteristics: (mean) Age: 45.5 yrs Gender: 31 women (52%) BMI: 26.2 Duration: 23.1 months (3.8 to 232.7) Right side: 44 (73%) Dominant hand involved: 45 (75%) Smoking: 15 current (25%), 20 previous (33%), 25 never (42%) Previous treatment: 14 had 1 Intervention: platelet-rich plasma injection using a peppering technique or steroid injection Length of treatment: one injection of either PRP or steroid or saline Comparison: Saline injection using peppering technique Co-interventions: all subjects had a local anaesthetic injection into the peritendon of the common tendon origin guided by ultrasound; posttreatment protocol same for all participants i.e. reduce use of arm 3-4 days then gradually return to normal activities; standard tennis elbow stretching & training programme; if analgesia was needed, paracetamol was recommended Mean difference in pain 1 month (95%CI; p-value) Mean difference in pain 3 months (95%CI; p-value) Mean change in 1 month (95%CI; p-value) Mean change in 3 months (95%CI; p-value) Mean change in tendon thickness Mean change in colour Doppler (Grade 0-4) Any additional pain caused by injection itself (rating scale 0-10) Steroid vs. saline -8.1 ( to -1.9; p=0.011) PRP vs. saline 1.2 (-5.0 to 7.3; p=0.703) Steroid vs. PRP -9.3 (-15.4 to -3.2; p=0.003) Steroid vs. saline -3.8 (-9.9 to 2.4; p=0.229) PRP vs. saline -2.7 (-8.8 to 3.5; p=0.395) Steroid vs. PRP -1.1 (-7.2 to 5.0; p=0.717) Steroid vs. saline (-30.6 to -6.3; p=0.003) PRP vs. saline -1.8 (-14.0 to 10.4; p=0.770) Steroid vs. PRP (-28.8 to -4.5; p=0.008) Steroid vs. saline -6.2 (-18.4 to 5.9; p=0.310) PRP vs. saline -9.0 (-21.2 to 3.1; p=0.144) Steroid vs. PRP 2.8 (-9.4 to 14.9; p=0.649) Steroid vs. saline -0.8 (-1.2 to -0.5; p<0.0001) PRP vs. saline -0.3 (-0.7 to -0.01; p=0.044) Steroid vs. PRP -0.5 (-0.8 to -0.2; p=0.002) Steroid vs. saline -2.0 (-2.5 to -1.6; p<0.0001) PRP vs. saline 0.6 (0.2 to 1.0; p=0.007) Steroid vs. PRP -2.6 (-3.1 to -2.2; p<0.0001) Steroid vs. saline -1.0 (-12.5 to 10.5) PRP vs. saline Authors' conclusion: " Neither injection of PRP nor glucocorticoid was superior to saline with regard to pain reduction in LE at the primary end point at 3 months. However, injection of glucocorticoid had a shortterm pain-reducing effect at 1 month in contrast to the other therapies. Injection of glucocorticoid in LE reduces both color Doppler activity and tendon thickness compared with PRP and saline." Reviewer's conclusion: No significant difference in pain or function (as measured by PRTEE questionnaire) between PRP, steroid and saline injections for LE at three months follow-up. Results at 6 and 12 months not reported due to high dropout rates High drop-out rates due to unsatisfactory effect i.e. no or little improvement in symptoms PRP caused the most additional pain compared with saline and steroid No serious adverse events reported Accident Compensation Corporation Page 35

36 Study type: RCT injection (23%), 21 had > 1 injection (35%) Co-morbidity: not reported Setting: Secondary care Adverse events 2.0 (1.0 to 3.0) PRP vs. steroid 3.0 (1.5 to 4.5) No serious adverse events reported No infections at injection site One person in steroid group had a minor rash around injection site that resolved spontaneously Skin atrophy observed in 3 of the 20 patients in the steroid group Loss of pigmentation in one (who had had 2 previous steroid injections) Comments: Adequate randomisation method & allocation concealment. Subjects & assessors 'blind' to allocation. Treating physician not 'blind' to treatment allocation. Patient characteristics reported as being similar at baseline (not statistical analysis), however mean duration of symptoms was greater (36 months) in the steroid group than both the saline (16 months) & PRP groups (18 months). Very large drop-out rate at 6 & 12 months, hence the authors' have reported results to 3 months only. External validity: participants were selected from referrals to one Rheumatology department from GPs or other orthopaedic/rheumatology departments and therefore may have more severe LE than seen in primary care. PRP = platelet-rich plasma; LE = lateral epicondylitis; PRTEE = Patient-Related Tennis Elbow Evaluation questionnaire; 95%CI = 95% confidence interval Accident Compensation Corporation Page 36

37 Reference and study design Lee, (2007). "Intralesional autologous blood injection compared to corticosteroid injection for treatment of chronic plantar fasciitis. A prospective, randomized, controlled trial." Foot & Ankle International 28(9): Turkey Level of evidence: 1+ Participants Intervention/comparison Outcome measure Results/effect size (PRP vs. steroid) Number of patients: n=64 Intervention: Autologous (n=30 ABI vs. n=31 steroid) blood injection (ABI) Mean VAS (pain) Inclusion criteria: chronic proximal plantar fasciitis i.e. plantar heel pain, worse in morning &/or after sitting/lying, present >6 weeks; site of maximal tenderness was the attachment of the plantar fascia on medial tubercle of the calcaneus Exclusion criteria: previous surgery for heel pain; nerverelated symptoms; regional pain syndrome; Achilles pathology; Rheumatoid, diabetes, infection, metabolic disorder, peripheral vascular disease; pregnancy; knee, ankle, or foot dysfunction; work-related or compensable injury Length of treatment: one initial injection of either treatment; repeat injection offered at 6-week intervals if pain not entirely relieved Comparison: Steroid injection Co-interventions: local anaesthetic administered with either intervention; NSAIDs if required for not more than 3 days; ice packs if required for pain; standardised stretching programme for Achilles tendon and plantar fascia Baseline: 7.3 vs. 6.9 [p=0.306] 6 weeks: 4.6 vs. 2.9 [p=0.011] 12 weeks: 4.3 vs. 2.3 [p=0.005] 24 weeks: 3.6 vs. 2.4 [p=0.094] Conclusions Author's conclusion: "Intralesional ABI was efficacious in lowering pain and tenderness in patients with chronic plantar fasciitis. However, corticosteroid was superior in terms of speed and probably extent of improvement. We, therefore, believe that intralesional ABI, although not as effective as corticosteroid, could be used as a safe and effective second-line treatment alternative for chronic plantar fasciitis." Dropouts: 5% (3/64) at 6 months Follow-up: 6 months Relevant characteristics: (ABI vs. steroid) Mean age: 48.3 vs yrs (range yrs) Gender (M/F): 4/28 vs. 29/2 Weight: 66.0 vs kg BMI: 26.0 vs kg/m 2 Ankle dorsiflexion: 21.7 vs Calcaneal spur (Yes/No): 18/12 vs. 15/16 Duration symptoms: 7.2 vs. 8.3 months Setting: Secondary care Tenderness threshold (kg/cm 2 ) Baseline: 3.1 vs. 3.7 [p=0.167] 6 weeks: 4.1 vs. 6.4 [p=0.003] 12 weeks: 5.5 vs. 7.9 [p=0.003] 24 weeks: 6.5 vs. 8.6 [p=0.008] Accident Compensation Corporation Page 37

38 Second injection ABI: 10% (3/30) Steroid: 6.5% (2/31) All repeat injections given at 3 months after initial injection Adverse events No fat pad atrophy, infections, or rupture of the plantar fascia Post-injection pain that needed analgesia, ice, or both: ABI: 16 (53%) lasting 7 days Steroid: 4 (13%) lasting 5 days Study type: RCT Comments: Computer-generated randomisation. Allocation concealment method not reported. Assessor 'blind' to treatment allocation. 5% drop-out rate. Per-protocol analysis. Chronic plantar fasciitis. VAS = visual analogue scale; NSAID = non-steroidal anti-inflammatory drug Accident Compensation Corporation Page 38

39 Reference and study design Martin, (2011). "Platelet rich plasma in treating tendinopathies." Richmond, BC: WorksafeBC Evidence-Based Practice Group, Canada Included studies: : Mishra 2006 (case series), Randelli 2008 (case series), Sanchez 2007 (case control), Volpi 2007 (case series) Level of evidence: 1+ Studies Intervention/comparison Results/effect size Conclusions Number of studies: N = 4 Total number of patients: n = 49 Inclusion criteria: Human studies investigating the efficacy/effectiveness of PRP* on tendinopathies *search terms included plasma rich growth factor, autologous platelet gel, autologous platelet concentrate Exclusion criteria: Expert reviews; no primary data available; whole blood injection Databases used: MEDLINE, Embase, & BIOSIS (up to July 2009) and reference lists reviewed Description of the methodological assessment of studies: WorkSafeBC Evidence-Based Practice Group levels of evidence Fixed or random effects: not applicable Intervention studied: Platelet-rich plasma, autologous platelet concentrate/gel, or platelet-rich growth factor Volpi 2007: small case series (n=8) of athletes with chronic patellar tendinosis recalcitrant to conservative treatments; single injection of PRP with individualised rehab protocol; improvement of average VISA score from (pre-injection) to 75.0 at 120 days post-injection Randelli 2008: small case series (n=14) of application of autologous PRP and thrombin during arthroscopic rotator cuff repair in addition to standardised rehab protocol; at 2 yr followup 13 patients showed an average 4.6 point improvement in VAS (pain), 16 point increase in UCLA Shoulder rating scale, and a 30 point increase in Constant score Sanchez 2007: small case-control study compared the application of PRP during Achilles tendon repair in 6 athletes with 6 historical controls who had an Achilles tendon repair alone; the PRP group recovered full ROM earlier (7 wks vs. 11 wks) and returned to gentle running earlier (11 wks vs. 18 wks) Mishra 2006: a small case series* of 15 people with elbow tendinosis treated with PRP reported a 93% reduction in their VAS pain score at final follow-up (12-38 months post-injection) *NB: planned as a case-control but ended up as a case series due to drop-outs in control group (3/5 dropped out at 8 weeks) Addendum: de Vos 2010b a good quality RCT of 54 people with chronic Achilles tendinopathy treated with eccentric exercise + PRP injection (n=27) vs. eccentric exercise + saline injection (n=27) found no significant improvement in pain and activity as measured by VISA-A score To date, with regard to the efficacy/effectiveness of PRP in treating tendinopathies in humans, there is some low quality and low level evidence on the efficacy of PRP in treating tendinopathies. Tendon healing is a complex process in which many growth factors are involved, and their respective roles still need to be elucidated. There is some laboratory evidence that PRP contains a higher concentration of these growth factors that may play significant roles in tissue healing, including tendon healing, especially in traumatic tendon disruption. There is also some evidence showing the level/concentration of these growth factors in PRP varies depending on the protocol and the devices used to spin the blood. Heterogeneity: not reported Study type: Systematic review Comments: Four small studies with significant methodological concerns i.e. small numbers, no control group or control group was different from the intervention group, potential selection bias, no blinding. de Vos 2010b is probably the best available evidence on efficacy of PRP treating tendinopathy PRP = platelet-rich plasma; VAS = visual analogue scale; ROM = range of movement; VISA-A = Victorian Institute of Sports Assessment Achilles score Accident Compensation Corporation Page 39

40 Reference and study design NICE, (2013). "Autologous blood injection for tendinopathy." Interventional procedure guidance 438. UK Included studies: RCTs - Creaney 2011, Gosens 2011, de Jonge 2011, Kazemi 2010, Thanasas 2011 Case series Kon 2009, Edwards 2003, Suresh 2006 Other studies deemed relevant but were not included: Brown 2010, Connell 2006, de Vos 2011, de Vos 2010a, de Vos 2010b, Filardo 2010, Gaweda 2010, Gosens 2012, Ibrahim 2012, James 2007, Mishra 2006, Monto 2012, Omar 2012, Owens 2011, Ozturan 2010, Pearson 2012, Peerbooms 2010, Randelli 2011, Sampson 2011, Schepull 2011, Sheth 2012, Volpi 2010, Wolf 2011 Level of evidence: unclear Studies Intervention/comparison Summary of results (RCTs only) Conclusions Number of studies: N = 8 (5 RCTs, 3 case series) Total number of patients: n = 460 Inclusion criteria: clinical studies of autologous blood injection in people with tendinopathy, with outcomes relevant to safety and/or efficacy Exclusion criteria: Narrative reviews, editorial, or laboratory or animal study; no clinical outcomes reported; non-english Databases used: MEDLINE, PREMEDLINE, EMBASE, Cochrane library and other databases (from their commencement to Sept 2012); trial registries and the worldwideweb were also searched Description of the methodological assessment of studies: see Interventional Procedures Program methods guide for details (essentially a descriptive analysis of anything considered important to the study's validity recorded under 'comments' column in the evidence table) Fixed or random effects: not relevant Heterogeneity: not assessed Intervention studied: autologous blood injection for treatment of tendinopathy Length of follow-up (range): varied Description of comparison: CST, PRP, or saline injection Co-interventions: none stated Creaney 2011: refractory tennis elbow n=130 (60 ABI vs. 70 PRP) 'Success' (i.e. reduction in PRTEE score of 25) at 6 months: ABI=72% vs. PRP=66%; p=0.59 'Fail' (i.e. reduction in PRTEE score of <25): ABI=8% vs. PRP=24% Progression to surgery: ABI=20% vs. PRP=10% PRTEE score at 6 months: ABI=46.8 vs. PRP=35.8; reported as significant Gosens 2011 : elbow tendinopathy n=100 (51 PRP vs. 49 CST) 'Success' (reduction of 25% on VAS pain score without a reintervention after 2 years): PRP=76% vs. CST=43%; p< 'Failure' (reoperation or reintervention): PRP=12% vs. CST=29% [p-value not reported] Initial worsening of pain was observed in the PRP group de Jonge 2011 : chronic Achilles tendinopathy n=54 (27 PRP vs. saline 27) VISA-A: PRP=78 vs. saline=78 [reported as not significant] Satisfaction: 59% of both groups were satisfied Return to sport: PRP=57% vs. placebo=42% Neovascularistion: no significant difference between groups "No complications were reported between 24-week and 1-year follow-up" Kazemi 2010: lateral elbow tendinopathy n=60 (30 ABI vs. 30 CST) Symptom severity (as measured by DASH): ABI=21 vs. CST=32 [p=0.004] at 4 weeks and 6.9 vs [p<0.001] at 8 weeks Severity of symptoms at 8 weeks: ABI significantly less severe than CST on all measures e.g. pain at rest, grip strength, function etc Thanasas 2011: chronic lateral elbow epicondylitis n=28 (14 ABI vs. 14 PRP) The evidence on autologous blood injection for tendinopathy raises no major safety concerns. The evidence on efficacy remains inadequate, with few studies available that use appropriate comparators. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. this is the 2 year follow-up of Peerbooms Peerbooms JC, et al. Positive effect of an autologous platelet concentrate in lateral epicondylitis in a double-blind randomized controlled trial: platelet-rich plasma versus corticosteroid injection with a 1-year follow-up. Am J Sports Med 2010;38(2): this is the 1 year follow-up of de Vos 2010b15. de Vos RJ, et al. Platelet-rich plasma injection for chronic Achilles tendinopathy: a randomized controlled trial. Jama 2010b;303(2): Accident Compensation Corporation Page 40

41 VAS score improvement: ABI=2.5 vs. PRP=3.8 [p<0.05] at 6 weeks; no significant difference at 3 or 6 months Liverpool elbow score: no significant difference at 6 weeks, 3 or 6 months Local pain/discomfort: ABI=29% vs. PRP=64% Study type: Rapid review of literature See NICE guidance for the case series studies included Comments: Rapid review including 5 RCTs and 3 case series from the published literature. ABI = autologous blood injection; PRP = platelet-rich plasma; PRTEE = patient-related tennis elbow evaluation; CST = corticosteroid injection; VISA-A = Victorian Institute of Sports Assessment Achilles; DASH=Disabilities of the Arm, Shoulder & Hand scale Accident Compensation Corporation Page 41

42 Reference and study design Participants Intervention/comparison Outcome measure Results/effect size Conclusions Omar, (2012). Number of patients: n=60 (30 Intervention: Platelet-rich Lateral Epicondylitis with LE; 30 with PF) plasma (PRP) injection - in each group 15 were VAS Decreased by 4.3 in steroid allocated randomly to receive Length of treatment: one group and 4.2 in PRP group either PRP (n=15) or steroid injection of either PRP or injection (n=15) steroid DASH "Local injection of autologous platelet rich plasma and corticosteroid in treatment of lateral epicondylitis and plantar fasciitis: Randomized clinical trial." Egyptian Rheumatologist 34 (2): Egypt Level of evidence: 1- Inclusion criteria: patients with lateral epicondylitis (LE) or plantar fasciitis (PF) Exclusion criteria: local steroid injections or NSAID for the 4 weeks prior to the study; history of anaemia, thrombocytopaenia, or bleeding dyscrasia, 'significant' cardiovascular, renal, or hepatic disease, malignancy Additional exclusions for PF group: previous surgery for PF, vascular insufficiency or neuropathy associated with heel pain, hypothyroidism, diabetes Dropouts: none reported Follow-up: 6 weeks Relevant characteristics: Lateral Epicondylitis Mean age 37.5 (steroid) vs yrs (PRP) Male:Female 5:10 vs. 6:9 Plantar Fasciitis Mean age 44.5 (steroid) vs yrs (PRP) Gender all women Right heel affected 7 vs. 11 Comparison: Corticosteroid injection Co-interventions: panadol for pain if required Plantar Fasciitis VAS FHSQ Decreased by 37.1 (steroid) and 39.0 (PRP) p>0.05 for both comparisons Decreased by 2.3 (steroid) & 5.6 (PRP) p=0.001 Decreased by 12.5 (steroid) & 33.4 (PRP) p<0.001 Authors' conclusion: "Local injection of autologous PRP proved to be a promising form of therapy for TE and PF. It is both safe and effective in relieving pain and improving function and superior to local steroids in PF." Reviewer's conclusion: Poorly conducted RCT with high risk of bias due to inadequate description of randomisation, no reporting of allocation concealment and method of blinding. Study type: RCT Setting: secondary care (outpatient clinic) Comments: Method of randomisation not reported. Allocation concealment and 'blinding' not reported. Limited information about how similar the treatment & comparison groups are for both conditions. No power calculation. Small sample. PRP = platelet-rich plasma; LE = lateral epicondylitis; VAS = visual analogue scale; DASH = Disabilities of the Arm, Shoulder & Hand outcome score; FHSQ = foot health status questionnaire; Accident Compensation Corporation Page 42

43 NSAID = non-steroidal anti-inflammatory drug NB: all included patients had x-rays to exclude other pathology as a cause of their elbow or heel pain e.g. calcific tendinitis in the case of LE & calcaneal bony abnormalities in PF Accident Compensation Corporation Page 43

44 Reference and study design Ozturan, (2010). "Autologous blood and corticosteroid injection and extracoporeal shock wave therapy in the treatment of lateral epicondylitis." Orthopedics 33(2): Turkey Level of evidence: 1+ Participants Intervention/comparison Outcome measure Results/effect size (steroid vs. ABI vs. ESTW) Number of patients: n=60 Interventions: Mean improvement in Thomsen (n=20 ABI vs. n=20 steroid 1. Autologous blood injection provocative test vs. n=20 extracorporeal (ABI) [success = 50% decrease in shock therapy 2. Extracorporeal shock Thomsen test VAS value] therapy (ESWT) Inclusion criteria: adults >18 yrs with a history of lateral epicondylitis for at least 6 months; tenderness on palpation of lateral epicondyle; >40mm on the VAS after applying the Thomsen provocation test (see below) Exclusion criteria: Pregnancy; steroid injection for LA in previous 3 months; physical therapy in previous 3 months; NSAID or panadol in last week; cervical spondylosis; history of x-ray of upper extremity & elbow arthritis; rheumatological disease; severe systemic disease; neurological pathology like carpal tunnel or cubital tunnel syndromes or radila nerve entrapment; previous surgery or elbow dislocation Dropouts: 5% (3/60) 2 from ABI group and 1 from the ESWT group Follow-up: 52 weeks Relevant characteristics: (steroid vs. ABI vs. ESWT) Mean age: 45.8 vs. 44 vs. 47 Women: 10 vs. 11 vs. 11 Dominant arm affected: 15 vs. 14 vs. 15 Mean duration: 9.5 vs. 10 vs. 9.6 months Previous episodes: 7 vs. 6 vs. 8 Heavy workers: 7 vs. 3 vs. 2 Setting: Unsure likely secondary care Length of treatment: single injection of either steroid or ABI using a peppering technique; ESWT once a week for 3 weeks Comparison: Steroid injection Co-interventions: All had local anaesthetic injection to skin and subcutaneous tissue prior to injection or ESWT; panadol as required for pain after intervention Second injection of either ABI or steroid in 2 patients in steroid group and 14 in ABI group at 6 week point (those who did not have a 50% reduction in the Thomsen test VAS value) Mean improvement in upper extremity functional score Accident Compensation Corporation Page 44 4 weeks: 58.5 vs vs Significantly greater improvement in steroid group compared to ABI and ESWT groups [p<0.001 for both comparisons] No significant difference between ABI & ESWT [p>0.05] 12 weeks: 46.5 vs vs No significant difference between any group [p>0.05] 26 weeks: 33.5 vs vs Significantly greater improvement in both ABI & ESWT groups compared to steroid [p<0.001 for both comparisons] No significant difference between ABI & ESWT [p>0.05] 52 weeks: 34.5 vs vs Significantly greater improvement in both ABI & ESWT groups compared to steroid [p<0.001 for both comparisons] No significant difference between ABI & ESWT [p>0.05] 4 weeks: 28.2 vs vs Steroid group significantly better improvement than either of ABI or ESWT [p<0.001 for each] No significant difference between ABI & ESWT [p>0.05] 12 weeks: 26 vs vs No significant difference between any group [p>0.05] 26 weeks: 19.5 vs vs Significant improvement in both ABI and ESWT compared to steroid [p<0.05 Conclusions Authors' conclusion: "Treatment with corticosteroid injection provided a high success rate in the short term. However, autologous blood injection and extracorporeal shock wave therapy gave better long-term results, especially considering the high recurrence rate with corticosteroid injection." Reviewer's conclusion: Both ABI and ESWT improved pain and function in people with LE significantly better than steroid injection at 1 yr follow-up. At one year follow-up, ESWT improved grip strength significantly better than steroid injection. Note that at 4 weeks steroid improved pain, function and grip strength significantly more than either ESWT & ABI. By 12 weeks, all treatments were not significantly different.

45 & p=0.001 respectively] No significant difference between ABI & ESWT [p>0.05] Mean improvement in maximal grip strength 52 weeks: 19.1 vs vs Significant improvement in both ABI and ESWT compared to steroid [p<0.001 for both] No significant difference between ABI & ESWT [p>0.05] 4 weeks: vs. 2.4 vs. 3.3 Improvement in steroid group was significantly greater than ABI or ESWT groups [p<0.05 for both] No significant differences between ABI and ESWT group [p>0.05] 12 weeks: 8.8 vs. 6.8 vs. 7 No significant differences in improvement between any group [p>0.05] 26 weeks: 3.7 vs. 6.3 vs. 7.3 Significantly greater improvement in steroid group compared to ESWT group [p<0.05] No significant differences between ABI and steroid or ESWT group [p>0.05] Adverse events 52 weeks: 3.4 vs. 6.1 vs. 9.7 Significantly better improvement in ESWT group compared to steroid group [p<0.05] No significant differences between ABI and steroid or ESWT groups [p>0.05] All patients in all groups reported temporary pain after treatment Study type: RCT Comments: Randomisation & allocation concealment method not reported. Blinding not reported. More heavy workers in steroid group (25% compared to 16% & 10% in other groups). On-treatment analysis. No placebo arm. ABI = autologous blood injection; ESWT = Extracorporeal shock therapy; VAS = visual analogue scale Thomsen provocation test = performed with the shoulder flexed at 60, the elbow extended, the forearm pronated, and the wrist extended to 30. Pressure was applied on the dorsum of the hand. Accident Compensation Corporation Page 45

46 The test was performed 3 times, with the patient recording the pain on a 100-mm visual analogue scale (VAS). The mean of the 3 measurements was recorded. Accident Compensation Corporation Page 46

47 Reference and study design Pearson, (2012). "Autologous blood injection to treat Achilles tendinopathy? A randomized controlled trial." Journal of Sport Rehabilitation 21(3): New Zealand Level of evidence: 1- Participants Intervention/comparison Outcome measure Results/effect size Conclusions Number of patients: n= 33 participants (with 40 injured Achilles tendons; n=20 ABI, n=20 control) Inclusion criteria: Clinical diagnosis of mid-portion Achilles tendinopathy* duration of at least 3 months *activity-related pain of gradual or semi-acute onset, postinactivity stiffness, and tenderness, swelling, and nodularity localised to mid-tendon Exclusion criteria: diagnostic uncertainty, concurrent insertional pathology, anticoagulant therapy, systemic disease that may contribute to pathology; being an elite sportsperson; having received any injection therapy for the tendon within the last 3 months Dropouts: 30% (12/40) Follow-up: 12 weeks Relevant characteristics: (ABI vs. control) Mean age: 49 vs. 51 yrs Men: 8 vs. 7 Duration: 13 vs. 9 months Right side: 9 vs. 10 Bilateral tendinopathy: n=7 (all women) Baseline VISA-A: 54 vs. 52 Setting: Private sports medicine clinic Intervention: Autologous blood injection (ABI) + eccentric strengthening programme Length of treatment: One ABI with option for another at 6 weeks (10 of 18 had extra injection) Comparison: Eccentric strengthening programme Co-interventions: Participants were permitted to continue non-surgical treatments already initiated except for taking NSAIDs Mean change in VISA-A score (95%CI) Side-effects 6 weeks: ABI: 7.7 (1.0 to 14.4) Control: 8.7 (-0.1 to 17.5) 12 weeks: ABI: 18.9 (11.5 to 26.3) Control: 9.4 (0.4 to 18.4) 21% (6/28) rated post-injection 'flare' as severe No infections or tendon ruptures reported Authors' conclusion: "There is some evidence for small short-term symptomatic improvements with the addition of autologous blood injection to standard treatment for Achilles tendinopathy, although double-blinded studies with longer followup and larger sample size are required." Reviewer's conclusion: Authors' used a "magnitude-based clinical inference" to analyse findings. However, the lower confidence interval of 'treatment minus control' for baseline to 12 weeks [see graph] crosses line of no effect i.e. '0' therefore cannot rule out chance effect. This coupled with the significant risk of bias (no allocation concealment or blinding, a variable number of injections administered, and a high drop-out rate) means that the findings of this study need to interpreted very cautiously. There is unlikely to be any added benefit of using autologous blood injection(s), in terms of improvement in pain and function, over and above that of the eccentric exercise for Achilles midportion tendinopathy. Study type: RCT Comments: Method of randomisation adequate. Allocation concealment lacking. Participants & investigators not blind to allocation. 30% drop-out rate. Per-protocol analysis. Variable number of Accident Compensation Corporation Page 47

48 injections (treatment) given. In the 7 people with bilateral tendinopathy, one tendon was used as the control. Other co-interventions not reported. 95%CI = 95% confidence interval; NSAIDs = non-steroidal anti-inflammatory drugs Accident Compensation Corporation Page 48

49 Reference and study design Rabago, (2009). "A systematic review of four injection therapies for lateral epicondylosis: prolotherapy, polidocanol, whole blood and platelet-rich plasma." British Journal of Sports Medicine 43(7): USA Included studies: Zeisig 2008, Zeisig 2006, Scarpone 2006, Glick 2008, Lyftogt 2007, Edwards 2003, Connell 2006, Gani 2007, Mishra 2006 Level of evidence: 1+ Studies Intervention/comparison Results/effect size Conclusions Number of studies: N = 9 (3 RCTs, one CCT, 5 prospective case series) Total number of patients: n = 208 Inclusion criteria: human clinical studies of any design assessing prolotherapy, polidocanol, whole blood and platelet-rich plasma injections for lateral epicondylosis Exclusion criteria: not stated Databases used: MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, Allied and Complementary Medicine (to 2008); reference lists of identified studies were also reviewed Description of the methodological assessment of studies: RCT strength assessed by Delphi controlled trial internal validity criteria (see below); overall evidence grade was assigned based on the SORT criteria (see below) Fixed or random effects: not relevant Heterogeneity: not formally assessed Intervention studied: Prolotherapy, polidocanol, autologous whole blood, or platelet-rich plasma injections for treatment of lateral epicondylitis Length of follow-up (range): 6 weeks to 9 months approximately Description of comparison: local anaesthetic or saline injection in the RCTs Co-interventions: local anaesthetic or exercise/stretching Accident Compensation Corporation Page 49 Polidocanol Zeisig 2008 RCT (n=16); polidocanol vs. lidocaine + adrenaline; control group offered polidocanol after 12 wks; no difference between groups in pain score, grip strength or satisfaction; Delphi score 9/9 Zeisig 2006 case series (n=11); pain, grip strength, structural defect, & degree of vascularity all improved at 12 & 35 wks; mean subject satisfaction 83%; Delphi score N/A Prolotherapy Scarpone 2008 RCT (n=24); prolotherapy injection (dextrose + sodium morrhuate) vs. saline injection at 0, 4 & 8 wks; significantly more pain improvement in treatment group compared to control at 16 wks [p<0.001]; better improvement in isometric strength at 16 wks [p<0.01] in the treatment group ; Delphi score 8/9 Glick 2008 RCT (n=8); prolotherapy injection vs. saline injection at 0, 3, & 6 wks; both groups employed athome stretching; McGill pain questionnaire improved more in prolotherapy group [p=0.086]; physical composite score of SF-36 improved more in prolotherapy group [p=0.05] ; Delphi score 7/9 Lyftogt 2007 case series (n=29); prolotherapy weekly (+ modified daily activity) for mean 8 wks; final follow-up at mean 19 months; pain improved compared to baseline; Delphi score N/A ABI Edwards 2003 case series (n=28); one to three ABIs + local anaesthetic; splint/motion restriction then stretching; 79% (22/28) were pain free at 9.5 months; both mean pain & Nirschl score improved by 71% & 69% respectively; Delphi score N/A Connell 2006 case series (n=35); two to three ABIs; significant improvement in both Nirschl and VAS scores at 6 months; Delphi score N/A Ul Gani 2007 case series (n=26); one to two ABIs; significant improvement in both Nirschl and pain scores at 8 months; Delphi score N/A PRP Mishra 2006 case series (n=15)*; PRP (n=10) vs. local anaesthetic (n=5); PRP showed better improvement in pain & Mayo score than control at 4 & 8 weeks; 93% of subjects satisfied; Delphi score 5/9 *NB: planned as a case-control but ended up as a case series due to drop-outs in control group (3/5 dropped out at 8 weeks) Authors' conclusions: There is strong pilot-level evidence supporting the use of prolotherapy, polidocanol, autologous whole blood and platelet-rich plasma injections in the treatment of lateral epicondylitis. Rigorous studies of sufficient sample size, assessing these injection therapies using validated clinical, radiological and biomechanical measures, and tissue injury/healing-responsive biomarkers, are needed to determine long-term effectiveness and safety, and whether these techniques can play a definitive role in the management of LE and other tendinopathies. Reviewer's conclusion: Only 3 RCTs located: 2 for prolotherapy and one for polidocanol. All of the rest are case series (NB: one is a case-control study with a high risk of bias with 3/5 of the control group dropping out of the study at 8 wks) which at best are hypothesis generating, not conclusive evidence of efficacy. Evidence statements for the 4 therapies are as follows: Limited evidence from 3 small case series that ABI may improve pain & function in lateral epicondylitis. Insufficient evidence from one poorly conducted casecontrol study that PRP may improve pain & function in

50 SORT recommendation: Polidocanol 2B Prolotherapy 1B ABI 3C PRP 2B lateral epicondylitis. There is evidence from one RCT that polidocanol was not more effective in the treatment of lateral epicondylitis than local anaesthetic + adrenaline injection. This conflicts with a small case series that found polidocanol improved pain & grip strength. Two small RCTs found that prolotherapy improved pain and function more than saline injections. One small case series supports this finding. Delphi controlled trial internal validity criteria (all answered with Yes/No/Don t know) 1. Treatment allocation a) Was a method of randomization performed? b) Was the treatment allocation concealed? 2. Were the groups similar at baseline regarding the most important prognostic indicators? 3. Were the eligibility criteria specified? 4. Was the outcome assessor blinded? 5. Was the care provider blinded? 6. Was the patient blinded? 7. Were point estimates and measures of variability presented for the primary outcome measures? 8. Did the analysis include an intention-to-treat analysis? Strength of Recommendation Taxonomy (SORT) Strength of recommendation: A = Recommendation based on consistent and good-quality patient-oriented evidence* B = Recommendation based on inconsistent or limited-quality patient-oriented evidence* C = Recommendation based on consensus, usual practice, opinion, disease-oriented evidence,* or case series for studies of diagnosis, treatment, prevention, or screening. Quality of individual studies: Level 1 good quality patient-oriented evidence = SR/meta-analysis of RCTs with consistent findings, or high-quality individual RCT, or all-or-none study Level 2 limited quality patient-oriented evidence = SR/meta-analysis of lower-quality clinical trials or of studies with inconsistent findings, or lower quality clinical trial, or cohort study, or case-control study Level 3 other evidence = consensus guidelines, extrapolations from bench research, usual practice, opinion, disease-orientated evidence (intermediate or physiologic outcomes only), or case series for studies of diagnosis, treatment, prevention, or screening Consistency: Consistent = Most studies found similar or at least coherent conclusions (coherence means that differences are explainable) or, If high-quality and up-to-date systematic reviews or meta-analyses exist, they support the recommendation Inconsistent = Considerable variation among study findings and lack of coherence, or If high-quality and up-to-date systematic reviews or meta-analyses exist, they do not find consistent evidence in favour of the recommendation * Patient-oriented evidence measures outcomes that matter to patients: morbidity, mortality, symptom improvement, cost reduction, and quality of life. Disease-oriented evidence measures intermediate, physiologic, or surrogate end points that may or may not reflect improvements in patient outcomes (e.g., blood pressure, blood chemistry, physiologic function, pathologic findings). High-quality RCT: allocation concealed, blinding if possible, intention-to-treat analysis, adequate statistical power, adequate follow-up (greater than 80 percent). In an all-or-none study, the treatment causes a dramatic change in outcomes, such as antibiotics for meningitis or surgery for appendicitis, which precludes study in a controlled trial. Study type: Systematic review Accident Compensation Corporation Page 50

51 Comments: Small number of studies located. Generally well-conducted systematic review with a narrative evidence synthesis. Conclusions are perhaps over-stated SORT = Strength of Recommendation Taxonomy; CCT, non-randomised clinical trial; RCT, randomised controlled trial; ABI, autologous blood injection; PRP, platelet-rich plasma; VAS, visual analogue scale; LA = local anaesthetic; N/A = not applicable Accident Compensation Corporation Page 51

52 Reference and study design Rha, (2013). "Comparison of the therapeutic effects of ultrasound-guided platelet-rich plasma injection and dry needling in rotator cuff disease: a randomized controlled trial." Clinical Rehabilitation 27(2): South Korea Level of evidence: 1+ Participants Intervention/comparison Outcome measure Results/effect size Conclusions Number of patients: n= 39 (n=20 PRP vs. n=19 dry needling) Inclusion criteria: >6 months shoulder pain; pain on VAS >5/10; painful arc &/or impingement sign; no weakness in rotator cuff muscles; supraspinatus tendon disease (tendinosis or partial thickness tear <1 cm on U/S; no or little response to conservative therapy for at least 3 months Exclusion criteria: other obvious rotator cuff pathology e.g. rheumatic diseases, fracture; referred pain from neck; previous surgery neck/shoulder; NSAID in last 2 weeks &/or steroid injection within 6 weeks; hypersensitivity to lidocaine; presence of unstable medical condition or uncontrolled systemic disease; any situations or conditions that may place the patient at significant risk during the study Dropouts: 23% (9/39) at 6 months 20% (4/20) for PRP arm 26% (5/19) for dry needling arm Follow-up: 6 months Relevant characteristics: (PRP vs. dry needling) Mean age: 52.2 vs yrs (range yrs) Gender (M/F): 9/11 vs. 8/11 Side affected (R/L): 6/14 vs. 6/13 Duration pain: 9.6 vs. 9.2 Intervention: Platelet-rich plasma (PRP) under U/S guidance into lesion in the supraspinatus or infiltrated around lesion Length of treatment: 2 PRP injections or dry needling twice with one month between injections Comparison: Dry needling (40-50 times through the tendon under U/S guidance) Co-interventions: local anaesthetic administered to supraspinatus tendon prior to PRP or dry needling; panadol or hydrocodone as required after injection; "selfexercise and posture correction" allowed during study Shoulder Pain & Disability Index No significant differences between PRP and dry needling groups at 0, 2 or 4 weeks Significant improvement in Index at 6, 12, & 24 weeks [p<0.05] "No significant difference between the 2 groups when the total pain score & total disability score were analysed separately" Improvement in Shoulder Pain & Disability Index Time 0 = first injection Time 1 = 2 weeks after 1st injection Time 2 = 4 weeks after 1st injection (second injection) Time 3 = 6 weeks after 1st injection Time 4 = 12 weeks after 1st injection Time 5 = 24 weeks after 1st injection Range of motion Internal rotation of the shoulder improved more at 12 weeks for PRP group compared to dry needling [p<0.05] Flexion of the shoulder improved more at 12 & 24 weeks for PRP group compared to dry needling [p<0.05] No significant differences at any time for external rotation or abduction of shoulder between PRP and dry needling groups Author's conclusion: " In conclusion, according to our double-blind, randomized, controlled study, platelet-rich plasma injections provided more significant pain relief and improved arm function, but not range of motion of the shoulder, in patients with supraspinatus tendon lesions (tendinosis or partial tear of less than 1.0 cm, but not a complete tear) when compared to dry needling." Accident Compensation Corporation Page 52

53 months Partial tears: n=15 Setting: Secondary care Adverse events Modest pain reported for an average of 3.3 days after PRP injection (range 1-10 days) and 4.1 days (range 2-10 days) for dry needling No long-term complications or serious adverse effects related to either procedure Study type: RCT Improvement at 6 months In PRP group: 2 partial tears improved to tendinosis, and 2 tendinosis improved to normal status In dry needling group: one tendinosis improved to normal status Comments: Randomisation and allocation concealment method adequate. Patients & assessor 'blind' to treatment allocation. High drop-out rate. Per-protocol analysis. People with chronic supraspinatus tendinosis or partial-thickness supraspinatus tendon tear. Small study. No power calculation. VAS = visual analogue scale; U/S = ultrasound; NSAID = non-steroidal anti-inflammatory drug; Accident Compensation Corporation Page 53

54 Reference and study design Sadoghi, (2013). "The role of platelets in the treatment of Achilles tendon injuries." Journal of Orthopaedic Research 31(1): USA Included studies: Human - de Jonge 2011, de Vos 2010b, Sanchez 2007, Schepull 2011 Animal - Aspenberg 2004, Lyras 2009a, Lyras 2009b, Lyras 2011, Sarrafian 2010, Suwalski 2010, Virchenko 2006a, Virchenko 2006b, Zhang 2003 Level of evidence: 1- Studies Intervention/comparison Outcome measure Results/effect size Conclusions Number of studies: N = 13 ***** (4 human studies and 9 animal studies) Total number of patients: n=92 human subjects in 4 studies Inclusion criteria: Reported on the use of platelets in Achilles tendon treatments, in either humans or animals, in a controlled trial; all types of treatments were admitted, but there had to be a defect or injury model. There was no limitation for follow-up duration. Exclusion criteria: Studies on PRP use in healthy tendons were not eligible, neither were longitudinal or cohort studies. Databases used: PubMed, MEDLINE, Embase, CINAHL, CENTRAL and CDSR (up to June 2010); handsearched bibliographies of included studies Description of the methodological assessment of studies: modified Jadad scale Fixed or random effects: not reported Intervention studied: Platelet concentrates including PRP Length of follow-up (range): 12 to 52 wk Description of comparison: saline injection Co-interventions: not reported VISA-A score (WMD; 95%CI) de Jonge ( wk 0.90 ( wk 6.60 ( wk de Vos 2010b ( wk 1.20 ( wk NB: Sanchez 2007 and Schepull 2011 were not included in the meta-analysis Poorly conducted systematic review: 1. Results from more than 1 time-point for each study have been combined in the metaanalysis {unit-of-analysis error) 2. the 2 studies used in the meta-analysis are the same study with different follow-up periods 3. other results were biomechanical outcomes in animal studies Authors' conclusion: "The key finding of our study is evidence in support of a statistically significant effect of platelet concentrates in the treatment of Achilles tendon ruptures in vivo in animal models and human application, consistent with a medium to large sized effect. This effect is most likely attributable to fastened and enhanced scar tissue maturation. There was no evidence for a beneficial effect of platelets in Achilles tendinopathy." Heterogeneity: I 2 statistic Study type: Systematic review with meta-analysis Comments: Poorly conducted systematic review CENTRAL = Cochrane Central Register of Controlled Trials; CDSR = Cochrane Database of Systematic Reviews; PRP = platelet-rich plasma; VISA-A = Victorian Institute of Sports Assessment Achilles; WMD = weighted mean difference; 95%CI = 95% confidence interval ***** 13 studies were published in 14 papers Accident Compensation Corporation Page 54

55 Accident Compensation Corporation Page 55

56 Reference and study design Sheth, (2012). "Efficacy of autologous platelet-rich plasma use for orthopaedic indications: a metaanalysis." Journal of Bone & Joint Surgery - American Volume 94(4): Canada Included studies: RCTs Cervellin 2011, Vogrin 2010, Nin 2009, Orrego 2008, Sys 2011, Tsai 2009, Feiz-Erfan 2007, D'Elia 2010, Dallari 2007, Savarino 2006, Lee 2007, Kiter 2006, Casticini 2011, Randelli 2011, Horstmann 2010, Peerbooms 2009, Schepull 2011, de Vos 2010, Peerbooms 2010, Zavadil 2007, Thomas 2009, Calori 2008, Everts 2008 Prospective Cohort Figueroa 2010, Radice 2010, Silva 2009, Hartmann 2010, Jenis 2006, Kalaci 2009, Jo 2011, Mishra 2006, Everts 2007, Filardo 2009 Level of evidence: 1++ Studies Intervention/comparison Outcome measure Results/effect size Conclusions Number of studies: N = 33 (23 RCTs, 10 prospective cohort studies) Total number of patients: n = 1416 (1416 RCT, 570 prospective cohort study) Inclusion criteria: published or unpublished RCTs & prospective cohort studies of PRP or similar product compared with a control (e.g. placebo, corticosteroid, or a standard procedure) in patients with orthopaedic injuries; English Exclusion criteria: none stated Databases used: MEDLINE & Embase (1996 & 1947, respectively, up to July 2011); handsearched annual meetings of 3 professional bodies; consulted experts; reference lists reviewed; PubMed "related articles" feature Description of the methodological assessment of studies: Detsky scale (RCTs), Newcastle-Ottawa scale (PCSs), & GRADE used to evaluate quality of available evidence Intervention studied: Plateletrich plasma, autologous blood injection, autologous platelet concentrate, autologous conditioned plasma, osteoinductive gel, plateletleukocyte gel, autologous platelet-derived growth factor, or platelet gel Length of follow-up (range): 5 days to 2 years Description of comparison: placebo, corticosteroid, or a standard procedure Co-interventions: none stated Pooled standardised mean difference (SMD) of visual analogue scale (VAS) - pain N=6 RCTs N=3 PCSs N=3 plantar fasciitis Imaging outcomes N=3, solid spinal fusion at 1 yr N=3, low MRI signal intensity (ACL autograft) SMD= 0.34 (95%CI, 0.75 to 0.06; p=0.10; I 2 = 70%) SMD = 0.20 (95%CI, 0.64 to 0.23; p=0.36; I 2 = 0%) SMD = 0.41 (95%CI, 0.01 to 0.83; p=0.05; I 2 = 33%) RR=1.06 (95%CI, 0.93 to 1.22; p=0.33; I 2 = 0%) RR=0.76 (95%CI, 0.50 to 1.15; p=0.19; I 2 = 0) In conclusion, current evidence is insufficient to discern whether autologous blood concentrates provide a clinical benefit in the treatment of orthopaedic conditions. Large and carefully designed randomized clinical trials are needed to draw definitive conclusions on the potential risks and benefits of autologous blood concentrates, such as platelet-rich plasma, in orthopaedics. Fixed or random effects: random-effects model Heterogeneity: I 2 statistic Study type: Systematic review with meta-analysis Comments: Well conducted systematic review. Arguable whether a meta-analysis was appropriate, particularly because of the presence of considerable heterogeneity. Possible publication bias. Accident Compensation Corporation Page 56

57 Reference and study design Taylor, (2011). "A systematic review of the use of platelet-rich plasma in sports medicine as a new treatment for tendon and ligament injuries." Clinical Journal of Sport Medicine 21(4): Canada Included studies: Banfi 2006, Mishra 2006, Maniscalco 2008, Randelli 2008, Sanchez 2007, Sanchez 2009, Orrego 2008, Silva 2009, Nin 2009, Kon 2009, Peerbooms 2010, de Vos 2010, Gaweda 2010 Level of evidence: 1+ Studies Intervention/comparison Results/effect size Conclusions Number of studies: N = 13 (4 RCTs, one CCT, one casecontrol, 5 case series, 2 case reports) Total number of patients: n = 1416 (362 RCT, 40 CCT, 12 case-control, 68 case series) Inclusion criteria: Englishlanguage articles of in vivo application of PRP in tendon and ligament injuries Exclusion criteria: nonhuman studies and articles that related to sports medicine; studies where additional cell types e.g. bone marrow were combined with PRP Databases used: Pubmed/MEDLINE & Embase (up to Sept 2010); handsearched reference lists of included papers Description of the methodological assessment of studies: not reported Fixed or random effects: not applicable Heterogeneity: not reported Intervention studied: Platelet-rich plasma Length of follow-up (range): 1 day to 2 years Description of comparison: placebo, corticosteroid, or a standard procedure Co-interventions: none stated Elbow Tendinopathy: Mishra 2006 case series (n=15)*; PRP (n=10) vs. local anaesthetic (n=5); PRP showed better improvement in pain, Mayo score than control at 4 & 8 weeks Peerbooms 2010 RCT; PRP injection (n=51) vs. corticosteroid injection (n=49); improvement in VAS in 73% PRP group and 49% steroid group at 1 year; improvement in DASH in 73% PRP group and 51% steroid group at 1 year *NB: planned as a case-control but ended up as a case series due to drop-outs in control group (3/5 dropped out at 8 weeks) Achilles Tendon Repair: Sanchez 2007 case-control; PRP (n=6 cases) vs. conventional repair (n=6 historical controls); time to full ROM, gentle running, & training all less in PRP group (7 vs. 11 wks; 11 vs. 18 wks; 14 vs. 22 wks respectively); 14 wks to return to pre-injury scores in PRP group vs. 22 wks for controls Sanchez case reports; thickening of tendon in 1 case on MRI; both returned to their sport Achilles Tendinopathy: de Vos 2010 (chronic) RCT; eccentric exercise + PRP (n=27) vs. eccentric exercise + saline injection (n=27); no significant difference in VISA-A score at 24 weeks follow-up Gaweda 2010 (non-insertional) case series (n=14); AOFAS score and VISA-A scale both improved at 18 months; normalisation of peri-tendon and tendon thickening on ultrasound Patellar Tendinopathy: Kon 2009 case series (n=20); Tegner score, EQ-VAS, & SF-36 all improved at 6 months Banfi 2006 laboratory case series (n=5); 4 patella & 1 elbow); VEGF & EGF serum concentration changed; no change in any other cytokine Authors' conclusion: Despite some benefits demonstrated to date, it must be acknowledged that the uses of PRP in soft tissue applications are still weakly supported. Inferences regarding the potential benefits and safety of this new therapy must consider the low number of studies, low sample numbers, and levels of evidence. Accident Compensation Corporation Page 57 ACL Reconstruction: Orrego 2008 RCT; ACL reconstruction alone (control, n=27) vs. ACL reconstruction + PRP (n=26) vs. ACL reconstruction + bone plug (n=28) vs. ACL reconstruction + PRP + bone plug (n=27); no differences were found among the groups regarding MRI maturation criteria at 3 months; at 6 months, 78% of controls vs. 100% of the PRP group had a lowintensity signal [p=0.036], tunnel widening occurred in

58 41% of controls vs. 11% of bone plug group [p=0.047] Silva 2009 CCT (n=40); ACL repair alone (n=10) vs. repair + PRP in femoral tunnel (n=10) vs. repair + PRP in femoral tunnel + intra-articular PRP (n=10) vs. repair + PRP + thrombin (n=10); no difference between the groups on MRI Nin 2009 RCT; arthroscopic patellar tendon allograft ACL reconstruction + PRP (n=50) vs. arthroscopic patellar tendon allograft ACL reconstruction alone (n=50); no difference in IKDC score, inflammatory parameters or MRI appearance between the groups Study type: Systematic review Rotator Cuff Repair: Maniscalco 2008 case report; reduction in pain & improvement in ROM at 6 months Randelli 2008 case series (n=14); VAS, UCLA & Constant scores all improved at 24 months; 3 subjects had an 'excellent' outcome and the rest a 'good' outcome according to UCLA score Comments: Reasonable systematic review but limited by lack of RCTs, small numbers in studies,& lack of relevant comparators. PRP = platelet-rich plasma; ACL = anterior cruciate ligament; ROM = range of movement; RCT = randomised controlled trial; CCT = controlled clinical trial; AOFAS, American Orthopaedic Foot and Ankle Society; DASH, disabilities of the arm, shoulder and hand score; ELISA, enzyme-linked immunosorbent assay; EQ-VAS, EuroQol visual analogue scale; IKDC, International Knee Documentation Committee; MRI, magnetic resonance imaging; PDUS, power Doppler ultrasonography; ROI, region of interest; SF 36, Short Form (36) Health Survey; UCLA, University of California at Los Angeles; VISA-A, Victorian Institute of Sports Assessment-Achilles. Accident Compensation Corporation Page 58

59 Reference and study design Thanasas, (2011). "Platelet-rich plasma versus autologous whole blood for the treatment of chronic lateral elbow epicondylitis: a randomized controlled clinical trial." American Journal of Sports Medicine 39(10): Greece Level of evidence: 1+ Participants Intervention/comparison Outcome measure Results/effect size (PRP vs. ABI) Number of patients: n=28 Intervention: Platelet-rich (n=14 PRP vs. n=14 ABI) plasma (PRP) injection Inclusion criteria: clinically diagnosed chronic lateral epicondylitis (LE) of duration 3 months; no history of trauma; no previous injection therapy of any kind; no history of rheumatic disorder; no signs of posterior interosseous nerve entrapment Exclusion criteria: recent onset (<3 months); history of trauma; medical comorbidities like rheumatic arthritis, previous local injection therapy; suspicion of nerve entrapment Dropouts: 1 from ABI group 6 month follow-up Follow-up: 6 months Relevant characteristics: Mean age 36.6 vs yrs (ABI vs. PRP) Male/female 11/3 vs. 10/5 Dominant arm 13 vs. 11 Duration 5.1 vs. 4.7 months Office/Labour/Housekeeping 8/2/4 vs. 7/1/6 Setting: Unclear Length of treatment: one injections of either ABI or PRP with peppering technique Comparison: Autologous blood injection (ABI) Co-interventions: panadol and ice therapy for pain as required; in addition, advised to refrain from heavy labour for 1 week; reassurance one week after injection plus programme of stretching and eccentric exercise (2x daily for 5 weeks) Change in VAS-pain score PRP vs. ABI (95%CI) [p-value] Group A = ABI Group B = PRP Change in Liverpool elbow score PRP vs. ABI (95%CI) [p-value] 6 weeks: 3.8 ( ) vs. 2.5 ( ) [p<0.05] 3 months: 4.2 ( ) vs. 3.2 ( ) [p=0.11] 6 months: 4.4 ( ) vs. 3.4 ( ) [p=0.32] 6 weeks: 2.02 ( ) vs ( ) [p=0.45] 3 months: 2.17 ( ) vs ( ) [p=0.45] 6 months: 2.3 ( ) vs ( ) [p=0.53] Conclusions Authors' conclusion: "Regarding pain reduction, PRP treatment seems to be an effective treatment for chronic LE and superior to ABI in the short term [at 6 weeks]." Reviewer's conclusion: No significant difference in improvement in pain when comparing PRP with ABI in chronic LE at 3 & 6 months. Statistically significant better improvement in pain at 6 weeks for PRP injection compared to ABI. Study type: RCT Comments: Block randomisation. Allocation concealment not reported. Single blind i.e. assessors 'blind' to treatment allocation. Power calculation. All subjects given programme of eccentric exercise/stretching. PRP = platelet-rich plasma; ABI = autologous blood injection; 95%CI = 95% confidence interval; VAS = visual analogue scale Accident Compensation Corporation Page 59

60 Reference and study design Vetrano, (2013). "Platelet-Rich Plasma Versus Focused Shock Waves in the Treatment of Jumper's Knee in Athletes." American Journal of Sports Medicine 41(4): Italy Level of evidence: 1+ Participants Intervention/comparison Outcome measure Results/effect size (PRP vs. ESWT) Number of patients: n= 46 Intervention: Platelet-rich (n=23 PRP vs. n=23 ESWT) plasma (PRP) Inclusion criteria: established diagnosis* of chronic jumper's knee (at the insertion of the patellar tendon at lower pole of the patella) for at least 6 months and failure of nonoperative treatment; nonoperative treatment had to be 12 weeks before start of this study; aged yrs; athletic participants involved in various sports, both elite and non-elite *confirmed by ultrasound Length of treatment: 1 PRP injection per week for 2 weeks (under ultrasound guidance); 3 sessions of ESWT at 48- to 72-hour intervals Comparison: Extracorporeal shockwave therapy (ESWT) Co-interventions: one week after last treatment session, all participants were given a standardised stretching and strengthening protocol VISA-P (mean, SD) [p value] 2 month: 76.2 (16.5) vs (19.1) [p=0.635] VAS (load-induced pain) 6 month: 86.7 (14.2) vs (19.9) [p=0.014] 12 month: 91.3 (9.9) vs (19.9) [p=0.026] 2 month: 3.2 (1.8) vs. 3.9 (1.9) [p=0.360] 6 month: 2.4 (1.9) vs. 3.9 (2.3) [p=0.028] 12 month:1.5 (1.7) vs. 3.2 (2.4) [p=0.009] Conclusions Author's conclusion: "Both PRP injections and ESWT are safe and effective in the treatment of athletes with jumper s knee. The analysis showed comparable results in both treatment groups at short term, with better results in the PRP group at 6 and 12 months of follow-up." Exclusion criteria: bilateral complaints; signs/symptoms of other coexisting knee lesions; knee surgery or steroid injections to knee in past 3 months; systemic disorders; therapy with anticoagulants; pregnancy Dropouts: 4% (2/46) at 12 months Follow-up: 12 months Relevant characteristics: (PRP vs. ESWT) Mean age: 26.9 vs yrs Men: 20 (87%) vs. 17 (74%) Duration: 18.9 vs months Left knee: 12 (52%) vs. 12 (52%) Previous treatments: CO 2 laser 8 s. 5 Tecar therapy 19 vs. 16 Ultrasound 3 vs. 5 Exercise 21 vs. 22 NSAIDs 9 vs. 12 Sport activity: elite 18 vs. 18 non-elite 5 vs. 5 Sport involved: Modified Blazina scale Response to treatment (% satisfactory results) Side effects No significant between-group differences at 2- and 6-months Significantly better results in treatment group (PRP) compared to ESWT at 12 months [p=0.015] 2 month: 47.8% vs. 43.4% [p=0.767] 6 month: 82.6% vs. 65.2% [p=0.314] 12 month:91.3% vs. 60.8% [p=0.035] "No clinically relevant side effects were seen in either group" Accident Compensation Corporation Page 60

61 basketball 11 vs. 12 volleyball 11 vs. 9 soccer 1 vs. 2 Setting: Secondary care Study type: RCT Comments: Randomisation method adequate. Allocation concealment not reported. Only assessor was 'blind' to treatment allocation. Unclear but either no drop-outs or very low drop-out rate of 4% (2/46). No power calculation. 'Athletic' participants only. NSAIDs = non-steroidal anti-inflammatory drugs; VISA-P = Victorian Institute of Sports Assessment-Patella questionnaire; SD = standard deviation Accident Compensation Corporation Page 61

62 Reference and study design Wolf, (2011). "Comparison of autologous blood, corticosteroid, and saline injection in the treatment of lateral epicondylitis: a prospective, randomized, controlled multicenter study." Journal of Hand Surgery - American Volume 36(8): USA Level of evidence: 1+ Participants Intervention/comparison Outcome measure/results/effect size (saline vs. ABI vs. steroid) Number of patients: n=28 DASH scores (n=9 saline vs. n=10 ABI vs. n=9 steroid) Inclusion criteria: consecutive adult patients with clinically diagnosed lateral epicondylitis (LE) who had not been treated with an injection for LE in the previous 6 months Exclusion criteria: history of surgery on lateral side of elbow, compressive neuropathy, inflammatory arthritis or autoimmune disease or chronic regional pain syndrome Dropouts: 6/34 (18%) 3 did not return after injection and 3 dropped out after the 2 week assessment Follow-up: 6 months Relevant characteristics: Mean age: 49 yrs (range 34-64) Setting: Secondary care (2 centres) Interventions: 1. Autologous blood injection (ABI) 2. Steroid injection Length of treatment: one injection of either ABI, steroid, or saline with peppering technique Comparison: Saline injection Co-interventions: I ml lidocaine in each of the injections; subjects given a standard sheet of stretching exercises; one subject out of each group requested reinjection at 2 months assessment they were given either steroid or ABI after discussion with the treatment physician and remained in their original groups (intention-to-treat analysis) No significant differences for the DASH scores among the groups [p=0.188] PRFE pain score No significant differences for the DASH scores among the groups [p=0.147] PRFE function score Conclusions Authors' conclusion: " In this prospective, randomized, controlled trial, autologous blood, corticosteroid, and saline injection [sic] provide no advantage over placebo saline injections in the treatment of lateral epicondylitis. Patients within each injection group demonstrated improved outcome scores over a 6-month period." Reviewer's conclusion: No additional benefit of ABI, steroid or saline injection in terms of improvement in pain or function for LE over and above that of eccentric exercise at 6 months (except functional scores on PRFE significantly better for saline compared to ABI at 6 months.) These results are possibly due to the study being under-powered i.e. a Type II error. In addition, there is a high risk of bias in this trial due to questions of representativeness (only 64% of those approached consented to take part in the trial), allocation Accident Compensation Corporation Page 62

63 concealment not reported, a drop-out rate of 18% and treating physician not being blind to the treatment allocation. Significantly better for saline compared to ABI at 6 months [p=0.048] No significant differences between saline & steroid groups [p=0.170] or between ABI & steroid groups [p=0.944] VAS pain score No significant differences among the groups [p=0.511] Study type: RCT Comments: 74 consecutive patients were asked to enroll in this study and only 35 (64%) consented. Small study. Randomisation & allocation concealment methods were adequate. Allocation concealment not reported. Patients & assessors 'blind' to treatment allocation. Moderate drop-out rate (18%). On-treatment analysis. Power calculation done but study is likely to be underpowered as a large effect size was assumed. ABI = autologous blood injection; DASH = Disabilities of the Arm, Shoulder & Hand outcome score; PRFE = Patient rated Forearm Evaluation questionnaire Accident Compensation Corporation Page 63