CADTH Health Technology Review

Platelet-Rich Plasma Injections for Chronic Tendinopathies in the Lower Extremities

Rapid Review

Authors: Sara D. Khangura, Sharon Bailey

Key Messages

• Findings from systematic reviews describing comparative clinical evidence for platelet-rich plasma injections (PRPis) in the treatment of chronic tendinopathies of the lower extremities were mixed.

• The systematic reviews we identified were often unclear concerning the components or treatment protocols used in the administration of PRPi, which may have contributed to the lack of a clear demonstration of effect.

• The variety of patient populations, comparisons, and outcomes in the included systematic reviews may also have contributed to the mixed findings.

• The lack of a clear demonstration of the comparative clinical effectiveness of PRPi in chronic tendinopathies of the lower extremities does not currently support decision-making in favour of its use.

Research Question

What is the clinical effectiveness of platelet-rich plasma injections (PRPis) for the treatment of adults with chronic tendinopathies in the lower extremities?

Context and Policy Issues

What Are Chronic Tendinopathies in the Lower Extremities?

Chronic, or persistent, tendinopathy is a common disorder that is characterized by pain and loss of function,¹ and has been described as accounting for 30% of musculoskeletal conditions.² Chronic tendinopathies represent a range of conditions, based on the location of the affected tendon, with chronic tendinopathies of the lower extremities occurring in the hip (e.g., gluteus), knee (e.g., patella), Achilles, and/or plantar fascia.^3-5 Chronic tendinopathies of the lower extremities can cause pain, swelling, and can interfere with the activities of daily life (including performance in exercise and sport), as well as quality of life.²

Causes of chronic tendinopathies may vary, but they are often believed to be the result of overuse^1,6 and/or impaired healing of an injury.^2,7,8 Risk factors for developing chronic tendinopathy include intrinsic factors, such as age and previous injury, and extrinsic factors, such as exposure to high-intensity exercise.¹

What Are PRPis?

Platelet-rich plasma (PRP) is a biologic treatment derived from blood products, and containing concentrated growth factors, which are thought to reduce inflammation and promote healing.^2,9 PRP has been described as a general term for therapy lacking standardization in its composition and administration.¹⁰

Multiple treatments are available for chronic tendinopathies — including those of the lower extremities — with conservative therapies including physiotherapy and/or systemic pharmacotherapy for pain.^3,11,12 Other nonsurgical treatments include injection therapies that may be used following more conservative therapies, such as local anesthetic, corticosteroid, dry needling, or PRPis.^6,13 While PRPi are not thought to be curative, it has been hypothesized that pain and function may be improved in response to their administration.¹³ PRPi has also been described as 1 of the most widely studied biologic therapies and can be used in surgical or nonsurgical settings.¹⁴ Nonetheless, PRPi has also been described as a costly intervention, incurring greater expense versus comparable therapies,¹⁵ and is not always reimbursed by payers or insurers.¹⁶

Why Is It Important to Do This Review?

The incidence of chronic tendinopathies, in general, has been on the rise and is thought to be associated with greater participation in recreational exercise and sports among middle-aged individuals.¹ While no Canadian data on the incidence or prevalence of chronic tendinopathies in the lower extremities were identified, a survey of Canadian adults indicated the knee and leg as the third and fourth most common sites of chronic pain.¹⁷ Notably, it has been suggested that tendinopathies of the lower extremities may respond differently to treatment than those of the upper extremities, based on factors associated with the central nervous system.³

Current recommendations for the nonsurgical management of chronic tendinopathies include physiotherapy and nonsteroidal anti-inflammatory drugs. Other treatment options, including PRPi, have been described as alternative treatments with limited evidence demonstrating clinical efficacy,^3,10 and making decisions concerning the use of PRPi in chronic tendinopathies of the lower extremities challenging.

In 2019, Health Canada clarified its classification of PRP as a drug, confirming its distinction from cell therapies.¹⁸ Nonetheless, concern has been raised about this classification, which renders PRP broadly available in Canada despite the purported lack of evidence demonstrating its effectiveness.¹⁹

Objective

To support decision-making about the use of PRPi in chronic tendinopathies of the lower extremities, we conducted this review to summarize recent, available evidence describing its clinical effectiveness.

Methods

Literature Search Methods

An information specialist conducted a literature search on key resources, including MEDLINE, Embase, the Cochrane Database of Systematic Reviews, the International HTA Database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search approach was customized to retrieve a limited set of results, balancing comprehensiveness with relevancy. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. Search concepts were developed based on the elements of the research questions and selection criteria. The main search concepts were PRPis and tendinopathies. Conference abstracts were excluded. Retrieval was limited to the human population. The search was completed on May 8, 2023, and limited to English-language documents published since January 1, 2018.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first screening level, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Table 1: Selection Criteria

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, were duplicate publications, or were published before 2018. Reports of acute tears and other injuries in which the tendon did not remain intact were interpreted as distinct from chronic tendinopathies and were therefore excluded.¹ Studies reporting PRPi comparisons with “alternative interventions” (i.e., not considered usual care), local anesthetic injections, whole blood injections, radiation, stem cell therapy, extracorporeal shockwave therapy and hyaluronic acid injection, as well as studies reporting no comparator (i.e., single-arm studies), were excluded. SRs in which all relevant studies were captured in other more recent or more comprehensive SRs were also excluded.

Critical Appraisal of Individual Studies

The included publications were critically assessed by 1 reviewer using the A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2)²⁰ for SRs, with additional considerations applied to overviews of reviews. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 408 citations were identified in the literature search. Following screening of titles and abstracts, 341 citations were excluded and 67 potentially relevant reports from the electronic search were retrieved for full-text review. There were no potentially relevant publications retrieved from the grey literature search for full-text review. Of these potentially relevant articles, 58 publications were excluded for various reasons, and 9 publications met the inclusion criteria and were included in this report. These comprised 1 overview of systematic reviews²¹ and 8 SRs.^22-29 Appendix 1 presents the PRISMA³⁰ flow chart of the study selection.

Additional references of potential interest are provided in Appendix 6.

Summary of Study Characteristics

This review identified and summarized 1 overview of SRs²¹ and 8 SRs.^22-29 Characteristics of included reviews are tabulated and detailed in Appendix 2.

Eight of the 9 reviews were broader in scope than the eligibility criteria for the current review^21-23,25-29 and so, only the subset of 37 unique included studies that were relevant to this report were summarized. Of the relevant included primary studies in the SRs, there was considerable overlap, which is characterized in a matrix presented in Appendix 5. In cases of overlap, the most comprehensive and/or recently published SRs were selected to inform the summary of relevant primary studies.

The included overview of SRs was conducted in the US and published in 2020, with a search that spanned database inception to February 2020.²¹ The 8 included SRs were conducted in India,^23,25 Italy,^22,29 China,^24,27 UK,²⁶ and Poland,²⁸ and were published between 2018 and 2023 with search time frames that ranged from 1966 (or database inception) to December 2022, when reported.^22-29

Patient populations included those with chronic tendinopathies of the hip,^23,26 patella,^25,28 Achilles,^21,23,24 and plantar fascia,^22,27,29 with ages either not reported^21,24,28 or with mean age ranging between 19 years and 62 years.^{22,23,25-27,29} All of the reviews reported on comparative investigations of PRPi versus a variety of comparators, including saline or placebo injections,^{21,24,25,28,29} steroids (either administered by injection or with mode of administration NR),^22,26,27,29 dry needling,^23,25,29 and/or physiotherapy (PT).²⁵

Outcomes included measures of function, including the Victorian Institute of Sports Assessment (VISA) with versions specific to the Achilles (VISA-A) or patella (VISA-P),^21,25 Foot Function Index (FFI),^22,28,29 or the American Orthopedic Foot and Ankle Society (AOFAS) score.²⁹ Pain was reported by the 8 SRs, all of which described the use of the visual analogue scale (VAS) for measurement.^22-29 Three SRs described composite measures (combining function, pain, and other measures), including the VISA-Achilles (VISA-A),²⁴ Harris Hip Score (HHS),²⁶ and AOFAS score.²⁷ Other outcomes included a return to exercise and/or sport,²⁴ patient satisfaction,²⁴ quality of life (QoL),²⁵ and adverse events.^25,27 Two SRs did not specify all outcomes that were measured; rather only provided the names of the measures that were used,^23,29 including the VISA^23,29 and the Foot and Ankle Ability Measurement (FAAM);²⁹ for these unspecified outcomes, the VISA was interpreted as a composite measure and the FAAM was interpreted as a measure of function in this report. One SR did not report on all of the measure(s) that were used, describing only the outcome; that is, pain.²³ Follow-up of outcomes ranged from between 1 week to 24 months in the 8 included SRs,^22-29 but was not reported in the overview of SRs.²¹

Summary of Critical Appraisal

Reporting

All of the included reviews provided some description of their inclusion criteria;^21-29 however, 3 reviews did not describe either the establishment of an a priori method or development of a review protocol.^21,26,29 A preestablished method is important for informing the conduct of reviews and allows readers to assess any protocol deviations that could introduce a risk of bias to the findings of the review.²⁰ The rationale for limiting inclusion of study designs was either not reported or not explicitly stated by the 8 included SRs,^22-29 whereas the overview of SRs did describe an implicit rationale for limiting included studies to SRs.²¹

Included studies were described in sufficient detail by 1 SR,²⁵ while some information describing the intervention and/or comparator(s) (e.g., number of injections, dose, frequency) was missing in 7 reviews.^21-24,26-28 Two reviews had information missing on either the outcomes measured (i.e., including only the outcome measure without a description of what was being measured) or the measures used.^23,29 One SR described patient satisfaction but did not provide detail as to how this outcome was measured, or what precisely was being measured.²⁴

Three of the included SRs reported their funding sources,^24,27,28 and 4 reported that no funding was received to support the conduct of the review.^21,23,25,26 Two reviews did not report any information about source(s) of funding.^22,29 This information is important for assessing any potential conflict of interest or risk of bias introduced by funding source(s).

Finally, the overview of SRs reported an analysis of overlap between primary studies in its included SRs.²¹

Search Strategy

While all of the included reviews performed searches in 2 or more relevant databases,^21-29 and all but 1²¹ reported the search keywords used,^22-29 only 1 SR described consultation with an expert biomedical librarian in the development of the search strategy.²³ A comprehensive search should draw from the expertise of an information specialist or scientist to ensure that the strategy uses adequate search terms and is sufficiently sensitive and specific.²⁰ And while search time frames were clearly and explicitly reported by 4 of the included reviews,^21,23,24,27 5 SRs did not clearly or completely report the dates of the search(es) conducted.^{22,25,26,28,29}

Review Methods

Study selection was performed by 2 independent reviewers in 7 included reviews,^21,23-27,29 whereas 2 reported no information on the number of reviewers that performed study selection.^22,28 Five reviews reported that data abstraction was performed by 2 independent reviewers,^{21,22,25,26,29} and 4 of them either reported no information on the number of reviewers who completed data abstraction, or reported that it was performed by 1 reviewer.^23,24,27,28 Similarly, while risk of bias (RoB) assessments were reported by all of the 9 included reviews summarized in this report,^21-29 and 2 independent reviewers performed the assessments in 8 included reviews,^21-23,25-29 1 SR did not describe whether the assessments were performed in duplicate or not.²⁴ Duplicate study selection, data abstraction and RoB assessment are important features of a robust method that reduce the risks of error and bias in the review.²⁰

Appropriate statistical methods were described for carrying out meta-analyses by 6 of the 7 SRs that performed them,^22,24-27,29 whereas 1 did not describe methods in detail.²⁸ For the 7 reviews that performed quantitative syntheses, 2 described assessment of the risk of publication bias,^22,24 though, none provided a description of the potential impact of publication bias on the findings of the reviews.^22,24-29

Heterogeneity between the included studies and its potential impact on the findings of the review was reported in sufficient detail by 3 of the included reviews,^26,27,29 while 6 made a cursory mention of heterogeneity and/or did not describe its potential impact on the review findings.^21-25,28

Additional details regarding the strengths and limitations of included reviews are provided in Appendix 3.

Summary of Findings

Clinical Effectiveness of PRPIs

Function

Measures of function were reported by 5 reviews, with 1 describing tendinopathy of the Achilles,²¹ 2 describing knee tendinopathies^25,28 and 2 describing plantar fasciitis.^22,29 Generally, findings describing function were mixed, with most findings describing no difference between PRPi and comparators, some indicating that PRPi was superior to comparators, and 1 reporting that saline injections were superior to PRPi.^{21,22,25,28,29}

The overview of SRs reported on function of the Achilles tendon, and found no difference between PRPi and saline groups at an unspecified duration of follow-up (1 SR with 4 randomized controlled trials [RCTs], 170 patients; Table 6).²¹

Of the 2 SRs reporting on function of the knee, 3 relevant RCTs were described (Table 6):

• There were no statistically significant differences in VISA-P scores between PRPi and dry needling at short-term (8 to 12 weeks) or 6 month follow-up (1 RCT with 19 patients).²⁵

• PRPi compared to saline injections showed mixed results.^25,28

  • One RCT found no statistically significant difference in VISA-P scores of 38 patients at short-term (8 to 12 weeks) or 6 months follow-up, but reported a statistically significant improvement in the control group at 1 year of follow-up.²⁵

  • One RCT included 36 patients and found a statistically significant improvement in VISA scores in the PRPi group at 6 months of follow-up.²⁸

Of the 2 SRs reporting on function in plantar fasciitis (based on 5 RCTs), neither provided supporting data, and mixed conclusions were observed (Table 6):

• PRPi was described as more effective than saline or dry needling for improving function (2 RCTs with 150 patients).²⁹

• PRPi was described as either no different than steroids (1 RCT with 79 patients²² and 1 RCT with 30 patients²⁹), or more effective than steroids for improving function (1 RCT with 80 patients).²⁹

Pain

Eight SRs reported on pain.^22-29 Two of the 8 included SRs described pain in chronic tendinopathies of the hip,^23,26 2 in the knee,^25,28 2 in the Achilles tendon,^23,24 and 3 in plantar fasciitis.^22,27,29 Overall, findings describing pain were mixed, with most describing no difference between PRPi and control groups, some indicating that PRPi was superior to comparators, and 1 reporting that dry needling was superior to PRPi.^22-29

Of the 2 SRs describing chronic tendinopathy of the hip, findings from 1 RCT²³ and a meta-analysis (MA) of 2 RCTs²⁶ were reported (Table 7):

• One RCT compared PRPi to dry needling in 30 patients, reporting both interventions as “equally effective” at reducing pain at up to 2 weeks of follow-up (i.e., specific timing was not specified).²³

• An MA of 2 RCTs comparing PRPi to steroids in 124 hips found no statistically significant difference in pain scores between groups at 2 to 6 months of follow-up.²⁶

Of the 2 SRs describing pain in chronic tendinopathy of the knee, findings from 2 RCTs and 1 nonrandomized study (NRS),^25,28 were reported (Table 7):

• One RCT compared PRPi to dry needling in 19 patients, reporting a statistically significant improvement in pain scores in the control group at 6 months of follow-up.²⁵

• One NRS compared PRPi to PT in 31 patients, reporting no statistically significant differences between groups at short-term (i.e., 8 to 12 weeks) or 6 months of follow-up.²⁵

• Another RCT compared PRPi to saline in 36 patients, reporting a statistically significant improvement in pain scores for those who received PRPi at 6 months of follow-up.²⁸

Of the 2 SRs describing pain in chronic tendinopathies of the Achilles, findings from 1 RCT²³ and 4 MAs of 3 RCTs²⁴ were reported (Table 7):

• One RCT of 84 patients comparing PRPi and dry needling showed that VAS scores were numerically similar between groups; however, study authors concluded that PRPi was slightly superior to dry needling for reducing pain, particularly in younger patients.²³

• The MAs of 3 RCTs comparing PRPi to placebo in 93 patients found:

  • no statistically significant differences between groups in pain scores at 6 weeks or 6 months of follow-up

  • a statistically significant improvement in pain scores for patients who received PRPi at 3 months of follow-up, as well as in a combined MA of data across all 3 follow-up time points (reported as 279 patients).²⁴

Of the 3 SRs describing pain in plantar fasciitis, findings from 4 RCTs,^22,29 and 2 MAs,^27,29were reported (Table 7):

• One RCT and both MAs reported no differences in pain between PRPi and steroids,^22,27 whereas another RCT found an improvement in patients who received PRPi as compared to steroids²⁹

• One SR concluded (without providing supporting data) that there was an improvement in patients who received PRPi as compared to the following:

  • dry needling in 30 patients at 3 months of follow-up (1 RCT)

  • saline in 120 patients at 6 months of follow-up (1 RCT).²⁹

Composite Measures

Composite measures were reported by 5 SRs with 1 describing chronic tendinopathy of the hip,²⁶ 2 the Achilles tendon,^23,24 and 2 plantar fasciitis^27,29 (Table 8). Overall, findings were mixed, with several demonstrating no effect of PRPi, some indicating a clinical improvement in patients who received PRPi and 1 reporting a comparative improvement in patients receiving steroids.

• There was a statistically significant improvement in a composite measure of function, pain and range of motion in hips that received PRPi as compared to steroids at a follow-up of 2 to 6 months (MA of 3 primary studies; 124 hips).²⁶

• Whereas 1 RCT in 1 SR reported a “marginal improvement” in VISA-A scores in patients with Achilles tendinopathy who received PRPi as compared to dry needling (no statistical testing reported),²⁴ another SR indicated there were no statistically significant differences between PRPi or placebo in VISA-A scores (4 MAs of 6 to 8 RCTs).²³

• The SRs describing a comparison of PRPi with steroids^27,29 in plantar fasciitis, reported the following:

  • no statistically significant difference was observed between groups in AOFAS scores (MA of 5 RCTs; 356 patients)²⁷

  • a statistically significant improvement in the AOFAS scores of the control group (MA of 3 RCTs; 252 patients)²⁷ and that PRPi was “more effective,” as measured by VISA scores, than steroids (1 RCT; 80 patients) (data not provided).²⁹

Return to Exercise and/or Sport

For patients with chronic tendinopathy of the Achilles, there were no statistically significant differences in return to exercise and/or sport between PRPi and placebo at 2 to 46 weeks of follow-up (1 SR with MA of 4 RCTs; Table 9).²⁴

Patient Satisfaction

For patients with chronic tendinopathy of the Achilles, there were no statistically significant differences in patient satisfaction between PRPI and placebo at 2 to 48 weeks of follow-up (1 SR with MA of 4 RCTs, 222 patients; Table 10).²⁴

Quality of Life

For patients with chronic tendinopathy of the knee, there were no statistically significant differences in QoL between PRPi and the control group at 8 to 12 weeks or 6 months of follow-up (1 SR with MA of 1 RCT and 1 NRS; Table 11).²⁵ Of note, the 2 primary studies included in the MAs used different QoL measures (EQ-VAS and SF-12) and different comparators (i.e., dry needling and PT).²⁵

Adverse Events

Of the 2 SRs reporting on adverse events,^25,27 findings from 3 primary studies in 1 SR²⁵ and 5 RCTs in the other²⁷ indicated that no adverse events were observed in either the PRPi or comparator groups^25,27 (Table 12).

Limitations

The literature describing PRPi treatment in chronic tendinopathies of the lower extremities is ample, with a broad variety of conditions, treatment protocols, comparators, and outcomes described. Two of the key limitations identified in this review of the literature on this topic included SRs describing primary studies with small sample sizes and variable findings, as well as a lack of clarity and standardization in the reporting and descriptions of interventions, comparators, outcomes, and measures.

The overview of SRs included in this report identified 1 unique SR of relevance to this report that summarized 4 RCTs describing 170 patients (with no detail on the sample sizes of each of the RCTs described).²¹ The 8 SRs identified and summarized in this report included 36 unique primary studies of relevance,^22-29 with 7 of these SRs including primary studies with sample sizes ranging between 19 and 120 patients,^22-25,27-29 and 1 SR reporting a range of 20 to 80 hips (rather than patients as the unit of analysis).²⁶ The expanding number of primary research studies with small sample sizes and effect sizes has been identified as a challenge to decision-making about optimal approaches to its use in other papers, as well,¹⁵ corroborating the findings of this review.

A lack of clarity in the description of chronic tendinopathies in the literature was observed, with broad references to tendinopathies, diseases or disorders often leaving it unclear as to whether the condition(s) being described were chronic or acute, for instance. This made the interpretation of some of the literature on this topic challenging and unclear as it concerned the populations of interest.

Variability in reporting was also a limitation identified in this review; for instance, authors of 1 included SR acknowledged that PRPi is described inconsistently in the literature, making interpretation of the composition of the intervention (e.g., leukocyte concentration) and treatment protocols challenging, and creating the potential to produce variable findings.²⁶ In this report, inconsistency was observed in the description of the use of PRPi, with several reviews not reporting on key features of the intervention, such as number(s) of injections, dose(s), frequency of injections, and/or intervals between multiple injections.^21-23,26-28 Similarly, comparator arms of relevant primary studies were not described sufficiently to understand their composition in most of the included reviews.^{21,22,24,26-29} These deficits in reporting leave uncertainty as to whether any possible differences in PRPi or comparison treatment protocols may have contributed to the variability in the findings of SRs included in this review. For instance, if 1 PRPi injection was used in some of the study treatment protocols, whereas multiple injections were used in another, the findings of these studies may have been impacted; however, because insufficient information was provided, the potential for this variability to impact findings and interpretation cannot be ascertained.

Likewise, unclear reporting of the outcomes and/or measures used in the included reviews was a limitation observed in this review.^21-29 For instance, while 2 of the SRs included in this review reported the use of the VISA score, the outcome being measured was not described,^23,29 necessitating an assumption as to the outcome being measured. In addition, whereas 3 reviews described the use of the VISA as a measurement of function,^21,25,28 another described the VISA as a composite measure of pain function and activity.²⁴ This variability in the description of what was measured in the reviews summarized in this report limits the clarity and interpretation of its findings.

In addition, there was a lack of evidence describing a comparison of PRPi with nonsteroidal anti-inflammatory drugs (NSAIDs), and limited evidence describing a comparison of PRPi with PT. Given that these treatments have been described as first-line, conservative therapies in the usual care of chronic tendinopathies,³ this lack of evidence describing their comparative clinical effectiveness with PRPi is a limitation of this report.

Finally, none of the 9 reviews summarized in this report were conducted in Canada.^21-29 Further, while 7 of the reviews did not describe the countries within which the primary studies were conducted,^21-23,26-29 2 SRs described relevant primary studies from countries outside Canada only.^24,25 This apparent lack of Canadian data may limit the generalizability of the findings of this report to the Canadian context.

Conclusions and Implications for Decision- or Policy-Making

This report identified and summarized 1 overview of SRs²¹ and 8 SRs of primary studies^22-29 describing the clinical effectiveness of PRPi for chronic tendinopathies of the lower extremities.

Findings across the included reviews and their relevant included studies were variable, with many of the reported findings demonstrating no observed comparative effect(s) of PRPi in chronic tendinopathies of the lower extremities.^21-27,29 Nonetheless, 4 reviews described findings that did demonstrate clinical improvement in patients to whom PRPi were administered,^24,26,28,29 and 2 SRs reported findings that demonstrated clinical improvement in patients to whom control interventions were administered.^25,27 It is possible that this variability in findings and conclusions may have been impacted by the variability in patient populations (i.e., various tendinopathies), interventions (e.g., various treatment protocols) and comparators (e.g., placebo and/or various active treatments) — as well as a variety of outcomes and measures. Nonetheless, there was no clear pattern of clinical effectiveness that could be identified among subgroups of patient populations, comparisons, or outcomes.^21-29

The proliferation of studies investigating the use of PRPi for chronic tendinopathies in recent years has been analyzed and commented on repeatedly in the literature;^14,15,31 similarly, the lack of consensus and certainty as to its clinical effectiveness has been highlighted.^8,32,33 Factors contributing to this uncertainty have been outlined in the relevant literature, and are similar to those identified in this report, for example, small RCTs of limited quality with no or small effect sizes,^2,6,8,34,35 as well as considerable lack of clarity and/or variability in PRPi components and treatment protocols,^{6,8,9,14,35-38} which has been identified as a challenge to drawing conclusions from the research investigating its effectiveness. On the other hand, this report identified several MAs that provide a more robust estimate of the clinical effectiveness of PRPi for chronic tendinopathies than is provided by smaller RCTs; though few demonstrated a statistically significant improvement in function among patients receiving PRPi.

CADTH has conducted past reviews of the clinical evidence describing PRPi for other indications, including orthopedic conditions, trauma³⁹ and low back pain.⁴⁰ While the conditions reviewed in those reports are not entirely relevant to the research question posed in this report, it is notable that both reports similarly identified a lack of conclusive evidence supporting the clinical effectiveness of PRPi, with both indicating some evidence to support its safety, but a lack of evidence to support efficacy.^39,40

Despite the variability of the findings in the literature summarized in this review, there may be potential for clinical effectiveness of PRPi, given that some of the findings summarized herein have demonstrated effectiveness. Specifically, 1 MA of 3 primary studies assessing pain in the Achilles tendon demonstrated a statistically significant improvement in patients who received PRPi as compared to placebo;²⁴ and another MA of 3 primary studies investigating the comparative effectiveness of PRPi versus steroids in patients with chronic tendinopathy of the hip demonstrated a clinical improvement in patients who received PRPi.²⁶ It may be that advances in the technology of platelet-rich therapies, such as platelet-rich fibrin⁴¹ and plasma gel⁴² could hold promise for clearer or more consistent improvement in clinical outcomes among musculoskeletal conditions. Nonetheless, measurement of effectiveness that can support clinical and other decisions concerning the use of PRPi in chronic tendinopathies is necessarily supported by high-quality RCTs that use robust methods with sufficient sample sizes and standardized treatment protocols, which remain a current limitation of the literature on this topic.^9,43 The inconclusive state of the current evidence describing PRPi for chronic tendinopathies, combined with its high cost, has been highlighted as a point of caution in interpreting the evidence — including assertions that the available evidence does not support the current use of PRPis.^15,44

Given the inconsistency across the findings reported in the current literature summarized in this report that describes the comparative clinical effectiveness of PRPis in chronic tendinopathies of the lower extremities, the evidence is likely insufficient at this time to support decision-making in favour of its use.

References

1.Scott A, Rees J. Overview of overuse (persistent) tendinopathy. In: Fields KB, ed. UpToDate. Waltham (MA): UpToDate; 2023: http://www.uptodate.com. Accessed 2023 May 24.

2.Dai W, Yan W, Leng X, et al. Efficacy of platelet-rich plasma versus placebo in the treatment of tendinopathy: A meta-analysis of randomized controlled trials. Clin J Sport Med. 2023;33(1):69-77. PubMed

3.Scott A, Purdam CR. Overview of the management of overuse (persistent) tendinopathy. In: Fields KB, ed. UpToDate. Waltham (MA): UpToDate; 2023: http://www.uptodate.com. Accessed 2023 May 25.

4.Vivek K, Padma V. Efficacy of autologous platelet rich plasma injection in lateral epicondylitis and plantar fasciitis. Indian J Public Health Res Dev. 2019;10(11):4241-4245. https://ijphrd.com/scripts/IJPHRD%20November_2019.pdf. Accessed 2023 May 11.

5.Torres A, Fernandez-Fairen M, Sueiro-Fernandez J. Greater trochanteric pain syndrome and gluteus medius and minimus tendinosis: Nonsurgical treatment. Pain Manag. 2018;8(1):45-55. PubMed

6.Lopez-Royo MP, Ortiz-Lucas M, Gomez-Trullen EM, Herrero P. The effectiveness of minimally invasive techniques in the treatment of patellar tendinopathy: A systematic review and meta-analysis of randomized controlled trials. Evid Based Complement Alternat Med. 2020;2020:8706283. PubMed

7.Abadin AA, Orr JP, Lloyd AR, Henning PT, Pourcho A. An evidence-based approach to orthobiologics for tendon disorders. Phys Med Rehabil Clin N Am. 2023;34(1):83-103. PubMed

8.Nauwelaers AK, Van Oost L, Peers K. Evidence for the use of PRP in chronic midsubstance Achilles tendinopathy: A systematic review with meta-analysis. J Foot Ankle Surg. 2021;27(5):486-495. PubMed

9.Collins T, Alexander D, Barkatali B. Platelet-rich plasma: A narrative review. EFORT Open Rev. 2021;6(4):225-235. PubMed

10.Cook J, Young M. Biologic therapies for tendon and muscle injury. In: Fricker P, ed. UpToDate. Waltham (MA): UpToDate; 2023: http://www.uptodate.com. Accessed 2023 Jun 16.

11.Fletcher AN, Cheah JW, Nho SJ, Mather RC, 3rd. Proximal hamstring injuries. Clin Sports Med. 2021;40(2):339-361. PubMed

12.Sheean AJ, Arner JW, Bradley JP. Proximal hamstring tendon injuries: Diagnosis and management. Arthroscopy. 2021;37(2):435-437. PubMed

13.Marcolina A, Vu K, Chang Chien G. Peripheral joint injections. Phys Med Rehabil Clin N Am. 2022;33(2):267-306. PubMed

14.Sheean AJ, Anz AW, Bradley JP. Platelet-rich plasma: Fundamentals and clinical applications. Arthroscopy. 2021;37(9):2732-2734. PubMed

15.LaBelle MW, Marcus RE. CORR synthesis: What is the role of platelet-rich plasma injection in the treatment of tendon disorders? Clin Orthop Relat Res. 2020;478(8):1817-1824. PubMed

16.Perry D, Ton J, Kolber MR. Platelet-rich plasma injections. Can Fam Physician. 2020;66(5):337. PubMed

17.Schopflocher D, Taenzer P, Jovey R. The prevalence of chronic pain in Canada. Pain Res Manag. 2011;16(6):445-450. PubMed

18.Health Canada. Information update: Health Canada clarifies position on platelet rich plasma treatments. 2019; https://recalls-rappels.canada.ca/en/alert-recall/health-canada-clarifies-position-platelet-rich-plasma-treatments. Accessed 2023 Jun 14.

19.CBC News. Platelet-rich plasma treatment classified as drug, Health Canada says. 2019; https://www.cbc.ca/news/health/platelet-rich-plasma-treatment-classification-1.5226906. Accessed 2023 Jun 15.

20.Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008. PubMed

21.Irby A, Gutierrez J, Chamberlin C, Thomas SJ, Rosen AB. Clinical management of tendinopathy: A systematic review of systematic reviews evaluating the effectiveness of tendinopathy treatments. Scand J Med Sci Sports. 2020;30(10):1810-1826. PubMed

22.Masiello F, Pati I, Veropalumbo E, Pupella S, Cruciani M, De Angelis V. Ultrasound-guided injection of platelet-rich plasma for tendinopathies: A systematic review and meta-analysis. Blood Transfus. 2023;21(2):119-136. PubMed

23.Nuhmani S, Khan MH, Ahsan M, Abualait TS, Muaidi Q. Dry needling in the management of tendinopathy: A systematic review of randomized control trials. J Bodyw Mov Ther. 2023;33:128-135. PubMed

24.Arthur Vithran DT, Xie W, Opoku M, Essien AE, He M, Li Y. The efficacy of platelet-rich plasma injection therapy in the treatment of patients with achilles tendinopathy: A systematic review and meta-analysis. J Clin Med. 2023;12(3):28. PubMed

25.Barman A, Sinha MK, Sahoo J, et al. Platelet-rich plasma injection in the treatment of patellar tendinopathy: A systematic review and meta-analysis. Knee Surg Relat Res. 2022;34(1):22. PubMed

26.Migliorini F, Kader N, Eschweiler J, Tingart M, Maffulli N. Platelet-rich plasma versus steroids injections for greater trochanter pain syndrome: A systematic review and meta-analysis. Br Med Bull. 2021;139(1):86-99. PubMed

27.Huang K, Giddins G, Wu LD. Platelet-rich plasma versus corticosteroid injections in the management of elbow epicondylitis and plantar fasciitis: An updated systematic review and meta-analysis. Am J Sports Med. 2020;48(10):2572-2585. PubMed

28.Trams E, Kulinski K, Kozar-Kaminska K, Pomianowski S, Kaminski R. The clinical use of platelet-rich plasma in knee disorders and surgery: A systematic review and meta-analysis. Life (Basel). 2020;10(6):94. PubMed

29.Franchini M, Cruciani M, Mengoli C, et al. Efficacy of platelet-rich plasma as conservative treatment in orthopaedics: A systematic review and meta-analysis. Blood Transfus. 2018;16(6):502-513. PubMed

30.Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1-e34. PubMed

31.Cash C, Scott L, Walden RL, Kuhn A, Bowman E. Bibliometric analysis of the top 50 highly cited articles on platelet-rich plasma in osteoarthritis and tendinopathy. Regen Med. 2022;17(7):491-506. PubMed

32.Wolfenden E, Vukelic B, DeMarco M, Knox J, Ose D. Does platelet-rich plasma improve patellar tendinopathy symptoms? J Fam Pract. 2022;71(4):188-189. PubMed

33.Filardo G, Di Matteo B, Kon E, Merli G, Marcacci M. Platelet-rich plasma in tendon-related disorders: Results and indications. Knee Surg Sports Traumatol Arthrosc. 2018;26(7):1984-1999. PubMed

34.Abate M, Di Carlo L, Belluati A, Salini V. Re: Factors associated with positive outcomes of platelet-rich plasma therapy in Achilles tendinopathy. Eur J Orthop Surg Traumatol. 2020;30(7):1319-1320. PubMed

35.Arthur Vithran DT, He M, Xie W, Essien AE, Opoku M, Li Y. Advances in the clinical application of platelet-rich plasma in the foot and ankle: A review. J Clin Med. 2023;12(3):1002. PubMed

36.Chen J, Wan Y, Jiang H. The effect of platelet-rich plasma injection on chronic Achilles tendinopathy and acute Achilles tendon rupture. Platelets. 2022;33(3):339-349. PubMed

37.Gremeaux V, Noel E, Kaux JF. Platelet-rich plasma injection vs sham injection and tendon dysfunction in patients with chronic midportion achilles tendinopathy. JAMA. 2021;326(19):1974. PubMed

38.Malanga GA, Mautner K, Buford D. Platelet-rich plasma injection vs sham injection and tendon dysfunction in patients with chronic midportion achilles tendinopathy. JAMA. 2021;326(19):1974-1975. PubMed

39.Platelet-rich plasma injections for wound healing and tissue rejuvenation: a review of clinical effectiveness, cost-effectiveness and guidelines. (CADTH Rapid response report: summary with critical appraisal). Ottawa (ON): CADTH; 2017: https://www.cadth.ca/platelet-rich-plasma-injections-wound-healing-and-tissue-rejuvenation-review-clinical-effectiveness. Accessed 2023 Jun 15.

40.Platelet rich plasma lumbar disc injections for lower back pain: Clinical effectiveness, safety, and guidelines. (CADTH Rapid response report: summary of abstracts). Ottawa (ON): CADTH; 2014: https://www.cadth.ca/sites/default/files/pdf/htis/mar-2014/RB0649%20Platelet%20Rich%20Plasma%20Final.pdf. Accessed 2023 Jun 15.

41.Narayanaswamy R, Patro BP, Jeyaraman N, et al. Evolution and clinical advances of platelet-rich fibrin in musculoskeletal regeneration. Bioengineering (Basel). 2023;10(1):58. PubMed

42.Godoi TTF, Rodrigues BL, Huber SC, et al. Platelet-rich plasma gel matrix (PRP-GM): Description of a new technique. Bioengineering (Basel). 2022;9(12):817. PubMed

43.Johnson LG, Buck EH, Anastasio AT, Abar B, Fletcher AN, Adams SB. Efficacy of platelet-rich plasma in soft tissue foot and ankle pathology. JBJS Rev. 2022;10(10). PubMed

44.Patricios J, Harmon KG, Drezner J. PRP use in sport and exercise medicine: Be wary of science becoming the sham. Br J Sports Med. 2022;56(2):66-67. PubMed

45.Iversen JV, Bartels EM, Langberg H. The Victorian Institute of Sports Assessment - Achilles questionnaire (VISA-A): A reliable tool for measuring Achilles tendinopathy. Int J Sports Phys Ther. 2012;7(1):76-84. PubMed

46.Van Lieshout EM, De Boer AS, Meuffels DE, et al. American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Score: A study protocol for the translation and validation of the Dutch language version. BMJ Open. 2017;7(2):e012884. PubMed

47.Saarinen AJ, Uimonen MM, Suominen EN, Sandelin H, Repo JP. Structural and construct validity of the foot and ankle ability measure (FAAM) with an emphasis on pain and functionality after foot surgery: A multicenter study. J Foot Ankle Surg. 2022;61(4):872-878. PubMed

48.AbilityLab. Foot function index. 2017; https://www.sralab.org/rehabilitation-measures/foot-function-index. Accessed 2023 Jun 23.

49.Vishwanathan K, Akbari K, Patel AJ. Is the modified Harris hip score valid and responsive instrument for outcome assessment in the Indian population with pertrochanteric fractures? J Orthop. 2018;15(1):40-46. PubMed

50.Soh S-E, Morello R, Ayton D, et al. Measurement properties of the 12-item Short Form Health Survey version 2 in Australians with lung cancer: A Rasch analysis. Health Qual Life Outcomes. 2021;19(1):157. PubMed

51.Delgado DA, Lambert BS, Boutris N, et al. Validation of digital visual analog scale pain scoring with a traditional paper-based visual analog scale in adults. J Am Acad Orthop Surg Glob Res Rev. 2018;2(3):e088. PubMed

52.Visentini PJ, Khan KM, Cook JL, Kiss ZS, Harcourt PR, Wark JD. The VISA score: An index of severity of symptoms in patients with jumper's knee (patellar tendinosis). J Sci Med Sport. 1998;1(1):22-28. PubMed

53.Hernandez-Sanchez S, Abat F, Hidalgo MD, et al. Confirmatory factor analysis of VISA-P scale and measurement invariance across sexes in athletes with patellar tendinopathy. J Sport Health Sci. 2017;6(3):365-371. PubMed

Appendix 1: Selection of Included Studies

Figure 1: Selection of Included Studies

Appendix 2: Characteristics of Included Publications

Note that this appendix has not been copy-edited.

Table 2: Characteristics of Included Overview of Systematic Reviews

CINAHL = Cumulated Index to Nursing and Allied Health Literature; PEDRo = Physiotherapy Evidence Database; NR = not reported; PRPi = platelet-rich plasma injection; RCT = randomized controlled trial; SR = systematic review; VISA-A = Victorian Institute of Sports Assessment–Achil

VISA-A: The VISA-A is scored using a numeric scale from 0 to 100, with 100 representing no symptoms and lower scores more deleterious symptoms.⁴⁵

Appendix 3: Critical Appraisal of Included Publications

Note that this appendix has not been copy-edited.

Table 4: Strengths and Limitations of Overview of Systematic Reviews Using AMSTAR 2²⁰ With Additional Items

PICOS = population(s), intervention(s), comparator(s), outcome(s), study design(s); RoB = risk of bias; SR = systematic review

Table 5: Strengths and Limitations of Systematic Reviews Using AMSTAR 2²⁰

AMSTAR 2 = A MeaSurement Tool to Assess systematic Reviews 2; GRADE = Grading of Recommendations, Assessment, Development, and Evaluations; MA = meta-analysis; MCID = minimal clinically important difference; n/N = number(s); NR = not reported; PEDro = Physiotherapy Evidence Database; PICOS = population(s), intervention(s), comparator(s), outcome(s), study design(s); PROSPERO = International prospective register of systematic reviews; RCT = randomized controlled trial; RoB = risk of bias; SR = systematic review.

Appendix 4: Main Study Findings

Note that this appendix has not been copy-edited.

Table 6: Summary of Findings by Outcome — Function

AOFAS = American Orthopedic Foot and Ankle Society; CI = confidence interval; DN = dry needling; FFI = Foot Function Index; mo = month(s); n/N = number(s); NR = not reported; NS = not significant; PRPi = platelet-rich plasma injection; RCT = randomized controlled trial; SD = standard deviation; SR = systematic review; SS = statistically significant; VISA = Victorian Institute of Sports Assessment; VISA-P = Victorian Institute of Sports Assessment–Patellar; wk = week(s).

^aResults for the 8 to 12 week and 6 months time frames were reported as being the same for both groups across both studies (with the exception of the 95% CIs in the mean differences reported for Dragoo 2014); this may or may not be in error but could not be ascertained.

Table 7: Summary of Findings by Outcome — Pain

CI = confidence interval; CS = corticosteroid; DN = dry needling; MA = meta-analysis; mo = month(s); n/N = number(s); NR = not reported; NRS = non-randomized study; NS = not significant; NSp = not specified; PRPi = platelet-rich plasma injection; PT = physiotherapy; RCT = randomized controlled trial; SD = standard deviation; SR = systematic review; SS = statistically significant; VAS = visual analogue scale; wk = week(s).

Table 8: Summary of Findings by Outcome — Composite Outcomes

AOFAS = American Orthopedic Foot and Ankle Society; CI = confidence interval; CS = corticosteroid; HHS = Harris Hip Score; MA = meta-analysis; mo = month(s); N = number; NR = not reported; NS = not significant; PRPi = platelet-rich plasma injection; RCT = randomized controlled trial; SD = standard deviation; SR = systematic review; SS = statistically significant; VISA = Victorian Institute of Sports Assessment; VISA-A = Victorian Institute of Sports Assessment–Achilles; wk = week(s).

Table 9: Summary of Findings by Outcome — Return to Exercise/Sport

CI = confidence interval; MA = meta-analysis; n/N = number(s); NS = not significant; PRPi = platelet-rich plasma injection; RCT = randomized controlled trial; RR = risk ratio; SD = standard deviation; SR = systematic review; wk = week(s).

Table 10: Summary of Findings by Outcome — Patient Satisfaction

CI = confidence interval; MA = meta-analysis; n/N = number(s); NS = not significant; PRPi = platelet-rich plasma injection; RCT = randomized controlled trial; RR = risk ratio; SR = systematic review; wk = week(s).

Table 11: Summary of Findings by Outcome — Quality of Life

CI = confidence interval; DN = dry needling; EQ-VAS = EuroQOL visual analogue scale; MA = meta-analysis; mo = month(s); n/N = number(s); NR = not reported; NS = not significant; PRPi = platelet-rich plasma injection; PT = physiotherapy; SF-12 = short form 12; SR = systematic review; wk = week(s).

Table 12: Summary of Findings by Outcome — Adverse Events

n/N = number(s); NR = not reported; SR = systematic review.

Appendix 6: References of Potential Interest

Previous CADTH Reports

PRPI for Indications Other Than Chronic Tendinopathies of the Lower Extremities

Platelet-rich plasma injections for wound healing and tissue rejuvenation: A review of clinical effectiveness, cost-effectiveness and guidelines. (CADTH Rapid response report: summary with critical appraisal). Ottawa (ON): CADTH; 2017: https://www.cadth.ca/platelet-rich-plasma-injections-wound-healing-and-tissue-rejuvenation-review-clinical-effectiveness

Platelet rich plasma lumbar disc injections for lower back pain: Clinical effectiveness, safety, and guidelines. (CADTH Rapid response report: summary of abstracts). Ottawa (ON): CADTH; 2014: https://www.cadth.ca/sites/default/files/pdf/htis/mar-2014/RB0649%20Platelet%20Rich%20Plasma%20Final.pdf

Review Articles

Narrative Reviews (i.e., No Systematic Review Method) of Relevance

Sneed D, Wong C. Platelet-rich plasma injections as a treatment for Achilles tendinopathy and plantar fasciitis in athletes. PM R. 2023;10.1002/pmrj.12965. PubMed

Hulsopple C. Musculoskeletal therapies: Musculoskeletal injection therapy. FP Essent. 2018;470:21-26. PubMed

Additional References

Methods Review Describing Statistical Challenges in PRPi Research

Xu AL, Ortiz-Babilonia C, Gupta A, Rogers D, Aiyer AA, Vulcano E. The statistical fragility of platelet-rich plasma as treatment for chronic noninsertional achilles tendinopathy: A systematic review and meta-analysis. Foot Ankle Orthop. 2022;7(3):24730114221119758. PubMed