Discussion
The results of this systematic review and meta-analysis provide level 1 evidence that injection of PRP is efficacious in patients with symptomatic tendinopathy. The treatment effects with PRP relative to controls in this meta-analysis suggest clinically meaningful improvements in patient symptoms.
Previous meta-analyses have drawn disparate conclusions regarding PRP efficacy, likely because of widely varying methodologies among studies.32–38 We designed the current review to minimise potential sources of bias, namely by excluding non-randomised studies, studies with non-injection control groups, or active injectable controls (eg, whole blood, PRP). Still, we identified significant heterogeneity in treatment effects. When evaluating patient, treatment and study design-related factors, female sex was the only variable that modified the efficacy of PRP for treatment of tendinopathy. The observation that PRP may be more efficacious in women has been previously reported. Wesner et al39 reported that the magnitude of pain reduction on a 0–10 scale was greater in women than men (2.8 vs 1.8, p=0.04) with PRP injection in degenerative tendinopathy. While no obvious explanation exists for this post hoc observation, exploration of gender differences with PRP injection should be explored in future studies.
Lateral epicondylar tendinopathy was evaluated in most comparisons (12 of 18 groups) and was the most responsive to PRP therapy (effect size=0.57). For comparison, rotator cuff (three groups; effect size=0.32), Achilles (two groups; effect size=0.22) and patellar tendon (one group; effect size=−0.13) pathology were less studied and had negligible to small effect sizes. In agreement with our findings, others have reported that PRP is particularly efficacious for lateral epicondylar tendinopathy.37 40 While this meta-analysis was underpowered to detect meaningful differences in treatment effects among anatomical sites, it is plausible that PRP efficacy may also be influenced by injection site.
Two randomised controlled trials that were included in this meta-analysis warrant additional discussion. First, in the study of Behera and colleagues,13 the treatment benefit of PRP relative to control was considerably greater than any other included study (effect size=2.2). Over 1-year follow-up, pain scores on a 0–100 scale decreased from 75±6 to 13±14 with PRP and from 76±7 to 41±12 with control (bupivacaine) injection. While exclusion of this study in a one-study removed analysis did not change the conclusions of this meta-analysis, heterogeneity in outcomes among the remaining studies was non-existent following removal of this study. Although no specific attributes of this study that may dramatically impact outcomes are readily observable, the inclusion of this study does introduce considerable inconsistency to our findings. Second, the study by Dragoo and colleagues15 reported an unprecedented and profound recovery in the bupivacaine control group at the final time point. For example, VAS pain scores in the control group were 3.0±2.3 at baseline, 2.3±1.6 at 12 weeks and 0.3±0.5 at 26 weeks. This 90% reduction in mean pain severity with control over a 6-month time frame was notably greater than in any other study of control injections. Complete recovery of a non-active control group in a randomised controlled trial for an orthopaedics indication is unanticipated. As before, exclusion of this study in a one-study removed analysis did not change the conclusions of this meta-analysis and no specific attributes of this study that may dramatically impact outcomes are readily observable.
The sample sizes of most PRP studies for symptomatic tendinopathy were too small to statistically detect clinically meaningful treatment effects. To detect the effect size of PRP observed in this meta-analysis, a sample size of 146 patients (73 per group) would be required. In this review, only 1 of 18 groups enrolled at least this number of patients. In fact, the median sample size in this review was only 35 patients. This observation likely explains why many individual studies showed no benefit of PRP, yet the results of the pooled analysis showed a statistically significant, moderate benefit relative to control injections.
A similar observation can be made about the systematic review by de Vos et al36 who concluded that there was strong evidence against PRP for chronic lateral epicondylar tendinopathy. This conclusion was based on the observation that only one of six included studies showed a positive benefit of PRP, yet no attempt was made at quantitative data synthesis. (What was the effect size and direction of the analysis when you reviewed it?) These results underscore the need for investigators to perform power analyses with realistic assumptions during study planning and for systematic reviewers to consider meta-analytic techniques, where appropriate, to quantify treatment effects with more precision than simple counts of positive studies.
Our meta-analysis is associated with several issues that may influence interpretation. Strengths of this meta-analysis are inclusion of only randomised, injection-controlled trials, structured data extraction methodology and comprehensive analysis of potentially confounding factors. There were also limitations inherent in the studies that were included in this review. First, the duration of tendinopathy symptoms was variable, frequently of short duration, and, in many cases, inadequately described. Thus, this meta-analysis was unable to discern the efficacy of PRP based on chronology of symptoms. Second, there was significant heterogeneity in efficacy outcomes among studies with PRP versus control injections. While subgroup and meta-regression identified female sex as a potential mediating factor, definitive conclusions cannot be drawn given the post hoc nature of the analysis. Third, the duration of patient follow-up may be an important determinant of PRP efficacy. Subgroup analyses demonstrated greater effect sizes with PRP with greater follow-up duration. Although the analysis was underpowered to detect important differences given the limited number of studies with varying follow-up durations, the magnitude of the effect size with PRP at 12 months and the effect size difference from 3 to 12 months suggests that PRP efficacy may continue to improve through at least 12 months follow-up. Thus, researchers are encouraged to enrol an adequate number of patients and continue follow-up through at least 1 year post-treatment. Third, we made no attempt to assess safety of PRP injections in this study. Generally, safety reporting in the PRP literature is inconsistent and inadequate. While treatment-related complications with PRP such as pain and swelling are generally infrequent, mild and transient, the potential for unreported complications remains a major limitation of the PRP literature in general and the consequent absence of pooled safety data is a limitation of this meta-analysis.