Characteristics of L-PRP preparations for treating Achilles tendon rupture within the PATH-2 study.

Platelet-rich plasma (PRP) is an autologous preparation that has been claimed to improve healing and mechanobiological properties of tendons both in vitro and in vivo. In this sub-study from the PATH-2 (PRP in Achilles Tendon Healing-2) trial, we report the cellular and growth factor content and quality of the Leukocyte-rich PRP (L-PRP) (N = 103) prepared using a standardized commercial preparation method across 19 different UK centers. Baseline whole blood cell counts (red cells, leukocyte and platelets) demonstrated that the two groups were well-matched. L-PRP analysis gave a mean platelet count of 852.6 x 109/L (SD 438.96), a mean leukocyte cell count of 15.13 x 109/L (SD 10.28) and a mean red blood cell count of 0.91 x 1012/L (SD 1.49). The activation status of the L-PRP gave either low or high expression levels of the degranulation marker CD62p before and after ex-vivo platelet activation respectively. TGF-ß, VEGF, PDGF, IGF and FGFb mean concentrations were 131.92 ng/ml, 0.98 ng/ml, 55.34 ng/ml, 78.2 ng/ml and 111.0 pg/ml respectively with expected correlations with both platelet and leukocyte counts. While PATH-2 results demonstrated that there was no evidence L-PRP is effective for improving clinical outcomes at 24 weeks after Achilles tendon rupture, our findings support that the majority of L-PRP properties were within the method specification and performance.

Platelet-rich plasma injection for acute Achilles tendon rupture : two-year follow-up of the PATH-2 randomized, placebo-controlled, superiority trial.

AIMS: To determine whether platelet-rich plasma (PRP) injection improves outcomes two years after acute Achilles tendon rupture. METHODS: A randomized multicentre two-arm parallel-group, participant- and assessor-blinded superiority trial was undertaken. Recruitment commenced on 28 July 2015 and two-year follow-up was completed in 21 October 2019. Participants were 230 adults aged 18 years and over, with acute Achilles tendon rupture managed with non-surgical treatment from 19 UK hospitals. Exclusions were insertion or musculotendinous junction injuries, major leg injury or deformity, diabetes, platelet or haematological disorder, medication with systemic corticosteroids, anticoagulation therapy treatment, and other contraindicating conditions. Participants were randomized via a central online system 1:1 to PRP or placebo injection. The main outcome measure was Achilles Tendon Rupture Score (ATRS) at two years via postal questionnaire. Other outcomes were pain, recovery goal attainment, and quality of life. Analysis was by intention-to-treat. RESULTS: A total of 230 participants were randomized, 114 to PRP and 116 to placebo. Two-year questionnaires were sent to 216 participants who completed a six-month questionnaire. Overall, 182/216 participants (84%) completed the two-year questionnaire. Participants were aged a mean of 46 years (SD 13.0) and 25% were female (57/230). The majority of participants received the allocated intervention (219/229, 96%). Mean ATRS scores at two years were 82.2 (SD 18.3) in the PRP group (n = 85) and 83.8 (SD 16.0) in the placebo group (n = 92). There was no evidence of a difference in the ATRS at two years (adjusted mean difference -0.752, 95% confidence interval -5.523 to 4.020; p = 0.757) or in other secondary outcomes, and there were no re-ruptures between 24 weeks and two years. CONCLUSION: PRP injection did not improve patient-reported function or quality of life two years after acute Achilles tendon rupture compared with placebo. The evidence from this study indicates that PRP offers no patient benefit in the longer term for patients with acute Achilles tendon rupture.Cite this article: Bone Joint J 2022;104-B(11):1256-1265.

Plaster cast versus functional bracing for Achilles tendon rupture: the UKSTAR RCT.

BACKGROUND: Achilles tendon rupture affects > 11,000 people each year in the UK, leading to prolonged periods away from work, sports and social activities. Traditionally, the ruptured tendon is held still in a plaster cast for ≥ 8 weeks. Functional bracing is an alternative treatment that allows patients to mobilise earlier, but there is little evidence about how bracing affects patients' recovery. OBJECTIVES: To measure the Achilles Tendon Rupture Score, quality of life, complications and resource use of patients receiving non-operative treatment for an Achilles tendon rupture treated with plaster cast compared with those treated with functional bracing. DESIGN: This was a multicentre, randomised, pragmatic, two-group superiority trial. SETTING: The setting was 39 NHS hospitals. PARTICIPANTS: A total of 540 adult patients treated non-operatively for Achilles tendon rupture were randomised from July 2016 to May 2018. Exclusion criteria included presenting after 14 days, having had previous rupture and being unable to complete questionnaires. INTERVENTIONS: A total of 266 participants had a plaster cast applied, with their toes initially pointing to the floor. The cast was changed over 8 weeks to bring the foot into a walking position. A total of 274 patients had a functional brace that facilitated immediate weight-bearing. The foot position was adjusted within the brace over the same 8-week period. MAIN OUTCOME MEASURES: Achilles Tendon Rupture Score is patient reported and assesses symptoms and physical activity related to the Achilles tendon (score 0-100, with 100 being the best possible outcome). The secondary outcomes were quality of life, complications and resource use at 8 weeks and at 3, 6 and 9 months. RESULTS: Participants had a mean age of 48.7 years, were predominantly male (79%) and had ruptured their tendon during sports (70%). Over 93% of participants completed follow-up. There was no statistically significant difference in Achilles Tendon Rupture Score at 9 months post injury (-1.38, 95% confidence interval -4.9 to 2.1). There was a statistically significant difference in Achilles Tendon Rupture Score at 8 weeks post injury in favour of the functional brace group (5.53, 95% confidence interval 2.0 to 9.1), but not at 3 or 6 months post injury. Quality of life showed the same pattern, with a statistically significant difference at 8 weeks post injury but not at later time points. Complication profiles were similar in both groups. Re-rupture of the tendon occurred 17 times in the plaster cast group and 13 times in the functional brace group. There was no difference in resource use. CONCLUSIONS: This trial provides strong evidence that early weight-bearing in a functional brace provides similar outcomes to traditional plaster casting and is safe for patients receiving non-operative treatment of Achilles tendon rupture. The probability that functional bracing is cost-effective exceeds 95% for the base-case imputed analysis, assuming a cost-effectiveness threshold of £20,000 per quality-adjusted life-year. On average, functional brace is associated with lower costs (-£103, 95% confidence interval -£290 to £84) and more quality-adjusted life-years (0.015, 95% confidence interval -0.0013 to 0.030) than plaster cast. LIMITATIONS: Some patients declined to participate in the trial, but only a small proportion of these declined because they had a preference for one treatment or another. Overall, 58% of eligible patients agreed to participate, so the participants are broadly representative of the population under investigation. FUTURE WORK: Although the UK Study of Tendo Achilles Rehabilitation provides guidance with regard to early management, rehabilitation following Achilles tendon rupture is prolonged and further research is required to define the optimal mode of rehabilitation after the initial cast/brace has been removed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN62639639. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 8. See the NIHR Journals Library website for further project information.

WHAT DID THE TRIAL FIND?: Patients recovered steadily after their injury but were still not back to normal at 9 months. The average Achilles Tendon Rupture Score rose from 38 out of 100 at 8 weeks to 73 out of 100 at 9 months. Patents who had the functional brace reported that their recovery was a little better at 8 weeks than did the patients having the plaster cast, but there was no evidence of a difference after that. There were 17 cases of re-rupture of the Achilles tendon in the plaster cast group and 13 cases in the functional brace group. There was no evidence of a difference in costs. In conclusion, this study provides strong evidence that early weight-bearing in a functional brace provides similar outcomes to traditional plaster casting and is safe for patients having treatment for Achilles tendon rupture.

Achilles tendon rupture affects > 11,000 people each year in the UK, leading to prolonged periods away from work, sports and social activities. Traditionally, after a ruptured tendon, the foot and ankle are held still in a plaster cast for ≥ 8 weeks. Functional bracing is an alternative treatment that allows patients to mobilise earlier, but there is little evidence about how it affects later recovery. This study aimed to compare traditional plaster casting with functional bracing for adult patients with Achilles tendon rupture. The participants reported their own recovery using the Achilles Tendon Rupture Score, which consists of 10 questions about symptoms and physical activity (in which a score of 100 is the best possible outcome). We also recorded quality of life, complications, including re-rupture of the tendon, and costs from both the NHS and the patients' perspective. A total of 540 patients, treated at 39 hospitals, agreed to take part and were assigned by chance to either plaster cast or functional brace. Patients reported their recovery at 8 weeks and at 3, 6 and 9 months.

Platelet rich plasma injection for acute Achilles tendon rupture: PATH-2 randomised, placebo controlled, superiority trial.

OBJECTIVE: To determine whether an injection of platelet rich plasma improves outcomes after acute Achilles tendon rupture. DESIGN: Randomised, placebo controlled, two arm, parallel group, participant and assessor masked, superiority trial. SETTING: Secondary care trauma units across 19 hospitals in the United Kingdom's health service. PARTICIPANTS: Recruitment commenced in July 2015 and follow-up was completed in March 2018. 230 adults aged 18 years and over were included, with acute Achilles tendon rupture presenting within 12 days of injury and managed with non-surgical treatment. Exclusions were injury at the insertion or musculotendinous junction, major leg injury or deformity, diabetes mellitus, platelet or haematological disorder, systemic corticosteroids, anticoagulation treatment, and other contraindicating conditions. INTERVENTIONS: Participants were randomised 1:1 to platelet rich plasma (n=114) or placebo (dry needle; n=116) injection. All participants received standard rehabilitation care (ankle immobilisation followed by physiotherapy). MAIN OUTCOMES AND MEASURES: Primary outcome was muscle tendon function at 24 weeks, measured objectively with the limb symmetry index (injured/uninjured×100) in maximal work done during the heel rise endurance test (an instrumented measure of repeated single leg heel rises until fatigue). Secondary outcomes included patient reported function (Achilles tendon rupture score), quality of life (short form 12 version 2®), pain (visual analogue scale), goal attainment (patient specific functional scale), and adverse events. A central laboratory analysed the quality and content of platelet rich plasma. Analyses were by modified intention to treat. RESULTS: Participants were 46 years old on average, and 57 (25%) of 230 were female. At 24 weeks, 202 (88%) participants completed the heel rise endurance test and 216 (94%) the patient reported outcomes. The platelet rich plasma was of good quality, with expected growth factor content. No difference was detected in muscle tendon function between participants receiving platelet rich plasma injections and those receiving placebo injections (limb symmetry index, mean 34.7% (standard deviation 17.7%) v 38.5% (22.8%); adjusted mean difference -3.9% (95% confidence interval -10.5% to 2.7%)) or in any secondary outcomes or adverse event rates. Complier average causal effect analyses gave similar findings. CONCLUSIONS: There is no evidence to indicate that injections of platelet rich plasma can improve objective muscle tendon function, patient reported function, or quality of life after acute Achilles tendon rupture compared with placebo, or that they offer any patient benefit. TRIAL REGISTRATION: ISRCTN54992179.

Platelet-rich plasma in Achilles tendon healing 2 (PATH-2) trial: statistical analysis plan for a multicentre, double-blinded, parallel-group, placebo-controlled randomised clinical trial.

BACKGROUND: There has been a recent steep growth in platelet-rich plasma (PRP) use for musculoskeletal conditions, but findings from high quality clinical trial data are lacking in the literature. Here, we describe the statistical analysis plan (SAP) for the Platelet-rich plasma in Achilles Tendon Healing 2 (PATH-2) trial. METHODS: PATH-2 is a pragmatic, parallel-group, multi-centre, double-blinded, randomised, placebo-controlled, superiority trial. The study aims to evaluate the clinical efficacy of PRP in acute Achilles tendon rupture in terms of muscle-tendon function. Patients are identified in the orthopaedic/trauma outpatient clinic. The primary outcome is muscle-tendon work capacity from the Heel Rise Endurance Test result, expressed as the Limb Symmetry Index (work, in joules), at 24 weeks post randomisation. Multivariate linear regression adjusting for the stratification factors (centre and age) and additional prognostic factors will be used to investigate the adjusted effect of the intervention. The analysis will be by modified intention-to-treat. Sensitivity analysis will assess the internal validity of the trial results by performing a per-protocol analysis. Safety will be summarised by treatment arm for all patients who started treatment. Secondary patient-reported outcome measures will be analysed using linear mixed effects models to allow all data collected at all follow-up points to be considered. Missing data will be summarised and reported by treatment arm. Missing data imputation will be performed, if appropriate. DISCUSSION: The PATH-2 trial will be reported in accordance with the CONSORT statement. This SAP publication will avoid bias arising from prior knowledge of the study results. Any changes or deviations from the current SAP will be described and justified in the final report. TRIAL REGISTRATION: ISRCTN registry: ISRCTN54992179 , assigned 12 January 2015. ClinicalTrials.gov: NCT02302664, received 18 November 2014. UK Clinical Research Network Study Portfolio Database: ID 17850.

Platelet rich Plasma in Achilles Tendon Healing 2 (PATH-2) trial: protocol for a multicentre, participant and assessor-blinded, parallel-group randomised clinical trial comparing platelet-rich plasma (PRP) injection versus placebo injection for Achilles tendon rupture.

BACKGROUND: Achilles tendon injuries give rise to substantial long-lasting morbidity and pose considerable challenges for clinicians and patients during the lengthy healing period. Current treatment strategies struggle to curb the burden of this injury on health systems and society due to lengthy rehabilitation, work absence and reinjury risk. Platelet-rich plasma (PRP) is an autologous preparation that has been shown to improve the mechanobiological properties of tendons in laboratory and animal studies. The use of PRP in musculoskeletal injuries is on the increase despite the lack of adequately powered clinical studies. METHODS AND DESIGN: This is a multicentre randomised controlled trial to evaluate the efficacy and mechanism of PRP in patients with acute Achilles tendon rupture (ATR). All adults with acute ATR presenting within 12 days of the injury who are to be treated non-operatively are eligible. A total of 230 consenting patients will be randomly allocated via a remote web-based service to receive PRP injection or placebo injection to the site of the injury. All participants will be blinded to the intervention and will receive standardised rehabilitation to reduce efficacy interference.Participants will be followed up with blinded assessments of muscle-tendon function, quality of life, pain and overall patient's functional goals at 4, 7, 13, 24 weeks and 24 months post-treatment. The primary outcome is the heel-rise endurance test (HRET), which will be supervised by a blinded assessor at 24 weeks. A subgroup of 16 participants in one centre will have needle biopsy under ultrasound guidance at 6 weeks. Blood and PRP will be analysed for cell count, platelet activation and growth factor concentrations. ETHICS AND DISSEMINATION: The protocol has been approved by the Oxfordshire Research Ethics Committee (Oxfordshire Research Ethics Committee A, reference no 14/SC/1333). The trial will be reported in accordance with the CONSORT statement and published in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: ISRCTN: 54992179, assigned 12 January 2015. ClinicalTrials.gov: NCT02302664, received 18 November 2014. UK Clinical Research Network Study Portfolio Database: ID 17850.