Ahmad, Shanaz

Allen, James

Alsousou, Joseph

Amor, Kelly

Attwal, Manjit

Austin, Martin

Badloe, Joanne

Ballal, Moez

Barnes, Simon

Barnfield, Steven

Beacham, Keira

Bhatia, Maneesh

Bradley-Potts, Joanne

Brear, Tracy

Brown, Janet

Brown, Sarah

Bunworth, Kerry

Butcher, Deborah

Carmichael, James

Carmont, Michael

Christie, Carla

Clarkson, Louise

Cleary, Cheryl

Coates, Katherine

Cook, Amanda

Dark, Jayne

Davies, Mark

de Feyter, Pascal

Dutton, Susan J

Earley, Joanne

Foster, Eliza

Frostick, Simon

Grice, Anna

Grp, PATH-2 Trial

Halliday, Ruth

Handley, Robert

Harrison, Paul

Heidari, Nima

Hepple, Steve

Hilton, Catherine

Hodgson, Helen

Hodgson, Paul

Hooper, Lucille

Hughes, Adrian

Hulley, Philippa Anne

Hutchison, Anne-Marie

James, Kate

Kassam, Jamila

Keene, David J

Kelly, Andrew

Lamb, Sarah E

Lewis, Kathryn

Lowe, Janet

Maitland, Kate

Mason, Lyndon

McCormick, Richard

McGowan, Kerri

Mestre, Maria

Muller, Doreeen

Nott, Claire

O'Connor, Heather M

O'Sullivan, Susie

Parsons, Scott R

Prasath, Sangeetha

Quinn, Leanne

Ravindran, Ranjith

Scanlon, Deborah

Schlussel, Michael Maia

Solan, Matthew

Spoors, Louise

Stables, Gareth

Stokes-Denson, Joanne

Storton, Sharon

Thompson, Jacqueline

Tonics, Louise

Topliss, Claire

Turner, Sylvia

Velpula, Jagan

Vertue, Mark

Wagland, Susan

Walker, Julie

Walker, Philip

Watson, Lisa

Whitcher, Alison

Whiteman, Jessica

Willett, Keith

Williamson, Georgina

Young, Jonathan

Young, Sophie

Zhang, Yuhan

ObjectiveTo determine whether an injection of platelet rich plasma improves outcomes after acute Achilles tendon rupture.DesignRandomised, placebo controlled, two arm, parallel group, participant and assessor masked, superiority trial.SettingSecondary care trauma units across 19 hospitals in the United Kingdom's health service.ParticipantsRecruitment 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.InterventionsParticipants 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 measuresPrimary 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.ResultsParticipants 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.ConclusionsThere 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 registrationISRCTN54992179

University of Liverpool Repository

UNCERTAINTIESHow effective are platelet rich plasma injections intreating musculoskeletal soft tissue injuries?David J KeeneNDORMS research fellow in trauma rehabilitation1, Joseph AlsousouNIHR academicclinical fellow in trauma and orthopaedic surgery 2, Keith Willett professor of orthopaedic traumasurgery 11Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK; 2Department of Molecular and ClinicalCancer Medicine, University of Liverpool, UKPlatelet-rich plasma (PRP) has become increasingly popular insports medicine and orthopaedic practice as treatment formuscle, tendon, and ligament injuries, and has received mediaattention because of its promise as a regenerative therapy.1 2PRP is an autologous preparation of a patient’s whole blood,which is centrifuged or filtered, allowing separation of a fractioncontaining a supraphysiological concentration of platelets (fig1⇓). PRP can be applied on its own, or as an adjunct to surgery,allowing a high “dose” of growth factors and other bioactiveproteins such as cytokines and chemokines to be delivered tothe target tissue. This has the potential to improve repair andregeneration, although evidence from in vitro and animal studieshas been conflicting.3-5As an autologous preparation, PRP has been introduced intoclinical practice without being subject to the stringentdevelopment required of new drugs. Many commerciallyavailable PRP preparation devices have US Food and DrugAdministration (FDA) approval, although this is based on deviceperformance and safety, not on a requirement for evidence ofclinical efficacy.6What is the evidence of uncertainty?Lack of evidence of effectivenessA 2014 Cochrane review identified 19 single centre randomisedtrials (1088 participants) that compared PRPwith placebo, wholeblood, dry needling, or no treatment for eight different soft tissueinjuries, either as a direct treatment (for elbow lateralepicondylitis, patellar tendinopathy, and Achilles tendontendinopathy) or as an adjunct to surgery (anterior cruciateligament reconstruction grafts and donor sites, rotator cuff repair,subacromial decompression, and Achilles rupture repair).7Comparisons with other active treatments were not included.Most trials were judged to be at high risk of bias, with lack ofstandardisation of PRP preparation. Overall, there was noclinically significant improvement in pain and function withPRP. The authors of the Cochrane review concluded that therewas insufficient evidence to support the use of PRP.In our review of a further 10 randomised controlled trials (476participants), we too had difficulty drawing clear conclusionsabout the efficacy of PRP, because of heterogeneousmusculoskeletal conditions and outcome measures,underpowered studies, and poor reporting. Only half of thesetrials included analyses of PRP content and quality, and theseshowed marked differences in platelet concentration and whitecell content; this is problematic, as different PRP preparationsand application techniques could affect effectiveness.2Possible harmsAutologous PRP is generally considered to carry a low risk ofharm, but there are no high quality large scale clinical studiesevaluating safety.8 Pooled data from the Cochrane review didnot show a significant difference between PRP and comparatorgroups.7 Use of PRP may risk introducing infection, reportedas an adverse event in two surgical randomised controlledtrials.9 10 A recent PRP randomised controlled trial found that2/160 (1%) of PRP samples were positive for microbial growth,Correspondence to: D J Keene, Kadoorie Centre for Critical Care Research and Education, John Radcliffe Hospital, Oxford OX3 9DUdavid.keene@ndorms.ox.ac.ukThis is one of a series of occasional articles that highlight areas of practice where management lacks convincing supporting evidence. The seriesadviser is David Tovey, editor in chief, the Cochrane Library. This paper is based on a research priority identified and commissioned by the NationalInstitute for Health Research’s Health Technology Assessment programme on an important clinical uncertainty. To suggest a topic for this series,please email us at uncertainties@bmj.com.For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2016;352:i517 doi: 10.1136/bmj.i517 (Published 17 February 2016) Page 1 of 4PracticePRACTICEWhat you need to know• Autologous platelet-rich plasma (PRP) is increasingly used to treat musculoskeletal soft tissue injuries, either on its own or as anadjunct to surgery• Routine use is not recommended as there is insufficient evidence of clinical efficacy; instead, its use should be restricted to researchsettings• Ensure patients receiving PRP are aware of the limited evidence of efficacy, so that they can make an informed decision about theircare• Clinicians should be aware of the concentration of PRP, and yield of bioactive proteins, produced by their selected preparation deviceSearch strategy and study selectionWe used the same search strategy and eligibility criteria as a Cochrane review of PRP (randomised controlled trials of platelet-rich plasma(PRP) versus no PRP or placebo)7 in Medline and the Cochrane Library and Central Register Of Controlled Trials (up to 27 May 2015). Wefound a further 10 randomised controlled trials (476 participants), investigating PRP use for rotator cuff tendinopathy15 16 and surgical repair,9-20acute hamstring injury,11 21 and elbow lateral epicondylitis.22although no clinical indicators of infection developed.11 Infectionrisk may also vary with different PRP preparations as somehave been shown to have antimicrobial properties in vitro.12Is ongoing research likely to providerelevant evidence?We searched the WHO International Clinical Trials Registerand identified several ongoing randomised controlled trialsevaluating PRP for a wide range of musculoskeletal soft tissueinjuries. We are currently conducting the PATH-2 study, arandomised controlled trial to compare the effects onmuscle-tendon function of a standardised PRP preparation versusdry needle injection (control) for non-operatively managed acuteAchilles tendon rupture (ISRCTN54992179).What should we do in the light of theuncertainty?Routine use of PRP in clinical practice for musculoskeletal softtissue injuries cannot be recommended given the lack of highquality clinical evidence supporting its efficacy. Thus the UK'sNational Institute for Health and Care Excellence (NICE)guidance for autologous blood injections, including PRP, forplantar fasciitis and tendinopathy states that it should “only beused with special arrangements for clinical governance, consentand audit or research,” even if there are nomajor safety concernswith use for these conditions.13 14We argue that patients should only be offered PRP formusculoskeletal soft tissue injuries within the context of welldesigned clinical trials, with informed consent, high qualityverbal explanations, and supporting written information. Advisepatients that there is currently insufficient evidence to show thatit is effective treatment for musculoskeletal soft tissue injuries.Clinicians offering PRP should ask manufacturers for theevidence of the platelet and growth factor concentrations, theconstitution, and the viability of their PRP product (plateletactivation levels).Contributors The idea for this article was formulated by KW in discussionwith M Chew (associate editor, BMJ), DJK, and JA. DJK wrote the firstdraft of the paper, and KW and JA commented on it. All authorsapproved the final version and are the guarantors.Competing interests: We have read and understood the BMJ policy ondeclaration of interests and declare the following interests: KW is chiefinvestigator and JA and DJK are co-investigators on the PATH-2 trialevaluating platelet-rich plasma (PRP) as a treatment for acute Achillestendon rupture. PATH-2 is funded by the Efficacy and MechanismEvaluation (EME) Programme, an MRC and NIHR partnership. KWreceives royalties from Zimmer for previous orthopaedic implant designwork.The views expressed in this publication are those of the authors andnot necessarily those of the MRC, NHS, NIHR or the Department ofHealth. PATH-2 uses the same PRP preparation device (supplied byFannin UK) at all recruitment sites to standardise the intervention. Nocontract or agreements have been made with the manufacturer orsupplier, nor will they have a role in the study design; data collection,access, analysis, or interpretation; writing of the report; or the decisionto publish.Provenance and peer review: Commissioned, externally peer reviewed.Patient consent: Patient consent obtained.1 Wallis C. The coming revolution in knee repair. Sci Am 2015;312:25-6doi:10.1038/scientificamerican0315-25. .26336679.2 Engebretsen L, Steffen K, Alsousou J, et al. IOC consensus paper on the use ofplatelet-rich plasma in sports medicine. Br J Sports Med 2010;44:1072-81. doi:10.1136/bjsm.2010.079822. 21106774.3 Alsousou J, Thompson M, Hulley P, Noble A, Willett K. The biology of platelet-rich plasmaand its application in trauma and orthopaedic surgery: a review of the literature. J BoneJoint Surg Br 2009;91:987-96. doi:10.1302/0301-620X.91B8.22546. 19651823.4 Alsousou J, Ali A, Willett K, Harrison P. The role of platelet-rich plasma in tissueregeneration. Platelets 2013;24:173-82. doi:10.3109/09537104.2012.684730. 22647081.5 Mosca MJ, Rodeo SA. Platelet-rich plasma for muscle injuries: game over or time out?CurrRev Musculoskelet Med 2015;8:145-53. doi:10.1007/s12178-015-9259-x. 25715983.6 Harm SK, Fung MK. Platelet-rich plasma injections: out of control and on theloose?Transfusion 2015;55:1596-8. doi:10.1111/trf.13160. 26172145.7 Moraes VY, Lenza M, Tamaoki MJ, Faloppa F, Belloti JC. Platelet-rich therapies formusculoskeletal soft tissue injuries. Cochrane Database Syst Rev2014;4:CD010071.24782334.8 Dhillon RS, Schwarz EM, Maloney MD. Platelet-rich plasma therapy - future ortrend?Arthritis Res Ther 2012;14:219. doi:10.1186/ar3914. 22894643.9 Rajaratnam K, Ayeni O, Moro J, et al. Platelet rich plasma following arthroscopic repairof rotator cuff tears: A double blind randomized controlled trial. Arthroscopy 2013;29(suppl.1):e46doi:10.1016/j.arthro.2013.07.025. .10 Schepull T, Kvist J, Norrman H, Trinks M, Berlin G, Aspenberg P. Autologous plateletshave no effect on the healing of human achilles tendon ruptures: a randomized single-blindstudy. Am J Sports Med 2011;39:38-47. doi:10.1177/0363546510383515. 21051425.11 Reurink G, Goudswaard GJ, Moen MH, et al. Dutch Hamstring Injection Therapy (HIT)Study Investigators. Platelet-rich plasma injections in acute muscle injury. N Engl J Med2014;370:2546-7. doi:10.1056/NEJMc1402340. 24963588.12 Drago L, Bortolin M, Vassena C, Romanò CL, Taschieri S, Del Fabbro M. Plasmacomponents and platelet activation are essential for the antimicrobial properties ofautologous platelet-rich plasma: an in vitro study. PLoS One 2014;9:e107813. doi:10.1371/journal.pone.0107813. 25232963.13 National Institute for Health and Care Excellence. Autologous blood injection for plantarfasciitis (interventional procedure guidance 437). 2013. www.nice.org.uk/guidance/ipg437.14 National Institute for Health and Care Excellence. Autologous blood injection fortendinopathy (interventional procedure guidance 438). 2013. www.nice.org.uk/guidance/ipg438.15 Kesikburun S, Tan AK, Yilmaz B, Yaşar E, Yazicioğlu K. Platelet-rich plasma injectionsin the treatment of chronic rotator cuff tendinopathy: a randomized controlled trial with1-year follow-up. Am J Sports Med 2013;41:2609-16. doi:10.1177/0363546513496542. 23893418.16 Rha DW, Park GY, Kim YK, Kim MT, Lee SC. Comparison of the therapeutic effects ofultrasound-guided platelet-rich plasma injection and dry needling in rotator cuff disease:a randomized controlled trial. Clin Rehabil 2013;27:113-22. doi:10.1177/0269215512448388. 23035005.17 Jo CH, Shin JS, Lee YG, et al. Platelet-rich plasma for arthroscopic repair of large tomassive rotator cuff tears: a randomized, single-blind, parallel-group trial. Am J SportsMed 2013;41:2240-8. doi:10.1177/0363546513497925. 23921338.For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2016;352:i517 doi: 10.1136/bmj.i517 (Published 17 February 2016) Page 2 of 4PRACTICERecommendations for further researchLarge multicentre randomised controlled trials with blinding of participants, outcome assessors, and where practical, clinical investigators—Patients with common high-burden musculoskeletal soft tissue injuries, receiving either platelet-rich plasma (PRP) or a placebo orinactive control intervention. Efficacy of PRP should be established before comparisons with other active interventions.Outcome measures—Pain, patient reported function scales, physical performance tests, and return to sport, work, and social activities.Trials should also evaluate:• What cell and growth factor concentrations and platelet activation levels in PRP optimise clinical efficacy• Optimal preparation process and delivery method for PRP (for example, whether injections need to be guided by imaging for someconditions)• Specific timing or dose of PRP, or need for repeated injections• Which validated clinical outcomes (such as recovery of musculoskeletal function) and outcomes important to patients (such as painand longer term risk of re-injury) are the most appropriate• The risk of adverse events, with careful monitoring and reporting of harms.Large scale collaboration are needed to facilitate multicentre randomised controlled trials, expanding networks of clinicians andresearchers.23How patients were involved in the creation of this articleA patient who previously had a tendon rupture and received PRP or a control treatment in a pilot randomised controlled trial gave feedbackon the manuscript, which we incorporated in the revised paper. She highlighted the value of differentiating between clinical outcomes andoutcomes important to patients, and the provision of clear verbal and written information to support patients.18 Ruiz-Moneo P, Molano-Muñoz J, Prieto E, Algorta J. Plasma rich in growth factors inarthroscopic rotator cuff repair: a randomized, double-blind, controlled clinical trial.Arthroscopy 2013;29:2-9. doi:10.1016/j.arthro.2012.08.014. 23276410.19 Weber SC, Kauffman JI, Parise C, Weber SJ, Katz SD. Platelet-rich fibrin matrix in themanagement of arthroscopic repair of the rotator cuff: a prospective, randomized,double-blinded study. Am J Sports Med 2013;41:263-70. doi:10.1177/0363546512467621. 23204506.20 Zumstein MA, Rumian A, Lesbats V, Schaer M, Boileau P. Increased vascularizationduring early healing after biologic augmentation in repair of chronic rotator cuff tears usingautologous leukocyte- and platelet-rich fibrin (L-PRF): a prospective randomized controlledpilot trial. J Shoulder Elbow Surg 2014;23:3-12. doi:10.1016/j.jse.2013.08.017. 24331121.21 A Hamid MS, Mohamed Ali MR, Yusof A, George J, Lee LP. Platelet-rich plasma injectionsfor the treatment of hamstring injuries: a randomized controlled trial. Am J Sports Med2014;42:2410-8. doi:10.1177/0363546514541540. 25073598.22 Raeissadat SA, Rayegani SM, Hassanabadi H, Rahimi R, Sedighipour L, Rostami K. Isplatelet-rich plasma superior to whole blood in the management of chronic tennis elbow:one year randomized clinical trial. BMC Sports Sci Med Rehabil 2014;6:12. doi:10.1186/2052-1847-6-12. 24635909.23 Rangan A, Jefferson L, Baker P, Cook L. Clinical trial networks in orthopaedic surgery.Bone Joint Res 2014;3:169-74. doi:10.1302/2046-3758.35.2000265. 24869466.Published by the BMJ Publishing Group Limited. For permission to use (where not alreadygranted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissionsFor personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2016;352:i517 doi: 10.1136/bmj.i517 (Published 17 February 2016) Page 3 of 4PRACTICEFigureFig 1Making autologous platelet-rich plasma (PRP): a whole blood sample is taken (a) then a specialised centrifuge (suchas the Magellan Autologous Platelet Separator System from Arteriocyte (b)) or filtration system is used to concentrate theplatelets, and the resulting PRP is collected in a syringe for injection into the target tissue (c)For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2016;352:i517 doi: 10.1136/bmj.i517 (Published 17 February 2016) Page 4 of 4PRACTICE

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

http://livrepository.liverpool.ac.uk/3077059/1/bmj.i517.full_DkKW_HowEffectPRP_Pub_17FEB2016.pdf

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

Abstract

Similar works

Full text

Available Versions

University of Liverpool Repository