Impact, diagnostic imaging and prognosis of Achilles tendinopathy Tjerk Sleeswijk Visser
Impact, diagnostic imaging and prognosis of Achilles tendinopathy Tjerk Sleeswijk Visser
Colophon ISBN: 978-94-6506-341-6 Cover design: Ridderprint | www.ridderprint.nl Layout and printing: Ridderprint | www.ridderprint.nl © Tjerk Sleeswijk Visser, the Netherlands, 2024. All rights reserved. No part of this thesis may be reproduced or transmitted in any form or by any means, without prior written permission by the author or the copyright-owning journals for previously published chapters Financial support for this thesis was provided by: Erasmus MC Foundation, Rotterdam Erasmus Trustfonds, Rotterdam Printing of this thesis was kindly supported by: Department of Orthopedics & Sports Medicine Erasmus University Medical Center, Erasmus University Rotterdam Graduate School, Xcelsior, van Dinter Den Haag, De Gangmakerij, LINK, LEUK Orthopedie, Bauerfeind, Push, ChipSoft, ABN AMRO and Wetenschapsfonds HMC
Impact, Diagnostic Imaging and Prognosis of Achilles Tendinopathy Impact, diagnostische beeldvorming en prognose van achilles tendinopathie Proefschrift Ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof.dr. A.L. Bredenoord en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op dinsdag 15 oktober 2024 15:30 uur door Tjerk Sieuwert Otmar Sleeswijk Visser geboren te Voorburg.
PROMOTIECOMMISSIE Promotoren Prof.dr. D. Eygendaal Overige leden Prof.dr. E.H.G. Oei Prof.dr. J. Zwerver Dr. M. van Middelkoop Copromotor Dr. R.J. de Vos
TABLE OF CONTENTS Chapter 1 General introduction 7 Chapter 2 ICON 2023—International Scientific Tendinopathy Symposium Consensus: the core outcome set for Achilles tendinopathy (COSAT) using a systematic review and a Delphi study of healthcare professionals and patients 21 Chapter 3 Normative values for calf muscle strength-endurance in the general population assessed with the Calf Raise Application: A large international cross-sectional study 45 Chapter 4 Impact of chronic Achilles tendinopathy on health-related quality of life, work performance, healthcare utilisation and costs 67 Chapter 5 Standardized pain mapping for diagnosing Achilles tendinopathy 85 Chapter 6 Measuring ultrasonographic Achilles tendon thickness of the insertion is less reliable than the midportion 101 Chapter 7 Normative ultrasound values for Achilles tendon thickness in the general population and Achilles tendinopathy patients: a large international cross-sectional study 121 Chapter 8 Low socioeconomic status is associated with worse treatment outcomes in patients with Achilles tendinopathy 137 Chapter 9 General discussion 157 APPENDICES Summary 176 Nederlandse samenvatting 180 PhD portfolio summary 184 List of publications 188 Dankwoord 190 Curriculum vitae 192
Chapter 1 General Introduction
8 Chapter 1 PREFACE "War will be always, until mankind reaches a point where it becomes extinct or destroys itself." This powerful saying by Achilles, a legendary Greek warrior known for his strength, in Homer's poem "The Iliad" reflects the nature of human struggle. The name "Achilles tendon" originates from his story, where he was struck in the heel by an arrow during the Trojan War. The arrow pierced the tendon, which connects the calf muscles to the heel bone, and led to his downfall. Consequently the tendon was named after him due to the belief that it was his only weak spot. The Achilles tendon is the largest tendon in the human body and is responsible for transmitting forces from the calf muscles to the heel bone, allowing for forceful propulsion during activities such as running and jumping.1 Just as Achilles faced the challenges of war, many people nowadays have their own battle, although on a different battleground – their struggles to stay healthy and physically active. One such battle is fought against a condition known as Achilles tendinopathy. Achilles tendinopathy is a condition that involves localized pain, thickening of the tendon, and impaired load-bearing capacity.2-4 While the cause of Achilles tendinopathy is not related to the mythological weakness of Achilles, the name serves as a reminder of the injury prone nature of the tendon. Clinicians and researchers are continuously trying to understand the exact causes and manage the effects of this often debilitating condition. This thesis explores the impact, diagnostic imaging modalities and prognosis of Achilles tendinopathy, aiming to contribute in the ongoing ´battle´ to alleviate its burden.
9 1 General Introduction IMPACT Achilles tendinopathy is commonly seen in physically active individuals in middle age, with an incidence rate of 2-3 cases per 1,000 Dutch general practice registered patients.5-7 The incidence of Achilles tendinopathy has increased in the past decade, partly due to the growing number of people participating in physical activities.5,6 However, not all patients with Achilles tendinopathy are physically active and the increased prevalence of potential intrinsic risk factors as body weight or insulin resistance may also play a role in the increased incidence.5,6 Runners have a high risk of experiencing an Achilles tendon injury in their lifetime, with a cumulative incidence rate of 52%.8 The impact of this condition on patients is often measured using various outcome measures.9 These measures, such as pain intensity, functional limitations, and quality of life, provide valuable insights into the severity and progression of the condition. However, an important issue in research and in the field of Achilles tendinopathy specifically is the heterogeneity of the outcome measures used which limits comparability of study’s findings.9 The treatment of Achilles tendinopathy is often variable in clinical practice and more uniformity is necessary.6 Several treatment options for Achilles tendinopathy are available with conservative treatment being the primary approach.6,10 Calf muscle strengthening exercises are an important part of the treatment of Achilles tendinopathy as patients with Achilles tendinopathy have large deficits in plantar flexor strength and endurance.11,12 The single-leg heel rise endurance test (HRET) is a frequently used test to assess calf muscle strength endurance.12,13 A problem in the assessment of calf muscle strength and endurance is that the non-symptomatic limb cannot generally be used as reference and normative values for the HRET are currently lacking.11,14 Achilles tendinopathy can cause severe pain and reduced load-bearing capacity, resulting in a decreased quality of life.2,7,8 Qualitative research indicates that some patients with this condition experience a negative impact on their social activities, self-perceived fitness levels, and overall sense of identity.15-17 One exploratory study showed that individuals with Achilles tendinopathy have lower quality of life scores compared to normative data.16 Similarly, other musculoskeletal conditions can also impact quality of life, albeit to varying degrees.18-21 Understanding how Achilles tendinopathy affects quality of life can guide scientific research and help develop targeted management plans that address specific domains. There is currently limited knowledge regarding the impact of Achilles tendinopathy on work performance, healthcare utilization, and costs.
10 Chapter 1 DIAGNOSTIC IMAGING Achilles tendinopathy can affect both the insertional and midportion region of the tendon (Figure 1), which have different anatomical features and loading profiles.22 Achilles tendinopathy is mainly a clinical diagnosis, with imaging being used to confirm the diagnosis.2,10 The diagnostic criteria for Achilles tendinopathy (local pain, thickening and impaired load-bearing capacity) are considered to be reliable.23 A key diagnostic criterion is the location of pain, as distinguishing between midportion and insertional Achilles tendinopathy affects initial treatment and prognosis.23,24 As subjective self-reported pain is one of the clinical criteria for establishing the diagnosis, it is essential to know if patients with Achilles tendinopathy can accurately localize their pain, information which is currently unknown. Figure 1. Visual presentation of the Achilles tendon with the light blue region representing the midportion part of the tendon and the dark blue region indicating the insertional part of the Achilles tendon. Physical examination typically involves assessing the thickness of the tendon and determining if there is tenderness upon palpation.3 The tendon is examined by applying gentle pressure between the index finger and thumb along the entire length of the tendon, from the musculotendinous junction to the calcaneal insertion.3 Patients are then asked if they feel any pain during palpation.3,23 Pain on palpation and self-reported (location of) pain are considered valid clinical tests.23 As the presence of tendon thickening is not always necessary to diagnose Achilles tendinopathy, experts agree that the clinical diagnosis can be established when there is localized pain during tendon-loading activities and
11 1 General Introduction recognizable tenderness upon Achilles tendon palpation. Despite the challenges inherent in diagnosing Achilles tendinopathy, experts concur that the above-mentioned criteria are reliable.2,3 The use of imaging to diagnose Achilles tendinopathy is a topic of debate.2 In cases where not all clinical diagnostic criteria are present, imaging can play an important role to confirm the diagnosis.2,25 When imaging is used, ultrasound is the preferred modality as it is a cheap and accessible method.25 Conventional X-rays are typically only used to exclude bony abnormalities and MRI may be considered if ultrasound is unavailable, prior to potential surgery or when the findings on ultrasound are not consistent with the clinical picture.25 The Ultrasound Tissue Characterization (UTC) procedure is a reliable technique that allows for accurate depiction of Achilles tendon geometry and structure.26-29 The UTC is a customized tracking and ultrasonographic data-collection device that provides objective, standardized measurements, which in practice are often translated to conventional ultrasound.26 The UTC procedure is carried out by positioning participants prone on an examination table with a maximal dorsiflexion angle of the ankle. A multi-frequency 5-16 MHz linear-array transducer is used, which is placed in a transverse position to the Achilles tendon (Figure 1). The transducer in the UTC tracking and data-collection device moves automatically from proximal to distal over a distance of 12 cm, collecting digital transverse images at regular intervals of 0.2 mm which result in a three-dimensional data block (Figure 2). Figure 2. The Ultrasound Tissue Characterization procedure. The typical appearance of the Achilles tendon on ultrasound is a pattern of parallel fibrillar lines in the longitudinal plane and a round-to-oval shape in the transverse plane.25 The
12 Chapter 1 Achilles tendon is typically viewed in two planes and the maximum anterior-posterior tendon thickness is commonly measured in the transversal plane (Figure 3). Achilles tendinopathy is ultrasonographically characterized by increased tendon thickness (Figure 3), decreased tendon structure and neovascularization.26,30,31 Doppler ultrasonography can detect the increased blood supply.31,32 However, a significant drawback of imaging is that findings suggestive for tendinopathy are present in 25% of asymptomatic Achilles tendons, which can lead to overdiagnosis and overtreatment.33 Another problem with imaging is that reference values for tendon geometry and structure are lacking for the general population.33 The current cut-off value of 6 mm in maximum Achilles tendon thickness is accepted as a reference standard, but is based on small crosssectional studies in specific populations, and it is likely that tendon geometry is influenced by personal characteristics.25 Figure 3. Visualisation of the Achilles tendon using Ultrasound Tissue Characterization in a healthy individual (A + B) and a patient with midportion Achilles tendinopathy (C + D), with increased tendon thickness. In image A + C the transversal view is shown and in image B + D the tendon is viewed in the longitudinal plane. The yellow line represents the border of the Achilles tendon. PROGNOSTIC FACTORS The conservative therapy for Achilles tendinopathy consists of load-management, education and exercise therapy. However, this treatment may not be very effective in first line care, as one-thirds of patients with new-onset Achilles tendinopathy continue to experience symptoms at one-year follow-up.34 At ten years of follow-up, even up to a quarter of patients remain symptomatic.35
13 1 General Introduction In clinical practice, it is essential to have the ability to anticipate the recovery of patients and identify those who will likely endure chronic symptoms. However, knowledge of prognostic factors for patients with Achilles tendinopathy is currently lacking, with imaging having no prognostic value, and only limited evidence for an association between having a metabolic disorder and developing persistent symptoms.34,36 The past years it has become increasingly clear that socio-economic status plays a role in prevalence of disease and treatment outcomes. Socio-economic factors such as income, age, level of education, ethnicity, and place of residence have been found to significantly affect the incidence and outcomes of various diseases.37-39 Individuals with low socioeconomic status are particularly vulnerable to chronic diseases and musculoskeletal conditions, resulting in worse outcomes.37,40 The role of socio-economic status in the occurrence and treatment of Achilles tendinopathy is still unclear.
14 Chapter 1 AIMS AND OUTLINE OF THIS THESIS The aims of this thesis are to evaluate the impact of Achilles tendinopathy, to assess the role of ultrasonographic imaging and to assess socio-economic status as prognostic factor in Achilles tendinopathy patients. Currently, there is considerable variation in the outcome measures used for Achilles tendinopathy, which can have implications for patient care, as healthcare professionals and researchers are unable to adequately interpret, compare, and synthesize study results for meta-analyses. In Chapter 2 we performed an international Delphi survey and consensus meeting to agree to a set of core outcome measures for clinical trials on Achilles tendinopathy. This will advance the comparability between future studies in this field. Calf muscle strengthening exercises are an important part of the treatment of Achilles tendinopathy. A frequently used test to assess calf muscle strength endurance is the single-leg heel rise endurance test (HRET). In Chapter 3 we established normative values for the HRET in a large population of healthy individuals as these are currently lacking for the general population. In Chapter 4 we investigated the impact of Achilles tendinopathy on quality of life and compared this to other prevalent musculoskeletal conditions. We also studied the impact of Achilles tendinopathy on work performance and health care utilization as well as the associated costs of Achilles tendinopathy. It is useful to know whether patients with Achilles tendinopathy can adequately localize their pain and distinguish between the insertional and midportion region as this effects prognosis and treatment. In Chapter 5 we evaluated the level of agreement between patient-reported pain using a standardized pain map and the physician-determined clinical diagnosis of Achilles tendinopathy. Ultrasound Tissue Characterization is a valid imaging method to evaluate tendon structure and is widely used in clinical research, but knowledge on the reliability of tendon thickness measurements is lacking. In Chapter 6 we determined the intra-rater and inter-rater reliability for Achilles tendon thickness measurements using UTC and assessed if these measurements can be reliably translated to conventional ultrasound. In Chapter 7 we obtained reference values for Achilles tendon thickness on ultrasound in a large asymptomatic population and compared these to patients with Achilles tendinopathy. These values can help clinicians distinguish between normal morphological changes and abnormalities and enhance the diagnostic process. Knowledge on health disparities between different populations can help clinicians to optimize treatment for the individual patient. In Chapter 8 we evaluated if socio-economic status, measured by factors such as place of residence, age, gender, education level and
15 1 General Introduction income, has effect on symptom severity and response to standardized treatment in patients with Achilles tendinopathy. The clinical implications and relevance of the findings of this thesis are discussed in Chapter 9 as well as perspectives for future research. In Chapter 10 a summary of the thesis in both English and Dutch language is presented.
16 Chapter 1 REFERENCES 1. O'Brien M. The anatomy of the Achilles tendon. Foot Ankle Clin. Jun 2005;10(2):225-38. 2. Scott A, Squier K, Alfredson H, et al. ICON 2019: International Scientific Tendinopathy Symposium Consensus: Clinical Terminology. Br J Sports Med. Mar 2020;54(5):260-262. 3. Maffulli N, Kenward MG, Testa V, Capasso G, Regine R, King JB. Clinical diagnosis of Achilles tendinopathy with tendinosis. Clin J Sport Med. Jan 2003;13(1):11-5. 4. Maffulli N, Khan KM, Puddu G. Overuse tendon conditions: time to change a confusing terminology. Arthroscopy. Nov-Dec 1998;14(8):840-3. 5. de Jonge S, van den Berg C, de Vos RJ, et al. Incidence of midportion Achilles tendinopathy in the general population. Br J Sports Med. Oct 2011;45(13):1026-8. 6. Maffulli N, Sharma P, Luscombe KL. Achilles tendinopathy: aetiology and management. J R Soc Med. Oct 2004;97(10):472-6. 7. d'Hooghe PPRN, Kerkhoffs GMMJ. The ankle in football. 2014. 8. Kujala UM, Sarna S, Kaprio J. Cumulative incidence of achilles tendon rupture and tendinopathy in male former elite athletes. Clin J Sport Med. May 2005;15(3):133-5. 9. Vicenzino B, de Vos RJ, Alfredson H, et al. ICON 2019-International Scientific Tendinopathy Symposium Consensus: There are nine core health-related domains for tendinopathy (CORE DOMAINS): Delphi study of healthcare professionals and patients. Br J Sports Med. Apr 2020;54(8):444-451. 10. Martin RL, Chimenti R, Cuddeford T, et al. Achilles Pain, Stiffness, and Muscle Power Deficits: Midportion Achilles Tendinopathy Revision 2018. J Orthop Sports Phys Ther. May 2018;48(5):A1-A38. 11. O'Neill S, Barry S, Watson P. Plantarflexor strength and endurance deficits associated with mid-portion Achilles tendinopathy: The role of soleus. Physical Therapy in Sport. 2019/05/01/ 2019;37:69-76. doi:10.1016/j.ptsp.2019.03.002 12. Silbernagel KG, Gustavsson A, Thomeé R, Karlsson J. Evaluation of lower leg function in patients with Achilles tendinopathy. Knee Surgery, Sports Traumatology, Arthroscopy. 2006/11/01 2006;14(11):1207-1217. doi:10.1007/s00167-006-0150-6 13. Hébert-Losier K, Newsham-West RJ, Schneiders AG, Sullivan SJ. Raising the standards of the calfraise test: a systematic review. J Sci Med Sport. Nov 2009;12(6):594-602. 14. Hébert-Losier K, Wessman C, Alricsson M, Svantesson U. Updated reliability and normative values for the standing heel-rise test in healthy adults. Physiotherapy. Dec 2017;103(4):446-452. 15. Mc Auliffe S, Synott A, Casey H, Mc Creesh K, Purtill H, O'Sullivan K. Beyond the tendon: Experiences and perceptions of people with persistent Achilles tendinopathy. Musculoskelet Sci Pract. Jun 2017;29:108-114. 16. Ceravolo ML, Gaida JE, Keegan RJ. Quality-of-Life in Achilles Tendinopathy: An Exploratory Study. Clin J Sport Med. Sep 2020;30(5):495-502. 17. Turner J, Malliaras P, Goulis J, Mc Auliffe S. "It's disappointing and it's pretty frustrating, because it feels like it's something that will never go away." A qualitative study exploring individuals' beliefs and experiences of Achilles tendinopathy. PLoS One. 2020;15(5):e0233459. 18. Cross M, Smith E, Hoy D, et al. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. Jul 2014;73(7):1323-30.
17 1 General Introduction 19. Beaudart C, Biver E, Bruyère O, et al. Quality of life assessment in musculo-skeletal health. Aging Clin Exp Res. May 2018;30(5):413-418. 20. Picavet HS, Hoeymans N. Health related quality of life in multiple musculoskeletal diseases: SF-36 and EQ-5D in the DMC3 study. Ann Rheum Dis. Jun 2004;63(6):723-9. 21. Salaffi F, De Angelis R, Stancati A, Grassi W, Pain MA, Prevalence IGs. Health-related quality of life in multiple musculoskeletal conditions: a cross-sectional population based epidemiological study. II. The MAPPING study. Clin Exp Rheumatol. Nov-Dec 2005;23(6):829-39. 22. Cook JL, Purdam CR. Is tendon pathology a continuum? A pathology model to explain the clinical presentation of load-induced tendinopathy. British Journal of Sports Medicine. 2009;43(6):409416. doi:10.1136/bjsm.2008.051193 23. Hutchison AM, Evans R, Bodger O, et al. What is the best clinical test for Achilles tendinopathy? Foot Ankle Surg. Jun 2013;19(2):112-7. 24. Fahlström M, Jonsson P, Lorentzon R, Alfredson H. Chronic Achilles tendon pain treated with eccentric calf-muscle training. Knee Surg Sports Traumatol Arthrosc. Sep 2003;11(5):327-33. 25. Bleakney RR, White LM. Imaging of the Achilles tendon. Foot Ankle Clin. Jun 2005;10(2):239-54. 26. van Schie HT, de Vos RJ, de Jonge S, et al. Ultrasonographic tissue characterisation of human Achilles tendons: quantification of tendon structure through a novel non-invasive approach. Br J Sports Med. Dec 2010;44(16):1153-9. 27. de Jonge S, de Vos RJ, Weir A, et al. One-Year Follow-up of Platelet-Rich Plasma Treatment in Chronic Achilles Tendinopathy:A Double-Blind Randomized Placebo-Controlled Trial. The American Journal of Sports Medicine. 2011;39(8):1623-1630. doi:10.1177/0363546511404877 28. de Vos RJ, Weir A, Tol JL, Verhaar JAN, Weinans H, van Schie HTM. No effects of PRP on ultrasonographic tendon structure and neovascularisation in chronic midportion Achilles tendinopathy. British Journal of Sports Medicine. 2011;45(5):387-392. doi:10.1136/ bjsm.2010.076398 29. Wezenbeek E, Willems T, Mahieu N, et al. The Role of the Vascular and Structural Response to Activity in the Development of Achilles Tendinopathy: A Prospective Study. Am J Sports Med. Mar 2018;46(4):947-954. 30. Maffulli N, Wong J, Almekinders LC. Types and epidemiology of tendinopathy. Clin Sports Med. Oct 2003;22(4):675-92. 31. Ohberg L, Lorentzon R, Alfredson H. Neovascularisation in Achilles tendons with painful tendinosis but not in normal tendons: an ultrasonographic investigation. Knee Surg Sports Traumatol Arthrosc. Jul 2001;9(4):233-8. 32. Hamper UM, DeJong MR, Caskey CI, Sheth S. Power Doppler imaging: clinical experience and correlation with color Doppler US and other imaging modalities. Radiographics. Mar-Apr 1997;17(2):499-513. 33. McAuliffe S, McCreesh K, Culloty F, Purtill H, O'Sullivan K. Can ultrasound imaging predict the development of Achilles and patellar tendinopathy? A systematic review and meta-analysis. Br J Sports Med. Dec 2016;50(24):1516-1523. 34. Lagas IF, Fokkema T, Bierma-Zeinstra SMA, Verhaar JAN, van Middelkoop M, de Vos RJ. How many runners with new-onset Achilles tendinopathy develop persisting symptoms? A large prospective cohort study. Scand J Med Sci Sports. Oct 2020;30(10):1939-1948. 35. Johannsen F, Jensen S, Wetke E. 10-year follow-up after standardised treatment for Achilles tendinopathy. BMJ Open Sport Exerc Med. 2018;4(1):e000415.
18 Chapter 1 36. de Vos RJ, Weir A, Cobben LP, Tol JL. The value of power Doppler ultrasonography in Achilles tendinopathy: a prospective study. Am J Sports Med. Oct 2007;35(10):1696-701. 37. Putrik P, Ramiro S, Chorus AM, Keszei AP, Boonen A. Socio-economic gradients in the presence of musculoskeletal and other chronic diseases: results from a cross-sectional study in the Netherlands. Clinical Rheumatology. 2018/12/01 2018;37(12):3173-3182. doi:10.1007/s10067-018-4158-3 38. Callahan LF, Cleveland RJ, Shreffler J, et al. Associations of educational attainment, occupation and community poverty with knee osteoarthritis in the Johnston County (North Carolina) osteoarthritis project. Arthritis Research & Therapy. 2011/10/19 2011;13(5):R169. doi:10.1186/ar3492 39. Harrison MJ, Tricker KJ, Davies L, et al. The relationship between social deprivation, disease outcome measures, and response to treatment in patients with stable, long-standing rheumatoid arthritis. J Rheumatol. Dec 2005;32(12):2330-6. 40. Katz JN. Lumbar Disc Disorders and Low-Back Pain: Socioeconomic Factors and Consequences. JBJS. 2006;88(suppl_2)
19 1 General Introduction
Chapter 2 ICON 2023—International Scientific Tendinopathy Symposium Consensus: the core outcome set for Achilles tendinopathy (COS-AT) using a systematic review and a Delphi study of healthcare professionals and patients Robert-Jan de Vos#, Karin Grävare Silbernagel#, Peter Malliaras#, Tjerk Sleeswijk Visser#, Håkan Alfredson, Inge van den Akker-Scheek, Mathijs van Ark, Annelie Brorsson, Ruth L. Chimenti, Sean Docking, Pernilla Eliasson, Kenneth Färnqvist, Zubair Haleem, Shawn Hanlon, Jean-Francois Kaux, Rebecca Kearney, Paul Kirwan, Kornelia Kulig, Bhavesh Kumar, Trevor Lewis, Umile Giuseppe Longo, Tun Hing Lui, Nicola Maffulli, Adrian Mallows, Lorenzo Masci, Dennis McGonagle, Dylan Morrissey, Myles Murphy, Richard Newsham-West, Katarina Nilsson Helander, Richard Norris, Francesco Oliva, Seth O’Neill, Koen Peers, Ebonie Rio, Igor Sancho, Alex Scott, Kayla Seymore, Sze-Ee Soh, Patrick Vallance, Jan Verhaar, Arco van der Vlist, Adam Weir, Jennifer Zellers and Bill Vicenzino #shared first authorship Under review
22 Chapter 2 ABSTRACT Objectives: To develop a core outcome set for Achilles tendinopathy (COS-AT) for use in clinical trials. Methods: We performed a five-step process including: (I) a systematic review on available outcome measurement instruments, (II) an online survey on truth and feasibility of the available measurement instruments, (III) an assessment of the methodological quality of the selected outcome measurement instruments, (IV) an online survey on the outcome measurement instruments as COS, and (V) a consensus in-person meeting. The OMERACT guidelines with 70% threshold for consensus were followed. Results: We identified 233 different outcome measurement instruments from 307 included studies; 177 were mapped within the ICON core domains. 31 participants (12 patients) completed the 1st online survey. 22/177 (12%) outcome measurement instruments were deemed truthful and feasible and their clinimetric properties were evaluated. 29 participants (12 patients) completed the 2nd online survey and three outcome measurement instruments were endorsed: the Victorian Institute of Sports AssessmentAchilles (VISA-A) questionnaire, the single-leg heel rise test, and evaluating pain after activity using a Visual Analogue Scale (VAS, 0-10). 12 participants (1 patient) attended the final consensus meeting, and 1 additional outcome measurement instrument was endorsed: evaluating pain on activity/loading using a VAS (0-10). Conclusion: It is strongly recommended that the identified COS-AT will be used in future clinical trials evaluating effectiveness of an intervention. This will facilitate pooling of data and progression of knowledge about Achilles tendinopathy. As COS-AT is implemented further evidence on clinimetric properties of included measures should lead to its review and refinement.
2 23 ICON 2023: Core Outcomes for Achilles Tendinopathy INTRODUCTION Achilles tendinopathy is the clinical diagnosis for load-related pain and disability localized to the Achilles tendon.1 This condition frequently leads to chronic symptoms with poor quality of life and substantial healthcare consumption.2,3 To effectively evaluate recovery of Achilles tendinopathy and treatment effectiveness, reliable and valid outcome measurement instruments are necessary.4-6 Currently, there is considerable variation in the outcome measures used to assess interventions; this can have implications for patient care, as healthcare professionals and researchers are unable to adequately interpret, compare, and synthesize study results in meta-analyses.5,7,8 The importance of developing a Core Outcome Set (COS) for clinical trials is emphasized by both the Outcome Measures in Rheumatology (OMERACT)9 and the Core Outcome Measures in Effectiveness Trials (COMET)10 initiative. These organizations also offer detailed guidelines for the development of a COS.10,11 For inclusion in a COS, outcome measurement instruments must be both feasible (considering cost, patient burden, and availability in the clinical setting) and of sufficient quality (valid, responsive, reliable, and interpretable).9,11 In 2018, a Delphi study was conducted at the International Scientific Tendinopathy Symposium Consensus (ICON) to establish core domains for tendinopathy.7 Expert clinicians and researchers in tendinopathy, as well as patients with tendinopathy at different anatomical sites, identified nine tendinopathy-specific core domains: patient overall rating, participation, pain on activity, disability, function, physical function capacity, quality of life, psychology, and pain over a specified time frame.7 The next step is to use these core domains as a guide to develop core outcome sets for each of the common tendinopathies. A core outcome set for Achilles tendinopathy (COS-AT) is currently lacking. The primary aim is to develop this COS-AT through a systematic search for outcome measurement instruments that map to core tendinopathy domains, methodological quality assessment and a 3-round Delphi including an in-person consensus meeting. After defining the COS-AT, it should be used in future clinical trials evaluating effectiveness of an intervention for Achilles tendinopathy. METHODS Study protocol At the International Scientific Tendinopathy Symposium (ISTS) 2018 an Achilles tendinopathy consensus group was formed.5 This group worked collaboratively on prospective registration of the study protocol on the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42020156763). The project was also registered in the COMET database (www.comet-initiative.org, reference number 1323).
24 Chapter 2 The medical ethical committee of Erasmus MC University Medical Center confirmed that the Medical Research Involving Human Subjects Act (WMO) did not apply to our study (MEC-2021-0279). To identify the core outcome set for Achilles tendinopathy, we predefined 5 steps based on recommended methodology9,11: 1) a systematic review on available outcome measurement instruments, 2) an online survey (1st round Delphi) on truth and feasibility, 3) assessing methodological quality of selected instruments, 4) an online survey (2nd round Delphi) on the core outcome set, and 5) an in-person consensus meeting (3rd round Delphi). The results of the first step have been published elsewhere.5 The process of the complete study is described in detail below. Panel selection The steering committee (KS, PM and RJDV) was formed in collaboration with the initiator of the COS development in tendinopathies (BV). The steering committee performed the recruitment and selection of the broader COS-AT consensus group. There was a call for potentially eligible participants during the International Scientific Tendinopathy Symposium (ISTS) in September 2018 in Groningen, the Netherlands. Some participants were also recruited afterwards via snowball methods and contacts of the steering group. The COS-AT consensus group was important for the design process and inclusion of patients throughout the project. For the Delphi parts of the process, an expert panel was selected. In the process of panel selection, our objective was to ensure a comprehensive representation of both clinicians and researchers (professional participants) and people with lived experience of having Achilles tendinopathy (referred to as patients). To achieve this, we employed a two-pronged approach. Firstly, to recruit patients, we enlisted the assistance of the COS-AT consensus group.5 This group was tasked with identifying and engaging potential patients for participation. To promote diversity, we strived to constitute a patient panel that exhibited a representative distribution in terms of gender and country of residence. Anticipating a substantial time gap between the two rounds of the Delphi survey and as we required patients with Achilles tendinopathy to have current or recent (<3 months) symptoms of Achilles tendinopathy, the individuals recruited for round 1 differed from those in round 2. We anticipated a minimum number of ten patient participants for both surveys and one for the in-person consensus meeting. Upon expressing their interest to participate, patients were promptly provided with a detailed email outlining the entirety of the process, along with an explicit explanation of their specific role within the panel. During all rounds, patients had equal voting rights as professional participants. Secondly, in the process of the selection of professional participants, we aimed to include representatives possessing varied backgrounds (both academic and clinical) and expertise,
2 25 ICON 2023: Core Outcomes for Achilles Tendinopathy striving to ensure an equitable and proportional distribution based on gender and country of residence. To identify suitable professional participants, we used www.expertscape. com, a website that ranks professionals from clinical and academic domains based on their publications within specific medical fields (search term ‘Achilles tendon’ with search date 1st June 2021). We contacted these selected professional participants via email, extending invitations to participate in the panel. Once professional participants expressed their interest to participate, they received an email with an explanation of the process and their exact role. Hereafter, informed consent from all participants (both patients and professional participants) was obtained. Systematic review Step 1 – A systematic review on all available outcome measurement instruments We set up a search strategy to identify all available outcome measurement instruments used in prospective studies including patients with Achilles tendinopathy.5 We mapped the outcome measurement instruments into predefined health-related core domains (data have been published elsewhere).7 Consensus process Step 2 – Online survey to evaluate Truth and Feasibility of outcome measurement instruments (first round Delphi procedure) All original outcome measurement instruments within the core domains for tendinopathy and identified by the systematic review5 were evaluated during an international online survey using LimeSurvey (LimeSurvey GmbH, Germany), a software package designed for safe distribution of online surveys. The description of the outcome measurement instruments from the literature was used verbatim, so the experts (patients and professional participants) could rate exactly what had been used in the literature. Within the identified outcome measurement instruments, there were instances where multiple outcome measurement instruments described similar aspects but with slight variations. For example, pain on palpation was assessed using different formats such as a yes/no responses, a 0-10 Visual Analogue Scale (VAS), and a 5-point Likert scale. To ensure a comprehensive evaluation, we separately assessed these variations in measurement and presented them exactly as they were used in the literature. The international panel consisting of the selected professional participants and patients was invited to complete the survey. The selection process of the outcome measurement instruments in this second step was initiated according to the OMERACT filters, which uses Truth, Discrimination, and Feasibility as the core or the pillars for instrument selection.9 In this step we focused on the pillars Truth (which core domain is covered and ‘Is there a match with the target domain?’) and Feasibility (‘Is the outcome measurement instrument practical to use?’). The specific outcome measurement instruments were displayed and these questions were
26 Chapter 2 asked for every identified outcome measurement instrument. The respondents to the survey had four response options for the specific outcome measurement instrument to be: 1) NOT truthful and NOT feasible, 2) truthful but NOT feasible, 3) NOT truthful but feasible or 4) truthful AND feasible. An outcome measurement instrument was assessed in step 3 if it met the a priori decision criteria: ≥70% agree the outcome measurement instrument is both truthful and feasible. Conversely, outcome measurement instruments that received agreement from less than 70% of the respondents were not assessed in step 3. Step 3 – Performing a quality assessment of the endorsed outcome measurement instruments For this step, we only used outcome measurement instruments that were found to have content and concept match (were found to be truthful) and were feasible to use. This step consisted of a systematic review to assess the measurement properties of the selected outcome measurement instruments. To ensure a standardized approach, we adhered to the OMERACT guideline for instrument selection in core outcome measurement sets.9,11 This guideline uses the pillars Truth (do the numeric scores make sense?) and Discrimination (can it discriminate between groups of interest?). A search strategy (online Supplementary file 1) was performed by a medical librarian, using a focused search that was based on the 1) specific patient population of Achilles tendinopathy; 2) outcome measurement instrument names and 3) measurement properties (construct validity, test-retest reliability, responsiveness, sensitivity to change, minimum important difference and patient acceptable state). The following databases were searched for published and unpublished trials up to 17 March 2022: Embase, Medline ALL, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, CINAHL and SPORTDiscus. After duplicate removal, two researchers (RJDV, TSV) independently screened the studies based on title and abstract. Disagreements were resolved by consensus. Studies were deemed eligible if they investigated the measurement properties of the outcome measurement instruments in a population of patients with Achilles tendinopathy. The same two reviewers independently applied the eligibility criteria to the full texts, with any disagreements settled through consensus or, if necessary, with the involvement of a third reviewer (KGS). The selected studies were then grouped based on the outcome measurement instrument examined. After this stage, the methods of the selected studies were critically appraised using the OMERACT and COSMIN (COnsensus-based Standards for the selection of health Measurement Instruments) guidelines.12 Two researchers (IvdAS, SES) with methodological expertise from the collaborating group independently assessed the methodological quality of the selected studies. Selected studies were assessed on the performance of the outcome
2 27 ICON 2023: Core Outcomes for Achilles Tendinopathy measurement instrument (adequate/equivocal/poor) and the quality of the methods used in the particular study (good/moderate/poor). Disagreements were resolved by consensus. Studies with a high risk of bias according to this quality assessment were excluded from evidence synthesis. Subsequently, a Summary of Measurement Properties table was made per outcome measurement instrument, based on the OMERACT guidelines. This table covered extracted data of the 1) Truth (target domain); 2) Feasibility; 3) Truth (construct validity which included hypothesis testing [convergent validity] and testing of known group differences) and 4) Discrimination (test-retest reliability, responsiveness, clinical trial discrimination and thresholds of meaning) per included study. We performed a best evidence synthesis, which was based on the quality of the included studies, the number of good quality studies, the consistency across studies and the performance in each property. This resulted in a final synthesis rating that was categorized as 1) Go (green), 2) Cautious (amber), 3) Stop (red) or 4) No data. As we expected evidence for certain outcome measurement instruments to be absent or very limited in the specific population of Achilles tendinopathy patients, we decided not to reject outcome measurement instruments with no available data on clinimetric properties at this stage. Step 4 – An online survey on outcome measurement instruments as COS-AT (second round Delphi procedure) The outcome measurement instruments identified during the systematic review (step 1) that were found to be feasible and within the relevant core domain for tendinopathy (step 2) and assessed for their methodological quality (step 3) were rated during an international Delphi survey. The same international panel of professional participants was invited to participate as well as a new sample (≥10) of patients with Achilles tendinopathy. For each included outcome measurement instrument, we displayed the results of step 1 and 2 to the participants and asked whether this outcome measurement instrument should be part of the COS. The respondents to the survey had three response options: agree (yes), disagree (no), or unsure. An outcome measurement instrument was regarded as part of the COS if it met the a priori criterion decision: ≥70% agree. An outcome measurement instrument was not regarded as part of COS if ≥70% disagree. If 30-70% agree, the outcome measurement instrument was discussed during the in-person meeting (step 5). Step 5 – Defining the COS-AT during a consensus meeting at ISTS 2023 (third round Delphi procedure) The results from the first three steps were collated and circulated to all members of the panel prior to the consensus meeting, which was held at the ISTS 2023 in Valencia (Spain) on November 9th 2023. All professional participants were asked to attend the meeting as well as several patients. At this consensus meeting, any item not already included or excluded from the outcome set (agreement between 30% and 70%), was
28 Chapter 2 discussed and voted upon. Voting at this meeting was anonymous and recorded using specific software (Mentimeter AB, Stockholm, Sweden). The choices at this meeting were only ‘agree’ or ‘disagree’ (with the outcome measurement instrument being part of the COS). An outcome measurement instrument was endorsed if ≥70% agreed. An outcome measurement instrument was provisionally endorsed if 30-70% agreed. An outcome measurement instrument was not endorsed if < 30% agreed. Equity, Diversity, and Inclusion statement The author group consist of a representative sample of men and women and both junior and experienced researchers from a variety of disciplines and from different countries. The panel consists of both patients and professional participants from different countries and with a representative distribution of gender and we strived for a diversity in country of residence. RESULTS We commenced this study in September 2018, with regular meetings by the steering committee to design the study, facilitate data collection and interpretation. The project was completed in November 2023. We contacted 68 professional participants based on the Expertscape search. 35 did not want to participate of did not respond. 33 professional participants were selected to participate in the panel. The characteristics of the professional participants and patients who completed the Delphi surveys and attended the in-person consensus meeting are displayed in Table 1.
2 29 ICON 2023: Core Outcomes for Achilles Tendinopathy Table 1. Characteristics of the participants completing the first and second Delphi survey. Abbreviations; PPs: professional participants, NA: Not applicable Survey 1 Survey 2 In-person consensus meeting Characteristic PPs Patients PPs Patients PPs Patients N 19 12 17 12 11 1 Gender: men (%) 10 (53) 8 (66) 12 (71) 6 (50) 8 (73) 1 (100) Age: median (minmax) years 48 (29-68) 42 (2856) 54 (30-69) 46 (2968) 54 (32-68) 49 Role Clinician and researcher 13 - 14 - 10 - Researcher/scientist only 6 - 3 - 1 - Tendinopathy cases per month NA NA None 7 4 1 At least 4 1 0 0 Between 5 and 10 3 3 2 Between 11 and 15 4 3 4 More than 16 2 5 1 Other† 2 2 3 Years managing tendon problems NA NA None 1 1 0 At least 4 2 0 0 Between 5 and 10 2 2 0 Between 11 and 15 1 1 3 More than 16 12 12 8 Other† 1 0 0 Profession NA NA Physiotherapist 12 8 7 Orthopaedic Surgeon 3 5 2 Sports physician 1 2 1 General Practitioner 1 1 0 Other 1 (Biomedicine) 1 (retired orthopaedic surgeon) 1 (rheumatologist) Currently have a tendon problem 1 12 - 12 - 1 History of a tendon problem 9 5 - 8 - 1
30 Chapter 2 Survey 1 Survey 2 In-person consensus meeting Characteristic PPs Patients PPs Patients PPs Patients Countries where work Australia 5 3 2 1 4 0 United Kingdom 3 5 2 3 2 0 United States of America 4 0 3 3 2 0 The Netherlands 2 0 4 2 1 0 Sweden 3 1 2 2 1 0 Italy 1 0 2 0 0 0 Canada 1 0 1 0 0 0 Belgium 0 1 0 1 0 0 Spain 0 1 0 0 0 1 Ireland 0 1 0 0 0 0 China 0 0 1 0 0 0 Denmark 0 0 0 0 1 0 † Not further specified. Step 1 – A systematic review on all available outcome measurement instruments In brief, there were 9,376 studies identified and 307 studies were finally included.5 233 different outcome measurement instruments across all domains were identified, and 177 outcome measurement instruments were selected within the predefined core domains – previously reported.7 These outcome measurement instruments were used for the next step in the COS-AT process. Step 2 – Online survey to evaluate Truth and Feasibility of outcome measurement instruments (first round Delphi procedure) The first online survey was sent to the participants at 1st November 2021. 31 participants completed the survey. 12 (39%) participants were patients and 19 were professional participants. In total, 13 (42%) participants were women and 18 (58%) man. 177 different outcome measurement instruments across all core domains were assessed. More than 70% of the participants agreed that 22 (12%) outcome measurement instruments are both truthful and feasible (online supplementary file 2). The full results of the survey are presented in online supplementary file 3.
2 31 ICON 2023: Core Outcomes for Achilles Tendinopathy Step 3 – Performing a quality assessment of the endorsed outcome measurement instruments We identified 4,878 potentially relevant publications for assessing the quality of the endorsed outcome measurement instruments in step 3. Figure 1 shows a flowchart of the article selection process. After duplicate removal, 2,119 publications were screened based on the title and abstract. Eight articles were relevant but were excluded because they were not original research articles (e.g. systematic review, scoping review). 42 articles were screened in the full text. 27 articles fulfilled the eligibility criteria and were critically appraised by the methodological experts using the COSMIN criteria.12 A summary of the methodological measurement properties, as also presented to the participants in the 2nd round of the Delphi procedure, was made and is presented in supplementary File 4. There were no available data on the quality of 13/22 (59%) outcome measurement instruments. The remaining 9 outcome measurement instruments showed low quality evidence on their clinimetric properties, with very few studies examining responsiveness, clinical trial discrimination and thresholds of meaning. Moreover, structural validity (when assessed) was not or only partially according to COSMIN guidelines.
32 Chapter 2 Figure 1. Flowchart of the article selection process for the research question related to the quality of the outcome measurement instruments. Abbreviations; AT: Achilles Tendinopathy. Step 4 - An online-survey on outcome measurement instruments as COS-AT (second round Delphi procedure) The second online survey was sent to the participants at 25th July 2023. For each included outcome measurement instrument, we displayed the results of step 2 and 3 to the participants and asked whether this outcome measurement instrument should be part of the COS-AT. 29 participants (12 patients (41%); 11 (38%) women and 18 (62%) men) completed the online survey of whom 11 (38%) were women and 18 (62%) were men. The results of this survey are displayed in online Supplementary File 5 (Table 1). More than 70% of the participants agreed that 3 of the 22 outcome measurement instruments should be included in the COS-AT. These outcome measurement instruments were 1) the (Victorian Institute of Sports Assessment-Achilles) VISA-A questionnaire13, 2) the single-leg heel rise
2 33 ICON 2023: Core Outcomes for Achilles Tendinopathy test14-16 and 3) evaluating pain after activity using a Visual Analogue Scale (VAS, from 0-10, with 0 indicating no pain). There were no measurements that were excluded at this stage (i.e., ≥70% disagreement). On 19 (86%) of the outcome measurement instruments, the a-priori decision criteria (either ≥70% agree or disagree) were not reached. These 19 outcome measurement instruments were evaluated in Step 5. Step 5 - Defining the COS-AT during a consensus meeting at ISTS 2023 (third and final round Delphi procedure) During the ISTS 2023 in Valencia (Spain) 11 professional participants (33% of the total clinician/researcher panel) and 1 patient (man) were present. All participants received an email with detailed information about the results of step 3 and 4. An introduction to the session was performed by the steering committee, and the 19 outcome measurement instruments not already included or excluded from the COS, were discussed and voted upon. 1 item was endorsed, 10 provisionally endorsed and 8 were not endorsed (online supplementary file 6, Table 1). In combination with the results of Step 4 a COS could be defined, comprising 4 outcome measurement instruments, which are displayed in Table 2. Table 2. Endorsed outcome measurement instruments for the Core Outcome Set for Achilles tendinopathy (COS-AT). Outcome measurement instrument Domain Endorsement (rate of agreement) VISA-A questionnaire. Disability Endorsed in 2nd Delphi round (86%) Single-leg heel rise test.* Physical function capacity Endorsed in 2nd Delphi round (76%) Evaluating pain after activity using a VAS (0 -10) Pain on activity/loading Endorsed in 2nd Delphi round (72%) Evaluating pain on activity/ loading using a VAS (0-10) Pain on activity/loading Endorsed after in-person consensus meeting (75%%) Abbreviations; VISA-A: Victorian Institute of Sports Assessment-Achilles, VAS: Visual Analog Scale, * Testing Calf muscle strength by asking the patient to perform a maximum number of single leg heel raises. [Unable/ Able, number of heel raises, Work (Joule), cm above the ground (measured from the heel)] Notes during the in-person consensus meeting During the final in-person consensus meeting, several key topics emerged, underlining the perspectives of the professional participants and the patient. All participants agreed that outcome measurement instruments should be as straightforward as possible; simpler measures are deemed more reliable, while those that are more extensive are often seen as having less construct validity. For example, a 0-10 Visual Analogue Scale (VAS), should be preferred over a 0-100 VAS. Additionally, there was a call for greater specificity in certain outcome measurement instruments, such as evaluating pain after activity.
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