VALUE-BASED HEALTHCARE IN INHERITED BLEEDING DISORDERS Evelien Shannon van Hoorn
Value-based healthcare in inherited bleeding disorders Evelien Shannon van Hoorn
Printing of this thesis was financially supported by the Department of Public Health, Erasmus MC and the Erasmus University. ISBN: 978-94-6506-409-3 Cover design: Joey Roberts | www.ridderprint.nl Lay-out and Print: Ridderprint | www.ridderprint.nl © Copyright 2024: Evelien Shannon van Hoorn, The Netherlands All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, by photocopying, recording, or otherwise, without the prior written permission of the author.
Waardegedreven zorg in aangeboren bloedstollingsstoornissen Value-based healthcare in inherited bleeding disorders 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 woensdag 27 november om 10:30 uur door Evelien Shannon van Hoorn geboren te Utrecht, Nederland.
Promotiecommissie Promotoren: Prof.dr. H.F. Lingsma Prof.dr. M.H. Cnossen Overige leden: Prof.dr. A. Franx Prof.dr. K. Fijnvandraat Dr. M.J.H.A Kruip Copromotor: Dr. S.C. Gouw
CONTENTS Chapter 1 General introduction 7 Part I Measuring patient-reported outcomes Chapter 2 Patient-reported outcomes in autosomal inherited bleeding disorders: A systematic literature review 23 Chapter 3 Patient-relevant health outcomes for von Willebrand disease, platelet function disorders and rare bleeding disorders: A Delphi study 67 Chapter 4 Harmonizing patient-reported outcome measurements in inherited bleeding disorders with PROMIS 111 Chapter 5 Psychometrics of patient-reported outcomes measurement information system in von Willebrand disease, inherited platelet function disorders, and rare bleeding disorders 123 Part II Patient experiences with patient-reported outcomes Chapter 6 Patient experiences with value-based healthcare interventions at the HIV outpatient clinic of the Erasmus Medical Center 173 Part III Variation in care provision Chapter 7 Hemophilia care in the Netherlands: Identification and visualization of the care pathway for young children with hemophilia 199 Chapter 8 General discussion 221 Addendum Summary (English) 240 Samenvatting (Dutch) 246 List of publications 252 PhD portfolio 254 About the author 260 Dankwoord 262
Chapter 1 General introduction
8 Chapter 1 VALUE-BASED HEALTHCARE THEORY Value-based healthcare (VBHC) is regarded as an important innovation to reform healthcare practices and policy 1. It was first introduced in 2006 by Michael Porter and Elizabeth Teisberg as a strategy to combat rising healthcare costs and unwanted variation in quality of care and outcomes 2. According to the VBHC framework, healthcare organizations should aim to maximize patient value, where value is defined as the health outcomes that matter to patients relative to the cost of achieving those outcomes 3. Within VBHC, value for patients is created over the entire cycle of care, and outcomes and costs should be measured across the full cycle of interdependent activities for patients with a specific medical condition 2,4,5. By maximizing patient value, VBHC can contribute to the achievement of the “quadruple aim” of improving both patient and healthcare professionals experiences with care, improving population health, as well as reducing the cost of care 6,7. To facilitate the transformation towards VBHC, Porter and Lee developed the value agenda, which consists of six interdependent and mutually reinforcing components: 1) organize care into integrated practice units (IPUs) around the patient’s medical condition, 2) measure outcomes and costs for every patient, 3) move to bundled payments across the whole care cycle, 4) integrate care delivery across separate facilities, 5) expand excellent services across geographical locations, and 6) build an enabling information technology (IT) platform 3. This value agenda, however, provides little guidance on which practical steps should be undertaken and what aspects should be prioritized to transform healthcare towards VBHC 8. In addition, the value agenda does not describe how the measurement of outcomes and costs for every patient can be used to improve quality of care 9. In 2022, van der Nat therefore proposed a new strategy agenda with four additional components: 1) set up value-based quality improvement, 2) integrate value in patient communication, 3) invest in a culture of value-delivery (education), and 4) build learning platforms for healthcare professionals 9 (Figure 1).
9 1 General introduction 1 Measure outcomes and cost for very patient 2 Set up valuebased quality improvement 3 Integrate value in patient communication 4 Organize care into Integrated Practice Units (IPUs) 5 Move to bundled payments for care cycles 6 Integrate care delivery across separate facilities 7 Expand excellent services across geographic 9 Build learning platforms for healthcare professionals 10 Build an enabling information technology (IT) platform 8 Invest in a culture of value delivery (education) Figure 1: The new strategic agenda as proposed by van der Nat, 2022. Figure was adapted based on van der Nat, 2022 and Porter and Lee, 2013. VALUE-BASED HEALTHCARE IN THE DUTCH CONTEXT This new strategy agenda is consistent with the Dutch interpretation of VBHC. This interpretation deviates slightly from the original concept, bypassing the immediate need to measure cost while advocating the collection and use of outcome information. More specifically in the Netherlands, emphasis is placed on the use of outcome information to support shared decision making, continuous learning and quality improvement 8-11. From 2011 onwards, hospitals in the Netherlands have been implementing VBHC principles into healthcare provided by medical professionals 12,13. Many hospitals have started with the systematic measurement of outcomes that matter to patients in routine care or by organizing care around medical conditions 9,14-17. The successes of some of these earlier initiatives, combined with the notion that VBHC is able to optimize both care for patients and resource allocation, has led to a widespread implementation of VBHC in the Netherlands 18. This development is supported by the Dutch Ministry of Health, Welfare and Sports with initiatives
10 Chapter 1 such as the Outcome-Based Healthcare program 19,20. Importantly, in 2022, the Ministry presented the “Integraal Zorgakkoord” which states that by 2025, all healthcare organizations in the Netherlands should routinely collect outcome information with the purpose to improve shared decision making by patients and healthcare professionals, and to create a culture of continuous learning and quality improvement among healthcare professionals and organizations 10,21. Measuring relevant health outcomes in routine clinical care Before healthcare organizations can start with the routine collection of outcome information in clinical care, it is first essential to determine which health outcomes should be measured. Consensus must be reached on which health outcomes are relevant for patients with a specific medical condition and how to measure these relevant health outcomes 2. Many researchers and organizations have aimed to facilitate the routine collection of health outcomes by defining sets of health outcomes that matter to patients with a specific medical condition 22-24. These outcome sets often consist of a combination of clinical and patient-reported outcomes. Patient-reported outcomes are direct reports from the patient about the experienced symptoms, functioning, health-related quality of life or other health aspects and are measured using patient-reported outcome measures (PROMs) 25-27. PROMs are standardized generic (i.e. applicable for everyone) or disease-specific (i.e. applicable for a certain disease, condition, or treatment) questionnaires that can be used to measure the various aspects of health 28. These PROMs can be implemented in routine clinical care to collect the relevant patient-reported outcomes at fixed moments during the patient care trajectory. The implementation of PROMs in routine clinical care is, however, often hindered by either the absence of a predefined outcome set with relevant clinical and patient-reported outcomes, or the presence of multiple outcome sets for a specific medical condition. Lack of harmonization across the sets can lead to differences and inconsistency in the selected clinical and patientreported outcomes, terminology used and recommended PROMs 22. To be able to routinely use collected outcome information in clinical care, it is therefore essential to obtain consensus on one set of health outcomes that are relevant for patients with a specific medical condition.
11 1 General introduction Continuous learning and improvement through the organization of care Subsequently, before healthcare organizations are able to use routinely collected outcome information, it is essential to gain insight into the current care provision 4,9. Insight into the entire care trajectory, or care pathway, that patients with a specific medical condition follow is essential to determine if there are any warranted or unwanted practice variations across healthcare professionals or healthcare organizations that may influence patient outcomes 29,30. In addition, before improvement initiatives can be derived from the routinely collected outcome information, it is important to determine if variation in patient outcomes reflects true differences in quality of care or if they can be attributed to other factors. Besides providing insight into practice variations, insight into the patient care pathways may support the implementation of routine outcome measurement. The care pathway provides guidance on the timing and frequency of the collection of outcome information as well as shared decision making moments 31. VBHC in rare medical conditions In the Netherlands, hospitals have started implementing VBHC-pilots to improve the value of care for patients with various medical conditions, including different types of cancer and cardiovascular diseases, stroke, chronic kidney disease, and multiple sclerosis 12-14,18,32-34. Little attention, however, has been given to the implementation of VBHC principles in rare diseases such as inherited bleeding disorders. INHERITED BLEEDING DISORDERS Inherited bleeding disorders are caused by abnormalities within the hemostatic process and consist of a heterogeneous group of rare coagulation disorders. In the Netherlands, approximately 2.089 patients are currently receiving care for an inherited bleeding disorder 35. The majority of these patients (72%) are diagnosed with hemophilia A and B, followed by patients with von Willebrand disease, rare bleeding disorders including disorders of the fibrinolytic system, and inherited platelet function disorders 35. Hemophilia A and B Hemophilia A and B are inherited bleeding disorders caused by a deficiency in respectively coagulation factor VIII (FVIII) or factor IX (FIX) 36,37. Hemophilia A is more common than hemophilia B and is estimated to account for
12 Chapter 1 80-85 percent of all hemophilia cases 38. In approximately 70% of all cases, hemophilia is the result of an inherited gene mutation on the X chromosome 38-40. The remaining 30% have no known familial history 38,39. Due to the X-linked inheritance, hemophilia generally affects men 41,42. Women are diagnosed with hemophilia when their FVIII/FIX levels are < 0.40 IU/mL and are often carriers of the disease 38. Hemophilia patients are classified according to the residual factor levels into severe (FVIII of FIX < 0.01 IU/mL), moderate (FVIII of FIX 0.01-0.05 IU/mL), and mild hemophilia (FVIII of FIX 0.06-0.40 IU/mL) 38,43,44. Patients with severe hemophilia suffer from (spontaneous) bleeding in especially joints and muscles 36,38,41. Patients with mild or moderate hemophilia mainly experience bleeds after trauma or surgery 36,38. Von Willebrand disease Von Willebrand disease, the most common inherited bleeding disorder worldwide, is caused by quantitative or qualitative deficiencies of von Willebrand factor (VWF) 45,46. Von Willebrand disease is traditionally classified into three types: type 1, type 2 and type 3 45,46. Most of the patients with von Willebrand disease are diagnosed with type 1. Less than 5% of the patients are diagnosed with the most severe type of von Willebrand disease, type 3 47. All types of von Willebrand disease have an autosomal inheritance pattern and therefore affect both men and women 48. Patients with von Willebrand disease most commonly experience mucocutaneous bleeding symptoms (e.g., epistaxis, easy bruising, gum bleeding and heavy menstrual bleeding), and/or bleeding after a hemostatic challenge such as childbirth, surgeries or invasive dental procedures. In addition, patients with von Willebrand disease may experience gastrointestinal or joint bleeding 47,48. Inherited platelet function disorders Inherited platelet function disorders are a heterogeneous group of diseases that exhibit an autosomal or X-linked inheritance pattern 49. Inherited platelet function disorders are caused by defects in the adhesion, activation, secretion or aggregation of platelets 50. The type of platelet defect determines the severity of the bleeding symptoms. Patients with an inherited platelet function disorder typically experience mucocutaneous bleeding symptoms and/or excessive bleeding after a hemostatic challenge 49-51. In contrast to patients with
13 1 General introduction a severe bleeding tendency, patients with a milder bleeding phenotype may experience excessive bleeding after some but not all hemostatic challenges 52,53. Spontaneous life-threatening bleeding symptoms such as intracranial hemorrhage or gastrointestinal bleeding are less common in patients with inherited platelet function disorders 49. Rare bleeding disorders Rare bleeding disorders are comprised of deficiencies of fibrinogen, prothrombin (FII), FV, combined FV and FVIII, FVII, FX, FXI, FXIII and fibrinolysis disorders (i.e. alpha2-antiplasmin deficiency, plasminogen activator inhibitor 1 deficiency and hyperfibrinolysis) 54-56. Most rare bleeding disorders have an autosomal inheritance pattern 54,55. Patients with rare bleeding disorders have varying clinical presentations. Similar to patients with von Willebrand disease and inherited platelet function disorders, patients with a rare bleeding disorder most commonly experience mucocutaneous bleeding symptoms. In contrast to patients with von Willebrand disease and inherited platelet function disorders who experience persistent bleeding after hemostatic challenges, patients with a fibrinolytic disorder typically experience delayed bleeding after hemostatic challenges 57. Spontaneous life-threatening or major bleeding only occur sporadic in patients with severe deficiencies 56. Research has historically focused on hemophilia Most studies in inherited bleeding disorders have historically focused on hemophilia A and B 57. This pattern is also observed with regard to research on the implementation of VBHC in inherited bleeding disorders. Previous research has identified which health outcomes are important for patients with hemophilia and investigated potential relevant and suitable PROMs to measure these health outcomes 37,58,59. Comparable studies have not yet been performed for patients with von Willebrand disease, inherited platelet function disorder or rare bleeding disorders. In addition, no attempt has yet been made to implement these PROMs in clinical routine care, and to evaluate if the routine collection of outcomes improves shared decision making and facilitates continuous learning and quality improvement in this patient population.
14 Chapter 1 AIM AND OUTLINE OF THIS THESIS The overall aim of this thesis is to study the added value of the implementation of VBHC, as defined within the Dutch healthcare context, in routine clinical care for patients with an inherited bleeding disorder. To achieve this aim, this thesis intends to address the following research questions: 1. Which health outcomes, including clinical and patient-reported outcomes, are important for patients with von Willebrand disease, inherited platelet function disorders, and rare bleeding disorders? 2. Which patient-reported outcome measures are suitable to measure patient-reported outcomes in patients with von Willebrand disease, inherited platelet function disorders, and rare bleeding disorders? 3. How do patients experience the implementation of patient-reported outcome measures in routine clinical care? 4. Are there meaningful differences in hemophilia care provided by the hemophilia treatment centers in the Netherlands that can be used to improve quality of care? Part I: Measuring patient-reported outcomes Part I focuses on identifying which health outcomes are important to measure by patients with von Willebrand disease, inherited platelet function disorder and rare bleeding disorders and on how to measure them. Part I therefore answers research questions 1 and 2. Chapter 2 provides a concise overview of which health outcomes might be impacted in patients with von Willebrand disease, inherited platelet function disorders and rare bleeding disorders as found in previous studies. Chapter 3 aims to identify which health outcomes are relevant for this patient population as seen from the patient, caregiver and healthcare professional perspectives. Chapter 4 introduces and describes the possible advantages of using a specific PROM measurement system, called Patient Reported Outcomes Measurement Information System (PROMIS) to measure the identified relevant patient-reported outcomes. In Chapter 5, we aim to identify if the PROMIS instruments are suitable to assess patientreported outcomes in patients with von Willebrand disease, inherited platelet function disorders and rare bleeding disorders. Part II: Patient experiences with patient-reported outcomes Part II investigates how patients experience the collection of outcome information in routine clinical care and answers research questions 3. Chapter 6 describes the experiences of HIV patients with the implementation of three
15 1 General introduction VBHC interventions, including the implementation of a PROM in routine clinical care. Part III: Variation in care provision Part III focuses on the care provision for patients with hemophilia in the Netherlands and answers research question 4. Chapter 7 provides an overview of the care pathway young patients with hemophilia and their caregivers follow within Dutch hemophilia treatment centers. This thesis concludes with a general discussion in Chapter 8 in which we summarize and discuss our findings and provide recommendations for further research regarding the implementation of VBHC by patients with inherited bleeding disorders.
16 Chapter 1 REFERENCES 1. van Elten HJ, Howard SW, de Loo I, Schaepkens F. Reflections on Managing the Performance of Value-Based Healthcare: A Scoping Review. International Journal of Health Policy and Management. 2023;12(Issue 1):1-10. doi:10.34172/ ijhpm.2023.7366 2. Porter ME, Teisberg EO. How physicians can change the future of health care. JAMA. 2007;297(10):1103-11. doi:10.1001/jama.297.10.1103 3. Porter ME, Lee TH. The strategy that will fix health care. Harv Bus Rev. 2013;91(10):119. 4. Steinmann G, Daniels K, Mieris F, Delnoij D, van de Bovenkamp H, van der Nat P. Redesigning value-based hospital structures: a qualitative study on value-based health care in the Netherlands. BMC Health Serv Res. 2022;22(1):1193. doi:10.1186/ s12913-022-08564-4 5. Porter ME, Teisberg EO. Redefining health care: creating value-based competition on results. Harvard business press; 2006. 6. Bodenheimer T, Sinsky C. From Triple to Quadruple Aim: Care of the Patient Requires Care of the Provider. The Annals of Family Medicine. 2014;12(6):573. doi:10.1370/afm.1713 7. Teisberg E, Wallace S, O'Hara S. Defining and Implementing Value-Based Health Care: A Strategic Framework. Acad Med. 2020;95(5):682-685. doi:10.1097/ ACM.0000000000003122 8. Steinmann G, Delnoij D, van de Bovenkamp H, Groote R, Ahaus K. Expert consensus on moving towards a value-based healthcare system in the Netherlands: a Delphi study. BMJ Open. 2021;11(4):e043367. doi:10.1136/bmjopen-2020-043367 9. van der Nat PB. The new strategic agenda for value transformation. Health Serv Manage Res. 2021;35(3):189-193. doi:10.1177/09514848211011739 10. Programma Uitkomstgerichte Zorg. Leren en verbeteren. Programma Uitkomstgerichte Zorg. Accessed February 6th, 2024. https://www. uitkomstgerichtezorg.nl/themas/leren-en-veranderen 11. Steinmann G. A Scramble for Value. On the interpretation and application of value-based health care in the Netherlands. Erasmus University Rotterdam; 2023. 12. van Veghel D, Soliman-Hamad M, Schulz DN, Cost B, Simmers TA, Dekker LRC. Improving clinical outcomes and patient satisfaction among patients with coronary artery disease: an example of enhancing regional integration between a cardiac centre and a referring hospital. BMC Health Serv Res. 2020;20(494):1-8. doi:10.1186/s12913-020-05352-w 13. van Egdom LSE, Lagendijk M, van der Kemp MH, et al. Implementation of Value Based Breast Cancer Care. Eur J Surg Oncol. 2019;45(7):1163-1170. doi:10.1016/j. ejso.2019.01.007 14. van Veghel HPA, Dekker LRC, Theunissen LJHJ, et al. Introducing a method for implementing value based health care principles in the full cycle of care: Using atrial fibrillation as a proof of concept. International Journal of Healthcare Management. 2020:1-9. doi:10.1080/20479700.2020.1810464 15. van Staalduinen DJ, van den Bekerom P, Groeneveld S, Kidanemariam M, Stiggelbout AM, van den Akker-van Marle ME. The implementation of value-based healthcare: a scoping review. BMC Health Serv Res. 2022;22(1):270. doi:10.1186/ s12913-022-07489-2
17 1 General introduction 16. Eijsink JFH, Fabian AM, Vervoort JPM, Al Khayat MNMT, Boersma C, Postma MJ. Value-based health care in Western countries: a scoping review on the implementation of patient-reported-outcomes sets for hospital-based interventions. Expert Rev Pharmacoecon Outcomes Res. 2023;23(1):1-13. doi:10.1 080/14737167.2023.2136168 17. Heijsters FACJ, van Breda FGF, van Nassau F, et al. A pragmatic approach for implementation of value-based healthcare in Amsterdam UMC, the Netherlands. BMC Health Serv Res. 2022;22(1):550. doi:10.1186/s12913-022-07919-1 18. Nederlandse Federatie van Universitair Medische Centra. Bouwstenen voor werken aan waardegedreven zorg. 2023. https://nfukwaliteit.nl/pdf/Bouwstenen_ voor_werken_aan_waardegedreven_zorg.pdf 19. Oude Voshaar M, Terwee CB, Haverman L, et al. Development of a standard set of PROs and generic PROMs for Dutch medical specialist care. Qual Life Res. 2023;doi:10.1007/s11136-022-03328-3 20. Programma Uitkomstgerichte Zorg. Home. Programma Uitkomstgerichte Zorg. Accessed April 13th, 2023. https://www.uitkomstgerichtezorg.nl/ 21. Dutch Ministry of Health Welfare and Sport. Integraal Zorgakkoord: Samen werken aan gezonde zorg. 2022:1-117. https://www.rijksoverheid.nl/documenten/ rapporten/2022/09/16/integraal-zorgakkoord-samen-werken-aan-gezonde-zorg 22. Terwee CB, Zuidgeest M, Vonkeman HE, Cella D, Haverman L, Roorda LD. Common patient-reported outcomes across ICHOM Standard Sets: the potential contribution of PROMIS(R). BMC Med Inform Decis Mak. 2021;21(1):259. doi:10.1186/ s12911-021-01624-5 23. Benning L, Das-Gupta Z, Sousa Fialho L, Wissig S, Tapela N, Gaunt S. Balancing adaptability and standardisation: insights from 27 routinely implemented ICHOM standard sets. BMC Health Serv Res. 2022;22(1):1424. doi:10.1186/s12913-022-08694-9 24. Webbe JWH, Duffy JMN, Afonso E, et al. Core outcomes in neonatology: development of a core outcome set for neonatal research. Archives of Disease in Childhood - Fetal and Neonatal Edition. 2020;105(4):425-431. doi:10.1136/ archdischild-2019-317501 25. Gensheimer SG, Wu AW, Snyder CF, Group P-EUGS, Group P-EUGW. Oh, the Places We'll Go: Patient-Reported Outcomes and Electronic Health Records. Patient. 2018;11(6):591-598. doi:10.1007/s40271-018-0321-9 26. Gibbons C, Porter I, Gonçalves-Bradley DC, et al. Routine provision of feedback from patient‐reported outcome measurements to healthcare providers and patients in clinical practice. Cochrane Database Syst Rev. 2021;(10) doi:10.1002/14651858.CD011589.pub2 27. Aaronson N, Choucair A, Elliott T, et al. User’s guide to implementing patientreported outcomes assessment in clinical practice. International Society for Quality Life Research. 2011; 28. van der Willik EM, Terwee CB, Bos WJW, et al. Patient-reported outcome measures (PROMs): making sense of individual PROM scores and changes in PROM scores over time. Nephrology. 2021;26(5):391-399. doi:10.1111/nep.13843 29. Sutherland K, Levesque J-F. Unwarranted clinical variation in health care: Definitions and proposal of an analytic framework. J Eval Clin Pract. 2020;26(3):687-696. doi:10.1111/jep.13181 30. Panella M, Marchisio S, Di Stanislao F. Reducing clinical variations with clinical pathways: do pathways work? Int J Qual Health Care. 2003;15(6):509-21. doi:10.1093/intqhc/mzg057
18 Chapter 1 31. Allen D, Gillen E, Rixson L. Systematic review of the effectiveness of integrated care pathways: what works, for whom, in which circumstances? Int J Evid Based Healthc. 2009;7(2):61-74. doi:10.1111/j.1744-1609.2009.00127.x 32. Westerink HJ, Garvelink MM, van Uden-Kraan CF, et al. Evaluating patient participation in value-based healthcare: Current state and lessons learned. Health Expect. 2024;27(1):e13945. doi:10.1111/hex.13945 33. Damman OC, Jani A, de Jong BA, et al. The use of PROMs and shared decisionmaking in medical encounters with patients: An opportunity to deliver valuebased health care to patients. J Eval Clin Pract. 2020;26(2):524-540. doi:10.1111/ jep.13321 34. Dronkers EAC, Baatenburg de Jong RJ, van der Poel EF, Sewnaik A, Offerman MPJ. Keys to successful implementation of routine symptom monitoring in head and neck oncology with "Healthcare Monitor" and patients' perspectives of quality of care. Head Neck. 2020;42(12):3590-3600. doi:10.1002/hed.26425 35. World Federation of Hemophilia. Report on the Annual Global Survey 2020. 2021. https://www1.wfh.org/publications/files/pdf-2045.pdf 36. Hassan S, van Balen EC, Smit C, et al. Health and treatment outcomes of patients with hemophilia in the Netherlands, 1972-2019. J Thromb Haemost. 2021;19(10):2394-2406. doi:10.1111/jth.15424 37. van Balen EC, O'Mahony B, Cnossen MH, et al. Patient-relevant health outcomes for hemophilia care: Development of an international standard outcomes set. Res Pract Thromb Haemost. 2021;5(4):e12488. doi:10.1002/rth2.12488 38. Santagostino E, Dougall A, Jackson M, et al. Comprehensive care of hemophilia. 3rd ed. WFH; 2020. Guidelines for the Management of Hemophilia. 39. O'Hara J, Walsh S, Camp C, et al. The impact of severe haemophilia and the presence of target joints on health-related quality-of-life. Health Qual Life Outcomes. 2018;16(1):84. doi:10.1186/s12955-018-0908-9 40. Sharathkumar AA, Carcao M. Clinical advances in hemophilia management. Pediatr Blood Cancer. 2011;57(6):910-20. doi:10.1002/pbc.23193 41. Mannucci PM. Hemophilia therapy: the future has begun. Haematologica. 2020;105(3):545-553. doi:10.3324/haematol.2019.232132 42. Sharathkumar AA, Pipe SW. Bleeding disorders. Pediatr Rev. 2008;29(4):121-29. doi:10.1542/pir.29-4-121 43. Nogami K, Shima M. Current and future therapies for haemophilia—Beyond factor replacement therapies. Br J Haematol. 2023;200(1):23-34. doi:10.1111/bjh.18379 44. Bauer KA. Current challenges in the management of hemophilia. Vol. 21. 2015:S11222. Am J Manag Care. 45. Fogarty H, Doherty D, O'Donnell JS. New developments in von Willebrand disease. Br J Haematol. 2020;191(3):329-339. doi:10.1111/bjh.16681 46. Denis CV, Susen S, Lenting PJ. von Willebrand disease: what does the future hold? Blood. 2021;137(17):2299-2306. doi:10.1182/blood.2020008501 47. Leebeek FW, Eikenboom JC. Von Willebrand's Disease. N Engl J Med. 2016;375(21):2067-2080. doi:10.1056/NEJMra1601561 48. Weyand AC, Flood VH. Von Willebrand Disease: Current Status of Diagnosis and Management. Hematol Oncol Clin North Am. 2021;35(6):1085-1101. doi:10.1016/j. hoc.2021.07.004 49. Freson K, Wijgaerts A, van Geet C. Update on the causes of platelet disorders and functional consequences. Int J Lab Hematol. 2014;36(3):313-325. doi:10.1111/ijlh.12213
19 1 General introduction 50. Blaauwgeers MW, Kruip M, Beckers EAM, et al. Congenital platelet disorders and health status-related quality of life. Res Pract Thromb Haemost. 2020;4(1):100-105. doi:10.1002/rth2.12281 51. Bolton-Maggs PH, Chalmers EA, Collins PW, et al. A review of inherited platelet disorders with guidelines for their management on behalf of the UKHCDO. Br J Haematol. 2006;135(5):603-33. doi:10.1111/j.1365-2141.2006.06343.x 52. Bourguignon A, Tasneem S, Hayward CP. Screening and diagnosis of inherited platelet disorders. Crit Rev Clin Lab Sci. 2022;59(6):405-444. doi:10.1080/104083 63.2022.2049199 53. Hayward CP, Rao AK, Cattaneo M. Congenital platelet disorders: overview of their mechanisms, diagnostic evaluation and treatment. Haemophilia. 2006;12 Suppl 3(s3):128-36. doi:10.1111/j.1365-2516.2006.01270.x 54. Maas DPMSM, Saes JL, Blijlevens NMA, et al. Treatment of patients with rare bleeding disorders in the Netherlands: Real-life data from the RBiN study. J Thromb Haemost. 2022;20(4):833-844. doi:10.1111/jth.15652 55. Saes JL, Verhagen MJA, Meijer K, et al. Bleeding severity in patients with rare bleeding disorders: real-life data from the RBiN study. Blood Adv. 2020;4(20):50255034. doi:10.1182/bloodadvances.2020002740 56. Maas DPMSM, Saes JL, Blijlevens NMA, et al. High prevalence of heavy menstrual bleeding in women with rare bleeding disorders in the Netherlands: retrospective data from the RBiN study. J Thromb Haemost. 2023;21(10):2726-2734. doi:10.1016/j. jtha.2023.07.014 57. Atiq F, Saes JL, Punt MC, et al. Major differences in clinical presentation, diagnosis and management of men and women with autosomal inherited bleeding disorders. E Clinical Medicine. 2021;32:100726. doi:10.1016/j.eclinm.2021.100726 58. van Balen EC, Haverman L, Hassan S, et al. Validation of PROMIS Profile-29 in adults with hemophilia in the Netherlands. J Thromb Haemost. 2021;19(11):26872701. doi:10.1111/jth.15454 59. Kuijlaars IAR, Teela L, van Vulpen LFD, et al. Generic PROMIS item banks in adults with hemophilia for patient-reported outcome assessment: Feasibility, measurement properties, and relevance. Res Pract Thromb Haemost. 2021;5(8):e12621. doi:10.1002/rth2.12621
Part I Measuring patient-reported outcomes
Chapter 2 Patient-reported outcomes in autosomal inherited bleeding disorders: A systematic literature review Evelien S. van Hoorn*, Maite E. Houwing*, Wala Al Arashi*, Frank W.G. Leebeek, Jan A. Hazelzet, Samantha C. Gouw, Roger E.G. Schutgens, Saskia E.M. Schols, Hester F. Lingsma and Marjon H. Cnossen, on behalf of the SYMPHONY consortium * Shared first authorship Heamophilia.2022; 28:197–214.
24 Chapter 2 ABSTRACT Aim Currently, it is unknown which patient-reported outcomes are important for patients with autosomal inherited bleeding disorders. Therefore, the purpose of this study is to systematically review the available literature assessing patient-reported outcomes and their measurement methods in autosomal inherited bleeding disorders. Methods The Embase, Medline ALL, Web of Science Core Collection, Cochrane Central Register of Controlled Trails and Google Scholar databases were searched from inception until 14 August 2020. Studies on patient-reported outcomes in patients with von Willebrand disease, inherited platelet function disorders and coagulation factor deficiencies were included. Results Twenty-one articles met the inclusion criteria. Three studies were assessed as having poor quality, and therefore a high risk of bias Nineteen studies had fair quality rating. Different measurements methods were used, ranging from predefined to self-developed questionnaires. The majority of included studies focused on von Willebrand disease. Patients with von Willebrand disease reported lower health-related quality of life compared to the general population. Overall, this trend was especially visible in the following domains: vitality, physical and social functioning and pain. Women with inherited bleeding disorders scored lower on health-related quality of life compared to men, especially women with heavy menstrual bleeding. Patients with joint bleeds or heavy menstrual bleeding reported an increased level of pain. Conclusion Patients with autosomal inherited bleeding disorders report lower health related quality of life, especially those with joint bleeds or heavy menstrual bleeding. Numerous measurement methods are used in patients with autosomal inherited bleeding disorders, highlighting the need for studies using established, standardized measurement methods.
25 PROMs in autosomal inherited bleeding disorders: A systematic literature review 2 INTRODUCTION The trend towards a more value-based healthcare system has led to an increasing emphasis on outcome measurement. Especially in the last few years, the interest to incorporate patient-reported outcomes (PROs) in medical practice and research has grown exponentially. 1-3 PROs are defined as “any report coming directly from patients, without interpretation by physicians or persons, about how the patient functions or feels in relation to a health condition and its treatment” 4. There are several types of PROs with the most common being self-reported symptoms, self-reported functioning, and healthrelated quality of life (HRQoL) 5. HRQoL is a broad multidimensional concept that incorporates various domains (e.g., physical, psychologic and social functioning) related to the health status of an individual. 6 PROs are often assessed using questionnaires, otherwise known as patientreported outcomes measures (PROMs) 7. PROMs can be classified as either generic or as disease-specific. Generic PROMs, such as Euro-QoL EQ-5D, consist of questions relevant to multiple disease groups or a healthy population. In contrary, disease specific PROMs focus on particular patient groups and consist of questions that are only related to a given disease, disability or surgery. 7,8 Incorporating PROs in clinical practice enables 1) the evaluation of the effectiveness of a healthcare intervention, 2) the assessment of the quality of care and the needs of different populations, 3) the improvement of clinical decision making, and 4) a better understanding and causes of variations in health 7,9. In addition, monitoring PROs may enhance patient engagement and shared decision making, which subsequently leads to a higher quality of care and more patient-centered care 8,10,11. For example, studies in oncology have shown that the systematic collection of PROs result in better symptom control, fewer hospitalizations and better quality of life 12. The increased attention on more patient-centered approaches in healthcare has led to more studies examining PROs and PROMs in a variety of diseases, including in patients with inherited bleeding disorders. Inherited bleeding disorders consist of a heterogeneous group of diseases affecting the primary and secondary hemostasis that include abnormalities or deficiencies of platelets or coagulation proteins. As hemophilia A and B are X-linked, the autosomal inherited bleeding disorders include von Willebrand disease (VWD), inherited platelet function disorders and various coagulation factor
26 Chapter 2 deficiencies. Severe disorders have a low prevalence and usually present in childhood, but milder forms are relatively more common and may not be clinically apparent until later in life when patients have hemostatic challenges (e.g. menstruation, dental procedures, surgery or trauma). 13 The clinical presentation of different types of bleeding disorders tends to overlap and symptoms range from more common features such as easy bruising, mucocutaneous bleedings and heavy menstrual bleeding to more severe and uncommon symptoms such as joint bleeds, gastrointestinal- and intracranial bleedings 14. Patients with similar diagnoses and comparable laboratory results do not always present with the same bleeding tendency 15-17. This inter-individual variability may complicate identifying the individual patient needs. Moreover, the commonly used measures such as bleeding assessment tools do not always reflect the impact of the disease on a patient’s daily life. Incorporating PROs in clinical practice, may support the physician to focus on patient’s (unidentified) needs, to identify the burden of disease for each individual patient and to monitor the treatment effect. Therefore, the implementation of PROs may lead to more personalized treatment in patients with autosomal inherited bleeding disorder. Until now, research on PROs and PROMs in inherited bleeding disorders has mainly focused on hemophilia 18,19. It is unknown which PROs are important for patients with autosomal inherited bleeding disorders and which PROMs are commonly used to measure PROs in this patient population. This systematic literature review aims to summarize the available literature assessing PROs and their measurement methods to identify which patient-reported outcomes could be important for patients with autosomal inherited bleeding disorders. METHODS Article retrieval This systematic review was registered in PROSPERO (registration number CRD42020199444) and followed the PRISMA methodology for systematic reviews and meta-analysis and the COSMIN methodology for systematic reviews of Patient-Reported Outcomes Measures 20. An information specialist experienced in systematic literature reviews co-designed and conducted the search strategy. The initial search was designed in Embase using a combination of Emtree and non-registered index terms and translated into
27 PROMs in autosomal inherited bleeding disorders: A systematic literature review 2 other databases’ syntax (Supplement 1). Key terms include congenital blood clotting disorders, blood clotting deficiency, patient-reported outcome and quality of life. The literature search was performed in Embase, Medline ALL, Web of Science Core Collection, Cochrane Central Register of Controlled Trails and Google Scholar. All databases were searched from inception until 14 August 2020. Study selection Two reviewers (ESvH and MEH) independently screened the articles on potential eligibility. Disagreements between the reviewers were discussed until uniform consensus was reached. English articles reporting on all different types of patient-reported outcomes in both adult and pediatric patients with autosomal inherited bleeding disorders including von Willebrand disease, inherited platelet function disorders and coagulation factor deficiencies, were included. Articles solemnly focusing on bleeding symptoms or bleeding assessment tools were not included in this study, since bleeding symptoms are not necessary patient-reported; they can also be reported by someone other than the patient himself/herself, for example in case of grading of bleeding after surgery. Case studies, commentaries, editorials, conference abstracts, economic evaluations and articles about acquired bleeding disorders were excluded. According to the COSMIN methodology, articles were excluded if less than 80 percent of the research population consisted of patients with autosomal inherited bleeding disorders. The reference lists of included studies identified by the search were checked for further relevant studies. Data assessment For each included study, the following information was collected: study design, characteristics of the patient population, mean or median age at study inclusion, used PROMs and measured PRO’s. In case the psychometric properties of a PROM were assessed, including its acceptability, internal consistency, reliability, validity and responsiveness this was also reported. Two reviewers (ESvH and MEH) read and abstracted each article; a third reviewer (WA) checked table entries for accuracy with regard to the original articles. Data were reviewed descriptively. Risk of bias assessment A single reviewer from the team (ESvH) assessed risk of bias of included publications using the National Institutes of Health (NIH) quality assessment tool for observation and cross-sectional studies. 21 Two other reviewers (MEH
28 Chapter 2 and WA) evaluated the assessment accuracy. Quality rating (good, fair or poor) was used to assess certainty of evidence. Any discrepancies were discussed with all reviewers (ESvH, MEH and WA) until consensus was reached. Studies were not excluded based on risk of bias assessment. Figure 1: PRISMA flow diagram for study identification. Abbreviation: PROs, patient-reported outcomes. RESULTS Data retrieval The systematic literature search yielded a total of 1959 non-duplicate references that were screened using predetermined inclusion- and exclusion criteria. The flow chart (Figure 1) shows the process of article selection from initial search to final inclusion or exclusion. A total of 21 articles met the inclusion criteria for this systematic review. All studies were published between 2000 and 2020 (Figure 2). Seven studies were conducted in the Netherlands 22-28, five in the United Kingdom 29-33, four in the United States 34-37, three in Canada 38-40, one in Sweden 41 and one in Iran 42. Figure 3 shows the risk of bias assessment of the included studies. Three studies were assessed as having poor quality and therefore a high risk of bias. The remaining articles had a fair quality rating. The most prevalent limitations
29 PROMs in autosomal inherited bleeding disorders: A systematic literature review 2 were found in items related to sample size justification, exposure assessment prior to outcome measurements and statistical analyses. Diseases studied The majority of included articles focused solely on von Willebrand disease (VWD) (n=13) 22,24-28,34,35,37-41. Other studies included patients with inherited platelet function disorders (n=2) 23,33, coagulation factor deficiencies (n=2) 32,42, or a combination of different autosomal inherited bleeding disorders (n=4) 29-31,39. Measurement methods Studies used different measurement methods including predefined, routinely assessed PROMs (n=11, 54%), self-developed PROMs (n=5, 23%), or a combination of both (n=2, 9%). Three studies used semi-structured questionnaires assessing PROs in an interview format (n=3, 14%). The most frequently used predefined PROMs were the Short Form-36 (SF-36) and the Health Utilities Index (HUI). Of the 21 included studies, two studies validated the applied PROMs specifically in patients with an inherited bleeding disorder 26,28. Assessment of the development and psychometric properties of each PROM are summarized in Table 1. Figure 2: Publication year of included studies.
30 Chapter 2 Figure 3: Risk of bias assessment using the National Institute of Health quality assessment tool for observational cohort and cross-sectional studies.
31 PROMs in autosomal inherited bleeding disorders: A systematic literature review 2 Patient-reported outcomes The included studies focused on several different PROs, such as HRQoL, physical functioning and pain. Table 2 provides an overview of PROs of included studies. Patient-reported outcomes in von Willebrand disease Health-related quality of life Three studies assessed HRQoL in adult patients with VWD 25,38,40 (Table 2). Compared to the general population, patients with VWD reported lower HRQoL, with the largest measured effects in the domains vitality, social functioning and pain 38,40. Barr et al. found that female patients scored lower compared to men in the domains emotion, cognition and pain 38. Two studies found a difference between the type of VWD and HRQoL measured 25,40. De Wee et al. found that patients with VWD type 3 scored significantly lower on the physical part of HRQoL and higher on pain levels compared to patients with VWD type 1 and 2 25. The study by Xu et al. supports this finding and also found that patients with VWD type 3 scored significantly lower on the physical domain of HRQoL compared to patients with VWD type 2 40. In contrast, two other studies found no difference in HRQoL between patients with VWD type 1, 2 and 3 38,39. One study 24 assessed HRQoL in children with VWD. They found that both preschool and school children had lower HRQoL compared to the general population in the domain general health perception. No difference was observed in HRQoL reported by parents of preschool children across the three types of VWD. In school children, parents of patients with VWD type 3 reported significantly lower HRQoL compared to the general population and patients with VWD type 1 and 2. No significant difference was found in HRQoL between boys and girls in both preschool and school children. 24 Self-perceived physical functioning Four studies 26-28,37 measured the influence of arthropathy and joint bleeds on self-perceived physical functioning in adult patients with VWD. Patients with a history of joint bleeds scored lower on functional abilities 26,28,37. The Von Willebrand in the Netherlands (WiN)-study found that patients with joint bleeds reported a lower overall HRQoL, especially with regard to social participation and physical limitation. In addition, they experienced more pain compared to patients without joint bleeds. 26,27
32 Chapter 2 The WiN study also assessed sports participation and physical activity in adult patients with VWD 22. Almost 70% of patients with VWD participated in various types of sports. No difference in sports participation among the three types of VWD was reported. Lack of time (47.4%), lack of motivation (27.4%), physical limitations (26.4%) and fear of bleeding (6.9%) and other reasons (8.6%) were reported as reasons why patients did not participate in sports. Factors that were independently associated with physical limitations included age, BMI and VWD type 3 22. Patients with VWD type 3 participated significantly less in sports due to fear of bleeding. Patient-reported outcomes in platelet function disorders Two studies 23,33 assessed PROs in inherited platelet function disorders. Patients with inherited platelet function disorders show decreased HRQoL compared to the general population. Significant differences were found in the following domains: physical functioning, limitations in daily activities, limitations in social activities, energy levels and fatigue, pain and general health status.23 Patient-reported outcomes in coagulation factor deficiencies Two studies 32,42 assessed PROs in coagulation factor deficiencies. Children with factor VII, X, XI, XIII and fibrinogen deficiencies had impaired HRQoL in the domains family and friends. Lower health status and being affected by the disease were significantly associated with HRQoL. No differences in HRQoL scores were reported between men and women, the different factor deficiencies and disease severity levels 42. Patient-reported outcomes specifically in women with autosomal inherited bleeding disorders Nine articles specifically focused on HRQoL in women because they face reproduction related hemostatic challenges including the menstrual cycle and child delivery 29-32,34-36,39,41. In women with inherited bleeding disorders, patients with heavy menstrual bleeding reported significantly lower HRQoL compared to those without heavy menstrual bleeding 30,34,39. Only Govorov et al. found no significant difference in HRQoL score between women with and without heavy menstrual bleeding 41. Menstruation and especially heavy menstrual bleeding were reported as debilitating with regard to daily activities 34-36,39,41, social relations 31,41, sport activities 22,32,33 and the ability to work or go to school 29,35,36,41.
33 PROMs in autosomal inherited bleeding disorders: A systematic literature review 2 Four studies reported a high prevalence of dysmenorrhea in women with heavy menstrual bleeding 29,30,32,39, and two studies evaluated the influence of treatment for heavy menstrual bleeding and dysmenorrhea on HRQoL 29,30. The study by Chi et al. used a combination of therapies including tranexamic acid, oral contraceptive pill, desmopressin nasal spray and factor concentrates 29, whereas Hug et al. used an ablative procedure as treatment for heavy menstrual bleeding 30. Both studies found that treatment improved general health, daily activity, dysmenorrhea, interference of dysmenorrhea with daily work and overall HRQoL 29,30 (Table 3). Association of bleeding scores and health-related quality of life Five publications assessed the correlation between bleeding assessment tools scores and HRQoL 23-25,40,42. Bleeding scores were determined using validated tools including the Tosetto Bleeding Score 24,25,42, the International Society on Thrombosis and Hemostasis Bleeding Assessment Tool (ISTH-BAT) 23,40 and the self-administered Bleeding Assessment Tool (Self-BAT) 40. Three studies found that a more severe bleeding phenotype (i.e. higher bleeding scores) was associated with lower HRQoL 24,25,42, two studies did not find such an association 23,40. Higher bleeding scores were associated with lower scores on physical and social functioning, bodily pain and general health in both children and adult patients with VWD 24,25. One study adjusted for age, gender, comorbidity, employment and educational status and still found significantly lower HRQoL scores in patients with higher bleeding scores 25.
34 Chapter 2 Table 1: Patient-reported outcome measures used in patients with autosomal inherited bleeding disorders. Name of instrument Type Aim Dimensions/ domains Items and scoring Studies (n), references Psychometric qualities* B-IPQ Generic To assess the cognitive and emotional representations of illness Consequences, timeline, personal control, treatment control, identity, concern, understanding, emotional response, and causal factors 9 items rated on a linear scale from 0 to 10; higher scores indicate negative illness perception expect for the dimensions personal control, treatment control and understanding 1 23 CES‐D Generic To assess severity of depressive symptoms Depression 20 items rated on 5-point Likert scale; higher scores indicate greater symptoms 1 34 CHQ-CF87 Generic To assess HRQoL in children General health perceptions, physical functioning, role/social physical functioning, bodily pain, role/social emotional functioning, role/social behavioral functioning, parent impact‐ time, parent impact‐emotional, self‐ esteem, mental health, behavior, family activities, family cohesion, and change in health 87 items rated on a 4- to 6-point Likert scale; higher scores indicate better or more positive health states 1 24 CHQ- PF50 Generic To assess caregiver’s perceptions of their child’s (ages 5-18) HRQoL General health perceptions, physical functioning, role/social physical functioning, bodily pain, role/social emotional functioning, role/social behavioral functioning, parent impacttime, parent impact-emotional, selfesteem, mental health, behavior, family activities, family cohesion, and change in health 50 items rated on a 4- to 6-point Likert scale; higher scores indicate better or more positive health states 1 24
www.ridderprint.nlRkJQdWJsaXNoZXIy MTk4NDMw