WFH Guidelines for the Management of Hemophilia, 3rd edition

Abstract

This new edition of the World Federation of Hemophilia (WFH) guidelines for the management of hemophilia comes at an exciting time in the evolution of the diagnosis and treatment of this condition. Since the publication of the second edition in 2012, tremendous advances have been made in several aspects of the management of hemophilia. These include genetic assessment as well as therapy with many innovative therapeutic products including extended half-­life factor VIII (FVIII) and factor IX (FIX) products, a bi-­specific antibody, and hemostasis rebalancing drugs now in clinical development. All of these allow for more effective hemostasis than was possible in the past. Laboratory monitoring of therapies is better defined and prophylaxis is accepted as the only way to change the natural history of bleeding. There are highly effective therapies for patients with inhibitors. Outcome assessment with validated clinimetric instruments is widely advocated and practiced. All these advances are reflected in this third edition of the WFH guidelines, with new chapters devoted to several of these topics along with a new chapter on principles of care that aims to provide a framework for development of a comprehensive healthcare system for hemophilia including advocacy and empowerment for people with hemophilia (PWH). The recommendations in this edition were all developed through a formal evidence-­informed and consensus-­based methodology involving multidisciplinary healthcare professionals (HCPs) and well-­informed PWH. While directed primarily at HCPs, these guidelines should also be very useful for PWH as well as advocacy organizations. KEYWORDS bleeding disorders, hemophilia, management guidelines, novel hemostasis products, outcomes, treatment This third edition of the WFH Guidelines for the Management of Hemophilia has been endorsed by the Asian-­Pacific Society on Thrombosis and Hemostasis, European Haemophilia Consortium, and National Hemophilia Foundation (USA). The World Federation of Hemophilia (WFH) does not endorse any particular treatment product or manufacturer; any reference to a product name is not an endorsement by the WFH. The WFH does not engage in the practice of medicine and under no circumstances recommends particular treatments for specific individuals. Guidelines are intended for general information only and are based on population level research, not for the care or treatment of any particular individual. Guidelines do not replace professional medical care and physician advice and/or product insert information, but should be used to educate and inform shared decision-­making between patients, caregivers, and healthcare providers. Furthermore, guidelines may not be complete or accurate because new research studies may have been published or treatments, devices, or indications approved after the cut-­off date for inclusion in these guidelines. Through a comprehensive and systematic literature review, WFH evidence-­informed clinical practice guidelines incorporate data from the existing peer-­reviewed literature. Although this literature met the pre-­specified inclusion criteria for the guideline, and the WFH considered this scientific content to be the best evidence available for general clinical information purposes at the time the guidelines were developed, this evidence is of varying quality and varying methodological rigor. The WFH and its officers, committees, members, employees, and guideline authors and reviewers (“WFH Parties”) disclaim all liability for the accuracy or completeness and disclaim all warranties, express or implied. The WFH Parties further disclaim all liability for any damages whatsoever (including, without limitation, direct, indirect, incidental, punitive, or consequential damages) arising out of the use, inability to use, or the results of use of a guideline, any references used in a guideline, or the materials, information, or procedures contained in a guideline, based on any legal theory whatsoever and whether or not there was advice on the possibility of such damages. Table of Contents List of Tables and Figures Alok Srivastava1 | Alain Weill2 | Glenn F. Pierce2 1Department of Haematology, Christian Medical College, Vellore, India 2World Federation of Hemophilia, Montreal, QC, Canada With more than one million print and online distributions in six languages and more than 1000 citations in peer-­reviewed articles since its publication in 2012, the World Federation of Hemophilia (WFH) clinical practice resource, Guidelines for the Management of Hemophilia, 2nd edition, has served the community of hemophilia care providers and people with hemophilia extensively. Endorsed by the International Society on Thrombosis and Haemostasis (ISTH), the WFH guidelines were also the first hemophilia management guidelines to be accepted by the National Guideline Clearinghouse (NGC), formerly run by the Agency for Healthcare Research and Quality (AHRQ) of the United States Department of Health and Human Services (https://www.ahrq.gov/gam/index.html). Over the past five years, unprecedented progress has been made not only in the development of newer therapeutics for hemophilia, but major paradigm shifts have also occurred in many of the principles governing the planning and philosophy of hemophilia treatment. Given the progress in genetic analysis technologies, in addition to much wider access, their applications in hemophilia have moved from the research arena to an increasingly greater role in the management of patients and their families. The advent of newer clotting factor concentrates (CFCs) with extended half-­life has not only led to decreased burden of care for patients; more importantly, extended half-­life CFCs have made it possible to maintain significantly higher factor trough levels on regular replacement therapy than has been possible with standard half-­life CFCs. The bar of hemostatic safety was raised even higher with the introduction of non-­CFC hemostatic agents such as the novel bispecific monoclonal antibody. This agent achieves hemostasis equivalent to approximately 15% FVIII levels, with subcutaneous administration and substantially less frequent dosing compared to CFCs. People with hemophilia treated with these newer therapies are now able to participate in many more activities than ever before without fear of bleeding. In addition, structured outcome assessment has been a relatively unevolved aspect of the management of hemophilia. With greater emphasis over the past few years on its significance in routine management of hemophilia, several clinimetric instruments are now being used for the standardized assessment and documentation of both hemostatic and musculoskeletal outcomes. To acknowledge these advances and establish them more firmly in clinical practice, several modifications have been made in the third edition of these guidelines. New chapters have been added to provide the required detail to the following topics: genetic assessment; prophylaxis with hemostatic agents to prevent bleeding; management of inhibitors; and assessment of outcomes. An additional chapter defines the principles of management of hemophilia to provide aspirational benchmarks during the evolution of these services, within the local contexts of countries around the world. Certain semantic changes introduced in this edition should be mentioned. The term “episodic” rather than “on demand” has been used to describe any hemostasis therapy after bleeding, as this term better reflects the concept of this practice. In keeping with the definition provided by the Scientific Standardization Committee of the ISTH, the term “exposure day” has been replaced with “exposure” to encompass all CFC replacement doses administered within 24 hours. To ensure that bias was avoided as much as possible, a rigorous consensus-­based methodology was adopted for formulating the final recommendations in these guidelines. An independent methods and process expert, unrelated to the field, was appointed alongside the content lead. All recommendations were informed by a comprehensive and systematic review of the relevant scientific literature and developed through an anonymous modified Delphi process resulting in evidence-­informed consensus-­based recommendations. Importantly, in addition to the experts in hemophilia care and related clinical disciplines, the Delphi panels included well-­informed patients who also had the opportunity to review the manuscripts and the literature, and vote on the recommendations. All these steps are described in detail in the Methodology chapter. It is also important to note that the final chapter drafts were reviewed internally both by the full panel and within the WFH, as well as by external subject experts prior to submission for publication. All these reviewers have been acknowledged at the end of the guidelines along with many others whose contributions have been invaluable to their development. A final round of independent peer review was also conducted by the journal before publication. It is also important to note that these guidelines have been endorsed by the Asian-Pacific Society on Thrombosis and Hemostasis, European Haemophilia Consortium, and National Hemophilia Foundation (USA). As a result of all these modifications, the guidelines have become more comprehensive than the previous edition. However, to preserve their easy readability, the text remains structured using short sentences in bullet points. Detailed mechanistic explanations or descriptions of the original data underlying recommendations have been avoided. However, all relevant references have been cited and are listed at the end of each chapter. It is hoped that the clinical care community, for whom these guidelines are primarily intended, will find them even more useful than the previous editions. These guidelines may also serve as a resource to support education, advocacy, and decision-­making related to hemophilia treatment and the delivery of care. In addition, they should help identify gaps in evidence upon which the recommendations have been formulated to help direct appropriate clinical research in these areas. As in the past, the electronic version of these guidelines is available on the WFH website (http://www.wfh.org). These guidelines will be updated, added to, or modified as significant new data or evidence justifying change become available. This will keep the guideline content current and cognizant of the advances that are expected in the coming years, particularly in the area of gene therapy for hemophilia, which will need to be included in more detail once the ongoing clinical trials are over and products are registered. Alok Srivastava1 | Gerard Dolan2 https://orcid.org/0000-0003-3270-6932 | Lisa Bagley3 | Margareth C. Ozelo4 https://orcid.org/0000-0001-5938-0675 | Emna Gouider5 https://orcid.org/0000-0001-7315-3479 | Debbie Hum6 | Steven W. Pipe7 | Bradley Rayner8 | Alison Street9 | Glenn F. Pierce6 1Department of Haematology, Christian Medical College, Vellore, India 2Guy's and St. Thomas’ Hospitals NHS Foundation Trust, London, UK 3London, UK 4INCT do Sangue Hemocentro UNICAMP, University of Campinas, Campinas, SP, Brazil 5Medical School, University of Tunis El Manar, Hemophilia Centre, Aziza Othmana Hospital, Tunis, Tunisia 6World Federation of Hemophilia, Montreal, QC, Canada 7Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, Michigan, USA 8Cape Town, South Africa 9Monash University, Melbourne, Victoria, Australia • These principles of care aim to provide globally relevant guidance based on current science and best practices in hemophilia diagnosis and treatment, as identified by the guidelines panel of the World Federation of Hemophilia (WFH). They include core concepts, requirements, and priorities in the delivery and management of hemophilia care, which together constitute a framework for implementing and advancing hemophilia treatment programs. • The principles build on the original tenets set out by the WFH and the World Health Organization (WHO) in 19901 and the updated guidelines and recommendations developed collaboratively by the WFH, WHO, and International Society on Thrombosis and Haemostasis (ISTH) in 2002.2 • The principles integrate core components of principled integrated care3 and primary health care, including: meeting people's lifetime health needs through comprehensive preventive, curative, and rehabilitative services as well as palliative care; addressing the broader determinants of health through multisectoral policy and action that engages relevant stakeholders and enables local communities to strengthen primary health care; and empowering individuals, families, and communities to take charge of their own health.4 • In addition, they align with the chronic care model's emphasis on the need to shift from acute, episodic, and reactive care towards care that embraces longitudinal, preventive, community-based, and integrated approaches.5 • In addition to guiding clinical practice, principles of care can also serve as a common foundation of understanding for patient organizations, healthcare providers, healthcare administrators, and policymakers; this in turn enables better discussion and collaboration on decisions surrounding allocation of resources for hemophilia programs, and priorities for achieving the best standards possible within the available resources. • Principles of care aim for ideal hemophilia management to ensure that patients have access to appropriate, sustained, and high-quality medical services and comprehensive care; however, it should also be recognized that the priorities and capabilities in each country determine what is practical at any point in time. • A coordinated hemophilia care program, administered through a designated agency and integrated within the existing healthcare system, improves outcomes for people with hemophilia.2,6-8 • Optimal hemophilia care within such a program requires the following key components2: ◦ comprehensive hemophilia care provided by a multidisciplinary team of specialists; ◦ a national or regional network of hemophilia treatment centres (HTCs); ◦ a national registry of patients with hemophilia; ◦ robust processes for the procurement and distribution of safe and effective therapies, particularly clotting factor concentrates (CFCs) and other types of hemostasis products used in hemophilia treatment; ◦ equitable access to these services and therapeutic products9; and ◦ recognition of the socioeconomic and cultural diversities within any given community, region, or country. • Treatment centres based on the multidisciplinary comprehensive care model should be established to ensure that people with hemophilia have access to the full range of clinical specialties and appropriate laboratory services.6 • See Principle 7: Multidisciplinary care for hemophilia and Chapter 2: Comprehensive Care of Hemophilia. • Hemophilia care is best provided through designated diagnostic and treatment centres with clearly defined treatment protocols, standards of care, and quality and audit activities.2 • Hospitals providing clinical care for people with hemophilia and related disorders are strongly encouraged to seek formal designation as a hemophilia treatment centre (HTC) or hemophilia comprehensive care centre (HCCC), as applicable, by the local health authorities6,9 (see Table 1-1). • Such centres can also serve the needs of patients with other congenital bleeding disorders. • Each country should have a national registry of patients with hemophilia, with standardized data collection by all hemophilia centres and centralized administration by a nationally mandated authority, or participate in a multinational or international registry.10-13 • The WFH's World Bleeding Disorders Registry (WBDR) provides an online platform for a network of HTCs around the world to collect uniform and standardized data to track treatment and management of patients, monitor patient outcomes, and guide clinical practice.13 The WBDR can be used as a patient registry for some or all HTCs within a country. • Patient registries are used to collect accurate data on people with hemophilia in terms of their treatment and outcomes including disease severity, type of treatment, bleeding episodes, adverse events, joint status, inhibitor status, comorbidities, and quality of life. • Registry data allow analysis of standards of care and can be used as a tool for auditing clinical and laboratory services; this in turn can support the development of better quality of care and facilitate resource planning and allocation.6 • Patient registries can help to advance understanding of the variations in hemophilia treatment; describe care patterns, including appropriateness and disparities in the delivery and quality of care; indicate factors that influence prognosis and quality of life; and provide evidence on resource utilization.14 • Adequate provision must be made for data privacy, confidentiality, and respect for human rights10 in compliance with national regulations and best ethical practices.6 • It is important to ensure that the patient and/or the parent or legal guardian (in the case of minors) understands a registry's purpose and uses and provides informed written consent for the collection and sharing of data related to the patient's care.10,15 • See Chapter 2: Comprehensive Care of Hemophilia and Chapter 11: Outcome Assessment. • Sustained availability of CFCs in sufficient quantities is strongly correlated with better outcomes for people with hemophilia.16 To ensure that people with hemophilia have reliable access to safe and effective CFCs and other hemostasis products, countries must establish a rigorous national or regional system for the procurement and distribution of hemophilia therapies.2 • Hemophilia treatment relies on essential life-saving medicines that are relatively expensive compared to medications for other conditions. • Setting up a national tender system or collaborating in a multinational system for the purchase of CFCs can help ensure that optimal products are selected at the best price.17 • The decision-making process for such tenders under the contracting authority (typically the Ministry of Health or other health authority) should include both well-informed hemophilia clinicians and patient representatives.9 • The WFH's Guide to National Tenders for the Purchase of Clotting Factor Concentrates describes tender and procurement systems around the world and explains how to set up a national procurement system and carry out tenders.17 • See Chapter 2: Comprehensive Care of Hemophilia and Chapter 5: Hemostatic Agents. • People with hemophilia must have access to safe and effective treatment with optimal efficacy in the prevention of bleeding and treatment of any spontaneous, breakthrough, or trauma-related bleeding. For many, this involves treatment with specific CFCs or other hemostasis products. • Both virus-inactivated plasma-derived and recombinant CFCs, as well as other hemostasis products when appropriate, can be used for treatment of bleeding and prophylaxis in people with hemophilia.16 • Prophylaxis is the standard of care for people with severe hemophilia, and for some people with moderate hemophilia, or for those with another congenital bleeding disorder that is associated with a severe bleeding phenotype and/or a high risk of spontaneous life-threatening bleeding. • Episodic CFC replacement should not be considered a long-term option for the management of hemophilia as it does not alter its natural history of spontaneous bleeding and related complications.18,19 • The WFH's Guide for the Assessment of Clotting Factor Concentrates should be carefully reviewed in the context of the healthcare system in each country and incorporated into tender processes for procurement of hemophilia therapies.16 • The WFH Online Registry of Clotting Factor Concentrates lists all currently available plasma-derived and recombinant CFCs and their product details.20 • See Chapter 5: Hemostatic Agents and Chapter 6: Prophylaxis in Hemophilia. • Emerging therapies in development with alternative modes of delivery (e.g., subcutaneous injection) and novel targets may overcome the limitations of standard CFC replacement therapy (i.e., need for intravenous administration, short half-life, risk of inhibitor formation). These emerging therapies offer markedly improved pharmacokinetic (PK) profiles with a very low burden of administration (e.g., up to monthly dosing); therefore, they may help reduce treatment burden and increase compliance. These therapies are discussed in Chapter 5: Hemostatic Agents, Chapter 6: Prophylaxis in Hemophilia, and Chapter 8: Inhibitors to Clotting Factor. • The development of gene therapies for hemophilia has advanced significantly, with product registration likely in the near future. Several clinical trials in both people with hemophilia A and B have demonstrated success with a favourable safety profile to date.21,22 • Gene therapy should make it possible for some people with hemophilia to aspire to and attain much better health outcomes and quality of life than that attainable with currently available hemophilia therapies. This will require evaluation through long-term follow-up as part of clinical trials and registries. • Given the ongoing advances transforming the hemophilia treatment landscape, it is important to establish systems to constantly monitor developments in emerging and gene therapies for hemophilia and make them available as soon as possible following approval by regulatory authorities. • See Chapter 5: Hemostatic Agents, Chapter 6: Prophylaxis in Hemophilia, and Chapter 8: Inhibitors to Clotting Factor. • The diagnosis and treatment of hemophilia require access to laboratory facilities that are equipped with appropriate resources and expertise to accurately perform factor assays and other coagulation tests. • Screening and testing for inhibitor development, now the most serious complication in hemophilia, is vital for any comprehensive hemophilia treatment program to be able to provide medical treatment and eradication of inhibitors23; however, most centres around the world do not have inhibitor testing capacities. • In many resource-constrained countries, centres and hospitals lack the appropriate technologies and capabilities for diagnosing hemophilia. Therefore, developing or enhancing existing laboratories with the capacity to perform coagulation tests with assured quality is an important priority in these countries.8 • Coagulation laboratories must have well-trained laboratory staff and appropriate resources, including suitable and readily available reagents. • Ideally, coagulation laboratories should be able to provide 24-hour services for coagulation tests and factor assays and be able to perform inhibitor assays in a timely manner.6 • It is essential to have good communication between the laboratory and the clinical team ordering the tests to ensure that the appropriate assays are carried out and that the results reported are correctly evaluated and well understood.24 • All coagulation laboratories should include quality assurance programs and be subject to external quality assessment. • See Chapter 3: Laboratory Diagnosis and Monitoring – Quality assurance. • Genetic assessment of hemophilia is important to define disease biology, establish diagnosis in difficult cases, predict risk of inhibitor development, and provide prenatal diagnosis if desired. Wherever possible, genotype analysis should be offered to all patients with hemophilia.9 (See Chapter 2: Comprehensive Care of Hemophilia and Chapter 3: Laboratory Diagnosis and Monitoring.) • Genetic testing will not always identify the underlying variant associated with the phenotype. Genetic counselling of the person with hemophilia referred for genetic testing should highlight this possibility. • The opportunity for discussion of the genetic analysis results between the clinical and the laboratory teams involved is an essential aspect of the genetic diagnostic service. • Advances in molecular genetic technologies are becoming routinely integrated into many genetic diagnostic laboratories. Full F8 or F9 gene screening is performed by polymerase chain reaction (PCR) and Sanger sequencing, or next-generation sequencing.25-29 Use of these techniques is evolving and increasing internationally. The approach and use of a specific technique depend on the available technical expertise and resources. Genetic counselling must include comprehensive discussion about the possibility of incidental findings in genes other than F8 or F9, depending on the methods being used for the assessment. • See Chapter 2: Comprehensive Care of Hemophilia, Chapter 3: Laboratory Diagnosis and Monitoring, Chapter 4: Genetic Assessment, Chapter 8: Inhibitors to Clotting Factor, and Chapter 9: Specific Management Issues. • As hemophilia is a rare disorder in which the availability of specialized care is a critical determinant of burden of disease,30 recruitment and training of medical specialists in hemophilia management are key to establishing, maintaining, and advancing standards of care to reduce morbidity and mortality among people with hemophilia in well-resourced and resource-constrained countries alike. • Recruitment of physicians, hematologists, and scientists in the area of thrombosis and hemostasis to the field of hemophilia is essential to ensure sustained, high-quality medical care, together with recruitment of medical laboratory specialists, nurses, physical therapists, occupational therapists, and other musculoskeletal specialists (e.g., orthopedic surgeons, rheumatologists, and physiatrists), dentists, and psychosocial counsellors. All are integral to multidisciplinary comprehensive care for hemophilia and require ongoing specialist education and development for practice in this field. • Hemophilia education for allied specialists needed to help address specific medical and health-related issues that may arise in some patients is also important. • Mentorship and fellowship opportunities are valuable and effective means to attract and retain new healthcare providers to the field of hemophilia. • A coordinated approach to advancing clinical expertise in hemophilia (i.e., continued education, training, and fellowship programs) based on local, regional, and/or national needs and priorities will provide the foundation for sustaining and improving standards of care. • Collaboration between hemophilia centres in resource-constrained and well-resourced countries and support from established expert bodies are effective avenues for advancing hemophilia knowledge, expertise, and standards of care.8 • The WFH works in many countries around the world to help develop and expand local, regional, and national capacities in laboratory diagnosis and treatment of hemophilia through its medical twinning program, humanitarian aid program,31 and multidisciplinary education and training workshops for healthcare providers.32 • See Principle 7: Multidisciplinary care for hemophilia and Chapter 2: Comprehensive Care of Hemophilia. • Evidence-based research in hemophilia is greatly needed, but it is hampered by significant challenges due to the small size of the patient population. • As most aspects of clinical management of hemophilia are empirical and lack high-level evidence, well-designed studies to generate the necessary evidence to evaluate current practices are needed.8 A mutual basic scheme, such as the WHO's International Classification of Functioning, Disability and Health (ICF), ensures that disciplines are connected by the same model. • Given the differences in priorities in practice around the world, it is important to promote locally relevant clinical research. • Standardization of outcome assessment will permit meaningful comparison across studies.33 • Priority areas for clinical research in hemophilia include optimization of clotting factor replacement therapy; better understanding and prevention of inhibitor formation; and clinical data collection on existing hemophilia therapies and clinical practices, newer therapies such as extended half-life CFCs and non-factor hemostasis products, and potential gene therapies. • Patient registries, with national and international collaboration between centres and countries, are an effective way to pool data to achieve the required sample size to conduct clinical research on rare disorders such as hemophilia. • The WFH's World Bleeding Disorders Registry allows researchers to address important questions around patient care, compare country-specific levels of care, and use the evidence to advocate for better hemophilia care.13 • See Chapter 5: Hemostatic Agents, Chapter 6: Prophylaxis in Hemophilia, Chapter 8: Inhibitors to Clotting Factor, and Chapter 11: Outcome Assessment. • In critical situations, people with hemophilia need immediate access to emergency medicines and treatment as well as to specialist care at hospital emergency departments.6 Lack of experience and knowledge of hemophilia management among medical professionals, particularly in emergency departments, may lead to serious treatment-related complications.8,34 • Therefore, it is essential to establish systems that are accessible around the clock for the management of acute life- or limb-threatening complications of hemophilia.8 • Treatment centres should develop protocols for emergency care for people with hemophilia, including those with inhibitors, that include management of serious acute complications such as intracranial hemorrhage (ICH) and other types of major internal hemorrhage and trauma.8 (See Principle 9: Management of patients with inhibitors.) • People with hemophilia should not be kept waiting in emergency departments and should be assessed immediately, even for