Standardization of Terminology, Definitions, and Outcome Criteria for Bleeding in Hereditary Hemorrhagic Telangiectasia: International Consensus Report

Abstract

Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) is the second most common inherited bleeding disorder worldwide, affecting approximately 1 in 5000 people. Development of disease-modifying and efficacious hemostatic agents to treat HHT has finally begun after decades without such medical therapies. However, the lack of consensus on standardized severity definitions, outcome criteria, and terminology remains a major obstacle to clinical investigation and therapeutic development in HHT. Additionally, with the ongoing repurposing of antiangiogenic agents and emerging development of novel HHT-specific therapies, comparative clinical trials are expected in the future. Therefore, to end the problematic heterogeneity hindering these efforts, the Global Research and Medical Advisory Board (GRMAB) of the Cure HHT Foundation, an international group of recognized HHT experts, convened a conference of expert HHT clinician-investigators from within GRMAB as well as invited external experts in HHT and bleeding disorders generally, patients with HHT, and patient advocates to define standard terminology and definitions for outcomes and severity classification for bleeding and anemia in HHT. These criteria and definitions should be adopted by regulators, investigators, and the pharmaceutical industry in the development and performance of interventional clinical trials and cohort studies to allow improved comparability between clinical trials, facilitate communication between clinicians and investigators, improve therapeutic guideline development, and provide a standardized framework for regulatory agencies. SEARCH STRATEGY AND SELECTION CRITERIA: Evidence for this report was systematically identified and evaluated utilizing two search strategies in Ovid MEDLINE, described in full detail in the Appendix, pp.4-13. The searches were conducted on January 7, 2025. The titles and abstracts of each record were reviewed, and the inclusion criteria were applied to all search results to identify full text articles to be retrieved for further review. All retrieved full texts were then reviewed to reach a final determination if a study met the inclusion criteria. Included references were then compiled into evidence tables, which were then utilized by the International Consensus Report Working Group throughout the development of report recommendations.

Keywords: HHT; Hereditary hemorrhagic telangiectasia; Osler‐Weber‐Rendu; anemia; angiogenesis; bleeding; epistaxis; gastrointestinal bleeding; iron deficiency.

FIGURE 1

Composite Hematologic Endpoints, the Hematologic Support Score (HSS) and Hematologic Impact Score (HIS). The HSS measures the total amount of hematologic support over a specified time frame (e.g., 3‐month HSS; any time frame may be used, but a minimum of 3 months/12 weeks is recommended in clinical studies); a higher number signifies more required hematologic support and worse overall bleeding. The HIS assesses the total hematologic impact over a reference time frame by integrating the change in hemoglobin and the change in the HSS over that period of time; a higher number signifies a greater improvement in hematologic status over the time period. Example: A person with HHT receives 2 units RBCs and 1000 mg elemental iron during a 6‐month period (T1), and at the end of the period her hemoglobin is 10.5 g/dL (Hemoglobin at T1). The 6‐month HSS for this person is 6.00 red‐cell unit equivalents, or RUEs (HSS at T1). She then enters a 6‐month interventional clinical trial, during which time she receives a novel therapeutic to treat bleeding. During the 6‐month trial period, she receives 0 units RBCs and 500 mg elemental iron, and at the end of the period her hemoglobin is 11.7 g/dL (Hemoglobin at T2). Her post‐intervention 6‐month HSS is 2.00 RUEs (HSS at T2). Her HSS improved by 67%, and her HIS is +5.2 RUEs, representative of an improvement in overall hematologic status of 5.2 RUEs during the 6 months receiving treatment on trial compared with the 6 months prior. Both the HSS and HIS demonstrate a substantial improvement in her hematologic status achieved through reduced bleeding (and a much greater improvement recognized than had a solitary hemoglobin endpoint been used). Of note, these composite endpoints must be adjusted for use in children, as red cell transfusion quantities in children are weight‐based and not given in standardized units. T1 = Time 1 (baseline), T2 = Time 2 (end). [Color figure can be viewed at wileyonlinelibrary.com]