Establishment of a framework for assessing mortality in persons with congenital hemophilia A and its application to an adverse event reporting database

Abstract

Background Despite recent therapeutic advances, life expectancy in persons with congenital hemophilia A (PwcHA) remains below that of the non‐HA population. As new therapies are introduced, a uniform approach to the assessment of mortality is required for comprehensive evaluation of risk–benefit profiles, timely identification of emerging safety signals, and comparisons between treatments. Objectives Develop and test a framework for consistent reporting and analysis of mortality across past, current, and future therapies. Patients/Methods We identified known causes of mortality in PwcHA through literature review, analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, and expert insights. Leading causes of death in general populations are those recognized by the Centers for Disease Control and Prevention and the World Health Organization. We developed an algorithm for assessing fatalities in PwcHA and used this to categorize FAERS data as a proof of concept. Results PwcHA share mortality causes with the non‐HA population including cardiovascular disease, malignancy, infections, pulmonary disease, dementias, and trauma/suicide. Causes associated with HA include hemorrhage, thrombosis, human immunodeficiency virus, hepatitis C virus, and liver dysfunction. We propose an algorithm employing these classes to categorize fatalities and use it to classify FAERS fatality data between 01/01/2000 and 03/31/2020; the most common causes were hemorrhage (22.2%) and thrombosis (10.4%). Conclusions A conceptual framework for examining mortality in PwcHA receiving any hemophilia therapy is proposed to analyze and interpret fatalities, enabling consistent and objective assessment. Application of the framework using FAERS data suggests a generally consistent pattern of reported mortality across HA treatments, supporting the utility of this unified approach.

All‐cause mortality and causes of death in persons with haemophilia: A systematic review and meta‐analysis

“…Misclassifications in current reports on causes of deaths (such as whether HCC was coded as cancer or chronic liver disease, haemorrhagic stroke was coded as a vascular event or ICH) frequently plague mortality data in PWH. This warrants the need for a unified approach to reporting causes of death 60 . The World Bleeding Disorders Registry provides a platform for standardized, uniform data collection, and may provide a more comprehensive understanding of the evolving changes over time aiming for representation of patients from around the world.…”

“…This warrants the need for a unified approach to reporting causes of death. 60 The World Bleeding Disorders Registry provides a platform for standardized, uniform data collection, and may provide a more comprehensive understanding of the evolving changes over time aiming for representation of patients from around the world.…”

Emicizumab state‐of‐the‐art update

“…Breakthrough bleeds do occur when using emicizumab; however, current data do not show an increased risk of adverse events when these bleeds are treated with diverse replacement haemostatic agents. Following several reports of thromboses, deaths and microangiopathies associated with emicizumab in the compassionate use programs and off label use, a group of global haemophilia experts reviewed the available data and put these events into context when using other haemostatic agents 24–26 . Except for microangiopathy, which is unique to an emicizumab‐aPCC interaction, the deaths and thromboses were comparable to those seen when using other haemostatic agents in haemophilia A patients.…”

Making treatment decisions in hemophilia based on available safety data

“…In the second paper the authors provide a framework to categorize causes of death enabling a separation into those which are related or unrelated to hemophilia. 2 This is rather artificial, and we have some issues such as the assignment of thrombosis as a hemophilia-related cause and malignancy as unrelated to hemophilia when one of the commonest malignancies in hemophilia is hepatitis C--related hepatocellular carcinoma. To us it would seem simpler to ignore the relatedness to hemophilia and simply compare the individual groups of causes between studies.…”

“…The mortality issue was recently addressed by three papers in this journal. [1][2][3] The first paper largely analyzes publications reporting on mortality in hemophilia since 2010. 1 As the authors identify, the cited literature shows significant heterogeneity and pooling the data can be problematic.…”