Mortality in congenital hemophilia A - a systematic literature review

Abstract

Against a background of a rapidly evolving treatment landscape, a contemporary, evidence-based consolidated understanding of mortality in people with congenital hemophilia A (PwcHA) is lacking. This systematic literature review examines the available data on mortality and causes of death in PwcHA to enable a better understanding of fatalities in PwcHA and evaluate the impact of new treatment paradigms on mortality. A systematic literature review of observational studies was conducted by searching Medline, Embase, and clinical trials registries for articles published from January 2010 to March 2020, using the search terms: hemophilia A (HA), mortality, cause of death. Interventional studies, studies not reporting fatalities, and those reporting only on hemophilia B, acquired HA, or mixed other coagulopathies were excluded. Overall, 7818 unique records were identified and 17 were analyzed. Of these, six reported mortality rates and five reported mortality ratios. Mortality generally decreased over time, despite a spike associated with human immunodeficiency virus (HIV)/hepatitis C virus (HCV) infection in the 1980s and 1990s. Mortality was strongly correlated with age and hemophilia severity. People with hemophilia had a raised mortality risk compared with the general population, particularly in severe hemophilia, and when infected with HIV or HCV. Causes of death varied across populations, countries, and time in 15 identified studies; however, incomplete and heterogeneous reporting limits evidence. Hemorrhage, HIV, HCV, and hepatic disease were the leading causes of death. A unified approach to reporting mortality and cause of death is needed to understand mortality in PwcHA as treatments continue to advance.

Keywords: benchmarking; cause of death; hemophilia A; mortality; systematic review.

FIGURE 1

Preferred Reporting Items for Systematic Reviews and Meta‐Analyses CONSORT diagram describing the search results and screening. A total of 10 083 records reporting on mortality and cause of death in PwcHA were identified searching both the Medline and Embase databases, as well as clinical trial registries (clinicaltrials.gov; Cochrane Central Register of Controlled Studies). A primary search identified 9512 of these; an updated search, limited to observational studies, identified a further 571. After the removal of duplicated records, a total of 7818 unique records were screened, and 1144 were excluded because they lacked discussion of hemophilia or mortality in their titles or abstracts. After all exclusions, 17 articles met the eligibility criteria for this systematic literature review. HA, hemophilia A; PwcHA, people with congenital hemophilia A

FIGURE 2

Primary cause of death in 15 observational studies. A, Primary cause of death in publications ordered by study period, from earliest to most recent. ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ³⁸ Number of deaths in each study is displayed across the top of the chart. B, Primary cause of death among studies that were conducted pre 2010 ²³ , ²⁹ , ³³ versus post 2010. ²⁵ , ²⁸ , ^{36 §} Publications with study periods that spanned across 2010 were excluded. *Lovdahl et al only reported the number of deaths for the five most frequent causes of death. ^†Of the nine deaths attributed to fulminant sepsis (“other infection”), all were people with HIV infection. ^‡Some people presented with more than one related cause of death. ^§Includes van de Putte et al, Lovdahl et al, and Tagliaferri et al pre 2010 and Lim et al, Miesbach et al, and Schramm et al 2013 post 2010. Ischemic heart disease and pulmonary embolism were categorized as “thrombosis,” and if exact cause of death was unclear, the death was categorized as “unknown.” HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; PwH, people with hemophilia