While publications have reported on mortality in PwcHA, a contemporary evidence-based understanding of mortality in congenital hemophilia A (HA) is absent. This systematic review aims to establish a benchmark of mortality rate and causes of death in PwcHA to enable comparisons and monitoring of mortality in a rapidly evolving treatment landscape.
We conducted a systematic literature review of observational studies by searching Medline, Embase, and clinical trials registries for articles published January 2010 through March 2020, using the search terms: 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. References of the included studies and literature reviews were checked.
Overall, 7,818 unique records were identified; 1,144 manuscripts passed screening and 20 were included (Figure). In these 20 records, 6 reported mortality rates, 5 reported mortality ratios, and 16 reported cause of death. All studies reporting mortality rates and ratios were population-based; their data collection periods spanned 1961–2018, and most focused on the developed world.
Only four reports provided crude mortality rates (unadjusted for age) in the overall HA population, ranging from 0.38–0.75/100 person-years; two reported age-specific mortality rates. Age-adjusted mortality ratios generally decreased over time as life expectancies of PwcHA approached the general population. Mortality was strongly correlated with age and increased hemophilia severity. Comparisons of the risk of death in PwcHA to that of the general male population (standardized mortality or hazard ratios, adjusted for differing age distributions) ranged from 1.1–2.2 in the overall HA population (five articles) and from 2.4–6.6 in the severe HA population (three articles), indicating a raised mortality risk, particularly in severe HA. Two articles provided inconsistent mortality rates by factor VIII inhibitor status. HIV/HCV infection and liver disease were risk factors for mortality. Studies describing mortality from 1980–2000 reported a higher proportion of deaths from human immunodeficiency virus (HIV)/ hepatitis C virus (HCV).
Causes of death among PwcHA varied across populations, countries, and time in the 16 identified studies; however, underreporting of long-term outcomes limits evidence on mortality in PwcHA. Hemorrhage, HIV, HCV, and cancer were leading causes, with prevalence of cancer similar to the general population.
Decreasing mortality ratios in PwcHA were observed across several decades, likely from advancements in detection, treatment and supportive care for hemophilia and related complications. Risk factors such as age and comorbidities should be considered when comparing mortality rates. Reporting of cause of death was highly heterogeneous, limiting practical categorization, hypothesis generation and actionable conclusions. A unified approach to reporting mortality and cause of death is needed to understand mortality in PwcHA and to monitor changes as treatments continue to advance.