key: cord-0747126-u1iy6qnj authors: Hassan, Shermarke; Monahan, Rory C.; Mauser‐Bunschoten, Evelien P.; van Vulpen, Lize F. D.; Eikenboom, Jeroen; Beckers, Erik A. M.; Hooimeijer, Louise; Ypma, Paula F.; Nieuwenhuizen, Laurens; Coppens, Michiel; Schols, Saskia E. M.; Leebeek, Frank W. G.; Smit, Cees; Driessens, Mariëtte H.; le Cessie, Saskia; van Balen, Erna C.; Rosendaal, Frits R.; van der Bom, Johanna G.; Gouw, Samantha C. title: Mortality, life expectancy, and causes of death of persons with hemophilia in the Netherlands 2001–2018 date: 2020-12-18 journal: J Thromb Haemost DOI: 10.1111/jth.15182 sha: 605564ba0b17bebfae86ac4c42e34fbb57100306 doc_id: 747126 cord_uid: u1iy6qnj BACKGROUND: Treatment of patients with hemophilia has advanced over the past decades, but it is unknown whether this has resulted in a normal life expectancy in the Netherlands. OBJECTIVE: This observational cohort study aimed to assess all‐cause and cause‐specific mortality in patients with hemophilia in the Netherlands between 2001 and 2018 and to compare mortality and life expectancy with previous survival assessments from 1973 onward. PATIENTS/METHODS: All 1066 patients with hemophilia who participated in a nationwide survey in 2001 were followed until July 2018. RESULTS: Information on 1031 individuals (97%) was available, of whom 142 (14%) deceased during follow‐up. Compared with the general Dutch male population, mortality of patients with hemophilia was still increased (standardized mortality ratio: 1.4, 95% confidence interval: 1.2–1.7). Intracranial bleeding and malignancies were the most common causes of death. Estimated median life expectancy of patients with hemophilia was 77 years, 6 years lower than the median life expectancy of the general Dutch male population (83 years). Over the past 45 years, death rates of patients with hemophilia have consistently decreased, approaching the survival experience of the general population. Over the past decades, mortality due to human immunodeficiency virus and hepatitis C virus infections has decreased, death due to intracranial hemorrhages has increased, and death due to ischemic heart disease has remained consistently low over time. CONCLUSIONS: Survival in patients with hemophilia in the Netherlands has improved over time but is still lower than that of the general population. Hemophilia is a hereditary disease caused by a deficiency of clotting factor VIII or IX. The introduction of clotting factor concentrates in the 1970s [1] [2] [3] and other improvements such as prophylactic treatment, home treatment, and low dose immune tolerance drastically improved life expectancy of patients. 2 Unfortunately, exposure to human immunodeficiency virus (HIV) and hepatitis C virus (HCV) through contaminated blood products in the 1980s led to a sharp increase in mortality. [4] [5] [6] [7] [8] [9] [10] Through the use of viral inactivation techniques, as well as the introduction of recombinant factor replacement products, the transmission of both HIV and HCV has been halted since 1992. 2 From 1999 onward, hemophilia treatment in the Netherlands was gradually centralized and quality criteria were introduced in comprehensive hemophilia treatment centers. 11 In addition, dosages for prophylactic treatment have steadily increased since the 1970s. 12 It is still insufficiently known whether these treatment advances have resulted in a completely normal life expectancy in the Netherlands. This observational cohort study aimed to evaluate all-cause and cause-specific mortality in patients with hemophilia in the Netherlands from 2001 to 2018 and to compare mortality and life expectancy over the past 45 years. In addition, we investigated potential determinants of mortality of patients with hemophilia during this period. This was an observational cohort study following patients from All male patients with mild, moderately severe, and severe hemophilia A and B who participated in the 2001 survey were included. The following self-reported information, obtained from the 2001 patient survey, was collected at baseline: date of birth, hemophilia Results: Information on 1031 individuals (97%) was available, of whom 142 (14%) deceased during follow-up. Compared with the general Dutch male population, mortality of patients with hemophilia was still increased (standardized mortality ratio: 1.4, 95% confidence interval: 1.2-1.7). Intracranial bleeding and malignancies were the most common causes of death. Estimated median life expectancy of patients with hemophilia was 77 years, 6 years lower than the median life expectancy of the general Dutch male population (83 years). Over the past 45 years, death rates of patients with hemophilia have consistently decreased, approaching the survival experience of the general population. Over the past decades, mortality due to human immunodeficiency virus and hepatitis C virus infections has decreased, death due to intracranial hemorrhages has increased, and death due to ischemic heart disease has remained consistently low over time. Conclusions: Survival in patients with hemophilia in the Netherlands has improved over time but is still lower than that of the general population. hemophilia, hepatitis C, HIV, life expectancy, mortality • This study aimed to assess mortality in patients with hemophilia. • Patients with hemophilia who participated in a survey in 2001 were followed until 2018. • Despite a decrease in death rates, hemophilia is still associated with a lower life expectancy. • Intracranial hemorrhage deaths have increased and ischemic heart deaths remain low. severity, HIV status, and HCV status. If the self-reported data on HIV or HCV were missing, then it was obtained from the medical files. Hemophilia severity was categorized as severe (<0.01 IU/mL), moderate (0.01-0.05 IU/mL), or mild (>0.05-0.40 IU/mL). Information on hemophilia severity and type were verified from the medical files. Patients born after 1985 or who reported no treatment with clotting factor between 1979 and 1985 were considered to be HIV negative. Patients born after 1992 or who reported no treatment with clotting factor before 1992 were considered to be HCV negative. If HIV/HCV status was missing, the information was obtained from the medical files. HCV status was categorized as "never infected with HCV," "HCV infection cleared," and "chronic hepatitis C." As a double-check, HCV status as reported by the patients was compared with HCV status from the medical files for a random sample of patients (N = 92). The standardized mortality ratio (SMR) is a measure of the change in mortality in a given population, with respect to a reference population. SMRs were calculated for the years 2001 to 2018 to estimate the risk of all-cause and cause-specific death among patients compared to the general male population, while adjusting for the age distributions of the two populations. The SMR is calculated by dividing the observed number of deaths in a study population by the expected number of deaths in the study population (which is based on the age distribution of the study population and the age-specific death rates of the general male population). When calculating cause-specific SMRs, other causes of death were censored. To assess all-cause and cause-specific death rates over time, we calculated crude death rates for the current and previous cohort studies, stratified by 15-year age categories. The median life expectancy at birth for the 2001-2018 cohort was calculated from a lifetime survival curve using age as the time scale. To calculate median life expectancy, patients had to survive until the start of the study observation period (2001) . A standard analysis of the data would have induced a type of bias, which is sometimes called length bias. 16 To correct for this problem, we adjusted for left truncation, ie, patients were included in the analysis from the start of the study observation period instead of their date of birth. Median life expectancy was defined as the age at which cumulative survival was 50%. To assess changes in median life expectancy over time, information on median life expectancy for the previous cohort studies was obtained from previously published data. 9,10,13 Severely ill patients may not have participated in the 2001 survey, which could have led to an underestimation of death rates during follow-up. We examined a possible "healthy cohort effect" by performing a sensitivity analysis in which we excluded the first 3 years of follow-up. In the current cohort study, we included 1031 out of 1066 (97%) patients with available data. Thirty-five patients with missing followup data were excluded. Eighty-seven percent of patients had hemophilia A and 13% had hemophilia B (Table 1 ). In total, 412 patients (40%) suffered from severe hemophilia, 175 (17%) from moderate hemophilia, and 444 (43%) from mild hemophilia. In 2001, 29 patients were known to be infected with HIV (3%) and 336 patients had chronic hepatitis C (33%). In the random sample of 92 patients of whom HCV status was verified from medical records, 92% (85/92) accurately reported their hepatitis C status. Stratified by HCV status, 93%, 75%, and 100% correctly reported their HCV status in patients with chronic HCV, patients who previously cleared the virus, and patients who were Figure S1 in supporting information. The total number of deaths per age group in the study population is presented in Figure S2 in supporting information. In total, 142 patients died during follow-up (14%) at a median age Table 2 ). Crude death rates for the period 1973-2018, stratified by age, are presented as a graph (Figure 2 ) and as a table (Table 3) . Overall, crude death rates followed a decreasing trend for all age categories. Median life expectancy from 1973 to 2018 is presented in Figure 3 and additional information on the number of deaths/total persontime is presented in Table 6 ). The sensitivity analysis excluding the first 3 years of follow-up yielded similar results as the overall analysis (Table S1 in supporting information). Hemophilia potentially complicates treatment of age-related conditions such as malignancies and ischemic heart disease, which are becoming more common as the population ages. [25] [26] [27] [28] [29] For example, patients with a malignancy may need additional hemostatic replacement during surgical interventions or after chemotherapy-induced thrombocytopenia. Bleeding symptoms will also develop at an earlier stage in patients with gastrointestinal malignancies. 30 In our cohort, the incidence of deaths due to non-hepatic malignancies is now similar to that of the Dutch male population. This is most likely due to the fact that patients are living longer, and due to fewer hemophilia-related deaths like bleeding-related complications or HCV/HCV. Based on the literature, it seems that patients with hemophilia have an unfavorable cardiovascular risk profile, compared to the general population. 31, 32 In our cohort, the mortality due to ischemic heart disease was lower than in the general population, which is also in line with literature. 30 The low clotting factor levels may hinder thrombus formation at the site of plaque rupture. 33 The optimal evidence-based anti-platelet/anti-coagulant therapy to reduce thrombotic risk as well as bleeding risk has not yet been identified. 30 Hemophilia severity, HIV status, and HCV status were independently associated with mortality. Compared to HCV-negative patients, the increased risk of mortality for HCV-positive patients was relatively minor. This is probably because the vast majority of patients were successfully treated with either (peg) interferon-based treatment and/or the newer direct acting antivirals. Pre-treatment severity of fibrosis is strongly associated with mortality after successful treatment. 34 As information on the extent of liver damage was not available, we were not able to assess this in our dataset. Our study has several strengths. First, due to the availability of data from 1972 onward we could study trends in mortality during the due to improvements in health care and novel treatment options. For example, direct-acting antivirals that are used to treat HCV have an almost 100% success rate. 36 Lastly, compared to treatment with clotting factor products, novel non-gene therapy options such as emicizumab offer better bleeding management (especially for patients with an inhibitor) and possibly a better safety profile as well. 37 In conclusion, a decrease in mortality and an increase in life expectancy in patients with hemophilia in the Netherlands over the period 1973 to 2018 was seen. However, survival is still lower than that of the general population and warrants further improvements in hemophilia care. We thank all participants and Dutch hemophilia treatment centers for their participation. and Shire/Takeda, of which the fees go to the university. He is member of a DSMB for a study from Roche. JGvdB Has been a teacher on educational activities of Bayer. For original data, please contact SCGouw@lumc.nl. 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