Mortality Trends of Hematological Malignancies and Those Complicated by Pulmonary Embolism: A Nationwide Population-Based Study

Mortality Trends of Hematological Malignancies and Those Complicated by Pulmonary Embolism: A Nationwide Population-Based Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Mortality Trends of Hematological Malignancies and Those Complicated by Pulmonary Embolism: A Nationwide Population-Based Study Xi Quan, Zhiming Luo, Nan Zhang, Ying Zhou, Shifeng Lou, Shiyi Yuan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7592454/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective The aim of this study was to analyze the mortality trends of hematological malignancies and those complicated by pulmonary embolism (PE) in the United States from 1999 to 2023. We also explores the mortality changes across multiple dimensions, including gender, age, region, urban-rural differences, and race. Methods Using death certificate data from the Centers for Disease Control’s Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) database, we analyzed the age-adjusted mortality rates (AAMR) of hematological malignancies and hematological malignancies with PE among individuals aged 25 and above in the United States from 1999 to 2023. We assessed mortality trends across different genders, age groups, regions, urban-rural differences, and racial groups by calculating the average annual percentage change (AAPC) and annual percentage change (APC). Results From 1999 to 2023, the AAMR of hematological malignancies among individuals aged 25 and above in the United States showed a steady decline, with an AAPC of -1.75 (95% confidence interval (CI): -1.81 to -1.69), reflecting the positive achievements in the diagnosis, treatment, and management of hematological malignancies. However, the mortality rate of hematological malignancies with PE showed a distinctly different upward trend. The mortality rate increased with a low slope from 1999 to 2017 (APC 0.75, 95% CI 0.17–1.33), followed by a significant acceleration from 2017 to 2023 (APC 3.02, 95% CI 0.51–5.58), indicating a sharp increase in the mortality burden during these six years. Mortality rates for hematological malignancies with PE increased across gender, age, region, urban-rural differences, and race, particularly among males, the Western region, and individuals aged 75 and above. Higher mortality rates were also observed in non-metropolitan areas and among non-Hispanic Black individuals. Conclusion Despite a significant decline in the overall mortality rate of patients with hematological malignancies over the past 24 years, the mortality rate of patients with hematological malignancies complicated by PE has shown an upward trend, with significant differences across different genders, age groups, regions, urban-rural differences, and race. Future research and public health policies need to focus on these differences and develop targeted intervention strategies to reduce the mortality rate of PE in such patients and optimize prognosis. Mortality Hematological malignancies Pulmonary embolism Database Gender differences Age differences Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Pulmonary embolism (PE) is a common and fatal clinical condition, for which timely treatment may be life-saving. The incidence of acute PE in the general population of North America is estimated to be 70 to 110 per 100,000 individuals[ 1 , 2 ]. In the United States, nearly one-third of hospitalized patients are at risk for venous thromboembolism (VTE), with up to 900,000 VTE cases diagnosed annually and 100,000 deaths associated with these conditions[ 3 , 4 ]. PE represents the most severe clinical manifestation of VTE and may lead to serious adverse events, such as heart failure, respiratory failure, and sudden death[ 5 ]. Cancer is an established cause of VTE and exacerbates the factors contributing to VTE formation: venous stasis, endothelial injury, and hypercoagulability (Virchow’s triad). Due to the hypercoagulable state associated with cancer, PE is a major cause of mortality in cancer patients, and VTE (including PE) is the second leading cause of death in cancer patients[ 6 ]. Multiple studies have reported a significantly increased risk of VTE in cancer patients compared with the general population. However, most of the literature has focused on solid tumors and has not included hematological malignancies[ 7 – 10 ]. The treatment of VTE in patients with hematological malignancies is more complex than that in patients with solid tumors[ 11 ]. Most existing guidelines consider thrombocytopenia to be associated with treatment-related toxicity, such as the use of antiangiogenic drugs, second- and third-generation BCR-ABL inhibitors, and immune checkpoint inhibitors[ 12 – 15 ]. In hematological malignancies, patients may also experience thrombocytopenia due to marrow infiltration, treatment-related factors, conditioning for hematopoietic stem cell transplantation, and immune-mediated mechanisms. Therefore, it is necessary to study the risk of acute pulmonary embolism in hematological malignancies. At present, there is a knowledge gap regarding the mortality associated with PE in patients with hematological malignancies. Therefore, it is essential to investigate the mortality associated with PE in patients with hematological malignancies. Additionally, hematological malignancies are among the most common cancers, and the burden of cancer, including hematological malignancies, on public health and the economy is increasing with the aging population[ 16 ]. This is a retrospective cohort study utilizing data from the CDC WONDER database to assess the mortality trends of PE in patients with hematological malignancies aged 25 and above (given the low thrombotic risk in younger patients) and to describe the mortality trends of hematological malignancies in individuals aged 25 and above, stratified by age, gender, race, and region. This study aims to fill the knowledge gap by comprehensively analyzing the mortality trends of hematological malignancies complicated by PE, providing insights for future research and public health policies. Materials and methods The CDC WONDER (Centers for Disease Control’s Wide-ranging Online Data for Epidemiologic Research) database is a comprehensive online database for epidemiologic research from the Centers for Disease Control and Prevention[ 17 ], can be utilized for the analysis of healthcare data.Based on the CDC WONDER database, we analyzed mortality data for adults (aged ≥ 25 years) in the United States with hematological malignancies complicated by PE from 1999 to 2023 and described mortality data for patients with hematological malignancies. Patient diagnoses were based on the 10th revision of the International Classification of Diseases (ICD-10).For the analysis of mortality in patients with hematological malignancies complicated by PE, we included decedents for whom hematological malignancies were the underlying cause of death and PE (I26) was a contributing cause of death. For the analysis of mortality in patients with hematological malignancies, hematological malignancies were the underlying cause of death. Hematological malignancies encompassed the following cancer types: lymphoma (C81-C85), multiple myeloma (C90), immunoproliferative neoplasms (C88), and leukemia (C91-C95). These cancer types were selected to cover the majority of hematologic malignancies. We further examined mortality stratified by gender (male vs. female), age, race, census region, and urbanization. We defined the following age groups: 10-year intervals within the range of 25 to 84 years, and individuals aged 85 years or older. We analyzed four US census regions (Northeast, Midwest, South, and West) along with urbanization status, classified according to the 2013 NCHS Urban–Rural Classification Scheme for Counties (non-core, micropolitan, small metro, medium metro, large fringe metro, and large central metro)[ 17 ]. The age-adjusted mortality rates (AAMR) per 100,000 population, standardized to the 2000 U.S. population, were calculated. Time trends were plotted using R (version 4.5.1). The time trends of AAMR were analyzed using the Joinpoint regression program (version 5.1.0, National Cancer Institute), which allows for the identification of up to four joinpoints within the 24-year study period, and estimates of the average annual percentage change (AAPC), annual percentage change (APC), and 95% Confidence Interval (CI) were obtained. Statistical significance was set at P ≤ 0.05. Institutional review board approval was not required for this study, as the CDC WONDER database contains anonymized data that are publicly available. The study's limitations include potential inaccuracies in death certificate reporting and the lack of patient-level data, which may affect the precision of our findings. Results Overall, from 1999 to 2023, a total of 1,384,189 deaths occurred among US patients with hematologic malignancies aged 25 years and older (Table 1), of which 13,379 deaths were attributed to hematologic malignancies with PE (Supplementary Table S1). The AAMR for patients with hematologic malignancies exhibited a gradual downward trend from 1999 to 2023 (Figure 1A). Specifically, the AAPC was -1.75 (95% CI, -1.81 to -1.69) during this period. This indicates that the mortality rate among patients with hematologic malignancies decreased at a relatively stable pace year by year, with an overall reduction in mortality burden. When analyzed by state, there were differences in disease burden among states, with New York State showing the largest decrease in AAMR (Figure 2). However, the AAMR for patients with hematologic malignancies complicated by PE in the US showed a two-phase upward trend (Figure 1B). For the entire population, there was a low-slope increase from 1999 to 2017 (APC, 0.75; 95% CI, 0.17 to 1.33), followed by a significant acceleration from 2017 to 2023 (APC, 3.02; 95% CI, 0.51 to 5.58) (Figure 1B, 1D), indicating a sharp increase in mortality burden in these 6 years. Gender stratified From 1999 to 2023, patients with hematologic malignancies, there were 769,105 male deaths and 615,084 female deaths in the united states (Supplementary Table 2). In terms of AAMR, in 1999, the AAMR for males was 39.54 (95% CI: 39.07–40.00) and for females was 25.16 (95% CI: 24.85–25.47); in 2023, the AAMR for males was 26.41 (95% CI: 26.12–26.71) and for females was 15.39 (95% CI: 15.19–15.59). During the period from 1999 to 2023, the AAPC in AAMR was -1.66 (95% CI: -1.78 to -1.55) for males, -2.00 (95% CI: -2.07 to -1.92) for females, and -1.75 (95% CI: -1.81 to -1.69) for the entire population, all showing a significant downward trend (Figure 1A, 1C), p<0.05. This sustained decline may be associated with a variety of factors, including advances in the diagnosis and treatment of hematologic malignancies, the introduction of new therapeutic drugs, and the optimization of overall management strategies for patients with hematologic malignancies. However, despite the overall positive trend, the mortality trend among patients with hematologic malignancies complicated by PE appears to be rather unfavorable. From 1999 to 2023, among US patients with hematologic malignancies complicated by PE, there were 7,327 male deaths and 6,052 female deaths (Supplementary Table S3). Specifically, in 1999, there were 192 male deaths and 174 female deaths; in 2023, there were 449 male deaths and 317 female deaths. Compared with 1999, the number of male deaths increased by 133.85%, while the number of female deaths increased by 82.18%.Among males, the AAMR increased from 0.23 in 1999 (95% CI: 0.19 to 0.26) to 0.34 in 2023 (95% CI: 0.31 to 0.38) (Figure 1B, 1D). Among females, the AAMR increased from 0.14 in 1999 (95% CI: 0.12 to 0.17) to 0.20 in 2023 (95% CI: 0.18 to 0.23) (Figure 1B, 1D). For males, the overall APC from 1999 to 2023 was 1.55 (95% CI: 1.03–2.06), p<0.05, and the AAMR was consistently higher than that of females, with a statistically significant trend (P<0.05). For females, the APC during the same period was 1.19 (95%CI: 0.60–1.78), p<0.05 (Figure 1B, 1D). The Joinpoint model indicated a steeper slope for males, with the gender gap widening over time. After 2017, the APC for the entire population surged above 3, with a more pronounced increase in males. This reflects a potential failure or delay in thromboprophylaxis, surveillance, or intervention measures related to the treatment of hematologic malignancies. There is an urgent need to conduct interventional studies targeting high-risk genders and the overall population to curb the rapid increase in PE mortality. Age group stratified Regarding age-specific mortality and its long-term changes, the AAMR among US patients with hematologic malignancies exhibited distinct age gradients and phased change characteristics from 1999 to 2023 (Figure 3A).25–34 years age group: The AAMR showed a trend of first decreasing and then increasing, but neither trend was statistically significant. 35–44 years age group: During 1999–2023, the APC was -2.88 (95% CI: -3.06 to -2.70), indicating a continuous decline in mortality at a relatively stable rate, with p<0.05, suggesting statistical significance. 45–54 years age group: From 1999 to 2015, the AAMR showed a gradual downward trend, but this trend was not statistically significant. From 2015 to 2023, the APC further decreased to -3.42 (95% CI: -4.08 to -2.77), with an accelerated decline in mortality that became statistically significant. Patients aged 55–84 years: The mortality rate showed a downward trend. 85 years and older age group: The APC was -0.17 (95% CI: -0.30 to -0.04), indicating a slight decline in mortality at a slower rate, but the trend was statistically significant (Figure 3A, 3C). Overall, from 1999 to 2023, the mortality rate among US patients with hematologic malignancies exhibited different trends across various age groups. The mortality rate in most age groups showed a significant downward trend, but the decline in some age groups did not reach statistical significance. From 1999 to 2023, the crude mortality rate among US patients with hematologic malignancies complicated by PE exhibited a strong age gradient (Figure 3B): The 45–54 and 55–64 years age groups consistently remained at the lowest plateau, while the group aged 75 years and older showed a marked increase with advancing age. The Joinpoint model did not identify any significant inflection points in any age group (0 joinpoints), indicating a monotonic linear trend across all age groups over the 25 years (Figure 3D). The APC in each age group was as follows: For the 45–54 years age group, the APC of the crude mortality rate was -0.04 (95% CI: -0.85 to 0.79), with no statistically significant trend (P>0.05), indicating no significant fluctuations in mortality in this age group over the past 24 years and an overall stable trend. For the 55–64 years age group, similar to the 45–54 years group, the mortality rate did not show a clear upward or downward trend during the study period. 65–74 year age group: The mortality rate in this group showed a slight upward trend, with an APC of 0.32 (95% CI: -0.16 to 0.79). However, since the confidence interval includes 0, the trend is not statistically significant (P>0.05), indicating that the increasing trend is not yet clear. 75–84 years age group: the mortality rate in this group exhibited a significant upward trend, with an APC of 1.79 (95% CI: 1.18 to 2.41), which is statistically significant (P<0.05). This group has one of the faster growth rates among middle-aged and older populations. 85 years and older age group: This group had the largest increase in mortality rate, with an APC of 3.58 (95% CI: 2.82 to 4.34), which is statistically significant (P<0.05). It is the group with the most significant increase in mortality rate across all age groups. In summary, from 1999 to 2023, there were significant age-specific differences in mortality among US patients with hematologic malignancies complicated by PE. The mortality rate remained stable among middle-aged and young adults (45–64 years), while the risk of death from pulmonary embolism continued to rise among the elderly population (≥75 years) over the past 24 years. The older the age group, the faster the growth rate, indicating that the current thromboprophylaxis strategies are insufficient for elderly patients with hematologic malignancies. Regional variation Overall, during the period from 1999 to 2023, the AAMR or patients with hematologic malignancies in the four major US census regions (Northeast, Midwest, South, and West) all exhibited significant downward trends (Figure 4A), with statistically significant changes. However, the rates of decline varied across regions. The West region showed the most pronounced decrease in AAMR, with an APC of -1.74 (95% CI: -1.83 to -1.66), which was the fastest decline among all regions (Figure 4C). This significant downward trend indicates that the West region has made greater progress in reducing mortality among patients with hematologic malignancies. However, from 1999 to 2023, the AAMR for patients with hematologic malignancies complicated by PE in the four major US census regions all exhibited significant upward trends (Figure 4B, Figure 4D), but the rates of increase varied across regions. Northeast region: The AAMR in this region showed a statistically significant increase, with APC of 1.06 (95% CI: 0.26 to 1.87). The upward trend was statistically significant (P<0.05), indicating a steady annual increase in mortality. Midwest region: The annual increase in AAMR was slightly lower than that in the Northeast, with an APC of 0.93 (95% CI: 0.14 to 1.74). This trend was also statistically significant (P<0.05), showing a sustained and clear upward trajectory. South region: The rate of increase in AAMR was the lowest among the four regions, with an APC of 0.84 (95% CI: 0.23 to 1.45). However, the upward trend remained statistically significant (P<0.05).West region: The increase in AAMR was the most pronounced, with an APC of 2.03 (95% CI: 1.44 to 2.62), which was the fastest among all regions. This significant upward trend suggests that the West region is more severely affected by the impact of PE on mortality. Although the western region has made greater progress in reducing the mortality rate of patients with hematological malignancies, the mortality rate of patients with hematological malignancies complicated by PE has significantly increased, highlighting the increasingly significant impact of pulmonary embolism complications on the mortality rate of patients with hematological malignancies. Joinpoint analysis revealed no inflection points in any region(Figure 4D), indicating that mortality trends remained unchanged during the study period due to interventions or other factors. Rural vs urban Overall, from 1999 to 2020, the AAMR of patients with hematologic malignancies in both non-metropolitan and metropolitan areas in the US exhibited significant downward trends (Figure 5A, Figure 5C), but the rates of decline varied between the two areas. Non-metropolitan areas: The AAMR in non-metropolitan areas showed a statistically significant decline, with an APC of -1.57 (95% CI: -1.65 to -1.49). The downward trend was statistically significant (P<0.05), indicating a steady annual decrease in mortality. Metropolitan areas: the decline in AAMR was more pronounced in metropolitan areas, with an APC of -1.86 (95% CI: -2.05 to -1.67), which was the fastest compared to non-metropolitan areas. This significant downward trend indicates that metropolitan areas have made greater progress in reducing mortality among patients with hematologic malignancies. During the period from 1999 to 2020, the AAMR for patients with hematologic malignancies complicated by PE increased in both urban (metropolitan) and non-urban (non-metropolitan) settings in the US (Figure 5B, Figure 5D). Metropolitan areas: The APC in AAMR was 0.89 (95% CI: 0.42 to 1.36), with a statistically significant upward trend (P<0.05). This indicates that in highly urbanized areas, the mortality rate increased steadily and significantly on an annual basis. Non-metropolitan areas: The increase in AAMR was more pronounced in non-metropolitan areas, with an APC of 1.23 (95% CI: 0.24 to 2.22), which was also statistically significant (P<0.05). Compared to metropolitan areas, the annual growth rate of mortality was higher in non-metropolitan areas, suggesting that the impact of pulmonary embolism on mortality among patients with hematologic malignancies is more severe and growing more rapidly in non-urban regions.Joinpoint model analysis revealed no significant inflection points (0 joinpoints) in either urban or non-urban settings during the study period (Figure 5D). This indicates that mortality rates in both environments exhibited a continuous upward trend without any notable fluctuations or events that altered the trend. These findings indicate that the mortality rate among patients with hematologic malignancies complicated by PE is increasing in both urban and non-urban areas, but the impact is more pronounced in non-urban areas. Race stratified Overall, from 1999 to 2023, the AAMR for patients with hematologic malignancies decreased significantly across all racial groups (Figure 6A, Figure 6C). Among them, the AAMR of non-Hispanic whites was always lower than that of other racial groups and had the fastest decline, indicating that this group has made significant progress in reducing the mortality rate of patients with hematologic malignancies. The AAMR for patients with hematologic malignancies complicated by PE increased across different races in the US (Figure 6B, Figure 6D). According to the Joinpoint model analysis, the increase in AAMR was statistically significant for non-Hispanic Blacks (NH Black) and non-Hispanic Whites (NH White), while data for other racial/ethnic groups were not included due to the inability to analyze (Figure 6D). The APC in AAMR for non-Hispanic Blacks was 1.62 (95% CI: 0.72 to 2.52), P<0.05. This indicates that among non-Hispanic Blacks, the mortality rate for patients with hematologic malignancies complicated by PE is increasing at a rate of 1.62% per year. The APC for non-Hispanic Whites was 1.59 (95% CI: 1.12 to 2.07), P<0.05. It can be seen that the AAMR for non-Hispanic Blacks has always been higher than that for non-Hispanic Whites, but the growth trends of the two are similar, both showing a stable upward trend. Discussion From 1999 to 2023, the age-adjusted mortality rate (AAMR) of hematological malignancies among individuals aged 25 and above in the United States exhibited a continuous downward trend, indicating a reduction in the overall mortality burden of hematological malignancies over this 24-year period. This positive trend reflects significant advancements in the diagnosis, treatment, and management of hematological malignancies. Improvements in diagnostic techniques, the introduction of novel therapeutic agents and modalities, and the optimization of patient care strategies are likely key factors driving this decline[18]. With the progress of screening, diagnostic, and therapeutic strategies, an increasing number of cancer patients are surviving. Acute pulmonary embolism is a significant cause of mortality among cancer survivors[19].In the United States, there are approximately 375,000 to 425,000 clinically suspected patients diagnosed with PE annually[20, 21]. During 2016 - 2018, 8.9% of US cancer patients hospitalized for acute PE had hematologic malignancies. This study showed that compared with those with hematologic malignancies, solid tumor patients had a greater risk of unstable PE and unfavorable discharge. However, there was no significant difference in the incidence of unstable PE between the two groups[22]. The co-occurrence of pulmonary embolism (PE) in patients with hematological malignancies is equally worthy of our attention. The incidence of venous thromboembolism (VTE) in patients with hematological malignancies is relatively high, and the latest data suggest that its pathogenesis and clinical manifestations may differ from those in solid tumors[23]. Regardless of the etiology or type of tumor, the prognosis for patients experiencing thrombotic events is always poorer[24, 25]. Many studies have focused on the causes of VTE in hematological malignancies. The plasma levels of antithrombin, fibrinogen, and plasminogen in patients with hematological diseases decrease in the presence of L-asparaginase [26], which overall increases the likelihood of thrombosis. Patients with aggressive lymphomas are usually more debilitated and more prone to reduced activity. Therefore, the risk of VTE may be higher in patients with lymphoma[27-29], tissue factor (TF) promotes cancer coagulopathy and angiogenesis[30], and acute myeloid leukemia (AML), multiple myeloma (MM), and other tumor cells have TF on their membranes and low tissue factor pathway inhibitor (TFPI), giving them a procoagulant phenotype[31]. Acute pulmonary embolism is an important component of VTE. To our knowledge, this is the first study to comprehensively describe the mortality trends of patients with hematological malignancies and those with hematological malignancies complicated by PE over the past two decades. We found that, although the mortality of patients with hematological malignancies is decreasing with the application of new drugs and technologies, the mortality of patients with hematological malignancies complicated by PE is on the rise. In addition, we revealed significant changes across multiple dimensions, including gender, age, region, urban-rural differences, and race. These findings will provide important evidence for optimizing the prevention and management strategies of PE in patients with hematological malignancies. Our study found that the AAMR for both male and female patients with hematological malignancies decreased significantly, but the decline was faster in females than in males. Multiple studies have also shown that the AAMR for non-Hodgkin lymphoma (NHL) is always higher in males than in females[32-34]，and this difference may be related to the different distributions of hematological malignancy types, treatment response differences, and overall health status between males and females[35, 36]. Regarding patients with hematological malignancies complicated by PE, our study found that the PE mortality rate was significantly higher in male patients with hematological malignancies than in females, and this gender difference continued to widen over time. The AAMR for male patients increased from 0.23 in 1999 to 0.34 in 2023, with an average annual growth rate of 1.55%; whereas the AAMR for females increased from 0.14 in 1999 to 0.20 in 2023, with an average annual growth rate of 1.19%. This gender difference may be related to differences in physiology, lifestyle, and treatment response between male and female patients. Previous studies have shown that females have a higher awareness of the clinical signs and symptoms of PE[37]. It is possible that timely medical care for females reduced their mortality. The lower awareness of PE signs in males may delay the time to receive appropriate care and increase male mortality[37]. Future research and clinical practice still need to increase education on the signs and symptoms of PE for all patients with hematological malignancies, with a particular focus on male patients, and explore targeted interventions to reduce mortality. Age-specific mortality analysis revealed complex patterns of mortality changes across different age groups. The most notable findings included the continued decline in the AAMR of patients with hematological malignancies in the 35–44 and 45–54 age groups. This downward trend may be related to the types of hematological malignancies in these age groups, the natural course of the diseases, and treatment responses. For example, younger patients may more readily benefit from novel treatments, while older patients may face a higher mortality risk due to the presence of multiple comorbidities. In addition, differences in sample size and data uncertainty across age groups may also affect the statistical significance of mortality changes. Age is a significant factor influencing the mortality rate of patients with hematologic malignancies complicated by PE. In this study, we found that the mortality rate of patients with hematological malignancies complicated by PE remained stable among the middle-aged and young group aged 45–64 years, while it increased significantly among the elderly group aged 75 years and older, especially in the age group of 85 years and above, with an annual increase rate of 3.58%. This indicates that with increasing age, the susceptibility of patients with hematologic malignancies to PE increases significantly. Previous studies have also shown that the incidence of VTE increases exponentially with age, and thus most VTE events occur in the elderly population, with the risk of potentially fatal bleeding events also being higher[38-40]. Moreover, the short-term mortality rate of acute PE is higher in elderly patients than in younger ones[41]. Elderly patients may be more prone to PE due to decreased physical function, increased chronic comorbidities, and reduced tolerance to treatment. In addition, the current thromboprophylaxis strategies may be less effective in very old patients. Therefore, there is an urgent need to include elderly patients with hematologic malignancies in the national thrombosis monitoring priority cohort, develop age-stratified guidelines for anticoagulation and early identification, and extend high-quality prevention and treatment resources to the primary care level to improve the prognosis of this group. Regional differences analysis shows that the AAMR of patients with hematological malignancies in the four major census regions of the United States are all on a significant downward trend, with the fastest decline in the Western region. This result may be related to the Western region's superior performance in medical resource allocation, the application of novel therapeutic technologies, and the implementation of patient management strategies. However, despite the overall positive trend, disparities in mortality rates still exist among different regions, which suggests the need for further research and optimization of medical resource allocation and patient management strategies across regions. However, mortality rates from hematologic malignancies with PE are on a significant upward trend across different regions in the United States, albeit at varying rates. The most pronounced increase is seen in the Western region, with a growth rate of 2.03%, while the Southern region experiences a relatively lower growth rate of 0.84%. This further underscores the link between PE mortality, access to healthcare, and socioeconomic inequality. Environmental factors, lifestyle, and dietary habits in different regions may also affect the risk of thrombosis in patients with hematologic malignancies. Therefore, it is necessary to develop differentiated public health interventions tailored to the characteristics of each region, especially in the Western region where mortality is growing more rapidly. Strengthen the prevention and management of PE to reduce its impact on the mortality rate of patients with hematological malignancies. Urbanization level analysis shows that AAMR of hematologic malignancies has significantly declined in both metropolitan and non - metropolitan areas. However, the decline is faster in metropolitan areas. This may be related to their advantages in medical resource accessibility, advanced medical technology, and patient education levels. Non - metropolitan areas may face issues such as insufficient medical resources and a shortage of professional medical staff. These factors can affect treatment outcomes and slow down the decline in mortality rates. The mortality rate of patients with hematological malignancies complicated with PE has significantly decreased in both urban and non-urban areas, and there are differences between urban and rural areas. The annual increase in mortality rate is higher in non - metropolitan areas than in metropolitan areas, indicating that PE has a more pronounced impact on mortality among patients with hematologic malignancies in non - metropolitan regions. Some studies have highlighted that the increased mortality in non - metropolitan areas may be due to delayed treatment, socioeconomic inequality in rural communities, physician shortages, and lack of health insurance in rural areas [42]. Patients in non - metropolitan areas may have difficulty accessing timely diagnosis and treatment, leading to disease progression. Therefore, it is essential to strengthen the development of medical resources in non - metropolitan areas, improve disease management, and promote effective preventive measures to reduce the mortality rate of PE in patients with hematologic malignancies in rural regions. Our studies have shown that the AAMR for hematologic malignancies decreases most rapidly among non-Hispanic whites (NH White), indicating significant progress in reducing mortality from hematologic malignancies in this group. In contrast, the decline in AAMR is relatively slower among other racial groups. This disparity may be associated with a variety of factors, including access to medical resources, socioeconomic status, health behaviors, and potential biological differences. Racial disparities are also evident in the mortality rate of hematologic malignancies complicated by PE. The AAMR for non-Hispanic blacks remains higher than that for non-Hispanic whites, and the average annual increase rate is also higher than that for non-Hispanic whites. Evidence suggests that compared with white patients, black patients with venous thromboembolism (VTE) and PE are less likely to receive adequate duration of anticoagulation therapy[43]. Insufficient anticoagulation therapy may increase their risk of developing PE and subsequently increase their mortality risk.Therefore, it is necessary to develop targeted interventions based on the characteristics of different racial groups, to strengthen the prevention and management of pulmonary embolism, and to mitigate its impact on mortality among patients with hematologic malignancies. Despite a significant decline in mortality among patients with hematologic malignancies over the past 24 years, disparities persist across different genders, age groups, regions, and levels of urbanization. These disparities may be associated with a variety of factors, including type of disease, treatment response, allocation of medical resources, socioeconomic status, and health behaviors. Future research needs to further investigate the impact of these factors on mortality from hematologic malignancies in order to develop more effective public health policies and medical interventions. Moreover, with the continuous emergence of novel therapeutic technologies, such as targeted therapy and immunotherapy, there is hope for further reductions in mortality from hematologic malignancies and improvements in patient prognosis in the future. However, the treatment and management of hematologic malignancies still face many challenges, such as the patient population with hematologic malignancies complicated by PE, which deserves our attention. This study reveals significant changes in mortality among US patients with hematologic malignancies complicated by PE across multiple dimensions, including gender, age, region, urban–rural differences, and race. These findings underscore the need for tailored interventions based on the characteristics of different populations and regions. Specific recommendations include: (1) prioritizing thromboprophylaxis and management for male patients; (2) incorporating elderly patients with hematologic malignancies into national thrombosis surveillance priority cohorts and developing age-stratified guidelines for anticoagulation and early identification; (3) strengthening medical resource construction in the western and non-urban regions to improve disease management levels; and (4) devising race-specific interventions based on the characteristics of different racial groups. These measures are expected to reduce the mortality from pulmonary embolism among patients with hematologic malignancies and improve patient prognosis. Our findings may directly inform clinical practice, with risk stratification and decisions regarding anticoagulant use for pulmonary embolism prophylaxis playing a central role. Future research should further explore the underlying mechanisms contributing to these disparities, including physiological, genetic, socioeconomic, and medical resource factors. Additionally, more intervention studies are needed to verify the effectiveness and feasibility of these measures. The limitations of this study is that the use of overall mortality data from death certificates in the CDC WONDER database, which relies on the accurate reporting and coding of death certificates by healthcare professionals. Therefore, different interpretations or errors may lead to inaccurate data. Furthermore, data from certain geographic areas or specific populations may be incomplete, which may affect the accuracy and reliability of the study results. Future studies should incorporate more patient-level data to explore how environmental exposure, healthcare access, and socioeconomic conditions affect the mortality of patients with hematologic malignancies complicated by PE in different regions. Conclusion This study shows that from 1999 to 2023, the overall mortality rate of hematologic malignancy patients aged 25 and above in the United States has been on the decline. This reflects significant progress in diagnosis, treatment, and management. However, disparities in mortality rates still exist across multiple dimensions, including gender, age, geographic region, urban-rural differences, and race. These disparities may be associated with a variety of factors, including access to medical resources, socioeconomic status, health behaviors, and biological factors. The treatment and management of hematologic malignancies still face many challenges. Although the overall mortality rate of hematologic malignancies has declined, the mortality trend of patients with hematologic malignancies complicated by PE is gradually increasing, especially in some high-risk subgroups. This highlights the necessity of managing and preventing pulmonary embolism in patients with hematologic malignancies. Future research should focus on identifying high-risk populations and devising personalized preventive strategies to further reduce the incidence and mortality of pulmonary embolism among patients with hematologic malignancies. Declarations Acknowledgements Not applicable. Author contributions X.Q. and S.L. wrote the main manuscript and prepared all figures/tables. S. Y. and Y.Z. assisted Z. L. and N.Z. in acquiring and interpreting the data.All authors reviewed the manuscript. Funding Not applicable. Data availability The datasets generated and/or analyzed during the current study are available on the CDC Wonder Database, https://wonder.cdc.gov/. 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I4-8. Klok, F.A., et al., Prediction of bleeding events in patients with venous thromboembolism on stable anticoagulation treatment. Eur Respir J, 2016. 48(5): p. 1369-1376. Klok, F.A., et al., Predicting anticoagulant-related bleeding in patients with venous thromboembolism: a clinically oriented review. Eur Respir J, 2015. 45(1): p. 201-10. Kniffin, W.J., et al., The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med, 1994. 154(8): p. 861-6. Gong, G., et al., Higher US Rural Mortality Rates Linked To Socioeconomic Status, Physician Shortages, And Lack Of Health Insurance. Health Aff (Millwood), 2019. 38(12): p. 2003-2010. White, R.H. and C.R. Keenan, Effects of race and ethnicity on the incidence of venous thromboembolism. Thromb Res, 2009. 123 Suppl 4: p. S11-7. Table Table 1 is available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files Supplementarytable.docx Table1.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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07:23:55","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":29797,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytable.docx","url":"https://assets-eu.researchsquare.com/files/rs-7592454/v1/b1e5711d6bc6f2c28a42f5da.docx"},{"id":93013031,"identity":"8bc23cb2-cf01-4f77-badc-fc32acd0c9ae","added_by":"auto","created_at":"2025-10-08 07:23:54","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":184059,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7592454/v1/6dc1574acfdb0cb280c5a58f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Mortality Trends of Hematological Malignancies and Those Complicated by Pulmonary Embolism: A Nationwide Population-Based Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePulmonary embolism (PE) is a common and fatal clinical condition, for which timely treatment may be life-saving. The incidence of acute PE in the general population of North America is estimated to be 70 to 110 per 100,000 individuals[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In the United States, nearly one-third of hospitalized patients are at risk for venous thromboembolism (VTE), with up to 900,000 VTE cases diagnosed annually and 100,000 deaths associated with these conditions[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. PE represents the most severe clinical manifestation of VTE and may lead to serious adverse events, such as heart failure, respiratory failure, and sudden death[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Cancer is an established cause of VTE and exacerbates the factors contributing to VTE formation: venous stasis, endothelial injury, and hypercoagulability (Virchow\u0026rsquo;s triad). Due to the hypercoagulable state associated with cancer, PE is a major cause of mortality in cancer patients, and VTE (including PE) is the second leading cause of death in cancer patients[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Multiple studies have reported a significantly increased risk of VTE in cancer patients compared with the general population. However, most of the literature has focused on solid tumors and has not included hematological malignancies[\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe treatment of VTE in patients with hematological malignancies is more complex than that in patients with solid tumors[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Most existing guidelines consider thrombocytopenia to be associated with treatment-related toxicity, such as the use of antiangiogenic drugs, second- and third-generation BCR-ABL inhibitors, and immune checkpoint inhibitors[\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In hematological malignancies, patients may also experience thrombocytopenia due to marrow infiltration, treatment-related factors, conditioning for hematopoietic stem cell transplantation, and immune-mediated mechanisms. Therefore, it is necessary to study the risk of acute pulmonary embolism in hematological malignancies. At present, there is a knowledge gap regarding the mortality associated with PE in patients with hematological malignancies.\u003c/p\u003e\u003cp\u003eTherefore, it is essential to investigate the mortality associated with PE in patients with hematological malignancies. Additionally, hematological malignancies are among the most common cancers, and the burden of cancer, including hematological malignancies, on public health and the economy is increasing with the aging population[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. This is a retrospective cohort study utilizing data from the CDC WONDER database to assess the mortality trends of PE in patients with hematological malignancies aged 25 and above (given the low thrombotic risk in younger patients) and to describe the mortality trends of hematological malignancies in individuals aged 25 and above, stratified by age, gender, race, and region. This study aims to fill the knowledge gap by comprehensively analyzing the mortality trends of hematological malignancies complicated by PE, providing insights for future research and public health policies.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eThe CDC WONDER (Centers for Disease Control\u0026rsquo;s Wide-ranging Online Data for Epidemiologic Research) database is a comprehensive online database for epidemiologic research from the Centers for Disease Control and Prevention[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], can be utilized for the analysis of healthcare data.Based on the CDC WONDER database, we analyzed mortality data for adults (aged\u0026thinsp;\u0026ge;\u0026thinsp;25 years) in the United States with hematological malignancies complicated by PE from 1999 to 2023 and described mortality data for patients with hematological malignancies. Patient diagnoses were based on the 10th revision of the International Classification of Diseases (ICD-10).For the analysis of mortality in patients with hematological malignancies complicated by PE, we included decedents for whom hematological malignancies were the underlying cause of death and PE (I26) was a contributing cause of death. For the analysis of mortality in patients with hematological malignancies, hematological malignancies were the underlying cause of death. Hematological malignancies encompassed the following cancer types: lymphoma (C81-C85), multiple myeloma (C90), immunoproliferative neoplasms (C88), and leukemia (C91-C95). These cancer types were selected to cover the majority of hematologic malignancies.\u003c/p\u003e\u003cp\u003eWe further examined mortality stratified by gender (male vs. female), age, race, census region, and urbanization. We defined the following age groups: 10-year intervals within the range of 25 to 84 years, and individuals aged 85 years or older. We analyzed four US census regions (Northeast, Midwest, South, and West) along with urbanization status, classified according to the 2013 NCHS Urban\u0026ndash;Rural Classification Scheme for Counties (non-core, micropolitan, small metro, medium metro, large fringe metro, and large central metro)[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe age-adjusted mortality rates (AAMR) per 100,000 population, standardized to the 2000 U.S. population, were calculated. Time trends were plotted using R (version 4.5.1). The time trends of AAMR were analyzed using the Joinpoint regression program (version 5.1.0, National Cancer Institute), which allows for the identification of up to four joinpoints within the 24-year study period, and estimates of the average annual percentage change (AAPC), annual percentage change (APC), and 95% Confidence Interval (CI) were obtained. Statistical significance was set at P\u0026thinsp;\u0026le;\u0026thinsp;0.05. Institutional review board approval was not required for this study, as the CDC WONDER database contains anonymized data that are publicly available. The study's limitations include potential inaccuracies in death certificate reporting and the lack of patient-level data, which may affect the precision of our findings.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eOverall, from 1999 to 2023, a total of 1,384,189 deaths occurred among US patients with hematologic malignancies aged 25 years and older (Table 1), of which 13,379 deaths were attributed to hematologic malignancies with PE (Supplementary Table S1). The AAMR for patients with hematologic malignancies exhibited a gradual downward trend from 1999 to 2023 (Figure 1A). Specifically, the AAPC was -1.75 (95% CI, -1.81 to -1.69) during this period. This indicates that the mortality rate among patients with hematologic malignancies decreased at a relatively stable pace year by year, with an overall reduction in mortality burden. When analyzed by state, there were differences in disease burden among states, with New York State showing the largest decrease in AAMR (Figure 2). However, the AAMR for patients with hematologic malignancies complicated by PE in the US showed a two-phase upward trend (Figure 1B). For the entire population, there was a low-slope increase from 1999 to 2017 (APC, 0.75; 95% CI, 0.17 to 1.33), followed by a significant acceleration from 2017 to 2023 (APC, 3.02; 95% CI, 0.51 to 5.58) (Figure 1B, 1D), indicating a sharp increase in mortality burden in these 6 years.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGender stratified\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFrom 1999 to 2023, patients with hematologic malignancies, there were 769,105 male deaths and 615,084 female deaths in the united states (Supplementary Table 2). In terms of AAMR, in 1999, the AAMR for males was 39.54 (95% CI: 39.07–40.00) and for females was 25.16 (95% CI: 24.85–25.47); in 2023, the AAMR for males was 26.41 (95% CI: 26.12–26.71) and for females was 15.39 (95% CI: 15.19–15.59). During the period from 1999 to 2023, the AAPC in AAMR was -1.66 (95% CI: -1.78 to -1.55) for males, -2.00 (95% CI: -2.07 to -1.92) for females, and -1.75 (95% CI: -1.81 to -1.69) for the entire population, all showing a significant downward trend (Figure 1A, 1C), p\u0026lt;0.05. This sustained decline may be associated with a variety of factors, including advances in the diagnosis and treatment of hematologic malignancies, the introduction of new therapeutic drugs, and the optimization of overall management strategies for patients with hematologic malignancies. However, despite the overall positive trend, the mortality trend among patients with hematologic malignancies complicated by PE appears to be rather unfavorable.\u003c/p\u003e\n\u003cp\u003eFrom 1999 to 2023, among US patients with hematologic malignancies complicated by PE, there were 7,327 male deaths and 6,052 female deaths (Supplementary Table S3). Specifically, in 1999, there were 192 male deaths and 174 female deaths; in 2023, there were 449 male deaths and 317 female deaths. Compared with 1999, the number of male deaths increased by 133.85%, while the number of female deaths increased by 82.18%.Among males, the AAMR increased from 0.23 in 1999 (95% CI: 0.19 to 0.26) to 0.34 in 2023 (95% CI: 0.31 to 0.38) (Figure 1B, 1D). Among females, the AAMR increased from 0.14 in 1999 (95% CI: 0.12 to 0.17) to 0.20 in 2023 (95% CI: 0.18 to 0.23) (Figure 1B, 1D). For males, the overall APC from 1999 to 2023 was 1.55 (95% CI: 1.03–2.06), p\u0026lt;0.05, and the AAMR was consistently higher than that of females, with a statistically significant trend (P\u0026lt;0.05). For females, the APC during the same period was 1.19 (95%CI: 0.60–1.78), p\u0026lt;0.05 (Figure 1B, 1D). The Joinpoint model indicated a steeper slope for males, with the gender gap widening over time. After 2017, the APC for the entire population surged above 3, with a more pronounced increase in males. This reflects a potential failure or delay in thromboprophylaxis, surveillance, or intervention measures related to the treatment of hematologic malignancies. There is an urgent need to conduct interventional studies targeting high-risk genders and the overall population to curb the rapid increase in PE mortality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAge group stratified\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRegarding age-specific mortality and its long-term changes, the AAMR among US patients with hematologic malignancies exhibited distinct age gradients and phased change characteristics from 1999 to 2023 (Figure 3A).25–34 years age group: The AAMR showed a trend of first decreasing and then increasing, but neither trend was statistically significant. 35–44 years age group: During 1999–2023, the APC was -2.88 (95% CI: -3.06 to -2.70), indicating a continuous decline in mortality at a relatively stable rate, with p\u0026lt;0.05, suggesting statistical significance. 45–54 years age group: From 1999 to 2015, the AAMR showed a gradual downward trend, but this trend was not statistically significant. From 2015 to 2023, the APC further decreased to -3.42 (95% CI: -4.08 to -2.77), with an accelerated decline in mortality that became statistically significant. Patients aged 55–84 years: The mortality rate showed a downward trend. 85 years and older age group: The APC was -0.17 (95% CI: -0.30 to -0.04), indicating a slight decline in mortality at a slower rate, but the trend was statistically significant (Figure 3A, 3C). Overall, from 1999 to 2023, the mortality rate among US patients with hematologic malignancies exhibited different trends across various age groups. The mortality rate in most age groups showed a significant downward trend, but the decline in some age groups did not reach statistical significance.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFrom 1999 to 2023, the crude mortality rate among US patients with hematologic malignancies complicated by PE exhibited a strong age gradient (Figure 3B): The 45–54 and 55–64 years age groups consistently remained at the lowest plateau, while the group aged 75 years and older showed a marked increase with advancing age. The Joinpoint model did not identify any significant inflection points in any age group (0 joinpoints), indicating a monotonic linear trend across all age groups over the 25 years (Figure 3D). The APC in each age group was as follows: For the 45–54 years age group, the APC of the crude mortality rate was -0.04 (95% CI: -0.85 to 0.79), with no statistically significant trend (P\u0026gt;0.05), indicating no significant fluctuations in mortality in this age group over the past 24 years and an overall stable trend. For the 55–64 years age group, similar to the 45–54 years group, the mortality rate did not show a clear upward or downward trend during the study period. 65–74 year age group: The mortality rate in this group showed a slight upward trend, with an APC of 0.32 (95% CI: -0.16 to 0.79). However, since the confidence interval includes 0, the trend is not statistically significant (P\u0026gt;0.05), indicating that the increasing trend is not yet clear. 75–84 years age group: the mortality rate in this group exhibited a significant upward trend, with an APC of 1.79 (95% CI: 1.18 to 2.41), which is statistically significant (P\u0026lt;0.05). This group has one of the faster growth rates among middle-aged and older populations. 85 years and older age group: This group had the largest increase in mortality rate, with an APC of 3.58 (95% CI: 2.82 to 4.34), which is statistically significant (P\u0026lt;0.05). It is the group with the most significant increase in mortality rate across all age groups.\u003c/p\u003e\n\u003cp\u003eIn summary, from 1999 to 2023, there were significant age-specific differences in mortality among US patients with hematologic malignancies complicated by PE. The mortality rate remained stable among middle-aged and young adults (45–64 years), while the risk of death from pulmonary embolism continued to rise among the elderly population (≥75 years) over the past 24 years. The older the age group, the faster the growth rate, indicating that the current thromboprophylaxis strategies are insufficient for elderly patients with hematologic malignancies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRegional variation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverall, during the period from 1999 to 2023, the AAMR\u0026nbsp;or patients with hematologic malignancies\u0026nbsp;in the four major US census regions (Northeast, Midwest, South, and West) all exhibited significant downward trends (Figure 4A), with statistically significant changes. However, the rates of decline varied across regions. The West region showed the most pronounced decrease in AAMR, with an APC of -1.74 (95% CI: -1.83 to -1.66), which was the fastest decline among all regions (Figure 4C). This significant downward trend indicates that the West region has made greater progress in reducing mortality among patients with hematologic malignancies.\u003c/p\u003e\n\u003cp\u003eHowever, from 1999 to 2023, the AAMR for patients with hematologic malignancies complicated by PE in the four major US census regions all exhibited significant upward trends (Figure 4B, Figure 4D), but the rates of increase varied across regions. Northeast region: The AAMR in this region showed a statistically significant increase, with APC of 1.06 (95% CI: 0.26 to 1.87). The upward trend was statistically significant (P\u0026lt;0.05), indicating a steady annual increase in mortality. Midwest region: The annual increase in AAMR was slightly lower than that in the Northeast, with an APC of 0.93 (95% CI: 0.14 to 1.74). This trend was also statistically significant (P\u0026lt;0.05), showing a sustained and clear upward trajectory. South region: The rate of increase in AAMR was the lowest among the four regions, with an APC of 0.84 (95% CI: 0.23 to 1.45). However, the upward trend remained statistically significant (P\u0026lt;0.05).West region: The increase in AAMR was the most pronounced, with an APC of 2.03 (95% CI: 1.44 to 2.62), which was the fastest among all regions. This significant upward trend suggests that the West region is more severely affected by the impact of PE on mortality.\u003c/p\u003e\n\u003cp\u003eAlthough the western region has made greater progress in reducing the mortality rate of patients with hematological malignancies, the mortality rate of patients with hematological malignancies complicated by PE has significantly increased, highlighting the increasingly significant impact of pulmonary embolism complications on the mortality rate of patients with hematological malignancies. Joinpoint analysis revealed no inflection points in any region(Figure 4D), indicating that mortality trends remained unchanged during the study period due to interventions or other factors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRural vs urban\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverall, from 1999 to 2020, the AAMR of patients with hematologic malignancies in both non-metropolitan and metropolitan areas in the US exhibited significant downward trends (Figure 5A, Figure 5C), but the rates of decline varied between the two areas. Non-metropolitan areas: The AAMR in non-metropolitan areas showed a statistically significant decline, with an APC of -1.57 (95% CI: -1.65 to -1.49). The downward trend was statistically significant (P\u0026lt;0.05), indicating a steady annual decrease in mortality. Metropolitan areas: the decline in AAMR was more pronounced in metropolitan areas, with an APC of -1.86 (95% CI: -2.05 to -1.67), which was the fastest compared to non-metropolitan areas. This significant downward trend indicates that metropolitan areas have made greater progress in reducing mortality among patients with hematologic malignancies.\u003c/p\u003e\n\u003cp\u003eDuring the period from 1999 to 2020, the AAMR for patients with hematologic malignancies complicated by PE increased in both urban (metropolitan) and non-urban (non-metropolitan) settings in the US (Figure 5B, Figure 5D). Metropolitan areas: The APC in AAMR was 0.89 (95% CI: 0.42 to 1.36), with a statistically significant upward trend (P\u0026lt;0.05). This indicates that in highly urbanized areas, the mortality rate increased steadily and significantly on an annual basis. Non-metropolitan areas: The increase in AAMR was more pronounced in non-metropolitan areas, with an APC of 1.23 (95% CI: 0.24 to 2.22), which was also statistically significant (P\u0026lt;0.05). Compared to metropolitan areas, the annual growth rate of mortality was higher in non-metropolitan areas, suggesting that the impact of pulmonary embolism on mortality among patients with hematologic malignancies is more severe and growing more rapidly in non-urban regions.Joinpoint model analysis revealed no significant inflection points (0 joinpoints) in either urban or non-urban settings during the study period (Figure 5D). This indicates that mortality rates in both environments exhibited a continuous upward trend without any notable fluctuations or events that altered the trend. These findings indicate that the mortality rate among patients with hematologic malignancies complicated by PE is increasing in both urban and non-urban areas, but the impact is more pronounced in non-urban areas.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRace stratified\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverall, from 1999 to 2023, the AAMR for patients with hematologic malignancies decreased significantly across all racial groups (Figure 6A, Figure 6C). Among them, the AAMR of non-Hispanic whites was always lower than that of other racial groups and had the fastest decline, indicating that this group has made significant progress in reducing the mortality rate of patients with hematologic malignancies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe AAMR for patients with hematologic malignancies complicated by PE increased across different races in the US (Figure 6B, Figure 6D). According to the Joinpoint model analysis, the increase in AAMR was statistically significant for non-Hispanic Blacks (NH Black) and non-Hispanic Whites (NH White), while data for other racial/ethnic groups were not included due to the inability to analyze (Figure 6D). The APC in AAMR for non-Hispanic Blacks was 1.62 (95% CI: 0.72 to 2.52), P\u0026lt;0.05. This indicates that among non-Hispanic Blacks, the mortality rate for patients with hematologic malignancies complicated by PE is increasing at a rate of 1.62% per year. The APC for non-Hispanic Whites was 1.59 (95% CI: 1.12 to 2.07), P\u0026lt;0.05. It can be seen that the AAMR for non-Hispanic Blacks has always been higher than that for non-Hispanic Whites, but the growth trends of the two are similar, both showing a stable upward trend.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eFrom 1999 to 2023, the age-adjusted mortality rate (AAMR) of hematological malignancies among individuals aged 25 and above in the United States exhibited a continuous downward trend, indicating a reduction in the overall mortality burden of hematological malignancies over this 24-year period. This positive trend reflects significant advancements in the diagnosis, treatment, and management of hematological malignancies. Improvements in diagnostic techniques, the introduction of novel therapeutic agents and modalities, and the optimization of patient care strategies are likely key factors driving this decline[18].\u003c/p\u003e\n\u003cp\u003eWith the progress of screening, diagnostic, and therapeutic strategies, an increasing number of cancer patients are surviving. Acute pulmonary embolism is a significant cause of mortality among cancer survivors[19].In the United States, there are approximately 375,000 to 425,000 clinically suspected patients diagnosed with PE annually[20, 21].\u0026nbsp;During 2016 - 2018, 8.9% of US cancer patients hospitalized for acute PE had hematologic malignancies. This study showed that compared with those with hematologic malignancies, solid tumor patients had a greater risk of unstable PE and unfavorable discharge. However, there was no significant difference in the incidence of unstable PE between the two groups[22]. The co-occurrence of pulmonary embolism (PE) in patients with hematological malignancies is equally worthy of our attention. The incidence of venous thromboembolism (VTE) in patients with hematological malignancies is relatively high, and the latest data suggest that its pathogenesis and clinical manifestations may differ from those in solid tumors[23]. Regardless of the etiology or type of tumor, the prognosis for patients experiencing thrombotic events is always poorer[24, 25]. Many studies have focused on the causes of VTE in hematological malignancies. The plasma levels of antithrombin, fibrinogen, and plasminogen in patients with hematological diseases decrease in the presence of L-asparaginase\u0026nbsp;[26], which overall increases the likelihood of thrombosis. Patients with aggressive lymphomas are usually more debilitated and more prone to reduced activity. Therefore, the risk of VTE may be higher in patients with lymphoma[27-29], tissue factor (TF) promotes cancer coagulopathy and angiogenesis[30], and acute myeloid leukemia (AML), multiple myeloma (MM), and other tumor cells have TF on their membranes and low tissue factor pathway inhibitor (TFPI), giving them a procoagulant phenotype[31].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAcute pulmonary embolism is an important component of VTE.\u0026nbsp;To our knowledge, this is the first study to comprehensively describe the mortality trends of patients with hematological malignancies and those with hematological malignancies complicated by PE over the past two decades. We found that, although the mortality of patients with hematological malignancies is decreasing with the application of new drugs and technologies, the mortality of patients with hematological malignancies complicated by PE is on the rise. In addition, we revealed significant changes across multiple dimensions, including gender, age, region, urban-rural differences, and race. These findings will provide important evidence for optimizing the prevention and management strategies of PE in patients with hematological malignancies.\u003c/p\u003e\n\u003cp\u003eOur study found that the AAMR for both male and female patients with hematological malignancies decreased significantly, but the decline was faster in females than in males. Multiple studies have also shown that the AAMR for non-Hodgkin lymphoma (NHL) is always higher in males than in females[32-34]，and this difference may be related to the different distributions of hematological malignancy types, treatment response differences, and overall health status between males and females[35, 36]. Regarding patients with hematological malignancies complicated by PE, our study found that the PE mortality rate was significantly higher in male patients with hematological malignancies than in females, and this gender difference continued to widen over time. The AAMR for male patients increased from 0.23 in 1999 to 0.34 in 2023, with an average annual growth rate of 1.55%; whereas the AAMR for females increased from 0.14 in 1999 to 0.20 in 2023, with an average annual growth rate of 1.19%. This gender difference may be related to differences in physiology, lifestyle, and treatment response between male and female patients. Previous studies have shown that females have a higher awareness of the clinical signs and symptoms of PE[37]. It is possible that timely medical care for females reduced their mortality. The lower awareness of PE signs in males may delay the time to receive appropriate care and increase male mortality[37]. Future research and clinical practice still need to increase education on the signs and symptoms of PE for all patients with hematological malignancies, with a particular focus on male patients, and explore targeted interventions to reduce mortality.\u003c/p\u003e\n\u003cp\u003eAge-specific mortality analysis revealed complex patterns of mortality changes across different age groups. The most notable findings included the continued decline in the AAMR of patients with hematological malignancies in the 35–44 and 45–54 age groups. This downward trend may be related to the types of hematological malignancies in these age groups, the natural course of the diseases, and treatment responses. For example, younger patients may more readily benefit from novel treatments, while older patients may face a higher mortality risk due to the presence of multiple comorbidities. In addition, differences in sample size and data uncertainty across age groups may also affect the statistical significance of mortality changes.\u003c/p\u003e\n\u003cp\u003eAge is a significant factor influencing the mortality rate of patients with hematologic malignancies complicated by PE. In this study, we found that the mortality rate of patients with hematological malignancies complicated by PE remained stable among the middle-aged and young group aged 45–64 years, while it increased significantly among the elderly group aged 75 years and older, especially in the age group of 85 years and above, with an annual increase rate of 3.58%. This indicates that with increasing age, the susceptibility of patients with hematologic malignancies to PE increases significantly. Previous studies have also shown that the incidence of VTE increases exponentially with age, and thus most VTE events occur in the elderly population, with the risk of potentially fatal bleeding events also being higher[38-40]. Moreover, the short-term mortality rate of acute PE is higher in elderly patients than in younger ones[41]. Elderly patients may be more prone to PE due to decreased physical function, increased chronic comorbidities, and reduced tolerance to treatment. In addition, the current thromboprophylaxis strategies may be less effective in very old patients. Therefore, there is an urgent need to include elderly patients with hematologic malignancies in the national thrombosis monitoring priority cohort, develop age-stratified guidelines for anticoagulation and early identification, and extend high-quality prevention and treatment resources to the primary care level to improve the prognosis of this group.\u003c/p\u003e\n\u003cp\u003eRegional differences analysis shows that the AAMR of patients with hematological malignancies in the four major census regions of the United States are all on a significant downward trend, with the fastest decline in the Western region. This result may be related to the Western region's superior performance in medical resource allocation, the application of novel therapeutic technologies, and the implementation of patient management strategies. However, despite the overall positive trend, disparities in mortality rates still exist among different regions, which suggests the need for further research and optimization of medical resource allocation and patient management strategies across regions. However, mortality rates from hematologic malignancies with PE are on a significant upward trend across different regions in the United States, albeit at varying rates. The most pronounced increase is seen in the Western region, with a growth rate of 2.03%, while the Southern region experiences a relatively lower growth rate of 0.84%. This further underscores the link between PE mortality, access to healthcare, and socioeconomic inequality. Environmental factors, lifestyle, and dietary habits in different regions may also affect the risk of thrombosis in patients with hematologic malignancies. Therefore, it is necessary to develop differentiated public health interventions tailored to the characteristics of each region, especially in the Western region where mortality is growing more rapidly. Strengthen the prevention and management of PE to reduce its impact on the mortality rate of patients with hematological malignancies.\u003c/p\u003e\n\u003cp\u003eUrbanization level analysis shows that AAMR of hematologic malignancies has significantly declined in both metropolitan and non - metropolitan areas. However, the decline is faster in metropolitan areas. This may be related to their advantages in medical resource accessibility, advanced medical technology, and patient education levels. Non - metropolitan areas may face issues such as insufficient medical resources and a shortage of professional medical staff. These factors can affect treatment outcomes and slow down the decline in mortality rates. The mortality rate of patients with hematological malignancies complicated with PE has significantly decreased in both urban and non-urban areas, and there are differences between urban and rural areas. The annual increase in mortality rate is higher in non - metropolitan areas than in metropolitan areas, indicating that PE has a more pronounced impact on mortality among patients with hematologic malignancies in non - metropolitan regions. Some studies have highlighted that the increased mortality in non - metropolitan areas may be due to delayed treatment, socioeconomic inequality in rural communities, physician shortages, and lack of health insurance in rural areas\u0026nbsp;[42].\u0026nbsp;Patients in non - metropolitan areas may have difficulty accessing timely diagnosis and treatment, leading to disease progression. Therefore, it is essential to strengthen the development of medical resources in non - metropolitan areas, improve disease management, and promote effective preventive measures to reduce the mortality rate of PE in patients with hematologic malignancies in rural regions.\u003c/p\u003e\n\u003cp\u003eOur studies have shown that the AAMR for hematologic malignancies decreases most rapidly among non-Hispanic whites (NH White), indicating significant progress in reducing mortality from hematologic malignancies in this group. In contrast, the decline in AAMR is relatively slower among other racial groups. This disparity may be associated with a variety of factors, including access to medical resources, socioeconomic status, health behaviors, and potential biological differences. Racial disparities are also evident in the mortality rate of hematologic malignancies complicated by PE. The AAMR for non-Hispanic blacks remains higher than that for non-Hispanic whites, and the average annual increase rate is also higher than that for non-Hispanic whites. Evidence suggests that compared with white patients, black patients with venous thromboembolism (VTE) and PE are less likely to receive adequate duration of anticoagulation therapy[43]. Insufficient anticoagulation therapy may increase their risk of developing PE and subsequently increase their mortality risk.Therefore, it is necessary to develop targeted interventions based on the characteristics of different racial groups, to strengthen the prevention and management of pulmonary embolism, and to mitigate its impact on mortality among patients with hematologic malignancies.\u003c/p\u003e\n\u003cp\u003eDespite a significant decline in mortality among patients with hematologic malignancies over the past 24 years, disparities persist across different genders, age groups, regions, and levels of urbanization. These disparities may be associated with a variety of factors, including type of disease, treatment response, allocation of medical resources, socioeconomic status, and health behaviors. Future research needs to further investigate the impact of these factors on mortality from hematologic malignancies in order to develop more effective public health policies and medical interventions. Moreover, with the continuous emergence of novel therapeutic technologies, such as targeted therapy and immunotherapy, there is hope for further reductions in mortality from hematologic malignancies and improvements in patient prognosis in the future. However, the treatment and management of hematologic malignancies still face many challenges, such as the patient population with hematologic malignancies complicated by PE, which deserves our attention. \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study reveals significant changes in mortality among US patients with hematologic malignancies complicated by PE across multiple dimensions, including gender, age, region, urban–rural differences, and race. These findings underscore the need for tailored interventions based on the characteristics of different populations and regions. Specific recommendations include: (1) prioritizing thromboprophylaxis and management for male patients; (2) incorporating elderly patients with hematologic malignancies into national thrombosis surveillance priority cohorts and developing age-stratified guidelines for anticoagulation and early identification; (3) strengthening medical resource construction in the western and non-urban regions to improve disease management levels; and (4) devising race-specific interventions based on the characteristics of different racial groups. These measures are expected to reduce the mortality from pulmonary embolism among patients with hematologic malignancies and improve patient prognosis. Our findings may directly inform clinical practice, with risk stratification and decisions regarding anticoagulant use for pulmonary embolism prophylaxis playing a central role. Future research should further explore the underlying mechanisms contributing to these disparities, including physiological, genetic, socioeconomic, and medical resource factors. Additionally, more intervention studies are needed to verify the effectiveness and feasibility of these measures.\u003c/p\u003e\n\u003cp\u003eThe limitations of this study is that the use of overall mortality data from death certificates in the CDC WONDER database, which relies on the accurate reporting and coding of death certificates by healthcare professionals. Therefore, different interpretations or errors may lead to inaccurate data. Furthermore, data from certain geographic areas or specific populations may be incomplete, which may affect the accuracy and reliability of the study results. Future studies should incorporate more patient-level data to explore how environmental exposure, healthcare access, and socioeconomic conditions affect the mortality of patients with hematologic malignancies complicated by PE in different regions.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study shows that from 1999 to 2023, the overall mortality rate of hematologic malignancy patients aged 25 and above in the United States has been on the decline. This reflects significant progress in diagnosis, treatment, and management. However, disparities in mortality rates still exist across multiple dimensions, including gender, age, geographic region, urban-rural differences, and race. These disparities may be associated with a variety of factors, including access to medical resources, socioeconomic status, health behaviors, and biological factors. The treatment and management of hematologic malignancies still face many challenges. Although the overall mortality rate of hematologic malignancies has declined, the mortality trend of patients with hematologic malignancies complicated by PE is gradually increasing, especially in some high-risk subgroups. This highlights the necessity of managing and preventing pulmonary embolism in patients with hematologic malignancies. Future research should focus on identifying high-risk populations and devising personalized preventive strategies to further reduce the incidence and mortality of pulmonary embolism among patients with hematologic malignancies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eX.Q.\u0026nbsp;and\u0026nbsp;S.L. wrote the main manuscript and prepared all figures/tables.\u0026nbsp;S. Y. and Y.Z.\u0026nbsp;assisted\u0026nbsp;Z. L.\u0026nbsp;and\u0026nbsp;N.Z.\u0026nbsp;in acquiring and interpreting the data.All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are available\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eon the CDC Wonder Database, https://wonder.cdc.gov/.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eStein, P.D., F. Matta and M.J. Hughes, Hospitalizations for High-Risk Pulmonary Embolism. Am J Med, 2021. 134(5): p. 621-625.\u003c/li\u003e\n\u003cli\u003eKonstantinides, S.V., et al., 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J, 2020. 41(4): p. 543-603.\u003c/li\u003e\n\u003cli\u003eBelohlavek, J., V. Dytrych and A. Linhart, Pulmonary embolism, part I: Epidemiology, risk factors and risk stratification, pathophysiology, clinical presentation, diagnosis and nonthrombotic pulmonary embolism. Exp Clin Cardiol, 2013. 18(2): p. 129-38.\u003c/li\u003e\n\u003cli\u003eKing, E., et al., Whole-body biomechanical differences between limbs exist 9 months after ACL reconstruction across jump/landing tasks. 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Hashmi, Evolution of survivorship in lymphoma, myeloma and leukemia: Metamorphosis of the field into long term follow-up care. Blood Rev, 2019. 33: p. 63-73.\u003c/li\u003e\n\u003cli\u003eCarroll, C.E., et al., Adoption of Innovative Therapies Across Oncology Practices-Evidence From Immunotherapy. JAMA Oncol, 2023. 9(3): p. 324-333.\u003c/li\u003e\n\u003cli\u003eGrosse, S.D., et al., The economic burden of incident venous thromboembolism in the United States: A review of estimated attributable healthcare costs. Thromb Res, 2016. 137: p. 3-10.\u003c/li\u003e\n\u003cli\u003eDi Nisio, M., et al., Diagnosis and treatment of incidental venous thromboembolism in cancer patients: guidance from the SSC of the ISTH. J Thromb Haemost, 2015. 13(5): p. 880-3.\u003c/li\u003e\n\u003cli\u003eHou, J., et al., Disparities in the Outcomes of Acute Pulmonary Embolism in Hospitalized Patients with Hematologic Malignancy and Solid Tumor. 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Haematologica, 2005. 90(11): p. 1549-56.\u003c/li\u003e\n\u003cli\u003eTan, J.Y., et al., Non-Hodgkin lymphoma mortality disparities across different sexes, races, and geographic locations. J Investig Med, 2024. 72(7): p. 723-729.\u003c/li\u003e\n\u003cli\u003eThandra, K.C., et al., Epidemiology of Non-Hodgkin\u0026apos;s Lymphoma. Med Sci (Basel), 2021. 9(1).\u003c/li\u003e\n\u003cli\u003eSun, H., et al., Global, regional and national burden of non-Hodgkin lymphoma from 1990 to 2017: estimates from global burden of disease study in 2017. Ann Med, 2022. 54(1): p. 633-645.\u003c/li\u003e\n\u003cli\u003eZhang, N., et al., Global burden of hematologic malignancies and evolution patterns over the past 30 years. Blood Cancer J, 2023. 13(1): p. 82.\u003c/li\u003e\n\u003cli\u003eStabellini, N., et al., Sex differences in adults with acute myeloid leukemia and the impact of sex on overall survival. Cancer Med, 2023. 12(6): p. 6711-6721.\u003c/li\u003e\n\u003cli\u003eWendelboe, A.M., et al., Global public awareness of venous thromboembolism. J Thromb Haemost, 2015. 13(8): p. 1365-71.\u003c/li\u003e\n\u003cli\u003eWhite, R.H., The epidemiology of venous thromboembolism. Circulation, 2003. 107(23 Suppl 1): p. I4-8.\u003c/li\u003e\n\u003cli\u003eKlok, F.A., et al., Prediction of bleeding events in patients with venous thromboembolism on stable anticoagulation treatment. Eur Respir J, 2016. 48(5): p. 1369-1376.\u003c/li\u003e\n\u003cli\u003eKlok, F.A., et al., Predicting anticoagulant-related bleeding in patients with venous thromboembolism: a clinically oriented review. Eur Respir J, 2015. 45(1): p. 201-10.\u003c/li\u003e\n\u003cli\u003eKniffin, W.J., et al., The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med, 1994. 154(8): p. 861-6.\u003c/li\u003e\n\u003cli\u003eGong, G., et al., Higher US Rural Mortality Rates Linked To Socioeconomic Status, Physician Shortages, And Lack Of Health Insurance. Health Aff (Millwood), 2019. 38(12): p. 2003-2010.\u003c/li\u003e\n\u003cli\u003eWhite, R.H. and C.R. Keenan, Effects of race and ethnicity on the incidence of venous thromboembolism. Thromb Res, 2009. 123 Suppl 4: p. S11-7.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Mortality, Hematological malignancies, Pulmonary embolism, Database, Gender differences, Age differences","lastPublishedDoi":"10.21203/rs.3.rs-7592454/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7592454/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eThe aim of this study was to analyze the mortality trends of hematological malignancies and those complicated by pulmonary embolism (PE) in the United States from 1999 to 2023. We also explores the mortality changes across multiple dimensions, including gender, age, region, urban-rural differences, and race.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eUsing death certificate data from the Centers for Disease Control\u0026rsquo;s Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) database, we analyzed the age-adjusted mortality rates (AAMR) of hematological malignancies and hematological malignancies with PE among individuals aged 25 and above in the United States from 1999 to 2023. We assessed mortality trends across different genders, age groups, regions, urban-rural differences, and racial groups by calculating the average annual percentage change (AAPC) and annual percentage change (APC).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eFrom 1999 to 2023, the AAMR of hematological malignancies among individuals aged 25 and above in the United States showed a steady decline, with an AAPC of -1.75 (95% confidence interval (CI): -1.81 to -1.69), reflecting the positive achievements in the diagnosis, treatment, and management of hematological malignancies. However, the mortality rate of hematological malignancies with PE showed a distinctly different upward trend. The mortality rate increased with a low slope from 1999 to 2017 (APC 0.75, 95% CI 0.17\u0026ndash;1.33), followed by a significant acceleration from 2017 to 2023 (APC 3.02, 95% CI 0.51\u0026ndash;5.58), indicating a sharp increase in the mortality burden during these six years. Mortality rates for hematological malignancies with PE increased across gender, age, region, urban-rural differences, and race, particularly among males, the Western region, and individuals aged 75 and above. Higher mortality rates were also observed in non-metropolitan areas and among non-Hispanic Black individuals.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eDespite a significant decline in the overall mortality rate of patients with hematological malignancies over the past 24 years, the mortality rate of patients with hematological malignancies complicated by PE has shown an upward trend, with significant differences across different genders, age groups, regions, urban-rural differences, and race. Future research and public health policies need to focus on these differences and develop targeted intervention strategies to reduce the mortality rate of PE in such patients and optimize prognosis.\u003c/p\u003e","manuscriptTitle":"Mortality Trends of Hematological Malignancies and Those Complicated by Pulmonary Embolism: A Nationwide Population-Based Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-08 07:23:19","doi":"10.21203/rs.3.rs-7592454/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"978a7d1a-611d-47b5-9bf2-3e3502d61f86","owner":[],"postedDate":"October 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-14T15:38:42+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-08 07:23:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7592454","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7592454","identity":"rs-7592454","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}