Temporal trends in hypertension and pulmonary embolism–related mortality in the United States: A population-based study using CDC WONDER, 2000–2020

Temporal trends in hypertension and pulmonary embolism–related mortality in the United States: A population-based study using CDC WONDER, 2000–2020 | 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 Temporal trends in hypertension and pulmonary embolism–related mortality in the United States: A population-based study using CDC WONDER, 2000–2020 Asim Sajjad, Muhammad Salik Uddin, Ammad Uddin, Shaheer Qureshi, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7622619/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 Background : Hypertension (HTN) is a major public health concern and a key risk factor for pulmonary embolism (PE), contributing substantially to cardiovascular mortality. Despite treatment advances, trends in related mortality remain underexplored. Objectives : This study examined national trends in HTN and PE-related mortality in the United States from 2000 to 2020 and assessed demographic and geographic disparities. Methods : A retrospective analysis of CDC WONDER data was performed, focusing on HTN (ICD I10-I15) and PE (ICD I26.0, I26.9, I82.8, I82.9). Joinpoint regression estimated age-adjusted mortality rates (AAMR) per 100,000 and annual percentage changes (APC). Data were stratified by year, sex, race/ethnicity, age, census region, urbanization, and state. Results : From 2000–2020, 92,181 HTN and PE-related deaths were recorded. AAMR rose from 1.3 to 3.6, with an average annual percent change (AAPC) of 4.5% (p < 0.001). Men consistently had higher mortality (1.4 vs. 1.2 in 2000; 3.9 vs. 3.2 in 2020). NH Black patients had the highest AAMR (4.6), while NH White patients showed the steepest rise (AAPC: 5.0, p < 0.001). Older adults had the highest AAMR (7.5), but younger adults showed the sharpest increase (AAPC: 6.0%, p < 0.001). The South had the highest AAMR (2.2), while the Midwest had the fastest growth (AAPC: 5.1%, p < 0.001). State-level AAMRs in 2020 ranged from 0.9 (Maine) to 5.5 (District of Columbia). Conclusion : HTN and PE-related mortality has risen markedly with disparities across age, sex, race, and geography, highlighting the need for equity-focused interventions. Hypertension Pulmonary Embolism Mortality Trends Health Disparities CDC WONDER Figures Figure 1 Figure 2 Figure 3 Highlights Significant increase in Mortality : HTN and PE-related mortality rates nearly tripled from 2000 to 2020. Persistent Racial Disparities : NH Black individuals had the highest mortality burden, compared to other races. Geographic Inequities : Southern states and nonmetropolitan areas showed significantly higher mortality rates and faster increases compared to other regions. Shifting Demographics : Younger and middle-aged adults demonstrated the most rapid acceleration in death rates, indicating an alarming epidemiological shift. Gender Pattern Changes : Men showed faster mortality acceleration than women during the study period. 1. INTRODUCTION Pulmonary embolism (PE) is a life-threatening condition initiated by the presence of blood clots in the pulmonary arteries, leading to severe morbidity and mortality [ 1 ]. The annual incidence of acute (PE), estimated at 115 cases per 100 000 people in the United States (U.S) [ 2 ] has been increasing globally over the past decades because of a longer life expectancy and an increase in sensitive diagnostic tests [ 3 ],4,5 Nevertheless, global awareness of PE and deep vein thrombosis remains deficient [ 6 ]. Hypertension (HTN) remains one of the most critical and pervasive risk factors for cardiovascular disease (CVD), affecting nearly half of all U.S. adults and contributing to substantial health and economic burdens [ 7 ]. Approximately 116 million (1 in 2) U.S. adults are affected by HTN, yet only about one in four have it under control [ 8 ]. The treatment of HTN imposes a significant financial burden, with annual costs for healthcare services, medications, and productivity losses due to premature death ranging from $ 131 billion to $ 198 billion [ 9 ]. It is predicted that by 2030, approximately 41.4% of adults in the US will be affected by HTN [ 10 ]. The pathogenesis of PE is dictated by Virchow’s triad that includes venous stasis, endothelial injury, and a hypercoagulable state [ 11 ]. There are various mechanisms described for the development of HTN, which include increased salt absorption resulting in volume expansion, an impaired response of the renin-angiotensin-aldosterone system (RAAS), and increased activation of the sympathetic nervous system. These changes lead to the development of increased total peripheral resistance and increased afterload, which in turn leads to the development of HTN [ 12 ]. Both HTN and PE are rooted in vascular dysfunction, involving impaired blood flow, inflammation, and thrombotic activity. Together, they represent a compounding threat to cardiovascular health and public healthcare systems. This study uses CDC WONDER data to explore mortality trends, demographic disparities, and potential correlations between HTN and PE. Insights gained may inform public health strategies, improve early detection efforts, and guide future policy on resource allocation and prevention. 2. METHODOLOGY 2.1 Study Setting and Population Deaths occurring within the U.S related to HTN and PE were extracted from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) database [ 13 ]. The Multiple Cause-of-Death Public Use record death certificates were analysed to identify cases where HTN and PE both were listed as the multiple cause of death. The definitions of HTN and PE used in this study are consistent with prior publications examining these conditions in the US. The study population included individuals with HTN and PE identified using International Classification of Diseases, 10th Revision (ICD-10) codes, including I10-I15 for hypertension and I26.0-I26.9, I82.8, and I82.9 for PE [ 14 ],15. [ 16 ] Geographic data were analyzed at both the state and regional levels, with all U.S. states included. States such as Alabama, Alaska, Arizona, Arkansas, California were examined individually for mortality trends. Regions were classified as Northeast, Midwest, South, and West based on U.S. Census Bureau definitions [ 17 ]. The National Center for Health Statistics Urban–Rural Classification Scheme was used to divide the population into urban (large metropolitan area [population ⩾ 1 million], medium/small metropolitan area [population 50,000–999,999]) and rural (population < 50,000) counties per the 2013 US census classification [ 18 ]. 2.2 Data Abstraction HTN and PE-related deaths, population sizes, and place of death were extracted from the CDC WONDER database, including deaths occurring in medical facilities (inpatient, outpatient or ER, dead on arrival Decedent's home, hospice facility, nursing home/long-term care and other facilities. Demographic variables such as age, sex, race/ethnicity, geographic location (state and urban-rural classifications), and cause of death rankings were also included. Age groups were categorized as younger adults (25–44), middle-aged adults (45–64), and older adults (65+), and sex was classified as male and female. Race and ethnicity classifications followed CDC WONDER standard categories, including NH Asian or pacific islander, NH Black or African, NH White, and Hispanic or Latino. The rankable cause of death feature in CDC WONDER was utilized to obtain death counts and rates for the top 15 leading causes of death among individuals with these conditions. 2.3 Statistical Analysis Crude and age-adjusted mortality rates (AAMRs) per 100,000 individuals were determined. Crude mortality rates were calculated by dividing the number of HTN and PE-related deaths by the corresponding U.S. population for each year. AAMRs were standardized to the 2000 U.S. population to account for differences in age distribution across years [ 19 ]. Trend analysis was conducted using log-linear regression models, and Annual Percent Change (APC) was calculated to evaluate significant changes in mortality rates over time. The Joinpoint Regression Program (Joinpoint version 5.2.0, National Cancer Institute [ 20 ] was used to detect inflection points where significant shifts in mortality trends occurred. APCs were considered to increase or decrease if the slope representing the change in mortality significantly deviated from zero, as determined by 2-tailed t-tests. A P-value of less than 0.05 indicated statistical significance. 3. RESULTS During the period 2000-2020, a total of 92,181 deaths took place. (Table 1) The AAMR for HTN and PE-related mortality was 1.3 (95% CI: 1.3 to 1.4) in 2000 and increased to 3.6 (95% CI:3.5 to 3.7) in 2020, reflecting a significant incline over the two decades with an AAPC of 4.5% (95% CI:4.0 to 4.9; p < 0.001). Overall AAMR exhibited distinct trends across different periods. From 2000 to 2018, there was a notable increase (APC: 2.7%; 95% CI: 2.2 to 3.1; p < 0.001), followed by a sharper incline from 2018 to 2020 (APC: 22.2%; 95% CI: 15.0 to 26.2; p < 0.001). (Figure 1, Supplementary Table 1, Supplementary Table 10) . 3.1.Sex Throughout the study period (2000–2020), men consistently exhibited higher AAMRs for HTN and PE-related mortality compared to women. The overall AAMR for men was 2.1 (95% CI: 2.0–2.1), while for women, it was 1.9 (95% CI: 1.9–1.9). In 2000, the AAMR for men was 1.2 (95% CI: 1.1–1.3), which increased to 3.9 (95% CI: 3.8–4.0) in 2020, reflecting an AAPC of 5.5% (95% CI: 5.0 to 5.9; p <0.001). For women, the AAMR rose from 1.4 (95% CI: 1.3–1.4) in 2000 to 3.2 (95% CI: 3.2–3.3) in 2020, with AAPC of 4.2% (95% CI: 3.7 to 5.0; p <0.001). (Figure 1, Table 1, Supplementary Table 2, Supplementary Table 10). 3.2 Race Throughout the study period, AAMRs for HTN and PE-related mortality was highest among NH Black or African American patients, followed by NH White, Hispanic or Latino, and NH Asian or Pacific Islander populations. Specifically, the AAMR for NH Black or African American individuals was 4.6 (95% CI: 4.5 to 4.7), while NH White individuals had an AAMR of 1.8 (95% CI: 1.8 to 1.9). Hispanic or Latino individuals had an AAMR of 1.4 (95% CI: 1.3 to1.4), and NH Asian or Pacific Islander individuals had the lowest AAMR at approximately 0.7 (95% CI: 0.7 to 0.7). (Table 1) The AAMR for the NH White population showed the most significant increase, with an AAPC of 5.0% (95% CI: 4.5 to 5.4; p < 0.001). Similarly, the Hispanic or Latino population experienced an increase in AAMR (AAPC: 4.4%; 95% CI: 3.3 to 5.5; p < 0.001), as did the NH Asian or Pacific Islander population (AAPC: 3.9%; 95% CI: 3.0 to 5.0; p < 0.001), and the NH Black or African American population (AAPC: 3.7%; 95% CI: 3.1 to 4.6; p < 0.001). (Figure 2, Supplementary Table 3, Supplementary Table 10). 3.3 Age Over the course of the study period, older adults (65+) consistently exhibited the highest AAMR for HTN and PE-related mortality, with rates reaching an overall AAMR of 7.5 (95% CI: 7.5 to 7.6). Middle-aged adults (45-64) experienced a significant burden as well, with an AAMR of 1.2 (95% CI: 1.2 to 1.3), while younger adults (25-44) had the lowest AAMR at 0.2 (95% CI: 0.2 to 0.2 ). (Table 1) Over time, an increase in mortality was observed across all age groups. In younger adults’ mortality increased with an AAPC 6.5% (95% CI: 5.7 to 7.5 p < 0.001). Middle-aged adults also showed incline, with an AAPC of 6.0% (95% CI: 5.6 to 6.4; p < 0.001). In older adults, an increased AAMR was seen, who experienced an AAPC of 4.6% (95% CI: 4.1 to 5.3; p < 0.001) (Supplementary Figure 1, Supplementary Table 4, Supplementary Table 10). 3.4 Census Region Over the course of the study period, the highest mortality related to HTN and PE was observed in the Southern region with an AAMR of 2.2 (95% CI: 2.2 to 2.2), followed by the Midwest region with an AAMR of 2.1 (95% CI: 2.0 to 2.1), Western region with an AAMR of 1.9 (95% CI: 1.9 to 1.9), and Northeast with an AAMR of 1.7 (95% CI: 1.7 to 1.7). (Table 1) The Midwestern region experienced a significant increase in mortality rates over the study period, with an AAPC of 5.1% (95% CI: 4.6 to 5.8; p < 0.001). Similarly, the Southern region showed a notable inclination (AAPC: 4.7%; 95% CI: 4.3 to 5.1; p < 0.001), as did the Western region (AAPC: 4.7%; 95% CI: 3.9 to 5.6; p < 0.001) and the Northeast region (AAPC: 4.3%; 95% CI: 3.2 to 5.1; p < 0.001). (Supplementary Figure 2, Supplementary Table 5, Supplementary Table 10). 3.5 Urbanization Nonmetropolitan areas had higher rates than metropolitan areas for HTN and PE-related mortality, with overall AAMRs of 22.4 (95% CI: 22.3 to 22.5) and 15.9 (95% CI: 15.9 to 15.9), respectively. AAMRs in nonmetropolitan areas showed a greater increase compared to metropolitan areas from 2000 to 2020 (nonmetropolitan: AAPC: 5.4%; 95% CI: 4.7 to 5.9; p < 0.001; metropolitan: AAPC: 4.3%; 95% CI: 3.8 to 4.7; p < 0.001) (Table 1, Supplementary Figure 3, Supplementary Table 6). 3.6 State Throughout the study period, a significant difference in AAMRs for HTN and PE-related mortality was observed across different states, with the AAMRs ranging from 0.9 (95% CI: 0.8 to 1.0) in Maine to 5.5 (95% CI: 5.0 to 6.1) in the District of Columbia. States that fell into the top 90th percentile, such as District of Columbia, Mississippi, Maryland, Oklahoma, and Wyoming, had significantly higher AAMRs compared to states in the lower 10th percentile, including Maine, Hawaii, Massachusetts, Florida, and Alaska. (Figure 3, Supplementary Table 7). 3.7 Place of Death Information on the location of death was available for 91,951 deaths. Of these, 52,039 deaths (56.6%) occurred in medical facilities, (22.7%) occurred in Decedent’s home, 20,843 deaths,13,156 deaths (14.3%) occurred in Nursing home/long term care, 3,022 (3.3%) deaths occurred in other locations and, 2,891 deaths (3.1%) occurred in hospices (Supplementary Table 8). 3.8 Underlying Causes of Death We analyzed the top 15 leading underlying causes of death in HTN and PE-related mortality. Our findings indicate that heart disease was the most prevalent cause, with an AAMR of 0.6 (95% CI: 0.6 to 0.6), followed by malignant neoplasms at 0.4 (95% CI: 0.3 to 0.4) and essential HTN and hypertensive at 0.1 (95% CI: 0.1 to 0.1) (Supplementary Table 9). DISCUSSION This study provides a comprehensive analysis of PE and HTN-related mortality among adults aged ≥ 25 years in the United States from 2000 to 2020, elucidating crucial temporal trends and demographic disparities. Our findings reveal a substantial and concerning escalation in the AAMR, which nearly tripled over the two-decade period, with a particularly sharp acceleration from 2018 to 2020. A majority of these deaths occurred in a medical facility, though a notable proportion also occurred in the decedent's home. The analysis underscores persistent disparities: men consistently experienced higher mortality rates than women, and NH Black individuals bore the highest mortality burden overall. While all racial groups saw increasing mortality, the most rapid rate of increase was observed in the NH White population. Geographically, the highest mortality burden was concentrated in the Southern states and non-metropolitan areas, the latter of which also saw a faster rise in mortality compared to metropolitan regions. Finally, while older adults had the highest absolute mortality, a disquieting trend emerged wherein the mortality rate accelerated fastest among younger and middle-aged adults. The rise in PE and HTN-related mortality among hypertensive individuals reflects several concurrent public health trends. A key long-term driver is the surging prevalence of obesity, a potent risk factor for VTE that has expanded the pool of at-risk hypertensive patients over the past two decades [ 21 ] , [ 22 ]. Concurrently, the widespread adoption of CT pulmonary angiography (CTPA) has improved PE detection but may also create a "detection bias" by identifying less severe emboli that are then recorded on death certificates [ 23 ]. However, these gradual factors do not fully explain the sharp mortality spike after 2018. This acceleration points to the COVID-19 pandemic, as the SARS-CoV-2 virus is a known driver of thrombo-inflammation and VTE, particularly among hypertensive individuals who were at high risk for severe infection [ 24 ]. Therefore, the observed mortality pattern is best explained by the interplay of a worsening baseline of population risk with the acute prothrombotic shock of the pandemic. PE and HTN-related mortality present a dynamic pattern rather than a static risk profile. While men demonstrated a higher and more rapidly accelerating mortality rate by the end of the study period, women initially exhibited a marginally higher rate in 2000. This risk inversion is a critical finding. The established male predisposition for VTE is often attributed to biological factors [ 25 ]. This inherent vulnerability may be particularly consequential in hypertensive patients, where the foundational vascular stress and endothelial dysfunction associated with high blood pressure are already present. The initially higher mortality in women could reflect the significant prothrombotic influence of female-specific factors, such as hormonal therapies, which may have posed a leading risk even in the presence of HTN during the earlier years of the study [ 26 ]. However, the subsequent, more rapid rise in male mortality suggests an important interaction with evolving comorbidities. As systemic conditions like obesity and metabolic syndrome became more prevalent, their addition to pre-existing HTN likely created a more potent prothrombotic state. The data suggest this "second hit" of metabolic disease on a hypertensive baseline had a more profound and lethal impact on men. This pattern points to an evolution in the drivers of fatal PE within this high-risk group, where the compounding burden of modern comorbidities appears to amplify mortality risk more severely in hypertensive men than in women [ 27 ]. Our analysis reveals a profound racial disparity, with NH Black individuals facing a PE and HTN-related mortality rate more than double that of NH White individuals. This gap likely stems from a convergence of factors: a higher burden of severe HTN and comorbidities in the Black community [ 28 ] , [ 29 ] which is exacerbated by adverse social determinants of health[ 30 ] and compounded by structural inequities that can lead to delayed diagnosis and undertreatment [ 31 ]. Paradoxically, the mortality rate increased fastest among NH White individuals. This trend likely reflects a broad intensification of national VTE risk factors rather than a closing of the health gap. It may be partially explained by a "saturation" effect in the high-burden Black population, as well as by worsening health trends like the "deaths of despair" crisis, which have been concentrated in non-metropolitan communities [ 32 ] , [ 33 ]. The findings thus present a dual narrative: a persistent, severe mortality crisis affecting NH Black Americans, alongside a newer, rapidly accelerating trend among NH White Americans. Mortality patterns by age revealed two distinct narratives: an expected high burden in older adults (65+) and, more alarmingly, a rapid acceleration of death rates in younger and middle-aged cohorts. The high mortality in the elderly aligns with the classic understanding of VTE as a disease of aging, a risk amplified by chronic HTN [ 34 ] , [ 35 ]. The more concerning trend is the acceleration in younger adults, which indicates a fundamental shift in the disease’s timeline propelled by a premature accumulation of risk factors. The early onset of metabolic syndrome, when superimposed on existing HTN, creates a highly prothrombotic state decades sooner [ 36 ] , [ 37 ] , [ 38 ]. This is compounded by increasingly sedentary lifestyles [ 39 ], while the risk of cancer-associated thrombosis represents another powerful driver in the middle-aged group [ 40 ]. Collectively, these findings suggest the clinical profile of a high-risk patient is expanding from a predominantly geriatric one to include younger, multi-morbid hypertensive individuals [ 41 ]. PE and HTN-related mortality clusters in the South and Midwest, paralleling the "Stroke Belt" and reflecting regional risk factors such as obesity and uncontrolled HTN [ 42 ] , [ 43 ]. Higher mortality in nonmetropolitan areas likely stems from limited access to specialized care and a greater prevalence of undertreated chronic illnesses predisposing to VTE [ 44 ] , [ 45 ]. The accelerated mortality increases in the Midwest, specifically, likely reflects a sharp, recent escalation of these regional risk factors, highlighting the interplay between geography, socioeconomic status, and public health infrastructure. At the state level, Mississippi typifies the rural Southern profile of obesity, HTN, and poverty[ 46 ]. In contrast, the District of Columbia demonstrates how concentrated socioeconomic and racial inequities can drive high urban mortality [ 47 ]. These contrast with lower-mortality states in the Northeast underscore geography as a marker of structural and demographic influences on health outcomes. The distribution of death locations provides insight into the clinical scenarios preceding fatal PE in this population. The finding that a majority of deaths occurred within inpatient medical settings suggests that PE manifests as an acute, catastrophic event during hospitalization for many hypertensive patients, either as a treatment complication or a failure of in-hospital VTE prophylaxis and rescue [ 48 ]. However, the substantial proportion of deaths occurring outside the hospital, particularly at the decedent's home or in a nursing facility, is of significant public health concern. These events likely represent sudden, unheralded deaths in the community where PE was either not suspected or progressed too rapidly for intervention [ 49 ]. This dual finding illustrates the two primary challenges in preventing PE mortality: mitigating the high risk of hospital-acquired thrombosis and improving risk stratification for sudden death in ambulatory and long-term care hypertensive patients. Analysis of the underlying causes of death further clarifies the clinical context, confirming that fatal PE and HTN typically occurs in the setting of significant multi-morbidity. The prominence of heart disease and HTN itself as the leading underlying causes underscores the deep mechanistic link between cardiovascular pathology and VTE. Chronic HTN-related conditions like heart failure are potent inducers of thrombosis via mechanisms of venous stasis and inflammation [ 50 ]. The development of malignant neoplasms as the second most frequent underlying cause is also clinically relevant, reflecting the appreciated risk of cancer-related thrombosis [ 51 ]. Aggregated, this information indicates that in this population, fatal PE is not an unexpected isolated occurrence; instead, it is usually the terminal thromboembolic complication in already severely impaired patients with advanced cardiovascular disease or cancer. The trends uncovered by this analysis are more than just statistics; they are a call to action. The rapid rise in deaths among younger adults, for example, is a clear warning to clinicians who can no longer consider fatal PE a predominantly geriatric event in hypertensive patients, especially when metabolic syndrome is present [ 52 ] , [ 53 ]. At the same time, the profound geographic and racial disparities demand that equity become a central component, not an afterthought, in VTE risk assessment. The overall trend points to a larger truth: our current strategies for the primary prevention of HTN and obesity are failing to protect the most vulnerable communities [ 54 ]. The path forward, therefore, must be multifaceted. A clear priority is the development of new risk stratification models that reflect the modern, multi-morbid hypertensive patient, as older tools may be obsolete [ 55 ]. We must also look beyond the fatal event to investigate long-term outcomes like post-PE syndrome and chronic thromboembolic pulmonary hypertension (CTEPH), as survivors may face a lifetime of complications [ 56 ][ 56 ]. Furthermore, there is a pressing need for trials to define the role of primary pharmacologic prophylaxis in high-risk outpatients, a major gap in current guidelines [ 57 ]. These research efforts must ultimately inform smarter, targeted interventions that embed VTE prevention within routine chronic disease care. LIMITATIONS A critical interpretation of this study requires acknowledging limitations inherent to the CDC WONDER database. First, the analysis is contingent on the accuracy of death certificate data, which is subject to diagnostic misclassification, meaning the true mortality burden could be misestimated. Second, the observed increase may be influenced by a surveillance artifact; growing clinical awareness of VTE over the past two decades may have led to more frequent documentation, a "coding drift" that could artificially inflate the trend. Furthermore, as an ecological analysis, this study identifies population-level associations but precludes claims of individual causality. This is compounded by the absence of granular clinical data, such as medication adherence or disease severity, which prevents a more sophisticated, confounder-adjusted analysis. The broad demographic and geographic categories may also mask important heterogeneity within these groups. Despite these constraints, the study’s principal strength remains its large, population-based design, which provides a comprehensive view of broad epidemiological trends that warrant further investigation. CONCLUSION This two-decade analysis paints a stark picture: death from PE and HTN has become far more common and profoundly inequitable. The age-adjusted mortality rate nearly tripled, a trend that accelerated alarmingly after 2018. This is not a uniform crisis. Its burden falls disproportionately on NH Black individuals, men, the elderly, and residents of Southern and nonmetropolitan regions. These are not disconnected statistics; they are the downstream consequences of the prothrombotic state induced by HTN, a rising tide of metabolic disease, and the acute shock of the COVID-19 pandemic. The disparities, in particular, tell a story of structural inequities and the undeniable influence of social determinants on health. Therefore, these findings must serve as a catalyst, shifting the focus from surveillance to the urgent implementation of strategies that integrate VTE prevention into chronic disease management and confront the systemic failures driving these fatal outcomes. Declarations Data Availability Statement: The data supporting the findings of this study were obtained from the CDC WONDER online database (Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research). The datasets used and analyzed during the current study are publicly available and can be accessed at [CDC WONDER] (https://wonder.cdc.gov). Conflicts of Interests: The authors declare no conflicts of interest. Funding: The authors received no funds, grants, or financial support for this study. Acknowledgments: Not applicable. Ethics Approval: Not applicable. Disclosures: All other authors have no conflicts of interest to declare. 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2","display":"","copyAsset":false,"role":"figure","size":95130,"visible":true,"origin":"","legend":"\u003cp\u003eTrends in HTN and PE-related AAMR per 100,000, stratified by race, in the United States from 2000-2020\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7622619/v1/5b5c5fccfe20374617739f5c.png"},{"id":91963435,"identity":"8286b15a-7223-4d41-8485-82a6bc4a93f7","added_by":"auto","created_at":"2025-09-23 08:06:42","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":120284,"visible":true,"origin":"","legend":"\u003cp\u003eHTN and PE-related AAMRs per 100,000 stratified by State in the United States from 2000 to 2020.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7622619/v1/21f648f56181556d46464856.png"},{"id":91984796,"identity":"41fdb102-f9b6-4944-b42b-0b670a6a2d3e","added_by":"auto","created_at":"2025-09-23 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08:06:42","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":641302,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCentral illustration\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Centralillustration.docx","url":"https://assets-eu.researchsquare.com/files/rs-7622619/v1/52b244b3e26dbcb72d3933d6.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Temporal trends in hypertension and pulmonary embolism–related mortality in the United States: A population-based study using CDC WONDER, 2000–2020","fulltext":[{"header":"Highlights","content":"\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eSignificant increase in Mortality\u003c/strong\u003e: HTN and PE-related mortality rates nearly tripled from 2000 to 2020.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePersistent Racial Disparities\u003c/strong\u003e: NH Black individuals had the highest mortality burden, compared to other races.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eGeographic Inequities\u003c/strong\u003e: Southern states and nonmetropolitan areas showed significantly higher mortality rates and faster increases compared to other regions.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eShifting Demographics\u003c/strong\u003e: Younger and middle-aged adults demonstrated the most rapid acceleration in death rates, indicating an alarming epidemiological shift.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eGender Pattern Changes\u003c/strong\u003e: Men showed faster mortality acceleration than women during the study period.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"1. INTRODUCTION","content":"\u003cp\u003ePulmonary embolism (PE) is a life-threatening condition initiated by the presence of blood clots in the pulmonary arteries, leading to severe morbidity and mortality [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The annual incidence of acute (PE), estimated at 115 cases per 100 000 people in the United States (U.S) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] has been increasing globally over the past decades because of a longer life expectancy and an increase in sensitive diagnostic tests [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e],4,5 Nevertheless, global awareness of PE and deep vein thrombosis remains deficient [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Hypertension (HTN) remains one of the most critical and pervasive risk factors for cardiovascular disease (CVD), affecting nearly half of all U.S. adults and contributing to substantial health and economic burdens [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Approximately 116\u0026nbsp;million (1 in 2) U.S. adults are affected by HTN, yet only about one in four have it under control [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The treatment of HTN imposes a significant financial burden, with annual costs for healthcare services, medications, and productivity losses due to premature death ranging from \u003cspan\u003e$\u003c/span\u003e131\u0026nbsp;billion to \u003cspan\u003e$\u003c/span\u003e198\u0026nbsp;billion [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. It is predicted that by 2030, approximately 41.4% of adults in the US will be affected by HTN [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe pathogenesis of PE is dictated by Virchow\u0026rsquo;s triad that includes venous stasis, endothelial injury, and a hypercoagulable state [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. There are various mechanisms described for the development of HTN, which include increased salt absorption resulting in volume expansion, an impaired response of the renin-angiotensin-aldosterone system (RAAS), and increased activation of the sympathetic nervous system. These changes lead to the development of increased total peripheral resistance and increased afterload, which in turn leads to the development of HTN [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eBoth HTN and PE are rooted in vascular dysfunction, involving impaired blood flow, inflammation, and thrombotic activity. Together, they represent a compounding threat to cardiovascular health and public healthcare systems. This study uses CDC WONDER data to explore mortality trends, demographic disparities, and potential correlations between HTN and PE. Insights gained may inform public health strategies, improve early detection efforts, and guide future policy on resource allocation and prevention.\u003c/p\u003e"},{"header":"2. METHODOLOGY","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Study Setting and Population\u003c/h2\u003e\u003cp\u003eDeaths occurring within the U.S related to HTN and PE were extracted from the Centers for Disease Control and Prevention\u0026rsquo;s Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) database [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The Multiple Cause-of-Death Public Use record death certificates were analysed to identify cases where HTN and PE both were listed as the multiple cause of death. The definitions of HTN and PE used in this study are consistent with prior publications examining these conditions in the US. The study population included individuals with HTN and PE identified using International Classification of Diseases, 10th Revision (ICD-10) codes, including I10-I15 for hypertension and I26.0-I26.9, I82.8, and I82.9 for PE [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e],15. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eGeographic data were analyzed at both the state and regional levels, with all U.S. states included. States such as Alabama, Alaska, Arizona, Arkansas, California were examined individually for mortality trends. Regions were classified as Northeast, Midwest, South, and West based on U.S. Census Bureau definitions [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The National Center for Health Statistics Urban\u0026ndash;Rural Classification Scheme was used to divide the population into urban (large metropolitan area [population ⩾ 1 million], medium/small metropolitan area [population 50,000\u0026ndash;999,999]) and rural (population\u0026thinsp;\u0026lt;\u0026thinsp;50,000) counties per the 2013 US census classification [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Data Abstraction\u003c/h2\u003e\u003cp\u003eHTN and PE-related deaths, population sizes, and place of death were extracted from the CDC WONDER database, including deaths occurring in medical facilities (inpatient, outpatient or ER, dead on arrival Decedent's home, hospice facility, nursing home/long-term care and other facilities. Demographic variables such as age, sex, race/ethnicity, geographic location (state and urban-rural classifications), and cause of death rankings were also included. Age groups were categorized as younger adults (25\u0026ndash;44), middle-aged adults (45\u0026ndash;64), and older adults (65+), and sex was classified as male and female. Race and ethnicity classifications followed CDC WONDER standard categories, including NH Asian or pacific islander, NH Black or African, NH White, and Hispanic or Latino. The rankable cause of death feature in CDC WONDER was utilized to obtain death counts and rates for the top 15 leading causes of death among individuals with these conditions.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Statistical Analysis\u003c/h2\u003e\u003cp\u003eCrude and age-adjusted mortality rates (AAMRs) per 100,000 individuals were determined. Crude mortality rates were calculated by dividing the number of HTN and PE-related deaths by the corresponding U.S. population for each year. AAMRs were standardized to the 2000 U.S. population to account for differences in age distribution across years [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Trend analysis was conducted using log-linear regression models, and Annual Percent Change (APC) was calculated to evaluate significant changes in mortality rates over time. The Joinpoint Regression Program (Joinpoint version 5.2.0, National Cancer Institute [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] was used to detect inflection points where significant shifts in mortality trends occurred. APCs were considered to increase or decrease if the slope representing the change in mortality significantly deviated from zero, as determined by 2-tailed t-tests. A P-value of less than 0.05 indicated statistical significance.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. RESULTS","content":"\u003cp\u003eDuring the period 2000-2020, a total of 92,181 deaths took place. \u003cstrong\u003e(Table 1)\u003c/strong\u003e The AAMR for HTN and PE-related mortality was 1.3 (95% CI: 1.3 to 1.4) in 2000 and increased to 3.6 (95% CI:3.5 to 3.7) in 2020, reflecting a significant incline over the two decades with an AAPC of 4.5% (95% CI:4.0 to 4.9; p \u0026lt; 0.001). Overall AAMR exhibited distinct trends across different periods. From 2000 to 2018, there was a notable increase (APC: 2.7%; 95% CI: 2.2 to 3.1; p \u0026lt; 0.001), followed by a sharper incline from 2018 to 2020 (APC: 22.2%; 95% CI: 15.0 to 26.2; p \u0026lt; 0.001).\u003cstrong\u003e\u0026nbsp;(Figure 1, Supplementary Table 1, Supplementary Table 10)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.1.Sex\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThroughout the study period (2000–2020), men consistently exhibited higher AAMRs for HTN and PE-related mortality compared to women. The overall AAMR for men was 2.1 (95% CI: 2.0–2.1), while for women, it was 1.9 (95% CI: 1.9–1.9). In 2000, the AAMR for men was 1.2 (95% CI: 1.1–1.3), which increased to 3.9 (95% CI: 3.8–4.0) in 2020, reflecting an AAPC of 5.5% (95% CI: 5.0 to 5.9; p \u0026lt;0.001). For women, the AAMR rose from 1.4 (95% CI: 1.3–1.4) in 2000 to 3.2 (95% CI: 3.2–3.3) in 2020, with AAPC of 4.2% (95% CI: 3.7 to 5.0; p \u0026lt;0.001).\u0026nbsp;\u003cstrong\u003e(Figure 1, Table 1, Supplementary Table 2, Supplementary Table 10).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2 Race\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u003c/strong\u003e Throughout the study period, AAMRs for HTN and PE-related mortality was highest among NH Black or African American patients, followed by NH White, Hispanic or Latino, and NH Asian or Pacific Islander populations. Specifically, the AAMR for NH Black or African American individuals was 4.6 (95% CI: 4.5 to 4.7), while NH White individuals had an AAMR of 1.8 (95% CI: 1.8 to 1.9). Hispanic or Latino individuals had an AAMR of 1.4 (95% CI: 1.3 to1.4), and NH Asian or Pacific Islander individuals had the lowest AAMR at approximately 0.7 (95% CI: 0.7 to 0.7).\u0026nbsp;\u003cstrong\u003e(Table 1)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe AAMR for the NH White population showed the most significant increase, with an AAPC of 5.0% (95% CI: 4.5 to 5.4; p \u0026lt; 0.001). Similarly, the Hispanic or Latino population experienced an increase in AAMR (AAPC: 4.4%; 95% CI: 3.3 to 5.5; p \u0026lt; 0.001), as did the NH Asian or Pacific Islander population (AAPC: 3.9%; 95% CI: 3.0 to 5.0; p \u0026lt; 0.001), and the NH Black or African American population (AAPC: 3.7%; 95% CI: 3.1 to 4.6; p \u0026lt; 0.001).\u003cstrong\u003e\u0026nbsp;(Figure 2, Supplementary Table 3, Supplementary Table 10).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3 Age\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOver the course of the study period, older adults (65+) consistently exhibited the highest AAMR for HTN and PE-related mortality, with rates reaching an overall AAMR of 7.5 (95% CI: 7.5 to 7.6). Middle-aged adults (45-64) experienced a significant burden as well, with an AAMR of 1.2 (95% CI: 1.2 to 1.3), while younger adults (25-44) had the lowest AAMR at 0.2 (95% CI: 0.2 to 0.2\u003cstrong\u003e).\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;(Table 1)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOver time, an increase in mortality was observed across all age groups. In younger adults’ mortality increased with an AAPC 6.5% (95% CI: 5.7 to 7.5 p \u0026lt; 0.001). Middle-aged adults also showed incline, with an AAPC of 6.0% (95% CI: 5.6 to 6.4; p \u0026lt; 0.001). In older adults, an increased AAMR was seen, who experienced an AAPC of 4.6% (95% CI: 4.1 to 5.3; p \u0026lt; 0.001)\u0026nbsp;\u003cstrong\u003e(Supplementary Figure 1, Supplementary Table 4, Supplementary Table 10).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.4 Census Region\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOver the course of the study period, the highest mortality related to HTN and PE was observed in the Southern region with an AAMR of 2.2 (95% CI: 2.2 to 2.2), followed by the Midwest region with an AAMR of 2.1 (95% CI: 2.0 to 2.1), Western region with an AAMR of 1.9 (95% CI: 1.9 to 1.9), and Northeast with an AAMR of 1.7 (95% CI: 1.7 to 1.7).\u0026nbsp;\u003cstrong\u003e(Table 1)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Midwestern region experienced a significant increase in mortality rates over the study period, with an AAPC of 5.1% (95% CI: 4.6 to 5.8; p \u0026lt; 0.001). Similarly, the Southern region showed a notable inclination (AAPC: 4.7%; 95% CI: 4.3 to 5.1; p \u0026lt; 0.001), as did the Western region (AAPC: 4.7%; 95% CI: 3.9 to 5.6; p \u0026lt; 0.001) and the Northeast region (AAPC: 4.3%; 95% CI: 3.2 to 5.1; p \u0026lt; 0.001).\u003cstrong\u003e(Supplementary Figure 2, Supplementary Table 5, Supplementary Table 10).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.5 Urbanization\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNonmetropolitan areas had higher rates than metropolitan areas for HTN and PE-related mortality, with overall AAMRs of 22.4 (95% CI: 22.3 to 22.5) and 15.9 (95% CI: 15.9 to 15.9), respectively. AAMRs in nonmetropolitan areas showed a greater increase compared to metropolitan areas from 2000 to 2020 (nonmetropolitan: AAPC: 5.4%; 95% CI: 4.7 to 5.9; p \u0026lt; 0.001; metropolitan: AAPC: 4.3%; 95% CI: 3.8 to 4.7; p \u0026lt; 0.001)\u003cstrong\u003e(Table 1, Supplementary Figure 3, Supplementary Table 6).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.6 State\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThroughout the study period, a significant difference in AAMRs for HTN and PE-related mortality was observed across different states, with the AAMRs ranging from 0.9 (95% CI: 0.8 to 1.0) in Maine to 5.5 (95% CI: 5.0 to 6.1) in the District of Columbia. States that fell into the top 90th percentile, such as District of Columbia, Mississippi, Maryland, Oklahoma, and Wyoming, had significantly higher AAMRs compared to states in the lower 10th percentile, including Maine, Hawaii, Massachusetts, Florida, and Alaska. \u003cstrong\u003e(Figure 3, Supplementary Table 7).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.7 Place of Death\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformation on the location of death was available for 91,951 deaths. Of these, 52,039 deaths (56.6%) occurred in medical facilities, (22.7%) occurred in Decedent’s home, 20,843 deaths,13,156 deaths (14.3%) occurred in Nursing home/long term care, 3,022 (3.3%) deaths occurred in other locations and, 2,891 deaths (3.1%) occurred in hospices\u003cstrong\u003e\u0026nbsp;(Supplementary Table 8).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.8 Underlying Causes of Death\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe analyzed the top 15 leading underlying causes of death in HTN and PE-related mortality. Our findings indicate that heart disease was the most prevalent cause, with an AAMR of 0.6 (95% CI: 0.6 to 0.6), followed by malignant neoplasms at 0.4 (95% CI: 0.3 to 0.4) and essential HTN and hypertensive at 0.1 (95% CI: 0.1 to 0.1)\u003cstrong\u003e\u0026nbsp;(Supplementary Table 9).\u003c/strong\u003e\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis study provides a comprehensive analysis of PE and HTN-related mortality among adults aged\u0026thinsp;\u0026ge;\u0026thinsp;25 years in the United States from 2000 to 2020, elucidating crucial temporal trends and demographic disparities. Our findings reveal a substantial and concerning escalation in the AAMR, which nearly tripled over the two-decade period, with a particularly sharp acceleration from 2018 to 2020. A majority of these deaths occurred in a medical facility, though a notable proportion also occurred in the decedent's home. The analysis underscores persistent disparities: men consistently experienced higher mortality rates than women, and NH Black individuals bore the highest mortality burden overall. While all racial groups saw increasing mortality, the most rapid rate of increase was observed in the NH White population. Geographically, the highest mortality burden was concentrated in the Southern states and non-metropolitan areas, the latter of which also saw a faster rise in mortality compared to metropolitan regions. Finally, while older adults had the highest absolute mortality, a disquieting trend emerged wherein the mortality rate accelerated fastest among younger and middle-aged adults.\u003c/p\u003e\u003cp\u003eThe rise in PE and HTN-related mortality among hypertensive individuals reflects several concurrent public health trends. A key long-term driver is the surging prevalence of obesity, a potent risk factor for VTE that has expanded the pool of at-risk hypertensive patients over the past two decades [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003csup\u003e,\u003c/sup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Concurrently, the widespread adoption of CT pulmonary angiography (CTPA) has improved PE detection but may also create a \"detection bias\" by identifying less severe emboli that are then recorded on death certificates [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. However, these gradual factors do not fully explain the sharp mortality spike after 2018. This acceleration points to the COVID-19 pandemic, as the SARS-CoV-2 virus is a known driver of thrombo-inflammation and VTE, particularly among hypertensive individuals who were at high risk for severe infection [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Therefore, the observed mortality pattern is best explained by the interplay of a worsening baseline of population risk with the acute prothrombotic shock of the pandemic.\u003c/p\u003e\u003cp\u003ePE and HTN-related mortality present a dynamic pattern rather than a static risk profile. While men demonstrated a higher and more rapidly accelerating mortality rate by the end of the study period, women initially exhibited a marginally higher rate in 2000. This risk inversion is a critical finding. The established male predisposition for VTE is often attributed to biological factors [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. This inherent vulnerability may be particularly consequential in hypertensive patients, where the foundational vascular stress and endothelial dysfunction associated with high blood pressure are already present. The initially higher mortality in women could reflect the significant prothrombotic influence of female-specific factors, such as hormonal therapies, which may have posed a leading risk even in the presence of HTN during the earlier years of the study [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. However, the subsequent, more rapid rise in male mortality suggests an important interaction with evolving comorbidities. As systemic conditions like obesity and metabolic syndrome became more prevalent, their addition to pre-existing HTN likely created a more potent prothrombotic state. The data suggest this \"second hit\" of metabolic disease on a hypertensive baseline had a more profound and lethal impact on men. This pattern points to an evolution in the drivers of fatal PE within this high-risk group, where the compounding burden of modern comorbidities appears to amplify mortality risk more severely in hypertensive men than in women [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOur analysis reveals a profound racial disparity, with NH Black individuals facing a PE and HTN-related mortality rate more than double that of NH White individuals. This gap likely stems from a convergence of factors: a higher burden of severe HTN and comorbidities in the Black community [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003csup\u003e,\u003c/sup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] which is exacerbated by adverse social determinants of health[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] and compounded by structural inequities that can lead to delayed diagnosis and undertreatment [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Paradoxically, the mortality rate increased fastest among NH White individuals. This trend likely reflects a broad intensification of national VTE risk factors rather than a closing of the health gap. It may be partially explained by a \"saturation\" effect in the high-burden Black population, as well as by worsening health trends like the \"deaths of despair\" crisis, which have been concentrated in non-metropolitan communities [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003csup\u003e,\u003c/sup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. The findings thus present a dual narrative: a persistent, severe mortality crisis affecting NH Black Americans, alongside a newer, rapidly accelerating trend among NH White Americans.\u003c/p\u003e\u003cp\u003eMortality patterns by age revealed two distinct narratives: an expected high burden in older adults (65+) and, more alarmingly, a rapid acceleration of death rates in younger and middle-aged cohorts. The high mortality in the elderly aligns with the classic understanding of VTE as a disease of aging, a risk amplified by chronic HTN [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003csup\u003e,\u003c/sup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. The more concerning trend is the acceleration in younger adults, which indicates a fundamental shift in the disease\u0026rsquo;s timeline propelled by a premature accumulation of risk factors. The early onset of metabolic syndrome, when superimposed on existing HTN, creates a highly prothrombotic state decades sooner [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003csup\u003e,\u003c/sup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003csup\u003e,\u003c/sup\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. This is compounded by increasingly sedentary lifestyles [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], while the risk of cancer-associated thrombosis represents another powerful driver in the middle-aged group [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Collectively, these findings suggest the clinical profile of a high-risk patient is expanding from a predominantly geriatric one to include younger, multi-morbid hypertensive individuals [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePE and HTN-related mortality clusters in the South and Midwest, paralleling the \"Stroke Belt\" and reflecting regional risk factors such as obesity and uncontrolled HTN [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003csup\u003e,\u003c/sup\u003e[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Higher mortality in nonmetropolitan areas likely stems from limited access to specialized care and a greater prevalence of undertreated chronic illnesses predisposing to VTE [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003csup\u003e,\u003c/sup\u003e[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. The accelerated mortality increases in the Midwest, specifically, likely reflects a sharp, recent escalation of these regional risk factors, highlighting the interplay between geography, socioeconomic status, and public health infrastructure. At the state level, Mississippi typifies the rural Southern profile of obesity, HTN, and poverty[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. In contrast, the District of Columbia demonstrates how concentrated socioeconomic and racial inequities can drive high urban mortality [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. These contrast with lower-mortality states in the Northeast underscore geography as a marker of structural and demographic influences on health outcomes.\u003c/p\u003e\u003cp\u003eThe distribution of death locations provides insight into the clinical scenarios preceding fatal PE in this population. The finding that a majority of deaths occurred within inpatient medical settings suggests that PE manifests as an acute, catastrophic event during hospitalization for many hypertensive patients, either as a treatment complication or a failure of in-hospital VTE prophylaxis and rescue [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. However, the substantial proportion of deaths occurring outside the hospital, particularly at the decedent's home or in a nursing facility, is of significant public health concern. These events likely represent sudden, unheralded deaths in the community where PE was either not suspected or progressed too rapidly for intervention [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. This dual finding illustrates the two primary challenges in preventing PE mortality: mitigating the high risk of hospital-acquired thrombosis and improving risk stratification for sudden death in ambulatory and long-term care hypertensive patients.\u003c/p\u003e\u003cp\u003eAnalysis of the underlying causes of death further clarifies the clinical context, confirming that fatal PE and HTN typically occurs in the setting of significant multi-morbidity. The prominence of heart disease and HTN itself as the leading underlying causes underscores the deep mechanistic link between cardiovascular pathology and VTE. Chronic HTN-related conditions like heart failure are potent inducers of thrombosis via mechanisms of venous stasis and inflammation [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. The development of malignant neoplasms as the second most frequent underlying cause is also clinically relevant, reflecting the appreciated risk of cancer-related thrombosis [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. Aggregated, this information indicates that in this population, fatal PE is not an unexpected isolated occurrence; instead, it is usually the terminal thromboembolic complication in already severely impaired patients with advanced cardiovascular disease or cancer.\u003c/p\u003e\u003cp\u003eThe trends uncovered by this analysis are more than just statistics; they are a call to action. The rapid rise in deaths among younger adults, for example, is a clear warning to clinicians who can no longer consider fatal PE a predominantly geriatric event in hypertensive patients, especially when metabolic syndrome is present [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]\u003csup\u003e,\u003c/sup\u003e[\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. At the same time, the profound geographic and racial disparities demand that equity become a central component, not an afterthought, in VTE risk assessment. The overall trend points to a larger truth: our current strategies for the primary prevention of HTN and obesity are failing to protect the most vulnerable communities [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. The path forward, therefore, must be multifaceted. A clear priority is the development of new risk stratification models that reflect the modern, multi-morbid hypertensive patient, as older tools may be obsolete [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. We must also look beyond the fatal event to investigate long-term outcomes like post-PE syndrome and chronic thromboembolic pulmonary hypertension (CTEPH), as survivors may face a lifetime of complications [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e][\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. Furthermore, there is a pressing need for trials to define the role of primary pharmacologic prophylaxis in high-risk outpatients, a major gap in current guidelines [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. These research efforts must ultimately inform smarter, targeted interventions that embed VTE prevention within routine chronic disease care.\u003c/p\u003e"},{"header":"LIMITATIONS","content":"\u003cp\u003eA critical interpretation of this study requires acknowledging limitations inherent to the CDC WONDER database. First, the analysis is contingent on the accuracy of death certificate data, which is subject to diagnostic misclassification, meaning the true mortality burden could be misestimated. Second, the observed increase may be influenced by a surveillance artifact; growing clinical awareness of VTE over the past two decades may have led to more frequent documentation, a \"coding drift\" that could artificially inflate the trend. Furthermore, as an ecological analysis, this study identifies population-level associations but precludes claims of individual causality. This is compounded by the absence of granular clinical data, such as medication adherence or disease severity, which prevents a more sophisticated, confounder-adjusted analysis. The broad demographic and geographic categories may also mask important heterogeneity within these groups. Despite these constraints, the study\u0026rsquo;s principal strength remains its large, population-based design, which provides a comprehensive view of broad epidemiological trends that warrant further investigation.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThis two-decade analysis paints a stark picture: death from PE and HTN has become far more common and profoundly inequitable. The age-adjusted mortality rate nearly tripled, a trend that accelerated alarmingly after 2018. This is not a uniform crisis. Its burden falls disproportionately on NH Black individuals, men, the elderly, and residents of Southern and nonmetropolitan regions. These are not disconnected statistics; they are the downstream consequences of the prothrombotic state induced by HTN, a rising tide of metabolic disease, and the acute shock of the COVID-19 pandemic. The disparities, in particular, tell a story of structural inequities and the undeniable influence of social determinants on health. Therefore, these findings must serve as a catalyst, shifting the focus from surveillance to the urgent implementation of strategies that integrate VTE prevention into chronic disease management and confront the systemic failures driving these fatal outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u0026nbsp;\u003c/strong\u003eThe data supporting the findings of this study were obtained from the CDC WONDER online database (Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research). The datasets used and analyzed during the current study are publicly available and can be accessed at [CDC WONDER] (https://wonder.cdc.gov).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interests:\u0026nbsp;\u003c/strong\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThe authors received no funds, grants, or financial support for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosures:\u0026nbsp;\u003c/strong\u003eAll other authors have no conflicts of interest to declare.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePeracaula M, Sebastian L, Francisco I, Vilaplana MB, Rodr\u0026iacute;guez-Chiarad\u0026iacute;a DA, Tura-Ceide O Decoding Pulmonary Embolism: Pathophysiology, Diagnosis, and Treatment, \u003cem\u003eBiomedicines 2024, Vol. 12, Page\u003c/em\u003e (1936), vol. 12, no. 9, p. 1936, Aug. 2024, doi:, vol. 12, no. 9, p. 1936, Aug. 2024. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/BIOMEDICINES12091936\u003c/span\u003e\u003cspan address=\"10.3390/BIOMEDICINES12091936\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWendelboe AM, Raskob GE (Apr. 2016) Global Burden of Thrombosis: Epidemiologic Aspects. 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Thromb Res 164:157\u0026ndash;162. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/J.THROMRES.2017.06.017\u003c/span\u003e\u003cspan address=\"10.1016/J.THROMRES.2017.06.017\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSch\u0026uuml;nemann HJ et al (2018) American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients, \u003cem\u003eBlood Adv\u003c/em\u003e, vol. 2, no. 22, pp. 3198\u0026ndash;3225, Nov. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1182/BLOODADVANCES.2018022954\u003c/span\u003e\u003cspan address=\"10.1182/BLOODADVANCES.2018022954\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"Hypertension, Pulmonary Embolism, Mortality Trends, Health Disparities, CDC WONDER","lastPublishedDoi":"10.21203/rs.3.rs-7622619/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7622619/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Hypertension (HTN) is a major public health concern and a key risk factor for pulmonary embolism (PE), contributing substantially to cardiovascular mortality. Despite treatment advances, trends in related mortality remain underexplored.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives\u003c/strong\u003e: This study examined national trends in HTN and PE-related mortality in the United States from 2000 to 2020 and assessed demographic and geographic disparities.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: A retrospective analysis of CDC WONDER data was performed, focusing on HTN (ICD I10-I15) and PE (ICD I26.0, I26.9, I82.8, I82.9). Joinpoint regression estimated age-adjusted mortality rates (AAMR) per 100,000 and annual percentage changes (APC). Data were stratified by year, sex, race/ethnicity, age, census region, urbanization, and state.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: From 2000–2020, 92,181 HTN and PE-related deaths were recorded. AAMR rose from 1.3 to 3.6, with an average annual percent change (AAPC) of 4.5% (p \u0026lt; 0.001). Men consistently had higher mortality (1.4 vs. 1.2 in 2000; 3.9 vs. 3.2 in 2020). NH Black patients had the highest AAMR (4.6), while NH White patients showed the steepest rise (AAPC: 5.0, p \u0026lt; 0.001). Older adults had the highest AAMR (7.5), but younger adults showed the sharpest increase (AAPC: 6.0%, p \u0026lt; 0.001). The South had the highest AAMR (2.2), while the Midwest had the fastest growth (AAPC: 5.1%, p \u0026lt; 0.001). State-level AAMRs in 2020 ranged from 0.9 (Maine) to 5.5 (District of Columbia).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: HTN and PE-related mortality has risen markedly with disparities across age, sex, race, and geography, highlighting the need for equity-focused interventions.\u003c/p\u003e","manuscriptTitle":"Temporal trends in hypertension and pulmonary embolism–related mortality in the United States: A population-based study using CDC WONDER, 2000–2020","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-23 07:58:37","doi":"10.21203/rs.3.rs-7622619/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":"ed614264-df5e-46b1-9e07-9cd15b573a3e","owner":[],"postedDate":"September 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-23T07:58:39+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-23 07:58:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7622619","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7622619","identity":"rs-7622619","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}