Over the past few years, there have been significant improvements in diagnostic approaches, medical care, and community health actions for many diseases [¹,²]. Although these advancements, leukemia and ischemic heart diseases (IHD) are considered the leading causes of death among the adult population in the United States (U.S.). Leukemia is a group of bone marrow and blood cancers that comprises several variants [³], including acute and chronic types [⁴]. It is considered as the primary contributor of cancer-associated fatalities worldwide [⁵,⁶], with an estimated 60,000 recently detected cases per year in the U.S. [⁷]. Furthermore, IHD is also referred to as coronary heart disease (CHD) which remains to be the primary cause of fatality, involving diseases like sudden cardiac arrest, heart failure, and heart attacks [⁸]. CHD accounted for 375,476 deaths in the U.S., representing about 42.1% of all mortality associated with cardiovascular disease [⁹]. There are nearly 805,000 individuals in the U.S. who suffer from a heart attack every year [¹⁰]. IHD has historically improved due to continuous enhancements in cardiovascular treatment, including pharmaceutical therapies [¹¹], procedural interventions [¹²], and initiatives aimed at addressing contributing factors. These initiatives addressed various conditions, including elevated cholesterol levels, diabetes, hypertension, tobacco consumption, and physical inactivity, that are strongly associated with IHD [¹³,¹⁴,¹⁵]. Likewise, improvements in targeted therapies, chemotherapy, immunologic treatment, and bone marrow transplantation have markedly enhanced longevity throughout past decades, yet the burden of leukemia continues to be considerably elevated [¹⁶]. Leukemia and cardiovascular diseases are closely linked. For example, several leukemia treatments, such as anthracyclines [¹⁷], tyrosine kinase inhibitors [¹⁸,¹⁹], and some targeted therapies [²⁰], can cause cardiotoxicity, leading to heart dysfunction, arrhythmias, and ischemic events. Furthermore, the current heart conditions can limit leukemia treatment and worsen outcomes [²¹]. These connections underscore the importance of integrated cardio-oncology care in monitoring and managing heart risks in leukemia patients.

These healthcare progresses resulted in consistent declines in age-standardized fatality rates for both diseases during the period between the late 1990s and the early 2010s. Nevertheless, recent findings suggest that this favorable trend may be declining or plateauing in certain populations, raising major concerns regarding the sustainability of medical enhancement [²²]. Furthermore, emerging evidence highlights an increase in cardiovascular mortality among adolescents and adults [⁹] and higher rates of leukemia-associated deaths in specific demographic groups [⁷]. These transitions may be linked to multiple interrelated variables, including expanding socioeconomic variations, changing disease risk patterns, the lasting consequences of the COVID-19 pandemic, and inequitable access to healthcare services [²³], which interrupted preventive and standard medical care.

Despite the importance of this evidence, most prior research has emphasized either leukemia or IHD separately, and there is a lack of comparative and comprehensive evaluations that explore fatality trends for both diseases concurrently among diverse demographics. Furthermore, the existing studies lack detailed stratification by sex, age, geographic region, race/ethnicity, and urban-rural residence [²⁴]. These factors are known to influence disease burden and its associated consequences. This results in a serious gap in interpreting whether the apparent decline in progress underscores a wider challenge in U.S. medical infrastructures. The combined analysis of IHD and leukemia is justified because they are both major causes of mortality in the U.S. Besides, they share common risk factors and healthcare influences, and have treatment-related overlaps. Studying these conditions concurrently offers a broader view of national health trends to guide policy and care.

To resolve this discrepancy, this study considered 22 years of nationwide fatality records from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC-WONDER) to assess mortality patterns for both IHD and leukemia among individuals aged \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\ge$\end{document}≥ 25 years old in the period between 1999 and 2020. Furthermore, we aim to identify whether there has been a decline in mortality rate improvement for IHD and leukemia, and to address which populations are most influenced. We hypothesize that after a period of steady decline, mortality rates for both IHD and leukemia have plateaued or increased in certain subgroups, reflecting emerging disparities in healthcare access, prevention, and treatment. Tracking mortality trends in IHD and leukemia helps clinicians target screening, prevention, and resources to populations at risk. For public health, these trends guide priority setting, integrated care planning, and policies to improve healthcare performance and equity.

This 22-year analysis provides an extensive examination of mortality trends in U.S adults with leukemia and ischemic heart disease (IHD), disease states that frequently co-occur owing to overlapping risk factors, older age, and treatment adverse effects. We observed a general decline in mortality from 1999 to 2018, with a marked reversal in the recent years (2018–2020), indicating the emergence of new concerns in survivorship and management of comorbidities.

Our findings build upon and refine the existing literature on cardiovascular mortality in patients with hematological malignancies. A recent, notable study by Doolub et al. examined temporal trends using a similar dataset and timeframe, reporting that overall cardiovascular mortality among patients with leukemia decreased by 31.8% between 1999 and 2020 [³¹]. However, our study differs in several critical aspects, revealing a more urgent and nuanced picture. First, while Doolub et al. took a broad approach by analyzing all cardiovascular causes of death across multiple hematological cancers [³¹], our study provides a more granular analysis by focusing specifically on the co-occurrence of leukemia and IHD. This focused scope, combined with a more powerful statistical method —“Joinpoint regression analysis” — allowed us to uncover a critical inflection point that was missed by the broader analysis. While Doolub et al.’s findings suggest a consistent decline, our analysis reveals that the long-term decrease in mortality for leukemia and IHD (AAPC = -1.30%) masks a significant and concerning reversal. Specifically, we identified a sharp increase in mortality of +7.62% per year from 2018 to 2020. This recent uptick suggests that the progress in managing this high-risk comorbidity may be stalling or reversing, a critical insight for contemporary cardio-oncology that is not apparent from studies that average trends over two decades.

The 1.39 to 0.95 per 100,000 decrease in age-adjusted mortality rate (AAMR) between 1999 and 2018 (APC = -2.18%) is in line with the national improvements in cancer outcomes and cardiovascular care, as advances in leukemia interventions, notably those for chronic lymphocytic leukemia (CLL) and acute promyelocytic leukemia (APL) have contributed to improved survival [³²]. Further, improved primary and secondary prevention of IHD, including greater use of statins, hypertension control, and added revascularization techniques, has likely decreased cardiovascular mortality [³³]. Nonetheless, the rise in AAMR from 0.95 in 2018 to 1.09 in 2020 (APC = +7.6%) is concerning.

Men had a significantly larger age-adjusted linked mortality rate (AAMR) than women (1.87 vs. 0.62), reflecting previous literature involving leukemia rates and prevalence of cardiovascular disease [³⁴,³⁵]. The slower annual percent change (AAPC) for men (-1.11%), in contrast to women (-2.35%), also suggests that female patients may have gained more from improvements in medical services during the study period. Significantly, the mortality change after the 2017 reversal was substantial for women (APC = +5.47%), but there was no change in men, indicating that women with comorbidities may be lagging in recent preventive or compensatory strategies [³⁶,³⁷].

Racial differences in mortality were evident throughout the study period. White non-Hispanic men and women were the largest group of deaths (47,998) and had the highest age-adjusted mortality risk (AAMR) score (1.25). While the long-term annual age adjusted percentage change (AAPC) of -1.01% shows that the number in this group had improved over time, the reversal in the post 2018 period (APC = +7.8%) highlights the fact that a rapidly aging population may have raised the overall number of women and men that die of IHD, which may exist at a higher prevalence in Whites [³⁸,³⁹]. Non-Hispanic Black adults showed a more consistent decline (AAPC = -2.55%), without joinpoints, which may reflect more uniform public health outreach in this subgroup or less data volatility due to smaller sample sizes. Hispanic adults demonstrated the steepest decline in AAMR (AAPC = -2.34%) over the time period for the group, as its AAPC demonstrates a trend that reflects what is widely termed and sometimes referred to as the "Hispanic Paradox," suggesting that this group has ’better health’ than their socioeconomic status would suggest [⁴⁰,⁴¹].

The area with the highest mortality burden was in the Midwest (AAMR = 1.3), while the South showed the largest increase in mortality after 2018 (APC = +10.99%). The differences between regions may be attributed to healthcare system differences including infrastructure, access to care, and disease burden, for example, states such as North Dakota and West Virginia, which had the largest state-level AAMRs, are rural Midwest states that had less specialist availability and have higher populations of smoking and obesity, which are two key contributors to both leukemia and IHD mortality [⁴²,⁴³]. By contrast, the West region showed a steady decrease over time, with no joinpoints (AAPC = -1.76%), indicating that this region has better access to tertiary care centers and has been willing to engage in aggressive, guideline-based treatments and standards of care.

As expected, the population aged 65 years and older represented most deaths (48,933) and had a crude mortality rate (CMR) of 5.27 versus 0.26 in the 45–64 age group. Older adults often carry multimorbidity, have a depressed physiological reserve, and have more exposure to cardiac toxicants (e.g., anthracyclines or tyrosine kinase inhibitors) [⁴⁴]. The rising mortality trend after 2018 (APC = +7.2%) was not statistically significant, but biologically plausible as treatment-related cardiovascular disease is often temporal to the end of life in cancer survivorship and therefore emphasizes an urgent need for cardioncology interventions and routine surveillance for older leukemia patients [⁴⁵,⁴⁶]. In contrast to standard oncologic care, these cardioncology interventions should include longitudinal cardiac monitoring (e.g., echocardiography, biomarkers), early referral to cardio-oncology services for high-risk individuals, and baseline cardiovascular risk assessment before starting chemotherapy [⁴⁷]. Long-term cardiac complications may be reduced by implementing structured survivorship programs that emphasize lifestyle modification, cardiotoxicity prevention, and the management of modifiable cardiovascular risk factors (such as diabetes, dyslipidemia, and hypertension). These tactics are particularly important for older adults, who are more susceptible to therapy-induced cardiotoxicity due to their decreased physiological reserve and preexisting comorbidities [⁴⁸].

The difference in rates between metropolitan (AAMR = 1.08) and non-metropolitan populations (AAMR = 1.34) aligns with existing health disparities. Patients in rural settings are likely to experience longer delays in diagnosis and treatment, as well as limited access to cardiologists and oncologists, and face financial or transportation barriers [⁴⁹]. Both regions experienced increases in mortality rates after 2018, but the increase in mortality was larger in rural areas (e.g., APC = +7.4%), indicating a need to expand telemedicine and decentralized care [⁵⁰].

It was noticed that 40% of deaths occurred outside inpatient settings—in people’s homes (14,919) or in long-term care facilities (9,130)—suggesting a significant burden of unmonitored or poorly managed end-of-life complication [⁵¹]. This matches trends in palliative care across the country, where patients with end-stage hematologic malignancies often deteriorate quickly without going to the hospital [⁵²,⁵³]. The level of deaths outside of hospice facilities (2,280 deaths) might reflect limited use of palliative services, which is a known deficit in hematologic oncology [⁵⁴,⁵⁵].

Previously identified, the strengths of this study stem from factors such as its population-level representativeness, 22-year duration, and stratification by important demographic and geographic factors. In addition, Joinpoint regression analyzes and statistically tests inflection points in mortality trajectories with great precision.

A significant limitation of our study is that our analysis combined all deaths where both leukemia and ischemic heart disease were listed on the death certificate, as we used Multiple Cause of Death (MCOD), without stratifying by the Underlying Cause of Death (UCOD). Therefore, our results represent the overall mortality trend for the co-occurrence of these conditions, but do not distinguish between patients dying from leukemia with IHD as a contributing factor and those dying from IHD with leukemia as a contributing factor. These two scenarios have different clinical and etiological implications, and their mortality trends may differ. Future studies using multiple-cause-of-death data should analyze these pathways separately to provide a more granular understanding of this comorbidity. Additionally, the study has limitations due to its ecological design, as the consistency of mortality reporting may be impacted by regional or temporal differences in ICD coding practices, and the use of death certificates may be susceptible to misclassification bias, especially in complex cases. Notably, no sensitivity analyses were conducted to account for potential modifications to coding standards during the 22-year study period.

Furthermore, important clinical factors crucial for assessing results, such as chemotherapy regimens, treatment adherence, baseline cardiac function, and cardiotoxicity monitoring, are not included in the database at the individual level. Information on particular leukemia subtypes, which may vary in prognosis and treatment-related mortality, is also missing. Furthermore, the evaluation of care disparities is limited by the lack of information on socioeconomic factors, such as income, insurance coverage, and access to healthcare. We were unable to directly assess treatment effects or link observed mortality trends to particular interventions due to the ecological nature of the data. These restrictions make it challenging to draw conclusions about causality and underscore the need for more comprehensive, patient-level research.

After twenty years of decreasing mortality from comorbid conditions of leukemia and ischemic heart disease, reversals in mortality among key subgroups, particularly those older than 65, women, non-Hispanic Whites, and those in the South and rural areas, have created an urgent need for renewed public health attention. Prioritizing the provision of cardio-oncology services, the equitable delivery of care, and planning for survivorship will be essential to ensure that previous gains are maintained and noted disparities are addressed for this medically disadvantaged population.