Background: Hematological malignancies pose a significant public health burden, with atrial fibrillation/flutter (AF/AFL) increasingly recognized as a critical comorbidity due to shared risk factors, cancer-related inflammation, and cardiotoxic treatments. It contributes to increased mortality in cancer patients through thromboembolic events, heart failure, and treatment interruptions. Despite this, long-term trends in AF/AFL-associated mortality in hematological cancer populations remain underexplored. This study examines two-decade mortality trends among U.S. patients with hematological malignancies and comorbid AF/AFL, identifying temporal inflection points and demographic disparities using national vital statistics data.

Methods: We conducted a cross-sectional analysis utilizing mortality data (2000-2020) extracted from the CDC's National Vital Statistics System Wide-Ranging Online Data for Epidemiologic Research (NVSS-WONDER) platform, identifying all deaths where hematological malignancies (ICD-10 C81-C96) were the underlying cause and atrial fibrillation or flutter (ICD-10 I48) was listed as either an underlying or contributing cause; we excluded cases lacking complete demographic data (age, sex, race, ethnicity) to enable a complete-case analysis. Using the National Cancer Institute's Joinpoint Regression Software (v4.9), we applied joinpoint regression models to pinpoint statistically significant inflection points (joinpoints) in annual mortality trends, calculating annual percent changes (APC) with 95% confidence intervals (CIs) to quantify trend magnitude. Model assumptions were verified with testing for autocorrelation using the Durbin-Watson statistic and assessing homoscedasticity via the Breusch-Pagan test. Furthermore, we constructed Poisson regression models based on pre-joinpoint trend segments to forecast expected mortality rates and computed observed-to-predicted mortality ratios to evaluate significant deviations from established trends; all statistical procedures, including assumption testing and Poisson modeling, were executed using IBM SPSS Statistics version 26. Significance level was set to α=0.05.

Results: A total of 31,720 cases were identified. The mean age at death was 79.82 years (SD = 9.25; 95% CI: 79.71–79.92). The age distribution was left-skewed (skewness = −0.66), with 25% of deaths occurring before age 74 (IQR = 12 years).

Demographic Disparities: Males constituted 57.2% (18,133/31,720) of deaths. Deaths among males increased by 379% (from 341 in 1999 to 1,633 in 2020), compared with a 220% increase among females (from 338 to 1,083). Non-Hispanic Whites accounted for 89.8% of deaths (28,479/31,720; crude rate: 0.6 per 100,000). Non-Hispanic Black individuals had a higher crude mortality rate (0.2 per 100,000) than other racial/ethnic groups (0.1 per 100,000).

Mortality Trends: Joinpoint regression identified four inflection points (2002, 2005, 2011, 2014), dividing the study period into five distinct phases.

  • 1999–2002: Rapid increase (APC = 8.10%; 95% CI: 5.3–11.0,p < 0.001).

  • 2003–2005: Slower growth (APC = 2.54%; 95% CI: 0.8–4.3, p = 0.006).

  • 2006–2011: Sharp resurgence (APC = 7.94%; 95% CI: 6.2–9.7, p < 0.001).

  • 2012–2014: Moderate rise (APC = 5.90%; 95% CI: 3.1–8.8, p < 0.001).

  • 2015–2020: Accelerated climb (APC = 7.58%; 95% CI: 6.0–9.2, p < 0.001).

Total deaths increased 299.7% (679 in 1999 to 2,716 in 2020). Observed-to-predicted ratios consistently exceeded 1.0 post-2011, confirming sustained upward deviations.Conclusion: Mortality among patients with hematological malignancies and comorbid AF/AFL increased by 300% from 1999 to 2020, with accelerating trends after 2011. Key drivers include aging populations, prolonged cancer survivorship exposing patients to cardiotoxic therapies, and improved AF/AFL detection. Pronounced sex disparities (3.6-fold greater mortality increase in males) and racial inequities (highest absolute burden among Non-Hispanic Whites) highlight the need for sex-specific cardio-oncology protocols and targeted screening in high-risk populations. The identified inflection points likely correspond to:

  • Introduction of novel targeted therapies (e.g., proteasome inhibitors, 2003–2005).

  • Updated AF management guidelines (2010–2014)

  • Immune checkpoint inhibitor adoption (post-2015).

Future initiatives should integrate cardiovascular risk mitigation into hematological cancer management and address demographic disparities via tailored interventions.

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2025
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