BACKGROUND: Atrial fibrillation (AF) is a significant contributor to ischemic stroke risk and mortality, particularly in aging populations. This study examines mortality trends from ischemic stroke secondary to AF in the U.S. from 1999 to 2020, focusing on demographic and regional disparities. METHODS: Using data from the CDC WONDER database, this cross-sectional analysis included individuals aged ≥ 65 years with death certificates indicating ischemic stroke (ICD I63) and AF (ICD I48) as contributing causes. Age-adjusted mortality rates (AAMR) were calculated, and temporal trends were analyzed using join-point regression to estimate annual percentage changes (APC). Data were stratified by age, sex, race/ethnicity, urbanization, and geographic regions. RESULTS: From 1999 to 2020, ischemic stroke with AF caused 62,443 deaths (AAMR: 6.75/100,000
95% CI: 6.70-6.80). Mortality rates increased significantly after 2010, peaking between 2014 and 2017 (APC: 31.3 for females, 28.1 for males). Older adults (≥ 85 years) exhibited the highest AAMR (43.2/100,000
95% CI: 41.6-44.8). Nonmetropolitan areas consistently showed higher mortality compared to metropolitan regions. Demographic disparities were evident, with higher AAMRs in females, Whites, and the Western U.S., though Hispanics had the sharpest APC increase during 2014-2017. CONCLUSION: Mortality rates from ischemic stroke with AF are rising in older adults, with significant demographic and regional disparities. The findings underscore the need for targeted public health strategies to mitigate AF-related stroke risks and improve healthcare equity.