Mortality trends in deaths attributed to adverse drug reactions with cardiovascular disease listed among multiple causes in the United States, 1999-2020.

Background: Adverse drug reactions (ADRs) represent a significant cause of preventable mortality and continue to pose a major challenge to medication safety. However, national temporal and demographic patterns of deaths in which an ADR was assigned as the underlying cause and cardiovascular disease (CVD) was also listed on the death certificate remain poorly characterized. Methods: We conducted a death certificate-based descriptive study using the CDC WONDER Multiple Cause of Death database from 1999 to 2020. Included records were deaths in which an ADR-related ICD-10 code (Y40-Y59) was assigned as the underlying cause of death and a CVD code (I00-I99) was listed among the multiple causes of death. Age-adjusted mortality rates (AAMRs) per 100,000 population were calculated using the 2000 U.S. standard population. Temporal trends were assessed with Joinpoint regression, estimating annual percent change (APC) and average APC (AAPC). Mortality patterns were further analyzed by age, sex, race, region, and urbanization level, and drug categories recorded on the included death certificates were summarized descriptively. Results: From 1999 to 2020, 3,976 CVD-listed ADR deaths were identified, corresponding to an overall AAMR of 0.057 per 100,000 U.S. population. The AAMR of these deaths increased significantly over the study period (AAPC = 4.755%, 95% CI: 3.513-6.428; Conclusion: CVD-listed ADR mortality in the United States rose significantly from 1999 to 2020. The burden was most pronounced in older adults and disproportionately high among males, Black individuals, and rural residents. Anticoagulants were the most frequently recorded specified drug category. These descriptive findings identify population-level patterns that warrant confirmation through studies incorporating medical records, prescribing data, and case-level clinical adjudication.