Rising Gastrointestinal Bleeding Mortality in the DOAC Era: A Population-Based Real-World Analysis of U.S. National Death Records, 2007–2020

Abstract Background: The widespread adoption of direct oral anticoagulants (DOACs) has transformed anticoagulation management in the United States; however, the population-level effects on gastrointestinal (GI) bleeding mortality remain unclear. Methods: We conducted a population-based, observational study using interrupted time series (ITS) analysis of U.S. national death records (CDC WONDER, 2007–2020). GI bleeding-related deaths were identified using prespecified ICD-10 codes and further restricted to decedents with clinical indications for anticoagulation (atrial fibrillation, pulmonary embolism, or deep vein thrombosis). Trends in age-adjusted GI bleeding mortality and anticoagulant utilization were assessed. Exposure-adjusted mortality among estimated DOAC users was calculated. Segmented regression was used to evaluate changes in mortality associated with the widespread adoption of DOACs (intervention point: 2014). Results: From 2010 to 2020, U.S. age-adjusted GI bleeding mortality rose from 0.6 to 1.3 per 100,000 population as DOAC use expanded to 72% of anticoagulant prescriptions. In contrast, exposure-adjusted mortality among DOAC users declined from 29.5 to 20.0 per 100,000 (2014–2020). Interrupted time-series analysis showed a significant pre-DOAC upward trend (p=0.047) but no significant post-DOAC slope change. A linear regression of 2014–2020 data demonstrated a near-significant decline (p=0.056), which reached significance when 2020 was excluded (p=0.014). Conclusions: Although the immediate and post-intervention changes in GI bleeding mortality after widespread DOAC adoption did not reach statistical significance, these findings are clinically reassuring: no detectable increase in fatal GI bleeding was observed at the population level. These results suggest that the transition to DOACs has not resulted in a large-scale increase in GI bleeding mortality. Future studies with larger datasets or pooled analyses will be important to confirm these trends and further define the population safety profile of DOACs.