The COMBINE-AF study pooled individual patient data from four major randomized trials comparing standard-dose DOACs with warfarin in a total of 71,683 patients with AF. Investigators focused on 5,913 participants who met three criteria: age 75 years or older, a high frailty score, and prior experience with vitamin K antagonists such as warfarin. Outcomes were compared with those of more than 52,000 patients who did not meet all three criteria.
The following were the key findings:
- Switching from warfarin to a standard-dose DOAC reduced the risk of stroke or systemic embolism similarly in both frail elderly patients and less frail patients during a median follow-up of 27 months.
- Mortality rates were comparable between DOAC and warfarin users.
- Fatal and intracranial bleeding were significantly lower in patients receiving DOACs across all subgroups.
- Major bleeding rates were similar between DOAC and warfarin in the frail elderly cohort.
- Gastrointestinal bleeding was higher in frail older adults on DOACs, nearly doubling compared with those on warfarin.
- The net clinical outcome, combining stroke, systemic embolism, major bleeding, and death, was similar between DOAC and warfarin in frail elderly patients but favored DOACs in younger or less frail participants.
These results suggest that despite an uptick in gastrointestinal bleeding, switching to a DOAC provides strong protection against stroke, systemic embolism, and the most serious types of bleeding.
The new findings contrast with the earlier FRAIL-AF trial, which reported higher rates of bleeding complications—particularly gastrointestinal, urogenital, and skin bleeds—after switching older frail patients from warfarin to a DOAC, with no clear benefit in ischemic outcomes. That study prompted European guidelines to recommend caution and to support continued warfarin use in such patients.
In an
accompanying editorial, experts from Liverpool Heart & Chest Hospital emphasized that treatment decisions for frail older adults should involve shared decision-making. They advised weighing the consistent stroke-prevention advantages of DOACs against the heightened gastrointestinal bleeding risk, while considering practical issues such as drug–food interactions, the need for routine monitoring, and patient adherence.
"Taken together, the COMBINE-AF analysis suggests that for many frail, elderly patients with AF, transitioning from warfarin to a newer oral anticoagulant is a reasonable—and potentially preferable—strategy to reduce the risk of stroke, intracranial bleeding, and death, provided that clinicians remain alert to the possibility of gastrointestinal complications," the authors concluded.
Reference:
Nicolau AM, Giugliano RP, Zimerman A, et al. Outcomes in older patients after switching to a newer anticoagulant or remaining on warfarin: the COMBINE-AF substudy. JACC. 2025;86:426-439.
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