Are frail older adults with atrial fibrillation (AF) better off sticking with warfarin, the tried-and-true vitamin K antagonist? Maybe not, according to new data in the Journal of the American College of Cardiology.

These findings come from a recent post hoc analysis of COMBINE-AF, a large dataset of patients with AF randomly assigned to receive warfarin or a direct-acting oral anticoagulant (DOAC). The study demonstrated switching from warfarin to a standard-dose DOAC is “a reasonable choice” for frail older adults who had been treated with warfarin to reduce stroke and systemic embolism, death, and the most serious types of bleeding, according to the researchers. 

Serious bleeding complications included a twofold increased risk for intracranial hemorrhage among patients using warfarin compared with a DOAC, Robert Giugliano, MD, SCM, a professor of medicine at Harvard Medical School in Boston, Massachusetts, and an investigator for COMBINE-AF, told Medscape Medical News. 

COMBINE-AF: Mega Dataset of AF Patients

The original COMBINE-AF meta-analysis, published in 2023, compared efficacy and bleeding risk from standard-dose DOAC and warfarin using data from pivotal trials of the four available DOACs: apixaban, dabigatran, edoxaban, and rivaroxaban. From this dataset of 71,683 patients, the COMBINE-AF post hoc analysis looked at 5913 patients who were aged 75 years or older, had a frailty index score above the median, and had been or were currently being treated with warfarin. The relative efficacy and bleeding risks of standard-dose DOACs and warfarin were compared in this group and then evaluated in 52,721 patients from the dataset who did not meet all three of these criteria. 

After a median follow-up of 27 months, frail older adults with AF who had been treated with warfarin and were switched to a standard-dose DOAC experienced significant reductions in rates of stroke or systemic embolism, fatal and intracranial bleeding, and death.

As expected, gastrointestinal bleeding rates were higher with standard-dose DOAC compared to warfarin, although this increase was less pronounced in an analysis restricted to apixaban and edoxaban. 

Rates of major bleeding and the primary net clinical outcome — a composite of stroke, systemic embolism, major bleeding, and death — were similar with DOACs and warfarin. Among the cohort of patients who did not meet all three criteria, use of a DOAC was associated with an 18% lower risk for major bleeding than was warfarin.

Conflicting Findings

The retrospective analysis of COMBINE-AF was inspired by a 2023 study, FRAIL-AF, which showed conflicting results. This prospective, randomized trial (n = 1330) found frail older adults with AF might fare better staying on vitamin K antagonist therapy to reduce the risk for major and clinically relevant bleeding events. 

Findings from FRAIL-AF formed the basis of a class IIb recommendation in the 2024 guidelines from the European Society of Cardiology, which stated: “Frail patients aged at least 75 with polypharmacy and stable on a vitamin K antagonist may remain on a vitamin K antagonist rather than switching to a DOAC.” 

FRAIL-AF had several limitations, said Giugliano, who is also a senior investigator with the Thrombolysis In Myocardial Infarction (TIMI) study group. He cited the trial’s open-label design, premature termination for futility, relatively small number of patients, and low number of nonbleeding events as specific issues.

“Because a modest number of patients were followed for a relatively short period of time, there were too few other events like stroke or death to draw any meaningful conclusions,” Giugliano told Medscape Medical News. “Since we assembled the largest individual dataset of patients randomized to DOAC vs warfarin, we felt compelled to analyze our data to confirm the FRAIL-AF trial findings.”

Giugliano put the European guideline into perspective. 

“Class IIb is the weakest recommendation level — meaning, you may consider using warfarin. Our data show that if patients remain on warfarin, their risk for overall and gastrointestinal bleeding might be lower, but their mortality risk is higher, and their risk for more dangerous intracranial hemorrhage is doubled.” 

He noted that a vitamin K antagonist is still the recommended anticoagulant in selected patient groups, including those with moderate-to-severe mitral stenosis or mechanical valve replacement.

Managing Frail Patients With AF

Frailty, defined as “increased vulnerability resulting from aging-associated decline in reserve and function,” is found in 40% of patients with AF and is associated with higher risks for thromboembolism, bleeding, and death. 

“The two most important issues in frail patients are falls and bleeding risk,” Elizabeth Pogge, PharmD, MPH, an Arizona-based pharmacist specializing in cardiology, told Medscape Medical News. Patients with frailty and AF are also at increased risk for underprescribing or underdosing of anticoagulants, she said. 

“When working with a frail older adult, I want to assess them for the most appropriate anticoagulant at the most appropriate dose,” she said.

Gastrointestinal bleeding risk is higher in older patients because of reduced vascular elasticity, comorbid conditions, and polypharmacy, Pogge added. In addition to their systemic anticoagulant effect, DOACs increase gastrointestinal bleeding risk through a direct local effect on the gut lining. 

“Apixaban and edoxaban have a lower gastrointestinal bleeding risk compared with rivaroxaban or dabigatran, especially in older adults,” Pogge said. “This may be related to differences in absorption rates among DOACs.” 

For some DOACs, once-daily dosing can help to reduce gastrointestinal bleeding. In the original COMBINE-AF analysis, 30 mg of edoxaban taken twice daily was associated with more bleeding than the same overall amount taken once daily. 

Anticoagulation Counseling for Frail Older Adults

“It’s critical to select an antithrombotic therapy that maximizes both efficacy and safety,” Giugliano stressed. “This is a discussion I have with patients every day. Many patients feel the higher cost of the DOAC is offset by lower risk of serious bleeding.” 

Other advantages include less need for frequent blood testing and dietary adjustments that come with the warfarin territory, according to Pogge. 

“My observation from working in warfarin clinics is that the added inconvenience of blood testing and drug–drug, drug–food and drug–disease interactions make warfarin inferior to DOACs,” she said. 

When counseling older adults with frailty, Pogge advised: 

• Awareness of bleeding risk, the most serious and common adverse effect of anticoagulation, and recognizing the signs and symptoms of bleeding and what to do if they experience bleeding.
• Over-the-counter medications and supplements to avoid that could increase their bleeding risk, such as nonsteroidal anti-inflammatory drugs, aspirin, and herbs with antiplatelet properties.
• Fall risk, a major factor contributing to serious bleeding, especially intracranial bleeding.
• Avoiding alcohol, which may increase risk for bleeding and recurrence of AF.
• Options for getting help with high prescription costs rather than skipping doses or discontinuing the anticoagulant.

Giugliano reports receiving research support from Anthos Therapeutics, Daiichi-Sankyo, and Novartis; honoraria for lectures from Daiichi-Sankyo, Medical Education Resources, Menarini, SAJA Pharmaceuticals, Shanghai Medical Technology and SUMMEET; and consulting fees from Artivion, Celecor, Daiichi-Sankyo, Novartis, Perosphere, PhaseBio Pharmaceuticals, Samsung, Sanofi, SFJ Pharmaceuticals, and Thrombosis Research Institute. 

Pogge reported no relevant financial relationships.

Katherine Wandersee has more than 30 years’ experience as a medical writer for professional medical audiences.