Frail Older Patients With AF May Fare Better Switching to DOAC

It’s reasonable, and perhaps preferable, to switch frail older patients with atrial fibrillation (AF) from a vitamin K antagonist like warfarin to a direct oral anticoagulant (DOAC) for stroke prevention, a post hoc analysis of the COMBINE-AF dataset suggests.

For patients who were at least 75 years old, frail, and taking warfarin, initiating DOAC therapy instead was associated with lower rates of stroke or systemic embolism, fatal or intracranial bleeding, and all-cause death, lead author Andre Nicolau, MD (Instituto do Coração, São Paulo, Brazil), and colleagues report.

That came at the cost of more GI bleeding, although there were no differences between the vitamin K antagonist and DOAC groups in major bleeding or a net clinical outcome incorporating efficacy and safety endpoints.

The findings, published online ahead of the August 12, 2025, issue of JACC, indicate that it’s reasonable to get patients who are frail and elderly to swap their warfarin for a DOAC, the researchers say.

That message runs counter to results of the FRAIL-AF trial, which unexpectedly showed that switching to a DOAC from a vitamin K antagonist increased major or clinically relevant nonmajor bleeding, driven by higher rates of GI, urogenital, and skin bleeds, in older, frail patients. There were no differences in ischemic events or mortality. Those results led to a new class IIb recommendation in the latest European Society of Cardiology AF guidelines that supported maintaining vitamin K antagonist treatment in such patients.

“The FRAIL-AF trial caught us a bit by surprise,” COMBINE-AF investigator Robert Giugliano, MD (Brigham and Women’s Hospital, Boston, MA), told TCTMD. But there were several limitations of the trial, said Giugliano, who detailed some of them in an editorial written with Lars Wallentin, MD, PhD (Uppsala University, Sweden). For instance, the trial had an open-label design, it was terminated prematurely for futility, and it included a relatively small number of patients (n = 1,330).

The COMBINE-AF dataset provided a unique opportunity to further explore the question in a significantly larger number of patients.

“We found a different message,” said Giugliano. The current paper “offers a counterweight to what was reported in the FRAIL-AF trial,” he said. “We felt we had a public service obligation here. We didn’t want the wider community to just be leaving elderly patients on a vitamin K antagonist when we think we have a better alternative. At a minimum, doctors should be having the discussion with elderly patients who are frail and say, ‘Look, there is a new class of drugs available. Here are the advantages. Here are the disadvantages. They are more costly. And so let’s think about what’s best for you.’”

In practice, Giugliano said, “the vast majority of my patients want to switch to a DOAC once we have this discussion. And it’s certainly what I would do personally for myself or family members.”

‘FRAIL-AF-Like’ Patients in COMBINE-AF

The COMBINE-AF dataset includes patient-level data from the four pivotal trials of apixaban (Eliquis; Bristol Myers Squibb/Pfizer), edoxaban (Savaysa; Daiichi Sankyo), rivaroxaban (Xarelto; Janssen/Bayer), and dabigatran (Pradaxa; Boehringer Ingelheim). In each trial, the DOAC was compared with warfarin.

Frailty wasn’t formally assessed as part of any of the four trials, so the COMBINE-AF researchers used a frailty index that tallied accumulated health deficits across 18 age-related conditions. Patients with at least six deficits were considered frail.

The current analysis included 5,913 patients who were at least 75 years old, frail, and had experience taking a vitamin K antagonist (the “FRAIL-AF-like” cohort) and 52,721 who didn’t meet all three of those criteria. FRAIL-AF-like patients had a higher mean age (80 vs 69 years) and were more likely to be women (41% vs 37%).

After a median follow-up of 26.7 months, the beneficial impact of DOACs versus warfarin was seen in both the FRAIL-AF-like and comparator groups when it came to stroke or systemic embolism and all-cause death (P = NS for both interactions). Nicolau et al conclude that these findings are consistent with the overall COMBINE-AF meta-analysis showing a relative reduction of 19% in risk of stroke or systemic embolism and of 8% in risk of all-cause death with DOACs.

Some differences between the FRAIL-AF-like and comparator patients emerged around safety, however. The rate of ISTH major bleeding was similar with DOACs and warfarin in the FRAIL-AF-like patients but lower with DOACs in those not meeting the FRAIL-AF definition (P = 0.007 for interaction). Fatal and intracranial bleeding were less likely to occur with DOACs than with warfarin in both cohorts of patients.

GI bleeding, however, was more frequent with DOACs versus warfarin regardless of frailty status, with a stronger impact in FRAIL-AF-like patients (P = 0.006 for interaction).

There was no difference based on type of anticoagulation for risk of a net clinical outcome incorporating stroke or systemic embolism, major bleeding, and death among FRAIL-AF-like patients but a lower risk with DOACs versus warfarin among those who didn’t meet those criteria (P = 0.028 for interaction).

Reconciling the Two Studies

The investigators pointed to several differences between FRAIL-AF and COMBINE-AF that might explain the discrepant results, including the way frailty was assessed. FRAIL-AF employed a dedicated tool designed for that purpose, whereas COMBINE-AF defined frailty based on accumulated health deficits.

In addition, patients in the COMBINE-AF dataset had a greater burden of risk factors for stroke and bleeding compared with those in FRAIL-AF, and the mix of DOACs used differed between the two studies. Also, a higher proportion of patients in COMBINE-AF were treated with apixaban or edoxaban, which were associated with a better safety profile in terms of bleeding in the current analysis.

Commenting for TCTMD, Adam Skolnick, MD (NYU Grossman School of Medicine, New York, NY), said “there’s a real need to understand the optimal strategy for stroke prevention in frail older adults,” but he cautioned against putting too much weight on the COMBINE-AF results when looking for an answer. FRAIL-AF had its limitations, but at least it was prospective and randomized, he said.

“I don’t think that you can compare a meta-analysis of preexisting studies, all of which had different inclusion and exclusion criteria, with a single prospective randomized study that was powered for the outcome it sought to assess,” Skolnick said. He also questioned the way frailty status was derived in the COMBINE-AF analysis.

Overall, he said, these new results are not practice-changing.

“In my own practice, if someone’s been stable for 20 years on warfarin with therapeutic INRs greater than 95% of the time, I don’t feel there’s a strong reason to switch that individual [to a DOAC],” Skolnick said. “We know from prior studies that switching in almost every study is associated with a higher rate of adverse outcomes. Unless there’s a real compelling reason where the person does not remain in therapeutic range or there’s some other intolerance or inability to remain on their previous regimen for anticoagulation, I don’t routinely switch all patients.”

Skolnick does have a discussion with patients about the pros and cons of swapping anticoagulants, but, he noted, most patients are already taking DOACs anyway, unless they have a reason not to (eg, a mechanical heart valve or hypercoagulable state).

In an accompanying editorial, Giulio Francesco Romiti, MD, and Gregory Lip, MD (both from Liverpool Heart & Chest Hospital, England), advise caution in combining the results of FRAIL-AF and COMBINE-AF.

“Taking these findings together, we believe that treatment choices in frail older individuals who are stable on vitamin K antagonist should be framed in the context of a shared decision-making process, considering the overall benefit of DOACs versus warfarin, and the consistent effect in reducing the risk of stroke and systemic embolism, intracranial bleeding, and fatal bleeding in frail older individuals, at the expense of a potential increase in the risk of gastrointestinal bleeding,” Romiti and Lip write.

“Even more, treatment choices should be made within a more holistic or integrated care approach to the management of the complex health needs of these patients,” they continue. “Physicians should consider other factors that may influence treatment efficacy and satisfaction (eg, simplicity of treatment, need for routine monitoring, drug and food interactions, and treatment compliance) and that the clinical risk of these patients require further efforts to improve their prognosis.”