In a Surprise, Study Finds Frail Elderly Have More Bleeding After Switching From VKAs to NOACs

In a study that will likely turn heads among cardiologists, findings being presented Sunday at the European Society of Cardiology (ESC) 2023 Congress showed that the risk of bleeding was 69% higher for the oldest, frailest patients if they switched from a vitamin K antagonist (VKA) to a novel oral anticoagulant (NOAC) to treat atrial fibrillation.

The results from the FRAIL-AF study also show that making such a switch was not only associated with more bleeding compared with keeping these patients on VKA therapy, but it also did not help prevent strokes.

Joosten

Geersing

“These were unexpected findings, given that previous trials in non-frail patients with atrial fibrillation showed that NOAC blood thinners were safer compared to VKAs,” the investigators stated in conclusions during a press briefing ahead of the presentation. “Without a clear indication, switching from VKA blood thinners to NOAC blood thinners should not be considered in frail elderly patients with atrial fibrillation.”

Current guidelines call for starting patients on NOACs if taking anticoagulants for the first time. Despite limited data, many elderly patients have been switched from VKAs to NOACs over the past decade since the first NOACs were approved a dozen years ago.

According to a press release from ESC, the organization’s current guidelines recommend considering switching to a NOAC, “especially if the time in therapeutic range is not well-controlled despite good drug adherence.”

The lack of data comparing VKAs and NOACs in the frailest elderly patients, and, specifically, the lack of evidence surrounding switching prompted the investigators from University Medical Center (UMC) in Utrecht, the Netherlands, to examine this question. With financial support from the Dutch government and unrestricted educational grants from pharmaceutical companies that make NOACs, they randomized 1330 patients 1:1 between January 2018 and April 2022 to either stay on a VKA or switch to a NOAC.

Clinicians were allowed to select the NOAC of their choice, and principal investigator Geert Jan Geersing, MD, PhD, of UMC Utrecht, who presented the results during a press briefing, said the team could draw no conclusions about relative safety of different NOACs used in the study.

The mean age of participants was 83 years, and 38.8% were women. Patients had to be at least 75 years of age and have a Groningen Frailty Indicator score of 3 or higher to participate. All patients were being managed with VKAs at 1 of 7 participating thrombosis centers in the Netherlands.

Linda Joosten, MD, of the Julius Center for Health Sciences and Primary Care in Utrecht, presented the findings in a hotline session Sunday.

Results. After 163 primary outcome events—101 among those who switched to NOACs and 62 among those who stayed on VKAs—the trial was halted for futility following advice from the Data Safety and Monitoring Board, per a prespecified futility analysis. Results were as follows:

• For the primary outcome of major or clinically relevant nonmajor bleeding: HR, 1.69 (95% CI, 1.23-2.32; P = .001) for switching to a NOAC relative to a VKA
• For the secondary outcome of thromboembolic events: HR, 1.26 (95% CI, 0.60-2.61)
• For the secondary outcome of all-cause mortality: HR, 0.96 (95% CI, 0.64-1.45)

Since NOACs arrived on the scene more than a decade ago, their use has been associated with better clinical benefit for patients with atrial fibrillation, due to lower rates of bleeding. NOACs also do not require the monitoring associated with VKAs, although the principal investigator told reporters that the absence of monitoring with NOACs could have contributed to the unexpected outcome.

“We are not comparing just molecules but also strategies,” said Geersing,

The frail elderly are especially vulnerable patients, Geersing said, as they have multiple chronic conditions, take many medications, and typically rely on others for assistance. Atrial fibrillation is common in this group; the condition affects 1 in every 4 to 5 persons, and stroke risk is high, he said.

Results will be published in the journal Circulation, the official publication of the American Heart Association.

Reference

Joosten LPT, Doorn S, van de Ven PM, et al. Safety of switching from a vitamin K antagonist to a non-vitamin K antagonist oral anticoagulant in frail older patients with atrial fibrillation: results of the FRAIL-AF randomized controlled trial. Circulation. 2023.