Switching frail patients with atrial fibrillation (AF) from anticoagulation therapy with vitamin K antagonists (VKAs) to a novel oral anticoagulant (NOAC) resulted in more bleeding without any reduction in thromboembolic complications or all-cause mortality, randomized trial results show.

The study, FRAIL-AF, is the first randomized NOAC trial to exclusively include frail older patients, said lead author Linda P.T. Joosten, MD, Julius Center for Health Sciences and Primary Care in Utrecht, the Netherlands, and these unexpected findings provide evidence that goes beyond what is currently available.

“Data from the FRAIL-AF trial showed that switching from a VKA to a NOAC should not be considered without a clear indication in frail older patients with AF, as switching to a NOAC leads to 69% more bleeding,” she concluded, without any benefit on secondary clinical endpoints, including thromboembolic events and all-cause mortality.

“The results turned out different than we expected,” Joosten said. “The hypothesis of this superiority trial was that switching from VKA therapy to a NOAC would result in less bleeding. However, we observed the opposite. After the interim analysis, the data and safety monitoring board advised to stop inclusion because switching from a VKA to a NOAC was clearly contraindicated with a hazard ratio of 1.69 and a highly significant P value of 0.001.”

Results of FRAIL-AF were presented at the European Society of Cardiology Congress 2023 and published online August 27 in the journal Circulation.

Session moderator Renate B. Schnabel, MD, interventional cardiologist with University Heart & Vascular Center Hamburg in Germany, congratulated the researchers on these “astonishing” data.

“The thing I want to emphasize here is that in the absence of randomized controlled trial data, we should be very cautious in extrapolating data from the landmark trials to populations not enrolled in those, and to rely on observational data only,” Schnabel told Joosten. “We need randomized controlled trials that sometimes give astonishing results.”

Frailty a Clinical Syndrome

Frailty is “a lot more than just aging, multiple comorbidities and polypharmacy,” Joosten explained. “It’s really a clinical syndrome, with people with a high biological vulnerability, dependency on significant others, and a reduced capacity to resist stressors, all leading to a reduced homeostatic reserve.”

Frailty is common in the community, with a prevalence of about 12%, she noted, “and even more important, AF in frail older people is very common, with a prevalence of 18%. And “without any doubt, we have to adequately anticoagulate frail AF patients, as they have a high stroke risk, with an incidence of 12.4% per year,” Joosten noted, compared with 3.9% per year among nonfrail AF patients.

NOACs are preferred over VKAs in nonfrail AF patients, after four major trials, RE-LY with dabigatran, ROCKET-AF with rivaroxaban, ARISTOTLE with apixaban, and ENGAGE-AF with edoxaban, showed that NOAC treatment resulted in less major bleeding while stroke risk was comparable to treatment with warfarin, she noted.

The 2023 European Heart Rhythm Association consensus document on management of arrhythmias in frailty syndrome concludes that the advantages of NOACs relative to VKAs are “likely consistent” in frail and nonfrail AF patients, but the level of evidence is low.  

So it’s unknown if NOACs are preferred over VKAs in frail AF patients, “and it’s even more questionable whether patients on VKAs should switch to NOAC therapy,” Joosten said.

This new trial aimed to answer the question of whether switching frail AF patients currently managed on a VKA to a NOAC would reduce bleeding. FRAIL-AF was a pragmatic, multicenter, open-label, randomized controlled superiority trial.

Older AF patients were deemed frail if they were 75 years of age or older and had a score of 3 or more on the validated Groningen Frailty Indicator (GFI). Patients with a glomerular filtration rate of less than 30 mL/min/1.73 m² or with valvular AF were excluded.

Eligible patients were then assigned randomly to switch from their International Normalized Ratio-guided VKA treatment with either 1 mg acenocoumarol or 3 mg phenprocoumon, to a NOAC, or to continue VKA treatment. They were followed for 12 months for the primary outcome — major bleeding or clinically relevant non-major bleeding complication, whichever came first — accounting for death as a competing risk.  

A total of 1330 patients were randomly assigned between January 2018 and June 2022. Their mean age was 83 years, and they had a median GFI of 4. After randomization, six patients in the switch-to-NOAC arm, and one in the continue-VKA arm were found to have exclusion criteria, so in the end, 662 patients were switched from a VKA to NOAC, while 661 continued on VKA therapy. The choice of NOAC was made by the treating physician.

Major bleeding was defined as a fatal bleeding; bleeding in a critical area or organ; bleeding leading to transfusion; and/or bleeding leading to a fall in hemoglobin level of 2 g/dL (1.24 mmol/L) or more. Non-major bleeding was bleeding not considered major but requiring face-to-face consultation, hospitalization or increased level of care, or medical intervention.

After a prespecified futility analysis planned after 163 primary outcome events, the trial was halted when it was seen that there were 101 primary outcome events in the switch arm compared to 62 in the continue arm, Joosten said. The difference appeared to be driven by clinically relevant non-major bleeding.

Table. FRAIL-AF: Primary Outcome

Endpoint	VKA Continue Arm n (%)	NOAC Switch Arm n (%)	Hazard Ratio (95% CI)	P value
Bleeding	62 (9.4)	101 (15.3)	1.69 (1.23 – 2.32)	.00112
Major Bleeding	16 (2.4)	24 (3.6)	1.52 (0.81 – 2.87)	—
Clinically Relevant Bleeding	49 (7.4)	84 (12.7)	1.77 (1.24 – 2.52)	—

 

Secondary outcomes of thromboembolic events and all-cause mortality were similar between the groups.

 

Table 2. FRAIL-AF: Secondary Outcomes
Endpoint	VKA Continue Arm  n (%)	NOAC Switch Arm  n (%)	Hazard Ratio (95% Cl)
Thromboembolic Events	13 (2.0)	16 (2.4)	1.26 (0.60 – 2.61)
All-Cause Mortality	46 (7.0)	44 (6.7)	0.96 (0.64 – 1.45)

Completely Different Patients

Discussant at the meeting for the presentation was Isabelle C. Van Gelder, MD, University Medical Centre Groningen, Groningen, the Netherlands. She said the results are important and relevant because it “provides data on an important gap of knowledge in our AF guidelines, and a note for all the cardiologists — this study was not done in the hospital. This trial was done in general practitioner practices, so that’s important to consider.”

Comparing FRAIL-AF patients with those of the four previous NOAC trials, “you see that enormous difference in age,” with an average age of 83 years vs 70-73 years in those trials. “These are completely different patients than have been included previously,” she said.

That GFI score of 4 or more includes patients on four or more different types of medication, as well as memory complaints, an inability to walk around the house, and problems with vision or hearing.

The finding of a 69% increase in bleeding with NOACs in FRAIL-AF was “completely unexpected, and I think that we as cardiologists and as NOAC believers did not expect it at all, but it is as clear as it is.” The curves don’t diverge immediately, but rather after 3 months or thereafter, “so it has nothing to do with the switching process. So why did it occur?”

The Netherlands has dedicated thrombosis services that might improve time in therapeutic range (TTR) for VKA patients, but there is no real difference in TTRs in FRAIL-AF vs the other NOAC trials, Van Gelder noted.

The most likely suspect in her view is frailty itself, in particular the tendency for patients to be on a high number of medications. A previous study showed, for example, that polypharmacy could be used as a proxy for the effect of frailty on bleeding risk; patients on 10 or more medications had a higher risk for bleeding on treatment with rivaroxaban vs those on 4 or fewer medications.

“Therefore, in my view, why was there such a high risk of bleeding? It’s because these are other patients than we are normally used to treat, we as cardiologists,” although GPs see these patients all the time. “It’s all about frailty.”

NOACs are still relatively new drugs, with possible unknown interactions, she added. Because of their frailty and polypharmacy, these patients may benefit from INR control, Van Gelder speculated. “Therefore, I agree with them that we should be careful; if such old, frail patients survive on VKA, do not change medications and do not switch!”

The study was supported by the Dutch government with additional and unrestricted educational grants from Boehringer Ingelheim, BMS-Pfizer, Bayer, and Daiichi-Sankyo. Joosten reports no relevant financial relationships. Disclosures for co-authors appear in the publication. Van Gelder reports no relevant financial relationships.

European Society of Cardiology Congress 2023: Hotline 6. Presented
August 27, 2023.

Circulation. Published online August 27, 2023. Abstract

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