Switching From VKA to NOAC in Frail Patients With AF: FRAIL-AF Trial

Quick Takes

  • Older, frail patients with AF experienced more bleeding when they switched from VKA to NOAC therapy rather than staying on VKA therapy.
  • Before switching a patient from VKA to NOAC therapy, it is important to carefully assess for drug-drug interactions and any bleeding risk factors.

Study Questions:

Should frail patients with atrial fibrillation (AF) be switched from a vitamin K antagonist (VKA) over to a non–vitamin K oral anticoagulant (NOAC)?


The authors performed a pragmatic, multicenter, open-label, randomized controlled superiority trial (FRAIL-AF). Included patients were older (age ≥75 years), with AF and frailty (Groningen Frailty Indicator score ≥3). These patients were randomized to switch from international normalized ratio (INR)-guided VKA therapy to a NOAC or to stay with VKA treatment. Patients were excluded if they had a glomerular filtration rate <30 mL/min/1.73 m2 or had valvular AF. Patients were followed for 12 months. The primary outcome was major or clinically relevant nonmajor bleeding complications, accounting for death as a competing risk. Secondary outcomes included thromboembolic events.


Between January 2018 and June 2022, a total of 2,621 patients were screened and 1,330 patients were randomized (median age, 83 years). In the VKA →NOAC arm, 8.6% switched to dabigatran, 50.2% to rivaroxaban, 17.4% to apixaban, and 16.5% to edoxaban. Off-label dosing was used in 6.6% of NOAC-treated patients. The trial was stopped after 163 primary outcome events, 101 in the VKA →NOAC arm and 62 in the VKA continue arm (hazard ratio [HR], 1.69; 95% CI, 1.23-2.32). There were 16 thromboembolic events in the VKA →NOAC arm and 13 in the VKA continue arm (HR, 1.26; 95% CI, 0.60-2.61).


The authors concluded that switching from INR-guided VKA to NOAC therapy in frail, older patients with AF was associated with more bleeding complications compared to continuing VKA therapy.


In the pivotal phase 3 trials comparing NOAC to VKA therapy in AF, NOAC therapy was consistently associated with lower rates of bleeding, especially intracranial hemorrhage. Therefore, many clinicians assume that patients who are using VKA therapy could reduce their risk of bleeding by switching to NOAC therapy. The FRAIL-AF study suggests that among older, frail patients who were tolerating VKA therapy, switching to NOACs actually leads to higher rates of bleeding. This likely reflects two important concepts. First, NOACs target a very specific spot in the coagulation cascade, and therefore, may have different risks of bleeding in different patients. Thus, a patient who is tolerating a VKA (which indirectly inhibits factors II, VII, IX, X) may actually experience bleeding with switching to a medication that directly inhibits factor Xa. Second, older, frail patients often are using several medications that may interact with NOACs. While these medications also interact with VKA, the use of frequent INR testing can quickly adjust for these interactions. Without laboratory monitoring, these drug-drug interactions may lead to elevated blood levels of the different DOAC medications.

Clinicians should be cautious about automatically switching older, frail patients with AF from VKA therapy to NOAC therapy if the patient is tolerating VKA therapy. For any patient being started on NOAC therapy, careful assessment for potential drug-drug interactions is critical.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardiovascular Care Team, Geriatric Cardiology, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias

Keywords: Aged, 80 and over, Anticoagulants, Arrhythmias, Cardiac, Atrial Fibrillation, ESC Congress, ESC23, Factor Xa Inhibitors, Frail Elderly, Frailty, Geriatrics, Glomerular Filtration Rate, Hemorrhage, Thromboembolism, Vascular Diseases

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