Are NOACs always the best strategy in elderly AF patients?

Cardioembolic stroke is a serious complication in atrial fibrillation (AF), and stroke prevention by oral anti-coagulants (OACs) is the cornerstone in the management of AF. Current guidelines recommend OACs for high risk AF patients, including those with aged ≥75 years. Data about the use of OACs among frail very elderly (≥85 years) with AF are limited because they were underrepresented in clinical trials, but considering the aging of the population, evidence to support a beneficial anticoagulation regimen in this population is needed. Among patients with AF ≥90 years of age, warfarin was associated with a lower risk of ischaemic stroke and positive net clinical benefit.1 However, OACs are underused in elderly patients with AF, mainly because of safety concerns related to fall risk, drug interactions, low adherence, and perceived bleeding risk.2 A network meta-analyses, using individual patient-level data from the randomized trials of non-vitamin K oral anti-coagulants (NOACs), showed standard-dose NOACs resulted in significant reductions in the risk of stroke/systemic embolism, intracranial bleeding, and all-cause death compared with vitamin K antagonists (VKAs), regardless of patient age.3 Real world data support the better net clinical benefits of NOACs in elderly patients with AF.1,4 These advantages are primarily observed in OAC-naïve patients. The FRAIL-AF trial was a pragmatic open-label randomized trial in frail elderly AF patients (mean age, 83 years; GFI score ≥ 3; mean CHADS2-VASc score, 4) in the Netherlands. The trial was conducted with well-established infrastructure for VKA treatment, and the time in therapeutic range (TTR) for the oldest patient groups ranged from 65 to 74% in clinical practice. This trial demonstrated that switching from VKAs to NOACs in patients who were stable on INR-guided VKA treatment was associated with more bleeding complications without an associated reduction in thromboembolic complications.5 This association was mainly attributed to an increase in gastrointestinal bleeding, with intracranial bleeding rates remaining similar between NOACs and VKAs. Thus, without a clear indication, well-controlled VKA treatment (TTR ≈ 70%) can be considered a valid treatment option instead of switching to a NOAC in elderly frail AF patients. However, there are concerns regarding continuation of VKA treatment in this patient group. First, maintaining an adequate TTR range is challenging in elderly frail patients, due to dietary variations and polypharmacy, leading to unstable international normalized ratio (INR) levels. Second, the risk of intracranial bleeding is reported to be higher with VKAs compared to NOACs, although the FRAIL-AF trial found similar intracranial bleeding rates between the two groups.5 In very elderly patients (aged ≥85 years) with AF, the benefit of OAC therapy on thromboembolic events outweighs the haemorrhagic risk.4 Evidence-based data showed that NOACs were associated with a significantly lower risk of stroke/systemic embolism and intracranial haemorrhage compared with warfarin, with no significant difference in major bleeding (Table 1).3,4 Because of the better net clinical benefit, NOACs represent a more favourable choice than VKAs in very elderly patients with AF except for those with contraindications (mechanical valve and severe renal dysfunction). For frail AF patients who are stable on VKA treatment, continuing VKAs is safe and effective, but switching to NOACs should be considered if INR become labile. NOACs would be preferable in OAC-naïve patients.6 Clinical data of OACs for elderly AF patients * Statistically significant. Abbreviations. CI = confidence interval; GFI = Groningen Frailty Indicator; HR = hazard ratio; IPTW = inverse probability of treatment weighting; LMWH = low molecular weight heparins; NOACs = non-vitamin K oral anti-coagulants; OR = odds ratio; RCTs = randomized clinical trials; SEE = systemic embolic events; TIA = transient ischaemic attacks; and VKAs = vitamin K antagonists. • Sardar P, Chatterjee S, Chaudhari S, Lip GY. New oral anticoagulants in elderly adults: evidence from a meta-analysis of randomized trials. J Am Geriatr Soc 2014;62:857–864. • Silverio A, Di Maio M, Prota C, et al. Safety and efficacy of non-vitamin K antagonist oral anticoagulants in elderly patients with atrial fibrillation: systematic review and meta-analysis of 22 studies and 440 281 patients. Eur Heart J Cardiovasc Pharmacother 2021;7:f20–f29. In very elderly Japanese patients with AF who were not appropriate candidates for a standard OAC regimen, low-dose edoxaban (15 mg od) was superior in preventing stroke or systemic embolism and did not result in a significantly higher incidence of major bleeding as compared with placebo.7 Thus, it could be considered as another therapeutic option in those without tolerance to standard OAC treatment. Conflict of interest: None of the authors has any relationship relevant to the content of this paper to disclose. No new data were generated or analysed in support of this research.