Non-vitamin K antagonist oral anticoagulants in older and frail patients with atrial fibrillation

Abstract

Elderly and frail patients with atrial fibrillation (AF) are at increased risk of thrombotic events, bleeding, and death compared to their counterparts, making their management challenging. With the introduction of non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) in the past decade, the risk:benefit balance in such high-risk patients with AF has tipped in favor of treating these patients with anticoagulation, and in most cases with a NOAC instead of a VKA. In patients ≥75 years of age with AF, each of the 4 approved NOACs reduced stroke or systemic embolism and vs warfarin in their landmark clinical trial and lowered mortality. However, only apixaban and edoxaban significantly reduced major bleeding vs warfarin. A similar pattern was seen in even older cohorts (≥80 and ≥85 years). Among patients age ≥80 who are not candidates for oral anticoagulants at the approved dose, edoxaban 15 mg may be a reasonable alternative. In elderly or frail individuals who are on multiple comedications (particularly if ≥1 moderate or strong cytochrome P-450 inhibitor), only edoxaban consistently reduced major bleeding compared to warfarin. Regardless of the specific OAC selected, appropriate dosing in the elderly (who frequently qualify for dose reduction per the prescribing label) is critical. In elderly and frail patients with AF, factors that may modify the efficacy-safety profile of specific oral OACs should be carefully considered to permit the optimal selection and dosing in these vulnerable patients.

Keywords: NOAC; atrial fibrillation; elderly; frail; oral anticoagulant.

Figure 1

Age-specific counts and rates of prevalent cases (A), incident cases (B), and deaths (C) of atrial fibrillation by sex, 2017. Error bars and shading represent 95% uncertainty intervals. Source: Dai et al. (with permission).

Figure 2

Influence of age on outcomes (warfarin group only) from the ENGAGE AF-TIMI 48 trial. Multivariable model included all baseline characteristics with univariate P < 0.05 (body mass index, sex, creatinine, hypertension, dyslipidaemia, diabetes, smoking, prior stroke or transient ischaemic attack, heart failure, type of atrial fibrillation, race, region, increased risk of falling, risk of neuropsychiatric disease, coronary artery disease, history of hepatic disease, history of non-intracranial haemorrhage, alcohol intake, and medication predisposing to bleeding). CI, confidence interval; HR, hazard ratio. Source: Kato et al. (with permission).

Figure 3

Forest plot of a trial-level meta-analysis of NOACs vs. warfarin in patients age ≥75 years from the RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48 trials. Panel A shows results for stroke or systemic embolic events and panel B for major bleeding. Source: Caldeira et al.^, (with permission).

Figure 4

Patient-level meta-analysis of standard-dose NOAC regimens vs. warfarin from the RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48 trials across the age range 50–100 years for the outcomes of stroke or systemic embolism (A), major bleeding (B), and death (C). Data exclude results with dabigatran 110 mg and edoxaban 30/15 mg. Source: Carnicelli et al. (with permission).

Graphical Abstract

In patients with atrial fibrillation who are elderly (age ≥ 75 years) and/or frail, first assess whether the patient is eligible for oral anticoagulation. If the patient is eligible for anticoagulation, non-vitamin K oral antagonists (NOACs) are preferred, unless there are absolute contraindications (e.g. mechanical heart valve), in which case a vitamin K antagonist should be used targeted an international normalized ratio of 2.0–3.0. In patients eligible for NOACs, apixaban or edoxaban are recommended given their consistent reduction in stroke or systemic embolism events, major bleeding, and mortality, regardless of age. In patients at low risk of bleeding, dabigatran 110 mg twice daily or rivaroxaban may be considered as alternatives to apixaban and edoxaban. When using a factor Xa inhibitors, it is critical to assess the criteria for dose reduction that are specific to each agent, and select the appropriate dose. In patients who are ineligible for standard oral anticoagulant regimens, either a non-pharmacologic therapy (e.g. left atrial appendage exclusion) or edoxaban 15 mg once daily may considered. Alternatives if low bleeding risk: Dabigatran 110 mg b.i.d. or rivaroxaban 20/15^a mg o.d. ^aReduced dose of factor Xa based on dose reduction criteria as described in the prescribing label. BID, twice daily; OD, once daily