Use of low-dose edoxaban in a 99-year-old AF patient with comorbidities and comedications

History, presentation and treatment
A 99-year-old Chinese female first presented in January 2022 with two episodes of sudden-onset transient left-sided weakness and dysarthria that resolved completely. At the age of 50 years, she was treated for pulmonary tuberculosis. She underwent resection of colon carcinoma at the age of 80 years and had remained in remission since.

The patient had a history of hypertension and was treated with amlodipine 5 mg daily. Her blood pressure was elevated at 160/80 mm Hg at presentation, with unremarkable findings from other neurological and cardiovascular examinations.

Noncontrast CT of the brain showed no acute ischaemic changes. Carotid and transcranial Doppler ultrasonography revealed minimal plaque in the left internal carotid artery, but otherwise there was no significant intra- or extracranial stenosis. Findings were consistent with a diagnosis of transient ischaemic attack (TIA).

Blood and coagulation tests revealed a haemoglobin level of 11.9 g/dL, platelet count of 158 x 10⁹/L, prothrombin time of 11.5 seconds and activated partial thromboplastin time of 26 seconds. Her HbA_1c level was 5.7 percent and LDL-cholesterol level was 2.7 mmol/L. Renal impairment was noted (creatinine clearance [CrCl], 20 mL/min). Upon extensive investigations and electrocardiography, a diagnosis of nonvalvular atrial fibrillation (NVAF) was reached, with a CHA₂DS₂-VASc score of 6 (age ≥75 years and prior TIA, 2 points for each; hypertension and female gender, 1 point for each).

Taking into consideration her advanced age, low body weight (45 kg) and renal impairment status, the patient was prescribed daily edoxaban 15 mg and pantoprazole 20 mg. She remained well without recurrent thromboembolic or bleeding events until March 2023, when she passed away due to pneumonia at the age of 101 years.

Discussion
AF is a common cardiac arrhythmia with a strongly age-dependent prevalence. The Global Burden of Disease 2019 Database revealed that individuals aged ≥65 years contributed to >70 percent of the global absolute AF prevalence.¹

Polypharmacy is common amongst individuals aged ≥65 years in Asia, including in Hong Kong.² According to ChiOTEAF registry data, which included 6,341 elderly AF patients (mean age, 74.7 years) in China, polypharmacy was reported in 35.7 percent of cases. Furthermore, 73.2 percent of patients had multimorbidity, which was identified as an independent predictor of adverse clinical outcomes, such as thromboembolism and major bleeding.³

Although clinical guidelines recommend non–vitamin K antagonist oral anticoagulants (NOACs) for prevention of stroke and systemic embolic events (SEE) in AF patients, latest data showed that approximately 80 percent of Hong Kong’s AF patients aged ≥80 years were not on prior antithrombotic agents or an antiplatelet agent before their index stroke.^4-6 Physicians are often reluctant to prescribe anticoagulants to these at-risk elderly patients, such as our patient above, because of their potential for adverse events due to history of falls and/or bleeding, frailty, renal impairment, and polypharmacy.

These patients, including ours, are deemed ineligible for standard-dose NOACs and have limited treatment options. The once-daily 15 mg dose of edoxaban was a particularly suitable NOAC regimen for our 99-year-old patient, given its proven efficacy in very elderly AF patients (aged ≥80 years) with comorbidities. The pivotal phase III ELDERCARE-AF trial compared edoxaban 15 mg daily with placebo in 984 very elderly Japanese AF patients (mean age, 86.6 years) who were ineligible for standard oral anticoagulants for one or more of the following reasons: low creatinine clearance (15–30 mL/min), history of bleeding from a critical area or organ or gastrointestinal (GI) bleeding, low body weight (≤45 kg), continuous use of NSAIDs, or current use of an antiplatelet drug.⁷

ELDERCARE-AF demonstrated superiority of edoxaban 15 mg daily vs placebo in reducing stroke/SEE (hazard ratio [HR], 0.34; 95 percent confidence interval [CI], 0.19–0.61; p<0.001) without a significantly increased risk of major bleeding (HR, 1.87; 95 percent CI, 0.90–3.89; p=0.09).⁷ (Figure) The strong anticoagulation benefits of edoxaban 15 mg daily vs placebo were also demonstrated in extremely old AF patients (aged ≥90 years) in a prespecified subanalysis of ELDERCARE-AF (stroke/SEE: HR, 0.23; 95 percent CI, 0.08–0.68; p=0.008).⁸

Polypharmacy has a high prevalence in elderly patients with AF.³ Drug-drug interactions (DDIs) could lead to higher levels of NOACs, and thus increase the risk of bleeding.⁹ However, a trial-level meta-analysis of NOACs showed that a greater number of comedications was associated with less protection from major bleeding with apixaban and rivaroxaban (both p_interaction>0.05), but this was not observed with edoxaban (p_interaction=0.83). The risk of major bleeding tended to be reduced with edoxaban vs warfarin, regardless of the number of comedications.¹⁰

Notably, edoxaban has the fewest DDIs vs all other NOACs, according to data in the 2021 European Heart Rhythm Association (EHRA) Guidelines.¹¹ Both apixaban and rivaroxaban rely heavily on the cytochrome P450 (CYP450) enzymes for metabolism (15 percent and 32 percent, respectively), while dabigatran and edoxaban require no to minimal CYP450 metabolism (0 percent and <4 percent, respectively).¹² Therefore, extra caution is required when prescribing apixaban and rivaroxaban to patients on strong cytochrome P450 inhibitors, but not with edoxaban and dabigatran. Additionally, although all NOACs interact with the P-glycoprotein (P-gp) transport system, only edoxaban was studied in a phase III trial using concomitant treatment with strong P-gp inhibitors (eg, verapamil, quinidine, dronedarone) as dose reduction criterion.¹¹

Among elderly AF patients, low body weight, renal insufficiency, polypharmacy and comorbidities are important risk factors for adverse clinical events.¹³ Regular use of proton pump inhibitors (eg, pantoprazole) can further reduce their risk of major GI bleeding.¹⁴ Appropriate use of oral anticoagulants should not be hampered by a perceived fear of bleeding or DDIs. As demonstrated by our patient’s case, edoxaban 15 mg is an efficacious and well-tolerated evidence-based NOAC for very elderly AF patients who are ineligible for standard-dose NOACs for stroke or SEE prevention, which does not significantly increase the likelihood of major bleeding. Edoxaban is a particularly suitable NOAC for elderly patients as it has the least DDIs compared with other agents in the class.