Nurose Karim, MD

Okumura K, Akao M, Yoshida T, Kawata M, Okazaki O, Akashi S, Eshima K, Tanizawa K, Fukuzawa M, Hayashi T, et al. Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation. N Engl J Med. 2020.

Treatment of atrial fibrillation (AF) in the elderly population has always been challenging. Fragile age, multiple comorbidities, and fall risk put them as a red flag whenever a decision to anticoagulate them is made. Edoxaban is a direct oral factor Xa inhibitor. Studies have been done comparing low dose Edoxaban with warfarin and have found Edoxaban once-daily regimens noninferior to warfarin with respect to the prevention of stroke or systemic embolism and have been associated with significantly lower rates of bleeding and death from cardiovascular causes.1

The Edoxaban Low-Dose for EldeR CARE AF patients (ELDERCARE-AF) study is a phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study comparing the safety and efficacy of once-daily edoxaban 15 mg versus placebo in Japanese patients with NVAF ≥80 years of age who are considered ineligible for standard oral anticoagulant therapy.2

CHADS2 index score (2 points, ≥3 points) is used as a factor. Primary endpoint is time to first onset of stroke or systemic embolic event. The primary safety endpoint is the incidence of major bleeding. It is an ongoing study and will continue until 65 patients reach the primary end-point.

Several studies have examined the cost effectiveness of Edoxaban compared with warfarin. In the United States, Edoxaban had a favorable incremental cost-effectiveness profile compared with warfarin in patients with moderate- to high-risk AF. In addition, Edoxaban and Apixaban were found to be the most ‘cost-effective NOACs’ from a German public healthcare insurance perspective, due to reductions in major bleeding events.3 The cost effectiveness of Edoxaban versus warfarin was also found in a study from a perspective of an Italian health system.4 There are no approved specific reversal agents for Edoxaban. Nonspecific reversal agents such as prothrombin complex concentrate (PCC), activated PCC, and recombinant activated factor VII were shown to reverse Edoxaban anticoagulant activity in ex vivo studies. This will be an interesting study and will open a new route of treatment for this age group if Edoxaban is found to be safe.

One limitation of this study is that the median body weight in this trial was ~50 kg, and all patients were east Asian. It is unclear if this dose would have the same efficacy among similar elderly patients in the United States.

References:

1. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-2104. doi:10.1056/NEJMoa1310907

2. Okumura K, Akao M, Yoshida T, et al. Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation [published online ahead of print, 2020 Aug 30]. N Engl J Med. 2020;10.1056/NEJMoa2012883. doi:10.1056/NEJMoa2012883

3. Krejczy M, Harenberg J, Wehling M, Obermann K, Lip GY. Cost-effectiveness of anticoagulation in patients with nonvalvular atrial fibrillation with edoxaban compared to warfarin in Germany. Biomed Res Int. 2015;2015:876923. doi: 10.1155/2015/876923. Epub 2015 Mar 17. PMID: 25853142; PMCID: PMC4380099.

4. Rognoni C, Marchetti M, Quaglini S, Liberato NL. Edoxaban versus warfarin for stroke prevention in non-valvular atrial fibrillation: a cost-effectiveness analysis. J Thromb Thrombolysis. 2015 Feb;39(2):149-54. doi: 10.1007/s11239-014-1104-3. PMID: 24973057.