Edoxaban Benefits AF Patients With Previous Stroke/TIA

August 02, 2016

A new subgroup analysis of the ENGAGE AF-TIMI 48 trial has shown that the new oral anticoagulant edoxaban shows similar — and maybe greater — benefits over warfarin in patients with atrial fibrillation (AF) and a history of cerebrovascular events compared with benefits in the main trial.

"Patients with history of IS [ischemic stroke] and TIA [transient ischemic attack] represent a vulnerable population of patients with AF, who are highly prone for recurrent cerebrovascular events. In this prespecified analysis of a large, randomized double-blind trial of patients with AF, we demonstrated that on account of higher ischemic and hemorrhagic event rates, patients with AF and a history of previous IS/TIA have generally greater absolute benefits from once-daily edoxaban versus well-managed warfarin, when compared with AF patients without a history of previous IS/TIA," the authors, led by Natalia S. Rost, MD, Massachusetts General Hospital, Boston, conclude.

The study was published online July 7 in Stroke. Edoxaban, known as Savaysa in the United States and Lixiana in Europe, is manufactured by Daiichi Sankyo.

As background to the new analysis, the researchers explain that vitamin K antagonists are effective in reducing recurrent stroke in patients with AF, but they require regular monitoring of anticoagulation level and are subject to multiple drug–drug and food–drug interactions. More important, their use is associated with an increased risk for serious bleeding events, including intracranial hemorrhage (ICH) and fatal systemic bleeding.

Non–vitamin K oral anticoagulants (NOACs) have been available since 2009 and are at least as effective as warfarin in preventing stroke or systemic embolic events in patients who have AF, with a lower risk for ICH.

Among the NOACs, the directly acting, once-daily oral factor Xa inhibitor edoxaban was noninferior to warfarin in preventing stroke or systemic embolic events, with lower rates of bleeding, ICH, cardiovascular mortality, and prespecified net clinical outcomes in patients with AF in the ENGAGE AF-TIMI 48 trial.

The current analysis focused on patients in that trial who had had a previous ischemic stroke or TIA.

Results showed that of the 21,105 patients in the ENGAGE trial, 5973 (28.3%) had had a previous ischemic stroke or TIA. Compared with the patients without a previous stroke/TIA, those with such an event were at higher risk for stroke/systemic embolic events (2.83% vs 1.42% per year), major bleeding (3.03% vs 2.64% per year), and intracranial hemorrhage (0.70% vs 0.40% per year).

The ENGAGE trial evaluated two doses of edoxaban, and the higher dose (60 mg daily) went on to receive US Food and Drug Administration approval. Therefore, for the current analysis of edoxaban vs warfarin, the researchers included only patients receiving the higher edoxaban dose.

Results of this analysis showed that patients with a previous stroke/TIA experienced a similar relative but greater absolute benefit of edoxaban vs warfarin when compared with patients without a previous stroke/TIA.

Among patients with previous stroke/TIA, the hazard ratios for edoxaban vs warfarin were 0.86 for stroke/systemic embolic events, 0.96 for primary ischemic stroke, and 0.52 for primary hemorrhagic stroke.

"The 2-fold higher rate of stroke/systemic embolic event among patients with a previous stroke/TIA translated into a numerically, but not significantly, larger absolute difference favouring edoxaban versus warfarin (41 vs 17 per 10 000 patient-years)," the investigators write.

The absolute risk reductions favoring edoxaban were also numerically magnified by a factor of 2- to 8-fold for several cerebrovascular and mortality endpoints, including stroke/systemic embolic events, all-cause mortality, cardiovascular death, and a variety of composite end points in patients with previous cerebrovascular events, they add.

Annualized ICH rates were 0.62% with edoxaban vs 1.09% with warfarin, an absolute risk difference of 47 per 10,000 patient-years (hazard ratio, 0.57; P = .02).

The authors note that there are limited data on NOAC use in patient populations at high risk for recurrent events.

"With exception of a recent analysis of rivaroxaban use in a number of higher-risk populations from the ROCKET-AF…trial, our study is the first to provide the dedicated data in support of safety and efficacy of NOAC use in patients with previous IS/TIA," they note.

"These data highlight an additional advantage of edoxaban's favorable safety profile in patients with previous IS/TIA, which along with the facilitation of patient compliance of once-daily dosing without need for routine monitoring, make edoxaban an attractive option for anticoagulation among patients with AF and a previous cerebrovascular ischemic event," the researchers conclude.

This study was supported by Daiichi Sankyo Pharma. Several of the authors report receiving grant support, honoraria, or consulting fees from Daiichi Sankyo. One author is an employee of Daiichi Sankyo and holds a pending patent related to the clinical properties of edoxaban.

Stroke. Published online July 7, 2016. Abstract

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