Clinical outcomes, edoxaban concentration, and anti-factor Xa activity of Asian patients with atrial fibrillation compared with non-Asians in the ENGAGE AF-TIMI 48 trial

Abstract

Aims Prior studies suggested that the risks of ischaemic stroke and bleeding in patients of Asian race with atrial fibrillation (AF) may be higher than that of non-Asians. In the analysis of ENGAGE AF-TIMI 48 trial, we compared clinical outcomes, edoxaban concentration, and anti-factor Xa (anti-FXa) activity, between Asian and non-Asian races. Methods and results There were 2909 patients of Asian race and 18 195 non-Asian race in the ENGAGE AF-TIMI 48 trial. The risks of thromboembolism and bleeding events were compared for Asians and non-Asians treated with warfarin. The trough levels of edoxaban concentration and anti-FXa activity were also compared and correlated with the efficacy and safety of edoxaban vs. warfarin. Compared to non-Asian patients, the Asian population was on average 2 years younger and 20 kg lighter. In the warfarin group, the adjusted risk of ischaemic stroke did not differ significantly for patients of Asian and non-Asian race [adjusted hazard ratio (aHR) = 1.12, P = 0.56). Asians treated with warfarin had a higher-adjusted risk of intracranial haemorrhage (ICH: aHR 1.71, P = 0.03) compared with non-Asians. The trough edoxaban concentration and anti-FXa activity were 20–25% lower for Asians compared with non-Asians. Compared to warfarin, higher dose edoxaban significantly reduced ICH while preserving the efficacy of stroke prevention in both Asians and non-Asians. Two of three net clinical outcomes appeared to be more favourably reduced with edoxaban in Asians compared with non-Asians (P int = 0.063 for primary, 0.037 for secondary, and 0.032 for third net clinical outcomes, respectively). Conclusion Compared to warfarin, higher dose edoxaban preserved the efficacy for stroke prevention and was associated with a favourable safety profile for Asians, which may be due to the lower trough edoxaban concentration and anti-FXa activity achieved in patients of Asian race.

The East Asian Paradox: An Updated Position Statement on the Challenges to the Current Antithrombotic Strategy in Patients with Cardiovascular Disease

“…Most antithrombotic agents have enhanced pharmacokinetic and pharmacodynamic profiles in East Asian versus Caucasian subjects, except for clopidogrel and edoxaban. [2][3][4]30 Achieving optimal balance between ischemic and bleeding risks in CVD patients is fundamental to determine whether one specific dose of antithrombotic agent can be administered as standard treatment. Considering the different thresholds between ischemic and bleeding risks, the therapeutic range of antithrombotic agents may be different between East Asians and Caucasians.…”

“…1). 3,30 The active metabolites of dabigatran and rivaroxaban were approximately 20 to 30% higher in Japanese versus Caucasians. 55,56 Apixaban shows a similar plasma concentration among Japanese and Caucasians.…”

“…Routine application of short-term dual antiplatelet therapy (DAPT) and addition of proton pump inhibitor (PPI) after percutaneous coronary intervention (PCI) can be typical examples. (Adapted from Levine et al 2 , Huo et al 4 , and Chao et al 30 . )…”

Effectiveness and Safety of Oral Anticoagulants in Older Patients With Atrial Fibrillation: A Systematic Review and Meta-Analysis

“…However, results from Asian studies cannot always be automatically generalized to other populations. For example, Asian AF patients seem to have higher stroke rates (especially haemorrhagic stroke) than Caucasian AF patients, and are also more prone to warfarin-related major bleeding events, especially intracranial bleeding (Hori et al, 2013;Chiang et al, 2014;Chao et al, 2019). Japanese guidelines therefore recommend a target INR of 1.6-2.6 in AF patients ≥70 years old [instead of 2.0-3.0 in Western countries] (Hori et al, 2012;Group JCSJW, 2014;Steffel et al, 2018).…”

“…Japanese guidelines therefore recommend a target INR of 1.6-2.6 in AF patients ≥70 years old [instead of 2.0-3.0 in Western countries] (Hori et al, 2012;Group JCSJW, 2014;Steffel et al, 2018). Moreover, the mean TTR in warfarin-treated Asian patients tends to be lower than in Caucasian patients (Chiang et al, 2014;Piccini et al, 2014;Chao et al, 2019). Due to these underlying ethnic differences, NOACs tend to have a better effectiveness and safety than VKAs in Asian patients.…”