Stroke prevention in AF: Of Asians and non-Asians

This editorial refers to ‘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’†, by T.-F. Chao et al., on page 1518. Non-vitamin K antagonist oral anticoagulants (NOACs) have revolutionized stroke prevention in atrial fibrillation (AF). Even before completion of the first phase III NOAC trial, the expectation was that Asians would derive particular benefit from these agents. Studies in the pre-NOAC era had demonstrated a higher risk of intracerebral haemorrhage in Asian compared with non-Asian warfarin users,1 accompanied by lower efficacy for the prevention of ischaemic strokes.2 The attenuated benefit of warfarin for ischaemic stroke prevention in Asians appeared to be explained by a lower time in therapeutic range (TTR), as well as a higher propensity for Asians to experience non-cardioembolic strokes, which are less responsive to warfarin than cardioembolic strokes. The four large phase III trials comparing NOACs with warfarin for stroke prevention in atrial fibrillation collectively involved >8600 Asian patients. As expected, the rates of both intracranial haemorrhage and ischaemic stroke were higher in Asian compared with non-Asian patients treated with warfarin (Figure 1).3–5 In addition, the reduction in bleeding with NOACs—particularly intracranial haemorrhage—was at least similar if not greater in Asians, thereby confirming the anticipated greater safety advantages of these newer agents in Asian compared with non-Asian patients. Major clinical outcomes in Asian and non-Asian patients from the four large-scale randomized clinical trial comparing NOACs with VKAs for stroke prevention in AF. Data are taken from the respective subanalyses of Re-LY3, ROCKET-AF4, ARISTOTLE,5 and ENGAGE AF-TIMI 48.6 For illustrative purpose only. No head-to-head comparisons. Populations as well as endpoint definitions varied between trials. In the current issue of the European Heart Journal, Chao and colleagues provide important additional insights into the efficacy and safety of edoxaban vs. warfarin in Asian compared with non-Asian patients enrolled in the ENGAGE AF-TIMI 48 trial, focusing on the 60 mg once daily dose of edoxaban (reduced to 30 mg in those with estimated creatinine clearance 30–50 mL/min, body weight ≤60 kg, or requiring concomitant use of verapamil, quinidine, or dronedarone) that is approved for clinical use.6 Unlike a previous analysis from the ENGAGE investigators, which classified patients as Asians according to the country in which they were recruited,7 Chao et al. classified patients as Asians (n = 2909) based on ethnicity, independent of their place of residence. The majority (98.7%) of Asians in these analyses were from the Asia-Pacific region and South Africa. Compared with non-Asians, Asians were more likely to have impaired renal function [936 (32.2%) vs. 3036 (16.7%)] and had markedly lower body weight (66.4 ± 13.1 kg vs. 86.7 ± 19.7 kg). After adjusting for these and other baseline differences, event rates during warfarin treatment in Asian compared with non-Asian patients were not significantly different for stroke or systemic embolism [adjusted hazard ratio (aHR) 1.30, 95% confidence interval (CI) 0.95–1.78; P = 0.096], ischaemic stroke (a HR 1.12; 95% CI 0.77–1.64; P = 0.56), and major bleeding (aHR 1.26; 95% CI 0.96–1.66; P = 0.096) (although in each case they were numerically higher in Asians), and significantly higher for intracranial haemorrhage (a HR 1.71; 95% CI 1.05–2.77; P = 0.03). Comparing the effects of edoxaban treatment in Asians vs. non-Asians, there were no interactions for the primary efficacy and safety endpoints, whereas significant interactions were evident for the pre-defined net clinical outcomes, suggesting a greater overall benefit of edoxaban in Asians. The authors also report edoxaban trough plasma levels according to ethnicity and edoxaban dose. Despite a higher prevalence of kidney dysfunction and lower body weights, Asians had lower drug levels than non-Asians, even after accounting for more frequent protocol-mandated dose reductions. The authors suggest that this may be explained by younger age and less frequent use of amiodarone (a P-glycoprotein inhibitor known to increase edoxaban plasma levels).8 Despite lower plasma levels, however, there was a consistent pattern of more bleeding in Asians compared with non-Asians, irrespective of treatment allocation. The only exception was gastrointestinal bleeding which was more common in non-Asians. The explanation for higher rates of bleeding despite lower drug levels is revealed by examining the risk of bleeding events according to plasma level. In Asians, there was a steep increase in major and intracranial bleeding with increasing trough edoxaban levels, whereas in non-Asians there was a less steep increase in major bleeding and no increase in intracranial bleeding with increasing trough edoxaban levels. In both Asians and non-Asians, ischaemic stroke was progressively lower with increasing trough edoxaban levels, but for the primary endpoint of stroke and systemic embolism (which includes both ischaemic and haemorrhagic stroke) this was counterbalanced in Asians by the increase in intracranial bleeding, so that the event rates for the combined endpoint were essentially independent of edoxaban trough concentration. The results of Chao and colleagues demonstrating consistent effects of edoxaban compared with warfarin for stroke or systemic embolism and major bleeding in Asians compared with non-Asians are consistent with an earlier report from the ENGAGE investigators that classified Asians according to the country of enrolment (Japan, China, Taiwan, and South Korea; n total = 1943).7 Building on these findings, they have now confirmed an overall net benefit in a larger population of Asians defined by ethnicity, and have demonstrated that Asians are more likely than their non-Asian counterparts to experience bleeding at a given concentration of edoxaban, particularly at higher edoxaban concentrations. What are the implications of these data for clinical practice? The results of the ENGAGE TIMI-48 study comparing edoxaban with warfarin in Asian patients with atrial fibrillation add to a growing body of evidence supporting the preferential use of NOACs in Asian patients. Trials comparing a NOAC with warfarin have consistently shown safety advantages of the NOACs, and this is even more evident in the Asian population. The quality of international normalized ratio (INR) control in Asian patients enrolled in the trials was inferior to that achieved in non-Asians and, because the TTR in community practice is consistently even lower than in trials,9 even greater benefits can be expected as these agents are more widely used. The 2016 European Society of Cardiology Guidelines recommend an NOAC over a vitamin K antagonist in patients newly started on anticoagulation (class I recommendation, level of evidence A).10 An impediment to their uptake in some Asian countries may be the cost of NOACs, but this will soon be less of a concern as these agents lose patent protection. The potential of NOACs to reduce morbidity and mortality11 , 12 in Asians is enormous, not only because of poor INR control in those presently treated with warfarin, but also because of the large number of patients with AF that are currently untreated. While we enthusiastically endorse the uptake of NOACs, it is important to remember that NOACs are not ‘fill and forget’ medication; great care needs to be taken in the proper usage and avoidance of pitfalls.13 Safe uptake of NOACs requires education on all levels, including specialists, general practitioners, nurses, and patients. Investment in this initiative is critical to expand the success story of NOACs to Asian populations. Conflict of interest: J.S. has received consultant and/or speaker fees from Abbott, Amgen, Astra-Zeneca, Atricure, Bayer, Biosense Webster, Biotronik, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Medscape, Medtronic, Merck/MSD, Novartis, Pfizer, Sanofi-Aventis, WebMD, and Zoll. He reports ownership of CorXL. He has received grant support through his institution from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, Daiichi Sankyo, and Medtronic. J.W.E. has received honoraria and grant support from Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol-Myers-Squibb/Pfizer, Daiichi Sankyo, Glaxo Smith Kline, Janssen, Sanofi-Aventis, and Eli Lilly, as well as a personnel award from the Heart and Stroke Foundation.

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