Regional differences in clinical outcomes in patients of asian race with atrial fibrillation randomized to direct oral anticoagulants vs warfarin: a patient-level meta-analyses from COMBINE AF

A previous report from the COMBINE AF database (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation), which includes data from RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF-TIMI 48, demonstrated that the advantages of direct oral anticoagulants (DOACs) over warfarin were more evident in Asian patients with atrial fibrillation (AF) than in non-Asians. However, Asia is a vast region, and randomized data comparing clinical outcomes among AF patients of Asian race across different regions within Asia remain limited.

Using the COMBINE AF database, we performed an individual patient-level meta-analysis to compare clinical outcomes in patients of Asian race from 4 regions: East Asia (China, Hong Kong, Taiwan), Northeast (NE) Asia (Japan, South Korea), Southeast (SE) Asia (Malaysia, Philippines, Singapore, Thailand) and South Asia (India).

There were 9,943 pts (64% males) of Asian race enrolled from 4 Asian regions (East: 3,388, NE: 2,751, SE: 1,673, South: 2,131) randomized to warfarin or DOACs. Patients in East Asia were older (median age: East 71 yrs, NE 70 yrs, SE 67, South 65; p<0.001), heavier (mean body weight: East 68.5kg, NE 65.7kg, SE 65.9kg, South 63.1kg; p<0.001) and had a higher prevalence of past history of stroke or transient ischemic attack (East 44.2%, NE 31%, SE 42%, South 31.1%; p<0.001) than those of other regions. The median times in therapeutic range with warfarin varied widely by regions in Asia (NE 62.5%, SE 60.1%, East 57.1%, South 48.6%; p<0.001). Compared to East Asia, regional differences for several clinical outcomes were observed (Fig 1). NE Asia had a lower risk of stroke/systemic embolic events (SEE)(adjusted hazard ratio [aHR] 0.70), ischemic stroke (0.73), intracranial hemorrhage (ICH)(0.62) and net clinical outcome (NCO: stroke/SEE, major bleeding [MB], or death)(0.79) compared to East Asia (all p values <0.05). SE Asia had a higher risk of NCO (aHR 1.27), while South Asia had a lower risk of stroke/SEE (0.73), ischemic stroke (0.68) but a higher risk of NCO (1.57) compared to East Asia (all p values <0.05).

Compared to warfarin, standard-dose (SD) DOACs significantly reduced the risks of stroke/SEE, MB, ICH, CV death and the NCO to a similar degree across Asian regions (each Pint >0.1, Fig 2). SD DOACs significantly reduced the risk of ischemic stroke in SE and South Asia, but not in East and NE Asia (Pint 0.013). The risk of GI bleeding with SD DOAC and warfarin were similar in Asia regions, with no heterogeneity (Pint 0.13).

Although the adjusted risks of clinical events in AF patients of Asian race differed significantly between Asian regions, the reductions in stroke/SEE, MB, ICH, and CV death with SD DOACs compared to warfarin were consistent across Asian regions.