Introduction

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, which increases the risk of ischemic stroke by around 5-fold.¹ The risk of AF-associated stroke is not homogeneous and depends on patients' age and comorbidities, which could be assessed using the CHA₂DS₂-VASc score. AF-related stroke can be effectively prevented by the appropriate use of oral anticoagulants (OACs), either with warfarin or non-vitamin K antagonist oral anticoagulants (NOACs). However, the benefit of stroke risk reduction with OAC use should be carefully weighed against the increased risk of bleeding. Recent data from registry studies and randomized trials suggest that the risk of ischemic stroke and bleeding with OAC use may be different between Asian and non-Asian AF patients.

Risk of Ischemic Stroke in Asian AF Patients

In two recent large-scale cohort studies, the annual stroke risks for patients with a CHA₂DS₂-VASc score of 0 were 1.15% and 2.41% in the Taiwan and Hong Kong cohorts, respectively.^2,3 These reported stroke risks for Asians were higher than that of other registry studies which mainly enrolled Caucasians, with stroke risks ranging from 0.04% to 0.66% per year.⁴ The consistently higher risk of ischemic stroke in Asians compared to non-Asians was also noted in patients who received NOACs in the randomized trials.⁵ In the Randomized Evaluation of Long-Term Anti-coagulation Therapy (RE-LY) trial, the risks of ischemic stroke in the dabigatran arm of Asians were higher than those of non-Asians (2.05%/year versus 1.14%/year for dabigatran 110 mg BID; 1.12%/year versus 0.81%/year for dabigatran 150 mg BID).⁶ In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial, the risk of ischemic stroke was higher in East Asians than non-Asians treated with rivaroxaban (2.12%/year versus 1.59%/year) despite the mean CHA₂DS₂-VASc score being lower (4.4 versus 4.9) in Asians than non-Asians.⁷ In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, the risk of ischemic stroke in Asians was higher than that of non-Asians treated with apixaban (2.22%/year versus 0.82%/year) despite a similar CHA₂DS₂-VASc score (3.3 for Asians and 3.4 for non-Asians).⁸ Lastly, a higher risk of ischemic stroke was also observed for East Asians compared to non-East Asians treated with the lower-dose edoxaban regimen (30/15 mg QD)(2.26%/year versus 1.35%/year) in the Effective Anti-coagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) study.⁹ Although the detailed mechanism(s) behind the higher risk of ischemic stroke for Asian AF patients remained unknown, a recent study from Taiwan has demonstrated that the age threshold for an increased risk of ischemic stroke for Asians may be lower than for non-Asians.¹⁰ For Chinese patients aged 50-64 years, the annual stroke risk was 1.78%, which may exceed the threshold for OAC use for stroke prevention. The annual risk of ischemic stroke for Asian patients with AF aged <50 years was 0.53%, which was "truly low-risk" and OACs could be omitted.¹⁰ Whether resetting the age threshold at 50 years could refine current clinical risk stratification for Asian AF patients deserves further study.

Risk of Bleeding in Asian AF Patients with Oral Anticoagulants

Serial evidence has suggested that the risk of bleeding with OAC use was higher for Asians than non-Asians. In a retrospective cohort study of warfarin-treated AF patients, the hazard ratio for intracranial hemorrhage (ICH) in Asians was 4.06 compared with Caucasians.¹¹ The consistently higher risk of bleeding in Asians compared to non-Asians was noted in patients who received warfarin and NOACs in the randomized trials. In the warfarin arms of the RE-LY, ROCKET-AF, and ARISTOTLE trials, the time in the therapeutic range (TTR) was generally lower in Asians compared to non-Asians. Asian patients spent more time with an international normalized ratio (INR) <2.0, and less time with an INR >3.0.⁵ Despite the practice of trial investigators in Asia to maintain an INR in the lower range to avoid bleeding, the annual risk of ICH was still higher in Asians than non-Asians (1.10% versus 0.71% in RE-LY; 2.46% versus 0.63% in ROCKET-AF; and 1.88% versus 0.67% in ARISTOTLE).^6-8 For patients receiving NOACs in these trials, the risks of ICH were also numerically higher for Asians than non-Asians (0.45%/year versus 0.29%/year in RE-LY (150 mg BID); 0.59%/year versus 0.49%/year in ROCKET-AF; 0.67%/year versus 0.30%/year in ARISTOTLE; 0.60%/year versus 0.37/year in ENGAGE AF-TIMI 48 (60/30 mg QD)).^6-9

NOACs Compared to Warfarin for Stroke Prevention in Asians

A recent meta-analysis which pooled data from the RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48 trials compared NOACs with warfarin in Asian (>8,000 patients) and non-Asian patients with regard to both efficacy and safety.¹² The results suggested that NOACs may be more effective and safer in Asians than in non-Asians compared to warfarin. While NOACs significantly reduced the risk of stroke/systemic embolism both in Asian and non-Asian patients, the reduction was more prominent in Asian patients than in non-Asian patients (odds ratio [OR] = 0.65 for Asians versus 0.85 for non-Asians; P interaction = 0.045). NOACs reduced major bleeding more in Asian than in non-Asian patients (OR = 0.57 for Asians versus 0.89 for non-Asian patients; P interaction = 0.004). ICH was significantly reduced in both cohorts with NOACs (OR = 0.33 for Asians versus 0.52 for non-Asian patients; P interaction = 0.059).

Conclusion

Stroke prevention in Asian AF patients is a big challenge considering a higher risk of ischemic stroke and bleeding than that of non-Asians. Compared to warfarin, NOACs provide a better choice for stroke prevention in Asians.

References

1. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983-988.
2. Siu CW, Lip GY, Lam KF, Tse HF. Risk of stroke and intracranial hemorrhage in 9727 Chinese with atrial fibrillation in Hong Kong. Heart Rhythm 2014;11:1401-8.
3. Chao TF, Liu CJ, Wang KL, et al. Using the CHA₂DS₂-VASc score for refining stroke risk stratification in 'low-risk' Asian patients with atrial fibrillation. J Am Coll Cardiol 2014;64:1658-65.
4. Nielsen PB, Chao TF. The risks of risk scores for stroke risk assessment in atrial fibrillation. Thromb Haemost 2015;113:1170-3.
5. Chiang CE, Wang KL, Lip GY. Stroke prevention in atrial fibrillation: an Asian perspective. Thromb Haemost 2014;111:789-97.
6. Hori M, Connolly SJ, Zhu J, et al. Dabigatran versus warfarin: effects on ischemic and hemorrhagic strokes and bleeding in Asians and non-Asians with atrial fibrillation. Stroke 2013;44:1891-6.
7. Wong KS, Hu DY, Oomman A, et al. Rivaroxaban for stroke prevention in East Asian patients from the ROCKET AF trial. Stroke 2014;45:1739-47.
8. Goto S, Zhu J, Liu L, et al. Efficacy and safety of apixaban compared with warfarin for stroke prevention in patients with atrial fibrillation from East Asia: a subanalysis of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial. Am Heart J 2014;168:303-9.
9. Yamashita T, Koretsune Y, Yang Y, et al. Edoxaban vs. Warfarin in East Asian Patients With Atrial Fibrillation - An ENGAGE AF-TIMI 48 Subanalysis. Circ J 2016 [Epub ahead of print].
10. Chao TF, Wang KL, Liu CJ, et al. Age Threshold for Increased Stroke Risk Among Patients With Atrial Fibrillation: A Nationwide Cohort Study From Taiwan. J Am Coll Cardiol 2015;66:1339-47.
11. Shen AY, Yao JF, Brar SS, Jorgensen MB, Chen W. Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation. J Am Coll Cardiol 2007;50:309-15.
12. Wang KL, Lip GY, Lin SJ, Chiang CE. Non-Vitamin K Antagonist Oral Anticoagulants for Stroke Prevention in Asian Patients With Nonvalvular Atrial Fibrillation: Meta-Analysis. Stroke 2015;46:2555-61.

Keywords: Anticoagulants, Asian Americans, Atrial Fibrillation, Cohort Studies, Comorbidity, Embolism, Factor Xa, Factor Xa Inhibitors, International Normalized Ratio, Intracranial Hemorrhages, Myocardial Infarction, Pyrazoles, Pyridines, Pyridones, Randomized Controlled Trials as Topic, Registries, Research Personnel, Retrospective Studies, Risk Reduction Behavior, Stroke, Thiazoles, Vitamin K, Warfarin

< Back to Listings