Comparison of non-vitamin K antagonist oral anticoagulants and warfarin on clinical outcomes in atrial fibrillation patients with renal dysfunction

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1 Europace (2015) 17, ii69 ii75 doi: /europace/euv198 SUPPLEMENT: CLINICAL RESEARCH Comparison of non-vitamin K antagonist oral anticoagulants and warfarin on clinical outcomes in atrial fibrillation patients with renal dysfunction Ki Hong Lee 1, Hyung Wook Park 1 *, Jeong Gwan Cho 1, Nam Sik Yoon 1, Sung Soo Kim 1, Mi Ran Kim 2, Min Chul Kim 1, Kyung Hoon Cho 1, Hyun Kuk Kim 1, Cheol Hwan Kim 1, Kyung Hwan Kim 1, Seung Jin Jun 1,WooJinKim 1, Kyoung Jin Lee 1, Hae Chang Jeong 1, Jae Yeong Cho 1, Keun-Ho Park 1,DoosunSim 1,HyunJuYoon 1,KyeHunKim 1, Young Joon Hong 1, Ju Han Kim 1, Youngkeun Ahn 1, Myung Ho Jeong 1,and Jong Chun Park 1 1 The Heart Center of Chonnam National University Hospital, 42 Jaebongro, Dong-gu, Gwangju , South Korea; and 2 Chunnam Techno University, Chonnam, South Korea Received 3 March 2015; accepted after revision 11 May 2015 Aims We aimed to compare the efficacy and safety between non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin in atrial fibrillation (AF) patients according to renal dysfunction.... Methods and We analysed 1319 patients who had been taken oral anticoagulants. They were classified into patients taking NOACs results (n ¼ 326) and warfarin (n ¼ 993). Renal dysfunction was defined as the estimated glomerular filtration rate,60 ml/ min by using the Chronic Kidney Disease Epidemiology Collaboration equation. The composite clinical outcomes were defined as the composite of death, hospitalization, and new-onset strokes. Safety outcomes were composed of major and minor bleeding. Subgroup analyses for clinical and safety outcomes were performed according to renal dysfunction during median 596 ( ) follow-up days. The prevalence of renal dysfunction was similar between the two groups. The incidences of death, hospitalization, and strokes were not different between the two groups. However, the incidences of major bleeding was significantly higher in patients taking warfarin. In the subgroup analysis with renal dysfunction, the use of NOACs significantly improved the composite clinical outcomes (adjusted hazard ratio, HR, 0.30, 95% confidence interval, CI, , interaction P ¼ 0.018) and major bleeding (adjusted HR 0.18, 95% CI , interaction P ¼ 0.199) even after the covariate adjustment. However, in patients without renal dysfunction, there were no differences in the incidences of the composite clinical outcomes between the two groups.... Conclusions The benefit of NOACs was more prominent in AF patients with renal dysfunction than without renal dysfunction. These results suggest that NOACs as the first choice oral anticoagulant in AF patients with renal dysfunction Keywords Atrial fibrillation Anticoagulation Chronic kidney disease Prognosis Safety Warfarin Introduction Impaired renal dysfunction has been an important prognostic factor affecting the clinical outcomes and occurrences of strokes in patients with atrial fibrillation (AF). 1 Oral anticoagulation agents are highly recommended to prevent strokes or systemic embolisms in patients with AF. 2 However, the co-existence of renal dysfunction increases the chance of major bleeding. 3 In particular, Asians are prone to bleeding when they are treated with warfarin, 4 7 and as such non-vitamin K antagonist oral anticoagulants (NOACs) have emerged as potential alternatives to warfarin to prevent strokes and reduce the risk for fatal bleeding in patients with AF. 2 Nonvitamin K antagonist oral anticoagulants have demonstrated a similar efficacy for reducing the risks of strokes or systemic embolisms, and * Corresponding author. Tel: ; fax: , address: mdhwp@chol.com Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com.

2 ii70 K.H. Lee et al. What s new? Non-vitamin K antagonist oral anticoagulants had comparable efficacy for reducing the risk of new-onset strokes compared with warfarin regardless of renal dysfunction. Non-vitamin K antagonist oral anticoagulants significantly improved the composite clinical outcomes compared with warfarin in patients with renal dysfunction. Safety outcomes including major bleeding were improved with NOACs regardless of renal dysfunction. have significantly lowered the risk of major bleeding. In addition, they provide a further convenience in that there is no need for dose adjustment, as is the case with the international normalized ratio (INR). However, there have been few reports comparing the efficacy and safety between warfarin and NOACs in patients with AF and renal dysfunction. Also, some concerns about the higher incidence of myocardial infarction (MI) have been expressed with the use of NOACs. 8 In this study, we aim to compare both clinical outcomes (death, hospitalization, new-onset strokes, and MIs) and safety outcomes (major or minor bleeding) between NOACs and warfarin according to the presence of renal dysfunction in patients with AF. Methods Study population We analysed 1319 AF patients ( years old, 857 males) who had been taking oral anticoagulants to prevent thromboembolisms from January 2011 to December 2012 at Chonnam National University Hospital, in Gwangju, South Korea. All patients had a CHA 2 DS 2 -VASc score.2 and received anticoagulants according to current guidelines. 2 Warfarin was used in 993 patients (75.3%), dabigatran was used in 267 patients (20.2%), and rivaroxaban was used in 59 patients (4.5%). These patients were classified as patients taking NOACs (n ¼ 326) and those taking warfarin (n ¼ 993). Clinical outcomes were evaluated after initiation of NOACs. Warfarin was adjusted to an INR of , and the dabigatran or rivaroxaban dosage was adjusted according to the estimated glomerular filtration rate (egfr) based on current guidelines. 2 Clinical outcomes were analysed after a median 596 ( ) days follow-up. All patients were followed up at least 1 year from the date of enrolment. Definition The composite clinical outcomes were defined as the composite of death, hospitalization, and new-onset strokes. Myocardial infarction was defined as symptoms including new electrocardiographic changes compatible with MI or cardiac markers at least twice the upper limit of normal, and were analysed separately from the composite clinical outcomes. Safety outcomes were the composite of major and minor bleeding, with major bleeding being defined according to International Society on Thrombosis and Haemostasis criteria, as clinically overt bleeding accompanied by a 2 g/dl decrease in the haemoglobin level or a transfusion of at least 2 units of packed red cells, occurring at a critical site or resulting in death. Minor bleeding was defined as clinically overt bleeding that did not meet major bleeding criteria. Renal dysfunction was defined as an egfr, 60 ml/min obtained by using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. 9 Hospitalization was defined as any heart failure-related admission. Newonset heart failure was defined as newly developed New York Heart Association class III/IV dyspnoea, orthopnoea, rales in greater than one-third lung fields, elevated jugular venous pressure, or pulmonary congestion in chest X-rays thought to be related to cardiac dysfunction. Statistical analysis For continuous variables, differences between groups were evaluated using an unpaired t-test or Mann Whitney rank-sum test. For discrete variables, differences were expressed as counts and percentages, and were analysed using a x 2 test or Fisher s exact test between groups, as appropriate. We constructed Kaplan Meier curves for clinical and safety outcomes, and differences among the groups were assessed using a log-rank test. As estimates for the clinical and safety outcomes, a Cox proportional hazards regression was used to analyse the hazard ratios (HRs). We controlled for baseline clinical characteristics and CHA 2 DS 2 - VASc score in the regression analysis. All variables considered potentiallyrelevantwereincluded:age,sex,hypertension, diabetes mellitus, dyslipidaemia, smoking, previous history of MI, heart failure, stroke or transient ischaemic attack (TIA), ventricular ejection fraction, and CHA 2 DS 2 -VASc score. Subgroup analyses for the clinical or safety outcomes were performed according to the presence of renal dysfunction. All statistical analyses were performed using SPSS 18.0 (Statistical Package for the Social Sciences, SPSS-PC Inc., Chicago, IL, USA). All analyses were two tailed, with clinical significance defined as values of P, Results Baseline clinical characteristics There were no differences between patients using warfarin or NOACs, and the median value of creatinine clearance was 83.2 ( ) ml/min. The prevalence of renal dysfunction was similar between the two groups (18.2 vs. 17.1%, P ¼ 0.675). Patients using NOACs were older, had a higher incidence of hypertension, and a previous history of heart failure and stroke. However, the incidence of diabetes mellitus and previous history of MI were similar between the two groups. Note also that there was no difference in the left ventricular ejection fraction between the two groups (Table 1). The CHA 2 DS 2 -VASc score was higher in patients using NOACs ( vs , P, 0.001). Clinical and safety outcomes according to renal dysfunction In all patients regardless of renal dysfunction, there were no difference in the incidences of MI between the two groups (0.8 vs. 0%, P ¼ 0.212). Furthermore, in the subgroup analysis according to renal dysfunction, there was no difference between the two groups in patients with renal dysfunction (1.2 vs. 0%, P ¼ 1.000) and without renal dysfunction (0.8 vs. 0%, P ¼ 0.346). In all patients regardless of renal dysfunction, there were no differences in the incidences of death, hospitalization, new-onset strokes between the two groups; the composite clinical outcomes were also similar (Table 2). The Kaplan Meier estimation further revealed that the cumulative incidence of new-onset strokes (log-rank P ¼ 0.881, Figure 1A) and the composite clinical outcomes (log-rank P ¼ 0.129, Figure 2A) were similar between the patients taking warfarin and the patients taking NOACs. However, the incidences

3 Renal dysfuction and anticoagulation in AF ii71 Table 1 Baseline characteristics Patients taking warfarin (n 5 993) Patients taking NOACs (n 5 326) P-value... Female, n (%) a 654 (65.9) 203 (62.3) Age (years) b , years old 711 (71.6) 262 (80.4) years old 356 (35.9) 145 (44.5) Medical history, n (%) a Hypertension 517 (52.1) 229 (70.2),0.001 Diabetes mellitus 213 (21.5) 82 (25.2) Smoking 267 (26.9) 58 (17.8) Previous history of MI 58 (5.8) 15 (4.6) Previous history of HF 91 (9.2) 46 (14.1) Previous history of TIA, stroke 320 (32.2) 215 (66.0),0.001 Echocardiographic findings Ejection fraction (%) b 63.2 ( ) 63.0 ( ) EF 45%, n (%) 69 (8.2) 23 (8.0) EF 35%, n (%) 32 (3.8) 8 (2.8) Laboratory findings Hs-CRP (mg/dl) b 0.2 ( ) 0.3 ( ),0.001 NT-proBNP (pg/ml) b ( ) ( ),0.001 Creatinine (mg/dl) 0.9 ( ) 0.9 ( ) CCl (ml/min) c 83.8 ( ) 82.1 ( ) CCl, creatinine clearance; EF, left ventricular ejection fraction; HF, heart failure; Hs-CRP, high sensitivity C-reactive protein; MI, myocardial infarction; MR, mitral regurgitation; NOACS, non-vitamin K antagonist oral anticoagulants; NT-proBNP, N-terminal pro-b-type natriuretic peptide; TIA, transient ischaemic attack. a Comparison made using x 2 test. b Median (25th 75th percentiles); comparison made using Mann Whitney test. c Mean (SD); comparison made using t-test. Table 2 Clinical and safety outcomes according to renal dysfunction All patients With renal dysfunction No renal dysfunction (egfr < 60 ml/min) (egfr 60 ml/min) warfarin NOACs P warfarin NOACs P warfarin NOACs P (n 5 993) (n 5 326) (n 5 174) (n 5 59) (n 5 789) (n 5 266)... Clinical outcomes Cardiac death 13 (1.3) 3 (0.9) (2.9) (1.0) 3 (1.1) Non-cardiac death 27 (2.7) 3 (0.9) (5.7) 2 (3.4) (2.2) 1 (0.4) Total death 40 (4.0) 6 (1.8) (8.6) 2 (3.4) (3.2) 4 (1.5) Hospitalization Any HF-related admission 47 (4.7) 12 (3.7) (13.8) 3 (5.1) (2.9) 9 (3.4) HF due to cardiac dysfunction 40 (4.0) 12 (3.7) (12.1) 3 (5.1) (2.4) 9 (3.4) New-onset strokes 41 (4.1) 14 (4.3) (5.7) 3 (5.1) (3.9) 11 (4.1) Composite clinical outcomes Any HF-related admission 111 (11.2) 28 (8.6) (23.6) 6 (10.2) (8.9) 22 (8.3) HF due to cardiac dysfunction 105 (10.6) 28 (8.6) (22.4) 6 (10.2) (8.4) 22 (8.3) Safety outcomes Major bleeding 124 (12.5) 11 (3.4), (21.3) 4 (6.8) (11.0) 7 (2.6),0.001 Minor bleeding 161 (16.2) 13 (4.0), (19.5) 2 (3.4) (15.6) 11 (4.1),0.001 Any bleeding 260 (26.2) 23 (7.1), (36.8) 6 (10.2), (24.3) 17 (6.4),0.001 egfr, estimated glomerular filtration rate; HF, heart failure; MI, myocardial infarction; NOACs, non-vitamin K antagonist oral anticoagulants; Pts, patients.

4 ii72 K.H. Lee et al. Figure 1 Kaplan Meier estimation for new-onset strokes. Cumulative incidences of new-onset strokes in (A) all patients regardless of renal dysfunction, (B) in patients with renal dysfunction, and (C ) in patients without renal dysfunction. NOAC, non-vitamin K antagonist oral anticoagulants. Figure 2 Kaplan Meier estimation for the clinical outcomes. Cumulative incidences of composite clinical outcomes in (A) all patients regardless of renal dysfunction, (B) in patients with renal dysfunction, and (C) in patients without renal dysfunction. NOAC, non-vitamin K antagonist oral anticoagulants. of major bleeding was significantly higher in patients taking warfarin (12.5 vs. 3.4%, P, 0.001, log-rank P, 0.001, Figure 3A) (Table 2). In patients with renal dysfunction, there was no difference in the incidences of death and new-onset strokes (log-rank P ¼ 0.826, Figure 1B). However, patients taking NOACs had significantly lower composite clinical outcomes (23.6 vs. 10.2%, P ¼ 0.027, log-rank P ¼ 0.020, Figure 2B) and hospitalization rates (13.8 vs. 5.1%, P ¼ 0.039). When patients with hospitalization associated with any bleeding events were excluded, patients taking NOACs had significantly lower composite clinical outcomes (22.4 vs. 10.2%, P ¼ 0.040, log-rank P ¼ 0.029). However, hospitalization rates own to cardiac dysfunction were not different between the patients taking warfarin and NOACs. The safety outcomes (36.8 vs. 10.2%, P, 0.001) and major bleeding rates (21.3 vs. 6.8%, P ¼ 0.010, log-rank P ¼ 0.005, Figure 3B) were significantly lower in the patients taking NOACs (Table 2). In patients without renal dysfunction, there was no difference in the incidences of death, hospitalization, and new-onset strokes (log-rank P ¼ 0.864, Figure 1C), with the composite clinical outcomes also being similar between patients taking warfarin and NOACs (log-rank P ¼ 0.645, Figure 2C). However, the incidences of major bleeding were significantly higher in patients taking warfarin (11.0 vs. 2.6%, P, 0.001, log-rank P, 0.001, Figure 3C; Table 2). Adjusted clinical and safety outcomes according to renal dysfunction In all patients regardless of renal dysfunction, the multivariate analysis using the Cox regression hazard model revealed that NOACs significantly lowered the composite clinical outcomes [adjusted HR 0.58, 95% confidence interval (CI) , P ¼ 0.022], safety outcomes (adjusted HR 0.16, 95% CI , P, 0.001), and

5 Renal dysfuction and anticoagulation in AF ii73 Figure 3 Kaplan Meier estimation for the major bleeding. Cumulative incidences of major bleeding in (A) all patients regardless of renal dysfunction, (B) in patients with renal dysfunction, and (C) in patients without renal dysfunction. NOAC, non-vitamin K antagonist oral anticoagulants. Composite clinical outcomes Adjusted HR (95% CI) Renal dysfunction (+) 0.30 ( ) P value for interaction Renal dysfunction ( ) Total 0.78 ( ) 0.58 ( ) New-onset stroke Renal dysfunction (+) Renal dysfunction ( ) Total 0.78 ( ) 0.67 ( ) 0.69 ( ) Safety outcomes Renal dysfunction (+) Renal dysfunction ( ) Total 0.18 ( ) 0.15 ( ) 0.16 ( ) Favour NOACs Favour warfarin Figure 4 Adjusted subgroup analysis for the composite clinical outcomes and safety outcomes according to renal dysfunction. Hazard ratios are shown on a logarithmic scale. HR, hazard ratio; NOAC, non-vitamin K antagonist oral anticoagulants. major bleeding rate (adjusted HR 0.17, 95% CI , P, 0.001). However, there was no difference in the rate of new-onset strokes, even after the covariate adjustment (Figure 4). In patients with renal dysfunction, the NOACs significantly improved the composite clinical outcomes (adjusted HR 0.30, 95% CI , P ¼ 0.013), safety outcomes (adjusted HR 0.18, 95% CI , P, 0.001), and major bleeding rate (adjusted HR 0.23, 95% CI , P ¼ 0.009). However, there was no difference in the rate of new-onset strokes, even after the covariate adjustment (Figure 4).

6 ii74 K.H. Lee et al. In patients without renal dysfunction, the use of NOACs significantly improved both the safety outcomes (adjusted HR 0.15, 95% CI , P, 0.001) and major bleeding rate (adjusted HR 0.15, 95% CI , P, 0.001) (Figure 3). However, there were no differences in the rate of new-onset strokes and composite clinical outcomes, even after the covariate adjustment (Figure 4). Discussion Renal dysfunction increases the risk of both cardiovascular disease and strokes. 1 Patients with renal dysfunction and AF are at an even greater risk for strokes. For this reason, current guidelines recommend the use of oral anticoagulants to prevent strokes or systemic thromboembolisms in high-risk patients with AF. 2 However, the effect of oral anticoagulants should be carefully monitored because they increase the risk of bleeding, and renal dysfunction itself increases the risk of major bleeding due to the altered pharmacokinetics of oral anticoagulants. 10 Numerous studies have demonstrated that Asians are especially susceptible to bleeding, 6,7 with more recent clinical trials demonstrating that the use of NOACs both significantly lowered the risk of bleeding as well as their superiority to warfarin in reducing thromboembolisms. 4,5 In the present study, we aimed to identify the different actions of warfarin and NOACs on either clinical or safety outcomes between patients with and without renal dysfunction in Asian patients with AF. The CKD-EPI equation was applied to measure the egfr; the CKD-EPI equation calculates the egfr more accurately than the Cockcroft-Gault and Modification of Diet in Renal Disease equations. 11 Consistent with previous trials, the clinical benefits for new-onset strokes were similar between warfarin and NOACs regardless of renal dysfunction. 8,12 14 In contrast to these trials, however, the present study included the composite clinical outcomes in addition to new-onset strokes in order to identify real clinical benefits. Composite clinical outcomes including death, hospitalization, and new-onset strokes were similar between all patients taking warfarin and NOACs. However, from the subgroup analysis, an important benefit of NOACs in reducing the risk of the composite clinical outcomes was not present in normal renal function but only in patients with renal dysfunction. Time event curves obtained by the Kaplan Meier estimation and Cox proportional multivariate adjustment supported the benefit of NOACs for the composite clinical outcomes in only patients with renal dysfunction. These analyses also revealed that NOACs significantly improved the safety outcomes and decreased the occurrences of major bleeding, regardless of renal dysfunction. Clinical and safety outcomes were improved as renal function decreased, and these results were consistent with previous findings. 14,15 In patients with renal dysfunction, the incidences of hospitalization were lower in patients taking NOACs compared with patients taking warfarin. Some patients with major or minor bleeding, and complaining of aggravated heart failure symptoms were included in the incidences of hospitalization because they needed both bleeding control and heart failure management. Bleeding events were definitely higher in patients taking warfarin, with patients with renal dysfunction being pre-disposed to higher bleeding risks. However, hospitalization rates own to cardiac dysfunction were not different between the patients taking NOACs and warfarin, when patients with hospitalization associated with any bleeding events were excluded. These results meant that NOACs might not have any superiority reducing hospitalization due to deterioration of heart function. There have been no reports that NOACs could reduce hospitalization or deterioration of cardiac function. Therefore, the results of the present study should not be interpreted that NOACs could reduce the risk of hospitalization. Nevertheless, patients taking NOACs had significantly lower composite clinical outcomes even after excluding hospitalization associated with any bleeding events. Patients taking NOACs had lower event rates at each component of clinical outcomes, although it did not reach statistical significance. It might be due to small sample size to make a statistical difference. Overall, the accumulation of differences in event rates contributed to make a statistical difference in the composite clinical outcomes between warfarin and NOACs in patients with renal dysfunction. Major or minor bleeding risks were greater in patients taking warfarin compared with other reported trials. 8,12,13 Notably, the higher bleeding risk in Asians was confirmed in the Japanese Rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation study, 15 the subgroup analysis in the randomized evaluation of long-term anticoagulation therapy (RE-LY) study, 7 and in the Japanese population in the RE-LY study. 16 The current study analysed Korean, as east-asia patients, which means that the bleeding complication rate might be higher than in other ethnic population. Genetic differences in warfarin sensitivity, and the fact that there are no factor V-Leiden mutations in Asians, might contribute to the higher bleeding risk in Asian patients taking warfarin. 17,18 The subgroup analysis in the RE-LY study in relation to baseline renal dysfunction reported that the relative reduction in major bleeding with dabigatran compared with warfarin was greater in patients with egfr 80 ml/min. 14 However, the study did not perform a subgroup analysis between Asians and non-asians; nevertheless, the subgroup analysis in the Japanese population in RE-LY study showed that dabigatran significantly reduced the risk of major bleeding compared with warfarin. 16 These benefits were greater than the global RE-LY study. Therefore, a greater risk reduction of bleeding when using NOACs is expected in Asians, even in patients with renal dysfunction. Nevertheless, few studies currently exist that compare NOACs and warfarin with regards to the risk reduction of major bleeding in renal dysfunction. As such, the present study is considered to add additional evidence of the benefit of NOACs in this population. Limitations Some limitations of the present study need to be addressed. First, the sample size was relatively small compared with global studies, though the sample size of NOACs was similar compared with the subgroup analysis for the Japanese population in the RE-LY study. 15 Second, the present study was analysed retrospectively, so the potential limitations include retrospective data collection with its inherent potential for missing cases and missing or miscoded data. Third, mean time in the therapeutic range (TTR) was not provided, which represents the quality of INR control. 2 Although warfarin was adjusted to an INR of , achievement of an individual TTR of.70% is recommended to ensure the best efficacy and safety. 2,19,20

7 Renal dysfuction and anticoagulation in AF ii75 Therefore, further prospective trials are needed, which include methods to obtain an optimal TTR in patients taking warfarin. Fourth, no subgroup analysis for various degrees of renal dysfunction was performed, as the sample size was too small to compare the clinical and safety outcomes among each renal dysfunction group. Conclusions Non-vitamin K antagonist oral anticoagulants displayed a comparable efficacy for reducing the risk of new-onset strokes compared with warfarin regardless of renal dysfunction. A greater risk reduction in the composite clinical outcomes with NOACs was present in patients with renal dysfunction. Overall, safety outcomes including the major bleeding rate were significantly reduced with NOACs regardless of renal dysfunction. Funding This study was supported by grants of the Korean Society of Cardiology, the Korea Centers for Disease Control and Prevention (2013-E ), and the Korean Health Technology R&D Project (HI13C1527), Ministry of Health & Welfare, Republic of Korea. Conflict of interest: none declared. References 1. Hart RG, Pearce LA, Asinger RW, Herzog CA. Warfarin in atrial fibrillation patients with moderate chronic kidney disease. J Am Soc Nephrol 2011;6: Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH et al focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Europace 2012;14: Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel userfriendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. 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