Target Intensity of Anticoagulation With Warfarin in Japanese Patients With Valvular Atrial Fibrillation

– Subanalysis of the J-RHYTHM Registry –

Abstract

Background: Warfarin is widely used for prevention of thromboembolism in patients with valvular atrial fibrillation (AF), and an international normalized ratio (INR) of prothrombin time between 2.0 and 3.0 is recommended. Optimal intensity of anticoagulation with warfarin in Japanese patients with valvular AF, however, has not been clarified thoroughly as yet.

Methods and Results: We evaluated the status of anti-thrombotic therapy and incidence rates of events in 410 patients with mitral stenosis and/or mechanical valve replacement (valvular AF) among 7,816 patients with AF followed in the J-RHYTHM Registry. Patients were divided into 5 groups based on INR (<1.6, 1.6–1.99, 2.0–2.59, 2.6–2.99, and ≥3.0) at the time of event or at the end of follow-up in order to determine the target INR for patients with valvular AF. Warfarin was prescribed in 407 (99.3%) of valvular AF patients. During a 2-year follow-up period, thromboembolism and major hemorrhage occurred in 12 (2.9%) and in 15 (3.7%) patients, respectively. Among patients receiving warfarin, 2-year incidence rates of thromboembolism were 10.3%, 1.6%, 0.6%, 3.0%, and 0.0% (P=0.003 for trend), and those of major hemorrhage were 1.5%, 1.6%, 3.2%, 6.1%, and 21.1% (P<0.001 for trend), respectively.

Conclusions: INR between 1.6 and 2.6 could be optimal to prevent thromboembolism without increasing major hemorrhage in Japanese patients with valvular AF. INR 2.6–2.99 would also be effective, but is associated with a modestly increased risk of major hemorrhage.

Valvular heart disease is an underlying etiology of atrial fibrillation (AF). Prosthetic heart valve replacement is performed in approximately 300,000 patients each year worldwide.¹ Although mechanical valves are more durable than bioprosthetic valves,² mechanical prostheses present a persistent risk of thromboembolic complications. Therefore, lifelong anticoagulation therapy is required to prevent the development of valve thrombosis, stroke, and systemic embolism in patients with mechanical valve replacement. Given that AF is also a risk of cardiogenic ischemic stroke,^3,4 patients with AF who undergo valve replacement should be considered at higher risk for thromboembolic complications.

Editorial p ???

Vitamin K antagonists (VKA) are the only oral anticoagulant approved for long-term treatment of patients with valve replacement. The use of VKA has shown excellent protection against thromboembolic events in patients with mechanical heart valves.⁵ Warfarin is the VKA available in Japan, and currently used most frequently worldwide in patients with valvular AF; an international normalized ratio (INR) of prothrombin time between 2.0 and 3.0 is recommended for these patients.^6–8 The optimal intensity of anticoagulation with warfarin in Japanese patients with valvular AF, however, was still unclear.

The aim of this study was therefore to investigate the present status of anticoagulation therapy in clinical practice and the optimal intensity of anticoagulation with warfarin in patients with valvular AF in the present, post-hoc analysis of the J-RHYTHM Registry.⁹

Methods

Study Design

The J-RHYTHM Registry was a prospective, observational nationwide study conducted by the Japanese Society of Electrocardiology. The details of study design and overall subject baseline characteristics have been reported elsewhere.^9,10 Briefly, subjects consisted of a consecutive series of outpatients with AF of any type, regardless of the use of anticoagulants. Anti-thrombotic drugs and dosages were selected at the discretion of treating cardiologists.

Definition of Valvular AF

Valvular AF has been defined as AF in patients with rheumatic valvular diseases (predominantly mitral stenosis) or prosthetic heart valves;⁸ in the present study, however, it was defined as AF in patients with mitral stenosis or mechanical heart valve replacement according to the 2008 Guidelines for Pharmacotherapy of Atrial Fibrillation of the Japanese Circulation Society.⁷ Patients with bioprosthetic valve replacement for treatment of valvular diseases other than mitral stenosis were defined as having non-valvular AF.

Follow-up and Definition of Endpoints

The patients were followed for 2 years or until a defined endpoint, whichever occurred first. The thromboembolic endpoints consisted of symptomatic stroke, transient ischemic attack, and systemic embolism. Major hemorrhage including intracranial hemorrhage, gastrointestinal bleeding, and others requiring hospitalization were selected as the safety endpoints. All-cause death and cardiovascular death were also identified. If any event occurred during the follow-up period, it was mandatory that the final clinical data, including INR at the time closest to the event, be collected.⁹ The diagnostic criteria for each event have been described previously.^9,10

Statistical Analysis

Data are presented as mean±SD. Patients receiving warfarin were divided into subgroups according to INR (<1.6, 1.6–1.99, 2.0–2.59, 2.6–2.99, and ≥3.0) or time in therapeutic range (TTR).¹¹ Statistical significance of differences in the means was analyzed using Student’s t-test or ANOVA as appropriate. Frequencies of parameters or events were compared with chi-squared test or Fisher’s exact test as appropriate. Odds ratios (ORs) were calculated with multivariate logistic regression analysis using the group with INR for which the combined event rate (thromboembolism plus major hemorrhage) was the lowest as a reference. CHADS₂ score (1 point each for the presence of congestive heart failure, hypertension, age 75 years or older, and diabetes mellitus and 2 points for history of stroke or transient ischemic attack) was included as an explanatory variable in the multivariate logistic regression analysis to determine OR. P<0.05 was considered to be statistically significant. All statistical analysis was done with SPSS version 15.0 (SPSS Inc, Chicago, IL, USA).

Results

A total of 7,937 patients with AF were enrolled in the J-RHYTHM Registry.¹⁰ Of these, 421 (5.3%) had valvular AF (274 with mitral stenosis, 214 with mechanical valves, and 67 with both). Eleven (2.6%) of 421 patients with valvular AF and 110 (1.5%) of 7,516 patients with non-valvular AF¹² were lost to follow-up. Therefore, 410 patients with valvular AF (269 with mitral stenosis including 66 after replacement with mechanical valves and 6 with bioprosthetic valves, and 141 with mechanical valve replacement for treatment of valvular diseases other than mitral stenosis) constituted the study group for subsequent analyses.

Baseline Characteristics and the Status of Anti-Thrombotic Therapy

Prevalence of female gender, permanent AF and heart failure, and mean CHADS₂ score were higher in patients with valvular AF than in those with non-valvular AF. In contrast, prevalence of hypertension, coronary artery disease, and cardiomyopathy was lower in patients with valvular AF than in those with non-valvular AF (Table 1). In the valvular AF group, only 3 (0.7%) were not taking warfarin at the time of enrollment; the rate of warfarin treatment was higher in valvular AF than in non-valvular AF (Table 2). In patients with valvular AF receiving warfarin, 47.9% had INR 2.0–3.0 but 46.9% had INR <2.0 at the time of enrollment. Mean INR was slightly but significantly higher in the valvular AF than in the non-valvular AF group at the time of enrollment, whereas daily warfarin dosage was not different between the valvular and non-valvular AF groups (Table 2).

Table 1. Baseline Patient Characteristics

	Overall	Valvular	Non-valvular	P-value†
No. patients	7,816	410 (5.2)	7,406 (94.8)
Age (years)	69.7±9.9 (19–116)	69.6±8.4 (28–90)	69.8±10.0 (19–116)	0.691
Male	5,382 (68.9)	141 (34.4)	5,241 (70.8)	<0.001
Type of AF
Paroxysmal	2,900 (37.1)	65 (15.9)	2,835 (38.3)	<0.001
Persistent	1,129 (14.4)	48 (11.7)	1,081 (14.6)
Permanent	3,787 (48.5)	297 (72.4)	3,490 (47.1)
Comorbidity
Hypertension	4,634 (59.3)	157 (38.3)	4,477 (60.5)	<0.001
Coronary artery disease	797 (10.2)	16 (3.9)	781 (10.5)	<0.001
Cardiomyopathy	643 (8.2)	9 (2.2)	634 (8.6)	0.003
HCM	266 (3.4)	2 (0.5)	264 (3.6)	0.001
DCM	377 (4.8)	7 (1.7)	370 (5.0)	0.004
Congenital heart disease	98 (1.3)	2 (0.5)	96 (1.3)	0.229
COPD	136 (1.7)	5 (1.2)	131 (1.8)	0.526
Hyperthyroidism	135 (1.7)	4 (1.0)	131 (1.8)	0.315
CHADS2 score
0	1,214 (15.5)	47 (11.5)	1,167 (15.8)	<0.001
1	2,658 (34.0)	111 (27.1)	2,547 (34.4)
2	2,174 (27.8)	134 (32.7)	2,040 (27.5)
3	1,131 (14.5)	82 (20.0)	1,049 (14.2)
4	452 (5.8)	29 (7.1)	423 (5.7)
5	160 (2.0)	6 (1.5)	154 (2.1)
6	27 (0.3)	1 (0.2)	26 (0.4)
Mean score	1.7±1.2	1.9±1.2	1.7±1.2	0.001
Risk factors for stroke
Heart failure	2,343 (30.0)	288 (70.2)	2,055 (27.7)	<0.001
Hypertension	4,634 (59.3)	157 (38.3)	4,477 (60.5)	<0.001
Age (≥75 years)	2,580 (33.0)	123 (30.0)	2,457 (33.2)	0.202
Diabetes mellitus	1,426 (18.2)	67 (16.3)	1,359 (18.3)	0.337
Stroke/TIA	1,093 (14.0)	71 (17.3)	1,022 (13.8)	0.054
Heart rate (beats/min)	72.5±13.2	73.3±13.1	72.5±13.2	0.232
SBP (mmHg)	125.8±16.2	121.9±15.5	126.0±16.2	<0.001
DBP (mmHg)	73.3±16.7	68.5±10.8	73.5±17.0	<0.001

Data given as n (%), mean±SD or mean±SD (range). ^†Valvular vs. non-valvular. AF, atrial fibrillation; CHADS₂, congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and history of stroke or TIA; COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; SBP, systolic blood pressure; TIA, transient ischemic attack.

Table 2. Anti-Thrombotic Therapy at Enrollment

	Overall	Valvular	Non-valvular	P-value†
No. patients	7,816	410	7,406
Anticoagulation therapy
Warfarin	6,811 (87.1)	407 (99.3)	6,404 (86.5)	<0.001
Dosage (mg/day)	2.9±1.2	2.9±1.2	2.9±1.2	1.000
INR	1.9±0.5	2.1±0.5	1.9±0.5	<0.001
<1.6	1,728 (25.4)	58 (14.3)	1,670 (26.1)	<0.001
1.6–1.99	2,481 (36.4)	133 (32.7)	2,348 (36.7)
2.0–2.59	2,018 (29.6)	164 (40.3)	1,854 (29.0)
2.6–2.99	394 (5.8)	31 (7.6)	363 (5.7)
≥3.0	190 (2.8)	21 (5.2)	169 (2.6)
Antiplatelet therapy
Any antiplatelet	2,028 (25.9)	91 (22.2)	1,937 (26.2)	0.085
Aspirin	1,749 (22.4)	74 (18.0)	1,675 (22.6)	0.036
Others	455 (5.8)	22 (5.4)	433 (5.8)	0.767
Warfarin+antiplatelet	1,447 (18.5)	89 (21.7)	1,358 (18.3)	0.100

Data given as n (%) or mean±SD. ^†Valvular vs. non-valvular. INR, international normalized ratio.

Thromboembolic Events and Major Hemorrhage

During a 2-year follow-up period, thromboembolic events were observed in 13 (3.2%), major hemorrhage in 15 (3.7%), and all-cause death in 11 (2.7%) among 410 patients with valvular AF (Table 3). Incidence rates of thromboembolism and major hemorrhage were significantly higher in patients with valvular AF than in those with non-valvular AF (thromboembolism: 3.2% vs. 1.7%, P=0.046; major hemorrhage: 3.7% vs. 1.9%, P=0.022).¹² This was also true when the analysis was confined to patients receiving warfarin at baseline, both rates were also significantly higher in patients with valvular AF than in those with non-valvular AF (thromboembolism: 2.9% vs. 1.5%, P<0.001; major hemorrhage: 3.7% vs. 2.1%, P=0.039).¹² All-cause mortality was similar between patients with valvular AF and those with non-valvular AF.

Table 3. Incidence Rates During 2-Year Follow-up

	Valvular AF	Non-warfarin	Warfarin
			All	INR‡					P-value†
				<1.6	1.6–1.99	2.0–2.59	2.6–2.99	≥3.0
No. patients	410	14	396	68	122	154	33	19
Thromboembolism	13 (3.2)	2 (14.3)	11 (2.8)	7 (10.3)	2 (1.6)	1 (0.6)	1 (3.0)	0 (0.0)	[0.003]
Cerebral infarction	10	2	8	6	2	0	0	0
TIA	1	0	1	0	0	1	0	0
Systemic embolism	2	0	2	1	0	0	1	0
Major hemorrhage	15 (3.7)	1 (7.1)	14 (3.5)	1 (1.5)	2 (1.6)	5 (3.2)	2 (6.1)	4 (21.1)	[<0.001]
Intracranial	5	0	5	0	0	3	0	2
Gastrointestinal	6	0	6	0	1	2	2	1
Others	4	0	3	1	1	0	0	1
Thromboembolism+major hemorrhage	28 (6.8)	3 (21.4)	25 (6.3)	8 (11.8)	4 (3.3)	6 (3.9)	3 (9.1)	4 (21.1)	0.007
All-cause death	11 (2.7)	3 (21.4)	8 (2.0)	1 (1.5)	1 (0.8)	3 (1.9)	0 (0.0)	3 (15.8)	<0.001
Cardiovascular death	6 (1.5)	2 (14.3)	4 (1.0)	1 (1.5)	1 (0.8)	0 (0.0)	0 (0.0)	2 (10.2)	<0.001

Data given as n (%). ^†Comparison among the 5 INR groups receiving warfarin (chi-squared test, [ ] for trend). ^‡At the time of event or at end of follow-up. Abbreviations as in Tables 1,2.

When the analysis was done according to the INR at the time of event or at the end of follow-up, incidence rates of both thromboembolism and major hemorrhage had an obvious association with INR (P=0.003 and P<0.001 for trend, respectively, Table 3). Rate of combined events (thromboembolism plus major hemorrhage) was lower in groups with INR 1.6–2.59 (P=0.007, Table 3).

Characteristics of patients with events are summarized in Table S1. Mean INR at the event was 3.4±2.6 in patients with major hemorrhage and 1.6±0.6 in those with thromboembolism. When the patients were divided into 5 groups according to TTR, there were no significant differences in incidence rates of either thromboembolism or major hemorrhage among the 5 groups (Table S2).

Target INR for Valvular AF

OR for each event showed a significant trend among the 5 INR groups. With INR 1.6–1.99 as the reference, INR <1.6 had a significantly higher OR for thromboembolism, while INR ≥3.0 did so for major hemorrhage (Table 4). Although statistically not significant, INR 2.6–2.99 had a 3-fold higher OR for combined events.

Table 4. ORs

	INR†					P-value
	<1.6	1.6–1.99	2.0–2.59	2.6–2.99	≥3.0
	OR (95% CI)	Reference	OR (95% CI)	OR (95% CI)	OR (95% CI)
Model 1: Crude
Thromboembolism	6.89 (1.39–34.15)	1.00	0.39 (0.04–4.38)	1.88 (0.17–21.34)	–	0.007
Major hemorrhage	0.90 (0.08–10.06)	1.00	2.01 (0.38–10.56)	3.87 (0.52–28.58)	16.00 (2.70–94.90)	0.022
Thromboembolism+major hemorrhage	3.93 (1.14–13.59)	1.00	1.20 (0.33–4.34)	2.95 (0.63–13.90)	7.87 (1.78–34.78)	0.026
All-cause death	1.81 (0.11–29.34)	1.00	2.40 (0.25–23.40)	–	22.69 (2.22–231.43)	0.039
Model 2: Adjusted by CHADS2 score
Thromboembolism	7.04 (1.41–35.13)	1.00	0.39 (0.04–4.33)	2.01 (0.18–23.10)	–	0.010
Major hemorrhage	0.90 (0.08–10.06)	1.00	2.01 (0.38–10.54)	3.90 (0.53–28.90)	15.83 (2.64–94.75)	0.042
Thromboembolism+major hemorrhage	3.95 (1.14–13.67)	1.00	1.19 (0.33–4.30)	3.06 (0.65–14.48)	7.49 (1.68–33.30)	0.031
All-cause death	1.95 (0.12–32.21)	1.00	2.43 (0.25–23.86)	–	20.40 (1.95–213.88)	0.020

^†At the time of event or at end of follow-up. CI, confidential interval; OR, odds ratio. Other abbreviations as in Tables 1,2.

Discussion

The major findings of the present study were as follows. First, patients with valvular AF (mitral stenosis and/or mechanical valves) accounted for 5% of all the patients enrolled in the J-RHYTHM Registry. Second, warfarin was prescribed in >99% of patients with valvular AF. The prevalence of target INR between 2.0 and 3.0,⁷ however, was <50%, similar to that for INR <2.0. Third, the OR for thromboembolism was significantly higher at INR <1.6, while that for major hemorrhage were higher at INR ≥3.0. The combined event rate of thromboembolism and major hemorrhage was lower at INR between 1.6 and 2.6.

Intensity of Anticoagulation and Events

In the European guidelines of the management of valvular heart disease (version 2012),¹³ an optimal INR range between 2.5 and 4.0 is recommended for patients with mechanical valves due to the combination of prosthesis thrombogenicity (bileaflet, tilting disc, etc) and patient-related risk factors. The patient-related risk factors included AF, tricuspid or mitral valve replacement, previous thromboembolism, mitral stenosis of any degree, and left ventricular dysfunction. Other investigators noted that optimal INR for patients with mechanical valve replacement was between 2.5 and 2.9, given that the lowest incidence of all events was found at INR 2.5–2.9.¹⁴ In several guidelines for management of AF including the Japanese guidelines,^6–8 however, INR 2.0–3.0 was recommended for patients with valvular AF as well as for those with non-valvular AF.

In the J-RHYTHM Registry, the prevalence of the currently recommended INR of between 2.0 and 3.0⁷ was <50% among Japanese patients with valvular AF. INR 1.6–2.6, however, was found in 73.0% of patients at the time of enrollment. Japanese guidelines recommended slightly lower INR for elderly patients (≥70 years old) with non-valvular AF:⁷ Japanese physicians and cardiologists seemed to adopt this lower INR as the target intensity, even for patients with valvular AF as well as for those with non-valvular AF.¹⁵ Shen et al demonstrated that non-Caucasian patients, especially Asian patients, with AF were at risk for intracranial hemorrhage under warfarin treatment with a target INR 2.0–3.0.¹⁶ In Japanese patients with non-valvular AF, INR ≥2.27 was an independent risk factor for major hemorrhage.¹⁷ Other Japanese investigators also found that an INR range of 1.5–2.5 appeared to be optimal after prosthetic valve replacement, regardless of AF.^18,19 Racial differences in drug response²⁰ would be similar between patients with valvular AF and with non-valvular AF. Indeed, the OR for major hemorrhage was approximately 4-fold higher for INR ≥2.6 as compared with INR 1.6–1.99 in the present study. In addition, the combined rate of thromboembolism and major hemorrhage was lower for INR between 1.6 and 2.6. Therefore, INR 1.6–2.6 may be optimal to prevent thromboembolism without increasing major hemorrhage in Japanese patients with valvular AF. INR 2.6–2.99 was also effective at preventing thromboembolism, but associated with a modestly increased risk of major hemorrhage.

In the present post-hoc analysis, INR at the time of events or at the end of the follow-up period were used; the main analysis of the J-RHYTHM Registry, however, included baseline INR for analysis.¹² This method using the baseline INR to determine target INR seemed not free from criticism,²¹ given that variation of INR and discontinuation or initiation of warfarin during the follow-up period were not taken into consideration. Therefore, the present post-hoc analysis utilized INR at the time of events or at the end of the follow-up period.

TTR is a sophisticated method for determining quality of warfarin control.¹¹ Therefore, in the present subanalysis TTR was calculated, but the results did not show a consistent trend (Table S2). Patients with TTR ≥90% had higher event rates for thromboembolism and major hemorrhage. A possible explanation for higher hemorrhagic event rate was that better quality of warfarin control at INR 2.6–2.99 could lead to higher TTR but higher risk for major hemorrhage among Japanese patients with valvular AF.¹⁷ In contrast, higher TTR but a sudden decrease in INR would lead to a thromboembolic event.²¹

Study Limitations

The present study had several limitations. First, the present study was performed in a single country and the registry was established only in 158 selected institutions in Japan. The participating physicians included cardiologists but not general practitioners: thus, the patient clinical background may not be extrapolated to Japanese patients with AF.¹⁵ Second, although this registry was large, enrolling a total of 7,937 patients with AF, the number of patients with valvular AF accounted for only 5% of the whole group. Consequently, the number of patients having events was small. This might have reduced the statistical power of the present study. Third, the study design was prospective but observational. Anti-thrombotic agents and INR for individual patients were selected at the discretion of the participating physicians. Consequently, warfarin was prescribed in 99.3% of patients at the time of enrollment. Therefore, it was difficult to analyze the non-warfarin group as a control in the present subanalysis. Fourth, 2.6% of patients were lost to follow-up in the present study, which could lead to underreporting of endpoints. Finally, there was no information about prosthesis thrombosis, type of prosthetic valve (eg, bileaflet or other types), or position of prosthetic valve. This might affect the incidence of thromboembolic events.

Conclusions

Although oral anticoagulation with warfarin was frequently used in Japanese patients with valvular AF, achieved INR was lower than the recommended guideline level of 2.0–3.0 in approximately half of the patients.^10,12 INR 1.6–2.6 may be optimal to prevent thromboembolism without increasing major hemorrhage in Japanese patients with valvular AF, as reported in elderly patients with non-valvular AF.¹² INR 2.6–2.99 is also effective at preventing thromboembolism, but is associated with a modestly increased risk of major hemorrhage.

Acknowledgments

The summary of this study was presented at the 78th Annual Scientific Meeting of the Japanese Circulation Society (Tokyo, Japan, 21 March 2014). Investigators in the J-RHYTHM Registry are listed in references.^9,10,22

Disclosures

The J-RHYTHM registry was supported by a grant from Japan Heart Foundation. Co-authors have potential conflict of interest: Dr Atarashi received research funding from Boehringer Ingelheim, and remuneration from Bayer Healthcare, Boehringer Ingelheim, and Daiichi-Sankyo; Dr Inoue received research funding from Boehringer Ingelheim and Daiichi-Sankyo, and remuneration from Daiichi-Sankyo, Bayer Healthcare, and Boehringer Ingelheim; Dr Okumura received research funding from Boehringer Ingelheim and Daiichi-Sankyo, and remuneration from Boehringer Ingelheim, Bayer Healthcare, Daiichi-Sankyo, and Pfizer; Dr Yamashita received research funding from Boehringer Ingelheim and Daiichi-Sankyo, and remuneration from Boehringer Ingelheim, Daiichi-Sankyo, Bayer Healthcare, Pfizer, Bristol-Myers Squibb, and Eisai.

Supplementary Files

Supplementary File 1

Table S1. Patient characteristics vs. presence of valvular AF and events

Table S2. Incidence rates and TTR

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-14-1057

References

• 1.    Sun  JC,  Davidson  MJ,  Lamy  A,  Eikelboom  JW. Antithrombotic management of patients with prosthetic heart valves: Current evidence and future trends. Lancet 2009; 374: 565–576.
• 2.    Stassano  P,  Di Tommaso  L,  Monaco  M,  Iorio  F,  Pepino  P,  Spampinato  N, et al. Aortic valve replacement: A prospective randomized evaluation of mechanical versus biological valves in patients ages 55 to 70 years. J Am Coll Cardiol 2009; 54: 1862–1868.
• 3.    Wolf  PA,  Abbott  RD,  Kannel  WB. Atrial fibrillation as an independent risk factor for stroke: The Framingham Study. Stroke 1991; 22: 983–988.
• 4.    Krahn  AD,  Manfreda  J,  Tate  RB,  Mathewson  FA,  Cuddy  TE. The natural history of atrial fibrillation: Incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am J Med 1995; 98: 476–484.
• 5.    Cannegieter  SC,  Rosendaal  FR,  Briet  E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation 1994; 89: 635–641.
• 6.    Fuster  V,  Ryden  LE,  Cannom  DS,  Crijns  HJ,  Curtis  AB,  Ellenbogen  KA, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006; 114: e257–e354, doi:10.1161/CIRCULATIONAHA.106.177292.
• 7.   JCS Joint Working Group. Guidelines for pharmacotherapy of atrial fibrillation (JCS 2008): Digest version. Circ J 2010; 74: 2479–2500.
• 8.    Camm  AJ,  Lip  GY,  De Caterina  R,  Savelieva  I,  Atar  D,  Hohnloser  SH, et al. 2012 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. Eur Heart J 2012; 33: 2719–2747.
• 9.    Atarashi  H,  Inoue  H,  Okumura  K,  Yamashita  T,  Origasa  H. Investigation of optimal anticoagulation strategy for stroke prevention in Japanese patients with atrial fibrillation: The J-RHYTHM Registry study design. J Cardiol 2011; 57: 95–99.
• 10.    Atarashi  H,  Inoue  H,  Okumura  K,  Yamashita  T,  Kumagai  N,  Origasa  H. Present status of anticoagulation treatment in Japanese patients with atrial fibrillation: A report from the J-RHYTHM Registry. Circ J 2011; 75: 1328–1333.
• 11.    Rosendaal  FR,  Cannegieter  SC,  van der Meer  FJ,  Briet  E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69: 236–239.
• 12.    Inoue  H,  Okumura  K,  Atarashi  H,  Yamashita  T,  Origasa  H,  Kumagai  N, et al. Target international normalized ratio values for preventing thromboembolic and hemorrhagic events in Japanese patients with non-valvular atrial fibrillation: Results of the J-RHYTHM Registry. Circ J 2013; 77: 2264–2270.
• 13.    Vahanian  A,  Alfieri  O,  Andreotti  F,  Antunes  MJ,  Baron-Esquivias  G,  Baumgartner  H, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012; 33: 2451–2496.
• 14.    Torn  M,  Cannegieter  SC,  Bollen  WL,  van der Meer  FJ,  van der Wall  EE,  Rosendaal  FR. Optimal level of oral anticoagulant therapy for the prevention of arterial thrombosis in patients with mechanical heart valve prostheses, atrial fibrillation, or myocardial infarction: A prospective study of 4202 patients. Arch Intern Med 2009; 169: 1203–1209.
• 15.    Akao  M,  Chun  YH,  Esato  M,  Abe  M,  Tsuji  H,  Wada  H, et al. Inappropriate use of oral anticoagulants for patients with atrial fibrillation. Circ J 2014; 78: 2166–2172.
• 16.    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: 309–315.
• 17.    Suzuki  S,  Yamashita  T,  Kato  T,  Fujino  T,  Sagara  K,  Sawada  H, et al. Incidence of major bleeding complication of warfarin therapy in Japanese patients with atrial fibrillation. Circ J 2007; 71: 761–765.
• 18.    Matsuyama  K,  Matsumoto  M,  Sugita  T,  Nishizawa  J,  Yoshida  K,  Tokuda  Y, et al. Anticoagulant therapy in Japanese patients with mechanical mitral valves. Circ J 2002; 66: 668–670.
• 19.    Mori  T,  Asano  M,  Ohtake  H,  Bitoh  A,  Sekiguchi  S,  Matsuo  Y, et al. Anticoagulant therapy after prosthetic valve replacement: Optimal PT-INR in Japanese patients. Ann Thorac Cardiovasc Surg 2002; 8: 83–87.
• 20.    Johnson  JA. Ethnic differences in cardiovascular drug response: Potential contribution of pharmacogenetics. Circulation 2008; 118: 1383–1393.
• 21.    Inoue  H,  Nozawa  T,  Hirai  T,  Iwasa  A,  Okumura  K,  Lee  JD, et al. Accumulation of risk factors increases risk of thromboembolic events in patients with nonvalvular atrial fibrillation. Circ J 2006; 70: 651–656.
• 22.   J-RHYTHM Registry Investigators. Determinants of warfarin use and international normalized ratio levels in atrial fibrillation patients in Japan: Subanalysis of the J-RHYTHM Registry. Circ J 2011; 75: 2357–2362.