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Address correspondence to Eitaro Kodani, Department of Internal Medicine and Cardiology, Nippon Medical School, Tama-Nagayama Hospital, 1-7-1 Nagayama, Tama-shi, Tokyo 206-8512, Japan.
Prior ischemic stroke or transient ischemic attack (TIA) is a high risk for thromboembolism in patients with nonvalvular atrial fibrillation (NVAF). To clarify rates of thromboembolic and hemorrhagic events, and target intensities of warfarin for secondary prevention, a subanalysis was performed using data from the J-RHYTHM Registry.
Methods
Of 7937 outpatients with atrial fibrillation, 7406 with NVAF (men 70.8%, 69.8 ± 10.0 years) were followed for 2 years or until an event occurred. Event rates and effect of warfarin were compared between patients with (secondary prevention) and without (primary prevention) prior stroke/TIA.
Results
Prevalence of male sex, diabetes mellitus, and mean age were higher in the secondary prevention group, showing a higher CHADS2 (congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and history of stroke or TIA) score than the primary prevention group (3.5 ± 1.0 versus 1.4 ± 1.0, P < .001). In the secondary prevention group, 93.4% of patients received warfarin and their time in therapeutic range was 62.8%. During follow-up, thromboembolism occurred more frequently in the secondary than in the primary prevention group (2.8% versus 1.5%, P = .004), especially in patients without warfarin. Major hemorrhage also occurred more frequently in the secondary prevention group (3.0% versus 1.7%, P = .006). Compared with patients not taking warfarin, combined rates of both events were lower at an international normalized ratio (INR) of 1.6-2.59 in patients taking warfarin in the secondary as well as in the primary prevention groups.
Conclusions
Both thromboembolism and major hemorrhage occurred more frequently in NVAF patients with prior ischemic stroke/TIA. Target INR should be 1.6-2.59 for secondary as well as primary prevention of thromboembolism in Japanese NVAF patients.
(congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and history of stroke or transient ischemic attack (TIA)) or CHA2DS2-VASc scores
Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation.
are widely used for risk stratification of ischemic stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). A history of ischemic stroke or TIA carries a stronger risk for ischemic stroke than other components of these scores.
Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation.
Once patients suffer from cardiogenic embolism, their condition is mostly severe, and mortality can be higher as compared with other types of ischemic stroke.
Therefore, prophylaxis with anticoagulation therapy is crucial for reducing AF-related ischemic stroke in patients with a history of stroke or TIA (stroke/TIA). Oral anticoagulation therapy with vitamin K antagonists, mainly warfarin, can reduce the risk of AF-related ischemic stroke by 60%-70%.
However, information regarding the incidence of thromboembolic and hemorrhagic events in Japanese NVAF patients with a history of ischemic stroke/TIA is still limited.
Optimal intensity of warfarin therapy for secondary prevention of stroke in patients with nonvalvular atrial fibrillation: a multicenter, prospective, randomized trial. Japanese nonvalvular atrial fibrillation-embolism secondary prevention cooperative study group.
Optimal intensity of international normalized ratio in warfarin therapy for secondary prevention of stroke in patients with non-valvular atrial fibrillation.
Therefore, we investigated the incidence of thromboembolic and hemorrhagic events in patients with and without a history of ischemic stroke/TIA, using a post hoc analysis of the J-RHYTHM Registry.
Investigation of optimal anticoagulation strategy for stroke prevention in Japanese patients with atrial fibrillation -The J-RHYTHM Registry study design.
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.
Additionally, optimal anticoagulation intensities of warfarin for patients with a history of ischemic stroke/TIA were determined, although these had previously been determined using a small number of Japanese patients.
Optimal intensity of international normalized ratio in warfarin therapy for secondary prevention of stroke in patients with non-valvular atrial fibrillation.
Because a target international normalized ratio (INR) of prothrombin time is different between NAVF patients aged younger than 70 and 70 years or older in the current Japanese guidelines,
we also investigated event rates in both age groups of younger than 70 and 70 years or older.
Methods
Study Design of the J-RHYTHM Registry
The J-RHYTHM Registry was a prospective, observational nationwide study. Study design and baseline characteristics have been reported in detail elsewhere.
Investigation of optimal anticoagulation strategy for stroke prevention in Japanese patients with atrial fibrillation -The J-RHYTHM Registry study design.
Briefly, the subjects were a consecutive series of outpatients with AF of any type, regardless of the use of antithrombotic drugs. Antithrombotic drugs and dosages were selected at the discretion of the treating cardiologists. Because no nonvitamin K antagonist oral anticoagulant (NOAC) was available when this registry was carried out in 2009, all anticoagulation therapies were performed with warfarin in this study. Patients with valvular AF, including mitral stenosis and mechanical prosthetic valves,
The patients were followed for 2 years, or until an endpoint, whichever occurred first. The thromboembolic endpoints consisted of symptomatic ischemic stroke, TIA, and systemic embolism. Major hemorrhage as the safety endpoint included intracranial hemorrhage, gastrointestinal hemorrhage, and others requiring hospitalization. All-cause mortality and cardiovascular mortality were also determined. If any event occurred during the follow-up period, the final clinical data, including INR at the time closest to the event, were collected.
Investigation of optimal anticoagulation strategy for stroke prevention in Japanese patients with atrial fibrillation -The J-RHYTHM Registry study design.
Investigation of optimal anticoagulation strategy for stroke prevention in Japanese patients with atrial fibrillation -The J-RHYTHM Registry study design.
Patients were divided into 2 groups, that is, the “primary” and “secondary” prevention groups, according to the history of ischemic stroke/TIA, and were divided further into 2 age groups of younger than 70 and 70 years or older. In addition, patients receiving warfarin were divided into 5 subgroups according to their INR (<1.6, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0). Correlation of endpoints with anticoagulation intensities was analyzed with INR at the time of events or at the end of follow-up. The time in therapeutic range (TTR) was determined with the method of Rosendaal et al.
For this determination, the target INR level was set at 1.6-2.6 for patients aged 70 years or older, and at 2.0-3.0 for patients aged younger than 70 years, following the Japanese guidelines.
Data are presented as mean ± standard deviation or median, if necessary. The statistical significance of differences in the mean values was analyzed using Student's t-test or analysis of variance, in the median values using the Mann–Whitney U-test or Kruskal–Wallis test, as appropriate. Frequencies of parameters or events were compared using the chi-square test or Fisher's exact test, as appropriate. Event-free rates of thromboembolism and major hemorrhage between the primary and secondary prevention groups were compared using the Kaplan–Meier method and log-rank test. A Cox proportional hazard model was used to examine whether a history of stroke/TIA was an independent risk factor for the events in a crude model (Model 1) and after adjustment for confounding factors, including the other components of CHADS2 (Model 2) and CHA2DS2-VASc scores (additionally, vascular disease [coronary artery disease], age 65-74 years, and female sex: Model 3), and warfarin and antiplatelet use (Model 4). To clarify the optimal INR level, a multivariate logistic regression analysis was performed. Two-sided P values less than .05 were considered to be statistically significant. All statistical analyses were performed with the IBM SPSS Statistics version 23.0 (IBM Corporation, Somers, NY).
Results
Of the 7937 patients with AF who had been enrolled in the J-RHYTHM Registry, 421 patients were excluded because they had valvular AF. Of the remaining 7516 patients with NVAF, 110 (1.5%) were lost to follow-up. Therefore, a total of 7406 patients with NVAF, that is, 6384 patients without and 1022 patients with a history of ischemic stroke/TIA, were eligible for the present analyses.
Baseline Characteristics and the Status of Antithrombotic Therapy
Baseline clinical characteristics and antithrombotic therapy at the time of enrollment are summarized in Tables 1 and 2, respectively. Mean age and the prevalence of male sex, diabetes mellitus, and coronary artery disease were higher in the secondary than in the primary prevention group. It was a matter of course that the CHADS2 score was 2 or higher in all patients of the secondary prevention group, giving a higher mean CHADS2 score of 3.5 ± 1.0, as compared with the primary prevention group (Table 1, Table 2). The frequency of warfarin use as well as antiplatelet drugs was higher in the secondary than in the primary prevention group (Table 2). Mean INR and TTR were slightly but significantly higher in the secondary than in the primary prevention group (Table 2).
Comparison between primary and secondary prevention groups.
Number of patients
7406
6384 (86.2)
1022 (13.8)
Age (years)
69.8 ± 10.0
69.3 ± 10.1
72.3 ± 8.8
<.001
Sex, male
5241 (70.8)
4479 (70.2)
762 (74.6)
.005
Type of atrial fibrillation
Paroxysmal
2835 (38.3)
2497 (39.1)
338 (33.1)
Persistent
1081 (14.6)
944 (14.8)
137 (13.4)
<.001
Permanent
3490 (47.1)
2943 (46.1)
547 (53.5)
Comorbidities
Coronary artery disease
781 (10.5)
647 (10.1)
134 (13.1)
.005
Cardiomyopathy
634 (8.6)
556 (8.7)
78 (7.6)
.279
HCM
264 (3.6)
217 (3.4)
47 (4.6)
.065
DCM
370 (5.0)
339 (5.3)
31 (3.0)
.002
Congenital heart disease
96 (1.3)
88 (1.4)
8 (.8)
.157
COPD
131 (1.8)
107 (1.7)
24 (2.3)
.166
Hyperthyroidism
131 (1.8)
119 (1.9)
12 (1.2)
.154
Risk factors for stroke
Heart failure
2055 (27.7)
1779 (27.9)
276 (27.0)
.594
Hypertension
4477 (60.5)
3835 (60.1)
642 (62.8)
.103
Age (≥75 years)
2565 (34.6)
2125 (33.3)
440 (43.1)
<.001
Diabetes mellitus
1359 (18.3)
1140 (17.9)
219 (21.4)
.007
Stroke/TIA
1022 (13.8)
0 (.0)
1022 (100.0)
<.001
CHADS2 score
0
1157 (15.6)
1157 (18.1)
0 (.0)
1
2512 (33.9)
2512 (39.3)
0 (.0)
2
2056 (27.8)
1891 (29.6)
165 (16.1)
3
1059 (14.3)
711 (11.1)
348 (34.1)
<.001
4
436 (5.9)
113 (1.8)
323 (31.6)
5
161 (2.2)
0 (.0)
161 (15.8)
6
25 (.3)
0 (.0)
25 (2.4)
Mean
1.7 ± 1.2
1.4 ± 1.0
3.5 ± 1.0
<.001
Median
2 [1-2]
1 [1-2]
3 [3-4]
<.001
Abbreviations: CHADS2, congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and history of stroke or TIA; COPD, chronic obstructive pulmonary disease; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; SD, standard deviation; TIA, transient ischemic attack.
Data are number of patients (%), mean ± SD, or median [interquartile range].
* Comparison between primary and secondary prevention groups.
During the 2-year follow-up period, thromboembolic events occurred in 126 patients (1.7%), major hemorrhage in 140 (1.9%), and all-cause death in 195 (2.6%), including cardiovascular death in 68 (.9%). The overall incidence of thromboembolism was significantly higher in the secondary than in the primary prevention group (2.8% versus 1.5%, P = .004). The incidence rate of major hemorrhage was also higher in the secondary than in the primary prevention group (3.0% versus 1.7%, P = .006). All-cause mortality was higher in the secondary than in the primary prevention group (3.9% versus 2.4%, P = .008), whereas cardiovascular mortality was comparable between the groups (1.0% versus .9%, P = .967). The Kaplan–Meier curves for endpoints are shown in Figure 1. Event-free rates of thromboembolism, major hemorrhage, and all-cause death in the secondary prevention group were significantly lower than those in the primary prevention group (P = .002, P = .003, and P = .004 by log-tank test, respectively; Fig 1, A-C). Cardiovascular mortality was comparable between the groups (Fig 1, D). As a whole group, hazard ratios (HRs) of a prior ischemic stroke/TIA for thromboembolism remained significantly high even in the most critical adjusting model (HR 1.82, P = .006 in Model 4). Although the HR for major hemorrhage in Model 4 did not reach statistical significance (HR 1.49, P = .055), HRs for combined events of thromboembolism plus major hemorrhage were consistently high even after adjustment for multiple confounding factors (HR 1.64, P = .001 in Model 4; Table 3). The HRs for all-cause death were significantly high in only the crude model (Model 1) and after adjustment for CHADS2 score (Model 2), whereas those for cardiovascular death were similar in any model. These results indicated that a history of ischemic stroke/TIA was an independent risk factor for thromboembolism and for combined events of thromboembolism and major hemorrhage (Table 3).
Figure 1Event-free curves for thromboembolism (A), major hemorrhage (B), all-cause death (C), and cardiovascular death (D) in the primary and secondary prevention groups using the Kaplan–Meier method. Additional boxes show the magnified event-free curves with 10-fold scale. P values: comparison between the primary and secondary groups by log-rank test.
Model 2: adjusted for the other components of CHADS2 score (congestive heart failure, hypertension, age 75 years or older, and diabetes mellitus).
Model 3: adjusted for the other components of CHA2DS2-VASc score (congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, vascular disease [coronary artery disease], age 65-74 years, and female sex).
Model 4: adjusted for the other components of CHA2DS2-VASc score, warfarin use, and antiplatelet use.
The characteristics of patients in the nonwarfarin and warfarin groups and 5 INR subgroups are summarized in Table 4. Twenty patients, including 18 without information on warfarin use and 2 lacking INR values at the end of follow-up, were excluded. Consequently, the remaining 7386 patients were used for post hoc analyses requiring INR values at the end of follow-up. In the primary prevention group, prevalence of all components of CHADS2 score except for prior stroke/TIA in patients on warfarin was higher than that in the nonwarfarin group, resulting in a higher CHADS2 score in patients on warfarin. By contrast, in the secondary prevention group, prevalence of patients aged 75 years or older and those with diabetes mellitus in the nonwarfarin group was higher than that in patients on warfarin, resulting in a higher CHADS2 score in the nonwarfarin group than in patients on warfarin (Table 4). Rates of thromboembolism and all-cause death were significantly higher in the secondary than in the primary prevention group (8.7% versus 2.5%, P = .002; and 17.5% versus 5.8%, P < .001, respectively), when warfarin was not given (Table 5). However, the rate of thromboembolic events was significantly lower in the warfarin group than in the nonwarfarin group, especially in the secondary prevention group (Fig 2, A). By contrast, rates of major hemorrhage in patients with and without warfarin were not different in either the primary or secondary prevention group (Fig 2, B). All-cause and cardiovascular mortality showed similar trends to that of thromboembolism (Fig 2, C,D).
Table 4Characteristics of nonwarfarin and warfarin groups, and 5 INR subgroups
Abbreviations: CHADS2, congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and history of stroke or TIA; INR, international normalized ratio of prothrombin time; SD, standard deviation; TIA, transient ischemic attack.
Data are number of patients (%), mean ± SD, or median [interquartile range].
* At the time of events or at the end of follow-up.
** Comparison among 6 groups (nonwarfarin group and 5 INR subgroups) in patients receiving warfarin.
Figure 2Two-year incidence of thromboembolism (A), major hemorrhage (B), all-cause death (C), and cardiovascular death (D). P values: comparison between patients with and without warfarin in each group.
In patients who received warfarin, cerebral infarction occurred eventually in 54 (1.0%/2 years) and 19 (2.1%/2 years) patients in the primary and secondary prevention groups, respectively (Table 5), including typical cardiogenic embolism in 18 and 7, atherothrombotic stroke in 5 and 2, lacunar infarction in 3 and 1, and undetermined in others.
Event Rates in INR Subgroups
Incidence rates of thromboembolism for both the primary and secondary prevention groups showed an obvious decreasing trend among the nonwarfarin group and 5 INR subgroups of patients receiving warfarin (P < .001 for trend in both groups, Table 5). Rates of major hemorrhage for both prevention groups also showed an apparent increasing trend among the nonwarfarin group and 5 INR subgroups in patients receiving warfarin (P < .001 and P = .009 for trend, respectively; Table 5). Consequently, the combined rates of thromboembolic and major hemorrhagic events were lower at INR levels of 1.6-2.59 in both prevention groups (Table 5). All-cause mortality was lower in patients on warfarin than in those without warfarin for both prevention groups (Table 5). This trend was negated at INR levels of 3.0 or higher in both prevention groups. Odds ratios (ORs) for thromboembolism were significantly lower in INR subgroups of 1.6-1.99 and 2.0-2.59 than in the nonwarfarin group, even after adjustment for confounding factors, in both the primary and secondary prevention groups (Table 6). By contrast, the significance of ORs for major hemorrhage in INR subgroups disappeared after adjustment for confounding factors in the secondary prevention group (Table 6). Consequently, ORs for thromboembolism plus major hemorrhage were significantly lower in INR subgroups of 1.6-2.59 than in the nonwarfarin group, even after adjustment for confounding factors, in both the primary and secondary prevention groups (Table 6). ORs for all-cause death were significantly lower in INR subgroups of lower than 3.0 in both prevention groups (Table 6).
Table 6Odds ratios for events in each INR subgroup
Abbreviations: INR, international normalized ratio of prothrombin time.
Data are odds ratios (95% confidence interval) adjusted for the components of CHA2DS2-VASc score (congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, vascular disease [coronary artery disease], age 65-74 years, and female sex) and antiplatelet use, using the nonwarfarin group as a reference.
* At the time of events or at the end of follow-up.
When the same analyses were performed in 2 age groups of younger than 70 and 70 years or older, rates of thromboembolism were significantly lower in patients taking warfarin than in the nonwarfarin group among patients aged 70 years or older in both the primary and secondary groups (Fig 3, A). By contrast, the differences did not reach a significant level even in the secondary group, although rates of major hemorrhage appeared to be slightly higher in patients on warfarin in all groups (Fig 3, B). All-cause death and cardiovascular mortality in both age groups showed similar trends to that of thromboembolism (Fig 3, C,D). Event rates among the nonwarfarin group and 5 INR subgroups are summarized in Table 7. There were significant trends in rates of thromboembolism and major hemorrhage in all age groups, except for major hemorrhage in patients aged younger than 70 years in the secondary group (Table 7).
Figure 3Two-year incidence of thromboembolism (A), major hemorrhage (B), all-cause death (C), and cardiovascular death (D) in each age group. P values: comparison between patients with and without warfarin in each group.
ORs for events in each age group and INR subgroup are summarized in Table 8. In patients aged younger than 70 years in the primary prevention group, ORs for thromboembolism, combined events of thromboembolism plus major hemorrhage, and all-cause death were significantly lower in INR subgroups of 1.6-1.99 and 2.0-2.59, whereas those for major hemorrhage were significantly higher in the INR subgroups of 2.6-3.0 and 3.0 or higher, as compared with the nonwarfarin group (Table 8, A). In patients aged younger than 70 years in the secondary prevention group, OR for all-cause death was significantly lower in only the INR subgroup of 2.0-2.59 because the numbers of patients and events were small (Table 8, B). In patients aged 70 years or older in both the primary and secondary prevention groups, ORs for thromboembolism were significantly lower in the INR subgroups of 1.6-1.99 and 2.0-2.59, and those for combined events of thromboembolism plus major hemorrhage were significantly lower in the INR subgroup of 1.6-1.99 (Table 8, A,B).
Table 8Odds ratios for events in each age group and INR subgroup
Abbreviations: INR, international normalized ratio of prothrombin time.
Data are odds ratios (95% confidence interval) adjusted for the components of CHA2DS2-VASc score (congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, vascular disease [coronary artery disease], age 65-74 years, and female sex) and antiplatelet use, using the nonwarfarin group as a reference.
* At the time of events or at the end of follow-up.
There were major findings in the present study. First, as expected, patients with a history of ischemic stroke/TIA were characterized as a high-risk population, with a CHADS2 score of 3.5 ± 1.0. Second, warfarin was prescribed in approximately 93%, and the TTR, based on the Japanese guidelines,
was 62.8% in the secondary prevention group. This indicates that anticoagulation therapy was performed frequently, and the quality of warfarin therapy seemed acceptable among NVAF patients with a history of ischemic stroke/TIA in Japan.
Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range.
However, rates of both thromboembolism and major hemorrhage were higher in the secondary than in the primary prevention group. Prior ischemic stroke/TIA emerged as an independent risk for both events after adjustment for multiple confounding factors. Third, for prevention of thromboembolism, an INR level of 1.6-2.59 would be optimal among Japanese NVAF patients in the secondary as well as in the primary prevention groups.
Efficacy and Safety of Warfarin
Although the use of NOACs is increasing worldwide,
and indicated for NVAF patients who have renal insufficiency and other comorbidities. Therefore, the present results would be practically important even in the era of NOACs.
In the present study, efficacy of warfarin for preventing thromboembolism was apparent in both the secondary and primary prevention groups (Fig 2). This salutary effect of warfarin was evident particularly in patients aged 70 years or older for both the primary and the secondary prevention of stroke (Fig 3). Although rates of thromboembolism in patients aged younger than 70 years on warfarin appeared to be lower than in those without warfarin in both the primary and secondary groups, these differences were not statistically significant (Fig 3, A). As the number of patients and events in each group was small, it could be explained that statistical power was insufficient when patients were divided into 2 prevention groups and an additional 2 age groups. In our previous subanalysis on event rates in age groups in patients with NVAF,
there was a significant difference in rates of thromboembolism between patients with and without warfarin even in patients aged younger than 70 years. Therefore, warfarin therapy would be beneficial in preventing thromboembolism even in patients aged younger than 70 years. However, it remains controversial whether warfarin therapy is really beneficial in younger patients aged younger than 65 years because the difference disappeared in younger patients when the cutoff age was 65 years.
A meta-analysis of 6 randomized controlled studies on the effects of warfarin in patients with NVAF showed comparable risk reduction of thromboembolism for primary prevention studies (including several % of patients with prior ischemic stroke) and a secondary prevention study, although target INR levels differed among the studies.
EAFT (European Atrial Fibrillation Trial) Study Group Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.
was a secondary prevention study with 1007 NVAF patients to determine the efficacy of warfarin and aspirin. The target INR level was set at 2.5-4.0, and aspirin was given at a dose of 300 mg. Warfarin was effective at preventing thromboembolic events, as compared to aspirin (HR .38, P < .001) and placebo (HR .34, P < .001). However, warfarin was associated with major hemorrhage more frequently (2.8%/year), as compared with aspirin (.9%/year) and placebo (.7%/year). In our secondary prevention group, somewhat different results were observed; overall, warfarin was associated with a significantly lower incidence of thromboembolic events (2.2%/2 years), but not with a higher incidence of major hemorrhage (3.2%/2 years). This could be attributed to lower INR levels in the secondary prevention group in the present study (1.97 ± .48).
Target Anticoagulation Intensity for Secondary Prevention
Current guidelines in Western countries for management of patients with AF recommend the same INR levels for the primary and secondary prevention of thromboembolism in NVAF patients with and without prior ischemic stroke/TIA.
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.
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.
target INR levels of 1.6-2.6 are recommended for patients aged 70 years or older; this is based on results of the secondary prevention study by Yasaka et al
Optimal intensity of international normalized ratio in warfarin therapy for secondary prevention of stroke in patients with non-valvular atrial fibrillation.
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.
Concentration of D-dimer as an index of fibrinolytic activity and prothrombin fragment F1+2 as an index of coagulation activity was not different between INR levels of 1.5-1.9 and 2.0 or higher in Japanese patients with NVAF.
This indicated that slightly lower anticoagulation intensities of warfarin could be effective at inhibiting prothrombotic activity in Japanese patients with NVAF.
NVAF patients with prior ischemic stroke/TIA are at higher risk for thromboembolism than those without prior ischemic events, and therefore anticoagulation therapy is indicated. One might ask whether higher INR values would be required for prevention of thromboembolism in the secondary prevention group as compared to the primary prevention group, but this was not the case. An INR level of 1.6-2.59 would be optimal for prevention of thromboembolism in the secondary as well as in the primary prevention group among Japanese NVAF patients.
The frequency of intracranial hemorrhage on warfarin therapy with a target INR level of 2.0-3.0 was 4-fold higher in Asian than in Caucasian patients.
also showed that INR levels of 2.27 or higher were associated with an increased risk of major hemorrhage in Japanese patients with NVAF. The present results showing that INR levels of 2.6 or higher were associated with higher rates of major hemorrhage are consistent with prior results.
The present study had several limitations. First, it was performed in a single country and the subjects were enrolled in only 158 institutions in Japan. Because most participating physicians were cardiologists, the patients' clinical backgrounds might not be extrapolated to a general Japanese patient population with NVAF. Therefore, generalizing from the present results of this specific population to individual clinical situations should be done carefully. Second, although this registry was relatively large, analyzing a total of 7406 patients with NVAF, the numbers of patients and events in INR subgroups were small especially in the secondary prevention group. This might have reduced the statistical power of the present study. Third, because the study design was prospective but observational, antithrombotic treatments with warfarin or antiplatelet agents were not randomized. Dosage of warfarin and clinical targets of INR levels for individual patients were selected at the discretion of treating physicians. Fourth, 1.5% of patients were lost to follow-up in the present study, which could have led to the underreporting of endpoints. Finally, the present study had been performed before NOACs were approved for clinical use in Japan. Therefore, the present results should be interpreted carefully in the era of NOACs.
Conclusions
Both thromboembolism and major hemorrhage occurred more frequently in NVAF patients with prior stroke/TIA even when TTR was higher as compared with those without prior stroke/TIA. A history of ischemic stroke/TIA is an independent risk factor for both events. Anticoagulation therapy with warfarin was performed frequently for the secondary prevention of stroke in Japan and could have a reducing effect for thromboembolism. An INR level of 1.6-2.59 would be optimal for preventing thromboembolism and for avoiding major hemorrhage in Japanese NVAF patients for the secondary as well as primary prevention of thromboembolism.
Acknowledgments
The present study was presented in part at the 62nd Annual Scientific Session of the Japanese College of Cardiology (in Sendai, Japan, September 27, 2014). Investigators in the J-RHYTHM Registry are listed in References
Investigation of optimal anticoagulation strategy for stroke prevention in Japanese patients with atrial fibrillation -The J-RHYTHM Registry study design.
Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation.
Optimal intensity of warfarin therapy for secondary prevention of stroke in patients with nonvalvular atrial fibrillation: a multicenter, prospective, randomized trial. Japanese nonvalvular atrial fibrillation-embolism secondary prevention cooperative study group.
Optimal intensity of international normalized ratio in warfarin therapy for secondary prevention of stroke in patients with non-valvular atrial fibrillation.
Investigation of optimal anticoagulation strategy for stroke prevention in Japanese patients with atrial fibrillation -The J-RHYTHM Registry study design.
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.
Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range.
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.
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.
Financial Disclosure: The J-RHYTHM registry was supported by a grant from the Japan Heart Foundation (No. 12080025). The coauthors have a potential conflict of interest: Dr. Atarashi has received research funding from Boehringer Ingelheim, and remuneration from Bayer Healthcare, Boehringer Ingelheim, and Daiichi-Sankyo; Dr. Inoue has received research funding from Boehringer Ingelheim and Daiichi-Sankyo, and remuneration from Daiichi-Sankyo, Bayer Healthcare, and Boehringer Ingelheim; Dr. Okumura has received research funding from Boehringer Ingelheim and Daiichi-Sankyo, and remuneration from Boehringer Ingelheim, Bayer Healthcare, Daiichi-Sankyo, and Pfizer; Dr. Yamashita has received research funding from Boehringer Ingelheim and Daiichi-Sankyo, and remuneration from Boehringer Ingelheim, Daiichi-Sankyo, Bayer Healthcare, Pfizer, Bristol-Myers Squibb, and Eisai; and Dr. Origasa has received lecture fees from Daiichi-Sankyo.
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