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To maximize protection against stroke with minimal bleeding, warfarin therapy in nonvalvular atrial fibrillation (NVAF) requires tight control within a narrow therapeutic range, which might depend on racial variations.
Methods
The J-RHYTHM Registry followed 6404 NVAF patients treated with warfarin for 2 years. Using international normalized ratios (INRs) at or closest to the embolic and intracranial hemorrhagic (ICH) events, we determined odds ratios for ischemic stroke/systemic embolism (SE) and ICH according to any given INR with a reference INR range including 2.0.
Results
Ischemic stroke and SE occurred in 97 of the patients and ICH occurred in 49. The estimated INR-risk relationships showed characteristics of Japanese NVAF patients. Compared to INR-risk relationships reported for Westerners, those observed in Japanese patients were virtually identical for ischemic stroke/SE and shifted leftward by approximately 0.5 INR for ICH.
Conclusion
This is the largest Japanese study providing fundamental data necessary to establish optimal anticoagulation intensities. Japanese NVAF patients may require narrower therapeutic ranges than Westerners.
Warfarin anticoagulation can prevent ischemic stroke and peripheral embolism in atrial fibrillation (AF) patients. AF management guidelines in Western countries recommend target prothrombin time-international normalized ratio (PT-INR) levels of 2–3, irrespective of age and CHADS2 score [
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.
]. However, racial differences have an impact on the risk of intracranial hemorrhage (ICH) under warfarin treatment, which is higher in Asians than in Caucasians [
J-RHYTHM Registry Investigators Investigation of optimal anticoagulation strategy for stroke prevention in Japanese patients with atrial fibrillation – the J-RHYTHM Registry study design.
J-RHYTHM Registry Investigators Present status of anticoagulation treatment in Japanese patients with atrial fibrillation: a report from the J-RHYTHM Registry.
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.
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.
]. However, optimal INR levels can be better evaluated using PT-INRs at or close to clinical events. We determined the odds ratios (ORs) for ischemic stroke/systemic embolism (SE) and ICH using INRs at or closest to embolic and hemorrhagic events in Japanese NVAF patients.
Materials and methods
Details of the study design and subjects’ baseline characteristics are reported elsewhere [
J-RHYTHM Registry Investigators Investigation of optimal anticoagulation strategy for stroke prevention in Japanese patients with atrial fibrillation – the J-RHYTHM Registry study design.
J-RHYTHM Registry Investigators Present status of anticoagulation treatment in Japanese patients with atrial fibrillation: a report from the J-RHYTHM Registry.
]. Consecutive AF patients were recruited from outpatient clinics of 158 participating institutions. The J-RHYTHM Registry enrolled 7937 AF patients (mean age, 69.7 years), including 421 with mitral stenosis or mechanical valve replacement. Of the 7516 NVAF patients, 6404 warfarin-treated patients were included in the present study. In the present study, ischemic stroke/SE and ICH including hemorrhagic stroke were analyzed. Using INRs at or closest before these events, ORs for ischemic stroke/SE and ICH were determined as previously reported [
Categorical and consecutive data are presented as number (%) and mean ± standard deviation, respectively. The chi-square and unpaired t-tests were used for group comparisons. INRs at the event or closest prior date were used for cases and INRs at the same follow-up period were used for event-free controls. ORs with 95% confidence intervals (CIs) were calculated by logistic regression with INR and CHADS2 score as variables. Similar to previous reports [
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.
], INRs were categorized by 0.2 and 0.5 INR steps for ischemic stroke/SE and ICH, respectively. The OR at each INR category was normalized to 1.0 at an INR range including 2.0 (1.8 < INR ≤ 2.0 for stroke/SE and 1.5 < INR ≤ 2.0 for ICH). Statistical significance was set at p < 0.05.
Results
During 2 years of warfarin treatment, 97 ischemic stroke/SE and 49 ICH events occurred in 6404 NVAF patients. Table 1 shows the characteristics of patients with and without these events. Compared with controls, ischemic stroke/SE patients were older and had higher CHADS2 scores with a greater prevalence of stroke/transient ischemic attack (TIA) history. ICH patients were older and had higher CHADS2 scores with greater prevalence of congestive heart failure and stroke/TIA history.
Ischemic stroke/TIA and ICH occurred at a median follow-up of 318 ± 181 days and 335 ± 215 days, respectively. INR at the event was obtained in 59 ischemic stroke/SE and 41 ICH patients. Among the remaining patients, the mean time-lag between events and the closest INR was 38 ± 35 days (n = 38) and 58 ± 59 days (n = 8), respectively. Using these PT-INRs, ORs for ischemic stroke/SE and ICH were estimated as a function of INR. Fig. 1 shows ORs for ischemic stroke/SE and ICH as compared to an INR including 2.0 after adjustment for CHADS2 score, and the detailed risk ratios are shown in Table 2. We observed no significant interaction between age and INR-risk relationships (data not shown).
Fig. 1Odds ratio for ischemic stroke/systemic embolism (left) and intracranial hemorrhage (right) vs. international normalized ratio (INR) value. This represents the odds of ischemic stroke/systemic embolism and intracranial hemorrhage as compared with INRs of 1.8–2.0 and 1.5–2.0, respectively. Each point in the X-axis indicates the median value of the investigated INR range. Lines indicate 95% confidence intervals.
The risk of ischemic stroke/SE rose gradually as INR values fell below 2.0 and steeply as they fell below 1.6. Patients with INRs of 1.2–1.4 had a high risk of 3.01 vs. those with INRs of 1.8–2.0 (95% CI 1.45–6.23). The risk of ICH rose as INR values exceeded 2.5. Patients with INRs of 2.5–3.0 had a remarkably high risk of 4.22 (95% CI 1.81–9.84) vs. those with INRs of 1.5–2.0. Even when we analyzed data excluding the case patients with only INRs at the closest day not at the events, we could not find any significant alterations in these INR-risk relationships.
Discussion
This study explored the relation of anticoagulation levels to ischemic stroke/SE and ICH for primary and secondary prevention in Japanese NVAF patients. The large size, prospective design, and analysis of event-nearest INRs emphasize study significance [
]. While the INR-risk relationships for ischemic stroke/SE were virtually identical to those in Westerners, ICH relationships shifted leftward by approximately 0.5 of INR.
Two retrospective studies suggested that appropriate INRs for minimizing major hemorrhages in elderly Japanese NVAF patients with a history of stroke/TIA [
Optimal intensity of international normalized ratio in warfarin therapy for secondary prevention of stroke in patients with non-valvular atrial fibrillation.
] would be lower than in Westerners. The present study supports this notion for many Japanese NVAF patients, showing an occurrence of ICH approximately four times greater at an INR >2.5 than at an INR of 1.5–2.0.
However, an important issue emerged regarding the lowest effective anticoagulation intensity for Japanese NVAF patients. We observed a tendency of gradual increase in risk of ischemic stroke/SE below an INR of 2.0, similar to Westerners. Moreover, no significant interaction was observed between patient age and INR-stroke/SE risk relationships. By contrast, the prior retrospective studies observed no stroke/SE increase in the 1.5–2.0 INR range [
Optimal intensity of international normalized ratio in warfarin therapy for secondary prevention of stroke in patients with non-valvular atrial fibrillation.
]. Differences in patient characteristics, study design (prospective/retrospective and multicenter/single center), and cohort size may explain this apparent difference.
Despite being large, the present study is not statistically powerful enough to determine risk differences around an INR of 2.0 and by patient age. Therefore, the lowest effective anticoagulation intensity for Japanese NVAF patients requires further study with longer follow-ups [
Fushimi AF Registry Investigators Current status of clinical background of patients with atrial fibrillation in a community-based survey: the Fushimi AF Registry.
Limitations include the observational design, physician-determined anticoagulation levels, and limited 2-year follow-up. In addition, the number of patients with INR >2.5 was relatively small as compared with other categories. Although limited, this is the largest study providing fundamental data on INR-event relationships in Japanese NVAF patients.
Conclusions
In Japanese NVAF patients as compared with Westerners, the estimated INR-risk relationships were virtually identical for ischemic stroke/SE but shifted leftward by approximately 0.5 INR for ICH, resulting in narrower therapeutic ranges with vitamin K antagonists.
Disclosures
Dr Yamashita received research funding from Boehringer Ingelheim and Daiichi-Sankyo, and remuneration from Boehringer Ingelheim, Daiichi-Sankyo, Bayer Healthcare, Pfizer, Bristol-Myers Squibb, Eisai, and Ono Pharmaceutical; 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 Atarashi received research funding from Daiichi-Sankyo and Boehringer Ingelheim, and lecture fees from Bayer Healthcare and Boehringer Ingelheim; Dr Origasa received lecture fees from Boehringer Ingelheim, and consultancy fees from Daiichi-Sankyo and Bayer Healthcare.
Acknowledgments
This study was planned by the Japanese Society of Electrocardiology and supported by a grant from the Japan Heart Foundation. We thank the Medi-Skette Corporation for data management and statistical advice.
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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.
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.
Optimal intensity of international normalized ratio in warfarin therapy for secondary prevention of stroke in patients with non-valvular atrial fibrillation.
Atrial fibrillation (AF) is an independent risk factor for ischemic strokes, making the prevention with an oral anticoagulant the mainstay of current clinical practice. An oral anticoagulant such as warfarin prolongs a healthy life expectancy and improves survival. The target intensity of anticoagulation involves a balance between prevention of ischemic strokes and systemic embolisms, and avoids hemorrhagic complications. In Caucasians, the maximum protection against ischemic strokes in AF is achieved with a prothrombin time-international normalized ratio (PT-INR) range of 2.0–3.0, whereas a PT-INR range of 1.6–2.5 is associated with incomplete efficacy [1].
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