Journal of Cardiology 65 (2015) 171–172
Contents lists available at ScienceDirect
Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Editorial
Small therapeutic window of warfarin in Japanese population
Keywords: Warfarin Stroke Bleeding Death
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]. Multiple studies, however, have reported that Asian people treated with warfarin are prone to experience more bleeding than Caucasians [2] and the optimal range of the PTINR is narrower than that for Caucasians [3,4]. Differences in CYP2C9 polymorphisms [5] or variations in vitamin K epoxide reductase complex 1 (VKORC1) [6] may be related to the lower warfarin dosage requirements and increased risk of bleeding. In addition to these genetic factors, Iso et al. [7] previously reported that the plasma level of factor VII, which initiates the process of coagulation in conjunction with tissue factors, is lower in the Japanese population than in Caucasians. A reduced level of factor VII, which is a vitamin K dependent protein and its production is affected by warfarin, may be associated with an increased risk of bleeding. The Japanese AF guidelines recommend a PT-INR range of 1.6– 2.6 for patients with non-valvular AF older than 70 years [8], based on the J-RHYTHM Registry [9–11], which is a nationwide prospective cohort study enrolling 8000 Japanese AF patients, to determine the optimal PT-INR levels for preventing thromboembolic and bleeding events. In this issue of the Journal of Cardiology, Yamashita [12] examined ischemic strokes and systemic thromboembolisms, and intracranial bleeding with different ranges of the PT-INR values on admission to the hospital from the J-RHYTHM Registry. They showed that the increased risk of an ischemic stroke/systemic thromboembolism below an INR of
DOI of original article: http://dx.doi.org/10.1016/j.jjcc.2014.07.013
2.0 and the risk of intracranial bleeding rose as the PT-INR exceeded 2.5. Of note, the rates of intracranial bleeding were approximately 4 times greater at a PT-INR > 2.5 than at a PT-INR of 1.5–2.0. They supported a previous finding that the therapeutic range of the PT-INR is narrower in Japanese than that for Caucasians (Fig. 1). The limited number of events resulted in wide confidence intervals for the odds ratios and prevented the determination of the lowest effective INR as was discussed in this article. The intensity of the PT-INR at the onset of a stroke provides important clinical information. Hannon et al. reported interesting data on the relationship between antithrombotic therapy at
Fig. 1. Adjusted odds ratios for ischemic strokes and intracranial bleeding in relation to the intensity of the anticoagulation. (A) A PT-INR target range of 2.0–3.0 is efficacious and relatively safe in Caucasians. Adapted from Fuster et al. [1]. (B) The JRHYTHM Registry data reproduced from this article. The PT-INR-risk relationships for ischemic strokes were similar to those in Caucasians, but the intracranial bleeding relationships shifted leftward by a PT-INR of approximately 0.5. The Japanese AF guidelines recommend a PT-INR range of 1.6–2.6 for patients with nonvalvular AF older than 70 years. PT-INR, prothrombin time-international normalized ratio; AF, atrial fibrillation.
http://dx.doi.org/10.1016/j.jjcc.2014.09.003 0914-5087/ß 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
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Editorial / Journal of Cardiology 65 (2015) 171–172
References
Fig. 2. Risk of death associated with different levels of anticoagulation. The curve was calculated from 1.25 million PT-INR measurements in 42,451 patients in warfarin clinics using the Poisson model. They had 3533 deaths due to all causes including intracranial bleeding. The minimum risk of death was attained at a PT-INR of 2.2 for all patients. Adapted from Oden and Fahlen [15].
the time of the onset of a stroke and the long-term disability and mortality after the stroke in hospital- and community-treated patients with AF-associated strokes in Ireland. They found that a PT-INR on admission of 2–3 at the onset of the stroke (both ischemic and hemorrhagic) was associated with a reduced severity of the neurological deficits or death at discharge, and a substantial improvement in the late survival [13]. In a detailed magnetic resonance imaging study [14], the therapeutic PT-INR at admission was associated with not only smaller lesion volumes in the acute phase, but also lower final infarct volumes in the remote phase. A possible explanation is that optimal warfarin treatment may accelerate the thrombolysis by inhibiting the thrombotic system and may lead to subsequent predominance of the fibrinolytic system. Moreover, Hannon et al. reported that the subtherapeutic PT-INR (
Contents lists available at ScienceDirect
Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Editorial
Small therapeutic window of warfarin in Japanese population
Keywords: Warfarin Stroke Bleeding Death
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]. Multiple studies, however, have reported that Asian people treated with warfarin are prone to experience more bleeding than Caucasians [2] and the optimal range of the PTINR is narrower than that for Caucasians [3,4]. Differences in CYP2C9 polymorphisms [5] or variations in vitamin K epoxide reductase complex 1 (VKORC1) [6] may be related to the lower warfarin dosage requirements and increased risk of bleeding. In addition to these genetic factors, Iso et al. [7] previously reported that the plasma level of factor VII, which initiates the process of coagulation in conjunction with tissue factors, is lower in the Japanese population than in Caucasians. A reduced level of factor VII, which is a vitamin K dependent protein and its production is affected by warfarin, may be associated with an increased risk of bleeding. The Japanese AF guidelines recommend a PT-INR range of 1.6– 2.6 for patients with non-valvular AF older than 70 years [8], based on the J-RHYTHM Registry [9–11], which is a nationwide prospective cohort study enrolling 8000 Japanese AF patients, to determine the optimal PT-INR levels for preventing thromboembolic and bleeding events. In this issue of the Journal of Cardiology, Yamashita [12] examined ischemic strokes and systemic thromboembolisms, and intracranial bleeding with different ranges of the PT-INR values on admission to the hospital from the J-RHYTHM Registry. They showed that the increased risk of an ischemic stroke/systemic thromboembolism below an INR of
DOI of original article: http://dx.doi.org/10.1016/j.jjcc.2014.07.013
2.0 and the risk of intracranial bleeding rose as the PT-INR exceeded 2.5. Of note, the rates of intracranial bleeding were approximately 4 times greater at a PT-INR > 2.5 than at a PT-INR of 1.5–2.0. They supported a previous finding that the therapeutic range of the PT-INR is narrower in Japanese than that for Caucasians (Fig. 1). The limited number of events resulted in wide confidence intervals for the odds ratios and prevented the determination of the lowest effective INR as was discussed in this article. The intensity of the PT-INR at the onset of a stroke provides important clinical information. Hannon et al. reported interesting data on the relationship between antithrombotic therapy at
Fig. 1. Adjusted odds ratios for ischemic strokes and intracranial bleeding in relation to the intensity of the anticoagulation. (A) A PT-INR target range of 2.0–3.0 is efficacious and relatively safe in Caucasians. Adapted from Fuster et al. [1]. (B) The JRHYTHM Registry data reproduced from this article. The PT-INR-risk relationships for ischemic strokes were similar to those in Caucasians, but the intracranial bleeding relationships shifted leftward by a PT-INR of approximately 0.5. The Japanese AF guidelines recommend a PT-INR range of 1.6–2.6 for patients with nonvalvular AF older than 70 years. PT-INR, prothrombin time-international normalized ratio; AF, atrial fibrillation.
http://dx.doi.org/10.1016/j.jjcc.2014.09.003 0914-5087/ß 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
172
Editorial / Journal of Cardiology 65 (2015) 171–172
References
Fig. 2. Risk of death associated with different levels of anticoagulation. The curve was calculated from 1.25 million PT-INR measurements in 42,451 patients in warfarin clinics using the Poisson model. They had 3533 deaths due to all causes including intracranial bleeding. The minimum risk of death was attained at a PT-INR of 2.2 for all patients. Adapted from Oden and Fahlen [15].
the time of the onset of a stroke and the long-term disability and mortality after the stroke in hospital- and community-treated patients with AF-associated strokes in Ireland. They found that a PT-INR on admission of 2–3 at the onset of the stroke (both ischemic and hemorrhagic) was associated with a reduced severity of the neurological deficits or death at discharge, and a substantial improvement in the late survival [13]. In a detailed magnetic resonance imaging study [14], the therapeutic PT-INR at admission was associated with not only smaller lesion volumes in the acute phase, but also lower final infarct volumes in the remote phase. A possible explanation is that optimal warfarin treatment may accelerate the thrombolysis by inhibiting the thrombotic system and may lead to subsequent predominance of the fibrinolytic system. Moreover, Hannon et al. reported that the subtherapeutic PT-INR (
