It is important to identify non-valvular atrial fibrillation (NVAF) patients at risk of thromboembolism, and to appropriately administer antithrombotic therapy to them. On the other hand, it is also important to identify truly low-risk patients because bleeding complications related to antithrombotic therapy are not uncommon. The CHA₂DS₂-VASc score has been proposed as a method of evaluating the risk levels of such patients, and this score includes vascular disease, age of 65–74 years, and female sex as risk items. Although a CHA₂DS₂-VASc score of 0 indicates an extremely low risk for thromboembolism, a woman would be allocated 1 point in this scoring system from the time that she was born. It is therefore apparent that the CHA₂DS₂-VASc scoring system has limited applications if it does not clarify at what age the risk of thromboembolism begins to increase in women.

Article p 1719

In this issue of the Journal, Tomita et al conduct an examination of 997 Japanese patients (mean age 68 years, 29% women) with NVAF who did not receive warfarin therapy, and found no significant sex difference in the annual incidence of thromboembolism (1.2% for women, 1.6% for men; odds ratio [OR] 0.72, 95% confidence interval [CI] 0.28–1.62; P=0.44).¹ The study also confirmed there was no significant difference between the CHA₂DS₂-VASc score and their proposed CHA₂DS₂-VA score (a modified risk scoring system that excludes female sex as a variable from the CHA₂DS₂-VASc score) in both men and women. They conclude that their CHA₂DS₂-VA score may be more useful in Japanese NVAF patients than the conventional CHA₂DS₂-VASc score, particularly in the identification of truly low-risk patients.

Previous studies from other countries have produced mixed results. In Sweden, Friberg et al reported that although there was no sex difference observed in stroke incidence for younger patients, women aged ≥75 years were found to have a higher stroke incidence than similarly aged men.² In a Canadian study, Avgil Tsadok et al³ examined the stroke incidence rate in older AF patients with and without warfarin therapy, and found no sex difference in stroke incidence for these patients within 30 days after discharge. However, stroke incidence was found to be significantly higher in women aged ≥75 years, regardless of warfarin therapy. In addition, validation of the CHA₂DS₂-VASc scoring system was conducted using a Danish study population in which the majority of women were at least 65 years of age.⁴ In a French study, Olesen et al calculated the event rates of stroke or thromboembolism for different age categories (<65, 65–74, and ≥75 years); in NVAF patients aged <65 years, the presence of heart failure, previous stroke, or vascular disease were found to be independent risk factors for stroke and thromboembolism.⁵ Those authors concluded that stroke risk stratification using the CHADS₂ score could be improved by adding the 2 risk factors of being aged 65–74 years and vascular disease.

Why is the incidence of stroke and thromboembolism higher in elderly women? Cove et al explored this question in an examination of the influence of menopause and hormone replacement therapy in a USA study population, but were unable to definitively clarify the reason.⁶ In Japan, Inoue et al⁷ investigated the influence of gender on the prognosis of NVAF patients.⁷ They performed a subanalysis of 7,406 NVAF patients using data from the J-RHYTHM registry to investigate the risk of thromboembolism and bleeding. Through multivariate logistic regression analysis, male sex was found to be an independent risk factor for major bleeding (OR 1.59; 95% CI 1.05–2.40; P=0.027) and all-cause mortality (OR 1.78; 95% CI 1.25–2.55; P<0.002). However, there was no significant difference between men and women for thromboembolic events (OR 1.24; 95% CI 0.83–1.86; P=0.29) or cardiovascular mortality (OR 0.96; 95% CI 0.56–1.66; P=0.89). Okumura et al⁸ validated the CHA₂DS₂-VASc and HAS-BLED scores in 7,384 Japanese NVAF patients enrolled in the J-RHYTHM Registry. Among patients with CHA₂DS₂-VASc scores of 0, 1, and ≥2, there were no significant differences in thromboembolic event rates regardless of whether or not female sex was included as a risk item for both the non-warfarin and warfarin treatment groups. That study concluded that the CHA₂DS₂-VASc score is useful for identifying Japanese NVAF patients at truly low-risk of thromboembolism, but that female sex may be excluded as a risk item from this score. Moreover, Suzuki et al⁹ performed a pooled analysis of 3,588 Japanese NVAF patients not undergoing antithrombotic therapy from the Shinken Database, J-RHYTHM Registry, and Fushimi AF Registry to determine the incidence rates of ischemic stroke. They reported that history of ischemic stroke or transient ischemic attack (hazard ratio [HR] 3.25; 95% CI 1.86–5.67), age ≥75 years (HR 2.31; 95% CI 1.18–4.52), and hypertension (HR 1.69; 95% CI: 1.01–2.86) were independent risk factors for ischemic stroke. In contrast, female sex was not identified as a risk factor for thromboembolism. The findings of these reports support the utilization of the CHA₂DS₂-VA score proposed by Tomita et al as a more appropriate tool for the risk assessment of thromboembolic events in Japanese NVAF patients.

In the studies described above, female g ender was not shown to be a risk for thromboembolism in elderly Japanese women, although women aged ≥75 years in Europe and North America have been reported to be at higher risk (Table). Currently, the 2012 ESC and 2014 AHA/ACC/HRS guidelines for the management of patients with AF have adopted the CHA₂DS₂-VASc score. However, the 2012 ESC guidelines do not recommend anticoagulation therapy for women under 65 years of age with lone AF, and the AHA/ACC/HRS guidelines have concluded that the risk of thromboembolism in women under 65 years of age requires further investigation.^10,11 In contrast, both the 2013 JCS (Figure) and 2014 CCS guidelines recommend evaluating the risk of thromboembolism in NVAF patients by including age and vascular diseases in the CHADS₂ score; these guidelines do not recommend the inclusion of female sex as a risk item.^12,13 The new risk stratification method proposed by Tomita et al is therefore in concordance with the recommendations of the 2013 JCS guidelines for Japanese NVAF patients.

Figure.

Antithrombotic therapy in atrial fibrillation (JCS 2013 guideline). *1: Vascular diseases include prior myocardial infarction, aortic plaque, and peripheral arterial disease. *2: Prosthetic valves include mechanical and bioprosthetic valves. AF, atrial fibrillation; INR, international normalized ratio; NOACs, new oral anticoagulants; TIA, transient ischemic attack. Reproduced with permission from JCS Joint Working Group.¹²

H.A. received research funding from Boehringer Ingelheim and Bristol-Myers Squibb.

Y.K. received remuneration from Boehringer Ingelheim, Bayer, Daiichi Sankyo, Pfizer, and Bristol-Myers Squibb, and research funding from Boehringer Ingelheim and Daiichi Sankyo.

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