Article ID: CR-25-0009
Background: The basis for the specific age threshold for increasing of ischemic stroke in non-valvular atrial fibrillation (NVAF) patients has not been fully evaluated.
Methods and Results: We conducted a pooled analysis of 3,588 Japanese NVAF patients without anticoagulation therapy from the Shinken Database (n=1,099), the J-RHYTHM Registry (n=1,002), and the Fushimi AF Registry (n=1,487) to determine the incidence of ischemic stroke by age group; patients aged between 31 and 90 years (n=3,455) were analyzed. During a follow-up period of 1.47 years, 69 ischemic strokes occurred (1.33% per year). The incidence of ischemic stroke exhibited triphasic changes as follows: first, it ranged from 0.00% per year to 0.41% per year across the age groups between 31–35 and 46–50 years. Second, it then rose to 1.58% per year in the 56–60-years age group, remaining around 1% per year across the age groups between 56–60 and 71–75 years, with rates ranging from 0.83% to 1.58% per year. Last, it further increased to 2.35% per year in the 76–80-year age group, remaining around 2.5% per year across the age groups between 76–80 and 86–90 years.
Conclusions: The incidence of ischemic stroke in NVAF patients exhibits triphasic changes with age, with notable increases observed in patients aged in their late 50s and late 70s.
Ischemic stroke is a critical complication of atrial fibrillation (AF), and its incidence increases with age. It is generally accepted that patients aged ≥75 years should receive anticoagulation therapy for stroke prevention.1,2 However, there is a lack of clear evidence to support this specific age threshold. Moreover, additional age thresholds such as 65 years3 or 85 years4,5 have been identified. We investigated whether there is basis for these age thresholds using data from AF patients not on anticoagulation therapy, derived from a pooled database of the J-RHYTHM registry, the Fushimi AF registry, and the Shinken Database.6,7
This study was performed in accordance with the Declaration of Helsinki (revised in 2013) and the Ethical Guidelines for Medical and Health Research Involving Human Subjects (Public Notice of the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health, Labour and Welfare, Japan, issued in 2017).
Study Patients and Outcome DataAt present, the J-RHYTHM Registry, Fushimi AF Registry, and Shinken Database are the largest AF patient databases in Japan. The registration criteria for each of the databases are determined as follows.
J-RHYTHM Registry8 The J-RHYTHM Registry is a prospective, observational registry with a 2-year follow-up period. The enrollment period was between January 2010 and July 2010. Patients aged ≥20 years who had at least 1 AF episode on a standard 12-lead electrocardiogram (ECG) were eligible for enrollment in the J-RHYTHM Registry. At each institution, a consecutive series of AF patients whose sinus rhythm was maintained for more than 1 year were enrolled. Patients were expected to undergo clinical observation in their outpatient clinic. Inpatients were excluded from the study. All AF patients were expected to return to their outpatient clinic for follow up. For events that occurred during the follow-up period, final clinical data at the time closest to the event were mandatorily sent to the data center.
Fushimi AF Registry9 The Fushimi AF Registry is a prospective, observational registry intended to identify the current status of AF patients in a community-based clinical setting. Patient enrollment began in March 2011. The inclusion criterion for the registry was documentation of AF on a 12-lead ECG or Holter monitor at any time. There were no exclusion criteria. A total of 76 institutions, all of which are members of Fushimi-Ishikai (Fushimi Medical Association), participated in the registry. All participating institutions tried to enroll consecutive AF patients under regular outpatient care or under admission to Fushimi-ku. Collection of follow-up information was mainly conducted through review of inpatient and outpatient medical records, and additional follow-up information was obtained through contact with patients, relatives, and/or referring physicians by mail or telephone. The study protocol was approved by the ethical committees of National Hospital Organization Kyoto Medical Center and Ijinkai Takeda General Hospital.
Shinken Database10 The Shinken Database was established by registering all new patients visiting The Cardiovascular Institute Hospital in Tokyo, Japan. Patients with active cancer and any foreign travelers were excluded. The principle aim of this hospital-based database is surveillance of the prevalence and prognosis of cardiovascular diseases in the urban areas of Japan. AF was diagnosed using electrocardiography recordings, including 12-lead surface ECGs and 24-h Holter recordings, within 3 months after the initial visit and medical history provided by the referring physicians. Patients diagnosed with new-onset AF (>3 months after the initial visit) were not included in the database. The registry started in June 2004 and patients continue to be registered into the database annually. Patient health status and incidence of cardiovascular events and mortality are maintained in the database through links to hospital medical records and by study documents of prognosis sent annually to patients who stopped hospital visits or were referred to other hospitals. The ethical committee of The Cardiovascular Institute Hospital approved the study, and all patients gave written informed consent.
In this study, we used the data of all patients registered in the J-RHYTHM Registry (non-valvular AF [NVAF], n=7,516), those with obtainable follow-up information in the Fushimi AF Registry (NVAF, n=3,189), and those registered in the Shinken Database between 2004 and 2012 (NVAF, n=2,244). The J-RHYTHM Registry was a closed cohort and its predetermined 2-year follow-up period was already completed. The Fushimi AF Registry and the Shinken Database are open cohorts and their registration and follow-up investigations are ongoing. From the acquired data, we extracted and combined the data of NVAF patients who were not on anticoagulant therapy at the time of registration and whose follow-up periods were >1 year on April 30, 2014 (follow-up data exceeding ≥2 years were excluded from the analysis). The number of patients analyzed was 3,588 (J-RHYTHM Registry, n=1,002; Fushimi AF Registry, n=1,487; Shinken Database, n=1,099).
In this study, we excluded patients aged <30 years and >95 years, as the number of patients in each 5-year age category within this range was fewer than 30, resulting in a total of 3,455 patients being analyzed.
Statistical AnalysisThe age categories were determined by 5-year intervals between 31–35 and 91–95 years. The incidence rate of ischemic stroke was calculated as % per year with 95% confidence intervals (CIs) and was determined in the entire patient population and according to age categories. The relative increase of the ischemic incidence rate and its 95% CIs were also calculated. The relative increase in incidence rate (% per year) was calculated as follows: (Relative increase in incidence rate [% per year]) = (Incidence of ischemic stroke in current age category) − (Incidence of ischemic stroke in previous age category). Therefore, it was not calculated for the age category of 31–35 years. All statistical analyses were performed using SPSS version 19.0 software (SPSS Inc., Chicago, IL, USA) for Windows (Microsoft Corp., Redmond, WA, USA). Statistical significance was set at a 2-sided P value of <0.05.
During the follow-up period of 1.47 years, 69 ischemic strokes occurred (1.33% per year). The distribution of the number of patients and ischemic stroke events according to age is presented in Figure A (details shown in Supplementary Table). The incidence rate of ischemic stroke by age is presented in Figure B (details shown in Supplementary Table). The incidence of ischemic stroke exhibited triphasic changes as follows: first, the incidence rate of ischemic stroke ranged from 0.00% per year to 0.41% per year across the age groups between 31–35 and 46–50 years. Second, it then increased to 1.58% per year in the 56–60-years age group, maintaining around 1% per year across the age groups between 56–60 and 71–75 years, with rates ranging from 0.83% to 1.58% per year. Last, it further increased to 2.35% per year in the 76–80-year age group, maintaining around 2.5% per year across the age groups between 76–80 and 86–90 years.
(A) Number of patients and ischemic stroke by age. (B) Incidence of ischemic stroke according to age. The solid line indicates the incidence rate of ischemic stroke (% per year), and the shaded area represents the 95% confidence intervals (CIs). (C) Relative increase in the incidence rate of ischemic stroke by age. The increase in incidence rate was calculated as the difference between the incidence in the current age category and that in the previous age category (% per year). The solid line indicates the incidence rate of ischemic stroke, and the shaded area represents the 95% CIs.
The relative increase in the incidence rate of ischemic stroke (calculated as the difference between the current and the previous age category) by age is presented in Figure C (details shown in Supplementary Table), showing a remarkable increase at ages 56–60 years (relative increase: 1.58% per year [95% CI 0.55, 2.61]) and 76–80 years (relative increase: 1.26% per year [95% CI −0.16, 2.67]). These figures consistently indicate that the incidence of ischemic stroke does not increase linearly but rather in a stepwise manner, with notable increases in patients aged in their late 50s and late 70s.
Several reports have suggested that age-related changes in humans have phasic alterations. For example, Lehallier et al.11 measured 2,925 plasma proteins from 4,263 healthy adults aged between 18 and 95 years and found prominent alterations in some of the proteins, with 3 inflection points at ages 34, 60, and 78 years. Similarly, Shen et al.12 conducted comprehensive multi-omics profiling in 108 healthy adults aged 25–75 years and found substantial dysregulation of molecular markers of aging at ages 44 and 60 years.
Age-related phasic changes have also been reported in view of cardiovascular risk. At a cardiovascular-specialized hospital, including both AF and non-AF patients, it has been shown that the estimated glomerular filtration rate declines significantly in patients aged in their 50s, 70s, and 80s.13 Notably, Bauer et al. reported sharp increases in F1+2 levels in individuals aged in their late 40s, 60s, and 70s among a cohort of 199 healthy subjects.14 These findings suggest that endothelial aging may also progress in a stepwise manner. Taken together, our results align with previous findings.
Our data showed that the incidence of ischemic stroke in NVAF patients follows a triphasic pattern with age, with increases in patients aged in their late 50s and late 70s, while remaining stable during other periods. Notably, the incidence does not rise during those aged in their 60s. This age-related pattern may partially explain why the age threshold of 65 years is less significant, while those of 75 and 85 years are more significant in Japanese patients.15 Traditionally, the age thresholds for ischemic stroke have been recognized as 65, 70, or 75 years.1 These thresholds are reflected in the CHADS2 and the CHA2DS2-VASc scores. In contrast, the ATRIA4 and the HELT-E2S2 scores15 identified an age threshold of 85 years. The increase in ischemic stroke incidence observed in patients aged in their late 70s in our data largely aligns with these traditional age thresholds.
Meanwhile, the increase in ischemic stroke incidence in patients aged in their late 50s may warrant more attention. Although the risk at this age has not been regarded as significant, the incidence of ischemic stroke in this study exceeded 1% per year. Two reports from Asian countries have identified an increase in ischemic stroke incidence in patients aged in their 50s compared with those aged <50 years. Chao et al. reported the incidence of ischemic stroke across different age groups among AF patients aged <65 years using data from a nationwide cohort in Taiwan.16 Their findings indicated that stroke risk increased notably for patients aged >50 years, with the receiver operating characteristic (ROC) curve identifying an age of 50 years as the optimal cut-off value.16 Similarly, Kim et al., using data from the National Health Insurance Service in Korea, reported an ischemic stroke incidence of 1.94 per 100 patient-years in the 55–59 age group among patients without non-gender-related risk factors in the CHA2DS2-VASc score (i.e., those with a CHA2DS2-VA score of 0).17 Their analysis showed a 2- to 3-fold increase in stroke incidence in the 50–54 age group compared with those aged <50 years.17 Thus, the observed rise in stroke risk in patients aged in their late 50 s in our data aligns with these previous reports from Asian countries. However, similar findings have not been demonstrated in Western populations. Although several previous studies have discussed the possibility of ethnic differences in stroke risk, the underlying reasons for these differences remain unclear.16,17
Study LimitationsThe present study has several limitations. First, the dataset comprised only Japanese patients, which may limit the generalizability of our findings to other populations. Second, selection bias was present because only patients not receiving anticoagulant therapy were included. This bias is particularly relevant for patients aged ≥75 years, where anticoagulation is strongly recommended according to Japanese guidelines. In this group, patients who were not anticoagulated likely included both very low-risk patients, for whom anticoagulation was deemed unnecessary, and very high-risk patients, for whom anticoagulation might have been withheld due to contraindications or bleeding risks.18 These mixed risk profiles may have led to outcomes that do not fully reflect the typical prognosis for this age group. In contrast, this bias is likely smaller in younger patients, for whom anticoagulation therapy is not as strongly recommended. Third, the data involved patients treated in the warfarin era, which may limit the applicability of our findings in settings where direct oral anticoagulants are now widely used. Last, the number of ischemic stroke events in our cohort was relatively small, necessitating careful interpretation to avoid overgeneralization.
The incidence of ischemic stroke in NVAF patients in this pooled data in Japanese registries without anticoagulation therapy followed a triphasic pattern with age, with increases in patients aged in their late 50s and 70s. While our data do not fully support the currently accepted age thresholds for ischemic stroke risk in Japanese NVAF patients, they contribute to a better understanding of age-specific patterns.
During the preparation of this work, the authors used CHAT-GPT to enhance the readability of the manuscript. After using this tool, the authors carefully reviewed and made any necessary edits to the content, taking full responsibility for the final version of the published article.
S.S. received remuneration from Daiichi Sankyo and Bristol-Myers Squibb. T.Y. received research funding from Bristol-Myers Squibb, Bayer, and Daiichi Sankyo, manuscript fees from Daiichi Sankyo and Bristol-Myers Squibb, and remuneration from Daiichi Sankyo, Bayer, Pfizer Japan, and Bristol-Myers Squibb. K.O. received remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, and Medtronic. H.A. received remuneration from Daiichi Sankyo. M.A. received research funding from Bayer and Daiichi Sankyo, and remuneration from Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Bayer, and Daiichi Sankyo. H.I. received remuneration and consultancy fees from Daiichi Sankyo.
S.S.: Methodology, formal analysis, visualization, and writing of the original draft. T.Y.: Conceptualization, and writing of the original draft. K.O., H.A., M.A., and H.I.: Writing, reviewing, and editing.
The present study was approved by The Ethics Committees of The Cardiovascular Institute (Reference no. 473).
Please find supplementary file(s);
https://doi.org/10.1253/circrep.CR-25-0009
