Risk Profile and 1-Year Outcome of Newly Diagnosed Atrial Fibrillation in Japan　― Insights From GARFIELD-AF ―

Abstract

Background: Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective non-interventional study of stroke prevention in patients with newly diagnosed non-valvular AF (NAVF) that is being conducted in 35 countries.

Methods and Results: A total of 52,081 patients with a new diagnosis of NVAF were enrolled prospectively in GARFIELD-AF. Of these, 4859 (9.3%) were recruited in Japan (2010–2016). In cohort 1 (2010–2011), few patients were on non-vitamin K antagonist oral anticoagulants (NOAC) globally. From cohort 2 onwards (2011–2016), however, there was a rapid increase in NOAC use around the globe, especially in Japan. By the last year of enrolment (2015–2016), 67.9% of patients in Japan and 43.1% of patients globally were on NOAC±antiplatelet therapy (AP). In Japan and globally, 17.0% and 12.2% of patients, respectively, did not receive stroke prevention treatment. Few patients in Japan (5.7%) received AP only. Compared with the other countries, the unadjusted rates of all-cause mortality and major bleeding were low, while rates of stroke/systemic embolism were similar after 1 year of follow-up.

Conclusions: GARFIELD-AF continues to provide important information on the homogeneity and heterogeneity of baseline characteristics and treatment patterns in patients with newly diagnosed NVAF. This diversity reflects the differences in outcomes in Japan compared with the rest of the world.

Atrial fibrillation (AF) is the most common arrhythmia worldwide.¹ The estimated prevalence in the Japanese general population is 1.6%² in patients >40 years and 2–3% in people >80 years of age.² As life expectancy increases, the number of AF patients in Japan is anticipated to exceed 1 million by 2050.³ Although the prevalence of AF in Asian countries is approximately half that in countries with predominantly Caucasian populations, nevertheless patients in Japan with AF have a higher overall disease burden compared with other countries because of its proportionally greater elderly population.^3,4 In Japan, for example, more patients with AF ≥60 years of age present with stroke in combination with AF, than in Western countries.⁵ AF-related stroke is more likely to be fatal or lead to long-term disability than stroke in people without this arrhythmia.⁶ Stroke prevention is therefore a principal goal in the management of patients with AF who are at high risk of stroke.⁷

The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective non-interventional study of stroke prevention in patients with newly diagnosed AF that is being conducted in 35 countries.⁸ In Japan, patients were enrolled between 2010 and 2016 from 301 representative care settings and are currently being followed up from a minimum of 2 years and up to 8 years after entry into the study. The aim of the study is to observe trends in stroke prevention strategies and also to record the burden of disease and outcomes associated with non-valvular AF (NVAF), both nationally and globally in represented countries. In this report, we describe the patient characteristics, treatment patterns in all patients enrolled in the registry from Japan, and their outcomes after 1 year of follow-up.

Methods

Study Design

Patients were enrolled from >1,000 centers in 35 countries worldwide, including from America, Europe, Africa and Asia. Eligible patients included men and women aged ≥18 years with AF diagnosed according to standard local procedures in the previous 6 weeks, and with at least 1 additional risk factor for stroke. Risk factors were neither pre-specified in the protocol nor were they limited to the components of existing risk stratification schemes. The registry excluded patients with a transient reversible cause of AF and those for whom follow-up was not envisaged or possible. Investigator sites were selected randomly and represented the different care settings in each participating country (office-based practice; hospital departments: neurology, cardiology, geriatrics, internal medicine, and emergency; anticoagulation clinics; and general or family practice).

Ethics

All patients provided written informed consent to participate. Independent ethics committee and hospital-based institutional review board approvals were obtained, as necessary, for the registry protocol. The registry is being conducted in accordance with the principles of the Declaration of Helsinki, local regulatory requirements, and the Ethical Guidelines for Clinical Research issued by the Ministry of Health, Labor and Welfare in Japan.

Procedure and Outcome Measures

Baseline data collected at inclusion included patients characteristics, medical history, care setting, type of AF, date and method of diagnosis, symptoms, and anticoagulant (AC) treatment (vitamin K antagonist [VKA], factor Xa inhibitors (FXaI), and direct thrombin inhibitors [DTI], as well as antiplatelet [AP] treatment). Ethnicity was classified by the investigator in agreement with the patient.⁸

Data on all components of the congestive heart failure (CHF), hypertension, age ≥75 years, diabetes and previous stroke or transient ischemic attack (TIA); CHADS₂,⁹ CHF, hypertension, diabetes, vascular disease, age 65–74 years and female gender, age ≥75 years and previous stroke or systemic embolism (SE); CHA₂DS₂-VASc¹⁰ and the HAS-BLED¹¹ risk stratification schemes were collected to assess the risks of stroke and bleeding retrospectively. Vascular disease was defined as peripheral artery disease and/or coronary artery disease (CAD) with a history of acute coronary syndrome (ACS). Hypertension was defined as a documented history of hypertension or blood pressure >140/90 mmHg at rest.

Collection of follow-up data occurred at 4-month intervals up to 24 months. Outcome measures included clinical events, therapy persistence, and health-care utilization.^8,12 The incidences of stroke/SE, pulmonary embolism, ACS, hospitalization, death (cardiovascular and non-cardiovascular), heart failure (occurrence), and bleeding (severity and location) were recorded. Submitted data were examined for completeness and accuracy by the coordinating center (Thrombosis Research Institute [TRI], London, UK), and data queries were sent to study sites.

Data Collection

GARFIELD-AF data were collected using an electronic case report form (eCRF) and captured by trained personnel. The eCRF was designed by Dendrite Clinical Systems, Henley-on-Thames, UK, the group also responsible for the ongoing database program management. Oversight of operations and data management are managed by the sponsor and coordinating center (TRI), with support from Quintiles (Durham, NC, USA), University of Birmingham Department of Primary Care Clinical Sciences (Birmingham, UK), Thrombosis Research Group-Brigham and Women’s Hospital (Boston, MA, USA), and AIXIAL (Paris, France).

The GARFIELD-AF protocol requires that 20% of all eCRF are monitored against source documentation, that there is an electronic audit trail for all data modifications, and that critical variables are subjected to additional audit.⁸ This study reports data from prospective patients enrolled between July 2010 and June 2016. The data were extracted from the study database on 30 June 2017.

Statistical Analysis

Continuous variables are expressed as mean±SD and categorical variables as frequency and percentage. Continuous measures of Japan vs. all other countries enrolled were compared using Wilcoxon rank-sum test, and categorical variables with the chi-squared test. Use of anti-thrombotic therapy at baseline was analyzed using CHA₂DS₂-VASc and modified HAS-BLED (excluding fluctuations in the international normalized ratio; INR) scores, calculated retrospectively from the data collected. Patients with missing values were not removed from the study.

Prothrombin time INR (PT-INR) readings during the first year of follow-up were included in the analysis. Implausible INR <0.8 or >20 were excluded. Patients on VKA treatment at enrolment, but with fewer than 3 readings during follow-up, were excluded from the analysis. Time in therapeutic range (TTR) was estimated between 2 consecutive INR readings only if the interval did not exceed 90 days. Patient-level TTR was estimated on linear interpolation according to Rosendaal et al¹³ using 2.0–3.0 as the target INR range for all countries, except Japan. For Japan, the Japanese Circulation Society (JCS) recommends an INR of 2.0–3.0 for all patients with AF except those aged ≥70 ears, for whom 1.6–2.6 is recommended,⁷ which is supported by the Asia Pacific Heart Rhythm Society statement on anti-thrombotic therapy of patients with NVAF.¹⁴ TTR was estimated using INR until discontinuation or interruption of VKA, an outcome event, or the end of follow-up. The distribution of INR is described by count and percentage below, in, and above the therapeutic range, and by mean±SD, and median (IQR).

Occurrence of major clinical events (primarily, stroke/SE, major bleeding, and all-cause mortality) is described using the number of events, the proportion of patients with the event divided by the population at risk at the beginning of the follow-up period, person-time event rate (per 100 person-years), and 95% CI. We estimated person-year rates using a Poisson model, with the number of events. Events were censored at 1 year to allow for a consistent length of follow-up across all patients enrolled. Cox proportional hazard models, applying previously developed adjustment models, were used to generated adjusted hazard ratios for the comparison of Japan vs. the other countries combined. Only the first occurrence of each event was taken into account. Data analysis was performed at TRI with SAS version 9.4 (SAS Institute, Cary, NC, USA).

Results

Baseline Patient Characteristics

In total, 52,081 patients with a new diagnosis of NVAF were enrolled in GARFIELD-AF globally as the prospective cohort. Of these, 4,859 (9.3%) were from Japan, recruited between 13 July 2010 and 20 June 2016 from 301 centers. The mean time between enrolment and recruitment was 2.1±1.7 weeks. The proportion of patients recruited by cohort is reported in Supplementary Figure 1. Japanese patients with NVAF were almost entirely managed by cardiologists (91%), and only a few were diagnosed and managed by internal medicine (7.9%), neurology (0.3%) and primary care specialists (0.8%). Approximately one-third of patients were managed in hospital and two-thirds were managed at the office. Globally in the GARFIELD-AF registry, cardiologists managed 65.7% of patients and primary care specialists, 14.2% (Table 1).

Table 1. Baseline GARFIELD-AF Subject Characteristics

Variable	Japan (n=4,859)	All other countries (n=47,222)
Age (years)	71.2±11.8	69.5±11.5
Age ≥75 years	42.0	36.8
Men	59.8	55.4
BMI (kg/m2)	24.0±3.8	28.2±5.7
History of hypertension	67.3	77.2
Hypercholesterolemia	29.2	42.9
Diabetes mellitus	18.3	22.6
History of CHF	24.6	19.5
CAD	10.3	22.8
Prior stroke/TIA	9.5	11.6
CKD (grade ≥3)	9.5	10.4
Mean CHADS2 score	1.8±1.2	1.9±1.1
CHADS2 score
0	11.9	7.6
1	32.5	34.1
2	31.7	34.6
3	15.5	15.0
4	6.2	6.5
5	1.9	2.0
6	0.3	0.3
Mean CHA2DS2-VASc score	3.0±1.6	3.2±1.6
CHA2DS2-VASc score
0	4.5	2.6
1	14.1	12.1
2	19.7	20.0
3	23.1	24.2
4	21.0	21.9
5	11.2	11.4
6–9	6.4	7.8
Mean HAS-BLED score	1.2±0.9	1.4±0.9
HAS-BLED score
0	19.5	14.6
1	48.5	43.0
2	24.0	31.1
3	7.1	9.5
4–9	1.0	1.7
Type of AF
Paroxysmal	61.1	24.0
Permanent	10.3	13.0
Persistent	23.0	14.1
New	5.6	48.9
Care setting at diagnosis
Cardiology	91.0	65.7
Geriatrics	–	0.4
Internal medicine	7.9	18.0
Neurology	0.3	1.7
Primary care/general practice	0.8	14.2

Data given as mean±SD or %. Differences between Japan and all other countries are statistically significant (P<0.001) for all baseline parameters except for the prevalence of grade ≥3 CKD, which was similar (P=0.061). ^†Peripheral artery disease or CAD. ^‡Renal function was assessed according to the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative classification by investigators at baseline. AF, atrial fibrillation; BMI, body mass index; CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; GARFIELD-AF, Global Anticoagulant Registry in the FIELD-Atrial Fibrillation; TIA, transient ischemic attack.

The baseline clinical characteristics of patients recruited in Japan and all other countries are listed in Table 1; differences between Japan and all other countries were significant (P<0.001) for all baseline parameters except for the prevalence of grade ≥3 chronic kidney disease, which was similar (P=0.061). In Japan, the majority (59.8%) of patients were men; mean age at diagnosis of NVAF was 71.2 years, and 42.0% of patients were ≥75 years. A modest body mass index (BMI) average of 24.0 kg/m² was observed in patients from Japan compared with a global BMI average of 28.2 kg/m². Hypertension was the most prevalent risk factor for NVAF in 67.3% of patients from Japan and in 77.2% of patients from all other countries. The prevalence of hypercholesterolemia and CAD was lower in Japan than in all other countries (raised cholesterol, 29.2% and 42.9%, respectively; CAD, 10.3% and 22.8%, respectively). In contrast CHF was more prevalent in patients from Japan (24.6%) than in all other countries (19.5%). Other patient characteristics observed at baseline were observed in a proportionally similar number in Japan and globally. In each group, approximately 20% of patients were diabetic, approximately 10% had moderate or severe kidney disease and around 10.5% had a history of TIA or prior stroke. The mean CHADS₂ scores in Japan and all other countries were 1.8±1.2 and 1.9±1.1, respectively (Table 1). Supplementary Figure 2 shows the distribution of patients across the range of CHA₂DS₂-VASc score in Japan and globally.

Most patients from Japan (94.4%) had a classification for the type of NVAF shortly after diagnosis. The most prevalent form of AF was paroxysmal AF in 61.1% of patients; 23% had persistent AF and 10.3% had permanent AF. On assessment of all other countries in GARFIELD-AF, nearly half of patients (48.9%) had new AF (which was unclassified by the investigator); paroxysmal AF was characterized in 24.0% of patients, and permanent and persistent AF in 13.0% and 14.1%, respectively.

Anti-Thrombotic Treatment

Between July 2010 and June 2016, patients were enrolled in 5 sequential cohorts: C1, 2010–2011 (n=248); C2, 2011–2012 (n=579); C3, 2013–2014 (n=1,119); C4, 2014–2015 (n=1,775); and C5, 2015–2016 (n=1,138). Figure 1 shows the patterns of anti-thrombotic treatment in each cohort for Japan and globally. In C1, 21 Japanese patients and 221 patients globally were on non-VKA oral AC (NOAC). From C2 onwards, however, there was a rapid increase of NOAC uptake, especially in Japan compared with the average globally in GARFIELD-AF over the same time period. By the last year of enrolment (2015–2016; cohort 5), 67.9% of patients in Japan and 43.1% of patients globally were on NOAC±AP. Overall, use of VKA±AP tended to be lower in patients from Japan in GARFIELD-AF (18.6% vs. 39.3%). Only a few patients in Japan received AP either alone (5.7% vs. 21.0%) or combined with AC (10.9% vs. 14.3%) compared with the global average. Between the first (2010) and last year of recruitment (2016), the proportion of patients on AP alone in Japan fell from 12.6% to 4.9%.

Figure 1.

Anti-thrombotic treatment at diagnosis of non-valvular atrial fibrillation (AF) in GARFIELD-AF patients by cohort. Cohort 1, 2010–2011; cohort 2, 2011–2012; cohort 3, 2013–2014; cohort 4, 2014–2015; cohort 5, 2015–2016. AP, antiplatelet; DTI, direct thrombin inhibitor; FXaI, factor Xa inhibitor; GARFIELD-AF, Global Anticoagulant Registry in the FIELD-Atrial Fibrillation; VKA, vitamin K antagonist.

Overall, 77.3% and 66.9% of patients in Japan and in all other countries, respectively, received AC with or without AP. In Japan and globally, 17.0% and 12.2% of patients, respectively, did not receive stroke prevention treatment.

Risk Profile and Treatment

Figure 2 shows the distribution of treatment according to CHADS₂ score. In Japan (Figure 2A), 34.7% patients with a very low stroke risk (CHADS₂ score 0) received no treatment. Beyond a CHADS₂ score of 1, approximately 80% of patients in Japan were on OAC±AP. Although few patients in Japan were on AP alone (5.7% overall), the proportion of these patients increased with increasing stroke risk from 2.3% (CHADS₂ score 0) to 16.7% (CHADS₂ score 5). The most commonly prescribed OAC in Japan were FXaI±AP (47.5% overall), ranging from 35.6% to 71.4% across all the risk strata.

Figure 2.

Treatment of newly diagnosed atrial fibrillation (AF) by CHADS₂ score in (A) Japan and (B) globally in the GARFIELD-AF registry. Abbreviations as in Figure 1.

In comparison, AP alone was frequently prescribed in patients globally, irrespective of stroke risk (Figure 2B) while OAC±AP prescribing rose from 52.7% of patients with a CHADS₂ score 0 to approximately 70.0% of patients with CHADS₂ score ≥3, reflecting over-prescribing of AC for patients at CHADS₂ score 0 and under-prescribing of AC for patients with a high risk of stroke. According to the GARFIELD-AF, VKA±AP continues to be a commonly prescribed OAC globally (in 39.3% of patients overall).

Thromboembolic and Bleeding Profile

As reflected in the mean HAS-BLED score, patients in Japan tend to have a lower risk of bleeding compared with the global average: 1.2±09 vs. 1.4±0.9 (Figure 3).

Figure 3.

Treatment of newly diagnosed atrial fibrillation (AF) by HAS-BLED score in (A) Japan and (B) globally in the GARFIELD-AF registry. Abbreviations as in Figure 1.

Japanese patients with a high risk of bleed are just as likely to receive AC±AP as patients with a low risk of bleed (Figure 3A), although the proportion of patients receiving AP alone rises with increasing bleed risk. In contrast, globally (Figure 3B), the proportion of patients receiving AC±AP diminishes as the risk of bleed increases. In Japan compared with globally, AP-only prescriptions were one-third lower, especially in patients with lowest bleed risk.

INR and TTR

A total of 5,028 INR readings were analyzed from 584 of the 899 Japanese patients receiving VKA; retaining those who had at ≥3 INR readings. Globally 157,134 INR readings were analyzed from a total of 11,886 of the 20,205 patients receiving VKA, with the same inclusion. Overall, median INR was 1.7 (IQR, 1.4–2.1) in Japan and 2.3 (IQR, 1.8–2.8), globally. Approximately one-third of INR readings (36.6%) were <1.6 and two-thirds (67.7%) ≤2.0 and 28.9%, 2.0–3.0 in Japan. Median patient-level TTR tended to be lower in Japan compared with globally (20.9% vs. 59.0%) when using the Rosendaal et al criteria,¹³ and similar when using the target INR according to the Japanese guidelines⁷ (50.3% vs. 59.9%). More than one-third of patients (37.3%) in Japan achieved TTR ≥65% using the Japanese age-related standards for INR control.

Event Rates at 1-Year Follow-up

Follow-up was available for 51,368 patients (98.6%) with a median 1-year follow-up of 365 days; 86.5% of survivors were followed for ≥365 days. The event rates per 100 person-years during the first year after diagnosis of AF in GARFIELD-AF are presented in Table 2 and causes of death are presented in Supplementary Table. On comparison between events between Japan and the rest of the world, expressed as unadjusted and adjusted hazard ratios (HR; Table 2), patients from Japan respond differently after the diagnosis of AF compared with patients from all other countries. For example, patients from Japan had a lower rate of all-cause mortality (adjusted HR, 0.65; 95% CI: 0.51–0.83) and of cardiovascular mortality (adjusted HR, 0.54; 95% CI: 0.35–0.83) compared with globally. Rates of stroke/SE were similar in Japan compared with the GARFIELD-AF global average (adjusted HR, 1.22; 95% CI: 0.87–1.72), but the rate of major bleed tended to be lower (adjusted HR, 0.43; 95% CI: 0.23–0.79). After adjustment for baseline confounders, however, we found that the GARFIELD-AF cohort from Japan and the rest of the world had a similar incidence of new-onset ACS (adjusted HR, 1.03; 95% CI: 0.92–1.62), and the incidence of new or worsening heart failure was higher in patients from Japan (adjusted HR, 1.77; 95% CI: 1.28–2.45; Table 2). These differences are likely to be multifactorial in cause.

Table 2. Event Rates per 100 Person-Years at 1-Year Follow-up After NVAF Diagnosis: Japan vs. Rest of the World

	Japan (n=4,859)		All other countries (n=47,222)		HR (95%CI)	Adjusted HR† (95% CI)
	Events	Rate (95% CI)	Events	Rate (95% CI)
All-cause mortality	95	2.13 (1.74–2.61)	2,008	4.61 (4.41–4.82)	0.46 (0.38–0.57)	0.65 (0.51–0.83)
Cardiovascular death	27	0.61 (0.42–0.88)	762	1.75 (1.63–1.88)	0.35 (0.24–0.51)	0.54 (0.35–0.83)
Non-cardiovascular death	38	0.85 (0.62–1.17)	733	1.68 (1.57–1.81)	0.51 (0.37–0.70)	0.78 (0.53–1.15)
Undetermined cause	30	0.67 (0.47–0.96)	513	1.18 (1.08–1.28)	0.57 (0.40–0.83)	0.63 (0.41–0.97)
Stroke/SE	56	1.26 (0.97–1.64)	594	1.37 (1.27–1.49)	0.92 (0.70–1.21)	1.22 (0.87–1.72)
Major bleeding	14	0.32 (0.19–0.53)	393	0.91 (0.82–1.00)	0.35 (0.21–0.59)	0.43 (0.23–0.79)
New diagnosis of ACS	15	0.34 (0.20–0.56)	363	0.84 (0.75–0.93)	0.41 (0.24–0.69)	1.03 (0.92–1.62)
New or worsening HF	67	1.51 (1.19–1.92)	985	2.29 (2.15–2.44)	0.66 (0.52–0.85)	1.77 (1.28–2.45)

^†Adjusted for age group, sex, race, smoking, diabetes, hypertension, history of bleeding, kidney disease, type of AF, heavy alcohol use, vascular disease, use of OAC. ACS, acute coronary syndrome; AF, atrial fibrillation; HF, heart failure; NVAF, non-valvular atrial fibrillation; OAC, oral anticoagulant; SE, systemic embolism.

Discussion

This is the first assessment of GARFIELD-AF data of patients from Japan. Patients from Japan represent approximately 1 in 10 of those entered into the registry. The use of OAC as the first treatment for stroke prevention after a diagnosis of NVAF has increased over time. These results concur with the findings from the Shinken Database, which has observed a steady increase in AC prescribing in Japan since 2004.¹⁵ During the last 5 years, however, GARFIELD-AF has recorded a substantial rise in NOAC use in patients who were predominantly managed by cardiologists (91% of patients in Japan and 65.7% all other countries). Notably, use of anti-FXaI agents in Japan was higher compared with the average globally in GARFIELD-AF over the same time period. By the last year of enrolment (2015–2016; cohort 5), two-thirds of patients in Japan compared with only 43.1% of patients globally were on NOAC±AP. This reflects the earlier availability of these treatments in Japan relative to all other countries in Asia and across the world: dabigatran (March 2011), rivaroxaban (April 2012), apixaban (February 2013) and edoxaban (September 2014). In the Fushimi AF registry, 26% of all patients overall with AF were treated with NOAC and 38% were on warfarin even in the year 2015; the GARFIED-AF, however, recruited only patients with newly diagnosed NVAF and, unlike the Fushimi AF registry, these patients were predominantly managed by cardiologists (rather than primary care specialists; 85% of sites in the Fushimi registry), which may explain the differences in results.¹⁶

In contrast, prescribing of VKA±AP as an initial treatment after diagnosis of NVAF at GARFIELD-AF centers tended to be lower in Japan than the global average (18.6% vs. 39.3%) and declined markedly over time; although notably, VKA tended to be more frequently prescribed in Japan in patients with a higher risk of bleed. The vast majority of patients on VKA in GARFIELD-AF were maintained at a low INR <2, and one-third of patients had INR <1.6 in Japan, just like other East Asian countries, as previously published.¹⁷ Hirano et al recently found that patients who switched to NOAC had both poor or inadequate INR control and higher risk factors of stroke, while patients maintained on warfarin had better INR control; although the majority of patients on warfarin did not achieve sufficient INR in the therapeutic range.¹⁸ In another study of >7,400 patients from 10 regions in Japan, mean INR and TTR were 1.9 and 60%, respectively.¹⁹

The use of AP only rapidly decreased from 12.6% to 4.9% between the first (2010) and last year of recruitment (2016), which suggests good concordance with the 2013 JCS guidelines, which no longer recommend AP for stroke prevention.

In Japan, however, like other countries in GARFIELD-AF, approximately 15–20% of patients did not receive any stroke prevention treatment, even those at the highest risk of stroke according to CHA₂DS₂-VASc score. Although the overall 1-year risk of stroke was slightly lower in Japan compared with the global average, these data indicate that there is still room for improvement in the use of AC for stroke prevention in Japan.¹⁹

Compared with the average in all other countries in the GARFIELD-AF, patients from Japan had a lower risk of bleed. There are a few potential reasons for this. First, patients from Japan tended to have a lower baseline risk of bleed. In addition, and perhaps as a consequence of a lower risk of bleed, patients in Japan tend to be treated more conservatively with AC with lower target INR for those on warfarin, especially in the elderly (for whom the INR target is 1.6–2.6). The JCS recommends INR 2.0–3.0 for all patients with AF except those aged ≥70 years, for whom 1.6–2.6 is recommended,⁷ which is supported by the Asia Pacific Heart Rhythm Society statement on anti-thrombotic therapy of patients with NVAF.¹⁴ Third, patients in Japan are less likely to receive AP either alone or in combination with AC.

In Japan, the rate of all-cause mortality in the year after a diagnosis of AF was less than half the global rate. This is despite the greater proportion of Japanese patients being >75 years and with corresponding greater burden of heart failure (at baseline and at follow-up). The lower incidence of mortality is probably due to lower burden of ischemic heart disease/vascular disease (at baseline), less bleeding, a greater use of OAC, free access to any of the hospitals or clinics in Japan, and longer longevity compared with patients from Europe and other regions, as previously demonstrated by the Reduction in Atherothrombosis for Continued Health (REACH) international longitudinal registry.²⁰

The unadjusted analyses from GARFIELD-AF show that patients from Japan respond differently after the onset of AF and these differences are likely multifactorial in cause. We performed a formal adjustment of confounders in order to assess differences in outcomes between Japan and the rest of the world. Although adjustments were made for multiple baseline variables (including age group, sex, race, smoking, diabetes, hypertension, history of bleeding, kidney disease, type of AF, heavy alcohol use, vascular disease, use of OAC), it is likely there are also additional differences between countries that are not collected, such as factors relating to the health system and to the patients (such as genetic differences). These factors likely also play an important part in outcomes. We would caution against the over-interpretation of some outcomes (such as new-onset ACS), for which the number of reported events in patients from Japan were low.

Conclusions

GARFIELD-AF continues to provide important information on the homogeneity and heterogeneity of baseline characteristics, treatment patterns and clinical outcomes in patients with newly diagnosed AF. The registry has recorded a substantial rise in NOAC use in Japan (between 2010 and 2016), with two-thirds of Japanese patients receiving NOAC therapy by the end of the recruitment period in 2016. The registry provides evidence of the lower mortality in newly diagnosed AF in Japan as compared with the global average in GARFIELD-AF.

Acknowledgments

We thank the physicians, nurses, and patients involved in the GARFIELD-AF registry. Editorial support was provided by Rae Hobbs (Thrombosis Research Institute, London, UK).

Disclosures

Y. Koretsune, research grant: Daiichi Sankyo and Boehringer Ingelheim; paid lecture: Daiichi Sankyo, Boehringer Ingelheim, Bayer, Bristol Meyers and Pfizer. I.S., paid lecture: Bayer, and Takeda. K.S.P., consultant for Thrombosis Research Institute, AstraZeneca, and Bayer. S.G., research grant from Bristol Meyers, Pfizer, Ono, and Sanofi; honoraria for speaking or participation at meetings from Bayer, and AstraZeneca. A.K.K., grants from Bayer AG, during the conduct of the study; grants and personal fees from Bayer AG, personal fees from Boehringer-Ingelheim Pharma, personal fees from Daiichi Sankyo Europe, personal fees from Janssen Pharma, personal fees from Sanofi SA, outside the submitted work. The other authors declare no conflicts of interest.

Funding

This work was supported by an unrestricted research grant from Bayer AG (Berlin, Germany) to the Thrombosis Research Institute (London, UK), which sponsors the GARFIELD-AF registry. The funding source had no involvement in the data collection, data analysis, or data interpretation.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-18-0655

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