Impact of the COVID-19 pandemic on the hospitalizations, time course, presenting symptoms, and mid-term outcomes in patients with myocardial infarctions in a Japanese multi-center registry.

To investigate the impact of the coronavirus disease 2019 (COVID-19) pandemic on myocardial infarctions (MIs), consecutive MI patients were retrospectively reviewed in a multi-center registry. The patient characteristics and 180-day mortality for both ST-segment elevation myocardial infarctions (STEMIs) and non-STEMIs (NSTEMIs) in the after-pandemic period (7 April 2020-6 April 2021) were compared to the pre-pandemic period (7 April 2019-6 April 2020). Inpatients with MIs, STEMIs, and NSTEMIs decreased by 9.5%, 12.5%, and 4.1% in the after-pandemic period. The type of the presenting symptoms (as classified as typical symptoms, atypical symptoms, and out-of-hospital cardiac arrests [OHCAs]) did not differ between the two time periods for both STEMIs and NSTEMIs, while the rate of OHCAs was numerically higher in the after-pandemic period for the STEMIs (12.1% vs. 8.0%, p = 0.30). The symptom-to-admission time (STAT) did not differ between the two time periods for both STEMIs and NSTEMIs, but the door-to-balloon time (DTBT) for STEMIs was significantly longer in the after-pandemic period (83.0 [67.0-100.7] min vs. 70.0 [59.0-88.7] min, p = 0.004). The 180-day mortality did not significantly differ between the two time periods for both STEMIs (15.9% vs. 11.4%, p = 0.14) and NSTEMIs (9.9% vs. 8.0%, p = 0.59). In conclusion, hospitalizations for MIs decreased after the COVID-19 pandemic. Although the DTBTs were significantly longer in the after-pandemic period, the mid-term outcomes for MIs were preserved.

Low alanine aminotransferase levels are independently associated with mortality risk in patients with atrial fibrillation.

Extremely low alanine aminotransferase (ALT) may reflect aging, frailty, sarcopenia, and malnutrition in several cardiovascular diseases, but the association between low ALT and patient characteristics, cardiovascular and all-cause mortality is not well investigated in the population with atrial fibrillation. We conducted a post hoc analysis of a prospective, observational multicenter study. Patients with nonvalvular AF in the SAKURA AF Registry (n = 3156) were classified into 3 tertiles according to baseline ALT: first (ALT ≤ 15 U/L, n = 1098), second (15 < ALT < 23 U/L, n = 1055), and third (ALT ≥ 23 U/L, n = 1003). The first tertile had an older age; lower body mass index (BMI); higher prevalence of heart failure; and lower hemoglobin, total cholesterol, and triglycerides (all P < 0.05). During median 39.2 months follow-up, the first tertile had significantly higher incidences of cardiovascular and all-cause mortality (log-rank P < 0.001). Lower ALT was significantly associated with the incidence of cardiovascular and all-cause mortality, even after adjusting for clinically relevant factors (P < 0.05). Low ALT may reflect aging, sarcopenia, and malnutrition and be independently associated with a high risk of all-cause mortality in patients with AF.

Edoxaban Monotherapy in Nonvalvular Atrial Fibrillation Patients with Coronary Artery Disease.

Background: Current guidelines recommend an oral anticoagulant (OAC) monotherapy in patients with nonvalvular atrial fibrillation (NVAF) and stable coronary artery disease (CAD) 1 year postpercutaneous coronary intervention (PCI). It might be possible to shorten the time for de-escalation from a dual therapy to monotherapy, but data regarding de-escalation to an edoxaban monotherapy are lacking. This study aimed to assess the clinical safety of an edoxaban monotherapy in patients with NVAF and stable CAD. Methods: A multicenter, prospective, randomized, open-label, and parallel group study was established to investigate the safety of an edoxaban monotherapy in patients with NVAF and stable CAD including over 6 months postimplantation of a third-generation DES and 1 year postimplantation of other stents (PRAEDO AF study). Between March 2018 and June 2020, 147 patients from 8 institutions in Japan were randomized to receive either an edoxaban monotherapy (n = 74) or combination therapy (edoxaban plus clopidogrel, n = 73). The primary study endpoint was the composite incidence of major bleeding and clinically significant bleeding, defined according to the ISTH criteria. Results: Major or clinically significant bleeding occurred in 2 patients in the monotherapy group (1.67% per patient-year) and in 5 patients in the combination therapy group (4.28% per patient-year) (hazard ratio, 0.39; 95% confidence interval, 0.08-2.02). There was no incidence of a myocardial infarction, stent thrombosis, unstable angina requiring revascularization, ischemic stroke, systemic stroke, or hemorrhagic stroke in either of the groups. Conclusions: The edoxaban monotherapy was shown to have acceptable clinical safety in patients with NVAF and stable CAD. The study was registered with the Japan Registry of Clinical Trials (jRCTs031180119).

Clinical outcomes for intracoronary imaging strategies at different medical facilities in Japanese patients with coronary artery disease: the SAKURA imaging PCI Registry.

The relationships between intracoronary imaging modalities and outcomes among Japanese patients with coronary artery disease (CAD) based on the type of medical facility providing outpatient care remain unclear. In this multicenter prospective study (SAKURA PCI Registry), we aimed to investigate the clinical outcomes of patients with CAD who underwent percutaneous coronary intervention (PCI) between April 2015 and December 2018. In this registry, we investigated differences in patient characteristics, intracoronary imaging modalities, and clinical outcomes between two types of medical facilities. Of the 414 patients enrolled in this registry, 196 were treated at two university hospitals, and 218 were treated at five community hospitals (median follow-up 11.0 months). The primary endpoint was clinically relevant events (CREs), including a composite of all-cause death, non-fatal myocardial infarction, clinically driven target lesion revascularization, stent thrombosis, stroke, and major bleeding. Patients treated at university hospitals had higher rates of diabetes (50% vs. 38%, p = 0.015) and malignant tumors (12% vs. 6%, p = 0.015) and more frequent use of multiple intracoronary imaging modalities than patients treated at community hospitals (21% vs. 0.5%, p < 0.001). The Kaplan-Meier incidence of CREs at 1 year was comparable between university hospitals and community hospitals (8.8% vs. 7.3%, p = 0.527, log-rank test). Despite the relatively higher risk among patients in university hospitals with frequent use of multi-intracoronary imaging modalities, adverse clinical events appeared to be comparable between patients with CAD treated at university and community hospitals in Japan.

Gastrointestinal Bleeding From Oral Anticoagulant Therapy Among Japanese Patients With Atrial Fibrillation Identified From the SAKURA Atrial Fibrillation Registry.

BACKGROUND: In the Japanese clinical setting, the prevalence, potential cofounders of gastrointestinal (GI) bleeding from anticoagulant therapy, including direct oral anticoagulants (DOACs) and warfarin, and prognosis after GI bleeding are unclear.Methods and Results:We examined about GI bleeding from anticoagulant therapy using data from the SAKURA AF Registry, a prospective multicenter registry in Japan. Among 3,237 enrollees, 48.8% (n=1,561) were warfarin users and 51.2% (n=1,676) DOAC users. GI bleeding was identified in 68 patients (2.1%). No incidental differences in GI bleeding were observed between the DOAC and warfarin users (32 [1.9%] patients [0.67 events per 100 person-years] vs. 36 [2.3%] patients [0.75 events per 100 person-years], respectively; P=0.43). Multivariate Cox proportional hazard model analysis revealed that creatinine (hazard ratio [HR] 1.379, 95% confidence interval [CI] 1.091-1.743 P=0.007) and hemoglobin (HR 0.814, 95% CI 0.705-0.941, P=0.005) remained independent determinants of GI bleeding. Patients experiencing GI bleeding events had a higher risk of all-cause death (18%) than those without GI bleeding (6%) (P=0.045). CONCLUSIONS: GI bleeding was strongly associated with anemia and renal impairment. Patients experiencing GI bleeding had higher risk for all-cause death than those without GI bleeding.

Association of renal resistance index and arterial stiffness on clinical outcomes in patients with mild-to-moderate renal dysfunction and presence or absence of heart failure with preserved ejection fraction.

The renal arterial resistance index (RI) and the brachial-ankle pulse wave velocity (baPWV) are known as indicators of renal vascular resistance/systemic vascular damage and systemic arterial stiffness. The clinical significance of those parameters on clinical outcomes is poorly known in patients with and without heart failure with preserved ejection fraction (HFpEF). Baseline clinical data and the RI assessed by renal Doppler data, baPWV were obtained in patients with (HFpEF group, n = 60) and without HFpEF (non-HFpEF group, n = 51) who had a reduced estimated glomerular filtration rate (eGFR) of > 30 and < 60 mL/min/1.73 m2). We investigated the association between the RI and baPWV and major clinical outcomes including hospitalization for heart failure, cardiovascular death, myocardial infarction or unstable angina or other cardiovascular events and death from another cause. The RI and baPWV were greater in the HFpEF group than in the non-HF group (0.75 ± 0.07 vs. 0.69 ± 0.08, p < 0.001; 2002 ± 430 vs. 1762 ± 300 cm/s, p = 0.001). The RI correlated significantly with baPWV in the HFpEF (r = 0.382, p = 0.003) and non-HFpEF groups (r = 0.414, p = 0.002). During the median follow-up period of 54 months, major clinical outcomes occurred in 41 (36.9%) patients. The RI value, statin use and the presence of HFpEF were major factors for predicting clinical outcomes by multivariate analysis. Among the patients who had mild-to-moderate renal dysfunction, an increased RI and baPWV were observed in HFpEF patients as compared to non-HFpEF patients, but the baPWV similarly correlated with the RI value regardless of HFpFE patients or not. The strong association between the high RI value and presence of HFpEF and major clinical outcomes, suggests that not only the presence of HFpEF but also the high RI value may help to identify the high-risk patients leading to poor clinical outcomes.

Prognostic Value of Serum N-Terminal Pro-Brain Natriuretic Peptide Level over Heart Failure for Stroke Events and Deaths in Patients with Atrial Fibrillation.

Atrial fibrillation (AF) and heart failure (HF) often coexist. The aims of this study were to explore the factors associated with the serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), and the association between prognosis and a history of HF or the serum NT-proBNP level in Japanese patients with AF.The present sub-study was based on the SAKURA AF Registry, a Japanese multicenter observational registry that included 3267 AF patients (median follow-up period: 39 months). All the patients were receiving warfarin or any of four direct oral anticoagulants. Serum NT-proBNP levels were available for 2417 patients, and the median value was 508 (interquartile range 202-1095) pg/mL at the time of enrollment. Log NT-proBNP was associated with non-paroxysmal AF, creatinine clearance > 60 mL/minute, history of HF and ischemic heart disease, antiarrhythmic drug use, anemia, being elderly female, and history of AF ablation. The relative risk of adverse clinical events, except major bleeding, was significantly higher in the highest NT-proBNP quartile as compared to the lowest quartile (adjusted hazard ratios: 2.87 for death, 2.39 for stroke), but a history of HF was associated only with a higher incidence of all-cause death.Concomitant HF was associated with a higher mortality, but the high NT-proBNP was associated with higher mortality and stroke events. In Japanese AF patients receiving anticoagulant treatment, high serum NT-proBNP levels predict the risk for both stroke events and deaths, and intensive follow-up is needed in such patients.

Impact of the Fibrosis-4 Index on Risk Stratification of Cardiovascular Events and Mortality in Patients with Atrial Fibrillation: Findings from a Japanese Multicenter Registry.

BACKGROUND: Liver diseases drive the development and progression of atrial fibrillation (AF). The Fibrosis-4 (FIB4) index is a non-invasive scoring method for detecting liver fibrosis, but the prognostic impact of using it for AF patients is still unknown. Herein, we evaluated using the FIB4 index as a risk assessment tool for cardiovascular events and mortality in patients with AF. METHODS: We performed a post-hoc analysis of a prospective, observational multicenter study. A total of 3067 patients enrolled in a multicenter Japanese registry were grouped as first tertile (FIB4 index < 1.75, n = 1022), second tertile (1.75 ≤ FIB4 index < 2.51, n = 1022), and third tertile (FIB4 index ≥ 2.51, n = 1023). RESULTS: The third tertile had statistically significant results: older age, lower body mass index, increased heart failure prevalence, and lower clearances of hemoglobin and creatinine (all p < 0.05). During the follow-up period, incidences of major bleeding, cardiovascular events, and all-cause mortality were significantly higher for the third tertile (all p < 0.05). After multivariate adjustment, the third tertile associated independently with cardiovascular events (HR 1.72; 95% CI 1.31-2.25) and all-cause mortality (HR 1.43; 95% CI 1.06-1.95). Adding the FIB4 index to a baseline model with CHA2DS2-VASc score improved the prediction of cardiovascular events and all-cause mortality, as shown by the significant increase in the C-statistic (all p < 0.05), net reclassification improvement (all p < 0.001), and integrated discrimination improvement (all p < 0.001). A FIB4 index ≥ 2.51 most strongly associated with cardiovascular events and all-cause mortality in AF patients with high CHADS2 scores (all p < 0.001). CONCLUSIONS: The FIB4 index is independently associated with risks of cardiovascular events and all-cause mortality in AF patients.

Association of patient satisfaction with direct oral anticoagulants and the clinical outcomes: Findings from the SAKURA AF registry.

BACKGROUND: The burden or benefit of anticoagulation treatment affects patient satisfaction, which may in turn affect the adherence to the treatment and subsequent outcomes. Thus, we hypothesized that the patient satisfaction with direct oral anticoagulants (DOACs) may influence the clinical outcome in patients with atrial fibrillation (AF). METHODS AND RESULTS: We investigated the clinical outcomes among 719 DOAC users (age 71.9 ± 9.1 years, 184 females, and 449 persistent AF) enrolled in the SAKURA AF Registry who completed a satisfaction questionnaire with anticoagulation therapy by means of the Anti-Clot Treatment Scale (ACTS), which included 12-item burden and 3-item benefit scales. During a 41.8-month-follow-up, a stroke/systemic embolism (SE) occurred in 27 patients (3.8%) and major bleeding events in 25 (3.5%). A univariate Cox regression analysis revealed that an older age, persistent AF, higher CHA2DS2-VASc score, no history of AF ablation, lower creatinine clearance, and lower ACTS benefit scores were significantly associated with an increased risk of a stroke/SE, but not with major bleeding events. A low benefit score remained an independent predictor of a stroke/SE even after a multivariate adjustment. The ACTS burden scores were not associated with any clinical events. CONCLUSIONS: We found a strong association between a low benefit satisfaction and increased stroke risk. We should follow patients carefully to educate them on treatment importance for patients unsatisfied with the benefits of DOACs for stroke prevention.

Relationship between the Renal Function and Adverse Clinical Events in Patients with Atrial Fibrillation: A Japanese Multicenter Registry Substudy.

BACKGROUND: Atrial fibrillation (AF) and chronic kidney disease (CKD) often coexist, but the real-world data after approval of direct oral anticoagulants (DOACs) are still lacking in Japan. We investigated the association of the baseline renal function and adverse clinical events and risk of adverse clinical events with DOACs compared to warfarin for each renal functional level in Japanese AF patients. METHODS: The present substudy was based on the SAKURA AF Registry, a Japanese multicenter observational registry (median follow-up period: 39 months). The creatinine clearance (CrCl) values were estimated by the Cockcroft-Gault formula, and divided into normal renal function, and mild and moderate-severe CKD (CrCl ≥ 80, 50-79, <50 mL/min). RESULTS: In the SAKURA AF Registry, the baseline CrCl data were available for 3242 patients (52% for DOAC and 48% for warfarin user). The relative risk of adverse clinical events was significantly higher in the patients with a CrCl < 50 mL/min as compared to those with a CrCl ≥ 80 mL/min (adjusted HRs: 2.53 for death, 2.53 for cardiovascular [CV] events, 2.13 for strokes, and 1.83 for major bleeding). Risks of all adverse clinical events were statistically even between DOAC and warfarin users for each renal function level. CONCLUSION: Moderate-severe CKD was associated with a higher mortality, CV events, strokes, and major bleeding than normal renal function. The safety and effectiveness of DOACs over warfarin were similar for each renal function level. By a worsening renal function, the incidence of adverse clinical events increased, especially deaths and CV events as compared to strokes and major bleeding.

University hospitals, general hospitals, private clinics: Place-based differences in patient characteristics and outcomes of AF-A SAKURA AF Registry Substudy.

BACKGROUND: Relations between characteristics and outcomes of patients in Japan with atrial fibrillation (AF) and the type of medical facility providing their outpatient care are unclear. METHODS AND RESULTS: We compared patient characteristics and outcomes between 2 university hospitals (n=1178), 20 general hospitals (n=1308), and 41 private clinics (n=751) (follow-up: 39.3 months) in the prospective SAKURA AF Registry. Private clinic patients were significantly older than university hospital and general hospital patients (73.4±9.2 vs. 70.3±9.8 and 72.6±8.9 years; p<0.001), and these patients' CHADS2 scores were significantly lower than general hospital, but higher than university hospital patients (1.8±1.1 vs. 2.0±1.2 and 1.6±1.1; p<0.001). The Kaplan-Meier incidences of stroke/systemic embolism (SE) (1.72 vs. 1.58 vs. 0.84 events per 100 patient-years; p=0.120), a cardiovascular event (4.09 vs. 2.44 vs. 1.40; p<0.001), and death were higher (2.39 vs. 2.21 vs. 1.24; p=0.015) for university and general hospital patients than for private clinic patients; the incidences of major bleeding were equivalent (1.78 vs. 1.33 vs. 1.16; p=0.273). After multivariate adjustments, this trend persisted. CONCLUSIONS: Adverse clinical events at small to large hospitals appear to be higher than those at private clinics, suggesting that careful attention for preventing stroke/SE and cardiovascular events should be paid to patients at a university or general hospital.

Comparison of continuous 24-h and 14-day monitoring for detection of otherwise unknown atrial fibrillation: a registry to identify Japanese concealed atrial fibrillation (REAL-AF)-based study.

Early detection of atrial fibrillation (AF) is desirable for preventing strokes. Not only does AF often go undetected in patients being followed up for various disease conditions, but the optimal detection method also remains to be elucidated. In a prospective observational study of 24-h Holter monitoring versus 14-day external loop recording performed for detection of previously undiagnosed AF in 868 Japanese outpatients (aged 75 ± 6 years), with a CHA2DS2-vasc score ≥ 1, but no prior AF episodes, AF was detected during the initial monitoring period in 16 (1.8%) patients, in 7 (1.1% [7/645]) by 24-h monitoring and 9 (4.0% [9/223]) by 14-day monitoring (P = 0.005), and overall in 32 (3.7%) during the 1-year study period. Absence of a beta-blocker therapy and the serum N-terminal pro-brain natriuretic peptide level were independent predictors of a new detection of AF. Oral anticoagulation (OAC) therapy was given to 22 (69%) of the 32 patients in whom AF was detected, and no difference in the incidence of subsequent major adverse events was found between the patients managed with and without oral OAC therapy. Previously unknown AF was documented at a prevalence of 3.7% per year among Japanese with a notable CHA2DS2-VASc score, and 14-day external loop monitoring was significantly more effective for detection of the disorder. A large-scale prospective AF screening study conducted to clarify the type or types of patients who would benefit from "early" OAC therapy for primary stroke prevention is warranted.

Adverse clinical events in Japanese atrial fibrillation patients with and without coronary artery disease-findings from the SAKURA AF Registry.

Background: Although atrial fibrillation (AF) and coronary artery disease (CAD) are increasing in prevalence in Japan, real-world data regarding clinical outcomes in Japanese AF patients with CAD are limited.Methods: The SAKURA AF Registry is a prospective multi-center registry created to investigate outcomes of oral anticoagulant (OAC) use in Japanese AF patients. A study was conducted involving 3237 enrollees from 63 Tokyo-area institutions who were followed up for a median of 39.3 months. Clinical adverse events were compared between the patients accompanied with (n = 312) and without CAD (n = 2925).Results: The incidence of cardiovascular events and all-cause mortality rates were significantly higher among patients with CAD than among those without CAD (5.98 vs 2.52 events per 100 patient-years, respectively, p < 0.001; 3.27 vs 1.94 deaths per 100 patient-years, respectively, p = 0.012), but there was no difference in strokes/transient ischemic attacks or systemic embolisms (1.70 vs 1.34). After a multivariate adjustment, CAD remained a risk factor for cardiovascular events (hazard ratio [HR] = 1.57, 95% confidence interval [CI] = 1.08-2.25, p = 0.018). Among CAD patients, the propensity score-adjusted risk for major bleeding was significantly decreased among direct oral anticoagulant (DOAC) users in comparison to that among warfarin users (HR = 0.29, 95% CI = 0.07-0.94, p = 0.04), but other adverse clinical events did not differ significantly between these two groups.Conclusions: CAD did not appear to be a major determinant of strokes/TIAs, major bleeding, or all-cause mortality, but appeared to increase the risk of cardiovascular events in Japanese AF patients. The risk of major bleeding in CAD patients appeared to decrease when a DOAC rather than warfarin was administered. The data suggested that patients with AF and concomitant CAD require careful management and follow-up to reduce cardiovascular risks, and DOACs may be a better choice over warfarin when considering the risk of major bleeding.

Worsening renal function, adverse clinical events and major determinants for changes of renal function in patients with atrial fibrillation: a Japanese multicenter registry substudy.

Objective: To explore factors related to changing renal function and the prognostic effect of worsening renal function in patients with atrial fibrillation (AF). Methods: The present substudy was based on the SAKURA AF Registry, a Japanese multicenter prospective observational registry that includes 3267 AF patients from 63 institutions in the Tokyo area. Worsening renal function was defined as an estimated glomerular filtration rate (eGFR) decrease equaling more than 20% of the patient's baseline eGFR. Results: During a median 39.3 month follow-up period, patients' eGFR decreased annually by a mean value of 1.07 mL/min/1.73 m2. Multivariable analysis showed that age ≥75 years, body weight ≤50 kg, a history of heart failure and initially preserved renal function (creatinine clearance [CrCl] ≥ 60 mL/min) were significantly associated with a decrease in eGFR, whereas a history of AF ablation was associated with a maintain in eGFR. The 194 patients with worsening renal function were at significantly increased risk of death, stroke and major bleeding (adjusted hazard ratios [HRs]: 2.06, 1.97 and 2.23, respectively). Conclusion: Age ≥75 years, body weight ≤50 kg, a history of heart failure and initially preserved renal function appear to promote renal dysfunction in patients with AF, but a history of AF ablation seems to have a favorable effect. Worsening renal function seems to increase AF patients' risk of adverse clinical events. Renal function can decline quickly; thus, early intervention including AF ablation is warranted.

Oral anticoagulant use and clinical outcomes in elderly Japanese patients: findings from the SAKURA AF Registry.

Direct-acting oral anticoagulants (DOACs) are widely used in aged Japanese patients with atrial fibrillation (AF), but outcome data for such patients are limited. We compared outcomes between 1895 (58.5%) patients aged < 75 years (non-elderly), 1078 (33.3%) 75-84 years (elderly) and 264 (8.2%) ≥ 85 years (very elderly) enrolled in a prospective multicenter registry. Kaplan-Meier analysis (median follow-up: 39.3 months) revealed a significantly high incidence of stroke/systemic embolism (SE) among the very elderly relative to that among the non-elderly or elderly (3.2 vs. 1.2 and 1.5 events per 100 patient-years, p < 0.001). Major bleeding in the non-elderly group was significantly infrequent relative to that among the elderly or very elderly group (1.1 vs. 1.6 vs. 1.8 events, p = 0.033). After multivariate adjustment, the stroke/SE incidence was comparable between DOAC and warfarin users, regardless of age, but major bleeding decreased significantly among very elderly DOAC users (adjusted HR 0.220, 95% CI 0.042-0.920). The greater increasing incidence of stroke/SE than major bleeding as patients age suggests that stroke prevention should outweigh the bleeding risk when anticoagulants are being considered for aged patients. Our data indicated that DOACs can be a therapeutic option for stroke prevention in very elderly patients.

Clinical Outcomes of Off-Label Dosing of Direct Oral Anticoagulant Therapy Among Japanese Patients With Atrial Fibrillation Identified From the SAKURA AF Registry.

BACKGROUND: Off-label dosing of direct oral anticoagulants (DOACs) is encountered clinically among patients with atrial fibrillation (AF), although data on the clinical outcomes of over- and under-dosing are lacking in Japan. Methods and Results: We examined the clinical outcomes of off-label DOAC dosing using the SAKURA AF Registry, a prospective multicenter registry in Japan. Among 3,237 enrollees, 1,676 under any of the 4 DOAC regimens were followed up for a median of 39.3 months: 746 (45.0%), appropriate standard-dose; 477 (28.7%), appropriate low-dose; 66 (4.0%), over-dose; and 369 (22.2%) under-dose. Compared with the standard-dose group, patients in the under- and over-dose groups were significantly older and had a higher stroke risk. After multivariate adjustment, stroke/systemic embolism (SE) and death events were equivalent between the standard- and under-dose groups, but major bleeding events tended to be lower in the under-dose group (hazard ratio [HR] 0.474, P=0.0739). Composite events (stroke/SE, major bleeding, or death) were higher in the over-dose than in the standard-dose group (HR 2.714, P=0.0081). CONCLUSIONS: Clinical outcomes were not worse for under-dose than for standard-dose users among patients with different backgrounds. Over-dose users, however, were at higher risk for all clinical events and required careful follow-up. Further studies are needed to clarify the safety and effectiveness of off-label DOAC dosing in Japan.

Different determinants of vascular and nonvascular deaths in patients with atrial fibrillation: A SAKURA AF Registry substudy.

BACKGROUND: The incidence and causes of death among patients in Japan treated for atrial fibrillation (AF), a major determinant of strokes and death, with direct oral anticoagulants (DOACs) are unclear. This study's aim was two-fold: to compare the incidence and causes of death between DOAC and warfarin users in Japan and to identify the factors associated with vascular and nonvascular death in the Japanese AF population. METHODS: The study was based on the SAKURA AF registry, in which clinical events were tracked in 3267 enrollees from 63 institutions for 2-4 years. Enrollees included warfarin users (n=1577) and users of any of 4 DOACs (n=1690). The incidence, cause, and major determinants of death were analyzed. RESULTS: During a median 39.3-month follow-up, 200 patients died, with most succumbing to cardiac death (25%), malignancies (21%), or respiratory infections (20%). There was no significant difference in deaths from any cause between warfarin and DOAC users (108 vs. 92 patients, p=0.34). An age ≥75 years was found to be a major determinant of death, but the relative risk (vs. <75 years) was greater for nonvascular death (hazard ratio: 2.85 and 4.97 for age 75-84 and ≥85 years, respectively) than vascular death (2.14 and 2.98 for 75-84 and ≥85 years, respectively). Heart failure, renal dysfunction, and the type of institution were major determinants of vascular death, and a male sex, weight <50kg, and anemia were major determinants of nonvascular death. CONCLUSIONS: The results of our AF registry-based study, in which two thirds of the enrolled patients succumbed to cardiac death, malignancies, or respiratory infections within 2- 4 years and use of DOACs rather than warfarin did not reduce the mortality, indicated that a management of AF that includes prophylaxis for vascular and nonvascular events in addition to strokes is warranted.

Patient Satisfaction with Direct Oral Anticoagulants and Warfarin.

The burden of anticoagulation treatment affects patient satisfaction, which in turn affects adherence to treatment. Thus, we must thoroughly understand the advantages of direct oral anticoagulants (DOACs) over vitamin K antagonists (VKAs)/warfarin given for stroke prevention in patients with atrial fibrillation (AF). We compared satisfaction with anticoagulation therapy between 654 DOAC and 821 warfarin users enrolled in the SAKURA AF Registry. Satisfaction was assessed by means of the Anti-Clot Treatment Scale (ACTS), which includes 12-item burdens and 3-item benefits scales, and the treatment satisfaction questionnaire for medication II (TSQM II), which includes 2-item effectiveness, 3-item side effects, 3-item convenience, and 2-item global satisfaction domains. There were no significant between-group differences in TSQM II convenience (67.6 ± 14.5 versus 68.9 ± 14.5, P = 0.280), effectiveness (65.0 ± 13.3 versus 66.0 ± 15.0, P = 0.422), side effects (93.6 ± 13.7 versus 92.8 ± 14.4, P = 0.067), and global satisfaction (64.7 ± 14.9 versus 66.0 ± 14.6, P = 0.407) scores. In contrast, although there was no significant between-group difference in the ACTS benefits scores (9.8 ± 3.1 versus 10.1 ± 3.2, P = 0.051), the ACTS burdens scores (54.5 ± 6.3 versus 52.7 ± 6.9, P < 0.0001) were significantly higher in the DOAC users, independent of age, sex, and DOAC type. We can expect greater burden satisfaction with anticoagulation treatment in patients given a DOAC versus VKA/warfarin. The reduced burden of treatment will translate to greater patient adherence to their treatment plans and a positive effect on clinical outcomes.

Three-Year Clinical Outcomes Associated With Warfarin vs. Direct Oral Anticoagulant Use Among Japanese Patients With Atrial Fibrillation　- Findings From the SAKURA AF Registry.

BACKGROUND: Although direct oral anticoagulants (DOACs) are widely used in Japanese patients with atrial fibrillation (AF), large-scale investigations into their use, with suitable follow-up times and rates, are lacking. Methods and Results: The SAKURA AF Registry is a prospective multicenter registry created to investigate therapeutic outcomes of oral anticoagulant (OAC) use in Japanese AF patients. We conducted a study involving 3,237 enrollees from 63 institutions in the Tokyo area being treated with any of 4 DOACs (n=1,676) or warfarin (n=1,561) and followed-up for a median of 39.3 months (range 28.5-43.6 months). Analyses of 1- and 2-year follow-up data available for 3,157 (97.5%) and 2,952 (91.2%) patients, respectively, showed no significant differences in rates of stroke or systemic embolism (SE), major bleeding, and all-cause mortality for DOAC vs. warfarin users (1.2 vs. 1.8%/year, 0.5 vs. 1.2%/year, and 2.1 vs. 1.7%/year, respectively). Under propensity score matching, the incidence of stroke or SE (P=0.679) and all-cause death (P=0.864) remained equivalent, but the incidence of major bleeding was significantly lower (P=0.014) among DOAC than warfarin users. CONCLUSIONS: A high follow-up rate allowed us to obtain reliable data on the status of OAC use and therapeutic outcomes among AF patients in Japan. Warfarin and DOACs appear to yield equivalent 3-year stroke and all-cause mortality rates, but DOACs appear to reduce the risk of major bleeding.

Current use of direct oral anticoagulants for atrial fibrillation in Japan: Findings from the SAKURA AF Registry.

BACKGROUND: Large-scale investigations on the use of oral anticoagulants including direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) have not included Japanese patients. METHODS: We established the multicenter SAKURA AF Registry to support prospective observational research on the status of anticoagulation treatment, especially with DOAC, for AF in Japan. We enrolled 3266 AF patients treated with warfarin (n=1577) or any of 4 DOACs (n=1689) from 63 institutions (2 cardiovascular centers, 13 affiliated hospitals or community hospitals, and 48 private clinics) in the Tokyo area. RESULTS: We conducted our first analysis of the registry data, and although we found equivalent mean age between the DOAC and warfarin users (71.8±9.5 vs. 72.3±9.4 years, p=0.2117), we found a slightly lower risk of stroke (CHADS2 score of 0 or 1 [46.9% vs. 39.4%, p<0.0001]) and significantly better creatinine clearance in DOAC users (70.4±27 vs. 65.6±25.7 mL/min, p<0.0001). Importantly, we documented under-dosing in 32% of warfarin users and inappropriate-low-dosing in 19.7-27.6% of DOAC users. CONCLUSIONS: Our initial analysis of the SAKURA AF Registry data clarified the real-world use of anticoagulants, which includes DOACs and warfarin in Japan. The DOAC users were at a lower risk for stroke than the warfarin users. In 20-30% of DOAC users, the dose was inappropriately reduced.