Effect of Catheter Ablation for Atrial Fibrillation in Heart Failure With Mid-Range or Preserved Ejection Fraction　- Pooled Analysis of the AF Frontier Ablation Registry and Hokuriku-Plus AF Registry.

BACKGROUND: A recent randomized trial demonstrated that catheter ablation for atrial fibrillation (AF) in patients with heart failure with reduced ejection fraction (EF) is associated with a reduction in death or heart failure. However, the effect of catheter ablation for AF in patients with heart failure with mid-range or preserved EF is unclear.Methods and Results: We screened 899 AF patients (72.4% male, mean age 68.4 years) with heart failure and left ventricular EF ≥40% from 2 Japanese multicenter AF registries: the Atrial Fibrillation registry to Follow the long-teRm Outcomes and use of aNTIcoagulants aftER Ablation (AF Frontier Ablation Registry) as the ablation group (525 patients who underwent ablation) and the Hokuriku-Plus AF Registry as the medical therapy group (374 patients who did not undergo ablation). Propensity score matching was performed in these 2 registries to yield 106 matched patient pairs. The primary endpoint was a composite of cardiovascular death and hospitalization for heart failure. At 24.6 months, the ablation group had a significantly lower incidence of the primary endpoint (hazard ratio 0.32; 95% confidence interval 0.13-0.70; P=0.004) than the medical therapy group. CONCLUSIONS: Compared with medical therapy, catheter ablation for AF in patients with heart failure and mid-range or preserved EF was associated with a significantly lower incidence of cardiovascular death or hospitalization for heart failure.

Erratum to "Twice- or once-daily dosing of direct oral anticoagulants and gastrointestinal bleeding in patient with atrial fibrillation" [Am. Heart J. Plus: Cardiol. Res. Pract. Volume 22, October 2022, 100203].

[This corrects the article DOI: 10.1016/j.ahjo.2022.100203.].

Sex-related difference in bleeding and thromboembolic risks in patients with atrial fibrillation treated with direct oral anticoagulants.

BACKGROUND: Sex-related difference in non-valvular atrial fibrillation (NVAF) patients treated with direct oral anticoagulants (DOACs) is still to be investigated. We aimed to investigate sex difference in patient characteristics and clinical outcomes of the NVAF patients treated with DOAC in the real-world Japanese clinical practice. METHODS AND RESULTS: We conducted a single-center prospective observational registry of NVAF patients treated with DOACs: the DIRECT registry (women, N = 806; men, N = 1410; follow-up duration, 407 ± 388 days). In the present study, all patients were stratified by sex. Women had significantly higher age, lower body weight, lower hemoglobin, lower creatinine clearance, and a higher bleeding risk estimate (ORBIT score) and higher thromboembolic risk estimates (CHADS2 score and CHA2DS2VAS score) than men. Albeit the different bleeding risk estimates by the ORBIT score between both sexes, the Kaplan-Meier estimates of bleeding events were similar between both sexes (Log-rank test P = 0.152 for clinically significant bleeding, and P = 0.122 for major bleeding). The Kaplan-Meier estimated 2 year rate of stroke/systemic embolism was higher in women than in men (4.9 ± 1.3% vs. 2.3 ± 0.6%, Log-rank test P = 0.048). CONCLUSIONS: Our real-world study of patients treated with DOAC showed that Japanese women experienced comparable bleeding events as compared to men despite the higher bleeding risk estimates. The higher thromboembolic risk estimates in women than in men translated into the higher thromboembolic event rates.Clinical trials identifier: UMIN000033283.

Quantitative Validation of the Coronary Angioscopic Yellow Plaque with Lipid Core Burden Index Assessed by Intracoronary Near-Infrared Spectroscopy.

AIM: We aimed to validate the subjective and qualitative angioscopic findings by the objective and quantitative near-infrared spectroscopic (NIRS) assessment to compensate each other's drawbacks. METHODS: This is a single-center prospective observational study. Patients undergoing a planned follow-up coronary angiography after percutaneous coronary intervention were prospectively enrolled from January 2018 to April 2019. The major three vessels were examined by NIRS-intravascular ultrasound, followed by coronary angioscopic evaluation. Yellow color grade on angioscopy was classified into four grades (0, white; 1, slight yellow; 2, yellow; and 3, intensive yellow) at a location of maximal lipid core burden index over 4 mm [LCBI (4)] on NIRS in each vessel. RESULTS: A total of 95 lesions in 44 patients (72.6±6.7 years, 75% male) were analyzed. LCBI (4) was significantly different among different yellow color grades by coronary angioscopy (ANOVA, p＜0.001). Positive correlation was found between angioscopic yellow color grade and LCBI (4) (beta coefficient 164.8, 95% confidence interval 122.9-206.7; p＜0.001). The best cutoff value of LCBI (4) to predict the presence of yellow plaque (yellow color grade ≥ 2) was 448 (sensitivity 79.3%, specificity 69.7%, C-statistic 0.800, 95% confidence interval 0.713-0.887, p＜0.001). CONCLUSION: The qualitative angioscopic assessment was objectively validated by the quantitative NIRS evaluation, which would be helpful for the reinterpretation of the existing evidences of both imaging modalities.

Impact of sinus rhythm maintenance on major adverse cardiac and cerebrovascular events after catheter ablation of atrial fibrillation: insights from AF frontier ablation registry.

The impact of catheter ablation for atrial fibrillation (AF) on cardiovascular events and mortality is controversial. We investigated the impact of sinus rhythm maintenance on major adverse cardiac and cerebrovascular events after AF ablation from a Japanese multicenter cohort of AF ablation. We investigated 3326 consecutive patients (25.8% female, mean age 63.3 ± 10.3 years) who underwent catheter ablation for AF from the atrial fibrillation registry to follow the long-term outcomes and use of anti coagulants after ablation (AF frontier ablation registry). The primary endpoint was a composite of stroke, transient ischemic attack, cardiovascular events, and all-cause death. During a mean follow-up of 24.0 months, 2339 (70.3%) patients were free from AF after catheter ablation, and the primary composite endpoint occurred in 144 (4.3%) patients. The AF nonrecurrence group had a significantly lower incidence of the primary endpoint (1.8 per 100 person-years) compared with the AF recurrence group (3.0 per 100 person-years, p = 0.003). The multivariate analysis revealed that freedom from AF (hazard ratio 0.61, 95% confidence interval 0.44-0.86, p = 0.005) was independently associated with the incidence of the composite event. In the multicenter cohort of AF ablation, sinus rhythm maintenance after catheter ablation was independently associated with lower rates of major adverse cardiac and cerebrovascular events.

Different Determinants of the Recurrence of Atrial Fibrillation and Adverse Clinical Events in the Mid-Term Period After Atrial Fibrillation Ablation.

BACKGROUND: It is unclear whether there are differences in the clinical factors between atrial fibrillation (AF) recurrence and adverse clinical events (AEs), including stroke/transient ischemic attack (TIA), major bleeding, and death, after AF ablation.Methods and Results:We examined the data from a retrospective multicenter Japanese registry conducted at 24 cardiovascular centers between 2011 and 2017. Of the 3,451 patients (74.1% men; 63.3±10.3 years) who underwent AF ablation, 1,046 (30.3%) had AF recurrence and 224 (6.5%) suffered AEs (51 strokes/TIAs, 71 major bleeding events, and 36 deaths) over a median follow-up of 20.7 months. After multivariate adjustment, female sex, persistent and long-lasting persistent AF (vs. paroxysmal AF), and stepwise increased left atrial diameter (LAd) quartiles were significantly associated with post-ablation recurrences. A multivariate analysis revealed that an age ≥75 years (vs. <65 years), body weight <50 kg, diabetes, vascular disease, left ventricular (LV) ejection fraction <40% (vs. ≥50%), Lad ≥44 mm (vs. <36 mm), and creatinine clearance <50 mL/min were independently associated with AE incidences, but not with recurrences. CONCLUSIONS: This study disclosed different determinants of post-ablation recurrence and AEs. Female sex, persistent AF, and enlarged LAd were determinants of post-ablation recurrence, whereas an old age, comorbidities, and LV and renal dysfunction rather than post-ablation recurrence were AEs determinants. These findings will help determine ablation indications and post-ablation management.

Comparison of Low-Dose Direct Oral Anticoagulants for Patients <80 Versus ≥80 Years of Age With Atrial Fibrillation.

Evidence on the efficacy and safety of low-dose direct oral anticoagulant (DOAC) in older patients with nonvalvular atrial fibrillation is still scarce. We conducted a single-center prospective registry of patients with nonvalvular atrial fibrillation treated with DOACs: the DIRECT registry (n = 2,216; follow-up, 407 ± 388 days, UMIN000033283). The whole population was divided into 2 groups: the older group (age ≥80 years, n = 548) versus the younger group (age <80 years, n = 1,668). Primary safety and efficacy end points were major bleeding according to the International Society on Thrombosis and Haemostasis criteria, and stroke or systemic embolism (SSE), respectively. Effects of known risk factors and low-dose DOAC on major bleeding and SSE were assessed using a multivariable Cox proportional hazards model. In the older group, low-dose DOAC was associated with lower bleeding events (hazard ratio 0.279, 95% confidence interval 0.087 to 0.892, p = 0.031) but was not associated with increased SSE (p = 0.894). In the younger group, low-dose DOAC was neither associated with risk of major bleeding nor SSE (both p >0.05). In conclusion, in older patients, low-dose DOAC was associated with reduced risk of major bleeding without compromising its efficacy.

Sex Differences in the Efficacy of Pulmonary Vein Isolation Alone vs. Extensive Catheter Ablation in Patients With Persistent Atrial Fibrillation.

BACKGROUND: Women experience more severe arrhythmogenic substrates. This study hypothesized that an extensive ablation strategy, such as linear ablation and/or complex fractionated atrial electrogram (CFAE) ablation in addition to pulmonary vein isolation (PVI-plus), might be effective for women, whereas the PVI alone strategy (PVI-alone) might be sufficient for men to maintain sinus rhythm. The aim of this study was to test this hypothesis.Methods and Results: This study is a post-hoc subanalysis of the EARNEST-PVI trial focusing on sex differences in the efficacies of different ablation strategies. The EARNEST-PVI trial was a prospective, multicenter, randomized, and open-label non-inferiority trial in patients with persistent AF. The primary endpoint was recurrence of AF, atrial flutter, or atrial tachycardia. The EARNEST-PVI trial randomized 376 (76%) men (PVI-alone 186, PVI-plus 190) and 121 (24%) women (PVI-alone 63, PVI-plus 58). The event rate was significantly lower for men and numerically lower for women in the PVI-plus than the PVI-alone group, and there was no interaction between men and women (hazard ratio, 0.641; 95% confidence interval, 0.417-0.985; P value, 0.043 for men vs. hazard ratio, 0.661; 95% confidence interval, 0.352-1.240; P value, 0.197 for women; P value for interaction, 0.989). CONCLUSIONS: The superiority of the extensive ablation strategy vs. the PVI-alone strategy for persistent AF was consistent across both sexes.

Twice- or once-daily dosing of direct oral anticoagulants and gastrointestinal bleeding in patient with atrial fibrillation.

Aims: Direct oral anticoagulant (DOAC) is widely used for the prevention of embolic stroke in non-valvular atrial fibrillation (NVAF) patients. However, the gastrointestinal bleeding risk in several DOAC regimens was higher than warfarin, especially in once-daily regimens. Methods and results: We conducted a single-center prospective registry of patients with NVAF treated with DOACs: the DIRECT registry (N = 2216; follow-up duration 650 [IQR 103-1574] days, UMIN000033283). All patients were divided into 2 groups: the twice-daily (BID) regimen group (dabigatran and apixaban) versus the once-daily (QD) regimen group (rivaroxaban and edoxaban). Out of 2216 patients, we successfully matched 904 patients in the QD group and 904 patients in the BID group using propensity score. The primary endpoint was gastrointestinal bleeding defined as any bleeding in the gastrointestinal tract that was identified through medical records regardless of bleeding site or severity. The BID group showed a significantly lower gastrointestinal bleeding rate than the QD group (3.5/100 person-year vs. 6.2/100 person-year, log-rank P < 0.0001). The secondary endpoints were all death, stroke, major bleeding, and any bleeding. The rate of major bleeding was significantly lower in patients with BID regimen group (log-rank P = 0.040). In contrast, all death, stroke, and any bleeding did not differ between both groups (log-rank P = 0.280, 0.520 and 0.066, respectively). Conclusions: The BID regimen as compared with the QD regimen was associated with reduced risk of gastrointestinal bleeding.

The efficacy and safety of left atrial low-voltage area guided ablation for recurrence prevention compared to pulmonary vein isolation alone in patients with persistent atrial fibrillation trial: Design and rationale.

Recurrence rates of atrial fibrillation (AF) after pulmonary vein isolation (PVI) are higher in patients with a left atrial low-voltage area (LVA) than those without. However, the efficacy of LVA guided ablation is still unknown. The purpose of this study-the Efficacy and Safety of Left Atrial Low-voltage Area Guided Ablation for Recurrence Prevention Compared to Pulmonary Vein Isolation Alone in Patients with Persistent Atrial Fibrillation trial (SUPPRESS-AF trial)-is to elucidate whether LVA guided ablation in addition to PVI is superior to PVI alone in patients with persistent AF. The Osaka Cardiovascular Conference will conduct a multicenter, randomized, open-label trial aiming to examine whether LVA guided ablation in addition to PVI is superior to PVI alone in patients with persistent AF and LVAs. The primary outcome is the recurrence of AF documented by scheduled or symptom-driven electrocardiography (ECG) during the 1 year follow-up period after the index ablation. The key secondary endpoints include all-cause death, symptomatic stroke, bleeding events, and other complications related to the procedure. A total of 340 patients with an LVA will be enrolled and followed up to 1 year. The SUPPRESS-AF trial is a randomized controlled trial designed to assess whether LVA guided ablation in addition to PVI is superior to PVI alone for patients with persistent AF and LVAs detected while undergoing their first catheter ablation.

Efficacy of Extensive Ablation for Persistent Atrial Fibrillation With Trigger-Based vs. Substrate-Based Mechanisms　- A Prespecified Subanalysis of the EARNEST-PVI Trial.

BACKGROUND: Extensive ablation in addition to pulmonary vein isolation (PVI) would be effective for modification of non-pulmonary vein (non-PV) substrates, whereas PVI might be sufficient for elimination of PV triggers. This study aimed to test the hypothesis that in patients with reproducible atrial fibrillation (AF) triggered by premature atrial contractions originating only from PVs, PVI alone can be sufficient to maintain sinus rhythm.Methods and Results:This study is a prespecified subanalysis of the EARNEST-PVI randomized controlled trial. This study investigated the efficacy of the PVI-alone strategy (PVI-alone) in comparison with the extensive strategy (PVI-plus) for persistent AF with a trigger-based mechanism vs. a substrate-based mechanism. Patients were stratified into 3 groups based on AF mechanisms: (1) Substrate group (N=236); (2) PV trigger group (N=236); and (3) non-PV trigger group (N=24). The hazard ratios for AF recurrence of the PVI-alone strategy with reference to the PVI-plus strategy were 1.456 (95% confidence interval [CI] [0.864-2.452]) in the substrate group, 1.648 (95% CI 0.969-2.801) in the PV trigger group, and 0.937 (95% CI 0.252-3.488) in the non-PV trigger group. No significant interaction between ablation strategy and AF mechanism was observed (P for interaction=0.748). CONCLUSIONS: This study indicated that the efficacies of the PVI-alone strategy compared with the PVI-plus strategy were consistent across persistent AF with trigger-based and substrate-based mechanisms.

Comparable neointimal healing in patients with stable coronary lesions and acute coronary syndrome: 3-month optical coherence tomography analysis.

We aimed to assess a possible difference of the neointimal coverage status and its quality after implantation of the current-generation metallic stents in patients with acute coronary syndrome (ACS) vs. stable coronary lesions (non-ACS). We comprehensively analyzed three prospective single-center observational studies RESTORE (UMIN000033009), HEAL-BioFreedom (UMIN000029692), and HEAL-BioFreedom ACS (UMIN000034769). All patients who received successful optical coherence tomography (OCT) examination at planned 3-month follow-up after stent implantation were analyzed. Study population was divided into two groups, ACS vs. non-ACS groups. We evaluated standard OCT variables, coverage percent, and the quantitative light property values including light intensity, attenuation, and backscatter of neointima. A total of 177 lesions from 154 patients (ACS 44 lesions vs. non-ACS 133 lesions) were analyzed. At 3-month follow-up, coverage percent (ACS 91.5  ±  9.5% vs. non-ACS 91.8  ±  9.0%, P = 0.722) and neointimal thickness (ACS 59.5  ±  32.3 µm vs. non-ACS 58.2  ±  32.3 µm, P = 0.760) did not significantly differ. Light property values were similar between both groups (light intensity 159.29  ±  72.20 vs. 159.45  ± 63.78, P = 0.654; light attenuation 0.88  ±  0.26 vs. 0.87  ±  0.24 m-1, P = 0.988; backscatter 4.86  ±  0.58 vs. 4.83  ±  0.57, P = 0.812). The similarity of the neointimal quality in ACS and non-ACS patients was consistent across the 6 different types of current-generation metallic stents (P for interaction > 0.05). Our findings suggested the comparable neointimal characteristics 3 months after implantation of the current-generation metallic stents in patients with ACS and stable coronary lesions by quantitative OCT methodology.

Pulmonary vein isolation alone vs. more extensive ablation with defragmentation and linear ablation of persistent atrial fibrillation: the EARNEST-PVI trial.

AIMS: Previous studies could not demonstrate any benefit of more intensive ablation in addition to pulmonary vein isolation (PVI) including complex fractionated atrial electrogram (CFAE) and linear ablation for recurrence in the initial catheter ablation of persistent atrial fibrillation (AF). This study aimed to establish the non-inferiority of PVI alone to PVI plus these additional ablation strategies. METHODS AND RESULTS: Patients with persistent AF who underwent an initial catheter ablation (n = 512, long-standing persistent AF; 128 cases) were randomly assigned in a 1:1 ratio to either PVI alone (PVI-alone group) or PVI plus CFAE and/or linear ablation (PVI-plus group). After excluding 15 cases who did not receive procedures, we analysed 249 and 248 patients, respectively. The primary endpoint was recurrence of AF, atrial flutter, and/or atrial tachycardia, and the non-inferior margin was set at a hazard ratio of 1.43. In the PVI-plus group, 85.1% of patients had linear ablation and 15.3% CFAE ablation. After 12 months, freedom from the primary endpoint occurred in 71.3% of patients in the PVI-alone group and in 78.3% in the PVI-plus group [hazard ratio = 1.56 (95% confidence interval: 1.10-2.24), non-inferior P = 0.3062]. The procedure-related complication rates were 2.0% in the PVI-alone group and 3.6% in the PVI-plus group (P = 0.199). CONCLUSION: This randomized trial did not establish the non-inferiority of PVI alone to PVI plus linear ablation or CFAE ablation in patients with persistent AF, but implied that the PVI plus strategy was promising to improve the clinical efficacy (NCT03514693).

Clinical outcomes of ablation versus non-ablation therapy for atrial fibrillation in Japan: analysis of pooled data from the AF Frontier Ablation Registry and SAKURA AF Registry.

Whether ablation for atrial fibrillation (AF) is, in terms of clinical outcomes, beneficial for Japanese patients has not been clarified. Drawing data from 2 Japanese AF registries (AF Frontier Ablation Registry and SAKURA AF Registry), we compared the incidence of clinically relevant events (CREs), including stroke/transient ischemic attack (TIA), major bleeding, cardiovascular events, and death, between patients who underwent ablation (n = 3451) and those who did not (n = 2930). We also compared propensity-score matched patients (n = 1414 in each group). In propensity-scored patients who underwent ablation and those who did not, mean follow-up times were 27.2 and 35.8 months, respectively. Annualized rates for stroke/TIA (1.04 vs. 1.06%), major bleeding (1.44 vs. 1.20%), cardiovascular events (2.15 vs. 2.49%) were similar (P = 0.96, 0.39, and 0.35, respectively), but annualized death rates were lower in the ablation group than in the non-ablation group (0.75 vs.1.28%, P = 0.028). After multivariate adjustment, the risk of CREs was statistically equivalent between the ablation and non-ablation groups (hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.71-1.11), but it was significantly low among patients who underwent ablation for paroxysmal AF (HR 0.68 [vs. persistent AF], 95% CI 0.49-0.94) and had a CHA2DS2-VASc score < 3 (HR 0.66 [vs. CHA2DS2-VASc score ≥ 3], 95% CI 0.43-0.98]). The 2-year risk reduction achieved by ablation may be small among Japanese patients, but AF ablation may benefit those with paroxysmal AF and a CHA2DS2-VASc score < 3.

Dose of Direct Oral Anticoagulants and Adverse Outcomes in Asia.

The present study aimed to assess the associations between dosing of DOACs and outcomes in patients with non-valvular atrial fibrillation (NVAF). Direct oral anticoagulants (DOACs) require dose adjustment according to patient or clinical factors for patients with NVAF. We conducted a single-center prospective registry of NVAF patients with DOACs: DIRECT registry (UMIN000033283). In the present analysis, we categorized the patients (n = 2,216) into 5 groups: appropriate standard-dose (n = 907, 40.9%), appropriate low-dose (n = 833, 37.6%), overdose (n = 117, 5.3%), underdose (n = 338, 15.3%), and contraindication (n = 21, 0.9%). The efficacy endpoints were major adverse cardiovascular event (MACE: a composite of all-cause death, myocardial infarction, and stroke/systemic embolism) and its individual components. The safety end points were adverse bleeding events including clinically significant bleeding, major bleeding, and gastro-intestinal bleeding. All NVAF patients treated with DOACs in our institution from 2011 to 2017 were enrolled (71.6 ± 10.8 years, 36.4% female, follow-up duration: 407.2 ± 388.3 days). Appropriate low-dose group were older, more likely female, had a higher CHADS2 and ORBIT scores than the other groups. MACE (7.4%) and clinically significant bleeding (26.2%) occurred most frequently in the appropriate low-dose group. However, after adjustment for various confounders, appropriate dose reduction of DOAC showed 35.4% risk reduction of clinically significant bleeding (adjusted hazard ratio 0.646, 95% CI [0.469 to 0.890], p = 0.007) with no impairment of efficacy end points. In the real-world Asian clinical practice, four fifths of the NVAF patients received appropriate dose of DOACs. Appropriate dose reduction was associated with decrease in clinically significant bleeding and no significant impairment in efficacy end points.

Clinical Outcomes of Off-Label Underdosing of Direct Oral Anticoagulants After Ablation for Atrial Fibrillation.

Direct oral anticoagulants (DOACs) are sometimes prescribed at off-label under-doses for patients who have undergone ablation for atrial fibrillation (AF). This practice may be an attempt to balance the risk of bleeding against that of stroke or AF recurrence.We examined outcomes of 1163 patients who continued use of a DOAC after ablation. The patients were enrolled in a large (3530 patients) multicenter registry in Japan. The study patients were classified as 749 (64.4%) appropriate standard-dose DOAC users, 216 (18.6%) off-label under-dose DOAC users, and 198 (17.0%) appropriate low-dose DOAC users.Age and CHA2DS2-VASc scores differed significantly between DOAC dosing regimens, with patients given an appropriate standard-dose being significantly younger (63.3 ± 9.4 versus 64.8 ± 9.5 versus 73.2 ± 6.8 years, P < 0.0001) and lower (2.1 ± 1.5 versus 2.4 ± 1.6 versus 3.4 ± 1.4, P < 0.0001) than those given an off-label under-dose or an appropriate low-dose. During the median 19.0-month follow-up period, the AF recurrence rate was similar between the appropriate standard-dose and off-label under-dose groups but relatively low in the appropriate low-dose group (42.5% versus 41.2% versus 35.4%, P = 0.08). Annualized rates of thromboembolic events, major bleeding, and death from any cause were 0.47%, 0.70%, and 0.23% in the off-label under-dose group, while those rates were 0.74%, 0.73%, and 0.65% in the appropriate standard-dose, and 1.58%, 2.12%, and 1.57% in the appropriate low-dose groups.In conclusion, the clinical adverse event rates for patients on an off-label under-dose DOAC regimen after ablation, predicated on careful patient evaluations, was not high as seen with that of patients on a standard DOAC dosing regimen.

Recurrent Fulminant Myocarditis Accompanied by Lymphoid Follicle Formation in Myocardium.

A 76-year-old man developed repeated fulminant myocarditis in a short period, and immunosuppressive therapy was remarkably effective. A pathologic evaluation showed that inflammatory cells had infiltrated the myocardium. Not only invasion of inflammatory cells but also the formation of lymphoid follicle was noted. Chronic myocardial inflammation was proven, but cardiac sarcoidosis was negative according to the results of various examinations. This is the first report of recurrent autoimmune myocarditis with a lymphoid follicle in the myocardium. These findings may suggest a novel pathogenesis of myocarditis.

Persistent Systemic Inflammation Is Associated With Bleeding Risk in Atrial Fibrillation Patients.

BACKGROUND: This study investigated the impact of systemic inflammation on bleeding risk in non-valvular atrial fibrillation (NVAF) patients treated with direct oral anticoagulants (DOAC).Methods and Results:We conducted a single-center prospective registry of 2,216 NVAF patients treated with DOAC: the DIRECT registry (UMIN000033283). High-sensitivity C-reactive protein (hsCRP) was measured ≤3 months before (pre-DOAC hsCRP) and 6±3 months after initiation of DOAC (post-DOAC hsCRP). Multivariate logistic regression model was used to assess the influence of systemic inflammation and conventional bleeding risk factors on major bleeding according to International Society on Thrombosis and Haemostasis criteria. Based on the findings, we created a new bleeding risk assessment score: the ORBIT-i score, which included post-DOAC hsCRP >0.100 mg/dL and all components of the ORBIT score. A total of 1,848 patients had both pre- and post-DOAC hsCRP data (follow-up duration, 460±388 days). Post-DOAC hsCRP was associated with major bleeding (OR, 2.770; 95% CI: 1.687-4.548, P<0.001). Patients with post-DOAC hsCRP >0.100 mg/dL more frequently had major bleeding than those without (log-rank test, P<0.001). ORBIT-i score had the highest C-index of 0.711 (95% CI, 0.654-0.769) compared with the ORBIT and HAS-BLED scores. CONCLUSIONS: Persistent systemic inflammation was associated with major bleeding risk. ORBIT-i score had a higher discriminative performance compared with the conventional bleeding risk scores.

Impact of Direct Oral Anticoagulant Off-Label Reduced Dose in Combination With Antiplatelet Agents on Clinical Outcome　- Propensity Score-Matching Analysis From the DIRECT Real-World Non-Valvular Atrial Fibrillation Registry.

Background: The association between direct oral anticoagulant (DOAC) dose and clinical outcomes when used with antiplatelets still remains to be investigated. Methods and Results: We conducted a prospective registry of non-valvular atrial fibrillation (AF) patients with DOAC: the DIRECT registry (n=2,216; follow-up, 407±388 days). We analyzed patients taking standard dose (n=907) and off-label reduced dose (n=338) DOAC in this sub-analysis. These patients were further stratified by add-on antiplatelets. Because DOAC dose was not randomly selected, potential confounding factors were eliminated through a propensity score-matching technique. The primary endpoint was clinically significant bleeding. The secondary endpoint was major adverse cardiovascular events (MACE; composite of all-cause death, all myocardial infarction, and stroke/systemic embolism). In patients with DOAC only/DOAC+antiplatelets, we successfully matched 212/62 patients who received off-label reduced dose DOAC with 212/62 standard dose patients. Off-label DOAC dose reduction did not have a significant impact on bleeding (HR, 1.123; 95% CI: 0.730-1.728, P=0.596) or MACE (HR, 1.107; 95% CI: 0.463-2.648, P=0.819) in patients with DOAC only, whereas in patients with add-on antiplatelets, off-label dose reduction significantly reduced bleeding (HR, 0.429; 95% CI: 0.212-0.868, P=0.019) without increasing MACE (HR, 2.205; 95% CI: 0.424-11.477, P=0.348). Conclusions: Reduced DOAC dose in combination with antiplatelet agents was associated with fewer bleeding complications than standard-dose therapy with no reduction in efficacy.

Comparison of Long-Term Outcomes Between Combination Antiplatelet and Anticoagulant Therapy and Anticoagulant Monotherapy in Patients With Atrial Fibrillation and Left Atrial Thrombi.

Background: Anticoagulation for patients with atrial fibrillation (AF) complicated by left atrial thrombi (LAT) is a frequent cause of bleeding complications, but risk factors remain unknown. Methods and Results: Of 3,139 AF patients who underwent transesophageal echocardiography, 82 with LAT under anticoagulation were included in this study. Patients treated with combination antiplatelet and anticoagulant therapy (n=31) were compared with those receiving anticoagulant monotherapy (n=51) to investigate the effects of antiplatelet agents during anticoagulation on bleeding complications. Over a mean (±SD) follow-up of 878±486 days, bleeding events occurred more frequently in the combination therapy than monotherapy group (58% vs. 20%; P<0.001), but there was no significant difference in embolic events (6.5% vs. 3.9%; P=0.606). Kaplan-Meier analysis also showed a significantly higher rate of bleeding events in the combination therapy group, but no significant difference in the rate of embolic events. Inverse probability of treatment weighting revealed that combination therapy was independently associated with an increased risk of bleeding (hazard ratio [HR] 2.98, 95% confidence interval [CI] 1.14-7.89, P=0.026), but not with the risk of embolic events (HR 0.30, 95% CI 0.04-2.59, P=0.275). Net clinical benefit analysis was almost negative for combination therapy vs. monotherapy. Conclusions: In patients with AF and LAT, combination therapy was significantly associated with an increased risk of bleeding events, but not with a reduced risk of embolic events.