Causes of Death in Elderly Patients With Non-Valvular Atrial Fibrillation　- Results From the ANAFIE Registry.

BACKGROUND: Previous studies on mortality in atrial fibrillation (AF) included a limited number of elderly patients receiving direct oral anticoagulants (DOACs). This subanalysis of the ANAFIE Registry evaluated 2-year mortality according to causes of death of elderly non-valvular AF (NVAF) patients in the DOAC era.Methods and Results: The ANAFIE Registry was a multicenter prospective observational study. Mean patient age was 81.5 years and 57.3% of patients were male. Of the 32,275 patients completing the study, 2,242 died. The most frequent causes of death were cardiovascular (CV) death (32.4%), followed by infection (17.1%) and malignancy (16.1%). Incidence rates of CV-, malignancy-, and infection-related death were 1.20, 0.60, and 0.63 per 100 person-years, respectively. Patients aged ≥85 years showed increased proportions of non-CV and non-malignancy deaths and a decreased proportion of malignancy deaths compared with patients aged <85 years. The incidence of death due to congestive heart failure/cardiogenic shock, infection, and renal disease was higher in patients aged ≥85 than those aged <85 years. Compared with warfarin, DOACs were associated with a significantly lower risk of death by intracranial hemorrhage, ischemic stroke, and renal disease. CONCLUSIONS: This subanalysis described the mortality according to causes of death of Japanese elderly NVAF patients in the DOAC era. Our results imply that a more holistic approach to comorbid conditions and stroke prevention are required in these patients.

Clinical risk factors of stroke and major bleeding in patients with non-valvular atrial fibrillation under rivaroxaban: the EXPAND Study sub-analysis.

For Japanese patients with non-valvular atrial fibrillation (NVAF), the risk of stroke and major bleeding events was assessed by using the CHADS2, CHA2DS2-VASc, and HAS-BLED scores. The risk factors for embolism and major bleeding under DOAC may be different from current reports. We analyzed the data set of the EXPAND Study to determine the risk factors for events among Japanese NVAF patients in the era of direct oral anticoagulant. Using the data of EXPAND Study, the validity for predictability of the CHADS2, CHA2DS2-VASc, and HAS-BLED scores was identified using the receiver operating characteristic curve analysis. Multivariate analysis was performed with the Cox proportional hazard model to determine the independent risk factors for stroke/systemic embolism and major bleeding among NVAF patients receiving rivaroxaban. Explanatory variables were selected based on the univariate analysis. A total of 7141 patients (mean age 71.6 ± 9.4 years, women 32.3%, and rivaroxaban 15 mg per day 56.5%) were included. Incidence rates of stroke/systemic embolism and major bleeding were 1.0%/year and 1.2%/year, respectively. The multivariate analysis revealed that only history of stroke was associated with stroke/systemic embolism (hazard ratio 3.4, 95% confidence interval 2.5-4.7, p < 0.0001). By contrast, age (1.7, 1.1-2.6, p = 0.0263), creatinine clearance (CrCl) 30-49 mL/min (1.6, 1.2-2.2, p = 0.0011), liver dysfunction (1.7, 1.1-2.8, p = 0.0320), history/disposition of bleeding (1.8, 1.0-3.0, p = 0.0348), and concomitant use of antiplatelet agents (1.6, 1.2-2.3, p = 0.0030) were associated with major bleeding. This sub-analysis showed that some components of the HAS-BLED score were independently associated with major bleeding in Japanese NVAF patients receiving anticoagulation therapy by rivaroxaban. Additionally, CrCl value of 30-49 mL/min was an independent predictor of major bleeding in patients receiving rivaroxaban.

The EXPAND study: Efficacy and safety of rivaroxaban in Japanese patients with non-valvular atrial fibrillation.

AIMS: The EXPAND study examined the real-world efficacy and safety of rivaroxaban for the prevention of stroke and systemic embolism (SE) in Japanese patients with non-valvular atrial fibrillation (NVAF). METHODS AND RESULTS: This multicenter, prospective, non-interventional, observational, cohort study was conducted at 684 medical centers in Japan. A total of 7141 NVAF patients ≥20 years of age (mean, 71.6 ±â€¯9.4 years) who were being or about to be treated with rivaroxaban (10 mg/day, 43.5%; 15 mg/day, 56.5%) were followed for an average of 897.1 (±206.8) days with a high follow-up rate (99.65%). The mean CHADS2 score at baseline was 2.1 (1.3) (0-1, 37%; 2, 29%; ≥3, 34%). The total incidence rate of symptomatic stroke and SE (primary efficacy endpoint) was 1.0%/year, and 0.5%, 0.9%, and 1.7%/year for those with CHADS2 scores of 0-1, 2, and ≥3, respectively. Cumulative incidence rates for major bleeding (primary safety endpoint) and non-major bleeding (secondary safety endpoint) were 1.2%/year and 4.9%/year, respectively. Differences were noted between new and current users only for major bleeding event rate (1.7% vs. 1.1%/year, P = 0.0024). Comparisons with previous studies suggested that rivaroxaban is effective and safe for low-risk patients (0-1 CHADS2), as shown for warfarin in the XANTUS international prospective post-marketing study. CONCLUSIONS: The EXPAND study demonstrated that low dosages of rivaroxaban for Japanese NVAF patients in real-world clinical practice, including those with CHADS2 scores 0-1, resulted in low rates of stroke and SE, and major and non-major bleeding.

Study Design and Baseline Characteristics of the EXPAND Study: Evaluation of Effectiveness and Safety of Xa Inhibitor, Rivaroxaban for the Prevention of Stroke and Systemic Embolism in a Nationwide Cohort of Japanese Patients Diagnosed as Non-Valvular Atrial Fibrillation.

The use of rivaroxaban, a factor Xa inhibitor, has been increasing for prevention of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF) in Japan. We conducted the nationwide multicenter study, termed as the EXPAND Study, to address its effectiveness and safety in the real-world practice of patients with non-valvular AF in Japan. The EXPAND Study is a prospective, non-interventional, observational cohort study to evaluate the effectiveness and safety of rivaroxaban in non-valvular AF patients in a real-world clinical practice. A total of 7,178 patients with non-valvular AF were enrolled in 684 medical institutes between November 20, 2012 and June 30, 2014. As for the baseline demographic and clinical characteristics of 7,164 patients, the proportion of female patients was 32.2%, and those of patients with creatinine clearance < 50 mL/min and non-paroxysmal (persistent or permanent) AF were 21.8% and 55.1%, respectively. The proportions of patients complicated with hypertension, congestive heart failure, diabetes mellitus, and a history of ischemic stroke were 70.9%, 25.9%, 24.3%, and 20.2%, respectively. The proportions of patients with a CHADS2 score ≤ 1 and a CHA2DS2-VASc score ≤ 1 were 37.3% and 13.6%, respectively. They were followed up until March 31, 2016 for a mean follow-up period of approximately 2.5 years. The findings of the EXPAND Study will help to establish an appropriate treatment with rivaroxaban for Japanese patients with non-valvular AF.

Number needed to entrain: a new criterion for entrainment mapping in patients with intra-atrial reentrant tachycardia.

BACKGROUND: Measuring postpacing intervals (PPIs) is the standard maneuver for localizing reentrant tachycardia circuits. However, changes or termination of the tachycardia during entrainment pacing, or difficulties in defining the correct local activity, limit the use of PPIs. METHODS AND RESULTS: We hypothesized that the number of pacing stimuli needed to entrain (NNE) was useful for mapping intra-atrial reentrant tachycardias. First, 10 patients with typical atrial flutter were studied to characterize the NNE. Next, 317 entrainment attempts in 30 patients with 76 intra-atrial reentrant tachycardias were analyzed to determine the efficacy of the NNE. The NNE was small at sites within the reentrant circuit (median 2) and large at remote sites during typical atrial flutter. The NNE depended on the pacing cycle length and coupling interval of the initial paced beat, where the NNE became smaller at shorter pacing cycle lengths and coupling intervals. The NNE highly correlated with the difference between the PPI and tachycardia cycle length (r = 0.906; P<0.001). When the pacing cycle length and coupling interval were 16 to 30 ms below the tachycardia cycle length, a NNE ≤2 and >3 predicted a PPI-tachycardia cycle length ≤20 and >20 ms, respectively, with 100% accuracy. Thirty-six (11%) entrainment attempts changed or terminated intra-atrial reentrant tachycardia. Importantly, the NNE remained valid in those cases. Furthermore, the NNE provided additional information in cases with some difficulties with PPI measurements. CONCLUSIONS: The NNE is a simple and reliable criterion, which facilitates mapping intra-atrial reentrant tachycardia. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT001747.

[Factor Xa inhibitor (rivaroxaban and drugs under investigation)].

The first factor Xa inhibitor, rivaroxaban had been released on market, and apixaban and edoxaban are preparing for clinical use in patients with atrial fibrillation. These newer antithrombotic agents are attractive for prevention of thromboembolism in patients with atrial fibrillation because of their favorable pharmacokinetic and pharmacodynamic profiles that seems to be better than that of direct thrombin inhibitor. The reports of rivaroxaban and apixaban have been showed noninferiority or superiority in their efficacy endpoints and also in safety endpoints even on fixed dose regimen without anticoagulation monitoring. There may be still present an important issue that we have to pay attention to find appropriate doses for the patients with renal impairment, aged or low body weight.

Spiritual activation in very elderly individuals assessed as heart rate variability and plasma IL/10/IL-6 ratios.

Proinflammatory cytokine responses might occur in elderly individuals with cardiovascular (CV) disease, cerebro-vascular (CVA) disease, and/or pulmonary disease (PD). Spiritual activation is an important coping mechanism, since psychiatric depression is an important risk factor for these individuals. Thirty-three very elderly individuals (87 ± 8 years) with previous CVD, CVA and/or PD participated in weekly 30 minute sermons by chaplains for over 20 months of chaplain liturgy (CL group). All underwent Holter ECG during the procedures and cardiac autonomic activities were assessed by maximum entropy analysis. Plasma IL-10 and IL-6 levels were compared with 26 age-matched (85 ± 10 years) individuals who did not participate in these activities (non-CL group). Both high frequency (HF) and pNN50 of heart rate variability (HRV) were higher in the CL group than in the non-CL group (HF, 190 ± 55 versus 92 ± 43 nu, P < 0.05; pNN50, 10.5 ± 16% versus 3.6 ± 3.8%, P < 0.05), whereas LF/HF was lower (1.4 ± 1.5 versus 2.2 ± 2.8, P < 0.05). Levels of IL-10/IL-6 were higher in the CL group (3.96 ± 5.0 versus 1.79 ± 1.6, P < 0.05). Hospitalization rates due to CVD and/or PD were lower in the CL group than in the non-CL group (4/33 versus 11/26, P < 0.05). We conclude that spiritual activation can modify proinflammatory cytokines and suppress CVD, CVA and/or PD via vagal modifications. Spiritual activation might be helpful for health in these very elderly individuals.

Effects of music therapy on autonomic nervous system activity, incidence of heart failure events, and plasma cytokine and catecholamine levels in elderly patients with cerebrovascular disease and dementia.

Music therapy (MT) has been used in geriatric nursing hospitals, but there has been no extensive research into whether it actually has beneficial effects on elderly patients with cerebrovascular disease (CVD) and dementia. We investigated the effects of MT on the autonomic nervous system and plasma cytokine and catecholamine levels in elderly patients with CVD and dementia, since these are related to aging and chronic geriatric disease. We also investigated the effects of MT on congestive heart failure (CHF) events.Eighty-seven patients with pre-existing CVD were enrolled in the study. We assigned patients into an MT group (n = 55) and non-MT group (n = 32). The MT group received MT at least once per week for 45 minutes over 10 times. Cardiac autonomic activity was assessed by heart rate variability (HRV). We measured plasma cytokine and catecholamine levels in both the MT group and non-MT group. We compared the incidence of CHF events between these two groups. In the MT group, rMSSD, pNN50, and HF were significantly increased by MT, whereas LF/HF was slightly decreased. In the non-MT group, there were no significant changes in any HRV parameters. Among cytokines, plasma interleukin-6 (IL-6) in the MT group was significantly lower than those in the non-MT group. Plasma adrenaline and noradrenaline levels were significantly lower in the MT group than in the non-MT group. CHF events were less frequent in the MT group than in the non-MT group (P < 0.05). These findings suggest that MT enhanced parasympathetic activities and decreased CHF by reducing plasma cytokine and catecholamine levels.

The VA relationship after differential atrial overdrive pacing: a novel tool for the diagnosis of atrial tachycardia in the electrophysiologic laboratory.

INTRODUCTION: Despite recent advances in clinical electrophysiology, diagnosis of atrial tachycardia (AT) originating near Koch's triangle remains challenging. We sought a novel technique for rapid and accurate diagnosis of AT in the electrophysiologic laboratory. METHODS: Sixty-two supraventricular tachycardias including 18 ATs (10 ATs arising from near Koch's triangle), 32 atrioventricular nodal reentrant tachycardias (AVNRTs), and 12 orthodromic reciprocating tachycardias (ORTs) were studied. Overdrive pacing during the tachycardia from different atrial sites was performed, and the maximal difference in the postpacing VA intervals (last captured ventricular electrogram to the earliest atrial electrogram of the initial beat after pacing) among the different pacing sites was calculated (delta-VA interval). RESULTS: The delta-VA intervals were >14 ms in all AT patients and <14 ms in all AVNRT/ORT patients, and thus, the delta-VA interval was diagnostic for AT with the sensitivity, specificity, and positive and negative predictive values all being 100%. When the diagnostic value of the delta-VA interval and conventional maneuvers were compared for differentiating AT from atypical AVNRT, both a delta-VA interval >14 ms and "atrial-atrial-ventricular" response after overdrive ventricular pacing during the tachycardia were diagnostic. However, the "atrial-atrial-ventricular" response criterion was available in only 52% of the patients because of poor ventriculoatrial conduction. CONCLUSIONS: The delta-VA interval was useful for diagnosing AT irrespective of patient conditions such as ventriculoatrial conduction.

Electrocardiographic and electrophysiological characteristics of atrial fibrillation organized into atrial flutter by oral administration of class I antiarrhythmic agents.

The aim of this study was to evaluate the electrocardiographic (ECG) and electrophysiological characteristics of atrial fibrillation (AF) that organized into atrial flutter during oral administration of class I antiarrhythmic agents. The former clinical study included 72 consecutive patients (58 paroxysmal AF, 14 persistent AF) in whom class I antiarrhythmic agents were orally administered in the outpatient clinic for termination or prophylaxis of AF. The clinical background and ECG variables were compared between the patients with and without atrial flutter during class I antiarrhythmic agents therapy. An electrophysiological study was performed in ten patients with paroxysmal AF (five with [group A] and five without atrial flutter [group B] during oral class I antiarrhythmic agents therapy. Local electrograms from five different atrial sites (high and low right free wall, high and low septum, and distal coronary sinus) were analyzed during induced AF. The activation pattern of the right free wall during AF was also analyzed using a Halo catheter. Atrial flutter was documented during class I antiarrhythmic agents therapy in 14 (24%) patients with paroxysmal AF, whereas in none with persistent AF. The mean cycle length (f-f interval) and amplitude of the fibrillation waves in leads II and V1 from the surface ECG were significantly greater in the patients with than in those without atrial flutter. In the electrophysiological study, the mean cycle lengths for the low and high right free wall were significantly longer in group A than in group B, whereas those for the low septums and distal coronary sinus did not differ between the two groups. During the induced AF, the ratio of time exhibiting a consistent activation pattern (cranio-caudal, caudo-cranial, or undetermined) along the right free wall was significantly greater in group A than in group B. Atrial flutter newly developed during class I antiarrhythmic agents therapy in patients with coarse AF on the surface ECG and a relatively organized activation in the right atrial free wall. The observation of these findings may facilitate the identification of candidates for hybrid pharmacologic and ablative therapies.