Antithrombotic therapy for stable coronary artery disease and atrial fibrillation in patients with and without revascularisation: the AFIRE trial.

BACKGROUND: The Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial demonstrated non-inferior efficacy endpoints for rivaroxaban monotherapy versus combination therapy (rivaroxaban plus a single antiplatelet) and superior safety endpoints in patients with atrial fibrillation and stable coronary artery disease. AIMS: This post hoc analysis investigated whether the AFIRE trial results reflected the presence or absence of prior revascularisation. METHODS: Among 2,215 patients, 1,697 (76.6%) had previously undergone revascularisation, and the remaining 518 (23.4%) had not undergone prior revascularisation. The primary efficacy endpoint was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularisation, or death from any cause, while the primary safety endpoint was major bleeding. RESULTS: In 1,697 patients with prior revascularisation, the efficacy and safety endpoints were superior for monotherapy versus combination therapy (efficacy: hazard ratio [HR] 0.62, 95% confidence interval [CI]: 0.45-0.85; p=0.003; safety: HR 0.62, 95% CI: 0.39-0.98; p=0.042). Among 518 without prior revascularisation, there were no significant differences in endpoints (efficacy: HR 1.19, 95% CI: 0.67-2.12; p=0.554; safety: HR 0.47, 95% CI: 0.18-1.26; p=0.134). There was borderline interaction of the efficacy endpoints (p=0.055) between two treatments. The safety benefit of monotherapy on any bleeding was significant in patients without prior revascularisation (HR 0.59, 95% CI: 0.38-0.93; p=0.022). CONCLUSIONS: In high-risk thrombosis patients with a history of prior revascularisation, rivaroxaban monotherapy versus combination therapy demonstrated favourable safety and efficacy outcomes.

Clinical utility of QRS duration normalized to left ventricular volume for predicting cardiac resynchronization therapy efficacy in patients with "mid-range" QRS duration.

BACKGROUND: Cardiac resynchronization therapy (CRT) is effective for patients with heart failure with QRS duration (QRSd) ≥150 ms. However, its beneficial effect seems to be limited for those with "mid-range" QRSd (120-149 ms). Recent studies have demonstrated that modifying QRSd to left ventricular end-diastolic volume (LVEDV)-modified QRSd-improves the prediction of clinical outcomes of CRT. OBJECTIVE: The purpose of this study was to investigate the clinical impact of the modified QRSd on the efficacy of CRT in patients with "mid-range" QRSd. METHODS: We conducted a retrospective, multicenter, observational study, with heart failure hospitalization (HFH) after CRT as the primary endpoint. Modified QRSd is defined as QRSd divided by LVEDV, determined through the Teichholtz method of echocardiography. RESULTS: Among the 506 consecutive patients considered, 119 (mean age 61 ± 15 years; 80% male, QRSd 135 ± 9 ms) with a "mid-range" QRSd who underwent de novo CRT device implantation were included for analysis. During median follow-up of 878 days [interquartile range 381-1663 days], HFH occurred in 45 patients (37%). Fine-Gray analysis revealed modified QRSd was an independent predictor of HFH (hazard ratio [HR] 0.97; 95% confidence interval [CI] 0.96-0.99; P <.01). Receiver operating characteristic curve analysis revealed a cutoff value of 0.65 ms/mL for the modified QRSd in predicting HFH. Patients above the threshold exhibited a significantly lower incidence of HFH than patients below the threshold (HR 0.46; 95% CI 0.25-0.86; P = .01). CONCLUSION: Modified QRSd can effectively predict the efficacy of CRT in patients with a "mid-range" QRSd.

Implications of ventricular arrhythmia after cardiac resynchronization therapy.

BACKGROUND: Conflicting data are available on whether ventricular arrhythmia (VA) or shock therapy increases mortality. Although cardiac resynchronization therapy (CRT) reduces the risk of VA, little is known about the prognostic value of VA among patients with CRT devices. OBJECTIVES: The purpose of this study was to evaluate the implications of VA as a prognostic marker for CRT. METHODS: We investigated 330 CRT patients within 1 year after CRT device implantation. The primary endpoint was the composite endpoint of all-cause death or hospitalization for heart failure. RESULTS: Forty-three patients had VA events. These patients had a significantly higher risk of the primary endpoint, even among CRT responders (P = .009). Fast VA compared to slow VA was associated with an increased risk of the primary endpoint (hazard ratio [HR] 2.14; 95% confidence interval [CI] 1.06-4.34; P = .035). Shock therapy was not associated with a primary endpoint (shock therapy vs antitachycardia pacing: HR 1.49; 95% CI 0.73-3.03; P = .269). The patients with VA had a lower prevalence of response to CRT (23 [53%] vs 202 [70%]; P = .031) and longer left ventricular paced conduction time (174 ± 23 ms vs 143 ± 36 ms; P = .003) than the patients without VA. CONCLUSION: VA occurrence within 1 year was related to paced electrical delay and poor response to CRT. VA could be associated with poor prognosis among CRT patients.

Two-Year Outcomes of Primary Prophylactic Use of Defibrillators for Ischemic and Non-Ischemic Cardiomyopathy　- Propensity Score-Matched Analysis From the Nippon Storm Study.

BACKGROUND: In 2016, the DANISH study reported negative results regarding the efficacy of implantable cardioverter-defibrillators (ICDs) in patients with non-ischemic cardiomyopathy (NICM) and reduced left ventricular ejection fraction (LVEF). In this study we determined the efficacy of using ICDs for primary prophylaxis in patients with NICM.Methods and Results: We selected 1,274 patients with underlying cardiac disease who were enrolled in the Nippon Storm Study. We analyzed the data of 451 patients with LVEF ≤35% due to NICM or ischemic cardiomyopathy (ICM) who underwent ICD implantation for primary prophylaxis (men, 78%; age, 65±12 years; LVEF, 25±6.4%; cardiac resynchronization therapy, 73%; ICM, 33%). After propensity score matching, we compared the baseline covariates between groups: NICM (132 patients) and ICM (132 patients). The 2-year appropriate ICD therapy risks were 27.7% and 12.2% in the NICM and ICM groups, respectively (hazard ratio, 0.390 [95% confidence interval, 0.218-0.701]; P=0.002). CONCLUSIONS: This subanalysis of propensity score-matched patients from the Nippon Storm Study revealed that the risk of appropriate ICD therapy was significantly higher in patients with NICM than in those with ICM.

Clinical Significance of Atrial Tachyarrhythmia Duration for Ventricular Arrhythmia in Patients With Cardiac Resynchronization Therapy.

BACKGROUND: Atrial tachyarrhythmias (ATAs) are reportedly associated with ventricular arrhythmias (VAs). However, little is known about the association between ATA duration and the risk of VA. We investigated the relationship between ATA duration and subsequent VA in patients with a cardiac resynchronization therapy defibrillator (CRT-D).Methods and Results: We investigated associations between the longest ATA duration during the first year after cardiac resynchronization therapy (CRT) implantation and VA and VA relevant to ATA (VAATA) in 160 CRT-D patients. ATAs occurred in 63 patients in the first year. During a median follow-up of 925 days from 1 year after CRT implantation, 40 patients experienced 483 VAs. Kaplan-Meier analysis showed a significantly higher risk of VA in patients with than without ATA in the first year (log rank P=0.0057). Hazard ratios (HR) of VA (HR 2.36, 2.10, and 3.04 for ATA >30s, >6 min and >24 h, respectively) and only VAATA (HR 4.50, 5.59, and 11.79 for ATA >30s, >6 min and >24 h, respectively) increased according to the duration of ATA. In multivariate analysis, ATA >24 h was an independent predictor of subsequent VA (HR 2.42; P=0.02). CONCLUSIONS: Patients with ATA >24 h in the first year after CRT had a higher risk of subsequent VA and VAATA. The risk of VA, including VAATA, increased with the longest ATA duration.

Interactive effects of two rodent species on the seed dispersal of Japanese walnut.

The effects of seed dispersers on plant fitness (seed dispersal effectiveness, SDE) have been evaluated based on the number (quantity) and recruitment probability (quality) of dispersed seeds. Although seeds of most zoochorous species are dispersed by two or more animal species, which may interact with each other, SDE has often been studied assuming a one-plant and one-animal species system. We compared the SDE of Japanese walnut (Juglans ailanthifolia) between squirrel-only and squirrel-mouse sites in natural forests of Hokkaido, Japan, and found that the SDE from the red squirrel (Sciurus vulgaris), considered a primary seed disperser, was altered by an alternative seed disperser species, the Japanese wood mouse (Apodemus speciosus). Seed removal rates at the squirrel-mouse site were significantly higher than those at the squirrel-only site, and both dispersed seeds and seedlings were less aggregated, with a strongly repulsive relationship with adult conspecific trees at the squirrel-mouse site. Seedlings established themselves at a location with fewer medium-sized trees (< 10 cm DBH) at the squirrel-mouse site. These results suggest that the interactive effect of the rodent species affects the SDE of Japanese walnut.

Interference of cardiac implantable electronic devices and computed tomography imaging in the current era with a phantom model.

Introduction: Cardiac implantable electronic devices are used in patients with cardiac rhythm disorders. Computed tomography irradiation is not prohibited for patients with cardiac implantable electronic devices, despite adverse events being reported. Hence, appropriate preparation and knowledge are required before computed tomography irradiation can be carried out in these patients. Since there is limited knowledge or literature about the influence of computed tomography irradiation in cases with recent cardiac implantable electronic devices, we aimed to evaluate the adverse events and elucidate the necessary and sufficient safety measures associated with this therapy. Methods and Results: We placed cardiac implantable electronic devices on an anthropomorphic phantom model and observed their electrical activity in electrograms, while various protocols of computed tomography irradiation were implemented and adverse events evaluated. Oversensing with pauses of up to 3.2 s was observed in standard computed tomography protocols, but ventricular tachyarrhythmia or other clinically significant events could not be confirmed. Oversensing with pauses of up to 8.0 s was observed and ventricular tachyarrhythmia was detected in the maximum-dose protocols. However, treatments such as antitachycardia pacing or shock therapy for ventricular tachyarrhythmia were not observed because of their absence. Conclusion: Computed tomography irradiation for patients using cardiac implantable electronic devices is highly unlikely to cause clinically significant adverse events with the device settings and computed tomography protocols currently being used. Changing or monitoring the device settings routinely before computed tomography irradiation is not necessarily required for most patients.

Use of Implantable Cardioverter-Defibrillators for Primary Prevention of Sudden Cardiac Death in Asia.

The effectiveness of primary prevention implantable cardioverter-defibrillators (ICDs) is well established. However, there are several unsolved problems related to ICD use for primary prevention in Asia, including ICD underuse, population differences in underlying heart disease, and the rate of appropriate ICD therapy compared with Western countries. Although the prevalence of ischemic cardiomyopathy in Asia is lower than in Europe and the United States, the mortality rate of Asian patients with ischemic heart disease has been increasing recently. As for the use of ICDs for primary prevention, there have been no randomized clinical trials, and limited data are available in Asia. This review focuses on the unmet needs related to ICD use for primary prevention in Asia.

Significance of effective cardiac resynchronization therapy pacing for clinical responses: An analysis based on the effective cardiac resynchronization therapy algorithm.

BACKGROUND: High percent ventricular pacing maximizes cardiac resynchronization therapy (CRT) response. An effective CRT algorithm classifies each left ventricular (LV) pace as effective or ineffective on the basis of the detection of QS or QS-r morphology on the electrogram; however, the relationship between percent effective CRT pacing (%e-CRT) and responses is unclear. OBJECTIVE: We aimed to clarify the association between %e-CRT and clinical outcomes. METHODS: Of the 136 consecutive CRT patients, 49 using the adaptive and effective CRT algorithm with percent ventricular pacing > 90% were evaluated. The primary and secondary outcomes were heart failure (HF) hospitalization and prevalence of CRT responders, defined as patients with an improvement in LV ejection fraction of ≥10% or a reduction in LV end-systolic volume of ≥15% after CRT device implantation, respectively. RESULTS: We divided the patients into the effective group (n = 25) and the less effective group (n = 24) by the median value of %e-CRT (97.4% [93.7%-98.3%]). During the median follow-up period of 507 days (interquartile range 335-730 days), the effective group had a significantly lower risk of HF hospitalization than the less effective group as revealed by Kaplan-Meier analysis (log-rank, P = .016). Univariate analysis revealed %e-CRT ≥ 97.4% (hazard ratio 0.12; 95% confidence interval 0.01-0.95; P = .045) as a predictor of HF hospitalization. The effective group had a higher prevalence of CRT responders than the less effective group (23 [92%] vs 9 [38%]; P < .001). Univariate analysis revealed that %e-CRT ≥ 97.4% (odds ratio 19.20; 95% confidence interval 3.63-101.00; P < .001) was a predictor of CRT response. CONCLUSION: High %e-CRT is associated with high CRT responder prevalence and low HF hospitalization risk.

In-hospital predictors for primary prevention of sudden death after acute myocardial infarction with cardiac dysfunction.

BACKGROUND: Current guidelines recommend prophylactic defibrillator implantation in patients with acute myocardial infarction (AMI) and left ventricular ejection fraction (LVEF) ≤40 % or LVEF ≤35 % plus heart failure symptoms or inducible ventricular tachyarrhythmias during an electrophysiology study at 40 days after AMI or 90 days after revascularization. In-hospital predictors of sudden cardiac death (SCD) after AMI during the index hospitalization remain unsettled. We sought to examine in-hospital predictors of SCD in patients with AMI and LVEF ≤40 % evaluated during the index hospitalization. METHODS: We retrospectively evaluated 441 consecutive patients with AMI and LVEF ≤40 % admitted to our hospital between 2001 and 2014 (77 % male gender; median age: 70 years; median hospitalization length: 23 days). The primary endpoint was a composite of SCD or aborted SCD at ≥30 days after AMI onset (composite arrhythmic event). LVEF and QRS duration (QRSd) on electrocardiography were measured at a median of 12 days and 18 days, respectively. RESULTS: During a median follow-up of 7.6 years, the incidence of composite arrhythmic events was 7.3 % (32 of 441 patients). In multivariable analysis, QRSd ≥100 msec (beta-coefficient = 1.54, p = 0.003), LVEF ≤23 % (beta-coefficient = 1.14, p = 0.007), and onset-reperfusion time > 5.5 h (beta-coefficient = 1.16, p = 0.035) were independent predictors of composite arrhythmic events. The combination of these 3 factors was associated with the highest rate of composite arrhythmic events compared with 0-2 factors (p < 0.001). CONCLUSIONS: The combination of QRSd ≥100 msec, LVEF ≤23 %, and onset-reperfusion time > 5.5 h during the index hospitalization provides precise risk stratification for SCD in patients early after AMI.

Cost-effectiveness analysis of cardiac implantable electronic devices with reactive atrial-based antitachycardia pacing.

AIMS: Reactive atrial-based anti-tachycardia pacing (rATP) in pacemakers (PMs) and cardiac resynchronization therapy defibrillators (CRT-Ds) has been reported to prevent progression of atrial fibrillation, and this reduced progression is expected to decrease the risk of complications such as stroke and heart failure (HF). This study aimed to assess the cost-effectiveness of rATP in PMs and CRT-Ds in the Japanese public health insurance system. METHODS AND RESULTS: We developed a Markov model comprising five states: bradycardia, post-stroke, mild HF, severe HF, and death. For devices with rATP and control devices without rATP, we compared the incremental cost-effectiveness ratio (ICER) from the payer's perspective. Costs were estimated from healthcare resource utilisation data in a Japanese claims database. We evaluated model uncertainty by analysing two scenarios for each device. The ICER was 763 729 JPY/QALY (5616 EUR/QALY) for PMs and 1,393 280 JPY/QALY (10 245 EUR/QALY) for CRT-Ds. In all scenarios, ICERs were below 5 million JPY/QALY (36 765 EUR/QALY), supporting robustness of the results. CONCLUSION: According to a willingness to pay threshold of 5 million JPY/QALY, the devices with rATP were cost-effective compared with control devices without rATP, showing that the higher reimbursement price of the functional categories with rATP is justified from a healthcare economic perspective.

Impact of Pre-Ablation Direct Current Cardioversion for Persistent Atrial Fibrillation to Predict Recurrence of Atrial Fibrillation after Catheter Ablation.

The efficacy of direct current (DC) cardioversion before catheter ablation (CA) for persistent atrial fibrillation (PerAF) patients remains controversial. We hypothesized that maintenance of sinus rhythm (SR) by pre-ablation DC cardioversion may predict the outcome of CA in patients with PerAF. A total of 383 PerAF patients with no or mild symptoms (EHRA I/II) who had undergone DC cardioversion before CA (301 males, 65 ± 10 years old, mean atrial fibrillation (AF) duration: 25 ± 47 months) were retrospectively enrolled. Whether or not SR was maintained at least 24 hour after DC cardioversion, patients were divided into two groups, namely, the DC-SR group and DC-AF group, and then all were followed until AF recurrence after CA. After DC cardioversion, 281 (73%) patients were categorized into the DC-SR group, and 102 (27%) were categorized into the DC-AF group. A total of 195 patients underwent CA at an average of 83 (54-145) days after DC cardioversion, including 161 (83%) in the DC-SR group and 34 (17%) in the DC-AF group. During follow-up (median: 15 [10-25] months), the number of patients who were free from AF was significantly higher in the DC-SR group compared with the DC-AF group (61.5% versus 38.3%, P < 0.0001). Multivariate analysis revealed that the DC-SR group (hazard ratio [HR]: 0.45, 95% confidence interval [CI]: 0.21-0.99, P = 0.047) and age at first AF diagnosis (HR: 0.95, 95% CI: 0.91-1.00, P = 0.039) were the independent predictors for being AF-free after CA. In conclusion, the 24-hour rhythm outcome of pre-ablation DC cardioversion and age at first AF diagnosis may predict the recurrence of AF after CA in patients with PerAF.

Pharmacokinetics and pharmacodynamics of amiodarone in patients with hypertriglyceridemia: Two case reports.

BACKGROUND: The antiarrhythmic drug amiodarone has noncardiac adverse effects, leading to restrictive therapeutic plasma ranges. Despite the significant positive correlation between triglyceride and amiodarone levels, the effect of fluctuations in amiodarone levels in patients with hypertriglyceridemia on amiodarone therapy has not been fully characterized. This study is the first to report on the effect of hypertriglyceridemia on the efficacy and safety of amiodarone therapy. CASE PRESENTATION: The first patient was a 58-year-old man with hypertriglyceridemia who was diagnosed with ventricular fibrillation (patient #1). The second patient with hypertriglyceridemia was a 72-year-old man with sustained ventricular tachycardia (patient #2). Both patients received implantable cardioverter-defibrillator therapy. During the study period, amiodarone and N-desethylamiodarone concentrations were measured 12 times in patient #1 and 26 times in patient #2. Triglyceride concentrations in patient #1 and patient #2 ranged from 102 to 765 mg/dL and from 125 to 752 mg/dL, respectively. For both patients, amiodarone dosage was maintained at 100 mg/day, and the administration of concomitant drugs that could affect amiodarone pharmacokinetics was neither initiated nor discontinued. However, amiodarone concentrations fluctuated (patient #1, 0.52 - 1.86 µg/mL; patient #2, 0.73 - 2.82 µg/mL). Although amiodarone concentrations fluctuated, neither of the patients had defibrillation shocks to stop the abnormal rhythm via an implantable cardioverter-defibrillator, and laboratory data showed that thyroid-stimulating hormone, free thyroxine, KL-6, and surfactant protein-D remained close to normal. CONCLUSION: In patients with hypertriglyceridemia, it may be necessary for clinicians to pay more attention to the clinical symptoms along with fluctuations in amiodarone levels and accordingly adjust amiodarone dosage.

Effectiveness of Implantable Cardioverter Defibrillator in Patients With Non-Ischemic Heart Failure With Systolic Dysfunction　- Subanalysis of the Nippon Storm Study.

BACKGROUND: The prospective observational Nippon Storm Study aggregated clinical data from Japanese patients receiving implantable cardioverter-defibrillator (ICD) therapy. This study investigated the usefulness of prophylactic ICD therapy in patients with non-ischemic heart failure (NIHF) enrolled in the study.Methods and Results: We analyzed 540 NIHF patients with systolic dysfunction (left ventricular ejection fraction <50%). Propensity score matching was used to select patient subgroups for comparison; 126 patients were analyzed in each of the primary (PP) and secondary (SP) prophylaxis groups. The incidence of appropriate ICD therapy during follow-up in the PP and SP groups was 21.4% and 31.7%, respectively (P=0.044). The incidence of electrical storm (ES) was higher in SP than PP patients (P=0.024). Cox proportional hazard analysis revealed that increased serum creatinine in SP patients (hazard ratio [HR] 1.18; 95% confidence interval [CI] 1.02-1.33; P=0.013) and anemia in PP patients (HR 0.92; 95% CI 0.86-0.98; P=0.008) increased the likelihood of appropriate ICD therapy, whereas long-lasting atrial fibrillation in PP patients (HR, 0.64 [95% CI, 0.45-0.91], P=0.013) decreased that likelihood. CONCLUSIONS: In propensity score-matched Japanese NIHF patients, the incidence of appropriate ICD therapy and ES was significantly higher in SP than PP patients. Impaired renal function in SP patients and anemia in PP patients increased the likelihood of appropriate ICD therapy, whereas long-lasting atrial fibrillation reduced that likelihood in PP patients.

Utilization and Efficacy of Cardiac Resynchronization Therapy in Patients With Chronic Heart Failure　- A Report From the CHART-2 Study.

Background: Although cardiac resynchronization therapy (CRT) is effective for patients with chronic heart failure (CHF) with reduced left ventricular ejection fraction and wide QRS (≥120 ms), data on the use of or long-term outcomes after CRT implantation in Japan are limited. Methods and Results: We examined proper CRT utilization and outcomes in 3,447 consecutive symptomatic CHF patients registered in the CHART-2 Study. We identified 167 potentially eligible patients and divided them into 4 groups according to the presence (+) or absence (-) of an indication for and implantation of CRT: Group A (reference group), (+)indication/(+)CRT; Group B, (+)indication/(-)CRT; Group C, (-)indication/(+)CRT; and Group D, (-)indication/(-)CRT. Based on the Japanese Circulation Society guidelines, 91 patients met the eligibility for CRT implantation, with 43 (47%) of them undergoing CRT implantation. After adjusting for confounders, age was significantly associated with no CRT use (odds ratio per 5-year increase 1.46; 95% confidence interval 1.11-2.05; P=0.012). Among the 4 groups, the cumulative incidence of cardiovascular death and CHF admission were highest in Group B and lowest in Group D (P=0.029). Conclusions: In this study, only half the eligible CHF patients properly received CRT. Aging was a significant risk factor for no CRT use. Patients without CRT despite having an indication could be at higher risk of mortality and CHF admission.

Sex-related differences in the prognosis of patients with cardiac sarcoidosis treated with cardiac resynchronization therapy.

BACKGROUND: Past studies have shown the sex-related difference in the efficacy of cardiac resynchronization therapy (CRT). However, the data for cardiac sarcoidosis (CS) are limited. OBJECTIVE: The purpose of this study was to assess the sex-related prognostic differences in CS patients with CRT. METHODS: This multicenter CS survey included 430 patients (295 females) who met the diagnostic criteria for CS. Patients were divided into those treated with primary CRT or upgraded CRT from the pacemaker (CRT group; n = 73) and others (control group; n = 357). Sex differences in the incidence of all-cause death, heart failure (HF) death including heart transplantation, ventricular arrhythmia events (VAEs) (sudden death, appropriate device therapy), cardiac adverse events (CAEs) (HF death, VAEs), changes in serum brain natriuretic peptide (BNP) levels, and left ventricular ejection fraction (LVEF) over the follow-up period were analyzed. RESULTS: During median follow-up of 5.2 years, males, but not females, in the CRT group had significantly worse all-cause mortality than patients in the control group (P <.001). In the CRT group, there was no significant sex-related difference in the incidence of HF death; however, females had significantly better VAE- and CAE-free survival than males (P = .033 and P = .008, respectively). Multivariate analysis of the CRT group showed that female sex (hazard ratio 0.37; 95% confidence interval 0.15-0.89; P = .02 and P = .6) independently predicted freedom from CAEs. During follow-up, BNP levels were significantly improved in all groups. LVEF was maintained in females with CRT. CONCLUSIONS: In CS patients with CRT, HF death-free survival was similar between sexes. However, females exhibited better VAE- and CAE-free survival than males.