NT-proBNP as a marker for atrial fibrillation and heart failure in four observational outpatient trials.

AIMS: Heart failure (HF) and atrial fibrillation (AF) frequently coexist and are both associated with increased levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP). It is known that AF impairs the diagnostic accuracy of NT-proBNP for HF. The aim of the present study was to compare the diagnostic and predictive accuracy of NT-proBNP for HF and AF in stable outpatients with cardiovascular risk factors. METHODS AND RESULTS: Data were obtained from the DIAST-CHF trial, a prospective cohort study that recruited individuals with cardiovascular risk factors and followed them up for 12 years. Data were validated in three independent population-based cohorts using the same inclusion/exclusion criteria: LIFE-Adult (n = 2869), SHIP (n = 2013), and SHIP-TREND (n = 2408). Serum levels of NT-proBNP were taken once at baseline. The DIAST-CHF study enrolled 1727 study participants (47.7% female, mean age 66.9 ± 8.1 years). At baseline, patients without AF or HF (n = 1375) had a median NT-proBNP of 94 pg/mL (interquartile range 51;181). In patients with AF (n = 93), NT-proBNP amounted to 667 (215;1130) pg/mL. It was significantly higher than in the first group (P < 0.001) and compared with those with only HF [n = 201; 158 (66;363) pg/mL; P < 0.001]. The highest levels of NT-proBNP [868 (213;1397) pg/mL] were measured in patients with concomitant HF and AF (n = 58; P < 0.001 vs. control and vs. HF, P = 1.0 vs. AF). In patients with AF, NT-proBNP levels did not differ between those with HF and preserved ejection fraction (EF) > 50% [n = 38; 603 (175;1070) pg/mL] and those without HF (P = 1.0). Receiver-operating characteristic curves of NT-proBNP showed a similar area under the curve (AUC) for the detection of AF at baseline (0.84, 95% CI [0.79-0.88]) and for HF with EF < 50% (0.78 [0.72-0.85]; P = 0.18). The AUC for HF with EF > 50% was significantly lower (0.61 [0.56-0.65]) than for AF (P = 0.001). During follow-up, AF was newly diagnosed in 157 (9.1%) and HF in 141 (9.6%) study participants. NT-proBNP was a better predictor of incident AF during the first 2 years (AUC: 0.79 [0.75-0.83]) than of newly diagnosed HF (0.59 [0.55-0.63]; P < 0.001). Data were validated in three independent population-based cohorts (LIFE-Adult, n = 2869; SHIP, n = 2013; and SHIP-TREND, n = 2408). CONCLUSIONS: In stable outpatients, NT-proBNP is a better marker for prevalent and incident AF than for HF. In AF patients, the diagnostic value of NT-proBNP for HF with EF > 50% is very limited.

Potential Contributors to Increased Pulmonary Embolism Hospitalizations During the COVID-19 Pandemic: Insights From the German-Wide Helios Hospital Network.

Background: After the first COVID-19 infection wave, a constant increase of pulmonary embolism (PE) hospitalizations not linked with active PCR-confirmed COVID-19 was observed, but potential contributors to this observation are unclear. Therefore, we analyzed associations between changes in PE hospitalizations and (1) the incidence of non-COVID-19 pneumonia, (2) the use of computed tomography pulmonary angiography (CTPA), (3) volume depletion, and (4) preceding COVID-19 infection numbers in Germany. Methods: Claims data of Helios hospitals in Germany were used, and consecutive cases with a hospital admission between May 6 and December 15, 2020 (PE surplus period), were analyzed and compared to corresponding periods covering the same weeks in 2016-2019 (control period). We analyzed the number of PE cases in the target period with multivariable Poisson general linear mixed models (GLMM) including (a) cohorts of 2020 versus 2016-2019, (b) the number of cases with pneumonia, (c) CTPA, and (d) volume depletion and adjusted for age and sex. In order to associate the daily number of PE cases in 2020 with the number of preceding SARS-CoV-2 infections in Germany, we calculated the average number of daily infections (divided by 10,000) occurring between 14 up to 90 days with increasing window sizes before PE cases and modeled the data with Poisson regression. Results: There were 2,404 PE hospitalizations between May 6 and December 15, 2020, as opposed to 2,112-2,236 (total 8,717) in the corresponding 2016-2019 control periods (crude rate ratio [CRR] 1.10, 95% CI 1.05-1.15, P < 0.01). With the use of multivariable Poisson GLMM adjusted for age, sex, and volume depletion, PE cases were significantly associated with the number of cases with pneumonia (CRR 1.09, 95% CI 1.07-1.10, P < 0.01) and with CTPA (CRR 1.10, 95% CI 1.09-1.10, P < 0.01). The increase of PE cases in 2020 compared with the control period remained significant (CRR 1.07, 95% CI 1.02-1.12, P < 0.01) when controlling for those factors. In the 2020 cohort, the number of preceding average daily COVID-19 infections was associated with increased PE case incidence in all investigated windows, i.e., including preceding infections from 14 to 90 days. The best model (log likelihood -576) was with a window size of 4 days, i.e., average COVID-19 infections 14-17 days before PE hospitalization had a risk of 1.20 (95% CI 1.12-1.29, P < 0.01). Conclusions: There is an increase in PE cases since early May 2020 compared to corresponding periods in 2016-2019. This surplus was significant even when controlling for changes in potential modulators such as demographics, volume depletion, non-COVID-19 pneumonia, CTPA use, and preceding COVID-19 infections. Future studies are needed (1) to investigate a potential causal link for increased risk of delayed PE with preceding SARS-CoV-2 infection and (2) to define optimal screening for SARS-CoV-2 in patients presenting with pneumonia and PE.

Characteristics of left atrial remodeling in patients with atrial fibrillation and hypertrophic cardiomyopathy in comparison to patients without hypertrophy.

Atrial fibrillation (AF) leads to remodeling characterized by changes in both size and shape of the left atrium (LA). Here we aimed to study the effect of hypertrophic cardiomyopathy (HCM) on the pattern of LA remodeling in AF-patients. HCM-patients (n = 23) undergoing AF ablation (2009-2012) were matched and compared with 125 Non-HCM patients from our prospective registry. Pre-procedural CT data were analyzed (EnSite Verismo, SJM, MN) to determine the maximal sagittal (anterior-posterior, AP), coronal (superior-inferior, SI and transversal, TV) dimensions and the sphericity index (LAS). Volume (LAV) was rendered after appendage (LAA) and pulmonary vein (PV) exclusion. A cutting plane, between PV ostia/LAA and parallel to the posterior wall, divided LAV into anterior- (LA-A) and posterior-LA (LA-P) parts. The ratio LA-A/LAV was defined as asymmetry index (ASI). HCM patients had a wider inter-ventricular septum and a smaller LV than Non-HCM patients. LA volume (LAV 166 ± 72 vs. 130 ± 36 ml, p = 0.03) and LA diameters were significantly larger in HCM patients. Anterior volume (LA-A: 112 ± 48 vs. 83 ± 26 ml, p < 0.001) differed significantly between groups, whereas the posterior volume LA-P (55 ± 28 vs. 47 ± 13 ml, p = 0.23) and LAS (75% vs. 78%, p = 0.089) was similar in both groups. As a result, ASI was significantly higher (67 ± 6 vs. 63 ± 6%, p = 0.01) in HCM than in Non-HCM patients. In conclusion, LA remodeling in patients with AF and HCM is characterized by asymmetric dilatation, driven by an anterior rather than a posterior dilatation. This can be characterized by three-dimensional imaging and could be used as surrogate of advanced atrial remodeling.

Protected risk stratification with the wearable cardioverter-defibrillator: results from the WEARIT-II-EUROPE registry.

BACKGROUND: The prospective WEARIT-II-EUROPE registry aimed to assess the value of the wearable cardioverter-defibrillator (WCD) prior to potential ICD implantation in patients with heart failure and reduced ejection fraction considered at risk of sudden arrhythmic death. METHODS AND RESULTS: 781 patients (77% men; mean age 59.3 ± 13.4 years) with heart failure and reduced left ventricular ejection fraction (LVEF) were consecutively enrolled. All patients received a WCD. Follow-up time for all patients was 12 months. Mean baseline LVEF was 26.9%. Mean WCD wearing time was 75 ± 47.7 days, mean daily WCD use 20.3 ± 4.6 h. WCD shocks terminated 13 VT/VF events in ten patients (1.3%). Two patients died during WCD prescription of non-arrhythmic cause. Mean LVEF increased from 26.9 to 36.3% at the end of WCD prescription (p < 0.01). After WCD use, ICDs were implanted in only 289 patients (37%). Forty patients (5.1%) died during follow-up. Five patients (1.7%) died with ICDs implanted, 33 patients (7%) had no ICD (no information on ICD in two patients). The majority of patients (75%) with the follow-up of 12 months after WCD prescription died from heart failure (15 patients) and non-cardiac death (15 patients). Only three patients (7%) died suddenly. In seven patients, the cause of death remained unknown. CONCLUSIONS: Mortality after WCD prescription was mainly driven by heart failure and non-cardiovascular death. In patients with HFrEF and a potential risk of sudden arrhythmic death, WCD protected observation of LVEF progression and appraisal of competing risks of potential non-arrhythmic death may enable improved selection for beneficial ICD implantation.

Genetic Susceptibility for Atrial Fibrillation in Patients Undergoing Atrial Fibrillation Ablation.

BACKGROUND: Ablation is a widely used therapy for atrial fibrillation (AF); however, arrhythmia recurrence and repeat procedures are common. Studies examining surrogate markers of genetic susceptibility to AF, such as family history and individual AF susceptibility alleles, suggest these may be associated with recurrence outcomes. Accordingly, the aim of this study was to test the association between AF genetic susceptibility and recurrence after ablation using a comprehensive polygenic risk score for AF. METHODS: Ten centers from the AF Genetics Consortium identified patients who had undergone de novo AF ablation. AF genetic susceptibility was measured using a previously described polygenic risk score (N=929 single-nucleotide polymorphisms) and tested for an association with clinical characteristics and time-to-recurrence with a 3 month blanking period. Recurrence was defined as >30 seconds of AF, atrial flutter, or atrial tachycardia. Multivariable analysis adjusted for age, sex, height, body mass index, persistent AF, hypertension, coronary disease, left atrial size, left ventricular ejection fraction, and year of ablation. RESULTS: Four thousand two hundred seventy-six patients were eligible for analysis of baseline characteristics and 3259 for recurrence outcomes. The overall arrhythmia recurrence rate between 3 and 12 months was 44% (1443/3259). Patients with higher AF genetic susceptibility were younger (P<0.001) and had fewer clinical risk factors for AF (P=0.001). Persistent AF (hazard ratio [HR], 1.39 [95% CI, 1.22-1.58]; P<0.001), left atrial size (per cm: HR, 1.32 [95% CI, 1.19-1.46]; P<0.001), and left ventricular ejection fraction (per 10%: HR, 0.88 [95% CI, 0.80-0.97]; P=0.008) were associated with increased risk of recurrence. In univariate analysis, higher AF genetic susceptibility trended towards a higher risk of recurrence (HR, 1.08 [95% CI, 0.99-1.18]; P=0.07), which became less significant in multivariable analysis (HR, 1.06 [95% CI, 0.98-1.15]; P=0.13). CONCLUSIONS: Higher AF genetic susceptibility was associated with younger age and fewer clinical risk factors but not recurrence. Arrhythmia recurrence after AF ablation may represent a genetically different phenotype compared to AF susceptibility.

Role of inducibility and its dynamic change in the outcome of catheter ablation of atrial fibrillation: a single center prospective study.

BACKGROUND: The role of atrial arrhythmia inducibility as an endpoint of catheter ablation of atrial fibrillation (AF) has been a controversial subject in many studies. Our goal is to evaluate the significance of inducibility, the impact of multiple sites or protocols of stimulation or the change in inducibility status in a prospective study including patients with AF undergoing first catheter ablation. METHODS: We studied 170 consecutive patients with AF (62.9% paroxysmal) undergoing catheter ablation. All patients underwent two separate stimulation protocols before and after the ablation from the coronary sinus ostium and the left atrial appendage: burst pacing at 300, 250, 200 milliseconds (or until refractoriness) for 10 seconds and ramp decrementing from 300 to 200 milliseconds in increments of 10 milliseconds every three beats for 10 seconds. Inducibility was defined as any sustained AF or organized atrial tachycardia (AT) lasting >30 seconds. RESULTS: We had AF/AT inducibility in 55 patients at baseline compared to 36 following ablation. After a mean of 41, 3 months follow-up, 115 patients were free of AF. Inducibility before or after the ablation or change in inducibility status did not influence AF recurrence. There were no significant differences regarding paroxysmal or persistent patients with AF. CONCLUSIONS: Non-inducibility of atrial arrhythmia or change in inducibility status following pulmonary vein (PV) isolation and substrate modification are not associated with long-term freedom from recurrent arrhythmia. Therefore, the use of induction of an endpoint in AF ablation is limited.

Atrial septum biopsy for direct substrate characterization in atrial fibrillation.

INTRODUCTION: The aim of this study was to describe and illustrate the technique of performing interatrial septum biopsy and to demonstrate its use for direct histological substrate characterization in atrial fibrillation (AF). METHODS AND RESULTS: Biopsies were performed in four patients who underwent AF catheter ablation. Bipal 7 bioptome was directed through a steerable sheath directly onto the septum. Fluoroscopic views as well as echocardiography-guided techniques were utilized to confirm that the tip was oriented towards the interatrial septum. The bioptome was then placed on the right atrial (RA) septum and maneuvered to obtain the specimens (at least 1 mm in size) from the posterior septal region of the RA, adjacent to the fossa ovalis. Bioptome placement and sample acquisition were successful in all patients at the first attempt. No patient developed any minor or major complications during the procedure and hospital stay. All the biopsy specimens had proper qualities for histological assessments and revealed a variety of pathologies including fibrosis, inflammation, and fatty infiltration. CONCLUSION: Atrial septum biopsies could be safely performed guided by fluoroscopy and transesophageal echocardiography. The obtained specimens allowed for a detailed localized substrate characterization which is of great interest in AF.

Initial rivaroxaban dosing in patients with atrial fibrillation.

BACKGROUND: Rivaroxaban is a non-vitamin K oral anticoagulant and has been approved for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF). Current labeling recommends 20 mg once a day (q.d.) as a standard dose and a reduced dose of 15 mg q.d. in patients with renal impairment. HYPOTHESIS: The aim of this study was to analyze the adherence to current labeling concerning initial rivaroxaban dosing and to determine whether potential lack of such adherence is medically justified. METHODS: Patients with AF initiated on rivaroxaban between January 1, 2016 and January 31, 2017, were identified in the Heart Center Leipzig database. Health records were screened to identify prescribed rivaroxaban dose, presence or absence of renal impairment, patient characteristics, further dosing-relevant diagnoses and co-medication with antiplatelet drugs and non-vitamin K oral anticoagulants (NOACs). RESULTS: We identified a total of 378 consecutive patients. In 282 cases (74.6%), rivaroxaban was prescribed in a standard dose and in 96 (25.4%) in a reduced dose. Out of 96 patients receiving a reduced dose, 50 (52.1%) did not meet labeling criteria for dose reduction. In uni- and multivariate regression analysis, estimated glomerular filtration rate (eGFR) (odds ratio [OR] 0.34, 95% confidence interval [CI] 0.12-0.95, P = .04) was the only independent predictor of rivaroxaban underdosage. CONCLUSIONS: In clinical practice, rivaroxaban dosing is frequently incoherent with labeling. In this study, rivaroxaban was often administered underdosed. Potentially inappropriate dose reduction was significantly associated with eGFR, the same factor that is used as criterion for dose adjustment.

Effect of Exercise on Outcome after Ventricular Tachycardia Ablation in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy.

Competitive sports and intensive exercise are associated with adverse outcomes in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). This study aimed to assess the role of exercise on long-term results of radiofrequency catheter ablation (RFCA) therapy of ventricular tachycardia (VT) in patients with ARVD/C. Exercise participation was evaluated by telephone or in-person interviews in patients from our ARVD/C registry with previous VT ablation (38 patients, 26 males, age 52.6±14.1years). Of 38 patients, 30 were involved in sports activities before RFCA. Only the minority of our patient population (21.1%) had a sedentary lifestyle before RFCA; 42.1 and 36.8% reported recreational or competitive sports, respectively. During the follow-up period of 52.5±31.4 months, 23 of the total 38 patients with previous RFCA (60.5%) remained free from VT recurrence. In univariate and binary logistic regression analysis, only advanced age was significantly associated with VT recurrence, with a hazard ratio of 1.15, and 95% confidence interval 1.05-1.26 (p=0.004). The results of our observational study indicate that recreational sports do not impair long-term results after RFCA treatment compared with a sedentary lifestyle. Furthermore, the dynamic component of recreational exercise did not affect the outcome of VT ablation in our patient population. Recreational exercise at low to moderate intensity is not associated with an increased risk for VT recurrence after catheter ablation in patients with ARVD/C.

Epicardial adipose tissue thickness as an independent predictor of ventricular tachycardia recurrence following ablation.

BACKGROUND: Although several investigations have shown a relationship between increased epicardial adipose tissue (EAT) and atrial fibrillation (AF), the association between EAT and ventricular tachycardia (VT) has not been evaluated. OBJECTIVE: We investigated the association between EAT and postablation VT recurrence. METHODS: Sixty-one consecutive patients (mean age = 62.0 ± 13.9 years) undergoing VT ablation with preprocedural cardiovascular magnetic resonance imaging (CMR) were recruited. EAT thickness was measured using CMR in the right and left atrioventricular grooves (AVGs), right ventricular free wall, and anterior, inferior, and superior interventricular grooves. RESULTS: During a mean follow-up period of 392.9 ± 180.2 days, postablation VT recurrence occurred in 15 (24.6%) patients. EAT thickness was significantly higher in the VT recurrence group than in the nonrecurrent VT group at the right (18.7 ± 5.7 mm vs 14.1 ± 4.4 mm; P = .012) and left (13.3 ± 3.9 mm vs 10.4 ± 4.1 mm; P = .020) AVGs. The best cut-off points for predicting VT recurrence were calculated as 15.5 mm for the right AVG (area under receiver operating characteristic [ROC] curve = 0.74) and 11.5 mm for the left AVG (area under ROC curve = 0.72). Multivariate Cox regression analysis showed that preprocedural right AVG-EAT (hazard ratio: 1.2; 95% confidence interval: [1.06-1.39], P = .004) was the only independent predictor of VT recurrence after adjustment for covariates. Kaplan-Meier analysis showed a difference for postablation VT recurrence between the 2 groups, with right AVG-EAT thickness cut-off value of <15.5 mm vs ≥15.5 mm (log-rank, P = .003). CONCLUSIONS: We suggested a new possible imaging marker for risk stratification of postablation VT recurrence. A higher EAT may be associated with VT recurrence after catheter ablation of VTs.

Time-dependent prediction of arrhythmia recurrences during long-term follow-up in patients undergoing catheter ablation of atrial fibrillation: The Leipzig Heart Center AF Ablation Registry.

The prediction of arrhythmia recurrences after catheter ablation of atrial fibrillation (AF) remains challenging. The aim of current analysis was to investigate the time-dependent prediction of arrhythmia recurrences after AF catheter ablation during long-term follow-up. The study included 879 patients (61 ± 10 years; 64% males; 39% persistent AF) undergoing first AF catheter ablation. Rhythm outcomes were documented using 7-days Holter monitoring. The APPLE score (Age, Persistent AF, imPaired eGFR, Left atrium (LA), EF) was calculated at baseline, while MB-LATER score (Male gender, Bundle branch block, LA, AF Type, Early Recurrences) 3 months after ablation. The median follow-up time was 37 months [95%CI 35;39]. ERAF and LRAF occurred in 45% and 64%, respectively. On multivariable analysis, ERAF (HR 2.095, 95%CI 1.762-2.490, p < 0.001) was strongly associated with LRAF. The APPLE (HR 1.385, 95%CI 1.276-1.505, p < 0.001) and MB-LATER (HR 1.326, 95%CI 1.239-1.419, p < 0.001) scores significantly predicted LRAF during follow-up. On the ROC analysis, APPLE (AUC 0.640, 95%CI 0.602-0.677, p < 0.001) and MB-LATER (AUC 0.654, 95%CI 0.616-0.691, p < 0.001) demonstrated moderate prediction. Summarizing, ERAF was the strongest predictor for LRAF in time-dependent manner. The APPLE and MB-LATER scores demonstrated moderate prediction of arrhythmia recurrences during long term follow-up.

Atrial fibrillation is associated with alterations in HDL function, metabolism, and particle number.

Increased morbidity and mortality in atrial fibrillation (AF) are related to the pro-fibrotic, pro-thrombotic, and pro-inflammatory processes that underpin the disease. High-density lipoproteins (HDL) have anti-inflammatory, anti-oxidative, and anti-thrombotic properties. Functional impairment of HDL may, therefore, associate with AF initiation or progression. We studied indices of HDL quality and quantity of AF patients and healthy controls, including HDL-particle number, HDL cholesterol, apolipoprotein (apo) A-I levels, serum amyloid A (SAA) content and HDL-cholesterol efflux capacity, and paraoxonase activity of apoB-depleted serum. Serum samples were collected from AF patients (n = 91) before catheter ablation and from age- and sex-matched control subjects (n = 54). HDL-cholesterol efflux capacity was assessed in a validated assay using [3H]-cholesterol-labeled J774 macrophages. Lecithin-cholesterol acyltransferase (LCAT) and paraoxonase activities were assessed using fluorometric assays, SAA levels were determined by ELISA, and total and subclass HDL-particle number was assessed by nuclear magnetic resonance spectroscopy. ApoA-I levels were determined by immunoturbidimetry. HDL-cholesterol efflux capacity, HDL-particle number, apoA-I levels, and LCAT activity were markedly reduced in AF patients when compared to healthy individuals (all p < 0.001), whereas HDL-associated paraoxonase activity and SAA content were not altered (p = 0.578, p = 0.681). Notably, cholesterol efflux capacity, HDL-particle number, apoA-I levels as well as LCAT activity recovered following restoration of sinus rhythm (all p < 0.001). We identified marked alterations in HDL function, HDL maturation, and HDL-particle number in AF patients. Assessing HDL-particle number and function in AF may be used as a surrogate marker of AF onset and progression and may help identifying patients at high risk.

Exercise-related sudden cardiac death of an American football player with arrhythmogenic right ventricular dysplasia/cardiomyopathy AND sarcoidosis.

This case emphasizes the value of cardiac MRI and genetic testing in the early phase of ARVD/C. It also emphasizes the increased risk of SCD for patients with ARVD/C participating in competitive sports, even with immediate cardiopulmonary resuscitation.

Association between echocardiographic parameters and biomarkers in probands with atrial fibrillation and different PR interval lengths: Insight from the epidemiologic LIFE Adult Study.

BACKGROUND: PR interval prolongation is associated with increased risk for atrial fibrillation (AF). Different biomarkers are used to predict AF incidence and its outcomes. The aim of this study was to investigate the association between echocardiographic parameters and blood biomarkers in PR interval groups and AF. METHODS: The LIFE-Adult-Study is a population-based cohort study of randomly selected participants from Leipzig, Germany. In this cross-sectional analysis, individuals ≥40 years with available echocardiographic (LA diameter, EF) and laboratory data (creatinine, Troponin, NT-proBNP) were included. RESULTS: The study population comprised 1.429 individuals (median age 56 (IQR 48-66) years, 40% males) with complete ECG, echocardiographic and laboratory data. There were 48 (3.4%) individuals with AF, 177 (12.4%) with short, 138 (9.7%) with prolonged and 1.066 (74.5%) with normal PR interval. Individuals with PR interval prolongation had larger LA diameter, higher Troponin and NT-proBNP levels than individuals with normal PR interval, but lower than AF group (p<0.001). In contrast, eGFR was significantly higher in the group with PR interval prolongation than in AF, but lower than in individuals with normal PR interval (p<0.001). In the multivariate analysis, PR interval prolongation and AF shared similar characteristics, the only parameter different between both groups was NT-proBNP. CONCLUSIONS: Individuals with PR interval prolongation and AF showed similarities in echocardiographic parameters, renal function and blood biomarker levels. Longitudinal studies are necessary to prove whether the PR interval prolongation may be considered as preliminary stage for AF.

Remote monitoring and clinical outcomes: details on information flow and workflow in the IN-TIME study.

AIMS: Randomized clinical trials investigating a possible outcome effect of remote monitoring in patients with implantable defibrillators have shown conflicting results. This study analyses the information flow and workflow details from the IN-TIME study and discusses whether differences of message content, information speed and completeness, and workflow may contribute to the heterogeneous results. METHODS AND RESULTS: IN-TIME randomized 664 patients with an implantable cardioverter/defibrillator indication to daily remote monitoring vs. control. After 12 months, a composite clinical score and all-cause mortality were improved in the remote monitoring arm. Messages were received on 83.1% of out-of-hospital days. Daily transmissions were interrupted 2.3 times per patient-year for more than 3 days. During 1 year, absolute transmission success declined by 3.3%. Information on medical events was available after 1 day (3 days) in 83.1% (94.3%) of the cases. On all working days, a central monitoring unit informed investigators of protocol defined events. Investigators contacted patients with a median delay of 1 day and arranged follow-ups, the majority of which took place within 1 week of the event being available. CONCLUSION: Only limited data on the information flow and workflow have been published from other studies which failed to improve outcome. However, a comparison of those data to IN-TIME suggest that the ability to see a patient early after clinical events may be inferior to the set-up in IN-TIME. These differences may be responsible for the heterogeneity found in clinical effectiveness of remote monitoring concepts.