Antonio D'Onofrio

Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) randomized controlled trial

Aim The neural cardiac therapy for heart failure (NECTAR-HF) was a randomized sham-controlled trial designed to evaluate whether a single dose of vagal nerve stimulation (VNS) would attenuate cardiac remodelling, improve cardiac function and increase exercise capacity in symptomatic heart failure patients with severe left ventricular (LV) systolic dysfunction despite guideline recommended medical therapy. Methods Patients were randomized in a 2 : 1 ratio to receive therapy (VNS ON) or control (VNS OFF) for a 6-month period. The primary endpoint was the change in LV end systolic diameter (LVESD) at 6 months for control vs. therapy, with secondary endpoints of other echocardiography measurements, exercise capacity, quality-of-life assessments, 24-h Holter, and circulating biomarkers. Results Of the 96 implanted patients, 87 had paired datasets for the primary endpoint. Change in LVESD from baseline to 6 months was −0.04 ± 0.25 cm in the therapy group compared with −0.08 ± 0.32 cm in the control group (P = 0.60). Additional echocardiographic parameters of LV end diastolic dimension, LV end systolic volume, left ventricular end diastolic volume, LV ejection fraction, peak V02, and N-terminal pro-hormone brain natriuretic peptide failed to show superiority compared to the control group. However, there were statistically significant improvements in quality of life for the Minnesota Living with Heart Failure Questionnaire (P = 0.049), New York Heart Association class (P = 0.032), and the SF-36 Physical Component (P = 0.016) in the therapy group. Conclusion Vagal nerve stimulation as delivered in the NECTAR-HF trial failed to demonstrate a significant effect on primary and secondary endpoint measures of cardiac remodelling and functional capacity in symptomatic heart failure patients, but quality-of-life measures showed significant improvement.

Effectiveness of remote monitoring of CIEDs in detection and treatment of clinical and device-related cardiovascular events in daily practice: the HomeGuide Registry.

Aims The HomeGuide Registry was a prospective study (NCT01459874), implementing a model for remote monitoring of cardiac implantable electronic devices (CIEDs) in daily clinical practice, to estimate effectiveness in major cardiovascular event detection and management. Methods and results The workflow for remote monitoring [Biotronik Home Monitoring (HM)] was based on primary nursing: each patient was assigned to an expert nurse for management and to a responsible physician for medical decisions. In-person visits were scheduled once a year. Seventy-five Italian sites enrolled 1650 patients [27% pacemakers, 27% single-chamber implantable cardioverter defibrillators (ICDs), 22% dual-chamber ICDs, 24% ICDs with cardiac resynchronization therapy]. Population resembled the expected characteristics of CIED patients. During a 20 ± 13 month follow-up, 2471 independently adjudicated events were collected in 838 patients (51%): 2033 (82%) were detected during HM sessions; 438 (18%) during in-person visits. Sixty were classified as false-positive, with generalized estimating equation-adjusted sensitivity and positive predictive value of 84.3% [confidence interval (CI), 82.5–86.0%] and 97.4% (CI, 96.5–98.2%), respectively. Overall, 95% of asymptomatic and 73% of actionable events were detected during HM sessions. Median reaction time was 3 days [interquartile range (IQR), 1–14 days]. Generalized estimating equation-adjusted incremental utility, calculated according to four properties of major clinical interest, was in favour of the HM sessions: +0.56 (CI, 0.53–0.58%), P < 0.0001. Resource consumption: 3364 HM sessions performed (76% by nurses), median committed monthly manpower of 55.5 (IQR, 22.0–107.0) min × health personnel/100 patients. Conclusion Home Monitoring was highly effective in detecting and managing clinical events in CIED patients in daily practice with remarkably low manpower and resource consumption.

Longevity of implantable cardioverter-defibrillators for cardiac resynchronization therapy in current clinical practice: an analysis according to influencing factors, device generation, and manufacturer

Aims Device replacement at the time of battery depletion of implantable cardioverter-defibrillators (ICDs) may carry a considerable risk of complications and engenders costs for healthcare systems. Therefore, ICD device longevity is extremely important both from a clinical and economic standpoint. Cardiac resynchronization therapy defibrillators (CRT-D) battery longevity is shorter than ICDs. We determined the rate of replacements for battery depletion and we identified possible determinants of early depletion in a series of patients who had undergone implantation of CRT-D devices. Methods and results We retrieved data on 1726 consecutive CRT-D systems implanted from January 2008 to March 2010 in nine centres. Five years after a successful CRT-D implantation procedure, 46% of devices were replaced due to battery depletion. The time to device replacement for battery depletion differed considerably among currently available CRT-D systems from different manufacturers, with rates of batteries still in service at 5 years ranging from 52 to 88% (log-rank test, P < 0.001). Left ventricular lead output and unipolar pacing configuration were independent determinants of early depletion [hazard ratio (HR): 1.96; 95% 95% confidence interval (CI): 1.57–2.46; P < 0.001 and HR: 1.58, 95% CI: 1.25–2.01; P < 0.001, respectively]. The implantation of a recent-generation device (HR: 0.57; 95% CI: 0.45–0.72; P < 0.001), the battery chemistry and the CRT-D manufacturer (HR: 0.64; 95% CI: 0.47–0.89; P = 0.008) were additional factors associated with replacement for battery depletion. Conclusion The device longevity at 5 years was 54%. High left ventricular lead output and unipolar pacing configuration were associated with early battery depletion, while recent-generation CRT-Ds displayed better longevity. Significant differences emerged among currently available CRT-D systems from different manufacturers.

Manpower and outpatient clinic workload for remote monitoring of patients with cardiac implantable electronic devices: data from the HomeGuide Registry.

This study aimed to assess manpower and resource consumption of the HomeGuide workflow model for remote monitoring (Biotronik Home Monitoring [HM], Biotronik SE & Co. KG, Berlin, Germany) of cardiac implantable electronic devices in daily clinical practice.

Rationale and design of the health economics evaluation registry for remote follow-up: TARIFF

Aims The aims of the study are to develop a cost-minimization analysis from the hospital perspective and a cost-effectiveness analysis from the third payer standpoint, based on direct estimates of costs and QOL associated with remote follow-ups, using Merlin@home and Merlin.net, compared with standard ambulatory follow-ups, in the management of ICD and CRT-D recipients. Methods and results Remote monitoring systems can replace ambulatory follow-ups, sparing human and economic resources, and increasing patient safety. TARIFF is a prospective, controlled, observational study aimed at measuring the direct and indirect costs and quality of life (QOL) of all participants by a 1-year economic evaluation. A detailed set of hospitalized and ambulatory healthcare costs and losses of productivity that could be directly influenced by the different means of follow-ups will be collected. The study consists of two phases, each including 100 patients, to measure the economic resources consumed during the first phase, associated with standard ambulatory follow-ups, vs. the second phase, associated with remote follow-ups. Conclusion Remote monitoring systems enable caregivers to better ensure patient safety and the healthcare to limit costs. TARIFF will allow defining the economic value of remote ICD follow-ups for Italian hospitals, third payers, and patients. The TARIFF study, based on a cost-minimization analysis, directly comparing remote follow-up with standard ambulatory visits, will validate the cost effectiveness of the Merlin.net technology, and define a proper reimbursement schedule applicable for the Italian healthcare system. Trial registration: NCT01075516.

Flecainide single oral dose for management of paroxysmal supraventricular tachycardia in children and young adults

The efficacy of a single oral dose of flecainide to terminate paroxysmal supraventricular tachycardia (PSVT) was evaluated in 25 children and young adults. The subjects were selected from a group of 35 patients with recurrent attacks of PSVT evaluated by means of electrophysiologic study and intravenous electropharmacologic testing with flecainide. In all 25 patients the induced PSVT was stopped by intravenous flecainide and was then no longer inducible or nonsustained. All patients had normal hearts. At least 48 hours after acute intravenous testing, 25 patients underwent electrophysiologic study with a transesophageal catheter and PSVT was induced in all of them: atrioventricular reentrant tachycardia in 16 and atrioventricular nodal reentrant tachycardia in nine. During stable tachycardia, a single oral dose of flecainide (2.9 +/- 0.3 mg/kg; 2.5 to 3.3 mg/kg) was administered. This approach was effective for termination of PSVT in 22 patients. The mean plasma level of flecainide at cessation of tachycardia was 277 +/- 92 ng/ml (150 to 500 mg/ml). All 22 patients who responded were given a single oral dose of flecainide for recurrences of PSVT during follow-up. During a period of 12 +/- 7 months (2 to 27 months) a total of 134 spontaneous episodes of PSVT were reported, and 127 of these episodes were terminated with periodic management. Thus oral periodic flecainide seems useful for management of PSVT in selected patients.

Changes in electrical activation modify the orientation of left ventricular flow momentum: novel observations using echocardiographic particle image velocimetry

AIMS Changes in electrical activation sequence are known to affect the timing of cardiac mechanical events. We aim to demonstrate that these also modify global properties of the intraventricular blood flow pattern. We also explore whether such global changes present a relationship with clinical outcome. METHODS AND RESULTS We investigated 30 heart failure patients followed up after cardiac resynchronization therapy (CRT). All subjects underwent echocardiography before implant and at follow-up after 6+ months. Left ventricular mechanics was investigated at follow-up during active CRT and was repeated after a temporary interruption <5 min later. Strain analysis, performed by speckle tracking, was used to assess the entity of contraction (global longitudinal strain) and its synchronicity (standard deviation of time to peak of radial strain). Intraventricular fluid dynamics, by echographic particle image velocimetry, was used to evaluate the directional distribution of global momentum associated with blood motion. The discontinuation of CRT pacing reflects into a reduction of deformation synchrony and into the deviation of blood flow momentum from the base-apex orientation with the development of transversal flow-mediated haemodynamic forces. The deviation of flow momentum presents a significant correlation with the degree of volumetric reduction after CRT. CONCLUSION Changes in electrical activation alter the orientation of blood flow momentum. The long-term CRT outcome correlates with the degree of re-alignment of haemodynamic forces. These preliminary results suggest that flow orientation could be used for optimizing the biventricular pacing setting. However, larger prospective studies are needed to confirm this hypothesis.

Stroke incidence in patients with cardiac implantable electronic devices remotely controlled with automatic alerts of atrial fibrillation. A sub-analysis of the HomeGuide study

BACKGROUND Remote Monitoring (RM) of cardiac implantable electronic devices (CIEDs) is recommended in management of Atrial Fibrillation (AF), which is a recognized risk factor for thromboembolism. We tried to elucidate whether stroke incidence observed in a large, remotely monitored population was consistent with the CHA2DS2VASc risk profile. METHODS Data from 1650 patients [76% male, age 72 (63-68), CHA2DS2VASc score 3.0 (2.0-4.0)] enrolled during the HomeGuide study and monitored with a daily-transmission RM system providing automatic alerts for AF, were analysed. Of those, 25% had a pacemaker and 75% an implantable cardioverter defibrillator with or without cardiac resynchronization. Estimations of the expected thromboembolic events were based on the population CHA2DS2VASc score profile used in a computer-simulated Markov model. RESULTS Eight thromboembolic events were observed with a 4-year cumulative stroke rate of 0.8% (confidence interval, 0.4%-1.5%). Simulations returned from 18.7 to 17.1 expected events, depending on the AF duration assumed to trigger anticoagulation (one-sample log-rank p<0.03). During the study period, 681 (84%) AF episodes and 129 (16%) atrial tachycardias were detected in 291 patients (18%): 93% of episodes were detected remotely in 269 patients, 66% of whom had no history of AF. Medical interventions were necessary in 305 episodes, 85% of which were detected remotely. Reaction time was 1 (0-6) days for remotely-detected episodes and 33 (14-121) days for episodes detected in clinic (p<0.0001). CONCLUSIONS In a large CIED population followed remotely for up to 4years, the incidence of thromboembolic events was less than half the estimations based on the CHA2DS2VASc risk profile.

Magnitude of QRS duration reduction after biventricular pacing identifies responders to cardiac resynchronization therapy

BACKGROUND Several studies have investigated the association between native QRS duration (QRSd) or QRS narrowing and response to biventricular pacing. However, their results have been conflicting. The aim of our study was to determine the association between the relative change in QRS narrowing index (QI) and clinical outcome and prognosis in patients who undergo cardiac resynchronization therapy (CRT) implantation. METHODS AND RESULTS We included 311 patients in whom a CRT device was implanted in accordance with current guidelines for CRT. On implantation, the native QRS, the QRSd and the QI during CRT were measured. After 6months, 220 (71%) patients showed a 10% reduction in LVESV. The median [25th-75th] QI was 14.3% [7.2-21.4] and was significantly related to reverse remodeling (r=+0.22; 95%CI: 0.11-0.32, p=0.0001). The cut-off value of QI that best predicted LV reverse remodeling after 6months of CRT was 12.5% (sensitivity=63.6%, specificity=57.1%, area under the curve=0.633, p=0.0002). The time to the event death or cardiovascular hospitalization was significantly longer among patients with QI>12.5% (log-rank test, p=0.0155), with a hazard ratio (HR) of 0.3 [95%CI: 0.11-0.78]. In the multivariate regression model adjusted for baseline parameters, a 10% increment in QI (HR=0.61[0.44-0.83], p=0.002) remained significantly associated with CRT response. CONCLUSIONS Patients with a larger decrease in QRSd after CRT initiation showed greater echocardiographic reverse remodeling and better outcome from death or cardiovascular hospitalization. QI is an easy-to-measure variable that could be used to predict CRT response at the time of pacing site selection or pacing configuration programming.

Transesophageal echocardiograpy in patients with persistent atrial fibrillation undergoing electrical cardioversion on new oral anticoagulants: A multi center registry☆

Increased risk of thrombo-embolism following cardioversion foratrial fibrillation (AF) is well recognized. Therefore, anticoagulation isconsidered mandatory before elective cardioversion for AF of N48 h orAF of unknown duration. Vitamin K antagonists (VKAs) (INR 2.0 to3.0) are recommended for at least 3 weeks prior to and 4 weeks aftercardioversion, regardless of the CHA2DS2-VASc score and the method(electrical or pharmacological) used to restore sinus rhythm [1,2].Therisk of thromboembolic events is high (up to 7%) if anticoagulation isinadequate, and is reduced to less than 1% if adequate anticoagulationis achieved [3]. Recently, new oral anticoagulants (NOACs) have beenintroduced intheclinical practiceandsuggestedalso inpatientsunder-going electrical cardioversion for AF. In this context compliance andadherence to treatment are crucial, as these drugs have a relativelyshort half-life. In fact patients missing more than one drug assumptioncannotbeconsideredunderanadequatetherapeuticregimen.Moreover,differently from VKA treatment, that can be followed through INRmeasurements,there are no effective hemoreological tests to assessther-apeutic anticoagulation. One way to assess the ef ficacy of anticoagulationtherapy is the direct search for left atrial thrombus by means oftransesophageal echocardiography (TEE). The aim of our study was toevaluate the incidence of left atrial (LA) thrombus in patients referredfor electrical cardioversion, while on treatment with NOACs, using apre-procedural TEE.Between January 2014 and December 2014 we collected the TEEdata of 219 consecutive patients with persistent AF referred to sevenItalian centers for elective electrical cardioversion, while on NOACs forat least 3 weeks before electrical cardioversion. This study followedtheprinciplesoutlinedinthelatestupdateoftheDeclarationofHelsinkiand all patients signed informed consent. This study was approved byour Institutional Review Boards. Main exclusion criteria were a historyof thromboembolic events, a history of LA thrombus diagnosed byTEE, a TEE procedure performed in the 21 days before starting NOACtherapy, and the need for anticoagulation other than AF. TEE wasperformed with a 5–7-MHz multiplane transducer connected to anultrasoundsystem.Multiplestandardtomographicplaneswereimaged.TheLAappendagepeakflowvelocity,presenceofthrombiintheLA,andseverityofspontaneousechocontrastintheLAweredetermined.Atrialcavityorappendagethrombiwereconsideredtobepresentwhenwell-circumscribed, echodense, intracavitary masses that were acousticallydistinct from the underlying endocardium and pectinate muscles wereidentified.The clinical characteristics of the study population are summarizedin Table 1. The mean duration of AF was 6.2 ± 4.3 months, and themean duration of NOAC therapy was 4.1 ± 3 months. NOACs usedwere dabigatran (86 patients, 39%), rivaroxaban (61 patients, 28%),and apixaban (73 patients, 33%). The daily dabigratan dose was220mgin21patients,and300mgin65patients;thedailyrivaroxabandose was 15 mg in 2 patients, and 20 mg in 59 patients; the dailyapixaban dose was 5 mg in 1 patient, and 10 mg in 72 patients. The