Innovative solutions for disease management.

The increasing prevalence of chronic diseases is a driver for emerging big data technologies for healthcare including digital platforms for data collection, systems for active patient engagement and education, therapy specific predictive models, optimized patient pathway models. Powerful bioelectronic medicine tools for data collection, analysis and visualization allow for joint processing of large volumes of heterogeneous data, which in turn can produce new insights about patient outcomes and alternative interpretations of clinical patterns that can lead to implementation of optimized clinical decisions and clinical patient pathway by healthcare professionals.With this perspective, we identify innovative solutions for disease management and evaluate their impact on patients, payers and society, by analyzing their impact in terms of clinical outcomes (effectiveness, safety, and quality of life) and economic outcomes (cost-effectiveness, savings, and productivity).As a result, we propose a new approach based on the main pillars of innovation in the disease management area, i.e. progressive patient care models, patient-centric approaches, bioelectronics for precise medicine, and lean management that, combined with an increase in appropriate private-public-citizen-partnership, leads towards Patient-Centric Healthcare.

Diagnosis of neurally mediated syncope at initial evaluation and with tilt table testing compared with that revealed by prolonged ECG monitoring. An analysis from the Third International Study on Syncope of Uncertain Etiology (ISSUE-3).

OBJECTIVE: According to the guidelines of the European Society of Cardiology, a presumed diagnosis of neurally mediated syncope (NMS) can be made when patients have a consistent history and competing diagnoses are excluded. In the present study, we compared the initial diagnosis of NMS by means of implantable loop recorder (ILR) documentation. METHODS: In this prospective multicentre observational study which involved 51 hospitals in nine countries in Europe and Canada, 504 NMS patients ≥40 years, who had suffered ≥3 syncopal episodes in the previous 2 years received an ILR and were followed up for a mean of 15±11 months. RESULTS: ILR recorded a spontaneous syncope in 187 cases, with an estimated diagnostic yield of 47% at 3 years. ILR findings were consistent with the initial diagnosis of presumed NMS in 162 (87%) patients whereas did not confirm NMS in another 25 (13%), who had an intrinsic cardiac arrhythmic cause (atrial tachyarrhythmias (#6), long pause on termination of tachyarrhythmia (#8), persistent bradycardia (#3), ventricular tachycardia (#4)) or a non-arrhythmic loss of consciousness (non-syncopal (#3), orthostatic hypotension (#1)). No clinical baseline feature was able to predict an intrinsic cardiac cause with the exception of more frequent non-syncopal atrial tachyarrhythmias on clinical history, which were present in 38% of cardiac versus 5% of NMS patients (p=0.001). Tilt table testing (TT) was positive in 76/136 (56%) presumed NMS and in 9/21 (43%) non-NMS patients (p=0.35); an asystolic response was present in 28/136 (21%) NMS and in 0/21 (0%) non-NMS patients (p=0.03). CONCLUSIONS: ILR findings showed results other than NMS in a small, although non-negligible, number of patients older than 40 years. TT was unable to discriminate between presumed NMS and non-NMS with the exception of an asystolic response which was highly specific.

Reproducibility of electrocardiographic findings in patients with suspected reflex neurally-mediated syncope.

The reproducibility of electrocardiographic (ECG) recordings in syncopal recurrences and the diagnostic role of nonsyncopal arrhythmias are not well known. The objective of this study was to analyse the reproducibility of the ECG findings recorded with implantable loop recorders in 41 patients with suspected neurally-mediated syncope who were included in the International Study on Syncope of Uncertain Origin-2 study and that had > or =2 events recorded by implantable loop recorders. In these patients, the electrocardiogram obtained with the first documented syncope (index syncope) was compared with other recorded events. Twenty-two patients had > or =2 syncopes, and their electrocardiograms were reproducible in 21 (95%): 15 with sinus rhythm, 5 with asystole, and 1 with ventricular tachycardia; 1 had asystole at first syncope and sinus rhythm at recurrent syncope. In 32 patients with nonsyncopal episodes, an arrhythmia was documented in 9, and all of them had the same arrhythmia during the index syncope (100% reproducibility); conversely, when sinus rhythm was documented (23 patients) during nonsyncopal episodes, an arrhythmia was still documented in 6 during the index syncope (70% reproducibility; p = 0.0004). In conclusion, the ECG findings during the first syncope are highly reproducible in subsequent syncopes. The presence of an arrhythmia during nonsyncopal episodes is also highly predictive of the mechanism of syncope, but the presence of sinus rhythm does not rule out the possibility of arrhythmia during syncope. Therefore the finding of an arrhythmia during a nonsyncopal episode allows the etiologic diagnosis of syncope, and eventually to anticipate treatment, without waiting for syncope.

The MINERVA study design and rationale: a controlled randomized trial to assess the clinical benefit of minimizing ventricular pacing in pacemaker patients with atrial tachyarrhythmias.

BACKGROUND: Dual-chamber (DDD) pacing has generally been regarded as "physiologic pacing" and therefore expected to be superior to ventricular pacing. Major randomized trials have so far failed to demonstrate significant reductions in the incidences of mortality, stroke, and heart failure. It has been shown that unnecessary ventricular pacing in patients with sinus node dysfunction or only intermittent atrioventricular block is associated with ventricular desynchronization and increased risk of atrial tachyarrhythmias (ATA). METHODS: The MINimizE Right Ventricular pacing to prevent Atrial fibrillation and heart failure (MINERVA) study is a prospective, multi-center, randomized, international, single-blind, controlled trial designed to determine whether physiologic pacing through the managed ventricular pacing (MVP) algorithm combined with preventive atrial pacing (PAP) and atrial antitachycardia pacing (ATP) is superior to standard DDD pacing in terms of 2-year reduction in death, permanent ATA, and cardiovascular hospitalizations. Patients with standard class I or II indications for permanent DDD pacing and history of ATA will receive a Medtronic EnRhythm implantable pacemaker (Medtronic, Minneapolis, MN). After a 1-month run-in period, patients will be randomized in a 1:1:1 manner to the DDD (control group, all OFF), the DDDRP (MVP + PAP + ATP ON), and the MVP group (only MVP ON). Up to 1,300 patients will be included in approximately 70 centers in Europe, the Middle East, and Asia. CONCLUSIONS: The MINERVA study will make an important contribution to the management of patients with paroxysmal ATA and accepted indications for dual-chamber pacemaker implantation by determining whether physiologic pacing combined with PAP and ATP is superior to standard DDD pacing in terms of reduction of mortality, incidence of permanent ATA, and cardiovascular hospitalizations.

Circadian pattern of atrial pacing threshold in the young.

AIM: The aim of this study was to evaluate the circadian variation of atrial pacing threshold in young patients. METHODS AND RESULTS: Atrial Capture Management (ACM) algorithm is a Medtronic EnPulse pacemaker (PM) feature that uses two algorithms: atrioventricular conduction (AVC) (atrial pacing and spontaneous AVC) and atrial chamber reset (ACR) [intrinsic atrial activity with atrioventricular block (AVB)]. For this prospective, non-randomized study, ACM automatically measured and recorded thresholds every 4 h. Data are reported as median (range) or mean +/- SD. In 2004-05, 14 consecutive patients (11 males, 79%), aged 12 years (1 day-24 years) received an EnPulse DDD/R PM for AVB (eight patients, 57%) or sinus node dysfunction. A new pacing system was implanted in eight patients (57%) and a replaced PM in six patients. Epicardial leads were implanted in 10 patients (71%). The follow-up duration is 11 (1-18) months: 9742 threshold measurements were attempted (6328 AVC, 3414 ACR), of which 3797 (39%) were successful (1807 AVC, 29%, 1990 ACR, 58%) in 11 (79%) patients. Three infants had no successful measurements. Measurement success was 42 +/- 34% (AVC 27 +/- 39%, ACR 41 +/- 29%). Higher thresholds were found between 00.00 and 12.00 a.m. and lower between 12.00 and 20.00. CONCLUSION: Young patients show a circadian variability of atrial threshold with higher thresholds between 00.00 and 12.00.

Daily, weekly, monthly, and seasonal patterns in the occurrence of vasovagal syncope in an older population.

AIMS: The aim of this study was to assess the frequency of vasovagal episodes over the day, week, month, and seasons. METHODS AND RESULTS: This study was part of the multi-centre International Study on Syncope of Uncertain Etiology-2 (ISSUE-2), which included patients, aged 30 years or older, with severe neurally mediated syncope between June 2002 and July 2004. The Implantable Loop Recorder (ILR) was used to document the syncope-related ECG periods. For this study patients with recorded syncopal episodes after ILR-implantation was selected. At least one episode was documented in 106 patients. A higher number of episodes were documented during the morning than during other periods of the day (P < 0.01). There was no difference between various days of the week, episodes per month, or between seasons. There was no difference between age and gender groups, although elderly patients seemed to be responsible for the peak in the morning. CONCLUSION: A circadian pattern in the frequency of vasovagal episodes exists, with a peak in the morning. This is in accordance with reports of diurnal variations in blood pressure and heart rate. No difference was observed in syncope distribution between days of the week, months, or seasons.

Cardioinhibitory carotid sinus hypersensitivity predicts an asystolic mechanism of spontaneous neurally mediated syncope.

AIMS: We correlated the finding of cardioinhibitory carotid sinus hypersensitivity (CSH) with that observed during a spontaneous syncopal relapse by means of an implantable loop recorder (ILR). METHODS AND RESULTS: We included 18 consecutive patients with suspected recurrent neurally mediated syncope and positive cardioinhibitory response during carotid sinus massage (max pause 5.5 +/- 1.6 s) who had subsequent documentation of a spontaneous syncope by means of an ILR. They were compared with a 2:1 age- and sex-matched group of 36 patients with a clinical diagnosis of recurrent neurally mediated syncope and negative response to carotid sinus massage, tilt testing and ATP test. Asystole >3 s was observed at the time of the spontaneous syncope in 16 (89%) of CSH patients and in 18 (50%) of the control group (P = 0.007). Sinus arrest was the most frequent finding among CSH patients but not among controls (72 vs. 28%, P = 0.003). After ILR documentation, 14 CSH patients with asystole received dual-chamber pacemaker implantation; during 35 +/- 22 months of follow-up, 2 syncopal episodes recurred in 2 patients (14%), and pre-syncope occurred in another 2 patients (14%). Syncope burden decreased from 1.68 (95% confidence interval 1.66 - 1.70) episodes per patient per year before to 0.04 (0.038-0.042) after pacemaker implant (98% relative risk reduction). CONCLUSIONS: In patients with suspected neurally mediated syncope, the finding of cardioinhibitory CSH predicts an asystolic mechanism at the time of spontaneous syncope and, consequently, suggests a possible benefit of cardiac pacing therapy.

Ventricular pacing threshold variations in the young.

Ventricular Capture Management (VCM) is a Medtronic Kappa pacemakers (PM) feature that automatically measures pacing threshold through detection of the evoked response after a pacing stimulus. The aim of this study was to evaluate the range of variation of ventricular pacing threshold in pediatric patients with endocardial and epicardial pacing leads. Thirty-one patients (median age 6.5 years) were implanted with a Kappa 901 PM for atrioventricular block or sinus node dysfunction. Congenital heart defects (CHD) were present in 58% of patients. Ventricular leads were epicardial in 52% of patients. VCM was programmed to automatically measure threshold every 2 hours. In a median follow-up of 12 months, 27,110 threshold measurements, 72% of which were successful, have been taken in 94% of patients. Measurement success was 99% in the endocardial leads group (age at implantation 12 +/- 6 years) and 31% in epicardial leads (age 4 +/- 5 years) (P < 0.05). Main reasons for unsuccessful measurements were high heart rate and, in a patient with an endocardial lead, competition with intrinsic rhythm. Undersensing or oversensing of the evoked responses was not detected. In all successful VCM measurements, epicardial pacing and CHD contributed to stability of thresholds (multivariate analysis). Pacing threshold showed specific circadian patterns: higher thresholds were found between 00.00 and 06.00 a.m., but the variation was low, 0.03 +/- 0.01 V. In conclusion, children and young patients show stable ventricular thresholds, especially in presence of CHD, and epicardial leads are at least as stable as endocardial leads. Ventricular pacing threshold showed a circadian variability similar to that described in adults, that does not seem to influence VCM functioning and PM programming.

Physiologic pacing for atrial fibrillation prevention in sinus node disease: long-term results.

BACKGROUND: Physiologic pacing has been demonstrated to be effective in preventing atrial fibrillation recurrences in patients with sinus bradycardia. Aim of the study was to evaluate long-term incidence of atrial fibrillation in a large population of patients affected by sinus node disease receiving physiologic pacing. Furthermore, predictors of arrhythmia recurrence and effect of pacing mode were investigated. POPULATION: Four hundred twenty-five patients (220 Male, 77 +/- 9 years) were retrospectively analyzed: implanted system was AAI in 20.5% and DDD in 79.5%. Thirty-four percent had atrial fibrillation before implant. RESULTS: Follow-up lasted on average 51 +/- 36 months (median 42, range 1 month-18 years). Sixty-six percent were on antiarrhythmic drug therapy. After 5 years, 89% survived, 74.5% had at least one episode of atrial fibrillation, 39.9% were submitted to electrical cardioversion, 67.2% were hospitalized because of cardiac causes, 33.3% developed permanent atrial fibrillation. Primary conduction system disease and valvular heart disease were independent predictors for atrial fibrillation recurrence. Preimplant atrial fibrillation predicted arrhythmia recurrence during the follow-up, but it did not predict development of permanent atrial fibrillation. AAI pacing, when compared with DDD, was associated to a lower rate of atrial fibrillation recurrences (AAI 28.7%, DDD 53.3%, P < 0.001). CONCLUSION: In spite of expected benefits of physiologic pacing, the development of atrial fibrillation and permanent atrial fibrillation were quite common. The additional benefits of multifunction pacemakers designed to prevent and treat atrial fibrillation should be evaluated in controlled studies.

Lack of correlation between the responses to tilt testing and adenosine triphosphate test and the mechanism of spontaneous neurally mediated syncope.

AIMS: We prospectively correlated the results of tilt testing (TT) and adenosine triphosphate test (ATP) with the findings observed during a spontaneous syncopal relapse by means of an implantable loop recorder (ILR) in patients with a clinical diagnosis of neurally mediated syncope. METHODS AND RESULTS: We included patients with three or more clinically severe syncopal episodes in the last 2 years without significant electrocardiographic and cardiac abnormalities. Patients with orthostatic hypotension and carotid sinus syncope were excluded. After ILR implantation, patients were followed until the first documented syncope. Among 392 enrolled patients, 343 underwent TT, which was positive in 164 (48%), and 180 ATP test, which was positive in 53 (29%). Syncope was documented by ILR in 106 (26%) patients after a median of 3 months. Patients with positive and negative TT had similar baseline characteristics, syncopal recurrence rate, and mechanism of syncope, but those with positive TT had more frequently no or slight rhythm variations during spontaneous syncope (45 vs. 21%, P=0.02). An asystolic pause was more frequently found during spontaneous syncope than during TT (45 vs. 21%, P=0.02), but there was a trend for those with an asystolic response during TT also to have an asystolic response during spontaneous syncope (75 vs. 37%, P=0.1). Patients with positive ATP test responses showed syncopal recurrence rates and mechanism of syncope similar to those with negative ATP tests. CONCLUSION: In patients with neurally mediated syncope, clinical characteristics, outcome, and mechanism of syncope are poorly correlated and not predicted by the results of TT and ATP test. Therefore, these tests are of little or no value in guiding specific therapy.

Effects of right ventricular pacing on intra-left ventricular electromechanical activation in patients with native narrow QRS.

Some patients with right ventricular (RV) apical pacing show contractile asynchrony of the left ventricle. Whether the asynchrony is due to RV pacing or was a preexistimg condition remains unknown. The aim of this study was to evaluate how much pacing from the RV apex affects left ventricular (LV) electromechanical activation and to assess whether the extent of LV asynchrony during RV pacing can be predicted by clinical, electrocardiographic, or echocardiographic findings obtained during spontaneous rhythm. We evaluated 56 patients with narrow QRS and preserved atrioventricular conduction who received permanent backup RV pacing. Intra-LV electromechanical activation was assessed during spontaneous rhythm and during pacing using tissue Doppler echocardiography. An abnormal intra-LV electromechanical delay (EMD) (defined as a >41-ms difference between the faster and slower activated LV wall) was found in 15 patients (27%) during spontaneous rhythm and 28 patients (50%) during RV pacing (p<0.001). Of the 9 baseline variables (age, gender, history of heart failure, QRS duration in spontaneous rhythm and during pacing, LV end-diastolic and end-systolic diameters, LV ejection fraction, and intra-LV EMD in spontaneous rhythm), an abnormal baseline intra-LV EMD and QRS duration of >85 ms were independent predictors of an abnormal intra-LV delay during RV pacing. RV apical pacing induces asynchrony of LV contractions in a substantial percentage of patients but not in all. Although normal baseline intra-LV electromechanical activation cannot exclude the development of significant asynchrony during RV pacing, the presence of preimplant LV asynchrony predicts for a worsening of this detrimental effect.

Is dual defibrillator better than conventional DDD pacing in brady-tachy syndrome? Results of the ICARUS Trial (Internal Cardioversion Antitachypacing and Prevention: Resource Utilization Study).

AIM OF THE STUDY: To compare the impact of dual defibrillator versus conventional DDD pacing on quality of life and hospitalizations in patients with sinus node disease and recurrent symptomatic atrial fibrillation. STUDY DESIGN: Prospective, parallel, controlled trial. METHODS: Sixty-three patients (41 M, mean age 71 +/- 8 years) with sinus node disease and at least three symptomatic episodes of atrial fibrillation during the last year were enrolled. Thirty-one consecutive patients received a dual defibrillator (group A) and 32 standard DDD pacing (group B). In group A, 12 patients received an external remote-control device in order to shock themselves in case of atrial fibrillation, while 19 were scheduled for early in-hospital manual shock. Seventy-five percent had been hospitalized during the last year and 57% had required electrical cardioversion. Atrial fibrillation was persistent in 63.5% and paroxysmal in 37.5%. The follow-up lasted 1 year. RESULTS: Atrial fibrillation recurred in 83.3% in group A and 79.3% in group B (p = ns). Electrical cardioversion was applied in 54.8% in group A and in 21.9% in group B (p < 0.05). On the whole, 89.5% of electrical cardioversions were delivered in the defibrillator group (p < 0.0001). In the whole population 27.0% patients had cardiac-related hospitalization (31.2% in the pacemaker group and 22.6% in the defibrillator group, p = n.s.). In patients with persistent atrial fibrillation, cardiac-related hospitalization rate was significantly lower in the group A (0% vs. 30%, p < 0.05). Considering Symptom Check List, symptoms significantly improved in the whole population, but symptom number and frequency improved significantly only in the group A. Similarly, SF-36 questionnaire scores showed a little higher quality of life improvement in the group A. CONCLUSIONS: Dual defibrillator showed consistent trends toward a higher effectiveness when compared with standard DDD pacing. Dual defibrillator was associated to reduced in-patient cardioversions and to better quality of life. All-cause hospitalizations were reduced only in patients with persistent atrial fibrillation.