Closed Loop Stimulation reduces the incidence of atrial high-rate episodes compared to conventional rate-adaptive pacing in patients with sinus node dysfunctions.

BACKGROUND AND AIMS: Subclinical atrial fibrillation (AF) is associated with increased risk of progression to clinical AF, stroke, and cardiovascular death. We hypothesized that in pacemaker patients requiring dual-chamber rate-adaptive (DDDR) pacing, Closed Loop Stimulation (CLS) integrated into the circulatory control system through intracardiac impedance monitoring would reduce the occurrence of atrial high-rate episodes (AHREs) compared to conventional DDDR pacing. METHODS: Patients with sinus node dysfunctions (SND) and an implanted pacemaker or defibrillator were randomly allocated to dual-chamber CLS (n=612) or accelerometer-based DDDR pacing (n=598) and followed for 3 years. The primary endpoint was time to the composite endpoint of first AHRE lasting ≥6 minutes, stroke, or transient ischemic attack (TIA). All AHREs were independently adjudicated using intracardiac electrograms. RESULTS: The incidence of the primary endpoint was lower in the CLS arm (50.6%) than in the DDDR arm (55.7%), primarily due to the reduction in AHREs lasting between 6 hours and 7 days. Unadjusted site-stratified hazard ratio (HR) for CLS versus DDDR was 0.84 (95%-CI, 0.72-0.99; p=0.035). After adjusting for CHA2DS2-VASc score, the HR remained 0.84 (95%-CI, 0.71-0.99; p=0.033). In subgroup analyses, the incremental benefit of CLS was greatest in patients without atrioventricular block (HR, 0.76; p=0.006) and in patients without AF history (HR, 0.73; p=0.010). The contribution of stroke/TIA to the primary endpoint (1.3%) was low and not statistically different between study arms. CONCLUSIONS: Dual-chamber CLS in patients with SND is associated with a significantly lower AHRE incidence than conventional DDDR pacing.

International cohort study on the effectiveness of dronedarone and other antiarrhythmic drugs for atrial fibrillation in real-world practice (EFFECT-AF).

AIMS: To evaluate the effectiveness and safety of dronedarone compared with other commonly used antiarrhythmic drugs (AADs) for preventing atrial fibrillation (AF) recurrences. METHODS AND RESULTS: An international observational cohort study in Germany, Spain, Italy, and the USA enrolling patients with AF receiving AAD therapy. Patients with New York Heart Association (NYHA) Class IV heart failure were excluded. Participants were followed for up to 18 months, regardless of discontinuation or subsequent AAD switches. Atrial fibrillation recurrence was captured by hospitalization, emergency room visit, or electrocardiogram-based documentation of AF. Confounding bias was controlled for in the analysis of AF recurrence using multivariate models of 19 variables for adjustment. A total of 1009 participants [mean age 67.2 (10.8) years, male to female ratio 1.3] were recruited from 170 centres, 693 (69%) of which were from across Europe and the remaining 316 (31%) from the USA. At the time of enrolment, participants were taking dronedarone (51%) or other AADs (49%) [flecainide or propafenone (42%), sotalol (11%), and amiodarone (47%)]. No significant differences in the risk of first confirmed AF recurrence with dronedarone vs. other AADs [crude hazard ratio (HR) 1.10 (95% confidence interval 0.85-1.42); adjusted HR 1.16 (0.87-1.55)] were found, irrespective of whether univariate or multivariate models were used. Reported safety events were in accordance with the known safety profile of dronedarone. CONCLUSION: In this population of patients from either Europe or the USA receiving dronedarone or another AAD, the effectiveness of dronedarone was comparable to that observed for other AADs in preventing first AF recurrence.

Safety and efficacy of dronedarone from clinical trials to real-world evidence: implications for its use in atrial fibrillation.

Efficacy and safety of dronedarone was shown in the ATHENA trial for paroxysmal or persistent atrial fibrillation (AF) patients. Further trials revealed safety concerns in patients with heart failure and permanent AF. This review summarizes insights from recent real-world studies and meta-analyses, including reports on efficacy, with focus on liver safety, mortality risk in patients with paroxysmal/persistent AF, and interactions of dronedarone with direct oral anticoagulants. Reports of rapidly progressing liver failure in dronedarone-prescribed patients in 2011 led to regulatory cautions about potential liver toxicity. Recent real-world evidence suggests dronedarone liver safety profile is similar to other antiarrhythmics and liver toxicity could be equally common with many Class III antiarrhythmics. Dronedarone safety concerns (increased mortality in patients with permanent AF) were raised based on randomized controlled trials (RCT) (ANDROMEDA and PALLAS), but comedication with digoxin may have increased the mortality rates in PALLAS, considering the dronedarone-digoxin pharmacokinetic (PK) interaction. Real-world data on apixaban-dronedarone interactions and edoxaban RCT observations suggest no significant safety risks for these drug combinations. Median trough plasma concentrations of dabigatran 110 mg during concomitant use with dronedarone are at acceptable levels, while PK data on the rivaroxaban-dronedarone interaction are unavailable. In RCTs and real-world studies, dronedarone significantly reduces AF burden and cardiovascular hospitalizations, and demonstrates a low risk for proarrhythmia in patients with paroxysmal or persistent AF. The concerns on liver safety must be balanced against the significant reduction in hospitalizations in patients with non-permanent AF and low risk for proarrhythmias following dronedarone treatment.

Quality of life in patients with atrial fibrillation: how to assess it and how to improve it.

Atrial fibrillation (AF) is the most frequent cardiac rhythm disorder and presents a considerable public health burden that is likely to increase in the next decades due to the ageing population. Current management strategies focus on the heart rate and rhythm control, thromboembolism prevention, and treatment of underlying diseases. The concept of quality of life (QoL) has gained significant importance in recent years as an outcome measure in AF studies evaluating therapeutic interventions and as a relevant component of a comprehensive treatment plan. Quality of life is impaired in the majority of patients with AF, and both rate and rhythm control strategies show significant improvement in QoL measures in highly symptomatic patients. This article reviews generic and specialized instruments for measuring QoL in the context of AF, discusses their applications and limitations to integration in clinical practice, and addresses the potential of early therapy for improving QoL outcomes. The development and validation of new QoL assessment tools will have a central role in the advancement of therapies and treatment guidelines for AF.

Second European Society of Cardiology Cardiac Resynchronization Therapy Survey: the Italian cohort.

AIM: Adherence to guidelines was not homogeneous in Europe, according to the survey on cardiac resynchronization therapy conducted in 2008-2009. The aim of our study was to compare the results in the Italian and European cohorts of the Second European Cardiac Resynchronization Therapy Survey. METHODS: Patients' characteristics, procedural data and follow-up were collected. Italian records were compared with European countries. RESULTS: Italian hospitals enrolled 526 patients. The italian cohort was older (71.6 ±â€Š9.5 vs. 68.4 ±â€Š10.8; P < 0.00001), had less severe NYHA class (>II 47.2 vs. 59.6%; P < 0.00001), higher ejection fraction (30.3 ±â€Š7.4 vs. 28.4 ±â€Š8.2%; P < 0.00001), and less atrial fibrillation prevalence (34.4 vs. 41.2%; P = 0.00197) than the European cohort. Italian patients were more frequently hospitalized for heart failure in the previous year (51.9 vs. 46.2%; P = 0.01118) and had lower mean QRS duration (151 ±â€Š26 vs. 157 ±â€Š27 ms; P < 0.0001). CRT-D were more often implanted in Italian patients (79.3 vs. 69.3%; P < 0.00001). The complication rate was similar (4.6% vs. 5.6%; ns). The rate of use of ACEi/ARBs in Italy was lower than in Europe (77.2 vs. 86.9%; P < 0.00001). Patients were followed up in the implantation centre (92.1 vs. 86%; P = 0.00014), but rarely with remote monitoring (25.9 vs. 30%; P = 0.04792). CONCLUSION: The survey demonstrates important similarities as well as substantial differences regarding most of the aspects evaluated. Efforts to implement adherence to guidelines will be endorsed in Italy.

Presence and duration of atrial fibrillation detected by continuous monitoring: crucial implications for the risk of thromboembolic events.

INTRODUCTION: Asymptomatic atrial fibrillation (AF) can expose patients to the risk of stroke. The primary objective of this study was to assess the incidence of thromboembolic events in relationship with CHADS(2) (congestive heart failure, hypertension, age >or=75 years, diabetes mellitus, and prior stroke, or transient ischemic attack) score and AF presence/duration. The secondary objective was to compare intermittent versus continuous monitoring strategies. METHODS AND RESULTS: Data from patients with an implanted pacemaker and a history of AF were analyzed. Thromboembolic risk was quantified through CHADS(2) score. Three AF groups were considered: patients with <5-minutes AF on 1 day (AF-free); patients with >5-minutes AF on 1 day but <24 hours (AF-5 minutes); patients with AF episodes >24 hours (AF-24 hours). Monitoring strategies involving 24-hour Holter, 1-week Holter, and 30-day Holter were simulated. Data from 568 patients continuously monitored for 1 year were analyzed: 171 (30%) had CHADS(2) score = 0; 269 (47%) had CHADS(2) score = 1; 111 (20%) had CHADS(2) score = 2; and 17 (3%) had CHADS(2) score >or= 3. During follow-up, 14 patients (2.5%) had an ischemic thromboembolic event. AF-24 hours patients numbered 223 (39.2%); AF-5 minutes, 179 (31.5%); and AF-free, 29.2%. By combining AF presence/duration with CHADS(2) score, two subpopulations with markedly different risks of events (0.8% vs 5%, P = 0.035) were identified, the former corresponding to AF-free with CHADS(2)5 minutes was 44.4%, 50.4%, and 65.1% for 24-hour Holter, 1-week Holter, and 1-month Holter monitoring, respectively. CONCLUSION: In patients with recurrent AF episodes, risk stratification for thromboembolic events can be improved by combining CHADS(2) score with AF presence/duration.

The VALID-CRT risk score reliably predicts response and outcome of cardiac resynchronization therapy in a real-world population.

OBJECTIVES: The aim of the study was to confirm the value of the VALID-cardiac resynchronization therapy (CRT) risk score in predicting outcome and to assess its association with clinical response (CR) in an unselected real-world CRT population. METHODS AND RESULTS: The present analysis comprised all consecutive CRT patients (pts) enrolled in the CRT-MORE registry from 2011 to 2013. Pts were stratified into five groups (quintiles 1-5) according to the VALID-CRT risk predictor index applied to the CRT-MORE population. In the analysis of clinical outcome, adverse events comprised death from any cause and non-fatal heart failure (HF) events requiring hospitalization. CR at 12-month follow-up was also assessed. We enrolled 905 pts. During a median follow-up of 1005 [627-1361] days, 134 patients died, and 79 had at least one HF hospitalization. At 12 months, 69% of pts displayed an improvement in their CR. The mean VALID-CRT risk score derived from the CRT-MOdular Registry (MORE) population was 0.317, ranging from -0.419 in Q1 to 2.59 in Q5. The risk-stratification algorithm was able to predict total mortality after CRT (survival ranging from 93%-Q1 to 77%-Q5; hazards ratio [HR] = 1.42, 95% confidence interval [CI]: 1.25-1.61, P < .0001), and HF hospitalization (ranging from 95% to 90%; HR = 1.24, 95% CI: 1.06-1.45, P = .009). CR was significantly lower in pts with a high-to-very high risk profile (Q4-5) than in pts with a low-to-intermediate risk profile (Q1-2-3) (55% vs 79%, P < .0001). CONCLUSION: The VALID-CRT risk-stratification algorithm reliably predicts outcome and CRT response after CRT in an unselected, real-world population.

The stricter criteria for Class I CRT indication suggested by the 2016 ESC Guidelines reliably exclude patients with a worse prognosis in comparison with the 2013 ESC indication criteria.

BACKGROUND: The European Society of Cardiology (ESC) Guidelines published in 2016 modified indications for cardiac resynchronization therapy (CRT) in comparison with the 2013 ESC Guidelines. The aim of this analysis was to evaluate the impact of the stricter criteria suggested by the 2016 ESC Guidelines on patient outcome in a real-world population. METHODS: We collected data on 930 consecutive patients with complete outcome information who had undergone CRT implantation from 2011 to 2013 from the CRT-MORE registry. Patients were classified according to 2013 (Reference) and 2016 (Current) ESC Guidelines. The primary end-point of the study was death from any cause and heart failure hospitalization. RESULTS: According to the Reference Guidelines, 650 (69.9%) patients met Class I indications, 190 (20.4%) Class IIa, 39 (4.2%) Class IIb and 51 (5.5%) Class III. According to the Current Guidelines, 563 (60.5%) patients met Class I indications, 145 (15.6%) Class IIa, 108 (11.6%) Class IIb and 114 (12.3%) Class III. On comparing the Reference and Current Guidelines, the 538 patients who confirmed their Class I indication had a better outcome in terms of freedom from the combined end-point of heart failure (HF) hospitalization or death from any cause (hazard ratio (HR) of 0.64; 95% CI 0.42 to 0.99; p = 0.0436) when compared to the 112 patients who lost their class I indication (84 moved to class IIb and 28 moved to class III). CONCLUSIONS: The stricter criteria for Class I CRT indication suggested by the 2016 ESC Guidelines excluded about 20% of patients with a worse prognosis. CLINICAL TRIAL REGISTRATION: CRT MORE: Cardiac Resynchronization Therapy Modular Registry URL: http://clinicaltrials.gov/Identifier:NCT01573091.

Outpatient treatment of recent-onset atrial fibrillation with the "pill-in-the-pocket" approach.

BACKGROUND: In-hospital administration of flecainide and propafenone in a single oral loading dose has been shown to be effective and superior to placebo in terminating atrial fibrillation. We evaluated the feasibility and the safety of self-administered oral loading of flecainide and propafenone in terminating atrial fibrillation of recent onset outside the hospital. METHODS: We administered either flecainide or propafenone orally to restore sinus rhythm in 268 patients with mild heart disease or none who came to the emergency room with atrial fibrillation of recent onset that was hemodynamically well tolerated. Of these patients, 58 (22 percent) were excluded from the study because of treatment failure or side effects. Out-of-hospital self-administration of flecainide or propafenone--the "pill-in-the-pocket" approach--after the onset of heart palpitations was evaluated in the remaining 210 patients (mean age [+/-SD], 59+/-11 years). RESULTS: During a mean follow-up of 15+/-5 months, 165 patients (79 percent) had a total of 618 episodes of arrhythmia; of those episodes, 569 (92 percent) were treated 36+/-93 minutes after the onset of symptoms. Treatment was successful in 534 episodes (94 percent); the time to resolution of symptoms was 113+/-84 minutes. Among the 165 patients with recurrences, the drug was effective during all the arrhythmic episodes in 139 patients (84 percent). Adverse effects were reported during one or more arrhythmic episodes by 12 patients (7 percent), including atrial flutter at a rapid ventricular rate in 1 patient and noncardiac side effects in 11 patients. The numbers of monthly visits to the emergency room and hospitalizations were significantly lower during follow-up than during the year before the target episode (P<0.001 for both comparisons). CONCLUSIONS: In a selected, risk-stratified population of patients with recurrent atrial fibrillation, pill-in-the-pocket treatment is feasible and safe, with a high rate of compliance by patients, a low rate of adverse events, and a marked reduction in emergency room visits and hospital admissions.

[Outpatient treatment of recurrent atrial fibrillation with the "pill-in-the-pocket" approach: practical aspects]. / Trattamento "pill-in-the-pocket" al di fuori dell'ospedale nei pazienti con fibrillazione atriale ricorrente: aspetti pratici.

In patients with not very frequent episodes of atrial fibrillation (AF), highly symptomatic for palpitation, hemodynamically well tolerated but long enough to require emergency room (ER) intervention, the best outpatient treatment appears to be the "pill-in-the-pocket" approach. In several studies, in-hospital administration of flecainide or propafenone in a single oral loading dose has been shown to be effective and superior to placebo in terminating recent-onset AF. Recently, a multicenter Italian study has been carried out to evaluate the feasibility and the safety of self-administered oral loading of flecainide or propafenone in terminating AF of recent onset outside the hospital. Either flecainide or propafenone were administered orally to restore sinus rhythm in 268 patients with mild heart disease or none, who came to the ER with AF of recent onset that was hemodynamically well tolerated. Of these patients, 21% were excluded from the study because of treatment failure or side effects. During a mean follow-up of 15 months, 94% of the arrhythmic episodes were interrupted by the oral loading of flecainide or propafenone; the mean time to resolution of symptoms was about 2 hours. Adverse effects were reported during one or more arrhythmic episodes by 7% of the patients, including atrial flutter at a rapid ventricular rate in 1 patient. The numbers of monthly visits to the ER and hospitalizations were 90% lower during follow-up than the year before enrollment. These results show that in a selected, risk-stratified population of patients with recurrent AF, the "pill-in-the-pocket" treatment is feasible and safe, with a high rate of compliance by patients, a low rate of adverse effects, and a marked reduction in ER visits. Some recommendations on the practical use of this type of treatment are given.

Managed ventricular pacing compared with conventional dual-chamber pacing for elective replacement in chronically paced patients: results of the Prefer for Elective Replacement Managed Ventricular Pacing randomized study.

BACKGROUND: Several studies have shown that unnecessary right ventricular pacing has detrimental effects. OBJECTIVE: To evaluate whether minimization of ventricular pacing as compared with standard dual-chamber pacing (DDD) improves clinical outcomes in patients referred for pacemaker or implantable cardioverter-defibrillator (ICD) replacement. METHODS: In an international single-blind, multicenter, randomized controlled trial, we compared DDD with managed ventricular pacing (MVP), a pacing mode developed to minimize ventricular pacing by promoting intrinsic atrioventricular conduction. We included patients referred for device replacement with >40% ventricular pacing, no cardiac resynchronization therapy upgrade indication, no permanent atrial fibrillation (AF), and no permanent complete atrioventricular block. Follow-up was for 2 years. The primary end point was cardiovascular hospitalization. The intention-to-treat analysis was performed by using Kaplan-Meier method and the log-rank test. RESULTS: We randomized 605 patients (556 referred for pacemaker and 49 referred for ICD replacement; mean age 75 ± 11 years; 365 [60%] men, at 7.7 ± 3.3 years from first device implantation) to MVP (n = 299) or DDD (n = 306). We found no significant differences in the primary end point cardiovascular hospitalization (MVP: 16.3% vs DDD: 14.5%; P = .72) and the secondary end point persistent AF (MVP: 15.4% vs DDD: 11.2%; P = .08), permanent AF (MVP: 4.1% vs DDD: 3.1%; P = .44), and composite of death and cardiovascular hospitalization (MVP: 23.9% vs DDD: 20.2%; P = .48). MVP reduced right ventricular pacing (median 5% vs 86%; Wilcoxon, P < .0001) as compared with DDD. CONCLUSIONS: In patients referred for pacemaker and ICD replacement with clinically well-tolerated long-term exposure to >40% ventricular pacing in the ventricle, a strategy to minimize ventricular pacing is not superior to standard DDD in reducing incidence of cardiovascular hospitalizations.

Intravenous administration of flecainide or propafenone in patients with recent-onset atrial fibrillation does not predict adverse effects during 'pill-in-the-pocket' treatment.

BACKGROUND: Pill-in-the-pocket treatment should be prescribed only if the administration of a loading oral dose of flecainide or propafenone has been proved safe in hospital, since major adverse effects have been reported in 5% of patients during in-hospital treatment. However, in emergency rooms, the oral administration of these drugs for the conversion of atrial fibrillation (AF) is very rarely used because it is time consuming. Objective To investigate whether tolerance to intravenous administration of flecainide or propafenone might predict the safety of pill-in-the-pocket treatment-the out-of-hospital self-administration of these drugs after the onset of palpitations-in patients with AF of recent onset. METHODS: One hundred and twenty-two patients with AF of recent onset who were successfully treated (conversion of AF within 2 h without major adverse effects) in hospital with intravenous flecainide or propafenone were discharged on pill-in-the-pocket treatment. RESULTS: During a mean follow-up of 11+/-4 months, 79 patients self-treated 213 arrhythmic episodes; treatment was successful in 201 episodes (94%). Major adverse events occurred in five patients (6%) and in four (5%) of these during the first oral treatment (one syncope, two presyncope, one sinus arrest). No patient reported symptoms attributable to bradyarrhythmia or hypotension during the self-treatment of arrhythmic recurrences when the first oral treatment was not accompanied by any major adverse effects. The study was prematurely terminated because of the high incidence of major adverse effects during the first out-of-hospital treatment. CONCLUSION: The patient's tolerance of intravenous administration of flecainide or propafenone does not seem to predict adverse effects during out-of-hospital self-administration of these drugs.