Unmet Clinical Needs in Elderly Patients Receiving Direct Oral Anticoagulants for Stroke Prevention in Non-valvular Atrial Fibrillation.

Vitamin K antagonists have been used for many years as the treatment of choice for long-term oral anticoagulation in patients with non-valvular atrial fibrillation. Unfortunately, the use of those drugs in the real-world setting, particularly among elderly patients, is suboptimal because of their limitations in management. Therefore, many patients were not adequately anticoagulated. Direct oral anticoagulants have been demonstrated to overcome almost all the limitations derived from the use of vitamin K antagonists. Direct oral anticoagulants are at least as effective as vitamin K antagonists in preventing thromboembolic events in patients with non-valvular atrial fibrillation and safer in reducing the risk of intracranial haemorrhage and all-cause mortality. However, as a result of the strict inclusion and exclusion criteria applied to patients, data coming from randomized controlled trials might not apply to the general population. Furthermore, elderly patients were scarcely represented in randomized controlled trials with direct oral anticoagulants. Therefore in elderly patients with non-valvular atrial fibrillation, unmet clinical needs still exist. This review article highlights some of them and provides potential answers based on the results coming from randomized clinical trials, real-world data, and the authors' clinical experience.

Prevention of long-lasting atrial fibrillation through antitachycardia pacing in DDDR pacemakers.

OBJECTIVE: The MINERVA trial showed that in pacemaker patients with atrial fibrillation (AF) history, DDDRP pacing combining three algorithms - (a) atrial antitachycardia pacing with Reactive ATP enabled, (b) atrial preventive pacing and (c) managed ventricular pacing (MVP)-may effectively delay progression to persistent/permanent AF compared with standard DDDR pacing. We performed a comparative non-randomised evaluation to evaluate if Reactive ATP can be the main driver of persistent/permanent AF reduction independently on preventive pacing. METHODS: Thirty-one centres included consecutive dual-chamber pacemaker patients with AF history. Reactive ATP was programmed in all patients while preventive atrial pacing was not enabled. These patients were compared with the three groups of MINERVA randomised trial (Control DDDR, MVP, and DDDRP). The main endpoint was the incidence of AF longer than 7 consecutive days. RESULTS: A total of 146 patients (73 years old, 54% male) were included and followed for a median observation period of 31 months. The 2-year incidence of AF > 7 days was 12% in the Reactive ATP group, very similar to that found in the DDDRP arm of the MINERVA trial (13.8%, P = .732) and significantly lower than AF incidence found in the MINERVA Control DDDR arm (25.8%, P = .012) and in the MINERVA MVP arm (25.9%, P = .025). CONCLUSIONS: In a real-world population of dual-chamber pacemaker patients with AF history, the use of Reactive ATP is associated with a low incidence of persistent AF, highlighting that the positive results of the MINERVA trial were related to the effectiveness of Reactive ATP rather than to preventive pacing.

Progression of Device-Detected Subclinical Atrial Fibrillation and the Risk of Heart Failure.

BACKGROUND: Long-term continuous monitoring detects short-lasting, subclinical atrial fibrillation (SCAF) in approximately one-third of older individuals with cardiovascular conditions. The relationship between SCAF, its progression, and the development of heart failure (HF) is unclear. OBJECTIVES: This study examined the relationship between progression from shorter to longer SCAF episodes and HF hospitalization. METHODS: Subjects in ASSERT (Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial) were ≥65 years old, had history of hypertension, no prior clinical AF, and an implanted pacemaker or defibrillator. We examined patients whose longest SCAF episode during the first year after enrollment was >6 min but ≤24 h (n = 415). Using time-dependent Cox models, we evaluated the relationship between subsequent development of SCAF >24 h or clinical AF and HF hospitalization. RESULTS: Over a mean follow-up of 2 years, 65 patients (15.7%) progressed to having SCAF episodes >24 h or clinical AF (incidence 8.8% per year). Older age, greater body mass index, and longer SCAF duration within the first year were independent predictors of SCAF progression. The rate of HF hospitalization among patients with SCAF progression was 8.9% per year compared with 2.5% per year for those without progression. After multivariable adjustment, SCAF progression was independently associated with HF hospitalization (hazard ratio [HR]: 4.58; 95% confidence interval [CI]: 1.64 to 12.80; p = 0.004). Similar results were observed when we excluded patients with prior history of HF (HR: 7.06; 95% CI: 1.82 to 27.30; p = 0.005) or when SCAF progression was defined as development of SCAF >24 h alone (HR: 3.68; 95% CI: 1.27 to 10.70; p = 0.016). CONCLUSIONS: In patients with a pacemaker or defibrillator, SCAF progression was strongly associated with HF hospitalization.

Clinically oriented device programming in bradycardia patients: part 1 (sinus node disease). Proposals from AIAC (Italian Association of Arrhythmology and Cardiac Pacing).

: Modern pacemakers have an increasing number of programable parameters and specific algorithms designed to optimize pacing therapy in relation to the individual characteristics of patients. When choosing the most appropriate pacemaker type and programing, the following variables must be taken into account: the type of bradyarrhythmia at the time of pacemaker implantation; the cardiac chamber requiring pacing, and the percentage of pacing actually needed to correct the rhythm disorder; the possible association of multiple rhythm disturbances and conduction diseases; the evolution of conduction disorders during follow-up. The goals of device programing are to preserve or restore the heart rate response to metabolic and hemodynamic demands; to maintain physiological conduction; to maximize device longevity; to detect, prevent, and treat atrial arrhythmia. In patients with sinus node disease, the optimal pacing mode is DDDR. Based on all the available evidence, in this setting, we consider appropriate the activation of the following algorithms: rate responsive function in patients with chronotropic incompetence; algorithms to maximize intrinsic atrioventricular conduction in the absence of atrioventricular blocks; mode-switch algorithms; algorithms for autoadaptive management of the atrial pacing output; algorithms for the prevention and treatment of atrial tachyarrhythmias in the subgroup of patients with atrial tachyarrhythmias/atrial fibrillation. The purpose of this two-part consensus document is to provide specific suggestions (based on an extensive literature review) on appropriate pacemaker setting in relation to patients' clinical features.

Clinically oriented device programming in bradycardia patients: part 2 (atrioventricular blocks and neurally mediated syncope). Proposals from AIAC (Italian Association of Arrhythmology and Cardiac Pacing).

: The purpose of this two-part consensus document is to provide specific suggestions (based on an extensive literature review) on appropriate pacemaker setting in relation to patients' clinical features. In part 2, criteria for pacemaker choice and programming in atrioventricular blocks and neurally mediate syncope are proposed. The atrioventricular blocks can be paroxysmal or persistent, isolated or associated with sinus node disease. Neurally mediated syncope can be related to carotid sinus syndrome or cardioinhibitory vasovagal syncope. In sinus rhythm, with persistent atrioventricular block, we considered appropriate the activation of mode-switch algorithms, and algorithms for auto-adaptive management of the ventricular pacing output. If the atrioventricular block is paroxysmal, in addition to algorithms mentioned above, algorithms to maximize intrinsic atrioventricular conduction should be activated. When sinus node disease is associated with atrioventricular block, the activation of rate-responsive function in patients with chronotropic incompetence is appropriate. In permanent atrial fibrillation with atrioventricular block, algorithms for auto-adaptive management of the ventricular pacing output should be activated. If the atrioventricular block is persistent, the activation of rate-responsive function is appropriate. In carotid sinus syndrome, adequate rate hysteresis should be programmed. In vasovagal syncope, specialized sensing and pacing algorithms designed for reflex syncope prevention should be activated.

The effects of gender on electrical therapies for the heart: procedural considerations, results and complications: A report from the XII Congress of the Italian Association on Arrhythmology and Cardiostimulation (AIAC).

Use of cardiac implantable devices and catheter ablation is steadily increasing in Western countries following the positive results of clinical trials. Despite the advances in scientific knowledge, tools development, and techniques improvement we still have some grey area in the field of electrical therapies for the heart. In particular, several reports highlighted differences both in medical behaviour and procedural outcomes between female and male candidates. Women are referred later for catheter ablation of supraventricular arrhythmias, especially atrial fibrillation, leading to suboptimal results. On the opposite females present greater response to cardiac resynchronization, while the benefit of implantable defibrillator in primary prevention seems to be less pronounced. Differences on aetiology, clinical profile, and development of myocardial scarring are the more plausible causes. This review will discuss all these aspects together with gender-related differences in terms of acute/late complications. We will also provide useful hints on plausible mechanisms and practical procedural aspects.

The effects of gender on electrical therapies for the heart: physiology, epidemiology, and access to therapies.

The difference between men and women is clear even just by looking at an electrocardiogram: females present higher resting heart rate, a shorter QRS complex length and greater corrected QT interval. The development of these differences from pubertal age onward suggests that sexual hormones play a key role, although their effect is far from being completely understood. Different incidences between sexes have been reported for many arrhythmias, both ventricular and supraventricular, and also for sudden cardiac death. Moreover, arrhythmias are an important issue during pregnancy, both for diagnosis and treatment. Interestingly, cardiovascular structural and electrophysiological remodelling promoted by exercise training enhances this 'gender effect'. Despite all these relevant issues, we lack gender specific recommendations in the current guidelines for electrical therapies for heart rhythm disorders and heart failure. Even more, we continue to see that fewer women are included in clinical trials and are less referred than men for these treatments.

Reduction in unnecessary ventricular pacing fails to affect hard clinical outcomes in patients with preserved left ventricular function: a meta-analysis.

Aims: Several pacing modalities across multiple manufacturers have been introduced to minimize unnecessary right ventricular pacing. We conducted a meta-analysis to assess whether ventricular pacing reduction modalities (VPRM) influence hard clinical outcomes in comparison to standard dual-chamber pacing (DDD). Methods and Results: An electronic search was performed using Cochrane Central Register, PubMed, Embase, and Scopus. Only randomized controlled trials (RCT) were included in this analysis. Outcomes of interest included: frequency of ventricular pacing (VP), incident persistent/permanent atrial fibrillation (PerAF), all-cause hospitalization and all-cause mortality. Odds ratios (OR) were reported for dichotomous variables. Seven RCTs involving 4119 adult patients were identified. Ventricular pacing reduction modalities were employed in 2069 patients: (MVP, Medtronic Inc.) in 1423 and (SafeR, Sorin CRM, Clamart) in 646 patients. Baseline demographics and clinical characteristics were similar between VPRM and DDD groups. The mean follow-up period was 2.5 ± 0.9 years. Ventricular pacing reduction modalities showed uniform reduction in VP in comparison to DDD groups among all individual studies. The incidence of PerAF was similar between both groups {8 vs. 10%, OR 0.84 [95% confidence interval (CI) 0.57; 1.24], P = 0.38}. Ventricular pacing reduction modalities showed no significant differences in comparison to DDD for all-cause hospitalization or all-cause mortality [9 vs. 11%, OR 0.82 (95% CI 0.65; 1.03), P= 0.09; 6 vs. 6%, OR 0.97 (95% CI 0.74; 1.28), P = 0.84, respectively]. Conclusion: Novel VPRM measures effectively reduce VP in comparison to standard DDD. When actively programmed, VPRM did not improve clinical outcomes and were not superior to standard DDD programming in reducing incidence of PerAF, all-cause hospitalization, or all-cause mortality.

Vagomimetic effects of fingolimod: physiology and clinical implications.

Fingolimod is a sphingosine 1-phosphate (S1P) receptor modulator approved to treat relapsing-remitting multiple sclerosis (MS). Initiation of treatment with fingolimod has been found to produce transient bradycardia and/or slowing of atrioventricular impulse conduction in a small proportion of patients. This effect is thought to be due to the interaction of fingolimod with S1P receptors on the surface membrane of atrial myocytes causing a vagomimetic effect, similar to the action of acetylcholine on muscarinic receptors. As a precaution, patients are under electrocardiogram (ECG) monitoring for 6 h after receiving their first dose. Fingolimod is contraindicated in patients with overt or concealed cardiac diseases. However, the Fingolimod Initiation and caRdiac Safety Trial (FIRST), which was designed specifically to investigate the cardiac profile of fingolimod, did not show an increased risk of clinically relevant cardiac events with fingolimod. This review examines the electrophysiology and pathophysiology of cardiac impulse formation in the context of fingolimod. It concludes that these vagomimetic effects should be considered benign and should not prevent the effective use of fingolimod in the treatment of patients with MS.

Incremental value of larger interventricular conduction time in improving cardiac resynchronization therapy outcome in patients with different QRS duration.

INTRODUCTION: The left ventricular (LV) pacing site and the magnitude of the electrical delay within the LV, as expressed by prolonged QRS duration, are major determinants of cardiac resynchronization therapy (CRT) efficacy. We investigated the incremental value of positioning the LV lead in areas of late activation in order to enhance the response to CRT in patients with different degrees of QRS complex lengthening. METHODS AND RESULTS: This analysis was performed on 301 heart failure patients who received a CRT defibrillator. On implantation, the right ventricular (RV)-to-LV interval was measured as the delay between local activations recorded through the RV and LV leads in the final position. After 1 year, 171 (57%) patients displayed reverse LV remodeling, as measured by a ≥15% reduction in the LV end-systolic volume. Both the RV-to-LV interval and its percentage value corrected for the QRS duration were significantly associated with a positive response to CRT. An RV-to-LV interval >80 milliseconds and an RV-to-LV interval/QRS >58% yielded the best prediction of reverse remodeling. Although the response to CRT decreased with shorter QRS duration in the overall population, patients with an RV-to-LV interval >80 milliseconds showed a response rate >65% in all QRS subgroups. CONCLUSION: A longer RV-to-LV interval is associated with reverse LV remodeling after CRT. On implantation attempts could be made to maximize it when selecting the LV lead position, especially in patients with shorter QRS duration, and thus less likely to respond positively to CRT.

Cardiac Resynchronization Therapy MOdular REgistry: ECG and Rx predictors of response to cardiac resynchronization therapy (NCT01573091).

AIMS: A variable proportion, up to 30%, of patients who undergo cardiac resynchronization therapy (CRT) do not benefit from treatment. The aim of the Cardiac Resynchronization Therapy MOdular REgistry (CRT MORE) is to determine whether specific electrocardiographic and radiographic parameters can be used to predict clinical and echocardiographic response to CRT. METHODS: The CRT MORE is a prospective, single-arm, multicenter cohort study designed to evaluate the electrocardiographic and radiographic predictors of response to CRT. All study patients receive a pacemaker or implantable defibrillator for CRT delivery in accordance with current guidelines. Enrollment started in December 2011 and is scheduled to end in November 2013. Approximately 1100 consecutive patients will be enrolled in 30 Italian centers and will be followed up for 60 months after implantation. The primary endpoint is the improvement in clinical (Clinical Composite Score) and echocardiographic (a decrease of ≥ 15% in left ventricular end-systolic volume) parameters at the 6-month follow-up visit. CONCLUSION: This study might provide important information about which electrocardiographic and radiographic parameters better predict CRT response.

Influence of time between last myocardial infarction and prophylactic implantable defibrillator implant on device detections and therapies. "Routine Practice" data from the SEARCH MI registry.

BACKGROUND: A multicenter European Registry, SEARCH-MI, was instituted in the year 2002 in order to assess patients' outcomes and ICD interventions in patients with a previous MI and depressed LV function, treated with an ICD according to MADIT II results. In this analysis, we evaluate the influence of the time elapsed between last myocardial infarction (MI) and prophylactic cardioverter defibrillator (ICD) implant on device activations. METHODS: 643 patients with left ventricular dysfunction (mean LVEF 26 ± 5%) and NYHA class I-III were prospectively followed for 1.8 ± 1.2 years in a multicenter registry. The population was divided into 3 groups according to the time between last MI and ICD implant: [1] from 40 days to less than 1.5 years; [2] from 1.5 to less than 7 years and [3] at least 7 years. RESULTS: The cumulative incidence of ventricular tachyarrhymias and appropriate device therapy (ATP or shock) were higher in patients implanted longer time from last MI (Gray's Test p=0.002 and p=0.013 respectively). No significant differences were seen in all cause mortality (Gray's Test p=0.618) or sudden cardiac death across the MI stratification groups (Gray's Test p=0.663). CONCLUSIONS: Patients implanted with an ICD longer after the MI have a higher chance of presenting ventricular tachyarrhythmias and appropriate ICD therapy, while no differences were seen in overall mortality. These observations may be important for improving patient targeting in sudden death prevention.

Impact of mitral regurgitation on the outcome of patients treated with CRT-D: data from the InSync ICD Italian Registry.

BACKGROUND: We assessed the influence of clinically significant mitral regurgitation (MR) on clinical-echocardiographic response and outcome in heart failure (HF) patients treated with a biventricular defibrillator (cardiac resynchronization therapy defibrillator [CRT-D]). METHODS AND RESULTS: A total of 659 HF patients underwent successful implantation of CRT-D and were enrolled in a multicenter prospective registry (median follow-up of 15 months). Following baseline echocardiographic evaluation, patients were stratified into two groups according to the severity of MR: 232 patients with more than mild MR (Group MR+: grade 2, 3, and 4 MR) versus 427 patients with mild (grade 1) or no functional MR (Group MR-). On 6- and 12-month echocardiographic evaluation, MR was seen to have improved in the vast majority of MR+ patients, while it remained unchanged in most MR- patients. On 12-month follow-up evaluation, a comparable response to CRT was observed in the two groups, in terms of the extent of left ventricular reverse remodeling and combined clinical and echocardiographic response. During long-term follow-up, event-free survival did not differ between MR+ and MR- patients, even when subpopulations of patients with ischemic heart disease and with dilated cardiomyopathy were analyzed separately. On multivariate analysis, the only independent predictor of death from any cause was the lack of ß-blocker use. CONCLUSIONS: This observational analysis supports the use of CRT-D in HF patients with clinically significant MR; MR had no major influence on patient outcome.

Cardiac resynchronization therapy in patients undergoing atrioventricular junction ablation for permanent atrial fibrillation: a randomized trial.

AIMS: On the basis of the current knowledge, cardiac resynchronization therapy (CRT) cannot be recommended as a first-line treatment for patients with severely symptomatic permanent atrial fibrillation undergoing atrioventricular (AV) junction ablation. We examined whether CRT was superior to conventional right ventricular (RV) pacing in reducing heart failure (HF) events. METHODS AND RESULTS: In this prospective, multi-centre study, we randomly assigned 186 patients, in whom AV junction ablation and CRT device implantation had been successfully performed, to receive optimized echo-guided CRT (97 patients) or RV apical pacing (89 patients). The data were analysed according to the intention-to-treat principle. During a median follow-up of 20 months (interquartile range 11-24), the primary composite endpoint of death from HF, hospitalization due to HF, or worsening HF occurred in 11 (11%) patients in the CRT group and 23 (26%) patients in the RV group [CRT vs. RV group: sub-hazard ratio (SHR) 0.37 ( 95% CI 0.18-0.73), P = 0.005]. In the CRT group, compared with the RV group, fewer patients had worsening HF [SHR 0.27 (95% CI 0.12-0.58), P = 0.001] and hospitalizations for HF [SHR 0.20 (95% CI 0.06-0.72), P = 0.013]. Total mortality was similar in both groups [hazard ratio (HR) 1.57 (95% CI 0.58-4.27), P = 0.372]. The beneficial effects of CRT were consistent in patients who had ejection fraction ≤35%, New York Heart Association Class ≥III and QRS width ≥120 and in those who did not. At multi-variable Cox regression, only CRT mode remained an independent predictor of absence of clinical failure during the follow-up [HR = 0.23 (95% CI 0.08-0.66), P = 0.007]. CONCLUSIONS: In patients undergoing 'Ablate and Pace' therapy for severely symptomatic permanent atrial fibrillation, CRT is superior to RV apical pacing in reducing the clinical manifestations of HF. (ClinicalTrials.gov number: NCT00111527).

Consensus statement of the European Heart Rhythm Association: updated recommendations for driving by patients with implantable cardioverter defibrillators.

Patients with an implantable cardioverter defibrillator (ICD) have an ongoing risk of sudden incapacitation that might cause harm to others while driving a car. Driving restrictions vary across different countries in Europe. The most recent recommendations for driving of ICD patients in Europe were published in 1997 and focused mainly on patients implanted for secondary prevention. In recent years there has been a vast increase in the number of patients with an ICD and in the percentage of patients implanted for primary prevention. The EHRA task force on ICD and driving was formed to reassess the risk of driving for ICD patients based on the literature available. The recommendations are summarized in the following table and are further explained in the document, (Table see text). Driving restrictions are perceived as difficult for patients and their families, and have an immediate consequence for their lifestyle. To increase the adherence to the driving restrictions, adequate discharge of education and follow-up of patients and family are pivotal. The task force members hope this document may serve as an instrument for European and national regulatory authorities to formulate uniform driving regulations.

Effectiveness of cardiac resynchronization therapy in heart failure patients with valvular heart disease: comparison with patients affected by ischaemic heart disease or dilated cardiomyopathy. The InSync/InSync ICD Italian Registry.

AIMS: To analyse the effectiveness of cardiac resynchronization therapy (CRT) in patients with valvular heart disease (a subset not specifically investigated in randomized controlled trials) in comparison with ischaemic heart disease or dilated cardiomyopathy patients. METHODS AND RESULTS: Patients enrolled in a national registry were evaluated during a median follow-up of 16 months after CRT implant. Patients with valvular heart disease treated with CRT (n = 108) in comparison with ischaemic heart disease (n = 737) and dilated cardiomyopathy (n = 635) patients presented: (i) a higher prevalence of chronic atrial fibrillation, with atrioventricular node ablation performed in around half of the cases; (ii) a similar clinical and echocardiographic profile at baseline; (iii) a similar improvement of LVEF and a similar reduction in ventricular volumes at 6-12 months; (iv) a favourable clinical response at 12 months with an improvement of the clinical composite score similar to that occurring in patients with dilated cardiomyopathy and more pronounced than that observed in patients with ischaemic heart disease; (v) a long-term outcome, in term of freedom from death or heart transplantation, similar to patients affected by ischaemic heart disease and basically more severe than that of patients affected by dilated cardiomyopathy. CONCLUSION: In 'real world' clinical practice, CRT appears to be effective also in patients with valvular heart disease. However, in this group of patients the outcome after CRT does not precisely overlap any of the two other groups of patients, for which much more data are currently available.