Early Rhythm-Control Therapy in Patients with Atrial Fibrillation.

BACKGROUND: Despite improvements in the management of atrial fibrillation, patients with this condition remain at increased risk for cardiovascular complications. It is unclear whether early rhythm-control therapy can reduce this risk. METHODS: In this international, investigator-initiated, parallel-group, open, blinded-outcome-assessment trial, we randomly assigned patients who had early atrial fibrillation (diagnosed ≤1 year before enrollment) and cardiovascular conditions to receive either early rhythm control or usual care. Early rhythm control included treatment with antiarrhythmic drugs or atrial fibrillation ablation after randomization. Usual care limited rhythm control to the management of atrial fibrillation-related symptoms. The first primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome; the second primary outcome was the number of nights spent in the hospital per year. The primary safety outcome was a composite of death, stroke, or serious adverse events related to rhythm-control therapy. Secondary outcomes, including symptoms and left ventricular function, were also evaluated. RESULTS: In 135 centers, 2789 patients with early atrial fibrillation (median time since diagnosis, 36 days) underwent randomization. The trial was stopped for efficacy at the third interim analysis after a median of 5.1 years of follow-up per patient. A first-primary-outcome event occurred in 249 of the patients assigned to early rhythm control (3.9 per 100 person-years) and in 316 patients assigned to usual care (5.0 per 100 person-years) (hazard ratio, 0.79; 96% confidence interval, 0.66 to 0.94; P = 0.005). The mean (±SD) number of nights spent in the hospital did not differ significantly between the groups (5.8±21.9 and 5.1±15.5 days per year, respectively; P = 0.23). The percentage of patients with a primary safety outcome event did not differ significantly between the groups; serious adverse events related to rhythm-control therapy occurred in 4.9% of the patients assigned to early rhythm control and 1.4% of the patients assigned to usual care. Symptoms and left ventricular function at 2 years did not differ significantly between the groups. CONCLUSIONS: Early rhythm-control therapy was associated with a lower risk of adverse cardiovascular outcomes than usual care among patients with early atrial fibrillation and cardiovascular conditions. (Funded by the German Ministry of Education and Research and others; EAST-AFNET 4 ISRCTN number, ISRCTN04708680; ClinicalTrials.gov number, NCT01288352; EudraCT number, 2010-021258-20.).

Apixaban in patients at risk of stroke undergoing atrial fibrillation ablation.

Aims: It is recommended to perform atrial fibrillation ablation with continuous anticoagulation. Continuous apixaban has not been tested. Methods and results: We compared continuous apixaban (5 mg b.i.d.) to vitamin K antagonists (VKA, international normalized ratio 2-3) in atrial fibrillation patients at risk of stroke a prospective, open, multi-centre study with blinded outcome assessment. Primary outcome was a composite of death, stroke, or bleeding (Bleeding Academic Research Consortium 2-5). A high-resolution brain magnetic resonance imaging (MRI) sub-study quantified acute brain lesions. Cognitive function was assessed by Montreal Cognitive Assessment (MoCA) at baseline and at end of follow-up. Overall, 674 patients (median age 64 years, 33% female, 42% non-paroxysmal atrial fibrillation, 49 sites) were randomized; 633 received study drug and underwent ablation; 335 undertook MRI (25 sites, 323 analysable scans). The primary outcome was observed in 22/318 patients randomized to apixaban, and in 23/315 randomized to VKA {difference -0.38% [90% confidence interval (CI) -4.0%, 3.3%], non-inferiority P = 0.0002 at the pre-specified absolute margin of 0.075}, including 2 (0.3%) deaths, 2 (0.3%) strokes, and 24 (3.8%) ISTH major bleeds. Acute small brain lesions were found in a similar number of patients in each arm [apixaban 44/162 (27.2%); VKA 40/161 (24.8%); P = 0.64]. Cognitive function increased at the end of follow-up (median 1 MoCA unit; P = 0.005) without differences between study groups. Conclusions: Continuous apixaban is safe and effective in patients undergoing atrial fibrillation ablation at risk of stroke with respect to bleeding, stroke, and cognitive function. Further research is needed to reduce ablation-related acute brain lesions.

A roadmap to improve the quality of atrial fibrillation management: proceedings from the fifth Atrial Fibrillation Network/European Heart Rhythm Association consensus conference.

At least 30 million people worldwide carry a diagnosis of atrial fibrillation (AF), and many more suffer from undiagnosed, subclinical, or 'silent' AF. Atrial fibrillation-related cardiovascular mortality and morbidity, including cardiovascular deaths, heart failure, stroke, and hospitalizations, remain unacceptably high, even when evidence-based therapies such as anticoagulation and rate control are used. Furthermore, it is still necessary to define how best to prevent AF, largely due to a lack of clinical measures that would allow identification of treatable causes of AF in any given patient. Hence, there are important unmet clinical and research needs in the evaluation and management of AF patients. The ensuing needs and opportunities for improving the quality of AF care were discussed during the fifth Atrial Fibrillation Network/European Heart Rhythm Association consensus conference in Nice, France, on 22 and 23 January 2015. Here, we report the outcome of this conference, with a focus on (i) learning from our 'neighbours' to improve AF care, (ii) patient-centred approaches to AF management, (iii) structured care of AF patients, (iv) improving the quality of AF treatment, and (v) personalization of AF management. This report ends with a list of priorities for research in AF patients.

Personalized management of atrial fibrillation: Proceedings from the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association consensus conference.

The management of atrial fibrillation (AF) has seen marked changes in past years, with the introduction of new oral anticoagulants, new antiarrhythmic drugs, and the emergence of catheter ablation as a common intervention for rhythm control. Furthermore, new technologies enhance our ability to detect AF. Most clinical management decisions in AF patients can be based on validated parameters that encompass type of presentation, clinical factors, electrocardiogram analysis, and cardiac imaging. Despite these advances, patients with AF are still at increased risk for death, stroke, heart failure, and hospitalizations. During the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association (AFNET/EHRA) consensus conference, we identified the following opportunities to personalize management of AF in a better manner with a view to improve outcomes by integrating atrial morphology and damage, brain imaging, information on genetic predisposition, systemic or local inflammation, and markers for cardiac strain. Each of these promising avenues requires validation in the context of existing risk factors in patients. More importantly, a new taxonomy of AF may be needed based on the pathophysiological type of AF to allow personalized management of AF to come to full fruition. Continued translational research efforts are needed to personalize management of this prevalent disease in a better manner. All the efforts are expected to improve the management of patients with AF based on personalized therapy.

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.

Changes in quality of life, cognition and functional status following catheter ablation of atrial fibrillation.

OBJECTIVE: To investigate changes in quality of life (QoL), cognition and functional status according to arrhythmia recurrence after atrial fibrillation (AF) ablation. METHODS: We compared QoL, cognition and functional status in patients with recurrent atrial tachycardia (AT)/AF versus those without recurrent AT/AF in the AXAFA-AFNET 5 clinical trial. We also sought to identify factors associated with improvement in QoL and functional status following AF ablation by overall change scores with and without analysis of covariance (ANCOVA). RESULTS: Among 518 patients who underwent AF ablation, 154 (29.7%) experienced recurrent AT/AF at 3 months. Patients with recurrent AT/AF had higher mean CHA2DS2-VASc scores (2.8 vs 2.3, p<0.001) and more persistent forms of AF (51 vs 39%, p=0.012). Median changes in the SF-12 physical (3 (25th, 75th: -1, 8) vs 1 (-5, 8), p=0.026) and mental scores (2 (-3, 9) vs 0 (-4, 5), p=0.004), EQ-5D (0 (0,2) vs 0 (-0.1, 0.1), p=0.027) and Karnofsky functional status scores (10 (0, 10) vs 0 (0, 10), p=0.001) were more favourable in patients without recurrent AT/AF. In the overall cohort, the proportion with at least mild cognitive impairment (Montreal Cognitive Assessment <26) declined from 30.3% (n=157) at baseline to 21.8% (n=113) at follow-up. ANCOVA identified greater improvement in Karnofsky functional status (p<0.001) but not SF-12 physical (p=0.238) or mental scores (p=0.065) in those without recurrent AT/AF compared with patients with recurrent AT/AF. CONCLUSIONS: Patients without recurrent AT/AF appear to experience greater improvement in functional status but similar QoL as those with recurrent AT/AF after AF ablation.

Prevalence Of Chronic Hypercapnia In Severe Chronic Obstructive Pulmonary Disease: Data From The HOmeVent Registry.

Background: Non-invasive ventilation (NIV) has been shown to improve survival and quality of life in COPD patients with chronic hypercapnic respiratory failure. However, the proportion of COPD patients with chronic hypercapnia is not yet known and clinical data enabling better identification of patients are scarce. The HOmeVent registry was initiated to determine the prevalence of chronic hypercapnia in COPD in an outpatient setting and to evaluate the predictors of hypercapnia. Methods: HOmeVent is a multicenter, prospective, observational, non-interventional patient registry that includes COPD patients in GOLD stage 3 or 4. Eligible patients were identified and enrolled in an outpatient setting during routine clinic visits. Assessments included blood gas analyses, pulmonary function testing and quality of life assessment. Results: Ten outpatient clinics in Germany enrolled 231 COPD patients in the registry (135 in GOLD stage 3 (58%) and 96 in GOLD stage 4 (42%)). Arterial carbon dioxide pressure (PaCO2) was ≥45 mmHg in 58 patients (25%); of these, 20 (9%) had PaCO2 ≥50 mmHg. The prevalence of hypercapnia at both cut-off values was numerically higher for patients in GOLD stage 4 versus 3. An increased body mass index, a decreased forced vital capacity and an increased bicarbonate level were significant independent predictors of hypercapnia. The proportion of patients who received NIV was 6% overall and 22% of those with hypercapnia. Conclusion: A relevant proportion of COPD patients in GOLD stage 3 and 4 exhibits chronic hypercapnia and might, therefore, be candidates for long-term domiciliary NIV treatment.

Angiotensin II antagonist in paroxysmal atrial fibrillation (ANTIPAF) trial: rationale and study design.

BACKGROUND AND OBJECTIVE: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Recent experimental data and retrospective analyses of clinical trials suggest that increased levels of angiotensin II can induce an arrhythmogenic atrial substrate, which favours the occurrence of AF. The purpose of the ANTIPAF (Angiotensin II Antagonist in Paroxysmal Atrial Fibrillation) trial is to prove the principal concept that blockade of angiotensin II type 1 receptors with olmesartan medoxomil 40 mg/day suppresses paroxysmal AF episodes during a 12-month follow-up. The ANTIPAF trial is the first placebo-controlled trial analysing the occurrence of AF as the primary study endpoint. METHODS: Examination of the study hypothesis in a prospective, randomised, placebo-controlled, double-blind group comparison in patients with documented paroxysmal AF (total of 422 patients) stratified by beta-adrenoceptor antagonist use. The primary endpoint of the study is the percentage of days with documented episodes of paroxysmal AF identified on daily transtelephonic tele-ECG recordings. Patients will record and transmit at least one 1-minute ECG per day independent of symptoms. Furthermore, tele-ECG recordings will be transmitted in any case of symptomatic AF. The present paper summarises the rationale and design of the ANTIPAF trial.

Targeted pharmacological reversal of electrical remodeling after cardioversion--rationale and design of the Flecainide Short-Long (Flec-SL) trial.

Persistent atrial fibrillation (AF) causes relevant mortality and cardiovascular and noncardiovascular morbidity. Therefore, maintenance of sinus rhythm is an important clinical goal, especially when the patient is symptomatic, despite the fact that current treatment strategies are not sufficient to completely prevent recurrent AF. In addition to underlying atrial disease that predisposes to AF, AF in itself induces structural and electrical adaptations ("electrical remodeling" and "structural remodeling"). Underlying disease processes and parts of structural remodeling are not always reversible. Electrical remodeling, in contrast, is reversed by a few weeks of maintenance of sinus rhythm under experimental conditions. This corresponds to the period when most of the recurrent episodes of AF occur after cardioversion. Antiarrhythmic drugs that prolong the atrial action potential can assist in the prevention of recurrent AF by promoting the reversal of electrical remodeling. Such drugs, which are currently used over long periods after cardioversion, may only be needed until the physiological action potential duration is restored, for example, during the first few weeks after cardioversion of persistent AF. This treatment concept that we call "targeted pharmacological reversal of electrical remodeling" would limit both cost and drug-induced side effects of antiarrhythmic drug therapy after cardioversion. The Flec-SL trial, ISECTN62728743, therefore tests the main hypothesis that targeted pharmacological reversal of electrical remodeling by short-term antiarrhythmic drug therapy for 4 weeks after cardioversion is not inferior to standard long-term antiarrhythmic drug therapy for the prevention of recurrent AF after cardioversion in a parallel group, randomized, multicenter, open, blinded end point analysis design. Based on its effectiveness and pharmacokinetic profile, flecainide is used to test the study hypothesis. The trial uses daily transtelephonic electrocardiographic monitoring for all patients and will be conducted within the German Atrial Fibrillation Competence NETwork (AFNET) to facilitate inclusion of patients from electrophysiologically oriented cardiology centers, ordinary hospitals, and office-based physicians.

Angiotensin II-antagonist in paroxysmal atrial fibrillation (ANTIPAF) trial.

BACKGROUND: Unlike antiarrhythmic drugs, the safety and beneficial effects of angiotensin II receptor blockade (ARB) in patients with structural heart disease is well established. The clinical efficacy of ARBs to prevent atrial fibrillation (AF) so far only has been shown in patients with structural heart disease. Here, we report the primary outcome of the Angiotensin II-Antagonist in Paroxysmal Atrial Fibrillation (ANTIPAF) trial, which investigated the effect of olmesartan medoxomil compared with placebo on AF burden in patients with paroxysmal AF without structural heart disease. METHODS AND RESULTS: The ANTIPAF trial was a prospective, randomized, placebo-controlled, multicenter trial analyzing the AF burden (percentage of days with documented episodes of paroxysmal AF) during a 12-month follow-up as the primary study end point. Four hundred thirty patients with documented paroxysmal AF without structural heart disease were randomized to placebo or 40 mg olmesartan per day. Concomitant therapy with ARBs, angiotensin-converting enzyme inhibitors, and antiarrhythmic drugs was prohibited. Patients were followed using daily transtelephonic ECG (tele-ECG) recordings independent of symptoms. The intention-to-treat population of the trial encompassed 425 patients (placebo group, n=211; olmesartan group, n=214). A total of 87 818 tele-ECGs were analyzed in these patients during follow-up (placebo group, 44 888 ECGs; olmesartan group, 42 930 ECGs). Thus, a mean of 207 tele-ECGs were recorded per patient. The primary end point (AF burden) was not different between the 2 groups (P=0.770). Secondary outcome parameters, including quality of life, also were not different. In particular, time to first AF recurrence, time to persistent AF, and number of hospitalizations were not different between the 2 groups. The time to prescription of recovery medication (amiodarone) was the only parameter showing an intergroup difference, with earlier prescription of amiodarone in the placebo group (P=0.022). CONCLUSIONS: One year of ARB therapy per se does not reduce the number of AF episodes in patients with documented paroxysmal AF without structural heart disease. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00098137.

Comparison between on-label versus off-label use of drug-eluting coronary stents in clinical practice: results from the German DES.DE-Registry.

BACKGROUND: Observational studies from the USA have demonstrated that off-label use of drug-eluting stents (DES) is common. Data on off-label use in Western Europe are limited. METHODS: We analyzed the data of consecutive patients receiving DES prospectively enrolled in the multicenter German DES.DE registry (Deutsches Drug-Eluting Stent Register) between October 2005 and October 2006. Off-label use was defined in the presence of one of the following criteria: ST-elevation myocardial infarction, in-stent stenosis, chronic total occlusion, lesions in a bypass graft, in bifurcation or left main stem, stent length per lesion ≥32 mm, and vessel diameter <2.5 or >3.5 mm. RESULTS: Overall, 4,295 patients were included in this analysis and divided into two groups: 2,366 (55.1%) received DES for off-label and 1,929 (44.9%) for on-label indications. There were substantial differences in the rates of off-label use at the participating hospitals. Patients with off-label DES more often presented with high-risk features such as acute coronary syndrome, cardiogenic shock, congestive heart failure, and more complex coronary anatomy. Among hospital survivors, the incidence of the composite endpoint of death, myocardial infarction and stroke (MACCE) (9.2 vs. 7.4%, p < 0.05), and target vessel revascularization (TVR) (11.3 vs. 9.1%, p < 0.05) was increased in the off-label group at the 1-year follow-up. However, in the multivariate analysis off-label use was not linked with an elevated risk for MACCE (hazard ratio 0.86, 95% confidence interval 0.62-1.18) and TVR (hazard ratio 1.05, 95% confidence interval 0.78-1.42). CONCLUSIONS: In clinical practice, DES was very frequently used off-label. After adjustment for confounding variables, off-label use was not associated with an increase of adverse events.

Clinical outcomes after sirolimus-eluting, paclitaxel-eluting, and bare metal stents (from the first phase of the prospective multicenter German DES.DE Registry).

The prospective multicenter German Drug-Eluting Stent (DES.DE) registry is an observational study to analyze and evaluate the therapeutic principle of the differential drug-eluting stents (sirolimus- and paclitaxel-eluting stents) and bare metal stents under real world conditions in the context of the German healthcare system. The baseline clinical and angiographic characteristics and follow-up events for 1 year were recorded for all enrolled patients. In addition, a health economics assessment was performed at 3, 6, 9, and 12 months after initial stent placement. The composite of death, myocardial infarction, and stroke, defined as major adverse cardiac and cerebrovascular events, and target vessel revascularization were used as the primary objectives. From October 2005 to October 2006, 6,384 patients were enrolled (sirolimus-eluting stents, n = 2,137; paclitaxel-eluting stents, n = 2,740; bare metal stents, n = 485) at 98 Deutsches Drug-Eluting Stent Register sites. With similar baseline clinical and descriptive morphology of coronary artery disease between both drug-eluting stent groups, no differences were present at 1 year of follow-up in the rates of overall mortality (3.8% vs 4.1%), target vessel revascularization (10.4% vs 10.4%), overall stent thrombosis (3.6% vs 3.8%), and major adverse cardiac and cerebrovascular events (8.1% vs 8.0%). Compared with the bare metal stent group, patients treated with drug-eluting stents had significantly lower rates of myocardial infarction (3.2% vs 6.0%; p <0.01), stroke (1.2% vs 2.7%; p <0.05), and target vessel revascularization (10.4% vs 14.9%; p <0.01) without any difference in the stent thrombosis rate (3.7% vs 4.3%; p = 0.57) or mortality rate (4.0% vs 5.2%; p = 0.21). In conclusion, the data generated from the German Drug-Eluting Stent registry revealed no differences between patients receiving a paclitaxel-eluting stent and sirolimus-eluting stent in a "real-world" setting with regard to the clinical outcomes at 1 year.

Prevention of atrial fibrillation after cardioversion: results of the PAFAC trial.

AIMS: In patients with persistent atrial fibrillation (AF), the efficacy and safety of two anti-arrhythmic drugs in preventing the recurrence of AF after successful direct current (DC) cardioversion was prospectively assessed in a multi-centre double-blind, placebo-controlled, randomised trial using daily trans-telephonic monitoring. METHODS AND RESULTS: 1182 patients with persistent AF were prospectively enrolled, 848 patients were successfully cardioverted and then randomised to either sotalol (383 patients), quinidine plus verapamil (377 patients) or placebo (88 patients). The primary outcome parameter was AF recurrence or death. All patients received an event recorder (Tele-ECG) and had to record and transmit via telephone at least one ECG per day during follow-up. The mean follow-up period was 266 days. A total of 191,103 Tele-ECGs were recorded and transmitted. The primary outcome parameter (AF recurrence of any kind or death) was observed in 572 patients (67%) in whom at least one episode of AF recurrence was documented during follow-up, in 348 patients (41%) AF recurrence was persistent. The recurrence rates after one year for any AF were 83% for placebo, 67% for sotalol and 65% for quinidine plus verapamil, the latter being statistically superior to placebo but not different from sotalol. The recurrence rates for the secondary outcome parameter persistent AF were 77%, 49% and 38%, respectively. Quinidine plus verapamil was significantly superior to placebo and to sotalol. About 95% of all AF recurrences were initially detected in the daily Tele-ECG, about 70% of all AF recurrences occurred completely asymptomatic. Adverse events on sotalol and quinidine plus verapamil were comparable with the exception that all torsade de pointes tachycardias occurred on sotalol. CONCLUSION: Anti-arrhythmic treatment after DC cardioversion of persistent AF significantly decreases the recurrence rates of persistent AF compared to placebo with superiority of quinidine plus verapamil compared to sotalol. Symptoms were not reliable as clinical surrogates to detect episodes of AF.