Rate Control Drugs Research Articles

Inflammation, Atrial Fibrillation and Cardiac Surgery: Current Medical and Invasive Approaches for the Treatment of Atrial Fibrillation.

Atrial fibrillation (AF) is a cardiac dysrhythmia commonly seen in clinical practice especially after cardiac surgery. It is associated with increased morbidity and mortality for the patients. The pathogenesis of AF is not exactly understood yet, but there is growing data about the relationship between AF and inflammation. Cardiac surgery itself is a big source for inflammation. It causes major surgical trauma, ischemia/reperfusion injury, hypothermia, low arterial pressure, and the equipment of cardiopulmonary bypass makes a large foreign surface thus it activates inflammatory response. There is a large number of data about the treatment options of AF and there are also strategies, which are related to reduction of inflammatory activation during cardiopulmonary bypass. In order to review the relationship between cardiac surgery, inflammation, AF and treatment strategies in patients with AF, we conducted a search through Pubmed for articles in English using the keywords: "atrial fibrillation, cardiac surgery, inflammation, medical therapy, surgical therapy, ablation therapy" from January 2012 to present. We also searched separately for each alternative treatment modality on Pubmed. To identify further articles, we also looked into related citations in review articles and commentaries. We searched thoroughly the guidelines published by the European Society of Cardiology (2016), and the American Heart Association/ American College of Cardiology/ Heart Rhythm Surgery (2014). Many studies concluded that inflammation contributes in the occurrence of AF. Inflammatory markers, such as CRP, interleukins and complements have high sensitivity and specificity for prediction of AF whether the patient having cardiac surgery or not. Betablockers, diltiazem and amiodarone are the most commonly used drugs for rate control in AF following surgery. Although there are some new therapeutic approaches to reduce postoperative inflammatory activation, such as the use of vitamins, fatty acids, statins, or technical improvements to cardiopulmonary bypass unit like miniaturized bypass circuits, heparin coating of the circuits, leukocyte filters, or various surgical approaches like off-pump coronary bypass surgery, we still need more effective strategies to reduce both postoperative inflammation and postoperative AF risk after cardiac surgery. Today we use more advanced invasive and surgical treatment strategies for AF although we need far more advanced technics to reduce perioperative inflammatory activation, which actually causes AF.

Novel drugs for heart rate control in heart failure.

In patients with heart failure, increased sympathetic activity is associated with a positive chronotropic stimulation leading to accelerated resting heart rate. Elevated heart rate (HR) is a risk factor for cardiovascular events, both in the general population and in patients with heart failure. Ivabradine is a pure HR-lowering agent, and it does not affect myocardial contractility, blood pressure, intracardiac conduction, or ventricular repolarization. In clinical trials such as BEAUTIFUL, CARVIVA HF, SHIFT, and INTENSIFY in patients with systolic left ventricular dysfunction, heart rate reduction with ivabradine brought positive outcomes. However, the results of the recent meta-analysis are rather neutral. In a diabetes mouse model of heart failure with preserved ejection fraction (HFpEF), selective heart rate reduction by If inhibition improved vascular stiffness, left ventricular (LV) contractility, and diastolic function. However, EDIFY (Effect of ivabradine in patients with heart rate with preserved ejection fraction) trial show that the use of ivabradine in patients with HFpEF is not supported. The further clinical trials investigating the use of ivabradine in heart failure should be carried out.

Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) Trial: Study Rationale and Design

The Catheter Ablation Versus Anti-arrhythmic Drug Therapy for Atrial Fibrillation (CABANA,NCT00911508)(1) trial is testing the hypothesis that the treatment strategy of percutaneous left atrial catheter ablation for the purpose of eliminating atrial fibrillation (AF) is superior to current state-of-the-art pharmacologic therapy. This international 140-center clinical trial was designed to randomize 2200 patients to a strategy of catheter ablation versus state-of-the-art rate or rhythm control drug therapy. Inclusion criteria include: 1) age> 65, or ≤65 with≥ 1 risk factor for stroke, 2) documented AF warranting treatment, and 3) eligibility for both catheter ablation and≥ 2 anti-arrhythmic or≥ 2 rate control drugs. Patients were followed every 3 to 6 months (median 4 years) and underwent repeat trans-telephonic monitoring, Holter monitoring, and CT/MR in a subgroup of patient studies to assess the impact of treatment on AF recurrence and atrial structure.With 1100 patients in each treatment arm, CABANA is projected to have 90% power for detecting a 30% relative reduction in the primary composite endpoint of total mortality, disabling stroke, serious bleeding, or cardiac arrest. Secondary endpoints include total mortality; mortality or cardiovascular hospitalization; a combination of mortality, stroke, hospitalization for heart failure or acute coronary artery events; cardiovascular death alone; and heart failure death, as well as AF recurrence, quality of life, and cost effectiveness. At a time when AF incidence is rising rapidly, CABANA will provide critical evidence with which to guide therapy and shape health care policy related to AF for years to come.

Outcomes of Rate-Control Treatment in Patients With Atrial Fibrillation and Heart Failure - A Nationwide Cohort Study.

Rate control is now a front-line therapy in the management of atrial fibrillation (AF). However, the survival benefits of different rate-control medications remain controversial, so we assessed the efficacy of rate-control medications in AF patients with concomitant heart failure (HF).Methods and Results:From January 2002 to December 2008, a total of 7,034 AF patients with a single type of rate-control drug or without rate-control treatment were enrolled from the Korea National Health Insurance Service database. The death rates over a mean follow-up of 4.5±1.2 years were 12.6% (580 of 4,593) and 29.0% (709 of 2,441) in non-HF and HF patients, respectively. Among the total subjects, the risk of death was lower in patients receiving β-blockers (adjusted hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.64-0.88) and calcium-channel blockers (adjusted HR 0.74, 95% CI 0.55-0.98) compared with those who did not receive rate-control medications. In patients without HF, use of rate-control medications did not affect the risk of death. In patients with HF, β-blockers significantly decreased the mortality risk (adjusted HR 0.63, 95% CI 0.50-0.79), whereas use of calcium-channel blockers or digoxin was not associated with death. The results were observed consistently among the cohorts after propensity matching. Use of β-blockers was associated with a reduced mortality rate for AF patient with HF but not for those without HF. These findings should be examined in a large randomized trial.

A dual stimuli-responsive amphiphilic polymer: reversible self-assembly and rate-controlled drug release

We report the dual stimuli-responsive self-assembly and rate-controlled drug release of a novel functionalized PEG amphiphilic polymer (FcC 11 AzoPEG) in aqueous solution. The novel FcC 11 AzoPEG amphiphilic polymer was synthesized by the esterification reaction of poly (ethylene glycol) methyl ether (PEG) and 4-(4′-(11-ferrocenyl-undecanoxy)) azobenzoic acid. The azobenzene (Azo) and ferrocene (Fc) moieties respectively afford the polymer a slow photo-response and a fast redox-response. Upon exposure to different stimuli (light irradiation, redox reaction, and a combination of light irradiation and redox reaction), FcC 11 AzoPEG in aqueous solution can reversibly self-assemble into various nanostructures and also disassemble either slowly by light irradiation or fast by redox reaction in an appropriate concentration range. Moreover, the drug release from the drug-loaded micelles can be precisely controlled by different stimuli: a slow release rate and a small amount of release for UV irradiation, a fast rate and a medium amount of release for oxidation by Fe2(SO4)3, and a large amount of release for the combined stimulation of UV irradiation and oxidation by Fe2(SO4)3. This work not only demonstrates the effect of stimuli-induced amphiphilicity change of functional groups on the solution aggregation behavior of functionalized PEG amphiphilic polymers but also provides a useful smart system with great potential application in drug delivery.

Drug therapy for atrial fibrillation: quo vadis?

Atrial fibrillation has always been the most common sustained cardiac arrhythmia, and its incidence is increasing worldwide. Despite evolving ablation techniques, the vastness of the number of cases entrenches drug therapy as the mainstay of treatment for the majority of cases both now and in the foreseeable future. Drug therapy for atrial fibrillation includes drugs for ventricular rate control, anti-coagulation, and cardioversion/maintenance of sinus rhythm (rhythm control). This review summarizes the available data on new drugs in each of these 3 areas. In the area of rhythm control, it is clear that primary prevention of atrial fibrillation is achieved by a number of drugs in common clinical usage in hypertension, heart failure, and vascular disease, viz. blockers of the renin-angiotensin system and statins. Primary prevention is also promising with novel therapies such as anti-inflammatory therapy, pirfenidone, and Ω-3 poly-unsaturated fatty acids. Secondary prevention with anti-arrhythmic drugs producing multiple channel blockade is proven to be efficacious, and atrial-selective anti-arrhythmic drugs are an attractive development and will avoid ventricular pro-arrhythmia. A number of new drugs with novel mechanisms of action have mostly not yet undergone clinical trials, but are discussed here, and include gap junction modulators, stretch-activated channel blockers, sodium-calcium exchange inhibitors and new ion channel blockers.

Evaluation of atrial fibrillation management and cardiovascular risk profile in atrial fibrillation patients: A cross-sectional survey

ObjectiveThe aim of this study to investigate the most frequent risk factors of atrial fibrillation (AF), co-morbidities, complications associated with AF and the use of anticoagulants and other medications in patients who were referred to university hospitals in Lithuania. Materials and methodsThis cross-sectional study enrolled consecutive inpatients and outpatients with AF presenting to cardiologists in the two biggest Lithuanian university hospitals from November 2013 to May 2014. AF diagnosis was confirmed by a 12-lead ECG or 24-h Holter with an episode duration of >30s. ResultsA total number of 575 patients were recruited, and complete data on clinical subtype were available for 515 patients (mean age of 70.7 years; 48.5% of women). Permanent AF was the most frequent type of AF (46.6%). Common comorbidities were hypertension (85.8%), heart failure (77.9%) and coronary artery disease (51.8%). Amiodarone was the most common antiarrhythmic agent used in 14.6% of the patients, while beta-blockers and digoxin were the most often used rate control drugs (59.6% and 10.7%, respectively). Oral anticoagulants were used by 53.3% of the patients; of them, 95.6% used vitamin K antagonists, while non-vitamin K antagonist were used by only 4.4%. The INR within a therapeutic range (2.0–3.0) was documented in 19.2% of the patients. Other antithrombotic drugs such as aspirin and clopidogrel were used in 13.7% and 2.0% of the patients, respectively; dual antiplatelet treatment was administered in 6.2% of the patients. Of the entire cohort, the mean CHA2DS2-VASc score was 3.97±1.6 and the mean HAS-BLED score was 2.25±1.0. ConclusionsCompliance with the treatment guidelines remains suboptimal and further patient education is needed.

Beta-blocker use and risk of symptomatic bradyarrhythmias: a hospital-based case-control study.

ObjectiveTo investigate the risk factors of symptomatic bradyarrhythmias in relation to β-blockers use.MethodsA hospital-based case-control study [228 patients: 108 with symptomatic bradyarrhythmias (cases) and 120 controls] was conducted in Sultanah Aminah Hospital, Malaysia between January 2011 and January 2014.ResultsThe mean age was 61.1 ± 13.3 years with a majority of men (68.9%). Cases were likely than control to be older, hypertensive, lower body mass index and concomitant use of rate-controlling drugs (such as digoxin, verapamil, diltiazem, ivabradine or amiodarone). Significantly higher level of serum potassium, urea, creatinine and lower level of estimated glomerular filtration rate (eGFR) were observed among cases as compared to controls. On univariate analysis among patients on β-blockers, older age (crude OR: 1.07; 95% CI: 1.03–1.11, P = 0.000), hypertension (crude OR: 5.6; 95% CI: 1.51–20.72, P = 0.010), lower sodium (crude OR: 0.04; 95% CI: 0.81–0.99, P = 0.036), higher potassium (crude OR: 2.36; 95% CI: 1.31–4.26, P = 0.004) and higher urea (crude OR: 1.23; 95% CI: 1.11–1.38, P = 0.000) were associated with increased risk of symptomatic bradyarrhythmias; eGFR was inversely and significantly associated with symptomatic bradyarrhythmias in both ‘β-blockers’ (crude OR: 0.97; 95% CI: 0.96–0.98, P = 0.000) and ‘non-β-blockers’ (crude OR: 0.99; 95% CI: 0.97–0.99, P = 0.023) arms. However, eGFR was not significantly associated with symptomatic bradyarrhythmias in the final model of both ‘β-blockers’ (adjusted OR: 0.98; 95% CI: 0.96–0.98, P = 0.103) and ‘non-β-blockers’ (adjusted OR: 0.99; 95% CI: 0.97–1.01, P = 0.328) arms. Importantly, older age was a significant predictor of symptomatic bradyarrhythmias in the ‘β-blockers’ as compared to the ‘non-β-blockers’ arms (adjusted OR: 1.09; 95% CI: 1.03–1.15, P = 0.003 vs. adjusted OR: 1.03; 95% CI: 0.98–1.09, P = 0.232, respectively).ConclusionOlder age was a significant predictor of symptomatic bradyarrhythmias in patients on β-blockers than those without β-blockers.

Clinical presentation, management, and outcomes in the Indian Heart Rhythm Society-Atrial Fibrillation (IHRS-AF) registry

AimA national atrial fibrillation (AF) registry was conducted under the aegis of the Indian Heart Rhythm Society (IHRS), to capture epidemiological data-type of AF, clinical presentation and comorbidities, current treatment practices, and 1-year follow-up outcomes. MethodsA total of 1537 patients were enrolled from 24 sites in India in the IHRS-AF registry from July 2011 to August 2012. Their baseline characteristics and follow-up data were recorded in case report forms and subsequently analyzed. ResultsThe average age of Indian AF patients was 54.7 years. There was a marginal female preponderance – 51.5% females and 48.5% males. At baseline, 20.4% had paroxysmal AF; 33% had persistent AF; 35.1% had permanent AF and 11% had first AF episode. At one-year follow-up, 45.6% patients had permanent AF.Rheumatic valvular heart disease (RHD) was present in 47.6% of patients. Hypertension, heart failure, coronary artery disease, and diabetes were seen in 31.4%, 18.7%, 16.2%, and 16.1%, respectively.Rate control was the strategy used in 75.2% patients, digoxin and beta-blockers being the most frequently prescribed rate-control drugs. Oral anticoagulation (OAC) drugs were used in 70% of patients. The annual mortality was 6.5%, hospitalization 8%, and incidence of stroke 1%. ConclusionsIn India, AF patients are younger and RHD is still the most frequent etiology. Almost two-third of the patients have persistent/permanent AF. At one-year follow-up, there is a significant mortality and morbidity in AF patients in India.

Drug Therapy for Rate and Rhythm Control in Nonvalvular Atrial Fibrillation: A Cross-sectional Study With Electronic Health Records in a Primary Care Cohort

PurposeThe purpose of this study is to describe the pharmacologic management of rate and rhythm and assess which factors are associated with the prescription of these drugs in patients with nonvalvular atrial fibrillation (AF) from the Effectiveness, Safety, and Costs in Atrial Fibrillation study. MethodsThis retrospective, cross-sectional study describes the pharmacologic rate and rhythm control management strategies adopted during 2012 in all patients diagnosed as having nonvalvular AF in 2007 to 2011. The data source is the Information System for the Improvement of Research in Primary Care database, which is based on primary care electronic health records. To answer the study objectives, 3 multivariate regression models to assess the independent factors associated with the prescription of these drugs were conducted for 2012. The rate and rhythm control drugs assessed were β-blockers, nondihydropyridine calcium channel blockers, antiarrhythmic agents, and digoxin. FindingsA total of 21,304 patients were diagnosed as having nonvalvular AF; 11,638 (54.6%) had at least one heart rate measure during 2012. Of them, 7777 (66.8%) received one or more rate and/or rhythm control drugs during 2012. Most patients (5751 [73.9%] of 7777) received only one drug for rate and/or rhythm control. Rate control agents were the most frequently used in 2012, with β-blockers the most prescribed group (4091 patients [52.6%]). A variety of different variables were associated with the prescription of rate and/or rhythm control drugs in the multivariate regression models. ImplicationsThe most used pharmacologic treatment of rate and rhythm control in our AF population is β-blockers, indicating that a rate control strategy is preferred in our setting, as widely recommended.

Formulation and In-Vitro Evaluation of Floating Tablet of Gabapentin

The present research work is an attempt to formulate rate controlled drug delivery system of Gabapentin which is primarily absorbed from stomach, so by increasing the GRT of the drug, the bioavailability can be increased. As the drug is stable in acidic pH and mostly absorbed with in pH 1–3, as the stomach is the major absorption site for the drug. Basing on this fact the drug is made to float in the stomach using the mechanism of buoyancy. The study also includes various evaluation studies of Gabapentin tablet and the effect of processing variables on it. A possible interaction between drug and polymers are also investigated by FTIR and DSC studies. So, the present work has been under taken with the objective of designing and evaluation of floating oral sustained release tablet drug delivery system of Gabapentin by using HPMC K15, NaCMC, Xanthun gum, sodium bicarbonate, citric acid. Lactose, ethyl cellulose etc.

Atrial fibrillation in older inpatients: are there any differences in clinical characteristics and pharmacological treatment between the frail and the non-frail?

Frailty is common in patients with atrial fibrillation and may impact on antithrombotic and anti-arrhythmic treatment. To describe differences in clinical characteristics, prescription of antithrombotic and anti-arrhythmic medications and incidence of haemorrhage and stroke, between frail and non-frail older inpatients. Prospective observational study in patients aged ≥65 years with atrial fibrillation admitted to a teaching hospital in Sydney, Australia. Frailty was assessed using the Reported Edmonton Frail Scale, stroke risk with CHA2DS2-VASc score and bleeding risk with HAS-BLED score. Participants were followed after 6 months for haemorrhages and strokes. We recruited 302 patients (mean age 84.7 ± 7.1 years, 53.3% frail, 50% female, mean CHA2DS2-VASc 4.61 ± 1.44, mean HAS-BLED 2.97 ± 1.04). Frail participants were older and had more co-morbidities and higher risk of stroke but not haemorrhage. Upon discharge, 55.7% participants were prescribed with anticoagulants (49.3% frail, 62.6% non-frail, P = 0.02). Thirty-three per cent received antiplatelets only and 11.1% no antithrombotics, with no difference by frailty status. For anti-arrhythmics, 52.6% received rate-control drugs only, 11.8% rhythm-control drugs only and 13.5% both and 22.1% were not prescribed either, with no difference by frailty status. On univariate logistic regression, frailty decreased the likelihood of anticoagulant prescription (odds ratio (OR) 0.58, 95%CI 0.36-0.93), but this was not significant on multivariate analysis (OR 0.66, 95%CI 0.40-1.11). After 6 months, overall incidence of ischaemic stroke was 2.1%, and in patients taking anticoagulants, incidence of major/severe bleeding was 6.3%, with no significant difference between frailty groups. Frailty status had little impact on antithrombotic prescription and no impact on anti-arrhythmic prescription.

A Statistical Atrioventricular Node Model Accounting for Pathway Switching During Atrial Fibrillation.

The atrioventricular (AV) node plays a central role in atrial fibrillation (AF), as it influences the conduction of impulses from the atria into the ventricles. In this paper, the statistical dual pathway AV node model, previously introduced by us, is modified so that it accounts for atrial impulse pathway switching even if the preceding impulse did not cause a ventricular activation. The proposed change in model structure implies that the number of model parameters subjected to maximum likelihood estimation is reduced from five to four. The model is evaluated using the data acquired in the RATe control in atrial fibrillation (RATAF) study, involving 24-h ECG recordings from 60 patients with permanent AF. When fitting the models to the RATAF database, similar results were obtained for both the present and the previous model, with a median fit of 86%. The results show that the parameter estimates characterizing refractory period prolongation exhibit considerably lower variation when using the present model, a finding that may be ascribed to fewer model parameters. The new model maintains the capability to model RR intervals, while providing more reliable parameters estimates. The model parameters are expected to convey novel clinical information, and may be useful for predicting the effect of rate control drugs.

Abstract 15704: Exploratory Analysis of the Efficacy of β-blockersin Patients With Post-infarction Systolic Dysfunction Plus Atrial Fibrillation

Introduction: β blocker therapy for patients with acute myocardial infarction (AMI) and reduced left ventricular ejection fraction (LVEF) was instituted after large randomized controlled trials showed a significant reduction in morbidity and mortality rates. Recently, their efficacy in patients with heart failure (HF) and atrial fibrillation (AF) has been questioned, based on the results of a large meta-analysis. We aim to analyze the efficacy of β blocker therapy in patients with post-AMI reduced LVEF and permanent AF. Methods: We studied all consecutive patients discharged with AMI and LVEF ≤ 40% from Hospital of Santiago de Compostela (2004-12) and Bellvitge Hospital of Barcelona (2009-14). The final cohort included 1,056 patients after excluding those without follow-up data. We analyzed the association between β blockers and follow-up (3.0 ± 2.5 years) mortality using Cox regression, adjusting by all confounding variables and by propensity score. Results: 782 patients (74.6%) were treated with β blockers. There were prescribed to 67.1% of patients in sinus rhythm (SR) and to 71.4% in AF. 140 patients (13.2%) had permanent AF at discharge. In SR group, β blockers were associated with lower mortality during follow-up (HR 0.42, 95% CI 0.31-0.53; p<0.001) after adjusting by the confounding variables (HR 0.50, 95% CI 0.32-0.96; p=0.028) and by propensity score (HR 0.68, 95% CI 0.51-0.92; p=0.010), but not in the AF group (HR 0.75, 95% CI 0.45-1.23; P=0.248) after adjusting by the confouding variables (HR 0.67, 95% CI 0.34-1.32; p=0.247) and propensity score (HR 0.81, 95% CI 0.47-1.40; p=0.459). Conclusion: β blocker therapy has no or minimal effect on mortality in patients with post-infarction reduced LVEF and AF, in contrast with its beneficial effects in SR. Thus, we call into question the preferential use of β blockers compared with other rate-control drugs in these patients (1A) and we emphasize the need for further trials to clarify it.

Circadian variation of variability and irregularity of heart rate in patients with permanent atrial fibrillation: relation to symptoms and rate control drugs.

The aim of the present study was to evaluate diurnal variations of the variability and irregularity of heart rate (HR) in patients with permanent atrial fibrillation (AF) with and without rate control drugs. Thirty-eight patients with permanent AF were part of an investigator-blind crossover study comparing diltiazem, verapamil, metoprolol, and carvedilol. We analyzed five Holter recordings per patient: at baseline (no rate control drug) and with each of the four drug regimens. HR, variability (SD; percentages of interval differences of successive RR intervals of >20, 50, and 80 ms; and root of the mean squared differences of successive RR intervals), and irregularity (approximate and sample entropy) parameters were computed in 20-min long nonoverlapping segments. Circadian rhythmicity was evaluated using cosinor analysis to each parameter series, which is characterized by the 24-h mean [midline statistic of rhythm (MESOR)] and excursion over the mean (amplitude). Arrhythmia-related symptoms were assessed by a questionnaire measuring symptom severity and frequency. HR and variability parameters showed a significant circadian variation in most patients, whereas only a small minority of the patients had circadian variations of irregularity parameters. Patients with circadian approximate entropy n at baseline had more severe symptoms (symptom severity: 9 ± 4 vs. 6 ± 5, P < 0.05, circadian vs. noncircadian variations). All drugs decreased the MESOR of HR and increased the MESOR of variability parameters. Only carvedilol and metoprolol decreased the normalized amplitude over 24 h of all parameters and HR. In conclusion, HR and RR variability parameters present a circadian variation in patients with permanent AF, whereas few patients demonstrated circadian fluctuations in irregularity parameters, suggesting different physiological mechanisms.

Noninvasive characterization of atrioventricular conduction in patients with atrial fibrillation

The atrioventricular (AV) node plays a fundamental role in patients with atrial fibrillation (AF), acting as a filter to the numerous irregular atrial impulses which bombard the node. A phenomenological approach to better understand AV nodal electrophysiology is to analyze the ventricular response with respect to irregularity. In different cohorts of AF patients, such analysis has been performed with the aim to evaluate the association between ventricular response characteristics and long-term clinical outcome and to determine whether irregularity is affected by rate-control drugs. Another approach to studying AV nodal characteristics is to employ a mathematical model which accounts for the refractory periods of the two AV nodal pathways. With atrial fibrillatory rate and RR intervals as input, the model has been considered for analyzing data during (i) rest and head-up tilt test, (ii) tecadenoson and esmolol, and (iii) rate-control drugs. The present paper provides an overview of our recent work on the characterization and assessment of AV nodal conduction using these two approaches.

Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation.

Atrial fibrillation is the most frequent sustained arrhythmia. Atrial fibrillation frequently recurs after restoration of normal sinus rhythm. Antiarrhythmic drugs have been widely used to prevent recurrence, but the effect of these drugs on mortality and other clinical outcomes is unclear. This is an update of a review previously published in 2008 and 2012. To determine in patients who have recovered sinus rhythm after having atrial fibrillation, the effects of long-term treatment with antiarrhythmic drugs on death, stroke, embolism, drug adverse effects and recurrence of atrial fibrillation. We updated the searches of CENTRAL in The Cochrane Library (2013, Issue 12 of 12), MEDLINE (to January 2014) and EMBASE (to January 2014). The reference lists of retrieved articles, recent reviews and meta-analyses were checked. Two independent authors selected randomised controlled trials comparing any antiarrhythmic drug with a control (no treatment, placebo, drugs for rate control) or with another antiarrhythmic drug in adults who had atrial fibrillation and in whom sinus rhythm was restored. Post-operative atrial fibrillation was excluded. Two authors independently assessed quality and extracted data. Studies were pooled, if appropriate, using Peto odds ratio (OR). All results were calculated at one year of follow-up. In this update three new studies, with 534 patients, were included making a total of 59 included studies comprising 21,305 patients. All included studies were randomised controlled trials. Allocation concealment was adequate in 17 trials, it was unclear in the remaining 42 trials. Risk of bias was assessed in all domains only in the trials included in this update.Compared with controls, class IA drugs quinidine and disopyramide (OR 2.39, 95% confidence interval (95% CI) 1.03 to 5.59, number needed to treat to harm (NNTH) 109, 95% CI 34 to 4985) and sotalol (OR 2.23, 95% CI 1.1 to 4.50, NNTH 169, 95% CI 60 to 2068) were associated with increased all-cause mortality. Other antiarrhythmics did not seem to modify mortality, but our data could be underpowered to detect mild increases in mortality for several of the drugs studied.Several class IA (disopyramide, quinidine), IC (flecainide, propafenone) and III (amiodarone, dofetilide, dronedarone, sotalol) drugs significantly reduced recurrence of atrial fibrillation (OR 0.19 to 0.70, number needed to treat to beneft (NNTB) 3 to 16). Beta-blockers (metoprolol) also significantly reduced atrial fibrillation recurrences (OR 0.62, 95% CI 0.44 to 0.88, NNTB 9).All analysed drugs increased withdrawals due to adverse affects and all but amiodarone, dronedarone and propafenone increased pro-arrhythmia. Only 11 trials reported data on stroke. None of them found any significant difference with the exception of a single trial than found less strokes in the group treated with dronedarone compared to placebo. This finding was not confirmed in others studies on dronedarone.We could not analyse heart failure and use of anticoagulation because few original studies reported on these measures. Several class IA, IC and III drugs, as well as class II drugs (beta-blockers), are moderately effective in maintaining sinus rhythm after conversion of atrial fibrillation. However, they increase adverse events, including pro-arrhythmia, and some of them (disopyramide, quinidine and sotalol) may increase mortality. Possible benefits on clinically relevant outcomes (stroke, embolism, heart failure) remain to be established.

Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF)

Digoxin is a widely used drug for ventricular rate control in patients with atrial fibrillation (AF), despite a scarcity of randomised trial data. We studied the use and outcomes of digoxin in patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). For this retrospective analysis, we included and classified patients from ROCKET AF on the basis of digoxin use at baseline and during the study. Patients in ROCKET AF were recruited from 45 countries and had AF and risk factors putting them at moderate-to-high risk of stroke, with or without heart failure. We used Cox proportional hazards regression models adjusted for baseline characteristics and drugs to investigate the association of digoxin with all-cause mortality, vascular death, and sudden death. ROCKET AF was registered with ClinicalTrials.gov, number NCT00403767. In 14,171 randomly assigned patients, digoxin was used at baseline in 5239 (37%). Patients given digoxin were more likely to be female (42% vs 38%) and have a history of heart failure (73% vs 56%), diabetes (43% vs 38%), and persistent AF (88% vs 77%; p<0·0001 for each comparison). After adjustment, digoxin was associated with increased all-cause mortality (5·41 vs 4·30 events per 100 patients-years; hazard ratio 1·17; 95% CI 1·04-1·32; p=0·0093), vascular death (3·55 vs 2·69 per 100 patient-years; 1·19; 1·03-1·39, p=0·0201), and sudden death (1·68 vs 1·12 events per 100 patient-years; 1·36; 1·08-1·70, p=0·0076). Digoxin treatment was associated with a significant increase in all-cause mortality, vascular death, and sudden death in patients with AF. This association was independent of other measured prognostic factors, and although residual confounding could account for these results, these data show the possibility of digoxin having these effects. A randomised trial of digoxin in treatment of AF patients with and without heart failure is needed. Janssen Research & Development and Bayer HealthCare AG.

Therapeutic management in ambulatory elderly patients with atrial fibrillation: the S.AGES cohort.

Few epidemiologic studies have specifically focused on very old community dwelling population with atrial fibrillation (AF). The objectives of the AF-S.AGES cohort were to describe real-life therapeutic management of non-institutionalized elderly patients with AF according to age groups, i.e., 65-79 and ≥ 80 and to determine the main factors associated with anticoagulant treatment in both groups. Observational study (N=1072) aged ≥ 65 years old, recruited by general practitioners. Characteristics of the sample were first evaluated in the overall sample and according to age (< 80 or ≥ 80 years) and to use of anticoagulant treatment at inclusion. Logistic models were used to analyze the determinants of anticoagulant prescription among age groups. Mean age was 78.0 (SD=6.5) years and 42% were ≥ 80 years. Nineteen percent had paroxysmal AF, 15% persistent, 56% permanent and 10% unknown type, 77% were treated with vitamin K antagonists (VKA), 17% with antiplatelet therapy with no differences between age groups. Rate-control drugs were more frequently used than rhythm-control drugs (55% vs. 37%, p < 0.001). VKA use was associated with permanent AF, younger age and cancer in patients ≥ 80 years old and with permanent AF and preserved functional autonomy in patients < 80 years old. Hemorrhagic scores were independently associated with non-use of VKA whereas thromboembolic scores were not associated with VKA use. In this elderly AF outpatient population, use of anticoagulant therapy was higher even after 80 years than in previous studies suggesting that recent international guidelines are better implemented in the elderly population.

0456: Therapeutic management in ambulatory elderly patients with atrial fibrillation: the S.AGES cohort

Few data on therapeutic management of patients over 80 years with nonvalvular atrial fibrillation (AF) are available in general population. The objectives of the AF-S.AGES cohort (Sujets AGES) were to describe real-life therapeutic management of non-institutionalized elderly subjects with AF according to age groups, i.e., 65-79 and ≥80 years and to determine factors associated with anticoagulant treatment. General practitioners recruited 1072 patients aged >65 years old between 2009 and 2011. General characteristics were first evaluated in the overall sample and according to age groups and use of anticoagulant treatment at inclusion. Mean age was 78.0 (SD 6.5) years and 42% were older than 80 years. In the overall sample, 19% of patients had paroxysmal AF, 15% persistent, 56% permanent and for 10% AF type was unknown. Vitamin K antagonists (VKA) were used in 77% of patients, antiplatelet therapy in 17% and 12% of patients did not receive any antithrombotic treatment. There were no differences between age-groups (< 80 or ≥80 years) for VKA (78 vs. 76%, p=0.58). Rate control drugs were more frequently used (55%) than rhythm control drugs (37%). Class I and class II antiarrhythmic drugs were less often used in octogenarians than in younger patients (5.6% vs. 12.3%, p<0.001 and 36 vs. 41%, p<0.05). Among patients ≥80 years old, VKA use was associated with permanent AF younger age and cancer. Among patients < 80 years old, the use of VKA was associated with permanent AF and preserved functional autonomy. HAS-BLED and HEMORR2HAGES scores were associated with non-use of VKA in subjects ≥80 and < 80 years, CHADS2 and CHA2DS2-VASc scores were not associated with VKA use in both groups. We observed a higher use of anticoagulant therapy in elderly AF outpatients even after 80 years when compared with previous studies. These results suggest that recent international guidelines are better implemented in the elderly population.