Clinical and economic outcomes associated with use of anti-arrhythmic drugs versus ablation in atrial fibrillation.

Aim: To evaluate the clinical and economic impact of antiarrhythmic drugs (AADs) compared with ablation both as individual treatments and as combination therapy without/with considering the order of treatment among patients with atrial fibrillation (AFib). Materials & methods: A budget impact model over a one-year time horizon was developed to assess the economic impact of AADs (amiodarone, dofetilide, dronedarone, flecainide, propafenone, sotalol, and as a group) versus ablation across three scenarios: direct comparisons of individual treatments, non-temporal combinations, and temporal combinations. The economic analysis was conducted in accordance with CHEERS guidance as per current model objectives. Results are reported as costs per patient per year (PPPY). The impact of individual parameters was evaluated using one-way sensitivity analysis (OWSA). Results: In direct comparisons, ablation had the highest annual medication/procedure cost ($29,432), followed by dofetilide ($7661), dronedarone ($6451), sotalol ($4552), propafenone ($3044), flecainide ($2563), and amiodarone ($2538). Flecainide had the highest costs for long-term clinical outcomes ($22,964), followed by dofetilide ($17,462), sotalol ($15,030), amiodarone ($12,450), dronedarone ($10,424), propafenone ($7678) and ablation ($9948). In the non-temporal scenario, total costs incurred for AADs (group) + ablation ($17,278) were lower compared with ablation alone ($39,380). In the temporal scenario, AADs (group) before ablation resulted in PPPY cost savings of ($22,858) compared with AADs (group) after ablation ($19,958). Key factors in OWSA were ablation costs, the proportion of patients having reablation, and withdrawal due to adverse events. Conclusion: Utilization of AADs as individual treatment or in combination with ablation demonstrated comparable clinical benefits along with costs savings in patients with AFib.

In Silico Assessment of Class I Antiarrhythmic Drug Effects on Pitx2-Induced Atrial Fibrillation: Insights from Populations of Electrophysiological Models of Human Atrial Cells and Tissues.

Electrical remodelling as a result of homeodomain transcription factor 2 (Pitx2)-dependent gene regulation was linked to atrial fibrillation (AF) and AF patients with single nucleotide polymorphisms at chromosome 4q25 responded favorably to class I antiarrhythmic drugs (AADs). The possible reasons behind this remain elusive. The purpose of this study was to assess the efficacy of the AADs disopyramide, quinidine, and propafenone on human atrial arrhythmias mediated by Pitx2-induced remodelling, from a single cell to the tissue level, using drug binding models with multi-channel pharmacology. Experimentally calibrated populations of human atrial action po-tential (AP) models in both sinus rhythm (SR) and Pitx2-induced AF conditions were constructed by using two distinct models to represent morphological subtypes of AP. Multi-channel pharmaco-logical effects of disopyramide, quinidine, and propafenone on ionic currents were considered. Simulated results showed that Pitx2-induced remodelling increased maximum upstroke velocity (dVdtmax), and decreased AP duration (APD), conduction velocity (CV), and wavelength (WL). At the concentrations tested in this study, these AADs decreased dVdtmax and CV and prolonged APD in the setting of Pitx2-induced AF. Our findings of alterations in WL indicated that disopyramide may be more effective against Pitx2-induced AF than propafenone and quinidine by prolonging WL.

Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation: results on health-related quality of life and symptom burden. The MANTRA-PAF trial.

AIMS: The Medical ANtiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation (MANTRA-PAF) trial assessed the long-term efficacy of an initial strategy of radiofrequency ablation (RFA) vs. antiarrhythmic drug therapy (AAD) as first-line treatment for patients with PAF. In this substudy, we evaluated the effect of these treatment modalities on the Health-Related Quality of Life (HRQoL) and symptom burden of patients at 12 and 24 months. METHODS AND RESULTS: During the study period, 294 patients were enrolled in the MANTRA-PAF trial and randomized to receive AAD (N = 148) or RFA (N = 146). Two generic questionnaires were used to assess the HRQoL [Short Form-36 (SF-36) and EuroQol-five dimensions (EQ-5D)], and the Arrhythmia-Specific questionnaire in Tachycardia and Arrhythmia (ASTA) was used to evaluate the symptoms appearing during the trial. All comparisons were made on an intention-to-treat basis. Both randomization groups showed significant improvements in assessments with both SF-36 and EQ-5D, at 24 months. Patients randomized to RFA showed significantly greater improvement in four physically related scales of the SF-36. The three most frequently reported symptoms were breathlessness during activity, pronounced tiredness, and worry/anxiety. In both groups, there was a significant reduction in ASTA symptom index and in the severity of seven of the eight symptoms over time. CONCLUSION: Both AAD and RFA as first-line treatment resulted in substantial improvement of HRQoL and symptom burden in patients with PAF. Patients randomized to RFA showed greater improvement in physical scales (SF-36) and the EQ-visual analogue scale. CLINICAL TRIAL REGISTRATION: URL http://www.clinicaltrials.gov. Unique identifier: NCT00133211.

Analysis of the cost-effectiveness of dronedarone versus amiodarone, propafenone, and sotalol in patients with atrial fibrillation: results for Serbia.

BACKGROUND: Recent studies have shown that dronedarone is associated with significantly fewer adverse effects and treatment discontinuations, and a trend toward reduced all-cause mortality, compared with amiodarone. Introduction of dronedarone in clinical practice is limited by its higher cost than amiodarone, propafenone, and sotalol. AIM: To estimate cost-effectiveness of dronedarone versus amiodarone, propafenone, and sotalol in patients with atrial fibrillation (AF). METHODS: We constructed a Markov model, which was then simulated by Monte Carlo simulation using 1,000 virtual patients. Costs and outcomes were estimated from the societal perspective and discounted at 3% annually. A lifetime horizon and three-month cycle length were used. The main outcome measurement was the number of years spent without stroke. Values of transition probabilities and therapy outcomes were estimated from available literature. The prices of health services and drugs were obtained from the Republic Institute for Health Insurance Tariff Book and Drug List A and from the drug developer. RESULTS: Cost-effectiveness shows that the dronedarone treatment option has the most advantageous relationship, where, for one year without a stroke, the total cost is €1,779.23. In the case of the amiodarone therapy option, for one year without a stroke €3,845.10 is needed, for propafenone €4,674.20, while for sotalol the sum is €14,973.89. Estimated annual costs for patients with first-detected AF in Serbia were €610. CONCLUSIONS: The results of our model indicate that dronedarone is a cost-effective therapy compared with amiodarone, propafenone, and sotalol in patients with AF, if the outcome measurement is the number of years spent without stroke.

Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation.

BACKGROUND: There are limited data comparing radiofrequency catheter ablation with antiarrhythmic drug therapy as first-line treatment in patients with paroxysmal atrial fibrillation. METHODS: We randomly assigned 294 patients with paroxysmal atrial fibrillation and no history of antiarrhythmic drug use to an initial treatment strategy of either radiofrequency catheter ablation (146 patients) or therapy with class IC or class III antiarrhythmic agents (148 patients). Follow-up included 7-day Holter-monitor recording at 3, 6, 12, 18, and 24 months. Primary end points were the cumulative and per-visit burden of atrial fibrillation (i.e., percentage of time in atrial fibrillation on Holter-monitor recordings). Analyses were performed on an intention-to-treat basis. RESULTS: There was no significant difference between the ablation and drug-therapy groups in the cumulative burden of atrial fibrillation (90th percentile of arrhythmia burden, 13% and 19%, respectively; P=0.10) or the burden at 3, 6, 12, or 18 months. At 24 months, the burden of atrial fibrillation was significantly lower in the ablation group than in the drug-therapy group (90th percentile, 9% vs. 18%; P=0.007), and more patients in the ablation group were free from any atrial fibrillation (85% vs. 71%, P=0.004) and from symptomatic atrial fibrillation (93% vs. 84%, P=0.01). One death in the ablation group was due to a procedure-related stroke; there were three cases of cardiac tamponade in the ablation group. In the drug-therapy group, 54 patients (36%) underwent supplementary ablation. CONCLUSIONS: In comparing radiofrequency ablation with antiarrhythmic drug therapy as first-line treatment in patients with paroxysmal atrial fibrillation, we found no significant difference between the treatment groups in the cumulative burden of atrial fibrillation over a period of 2 years. (Funded by the Danish Heart Foundation and others; MANTRA-PAF ClinicalTrials.gov number, NCT00133211.).

Cost evaluation of rhythm control methods for atrial fibrillation: evidence from CTAF.

Atrial fibrillation (AF) is a highly prevalent arrhythmia that is difficult to treat and generates important health care costs. One consideration in the selection of various therapeutic options is the cost of a given treatment compared to that of alternatives. The Canadian Trial of Atrial Fibrillation (CTAF) evaluated the effectiveness of sinus rhythm maintenance with amiodarone compared to propafenone or sotalol in a prospective, randomized fashion. A subsequent CTAF substudy of the medical costs associated with amiodarone vs. propafenone/sotalol found that amiodarone decreased AF-related costs. This paper reviews the results of the CTAF cost-analysis substudy in the context of other analyses in the literature of the cost effectiveness of amiodarone in AF. The costs associated with amiodarone therapy are no greater than for other sinus rhythm maintenance drugs, and for some cost categories and some patient subgroups are likely to be less, despite amiodarone's greater therapeutic efficacy. However, additional considerations are important in evaluating the clinical place of amiodarone, including its adverse effect and pharmacokinetic profile. As well, the results of recent randomized clinical trials have highlighted the limitations of sinus rhythm maintenance as a primary therapeutic objective in AF. The decision about whether and at what point to use amiodarone in a given patient requires a careful analysis of the individual case, in terms of symptomatology during AF, the response to previous treatment regimes, and risk factors for various forms of adverse drug reactions.

Amiodarone reduces procedures and costs related to atrial fibrillation in a controlled clinical trial.

BACKGROUND: Atrial fibrillation is the most common sustained cardiac arrhythmia, and engenders significant health care costs. The impact of various treatment options for atrial fibrillation on hospital costs has not been evaluated in a randomized trial. METHODS: We analysed 1-year follow-up data on 392 patients randomized to low dose amiodarone (200 mg. day(-1)) or alternative first-line therapy (sotalol or propafenone) in a multicentre trial (Canadian Trial of Atrial Fibrillation, CTAF). RESULTS: Patients in the amiodarone group had fewer electrical cardioversions (65 vs 109 for patients in the sotalol/propafenone group, P<0.0001), and pacemaker insertions (4 vs 11, P=0.07). The average amiodarone patient spent fewer days in hospital (0.47 vs 0.97, P=0.01), and incurred lower costs ($532 vs $898, P=0.03), for admissions where atrial fibrillation was the admitting diagnosis. Average total hospital costs per patient for all admissions, as well as average combined hospital and physician costs per patient, showed wide variations within the treatment arms and were not significantly different between groups. CONCLUSION: For patients in whom antiarrhythmic drug therapy is indicated, low dose amiodarone significantly reduces atrial fibrillation-related costs by reducing the number of atrial fibrillation-related procedures.

Oral loading with propafenone for conversion of recent-onset atrial fibrillation: a review on in-hospital treatment.

Atrial fibrillation (AF) is a very common arrhythmia. In order to treat acute AF rapidly, effective drug regimens are required. Propafenone is a class IC antiarrhythmic agent that is suitable for oral loading as it reaches peak plasma concentrations within 2 to 4 hours of administration. The use of propafenone loading in patients with AF must be based on appropriate patient selection in view of the negative inotropic effect and the potential proarrhythmic effects of the drug. A series of controlled trials in patients with recent-onset AF without heart failure who were hospitalised with enforced bed rest has shown that orally loaded propafenone (450 to 600 mg as single dose) exerts a relatively quick effect (within 3 to 4 hours) and a high rate of efficacy (72 to 78% within 8 hours). A potentially harmful effect of class IC agents is the risk of transforming AF into atrial flutter (3.5 to 5% of patients). However, atrial flutter with 1 : 1 atrioventricular response was observed in only two of 709 patients receiving propafenone (0.3% incidence). Nevertheless, the potential negative inotropic effect of propafenone demands careful patient selection, with systematic exclusion of patients with left ventricular dysfunction or congestive heart failure. Oral loading with propafenone can be considered as an episodic treatment in patients with AF recurrences, as has been proposed for other drugs in the past. However, the safety of oral loading with propafenone as an outpatient treatment in appropriately selected patients has to be assessed by appropriately designed prospective studies.

[Comparison of efficacy, safety and cost-effectiveness of intravenous versus oral propafenone in paroxysmal atrial fibrillation]. / Porównanie skutecznosci, bezpieczenstwa i kosztów leczenia dozylna i doustna postacia propafenonu u chorych z napadowym migotaniem przedsionków.

The purpose of this study was to investigate the efficacy, safety and cost-effectiveness of intravenous and oral propafenone in the conversion of paroxysmal atrial fibrillation propafenone to sinus rhythm. We analysed two groups of 100 consecutive patients (pts) treated because of propafenone with duration < 48 h. The first group was treated with intravenous PFN (bolus of 70 to 140 mg) and the second group was treated with oral PFN (300 to 600 mg). These 2 groups were comparable in age, sex, evidence of CAD, hypertension, mitral valve disease, history of hyperthyroidism and the level of K+ at admittance. Conversion to sinus rhythm was achieved in 64 (64%) pts who received i.v. propafenone and in 77 (77%) who received oral propafenone (p < 0.05). We conclude that oral and intravenous propafenone is safe in the termination of propafenone. Oral route of administration appears to be superior to intravenous because of greater efficacy and cost-effectiveness.

Cost-effective management of acute atrial fibrillation: role of rate control, spontaneous conversion, medical and direct current cardioversion, transesophageal echocardiography, and antiembolic therapy.

Management strategies for the acute treatment of atrial fibrillation (AF) include: (1) the use of intravenous drugs for rate control, (2) drug termination, or (3) direct current (DC) cardioversion. Delays in cardioversion can promote atrial remodeling and add thromboembolic risk. Rate control awaiting spontaneous or pharmacologic conversion may be a cost-effective strategy in patients presenting with recent onset of symptoms. Early DC cardioversion can be cost-effective and minimize antiembolic therapy issues in the acute setting. In patients presenting with AF of unknown or >48 hours' duration, rate control and therapeutic warfarin for 3-4 weeks followed by medical or DC cardioversion is standard practice. However, delays in conversion promote atrial remodeling that makes restoration of sinus rhythm more difficult and increases the likelihood of postcardioversion AF recurrence. Transesophageal echocardiography can identify patients at low risk for a cardioversion-related embolic event and allows cardioversion to be performed earlier, thereby minimizing atrial remodeling.

Conversion of recent onset atrial fibrillation with single loading oral dose of propafenone: is in-hospital admission absolutely necessary?

A population of 283 patients with recent onset (< 72 hours) AF, without heart failure, who received a single 450- or 600-mg oral dose of propafenone, or digoxin 1 mg, or placebo for conversion to sinus rhythm (SR), was studied to determine whether a routine admission to the hospital for drug administration is justified. Previous bradyarrhythmias or sick sinus syndrome (SSS), and concomitant use of antiarrhythmic drugs were exclusion criteria. None of the 283 patients studied experienced VT or VF and none of them needed implantation of a temporary pacemaker. Periods of atrial tachyarrhythmias with regularization of atrial waves and 1:1 AV conduction were observed in only two cases, both receiving placebo. No predictor of proarrhythmia was found among the clinical variables considered (age, etiology, arrhythmia duration, atrial dimension, and blood potassium). No serious hemodynamic adverse effects were noted in either group. The rates of conversion to SR after 4 hours were: 80 (57%) of 141 patients who received propafenone and 35 (25%) of 142 patients who received digoxin or placebo (P < 0.001). Acute oral treatment with propafenone is simple and effective for the conversion of recent onset AF to SR in patients without clinical signs of heart failure. The routine admission of these patients to the hospital is not necessary. Home-based administration of oral propafenone to a selected group of patients could significantly increase the cost effectiveness of this treatment.

Acute and long-term efficacy of propafenone in patients with sustained ventricular tachyarrhythmias: assessment with programmed ventricular stimulation.

To determine the electrophysiological properties of oral propafenone, 50 patients (39 male and 11 female, aged 31 to 80 years) with sustained ventricular tachycardia or ventricular fibrillation underwent serial electrophysiological drug testing, using propafenone (750 to 900 mg daily) as the anti-arrhythmic regimen of first choice. During baseline study, all patients had inducible sustained ventricular tachyarrhythmias. After oral loading of propafenone, 37 patients (74%) remained inducible whereas 13 were rendered non-inducible. Among the still inducible patients, the mean VT rate decreased from 223 +/- 38 b.min-1 (baseline) to 172 +/- 32 b.min +/- 1 (P less than 0.001). Four patients showed an increase of VT rate during propafenone compared to the VT rate at control. Non-inducible patients were discharged on propafenone. During a mean follow-up period of 20 +/- 15 months, there were three non-fatal VT recurrences among the responders, two of them due to non-compliance. Thus, propafenone used as the anti-arrhythmic agent of first choice among patients undergoing serial electrophysiological drug testing for ventricular tachyarrhythmias proved effective in suppressing VT induction in 26%. With regard to arrhythmic events, these patients have a favourable outcome.