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.

In-silico assessment of the dynamic effects of amiodarone and dronedarone on human atrial patho-electrophysiology.

AIMS: The clinical efficacy in preventing the recurrence of atrial fibrillation (AF) is higher for amiodarone than for dronedarone. Moreover, pharmacotherapy with these drugs is less successful in patients with remodelled substrate induced by chronic AF (cAF) and patients suffering from familial AF. To date, the reasons for these phenomena are only incompletely understood. We analyse the effects of the drugs in a computational model of atrial electrophysiology. METHODS AND RESULTS: The Courtemanche-Ramirez-Nattel model was adapted to represent cAF remodelled tissue and hERG mutations N588K and L532P. The pharmacodynamics of amiodarone and dronedarone were investigated with respect to their dose and heart rate dependence by evaluating 10 descriptors of action potential morphology and conduction properties. An arrhythmia score was computed based on a subset of these biomarkers and analysed regarding circadian variation of drug concentration and heart rate. Action potential alternans at high frequencies was observed over the whole dronedarone concentration range at high frequencies, while amiodarone caused alternans only in a narrow range. The total score of dronedarone reached critical values in most of the investigated dynamic scenarios, while amiodarone caused only minor score oscillations. Compared with the other substrates, cAF showed significantly different characteristics resulting in a lower amiodarone but higher dronedarone concentration yielding the lowest score. CONCLUSION: Significant differences exist in the frequency and concentration-dependent effects between amiodarone and dronedarone and between different atrial substrates. Our results provide possible explanations for the superior efficacy of amiodarone and may aid in the design of substrate-specific pharmacotherapy for AF.

Pharmacokinetic and pharmacodynamic profile of dronedarone , a new antiarrhythmic agent for the treatment of atrial fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is the most common arrhythmia and is associated with increased morbidity and mortality. Dronedarone is a recent antiarrhythmic drug that has been developed for treatment of AF, with electrophysiological properties similar to amiodarone but with a lower incidence of side effects. AREAS COVERED: This review evaluates the efficacy, safety, tolerability and side effects of dronedarone in the treatment of AF. In particular, the review includes studies comparing: dronedarone and placebo (ANDROMEDA, ATHENA, DAFNE, ERATO, EURIDIS/ADONIS, HESTIA, PALLAS trials), dronedarone and amiodarone (DIONYSOS trial), ranolazine and dronedarone given alone and in combination (HARMONY trial). EXPERT OPINION: Dronedarone is an interesting antiarrhythmic agent in well-selected groups of patients. It also has several other pleiotropic effects that may potentially be beneficial in clinical practice, such as the reduction of the risk of stroke and acute coronary syndromes. In addition, combination therapies such as those with dronedarone and ranolazine, currently being investigated in the HARMONY trial, may provide another interesting approach to increase the antiarrhythmic efficacy and further reduce the incidence of side effects. A better understanding of the mechanisms underlying dronedarone's pleiotropic actions is expected to facilitate the selection of patients benefiting from dronedarone, as well as the development of novel antiarrhythmic drugs for AF.

Assessment of dronedarone utilization using US claims databases.

BACKGROUND: A dronedarone utilization study using US MarketScan and InVision Data Mart databases was conducted to estimate the prevalence of the following: (1) dronedarone use in contraindicated patients with worsening heart failure (HF) or hospitalization for HF within 1 month before dronedarone prescription; (2) concomitant prescribing of contraindicated drugs; and (3) recommended creatinine testing after dronedarone initiation among dronedarone users. METHODS: In this retrospective cohort study, data in the MarketScan database between July 20, 2009, and December 31, 2011, and in the InVision Data Mart database between July 20, 2009, and March 31, 2012, were analyzed. The study population included patients who received ≥1 dronedarone prescription during the study period. The following variables were reported: worsening of or hospitalization for HF, concomitant prescribing of potent cytochrome P450 CYP 3A4 inhibitors or QT-prolonging drugs, and creatinine testing. RESULTS: There were 31,408 and 7025 dronedarone users identified in the MarketScan and InVision Data Mart databases, respectively. Approximately 86% to 90% of patients had a diagnosis of atrial fibrillation in each database. In the MarketScan database, 40% were women and 54% were aged ≥65 years. In the InVision Data Mart database, 31% were women and 32% were aged ≥65 years. The corresponding prevalence of worsening or hospitalization for HF was 6.4% (95% CI, 6.2-6.7) and 4.7% (95% CI, 4.2-5.2) in each database, respectively. The corresponding estimates of concomitant prescribing of potent cytochrome P450 CYP 3A4 inhibitors and QT-prolonging drugs within 30 days before initiation or refilling of dronedarone were 2.0% (95% CI, 1.8-2.1) and 10.0% (95% CI, 9.7-10.4), respectively, in the MarketScan database, and 2.3% (95% CI, 2.0-2.7) and 11.2% (95% CI, 10.5-12.0) in the InVision Data Mart database. More than 50% of patients in each database had serum creatinine tests conducted after dronedarone initiation. CONCLUSIONS: The results of the present analysis based on a long-term follow-up (nearly 3 years) were consistent with the previous findings that dronedarone has mostly been used appropriately in compliance with US prescribing in the target populations.

Estimation of potential cost savings associated with reduced rates of cardiovascular hospitalization among atrial fibrillation/flutter patients treated with dronedarone in the ATHENA trial.

The aim of this study was to estimate, from a US payer perspective, potential cost savings resulting from the reduction in cardiovascular (CV) hospitalizations obtained with dronedarone in the ATHENA (A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death from any Cause in PatiENts with Atrial Fibrillation/Atrial Flutter) trial. ATHENA randomized atrial fibrillation/flutter patients to dronedarone (n=2301) or placebo (n=2327) plus standard care. Dronedarone significantly reduced first CV hospitalization/all-cause mortality over 12-30 months of follow-up. CV hospitalization costs (2008 values) from a US cohort of ATHENA-like atrial fibrillation/flutter patients with Medicare supplemental insurance (n=10,200) and diagnosis-related group costs of adverse event-related hospitalizations were applied to hospitalizations occurring in ATHENA. The impact of cost variation was assessed using Monte Carlo simulation. In ATHENA, dronedarone reduced the overall CV hospitalization rate (vs. placebo) by 29% over the first 12 months (33.36 vs. 47.19 events per 100 patients) and by 25% over the full study (51.15 vs. 68.55 events per 100 patients). Adverse event-related hospitalization rates (dronedarone vs. placebo) were low (0.48 vs. 0.21 and 0.56 vs. 0.26 events per 100 patients over 12 months and the full study, respectively). Overall hospitalization cost savings were estimated at $1329 and $1763 per patient over 12 months and the full study, respectively. Cost savings were relatively stable [mean (95% confidence interval): $1330 ($994-$1676) for the first 12 months and $1763 ($1369-$2184) for the full study] over 10,000 cycles of random variation.

Cost-effectiveness of dronedarone in patients with atrial fibrillation in the ATHENA trial.

BACKGROUND: The ATHENA trial randomized 4628 patients with atrial fibrillation (AF) or atrial flutter, aged ≥ 70 years with risk factors or ≥ 75 years without risk factors, to receive 400 mg dronedarone twice daily or placebo in addition to standard therapy. Our objective was to evaluate the cost-effectiveness of dronedarone from a Canadian health care perspective based on resource utilization and cardiovascular hospitalization or death in ATHENA. METHODS: Data on medical resource utilization (cardiovascular hospitalizations, hospitalization because of treatment-related adverse events, outpatient examinations and procedures, study drug and concomitant medications) were aggregated for all randomized patients during the entire trial period (mean 21 months). Effectiveness was measured using the total number of avoided cardiovascular hospitalizations and deaths from any cause, and projected survival and quality-adjusted survival using life tables adjusted for AF mortality and data on determinants of utility in AF. We used standard unit costs from Canada (2008), discounting costs and effects at 5% per year. RESULTS: Patients receiving dronedarone incurred a mean total cost (undiscounted) of CAD $7402 during the trial period, compared with CAD $6708 for patients receiving placebo. The cost of dronedarone was partly offset by savings for cardiovascular hospitalizations and concomitant medications. On average, patients taking dronedarone experienced 0.18 fewer events (cardiovascular hospitalizations or death). The cost per event avoided was CAD $3807, the cost per life-year gained was CAD $5204, and the cost per quality-adjusted life-years was CAD $7560. CONCLUSIONS: Compared with generally accepted thresholds, our results indicate that treatment with dronedarone as in ATHENA is cost-effective.

Benefit-risk assessment of dronedarone in the treatment of atrial fibrillation.

Rhythm control in atrial fibrillation (AF) can be achieved using pharmacological therapy. Amiodarone is the most efficacious anti-arrhythmic agent; however, its use is limited due to an unfavourable safety profile, including pro-arrhythmia, thyroid, liver, skin and pulmonary complications. Dronedarone, which is structurally similar to amiodarone, was developed to try and achieve a favourable balance of efficacy and risk. Dronedarone has been evaluated in several large clinical trials, which have shown reduced mortality and hospitalization rates in patients with non-permanent AF. In patients with permanent AF and/or heart failure, dronedarone has been shown to cause increased mortality and morbidity and should not be used in these groups. Compared with amiodarone, dronedarone has fewer toxic effects (thyroid, skin, pulmonary) and, although less efficacious, may be used as first-line therapy for maintenance of sinus rhythm in patients with non-permanent AF. Clinicians must be vigilant in monitoring their patients to ensure they do not develop permanent AF or heart failure.

Cost-effectiveness analysis of dronedarone versus other anti-arrhythmic drugs for the treatment of atrial fibrillation--results for Canada, Italy, Sweden and Switzerland.

The ATHENA clinical trial enrolled 4,628 patients in 37 countries and evaluated the efficacy of dronedarone 400 mg twice daily versus placebo for the prevention of cardiovascular hospitalisation or death from any cause in patients with paroxysmal or persistent atrial fibrillation or atrial flutter. The trial showed a statistically significant 24% reduction in the primary endpoint cardiovascular hospitalisations or all-cause death. In the current paper, parameters that drive the cost-effectiveness of dronedarone on top of standard therapy versus likely comparators, i.e. amiodarone, sotalol and flecainide, were investigated by means of a health economic model based on the ATHENA clinical trial. Dronedarone is cost-effective, and ICERs are low versus amiodarone with €5,340; €4,620; €3,850 and €5,630 per QALY gained for Canada, Italy, Sweden and Switzerland, respectively. The most significant driving factor for the cost-effectiveness of dronedarone is the increased survival rate for patients on dronedarone.

Trends in antiarrhythmic drug use after marketing authorization of dronedarone: comparison between Emilia Romagna (Italy) and Sweden.

PURPOSE: Our aim was to evaluate whether dronedarone authorization impacts antiarrhythmic drug prescribing in Sweden and Emilia Romagna (Italy). METHODS: Prescriptions of classes I and III antiarrhythmics, expressed as defined daily doses per thousand inhabitants per day (DDD/TID) were monthly using information collected from pharmacy-reimbursed databases. Interrupted time series analysis was applied to compare prescription data over the 2009-2011 period. RESULTS: In Emilia Romagna, the overall consumption of antiarrhythmics was six times as high as in Sweden (7.6 vs. 1.2 DDD/TID). In the first year on the market, dronedarone represented 1.0 % in Italy and 10.7 % in Sweden of the overall antiarrhythmic prescriptions. In Sweden, dronedarone authorization generated an increase in the prescription trend of antiarrhythmics (trend change +0.02; p < 0.001) without variation in amiodarone use In Emilia Romagna, dronedarone marketing did not influence the prescription pattern of either overall antiarrhythmics or amiodarone. CONCLUSIONS: Emilia Romagna and Sweden substantially differ in terms of overall antiarrhythmic use. Although clinical guidelines place dronedarone among first-choice treatments for atrial fibrillation, amiodarone prescribing was not affected in either country by the entry of dronedarone, probably due to a cautious approach by clinicians in line with regulatory recommendations and safety warnings.

Cost-effectiveness of dronedarone in atrial fibrillation: results for Canada, Italy, Sweden, and Switzerland.

BACKGROUND: Dronedarone is a therapy for the treatment of patients with paroxysmal and persistent atrial fibrillation or atrial flutter. According to results in the ATHENA trial, dronedarone on top of standard of care (SOC) decreases the risk of cardiovascular hospitalizations or death by 24% compared with SOC alone. OBJECTIVES: A patient-level health economic model was developed to evaluate the cost-effectiveness of dronedarone on top of SOC versus SOC alone. METHODS: The risk of experiencing stroke, congestive heart failure, acute coronary syndromes, treatment discontinuation, and death was modeled by separate health states, whereas adverse events were included as 1-time cost and utility decrements. State transition probabilities were primarily deduced from the patient-level data from ATHENA using survival analysis. Four sets of analyses were performed to reflect costs and treatment effects in Canada, Italy, Sweden, and Switzerland. Cost-effectiveness analysis was also conducted in a newly defined patient population identified by the European Medicines Agency (EMA) to avoid the use of dronedarone in permanent AF patients resembling those in the PALLAS study. RESULTS: The predicted survival time was, for the Canadian cohort, extended from 10.11 to 10.24 years when dronedarone was added to SOC. Similar results were found for the other countries, resulting in incremental cost-effectiveness ratios (ICERs) of €5828, €5873, €14,970, and €8554 per QALYs for Canada, Italy, Sweden, and, Switzerland, respectively. These results are all well below current established cost-effectiveness thresholds. In the EMA-restricted population, all patients were predicted to live longer, and the ICER increased but remained within established thresholds, with an average cost per QALY gained of €15,900. CONCLUSIONS: Dronedarone on top of SOC appears to be a cost-effective treatment for atrial fibrillation compared with SOC alone. Despite the differences in the local settings considered, the results were consistent among all the countries included in the study. ClinicalTrials.gov identifier: NCT00174785.

Dronedarone for the treatment of atrial fibrillation: a NICE single technology appraisal.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of dronedarone (Multaq®, Sanofi-Aventis Limited, UK) to submit evidence on the clinical and cost effectiveness of the anti-arrhythmic drug (AAD) for the treatment of atrial fibrillation (AF) and atrial flutter, as part of the Institute's single technology appraisal (STA) process. The Centre for Reviews and Dissemination and the Centre for Health Economics, both at the University of York, were commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE's subsequent decisions regarding the use of dronedarone within the UK NHS. The ERG review comprised a critique of the submitted evidence on the clinical effectiveness and cost effectiveness of dronedarone. The ERG examined the search strategy used to obtain relevant evidence, the selection of studies included in the assessment, outcome measures chosen and statistical methods employed. The ERG also validated the manufacturer's decision analytic model and used it to explore the robustness of the cost-effectiveness results to key assumptions. The main clinical effectiveness evidence supporting the use of dronedarone as a treatment for AF came from four randomized controlled trials. These trials were compared with a broader set of trials examining the effectiveness of other AADs for AF: amiodarone, sotalol and class 1c agents (flecainide and propafenone). The evidence suggested that all AADs decreased the recurrence of AF but dronedarone had the smallest effect. A mixed treatment comparison analysis of the trials showed that dronedarone was associated with a lower risk of all-cause mortality than other AADs, but this was highly uncertain. There was limited evidence to assess the effect of dronedarone on stroke, and no statistically significant differences between dronedarone and other AADs were found for treatment discontinuation. From the evidence presented by the manufacturer, dronedarone appeared highly cost effective in each of the population groups examined compared with using standard baseline therapy alone as first-line treatment, or compared with sotalol or amiodarone as first-line AAD, with incremental cost-effectiveness ratios (ICERs) well below £20,000 per QALY gained. The ICER for dronedarone relative to class 1c agents was around £19,000 per QALY. Although the evidence presented by the manufacturer indicated that dronedarone was cost effective, the estimates of treatment effect relative to other AADs and safety in the longer term were highly uncertain. The NICE Appraisal Committee in its preliminary guidance did not recommend the use of dronedarone for AF. However, following the response from a large number of consultees and commentators, NICE revised its preliminary guidance to allow the use of the drug in a specific subgroup of AF patients with additional cardiovascular risk factors.

Evaluation of dronedarone use in the US patient population between 2009 and 2010: a descriptive study using a claims database.

BACKGROUND: The utilization pattern of dronedarone was unknown, especially regarding prescribers' compliance with the product's prescribing information (PI) following its availability and the implementation of the Food and Drug Administration-approved risk evaluation and mitigation strategy for the drug in the United States. OBJECTIVE: This study was designed to evaluate the dronedarone prescribers' adherence to PI regarding the following contraindications: (1) patients with heart failure (HF) with a recent decompensation requiring hospitalization or referral to a specialist, (2) concomitant use of potent CYP3A4 inhibitors, and (3) concomitant use of QT-prolonging drugs. METHODS: Patients prescribed dronedarone between July 2009 and August 2010 were identified through LabRx. The following rates surrounding dronedarone use were examined: (1) atrial fibrillation or atrial flutter in the past year, (2) worsening or hospitalization for HF within the month before prescription, and (3) concomitant prescription of potent CYP3A4 inhibitors and concomitant prescription of QT-prolonging drugs within the following month. RESULTS: A total of 4595 dronedarone prescriptions were filled by 1820 patients. More than 94% of the participants had ≥1 diagnosis of atrial fibrillation or atrial flutter in the previous year. Worsening of or hospitalization for HF was found in 61 (3.4%) patients within the month before receiving dronedarone, including 18 patients with HF as the primary cause for hospitalization. Potent CYP3A4 inhibitors were prescribed to 10 (0.6%) patients within a month following dronedarone initiation, 6 of whom received them for topical use only. QT-prolonging drugs were prescribed to 67 (3.7%) patients within a month following dronedarone initiation, among which >90% were other antiarrhythmics. CONCLUSIONS: Dronedarone was used mostly in compliance with PI and risk evaluation and mitigation strategy in the studied population. In the LabRx database, dronedarone was commonly dispensed to patients with cardiovascular risk factors and rarely dispensed to patients with contraindications such as worsening HF or hospitalization for HF or with concomitant prescriptions of potent CYP3A4 inhibitors, QT-prolonging drugs, or both.

Dronedarone for atrial fibrillation: How does it compare with amiodarone?

Dronedarone (Multaq), an analogue of amiodarone (Cordarone), was designed to cause fewer adverse effects than the parent compound. Studies have indeed shown dronedarone to be safer than amiodarone, but less effective. Its official indication is to reduce the risk of hospitalization in patients with paroxysmal or persistent atrial fibrillation or atrial flutter and other cardiovascular risk factors, reflecting the parameters of its effectiveness in clinical trials.

Dronedarone for the treatment of atrial fibrillation and atrial flutter.

This paper presents a summary of the evidence review group (ERG) report on the clinical effectiveness and cost-effectiveness of dronedarone for the treatment of atrial fibrillation (AF) or atrial flutter based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The population considered in the submission were adult clinically stable patients with a recent history of or current non-permanent AF. Comparators were the current available anti-arrhythmic drugs: class 1c agents (flecainide and propafenone), sotalol and amiodarone. Outcomes were AF recurrence, all-cause mortality, stroke, treatment discontinuations (due to any cause or due to adverse events) and serious adverse events. The main evidence came from four phase III randomised controlled trials, direct and indirect meta-analyses from a systematic review, and a synthesis of the direct and indirect evidence using a mixed-treatment comparison. Overall, the results from the different synthesis approaches showed that the odds of AF recurrence appeared statistically significantly lower with dronedarone and other anti-arrhythmic drugs than with non-active control, and that the odds of AF recurrence are statistically significantly higher for dronedarone than for amiodarone. However, the results for outcomes of all-cause mortality, stroke and treatment discontinuations and serious adverse events were all uncertain. A discrete event simulation model was used to evaluate dronedarone versus antiarrhythmic drugs and standard therapy alone. The incremental cost-effectiveness ratio of dronedarone was relatively robust and less than 20,000 pounds per quality-adjusted life-year. Exploratory work undertaken by the ERG identified that the main drivers of cost-effectiveness were the benefits assigned to dronedarone for all-cause mortality and stroke. Dronedarone is not cost-effective relative to its comparators when the only effect of treatment is a reduction in AF recurrences. In conclusion, uncertainties remain in the clinical effectiveness and cost-effectiveness of dronedarone. In particular, the clinical evidence for the major drivers of cost-effectiveness (all-cause mortality and stroke), and consequently the additional benefits attributed in the economic model to dronedarone compared to other anti-arrhythmic drugs are highly uncertain. The final guidance, issued by NICE on 25 August 2010, states that: Dronedarone is recommended as an option for the treatment of non-permanent atrial fibrillation only in people: whose atrial fibrillation is not controlled by first-line therapy (usually including beta-blockers), that is, as a second-line treatment option, and who have at least one of the following cardiovascular risk factors: - hypertension requiring drugs of at least two different classes, diabetes mellitus, previous transient ischaemic attack, stroke or systemic embolism, left atrial diameter of 50 mm or greater, left ventricular ejection fraction less than 40% (noting that the summary of product characteristics [SPC] does not recommend dronedarone for people with left ventricular ejection fraction less than 35% because of limited experience of using it in this group) or age 70 years or older, and who do not have unstable New York Heart Association (NYHA) class III or IV heart failure. Furthermore, 'People who do not meet the criteria above who are currently receiving dronedarone should have the option to continue treatment until they and their clinicians consider it appropriate to stop'.

Cost burden of cardiovascular hospitalization and mortality in ATHENA-like patients with atrial fibrillation/atrial flutter in the United States.

BACKGROUND: The ATHENA trial (A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter) demonstrated that dronedarone reduced the risk of cardiovascular (CV) hospitalization/death by 24% (P < 0.001) in patients with atrial fibrillation (AF) and atrial flutter (AFL). HYPOTHESIS: In order to estimate the cost savings associated with dronedarone use, we estimated the costs associated with CV hospitalizations and inpatient mortality in a large cohort of ATHENA-like patients. METHODS: In this retrospective analysis, we evaluated the cost of CV hospitalization/mortality in real-world ATHENA-like patients without heart failure and with employer-sponsored Medicare supplemental insurance in the United States. Patients similar to those in ATHENA (age > or = 70 years with AF/AFL and > or = 1 stroke risk factor, without heart failure) who were hospitalized between January 2, 2005, and January 1, 2007, were identified from the MarketScan databases from Thomson Reuters. Health care costs were evaluated during the 12 months following the index hospitalization. RESULTS: The analysis included 10 200 ATHENA-like patients. Hospitalization for CV causes occurred in 53.9% of patients, with a total of 6700 CV hospitalizations for fatal/nonfatal causes. The most common nonfatal causes of CV hospitalizations were AF/other supraventricular rhythm disorders (20.2% of all CV hospitalizations), congestive heart failure (CHF; 14.3%), and transient ischemic attack (TIA)/stroke (10.7%). Mean costs per CV hospitalization for nonfatal causes were $10,908. Inpatient deaths from CV causes occurred in 264 (2.6%) patients; the most common causes of CV inpatient death were intracranial/gastrointestinal hemorrhage (24.2% of CV deaths), TIA/stroke (17.0%), and CHF (15.9%). Mean hospitalization costs per CV inpatient death were $18,565. CONCLUSIONS: Health care costs associated with CV hospitalizations and inpatient deaths among ATHENA-like patients in the US are high. Novel antiarrhythmic therapies such as dronedarone, with the potential to reduce CV hospitalizations/mortality in similar patients, could decrease health care costs if adopted in clinical practice.

Assessment of the inactivation potential of desethylamiodarone on human CYP1A1.

Desethylamiodarone was reported to inactivate human CYP1A1. To assess this, two protocols were implemented employing dilution and non-dilution of the preincubation mixture. Inactivation studies performed with diluted preincubation mixtures showed no inactivation of CYP1A1 by desethylamiodarone. However there was evidence for a mixed competitive inhibition (competitive and the uncompetitive inhibition constants of 2.1 microM and 9.6 microM, respectively) of CYP1A1 by desethylamiodarone. NADPH addition and/or replenishment were found to be important factors in determining the control activity in inactivation studies.

A preliminary assessment of the effects of ATI-2042 in subjects with paroxysmal atrial fibrillation using implanted pacemaker methodology.

AIMS: ATI-2042 (budiodarone) is a chemical analogue of amiodarone with a half life of 7 h. It is electrophysiologically similar to amiodarone, but may not have metabolic and interaction side effects. The sophisticated electrocardiograph logs of advanced DDDRP pacemakers were used to monitor the efficacy of ATI-2042. The aim of this study was to determine the preliminary efficacy and safety of ATI-2042 in patients with paroxsymal atrial fibrillation (PAF) and pacemakers. METHODS AND RESULTS: Six women with AF burden (AFB) between 1 and 50% underwent six sequential 2-week study periods. Patients received 200 mg bid of ATI-2042 during Period 2 (p2), 400 mg bid during p3, 600 mg bid during p4, 800 mg bid during p5, and no drug during baseline and washout (p1 and p6). Pacemaker data for the primary outcome measure AFB were downloaded during each period. Mean AFB decreased between baseline and all doses: AFB at baseline (SD) was 20.3 +/- 14.6% and mean AFB at 200 mg bid was 5.2 +/- 4.2%, at 400 mg bid 5.2 +/- 5.2%, at 600 mg bid 2.8 +/- 3.4%, and at 800 mg bid 1.5 +/- 0.5%. The mean reductions in AFB at all doses of ATI-2042 were statistically significant (P < 0.005). Atrial fibrillation burden increased in washout. Atrial fibrillation episodes tended to increase with ATI-2042, but this was offset by substantial decreases in episode duration. ATI-2042 was generally well tolerated. CONCLUSION: ATI-2042 effectively reduced AFB over all doses studied by reducing mean episode duration. A large-scale study will be required to confirm this effect.

A benefit-risk assessment of class III antiarrhythmic agents.

The prevalence of arrhythmia in the population is increasing as more people survive for longer with cardiovascular disease. It was once thought that antiarrhythmic therapy could save life, however, it is now evident that antiarrhythmic therapy should be administrated with the purpose of symptomatic relief. Since many patients experience a decrease in physical performance as well as a diminished quality of life during arrhythmia there is still a need for antiarrhythmic drug therapy. The development of new antiarrhythmic agents has changed the focus from class I to class III agents since it became evident that with class I drug therapy the prevalence of mortality is considerably higher. This review focuses on the benefits and risks of known and newer class III antiarrhythmic agents. The benefits discussed include the ability to maintain sinus rhythm in persistent atrial fibrillation patients, and reducing the need for implantable cardioverter defibrillator shock/antitachycardia therapy, since no class III antiarrhythmic agents have proven survival benefit. The risks discussed mainly focus on pro-arrhythmia as torsade de pointes ventricular tachycardia.