Dofetilide: a class III anti-arrhythmic drug for the treatment of atrial fibrillation

Dofetilide is a class III anti-arrhythmic drug that has been approved for the treatment of atrial fibrillation. Two clinical studies, which enrolled 996 patients, demonstrated pharmacological conversion to sinus rhythm to occur in 30% of patients. Following pharmacological or electrical conversion, median time to relapse exceeded one year. Two large clinical studies that enrolled 3028 patients have been performed in high-risk patients with severe heart failure and large myocardial infarctions. The outcomes of these studies were neutral with respect to survival and demonstrated the safety of dofetilide. After pharmacological or electrical conversion of atrial fibrillation to sinus rhythm in these studies, the probability of remaining in sinus rhythm during the following year was 75%. Dofetilide has a single significant side effect: risk of developing torsade de pointes ventricular tachycardia. Therefore, dosage must be carefully adjusted to the length of QTc interval, calculated creatinine clearance and the presence of heart failure or recent infarction. In addition, treatment must be initiated in hospital with three days of continuous telemetry. Dofetilide can be co-administered with digoxin and beta-blockers. Other anti-arrhythmic drugs, as well as drugs that interfere with the renal elimination or the metabolism of dofetilide, must be avoided. Dofetilide is an option when persistent atrial fibrillation is a clinical problem. In the setting of severe heart failure and large myocardial infarctions, only amiodarone and dofetilide have proven safety and dofetilide is a strong candidate for first choice treatment when the aim is to achieve sinus rhythm.     

Azimilide dihydrochloride: a new class III anti-arrhythmic agent

Azimilide dihydrochloride (Stedicor?) is a new class III anti-arrhythmic agent that is being developed by Proctor & Gamble to treat supraventricular and ventricular arrhythmias. Development of this agent is being undertaken due to the high prevalence of atrial fibrillation and the lack of satisfactory therapy for this arrhythmia, along with the desire to develop therapy to reduce the risk of life-threatening ventricular arrhythmias in patients following myocardial infarction. The mechanism of action of azimilide is to block both the slowly conducting (I_Ks) and rapidly conducting (I_Kr) rectifier potassium currents in cardiac cells. This differs from other class III agents that block I_Kr exclusively or in combination with sodium, calcium, or transient outward (I_to) potassium current channels. Azimilide is distinguished by a relative lack of reverse use-dependence, excellent oral absorption, no need for dose titration, an option for out-patient initiation, no need for adjustment associated with renal or liver failure and a lack of interaction with warfarin or digoxin. It carries some risk of torsade de pointes and rarely, neutropoenia. Azimilide has shown dose-related efficacy in prolonging the time to recurrence of atrial fibrillation. A large trial examining the impact of azimilide on mortality in high-risk patients following myocardial infarction has completed enrolment and should yield data in the next couple of years and further studies are planned. Even if this trial fails to show a survival benefit, a neutral effect on mortality will make the agent attractive for atrial arrhythmias.     

非瓣膜性房颤的规范化药物治疗

房颤(AF)是最常见的可持续的心律失常,目前药物治疗仍是其基础治疗,而其中抗凝药物是各种治疗的基础和核心。国内关于AF的规范化药物治疗与国际指南要求尚有一定差距。本文综述AF的规范化药物治疗。     

心房颤动的药物治疗进展

第Ⅲ类抗心律失常药物是通过延长心房组织的有效不应期 ,使心房颤动转律的最有效药物。本文对多非利特、索他洛尔、伊布利特等新的治疗心房颤动的药物的药理作用、临床研究情况作一介绍。     

房颤的药物治疗进展

房颤（AF）的治疗策略包括节律控制和控制心室率同时联合抗凝治疗。药物治疗经济且效果肯定,仍是现阶段AF治疗的主要方案。本文综述近年AF药物治疗的主要进展。     

Pharmacokinetic drug evaluation of bucindolol for the treatment of atrial fibrillation in heart failure patients

Introduction: Atrial fibrillation (AF) and heart failure (HF) often coexist. When AF and HF are both present, they are associated with negative outcomes, increased hospitalizations and mortality. As β-blockade is effective inF and may be useful in presence of AF, bucindolol, a non-selective β-blocker with α-1 vasodilatory effect, may be used.

Area covered: This review evaluates the efficacy and safety of bucindolol in HF patients with AF. The largest amount of data comes from BEST trial which evaluated the efficacy of bucindolol in HF patients. Since bucindolol’s effects are genetically modulated by β1 and α2c-adrenergic receptor polymorphisms BEST genetic substudy arose.

Expert opinion: In the BEST Trial, bucindolol demonstrated efficacy in HF patients showing a 74% reduction in new-onset atrial fibrillation events particularly in β1 389 Arg/Arg homozygous. GENETIC-AF study was designed to determine whether bucindolol therapy is superior to metoprolol in preventing recurrent AF in a genetically targeted population of HF patients. Furthermore, this drug is safe, but presents the same side effects as all β-blockers and has showed no clear benefits in African-Americans and in class IV NYHA patients. Further studies are needed to confirm and validate the role of bucindolol and its economic implications.     

Ranolazine for the treatment of atrial fibrillation

Introduction: Atrial fibrillation (AF) is a frequent occurrence with advancing age and is associated with increased morbidity and mortality. Unfortunately, the currently available AF therapies have a great deal of side effects.

Areas covered: In this review, the authors discuss the evidence upon which the use of Ranolazine as an anti-arrhythmic drug is based. Specifically, the authors review the Phase I–III trials that studied ranolazine as potential treatment for AF. They also discuss the efficacy, safety, tolerability and side effects and compare the MERLIN TIMI 36, HARMONY and ROLE trials.

Expert opinion: Although ranolazine is considered an anti-angina drug, it may also be, according to the available data, used in patients with AF. Ranolazine has anti-AF efficacy, both alone or in combination with other drugs such as amiodarone and dronedarone. Indeed, its efficacy has been demonstrated in various settings such as the termination of paroxysmal AF, the facilitation of AF electrical cardioversion, and postoperative AF prevention. Although there is a great deal of evidence from pioneering experimental studies, the clinical evidence of the AF-suppressing effect of ranolazine is derived from studies with small sample size or from secondary analyses. A better understanding of the role of ranolazine as an anti-AF drug will be obtained through larger, prospective, placebo-controlled clinical trials in different populations.     

Dofetilide: a new drug to control cardiac arrhythmia

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Mortality, and especially morbidity caused by AF, are major and growing health problems in the western world. AF is strongly associated with arterial hypertension, congestive heart failure, valvular heart disease, ischaemic heart disease, and with prevalence increasing with age. A variety of drugs have been used to terminate or prevent AF but, as many antiarrhythmic agents have the potential life-threatening pro-arrhythmia, safety problems remain. Dofetilide (Tikosyn^®, Pfizer), a new Vaughan Williams class III antiarrhythmic agent, has been developed and approved for the treatment of AF. In contrast to most antiarrhythmic agents, the development programme included two safety studies in high-risk patients. Dofetilide is effective and safe when an elaborate procedure for dosing is implemented. Along with amiodarone and β-blockers, dofetilide is the only antiarrhythmic drug, which is recommended by guidelines for the treatment of AF in a wide range of patients.     

静脉注射胺碘酮治疗心力衰竭伴快速性心房颤动的疗效观察

目的观察心力衰竭伴快速性心房颤动患者静脉注射胺碘酮转复或控制心室率治疗心力衰竭的疗效,包括心房颤动的转复率、转复时间、心室率的控制、不良反应及安全性。方法心力衰竭伴快速性心房颤动患者48例,胺碘酮150mg加50g.L-1葡萄糖注射液20mL静脉注射,患者30min后房颤未转复即再应用1次,继以0.5～1mg.min-1维持静滴48h,观察用药后1,2,6,12,24和48h转复率、心室率、心力衰竭症状的缓解及不良反应。结果胺碘酮可快速有效使快速房颤转复为窦性心律,控制心室率,纠正心力衰竭,且无严重不良反应发生。结论心力衰竭伴快速性心房纤颤患者静脉注射胺碘酮治疗安全有效,尤其适用于合并器质性心脏病患者。     

决奈达隆：治疗房颤的新型抗心律失常药

决奈达隆为不含碘的苯并呋喃类衍生物，其结构和特征与胺碘酮类似，但减少了碘源性的器官毒性，目前已经完成动物实验和部分临床试验。研究结果表明，在房颤患者中应用决奈达隆800mg／d安全而有效，不良反应少。     

Drug Evaluation Cardiovascular & Renal: Ibutilide fumarate: a new class III agent for termination of atrial fibrillation and atrial flutter

Ibutilide fumarate (Corver?, Pharmacia & Upjohn Company, Kalamazoo, MI, USA) is a novel class III methanesulfonamide antiarrhythmic agent clinically indicated for the rapid termination of atrial fibrillation and atrial flutter. This agent prolongs atrial and ventricular refractoriness and action potential duration. Ibutilide's mechanism of action is controversial, but may include potentiation of a slow inward Na+ current and inhibition of an outward K+ current (I_kr). Activation of an outward K+ current at high concentrations has also been reported. Ibutilide has no significant effects on cardiovascular autonomic function, myocardial contractility or systemic haemodynamics and has minimal effects on myocardial conduction velocity except at high concentrations. In large, randomised, placebo-controlled clinical trials, ibutilide produces arrhythmia termination in 29 - 31% of patients with atrial fibrillation and 36 - 63% of patients with atrial flutter. Conversion appears more likely for arrhythmias of shorter duration. Preliminary data suggest that ibutilide may prevent inducible ventricular tachycardia in 44% of patients, and, in animal models, ibutilide appears to reduce the energy requirements for ventricular defibrillation. In clinical studies, ibutilide is associated with sustained polymorphic ventricular tachycardia in 1.7% of patients. Heart block (1.5%), hypotension (2.0%), and bradycardia (1.2%) are uncommon.     

静脉滴注胺碘酮治疗急性心肌梗死伴发房颤的临床疗效

目的探讨静脉滴注胺碘酮治疗急性心肌梗死并新发房颤的临床疗效及其安全性。方法60例急性心肌梗死伴新发快速房颤,静脉应用胺碘酮,先静脉推注负荷量后,继以静脉滴注维持,观察房颤转复、心室率控制、血压及Q-T间期变化情况及药物不良反应。结果60例患者用药后0．25、1、2、24h的心室率分别是（136．2±19．4）、（119．4±15．9）、（101．5±14．1）、（82．7±20．8）次·min-1,较用药前心室率（140．3±17．5）次·min-1明显下降（P〈0．01）;44例（占73．3％）转复窦性心律;血压、啦T间期在用药前后差异无统计学意义（P〉0．05）。本组患者中1例出现窦性心动过缓;1例出现长R-R间期,经停药后恢复正常;1例用药期间发生静脉炎。结论静脉滴注胺碘酮治疗急性心肌梗死并新发快速房颤是安全及有效的。     

叶酸对急性心肌梗死合并心房颤动患者的疗效观察

目的 探讨叶酸对急性心肌梗死（acute myocardial infarction,AMI）合并阵发性心房颤动（atrial fibrillation,AF）患者的临床疗效.方法 AMI合并AF 60例,随机分为对照组和治疗组,各30例,对照组常规治疗,治疗组在对照组基础上口服叶酸（10 mg/次,3次/d）.结果 治疗组5 d转复率高于对照组（93.33% VS 66.67%）,差异有统计学意义（P＜0.05）;住院天数低于对照组[（10.97±2.31）d VS（16.21±3.40）d],差异有统计学意义（P＜0.05）;阵发性房颤复发率和转为持续性或永久性房颤的发生率低于对照组（6.67% VS 30.00%）,差异有统计学意义（P＜0.05）;缺血事件发生率低于对照组（16.67% VS 43.33%）,差异有统计学意义（P＜0.05）.结论 叶酸治疗AMI合并AF,既能够提高转复率,减少住院时间,又能降低房颤的复发与维持疗效,降低缺血事件的发生率.     

治疗心房纤颤和扑动的新药决奈达隆

决奈达隆为胺碘酮的类似物,结构中不含碘,减少了碘所致的器官毒性,为新型的抗心律失常药。2009年7月1日获FDA批准,用于治疗心房纤颤或心房扑动的心脏病患者。本文通过对决奈达隆进行文献检索,对其药理作用、药动学、临床评价、药物相互作用、不良反应等方面进行了综述。     

他汀类药物对新发房颤的治疗效果与CHADS2评分的关系分析

目的 探讨CHADS2评分与新发房颤是否存在关系,及CHADS2评分是否可以运用到他汀类药物对急性心肌梗死患者心律失常的预防.方法 选取213例急性心肌梗死患者,根据CHADS2评分分为3组,其中A组61例患者的CHADS2评分为0分,B组83例患者的CHADS2评分为1-2分,C组69例患者的CHADS2评分为3-6分.对所有患者均使用他汀类和非他汀类药物治疗,观察他汀类药物的治疗效果与CHADS2评分之间的关系.结果 CHADS2评分越高的急性心肌梗死患者的新发房颤发病率越高（P＜0.05）;CHADS2评分≤2的急性心肌梗死患者服用他汀类药物后,新发房颤的发病率远低于未服用他汀类药物的患者（P＜0.05）,而CHADS2评分≥3的患者中,他汀类药物则不存在此效果（P ＞0.05）;CHADS2评分≤2的急性心肌梗死患者服用他汀类药物后,C反应蛋白的水平远低于未服用他汀类药物的患者（P＜0.05）,而CHADS2评分≥3的患者中,他汀类药物则不存在此效果（P＞0.05）.结论 CHADS2评分能够很好地预测新发房颤的发病率,并且其还能很好地评价他汀类药物对急性心肌梗死心律失常患者的预防效果.     

治疗心房颤动新药决奈达隆

决奈达隆为新型苯并呋喃衍生物,结构与胺碘酮相似。决奈达隆具有多通道阻滞的电生理特性。Ⅲ期临床试验证实,决奈达隆能有效减少心房颤动(Af)或心房扑动(AF)的复发,减慢Af/AF的心室率,减低心血管发病率及病死率。但在一项纳入重度心力衰竭(HF)及左室功能障碍患者的研究中,决奈达隆使病死率升高。决奈达隆耐受性好,不明显延长QTc间期,无显著肺、甲状腺、肝、眼和神经系统毒性,最常见的不良反应为腹泻、恶心及呕吐。决奈达隆可选择性用于Af/AF的治疗。但在预防Af复发时,决奈达隆疗效逊于胺碘酮,尚需更多有关决奈达隆与胺碘酮疗效的对比研究以确立决奈达隆在治疗中的地位。     

慢性心衰患者发生房颤的多因素分析

目的通过回顾性分析慢性心衰患者的临床资料,对慢性心衰患者发生房颤的因素进行分析。方法选择2009年1月至2011年1月期间该院心脏科收治的慢性心力衰竭（NYHAII-IV）患者330例,根据患者是否发生心房颤动（AF）将其分为AF组与非AF组两组,并对两组患者的临床资料进行统计分析。结果 330慢性心力衰竭患者中共发生房颤85例（25.76%）为AF组,其余245例未发生房颤者则为非AF组。单因素COX回归分析表明患者重度心衰（III＋IV级别）、年龄、糖尿病、左室肥厚、左房直径、尿素氮、血肌酐、血尿酸、安体舒通为房颤发生的危险因素。而ACEI、洋地黄、血钠、血氯为房颤发生的保护因素。Logistic回归分析表明ACEI为心力衰竭患者初发AF的独立保护因素,重度心衰、左心室肥厚左心房直径则为AF发生的危险因素。结论重度心衰、左心室肥厚左心房直径则为AF发生的危险因素;ACEI为心力衰竭患者初发AF的独立保护因素,其能降低AF的发生。     

Drug therapy for atrial fibrillation

Although the maintenance of sinus rhythm would be the ideal scenario for patients with atrial fibrillation (AF), recent randomised trials have questioned the value of this approach. A careful interpretation of their results showed the limited efficacy of currently available antiarrhythmic drugs in maintaining sinus rhythm, as well as their potentially serious side effects. Therefore, it is imperative to develop safer and more effective drugs for AF. Based on our improved understanding of the pathophysiology of AF and the mechanism of action of antiarrhythmic drugs, significant efforts are being made to develop new antiarrhythmic agents that would prevent electrophysiological remodelling, would be selective for the atria and, therefore, would not prolong ventricular repolarisation, thus lacking any proarrhythmic effect.     

Emerging pharmacotherapies for the treatment of atrial fibrillation

Introduction: The main aim of current research on the field of atrial fibrillation (AF) treatment is to find new antiarrhythmic drugs with less side effects.

Areas covered: Dronedarone and vernakalant showed promising result in term of efficacy and safety in selected patients. Ranolazine and colchicine are obtaining a role as a potential antiarrhythmic drug. Ivabradine is used in experimental studies for the rate control of AF. Moreover, new compounds (vanoxerine, moxonidine, budiodarone) are still under investigation. Monoclonal antibodies or selective antagonist of potassium channel are under investigation for long term maintenance of sinus rhythm. Clinical evidence and new pharmacological investigation on new drugs will be accurately reviewed in this article.

Expert opinion: Dronedarone use is not recommended in patients with symptomatic heart failure (HF), NYHA class III-IV, depressed ventricular function and permanent AF, especially in patients assuming a concomitant therapy with digoxin. Vernakalant had superior efficacy than amiodarone, flecainide and propafenone in single studies and similar efficacy to direct current cardioversion. Several of the developing drugs examined in this paper show an interesting potential, in particular the research on selective ionic channel inhibition and on compounds which reduce the inflammation state, especially after ablation or surgery.     

Dronedarone or amiodarone for rhythm control for atrial fibrillation: implications from the DIONYSOS study

Management of persistent AF involves rhythm or rate control strategies and thromboprophylaxis for cardioembolic events. Although amiodarone appears to be more effective than other current antiarrhythmics for a rhythm control approach in AF patients, many side effects limit its long-term use. Dronedarone is a new antiarrhythmic drug that may offer advantages for rhythm control, given its relative safety (although not in patients with decompensated heart failure), efficacy and tolerability. With regard to the latter, dronedarone has fewer adverse effects and is better tolerated than amiodarone. Nonetheless, in one head-to-head comparison of dronedarone and amiodarone, the latter drug was superior to dronedarone for maintenance of sinus rhythm post cardioversion, but dronedarone was safer and better tolerated, with useful benefit to decrease hospitalizations and thus healthcare costs. This provides clinicians (and patients) with a new option when choosing antiarrhythmic therapy.