Management of atrial fibrillation, what to know on old and new antiarrhythmics

The management of atrial fibrillation, despite the development of ablative techniques, is mainly a pharmacological issue. For the last 25 years, no new oral antiarrhythmic drug has been launched in France. Class I antiarrhythmic drugs are efficient and safe if they are prescribed taking into account their contra-indications, but their therapeutic index is narrow. Class III antiarrhythmic drugs have limits, mainly due to the repolarization prolongation they induce and the risk of torsades de pointes. The mode of action of new antiarrhythmic drugs are based on an IKur blocking approach or on a multichannel blockade approach like that of dronedarone which is the only antiarrhythmic drug, to date, to have demonstrated an interest in terms of morbi-mortality in atrial fibrillation.     

Chronic ischemic heart disease: from concept to fact

The development and refinement of techniques relating the determinants of increased myocardial oxygen demand to primary or secondary manifestations of inadequate myocardial blood flow made possible certain major advances in the management of chronic ischemic heart disease over the past 25 years. These include objective and quantitative evaluation of the anatomic basis and the functional consequences of ischemic heart disease, risk stratification for patient subgroups and documentation of the effects of therapy. In addition, studies in which ischemic manifestations were shown to be dissociated from increased myocardial oxygen demand have redirected attention to the supply component of the supply to demand balance for myocardial oxygenation.Diagnostic techniques, management schemata and therapeutic evaluation methods for the electrophysiologic alterations of ischemic heart disease have matured more slowly than those for the ischemic manifestations. While the pathophysiologic concepts underlying knowledge of the ischemic manifestations of coronary artery disease were formulated 25 years ago, in the case of arrhythmias, new concepts needed to be developed to provide the direction for technologic and therapeutic advances. Although the patients at risk for serious arrhythmias and sudden cardiac events are known to be those with severe coronary artery disease, impaired left ventricular function and preexisting electrical instability as manifested by frequent and complex ventricular arrhythmias, the sensitivity and specificity for any single factor as a predictor of risk remain to be established. Similarly, methods to predict efficacy of therapy are still under development. Progress will accelerate when specific factors that predict risk are identified and the methods for measuring those factors are developed and applied to the patient in an organized and systematic manner.The thesis underlying this broad conceptional review is that the fostering of the full-time clinical investigator that occurred during the 1960s and the first half of the 1970s and the consequent systematic development and application of quantitative methods to the study of disease in human beings were major forces for the remarkable progress that has been made in the management of all aspects of cardiovascular disease.     

利用因特网了解抗心律失常药的应用现状

利用因特网了解抗心律失常药的应用现状 ,为临床应用提供有价值的信息。从MEDLINE上检索目前仍在应用的Ⅰ、Ⅱ、Ⅲ、Ⅳ类药物 ,时间限定 10年。比较近 5年和前 5年引用文献数的变化。检索抗心律失常药文献总数6 5 0 9篇 ,名列前 3位的药物依次为胺碘酮 (2 1.41% )、维拉帕米 (12 .39% )与索他洛尔 (9.95 % )。临床试验中抗心律失常药的总文献数 10 2 7篇 ,名列前 3位的药物依次为胺碘酮 (17.2 3% )、索他洛尔 (10 .81% )与普罗帕酮 (10 .71% )。Ⅲ类抗心律失常药的应用日益受到重视。治疗室性心律失常及心房颤动的药物中均以胺碘酮应用最多     

Future of antiarrhythmic drugs

PURPOSE OF REVIEW: This article briefly summarizes the principal mechanisms of action of contemporary antiarrhythmic agents, delineates their limitations in the treatment of cardiac arrhythmias, and discusses why there is a need for new cardiac antiarrhythmic drugs. RECENT FINDINGS: In recent years, the limited efficacy and proarrhythmic potential of classic antiarrhythmic drugs have focused attention on nonpharmacologic approaches to treatment of cardiac arrhythmias. Despite the current success of ablative therapy and implantable defibrillators, the need is still pressing for new antiarrhythmic drugs. Evolving knowledge about the molecular mechanisms of cardiac arrhythmias provides innovative strategies for discovering new cardiac antiarrhythmic drugs. Some of these have already led to the development of new compounds on the verge of clinical use, and others hold great promise for future drug development. SUMMARY: Cardiac arrhythmias are associated with significant morbidity and mortality in developed countries. Antiarrhythmic drug therapy was traditionally the mainstay of arrhythmia treatment; however, the inefficacy of drug treatment and the potential that antiarrhythmic drugs can provoke life-threatening arrhythmias have generated interest in new approaches to antiarrhythmic drug development. Improved understanding of the cellular and molecular basis of cardiac arrhythmias holds the promise of identifying novel approaches for the treatment of cardiac arrhythmias. These approaches may target traditional and newly discovered cardiac ion channels, as well as new molecular and signaling pathways that modulate arrhythmic substrates.     

Possibilities and limitations of treatment for arrhythmia

Antiarrhythmic therapy for tachyarrhythmias is more effective, but at the same time more complicated, than it was a few years ago. This is equally true for the indication of therapy in general, for the decision to apply a particular therapeutic tool, and for the control of antiarrhythmic treatment itself. An effective, long-lasting control of cardiac arrhythmias requires carefully selected therapeutic approaches. Primary treatment aims at the underlying disease. The causal therapy must, of course, be directed to the conditions responsible for the disease, that is, for example, therapy for coronary artery disease, treatment of myocarditis, elimination of glycoside intoxication or electrolyte disturbances, normalization of thyroid dysfunction, or revision of an ineffective pacemaker. The symptomatic therapy for cardiac arrhythmias is subdivided into drug therapy, electro-therapeutic measures (cardiac pacemaker, implantable cardioverter/defibrillator, fulguration) and antiarrhythmic surgery or, in special cases even heart transplantation. In the pharmaceutical sector, progress has been made by introducing new antiarrhythmic substances, such as encainide and flecainide, tocainide, amiodarone, sotalol, and especially by the combination of antiarrhythmic agents. The combination of antiarrhythmic substances allows the use of smaller dosage of one or both of the drugs. Despite potential proarrhythmic effects with combination of antiarrhythmic agents, this risk seems to be lower by using reduced dosages. Thus, the conventional spectrum of antiarrhythmic therapy has to be reconsidered with respect to new approaches in the control of cardiac dysrhythmias.     

New antiarrhythmic agents: amiodarone, aprindine, disopyramide, ethmozin, mexiletine, tocainide, verapamil.

The present status, clinical experience, side effects, clinical pharmacology and electrophysiologic actions of seven new antiarrhythmic agents are reviewed. The drugs selected for comment are amiodarone, aprindine, disopyramide, ethmozin, mexiletine, tocainide and verapamil. Each drug has been shown to have clinical efficacy in suppressing cardiac arrhythmias.     

The role of angiotensin II inhibitors in arterial hypertension: clinical trials and guidelines

Despite many outstanding favorable results obtained over the past 30-40 years in the treatment of hypertension, several goals of antihypertensive therapy remain unmet. One of them concerns the epidemiological evidence that only 25% of treated hypertensive patients have optimal blood pressure control. Clinical use of new antihypertensive drugs is aimed at achieving the above-mentioned goals, and in particular, at providing more effective blood pressure control, greater cardiovascular protection, and better patient compliance to antihypertensive drug treatment. This paper will examine the main clinical features of angiotensin II receptor blockers, highlighting the results of clinical studies performed thus far, and the main goals of ongoing clinical trials with these drugs. Finally, the role of these compounds in the therapeutic approach to the hypertensive state according to the recent guidelines of the World Health Organization/International Society of Hypertension will be outlined.     

心房颤动口服药物治疗的新选择

近年来,尽管导管消融和外科手术在心房颤动(房颤)的治疗中取得了令人瞩目的进展,但并未广泛应用,药物治疗依然处于首要地位。由于传统抗凝药和抗心律失常药的自身局限性,该领域新型药物的开发成为研究热点,而近年来多种新型口服药物的开发研制和临床试验的成功,为房颤的药物治疗带来新的希望。本文对此加以综述。     

Atrial fibrillation

The management of atrial fibrillation has evolved greatly in the past few years, and many areas have had substantial advances or developments. Recognition of the limitations of aspirin and the availability of new oral anticoagulant drugs that overcome the inherent drawbacks associated with warfarin will enable widespread application of effective thromboprophylaxis with oral anticoagulants. The emphasis on stroke risk stratification has shifted towards identification of so-called truly low-risk patients with atrial fibrillation who do not need antithrombotic therapy, whereas oral anticoagulation therapy should be considered in patients with one or more risk factors for stroke. New antiarrhythmic drugs, such as dronedarone and vernakalant, have provided some additional opportunities for rhythm control in atrial fibrillation. However, the management of the disorder is increasingly driven by symptoms. The availability of non-pharmacological approaches, such as ablation, has allowed additional options for the management of atrial fibrillation in patients who are unsuitable for or intolerant of drug approaches.     

Efficacy of antiarrhythmic drugs in patients with arrhythmogenic right ventricular disease. Results in patients with inducible and noninducible ventricular tachycardia.

BACKGROUND. Ventricular tachyarrhythmias are the major clinical manifestation of arrhythmogenic right ventricular disease. Although antiarrhythmic therapy has been widely advocated, there is only limited information available on the efficacy of antiarrhythmic drugs in these patients. METHODS AND RESULTS. The short- and long-term efficacies of various antiarrhythmic agents were retrospectively and prospectively analyzed in 81 patients (mean age, 39 +/- 14 years; range, 16-68 years; 61.7% males) with arrhythmogenic right ventricular disease. In 42 patients with inducible ventricular tachycardia during programmed ventricular stimulation, the following efficacy rates were obtained: class Ia and Ib drugs (n = 18), 5.6%; class Ic drugs (n = 25), 12%; beta-blockers (n = 8), 0%; sotalol (n = 38), 68.4%; amiodarone (n = 13), 15.4%; verapamil (n = 5), 0%; and drug combinations (n = 26), 15.4%. Only one of the 10 patients not responding to sotalol was treated effectively by amiodarone, whereas the remaining nine patients proved to be drug refractory toward all other drugs tested (3.8 +/- 2.3 drugs, including amiodarone in five cases) and underwent nonpharmacological therapy. During a follow-up of 34 +/- 25 months, three of the 31 patients (9.7%) discharged on pharmacological therapy had nonfatal recurrences of ventricular tachycardia after 0.5, 51, and 63 months, respectively. In 39 patients with noninducible ventricular tachycardia during programmed ventricular stimulation, the following efficacy rates were observed: class Ia and Ib drugs (n = 16), 0%; class Ic agents (n = 23), 17.4%; beta-blockers (n = 7), 28.6%; sotalol (n = 35), 82.8%; amiodarone (n = 4), 25%; verapamil (n = 24), 50%; and drug combinations (n = 11), 9.1%. During a follow-up of 14 +/- 13 months, four of 33 patients (12.1%) discharged on antiarrhythmic drugs had nonfatal relapses of their clinical ventricular arrhythmia. CONCLUSIONS. Thus, in arrhythmogenic right ventricular disease, sotalol proved to be highly effective in patients with inducible as well as noninducible ventricular tachycardia. Patients with inducible ventricular tachycardia not responding to sotalol are likely to not respond to other antiarrhythmic drugs and should be considered for nonpharmacological therapy without further drug testing. Amiodarone did not prove to be more effective than sotalol and may not be an alternative because of frequent side effects during long-term therapy, especially in young patients. Verapamil and beta-blockers were effective in a considerable number of patients with noninducible ventricular tachycardia and may be a therapeutic alternative in this subgroup. Class I agents appear to be rarely effective in the treatment of both inducible and noninducible ventricular tachycardia in arrhythmogenic right ventricular disease.     

The patient at risk of sudden death:value of drug therapy]

The evaluation of antiarrhythmic therapy should be based on its effects on total mortality assessed by controlled trials. The author reviews the large trials on antiarrhythmic drugs, during the past ten years, and concludes with the current importance of such therapy. Trials have been conducted in three kinds of high-risk populations: patients with malignant ventricular arrhythmias, survivors of myocardial infarction and patients with congestive heart failure. The results have been disappointing, showing either an increase in mortality with antiarrhythmic drugs (class I, d-sotalol) or a neutral effect (amiodarone). Trials conducted in patients with malignant arrhythmias have shown that the implantable cardioverter-defibrillator was superior to the best available antiarrhythmic therapy. In other high-risk populations, the only drugs that consistently reduced mortality were betablockers, which might have other mechanisms of action besides the antiarrhythmic effect. Amiodarone, the most potent suppressor of ventricular arrhythmias, is indicated in highly symptomatic patients; dl-sotalol is a good alternative to amiodarone. We may conclude from these large trials that study endpoints must be correctly chosen in order to assess the real value of an antiarrhythmic drug. The study population must have a high risk of sudden death and be within an appropriate time window of maximal risk. Antiarrhythmic trials must proceed, learning the lessons from the old studies, trying to test new drugs or new therapeutic strategies, better selecting study populations and new risk markers superior to those currently available.     

Monophasic action potential recordings: evaluation of antiarrhythmic drugs

The use of MAP recording techniques has been said to have bridged the gap between basic in vitro investigation of the transmembrane action potential and observations made in situ from the beating heart. With regard to antiarrhythmic agents, MAP recordings are particularly useful in evaluating drugs which prolong repolarization. The simultaneous measurement of MAP and ERP at the same site permits the comparison of drug effects on repolarization and refractoriness. The ability to safely and reliably record the MAP contributes importantly to the evaluation and classification of antiarrhythmic drug effects in vivo and may ultimately lead to more rational selection of drug therapy for individual patients. Antiarrhythmic drug effects demonstrated with MAP recordings have generally shown good agreement with the Vaughan Williams classification of electrophysiological actions. An important key to drug efficacy may be that some drugs prolong refractoriness beyond their effect on repolarization. Conversely, a potential explanation for proarrhythmia may lie in slowing of conduction without the concomitant protective effect of postrepolarization refractoriness. The phenomenon of use dependence, which has been demonstrated for many drugs, suggests why an agent that prevents induction of arrhythmia during programmed stimulation in the electrophysiology laboratory may not prevent spontaneous arrhythmia initiation at slower heart rates. The paramount task of clinical electrophysiology is the successful treatment of rhythm disturbances. The more detailed and quantitative evaluation of drug effects afforded by MAP recordings may ultimately result in the more effective use of antiarrhythmic drugs in general and to more precise tailoring of therapy for individual patients.     

Long-term pharmacologic management of atrial fibrillation in the elderly

The first decision to be made in treating atrial fibrillation in the elderly is to determine whether to pursue a treatment strategy of rate control or rhythm control. Both strategies require use of anticoagulation therapy with warfarin (target international normalized ratio, 2.5; range 2–3). If a decision is made for rhythm control, the critical therapy is almost always with an antiarrhythmic drug. Before selecting an antiarrhythmic drug for use, it is first necessary to determine the presence or absence of underlying structural heart disease, as that will affect the available options for antiarrhythmic drug use. If there is no underlying structural heart disease, any of the available antiarrhythmic drugs may be used, although a clinically reasoned approach is suggested. If there is underlying structural heart disease, not all antiarrhythmic drugs are appropriate for use. A clinically reasoned approach is suggested in the presence of coronary artery disease, left ventricular dysfunction/congestive heart failure, or hypertension based largely on the risk/benefit profile of the drugs.     

Medical treatment of chronic heart insufficiency

The treatment of chronic heart failure by alteration of systolic function has made remarkable progress over the past ten years; this progress has been linked to the results of large-scale clinical trials involving tens of thousands of patients. The medical approach to heart failure is therefore based on established clinical data. The therapeutic aims have been extended: not only should treatment relieve the symptoms of the disease, but also reduce the frequency of relapse and hospitalization, and prolong survival duration. At the onset of the third millennium, three therapeutic classes have emerged: conversion enzyme inhibitors, spironolactone, and beta-blockers, which although counter-indicated only a short while ago, now constitute the revolutionary aspect of the approach to treatment of chronic heart failure. In addition to drug therapy and as in the case of other chronic diseases, the significant role of patient awareness, i.e., the information and education that is made available to the individual regarding his or her illness, should also be taken into consideration. Regarding the latter aspect, the experience gained in this field by the care systems can be utilized. However, recent epidemiological data have shown that the advances made in the treatment of heart failure only concern a minority of patients; and that elderly subjects, women, and patients suffering from heart failure in spite of normal systolic function, which constitute the majority of cases, have not been considered in these trials.     

Perspectives on the current treatment of cardiac arrhythmias

Our current understanding of human cardiac arrhythmias is primitive and their treatment is largely empirical. For a few arrhythmias for which the mechanism is known, this information is valuable in selecting therapy. Primary methods for arrhythmia detection are 24-hour electrocardiographic recordings, patient-activated recordings, exercise and cardiac electrophysiologic studies. A search for removable causes of arrhythmia should be sought before instituting specific treatment with antiarrhythmic drugs, surgery or implantable devices. Over the past 20 years, the spectrum of antiarrhythmic drug action has broadened; sodium channel blockers, β-adrenergic blockers and calcium channel blockers have extended our therapeutic options, but the ideal drug has yet to appear. Efficacy and convenience of antiarrhythmic drugs have improved significantly, but adverse effects and drug interactions still occur much too frequently. The outlook for patients with malignant arrhythmias has improved significantly. However, the 2 methods for evaluating therapy of malignant arrhythmias are time-consuming, uncomfortable and expensive. Basic and clinical research is rapidly advancing our knowledge and effectiveness in dealing with cardiac arrhythmias. As a result, we can expect substantial improvements in arrhythmia control in the future.     

Statistical Distribution of Ventricular Ectopic Beats Assessed by Computer Analysis of Long-Term Electrocardiograms: Problems Related to the Definition of Arrhythmogenesis

The severity and clinical importance of arrhythmogenic effects of antiarrhythmic drugs have been well recognized, but only empirical and naive approaches have been used to define antiarrhythmic and proarrhythmic effects when comparing baseline and on-therapy Holter recordings. This article suggests a new method for the assessment of these effects, based upon comparisons of statistical distributions of ectopic beats recorded on long-term electrocardiograms. Since these distributions are very individual, the Smirov test was used for their comparison. This enables the antiarrhythmic and arrhythmogenic effects to be defined on a precise statistical basis. To demonstrate this method, an analysis is reported of Holter recordings made on six patients suffering from different types of ventricular arrhythmia. In each of these patients, one baseline Holter recording and one recording on each of three different drugs (flecainide, sotalol, and verapamil) were made. The records were digitized using a commercially available system for the analysis of long-term electrocardiograms and random sampling was used to obtain independent samples of arrhythmic episodes that were subsequently statistically analyzed. The results show that the problem of the definition of arrhythmogenesis can be partly addressed in a precise mathematical way and that treatment with an antiarrhythmic preparation may not only have general antiarrhythmic or arrhythmogenic effects, but may also cause a significant change in the character of arrhythmia that can neither be classified as antiarrhythmic nor as arrhythmogenic influence. The clinical implications of this approach are discussed.     

Incidence and clinical significance of transformation of atrial fibrillation to atrial flutter in patients undergoing long-term antiarrhythmic drug treatment.

AIMS: To investigate the rate of transformation of atrial fibrillation to atrial flutter in patients taking antiarrhythmic drugs for the prophylaxis of atrial fibrillation, we retrospectively analysed data from 305 consecutive patients with paroxysmal atrial fibrillation (155 male; mean age 63 +/- 11 years) treated with ventricular rate controlling drugs, antiarrhythmic drugs, or without drugs. METHODS AND RESULTS: At a mean follow-up of 9 months (range 1-24) all patients experienced recurrence of arrhythmia: 48 (14.6%, Group A) suffered Type 1 atrial flutter, and 257 (85.4%, Group B) atrial fibrillation. The relative rate of recurrence of atrial flutter vs atrial fibrillation was similar in patients without treatment or with ventricular rate controlling drugs (from 6.8% to 14.6%, P=ns). However, recurrence was higher (25%) in patients administered antiarrhythmic drug therapy. The relative risk in these patients was 3.02 times greater, compared with patients without treatment, or treated with rate controlling drugs (P<0.001). There were no differences between groups concerning the baseline clinical characteristics and the clinical consequences of the recurrence; patients with atrial flutter had a lower rate of conversion to sinus rhythm (42% vs 64%) and a higher rate of hospital admission (69% vs 36%) compared with those with atrial fibrillation. Six patients (8.5%) experienced 1:1 atrioventricular conduction during atrial flutter with a ventricular rate of 240-280 beats x min(-1). CONCLUSION: Our data suggest that the use of antiarrhythmic drugs for the prophylaxis of atrial fibrillation is associated with a threefold increase in the probability of Type 1 atrial flutter recurrence, as opposed to atrial fibrillation, which may have important clinical consequences, but which did not in our study.     

Treatment and prophylaxis of ventricular arrhythmias in acute myocardial infarction

Remarkable advances have been made in the management of cardiac disease in the last 20 years, but antiarrhythmic drug strategy in the acute phase of myocardial infarction remains less than satisfactory. Primary ventricular fibrillation (VF), once considered predictable on the basis of detection of “warning arrhythmias,” cannot be anticipated. Management must be either expectant or prophylactic. Restriction of drug use to selected patients and the apparent lack of effect of VF on late prognosis argue for the former approach, yet safe and effective prevention of VF is an attractive therapeutic goal. High-dose intravenous lidocaine probably offers efficacy but the risk-benefit ratio of this regimen is still debated. Adoption of a prophylactic regimen mandates drug administration to a large number of patients who either are not at risk of developing VF (noninfarct patients) or who are destined not to develop VF (70 to 95% of infarct patients). Ventricular arrhythmias other than VF are common in acute infarction and, for emotional rather than scientific reasons, often are aggressively treated. Little evidence exists to support this management. Few ventricular arrhythmias at this time in infarction have either immediate importance or prognostic significance. Reevaluation of antiarrhythmic drug use and arrhythmia treatment in acute myocardial infarction is long overdue. However, there is a paucity of controlled data upon which to base new strategies, and clinical research in this field is hampered by ethical considerations, by rigidly held but unscientifically based beliefs and by a lack of fundamental knowledge of arrhythmia mechanisms and their significance.     

Contemporary approach to treating heart failure

Over the past several decades, important advances have been made in the treatment of patients with heart failure (HF). Whereas in the past, the main goal of drug therapy was to relieve congestion, there is now compelling evidence from randomized clinical trials (RCTs) showing that several classes of drugs, most of which work predominantly by blocking or modulating neurohormonal activity, can substantially reduce morbidity and mortality as well as improve quality of life in patients with HF. Most of these trials, however, separated patients according to whether their ejection fraction (EF) was reduced (HFrEF) or preserved (HFpEF) and for the most part, favorable effects on clinical outcomes were demonstrated only in patients with HFrEF. In addition to the paucity of effective agents for managing patients with HFpEF, it has become apparent that underutilization of available therapies has greatly limited the overall impact of medical therapy on outcomes. This review provides an overview of current medical management of HF across the spectrum of EF, including the underutilization of treatment modalities. The focus is to provide clinicians the rationale for the use of specific agents and to present a practical approach for patient management. The strategies discussed are based on results of RCTs, guideline recommendations and the authors’ own experience in managing patients with HF over the years.     

Evaluation of Antiarrhythmic Drug Efficacy in Patients with an ICD:

There are a number of novel ways in which implantable cardioverter defibrillator (ICD) endpoints can be used in clinical trials to evaluate antiarrhythmic drugs. The advances in ICD technology (storage, retrieval, and accurate interpretation of ICD electrograms) expand the potential to include the use of an ICD endpoint as a clinical surrogate for sudden death. The ICD also provides the necessary safety net to test new drugs. The frequent need for antiarrhythmic drugs in patients already fitted with an ICD (e.g., for atrial fibrillation) necessitates knowledge of the drugs' effect on defibrillator threshold. There are interpretative problems and challenges associated with all types of ICD trials. A particular difficult issue is the degree to which the results of data on antiarrhythmic drug efficacy and safety acquired in the context of an ICD endpoint trial might be extrapolated to patient populations in which the device is not used. These and other challenging issues are discussed, with the goal of enhancing the design and interpretation of clinical trials featuring ICD endpoints.