Antiarrhythmic Therapy—Future Trends and Forecast for the 21st Century

Antiarrhythmic Therapy—Future Trends and Forecast for the 21st Century Dirk Böcker,

MD,

Michael Block, MD, Gerhard Hindricks, and Gu¨nter Breithardt, MD

MD,

Martin Borggrefe,

MD,

This article discusses recent changes in antiarrhythmic therapy, with a focus on nonpharmacologic therapy (electrode catheter ablation, implantable cardioverterdefibrillators [ICDs]), and puts them into perspective for the coming years. The treatment of supraventricular tachycardias and tachycardia involving accessory pathways is likely to remain the domain of catheter ablation. With promising new techniques under investigation, the

spectrum of arrhythmias that can be cured will probably be expanded. Treatment of life-threatening ventricular arrhythmias is likely to remain the domain of the ICD in the foreseeable future. With the safety net of the ICD in place, new antiarrhythmic drugs or other forms of antiarrhythmic therapy can be developed and tested. Q1997 by Excerpta Medica, Inc. Am J Cardiol 1997;80(8A):99G–104G

he treatment of tachyarrhythmias has changed proT foundly during the last decade. Emphasis has shifted from pharmacologic therapy to nonpharmaco-

ablation carries a significantly lower risk than fast pathway ablation, and, therefore, the slow pathway should be the initial target site. More recently, atrial flutter has become amenable to radiofrequency catheter ablation targeting a discrete area in the lower posteroseptal right atrium.13–16 Experience with using radiofrequency ablation to treat atrial flutter is still limited, and the duration of the follow-up period is relatively short, but the results reported so far are very promising. Because preliminary results with their treatment have been promising, ectopic atrial tachycardia17–19 and intraatrial or sinoatrial reentrant tachycardia20 –22 have also been included in the spectrum of supraventricular tachycardias that can be ablated. However, both types of tachycardia are relatively rare. For the treatment of atrial fibrillation, the most common arrhythmia, the use of catheter ablation techniques for curative treatment, that is, direct ablation of the arrhythmia, remains highly investigational. The intraoperative induction of long continuous lines of complete conduction block in both the left and the right atrium, achieved by dissecting parts of the atrial muscle during cardiac surgery as done in the maze procedure described by Cox et al,23 has been shown to be very effective for the curative treatment of atrial fibrillation. Long-term follow-up of .3 years after the maze operation revealed that .95% of patients were in sinus rhythm. Based on these findings, several percutaneous catheter-based approaches are currently under intense experimental and clinical investigation. The first case report on successful ablation of paroxysmal atrial fibrillation was reported by Haissaguerre and coworkers in 1994.24 Haissaguerre also reported on the clinical efficacy of several right atrial approaches to cure atrial fibrillation. Interestingly, the induction of lesion lines restricted to the right atrium seems to be of limited efficacy; with 3 different right atrial approaches, the success rate for curative treatment of atrial fibrillation was as low as 10%. When left atrial lesions were added, however, the efficacy increased to 40%. A different concept has been recently introduced by Swartz and colleagues.25 This group reported on the efficacy of left and right atrial

logic therapy of supraventricular as well as ventricular tachyarrhythmias. The numbers of radiofrequency catheter ablations and defibrillator implantations have increased dramatically since the late 1980s. These developments were triggered by technological advances in nonpharmacologic arrhythmia therapy paralleled by reports of studies demonstrating an excess mortality with the use of antiarrhythmic drugs.1,2 The purpose of this report is to describe briefly recent changes in antiarrhythmic therapy, with a focus on nonpharmacologic therapy, and put them into perspective for the coming years.

ELECTRODE CATHETER ABLATION Since its first use in humans in 1987,3–5 radiofrequency catheter ablation has become a curative treatment for patients with a variety of supraventricular tachyarrhythmias. In fact, it is now the established first-line treatment modality for definite cure of patients with accessory atrioventricular (AV) connections. Patients with the Wolff-Parkinson-White syndrome or accessory pathways that only conduct retrogradely often present with drug-refractory AV reentrant tachycardia or atrial fibrillation with rapid antegrade conduction via the accessory pathway. In experienced centers, the overall success rate for ablation of left- and right-sided accessory pathways exceeds 90%.6 – 8 An equally high success rate has been reported for AV nodal reentrant tachycardia, which can be cured by selective ablation of either the slow or the fast pathway of the AV node. When performed in experienced centers, slow and fast pathway ablation is associated with a risk of complete AV block #2%.9 –11 As clearly indicated by the Multicentre European Radiofrequency Survey,12 slow pathway From the Department of Cardiology and Angiology and Institute for Arteriosclerosis Research, Hospital of the Westfälische Wilhelms-University, Mu¨nster, Germany. Address for reprints: Professor Gu¨nter Breithardt, Universitätsklinik Mu¨nster, Medizinische Klinik C, D-48129 Mu¨nster, Germany. ©1997 by Excerpta Medica, Inc. All rights reserved.

0002-9149/97/$17.00 PII S002-9149(97)00719-4

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lesion lines in 36 patients with chronic atrial fibrillation. Successful ablation of atrial fibrillation was achieved in .80% of patients. However, in .50% of the patients, intraatrial reentrant tachycardia occurred after successful ablation of atrial fibrillation, requiring a second ablation procedure. In addition, both the duration of the ablation session (mean, 12 hours) and the duration of radiation exposure (mean, 2 hours) were extremely long, which certainly limits the feasibility of the procedure. A high incidence of severe procedure-related complications (15%) was observed in this series. Few clinical results are available regarding the success of direct catheter ablation of atrial fibrillation. However, it is reasonable to expect that with further improvement of ablation technology, catheter ablation will become a feasible approach to curing this arrhythmia. Catheter ablation has also become an attractive curative therapeutic tool for the treatment of idiopathic right and left ventricular tachycardia (VT). Its success rate in curing idiopathic VT exceeds 70%,26 –28 but the procedure is less effective in patients with VT in the presence of severe organic heart disease. Although our understanding of the pathophysiology of VT in patients with organic heart disease has grown significantly in the last decade, catheter ablation is only effective in approximately 30 – 40% of these patients.29 –31 Major limitations of the currently available ablation technology in patients with VT in the setting of organic heart disease include the inability to localize adequately the areas critical to the maintenance of the arrhythmia as well as problems in reaching and/or destroying adequate target sites. Significant progress can be expected to result from new mapping techniques that have been introduced very recently. One promising concept is a new 3dimensional electromagnetic mapping technique, the CARTO-system.32 The CARTO-system consists of an ultralow-intensity magnetic field generator, which is placed underneath the patient’s bed, and a set of 2 steerable 8Fr catheters modified by inserting a miniature magnetic sensor into the tip. When the mapping and ablation catheter is positioned in the region of the electromagnetic field induced by the location pad, the signal picked up by the sensor identifies the location and orientation of the tip of the catheter. All coordinates from the reference catheter and the mapping catheter are reported to a processing unit, which then allows the nonfluoroscopic visualization of the mapping catheter on a computer screen. The heart chambers can be reconstructed in a 3-dimensional fashion by picking up serial mapping points. Davies and colleagues33 have recently introduced another technique in which noncontact mapping allows the complete reconstruction of the excitation of a heart chamber from a single beat. The significant advantage of this new procedure is that it is no longer necessary to reconstruct the flow of excitation by the serial acquisition of mapping points. The first clinical results obtained in patients with VT in the setting of ischemic heart disease are very promising. 100G THE AMERICAN JOURNAL OF CARDIOLOGYT

IMPLANTABLE DEVICES There have been dramatic technological improvements since the first implantation of an automatic defibrillator in humans.34 The first implantable cardioverter-defibrillators (ICDs) had no cardioversion capability and defibrillated the patient once a rhythm was observed above a fixed nonprogrammable heart rate.34 Defibrillation occurred after a fixed duration of the heart rate with a fixed energy. Implantation involved a thoracotomy because at least 1 defibrillation patch had to be positioned epicardially. The device itself, due to its volume of 145 mL, had to be implanted abdominally. In 1988, detection rate, duration of heart rate until defibrillation, and energy became programmable. Before 1988, these values could not be changed once the device was implanted. Transvenoussubcutaneous defibrillation leads were introduced in the same year, enabling implantation of a device without thoracotomy. Once antitachycardia pacing was integrated into third-generation ICDs in 1989, many patients were treated primarily with this approach. Very fast termination of VT became possible, and symptoms related to VTs could be completely suppressed in many instances. Biphasic defibrillation waveforms (introduced in 1990) practically abolished the need for thoracotomy because they improved defibrillation efficacy and increased the defibrillation thresholds possible with transvenous-subcutaneous defibrillation leads. Since a significant reduction in ICD volume in 1993, pectoral instead of abdominal implantation became possible, leading to greater patient comfort and fewer device-related infections. Devices with ventricular and atrial sensing and pacing were introduced in 1996, and early in 1997 a device with the capability to cardiovert/defibrillate in the atria and the ventricle was introduced to clinical investigation. These advances reduced the mortality and morbidity associated with the implantation of an automatic defibrillator. Some experts now consider ICD implantation to be the therapy of first choice in patients with ventricular tachyarrhythmias.35 However, the management of patients with an ICD can still be troublesome, and further technological improvements can be expected. Approximately 10 –30% of all patients experience inappropriate ICD therapies.36 Inappropriate ICD therapies due to sinus tachycardia or rapidly conducted atrial fibrillation might be avoided to a substantial degree by using the onset and stability criteria of current devices.37,38 Ideally, an atrial signal should be integrated into the algorithm for distinction between atrial and ventricular tachyarrhythmias.39 Since 1995, devices using a dual-chamber lead system have been available. To prevent the lead positioning and stability problems inherent in bifocal pacing lead systems, a single-pass lead system, including an atrial sensor (as in atrial synchronous ventricular inhibited [VDD] pacing systems), might be used in future ICD models. Dual-lead systems might be restricted to those patients who require dual-chamber pacing. ICDs are implanted to terminate VT and ventricu-

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lar fibrillation by cardioversion or defibrillation. However, as shocks are painful and energy-consuming, the number of shocks should be minimized. Antitachycardia pacing has reduced the number of shocks needed in many patients.36,40 Pacing algorithms designed to prevent the occurrence of ventricular tachyarrhythmias by preventing short-long RR interval sequences are currently being investigated and might be integrated into future ICD models.41 Other techniques of VT prevention, such as high current strength pacing or ultrarapid subthreshold stimulation, are feasible with epicardial electrodes;42 however, pacing close to a critical site of the VT circuit would be necessary and might not be achieved from the right ventricle. Prevention of VT might also be achieved by continuous administration of antiarrhythmic drugs from the leads43 or by drug delivery44 by infusion into the coronary sinus initiated once precursors of ventricular tachyarrhythmias, such as low heart rate variability, ventricular runs, or myocardial ischemia,45 have been detected. In the last decade, ICD volume declined from 145 mL to about 55 mL. In order to achieve further volume reductions, new capacitor technologies (flat capacitors) will be used. Devices with a reduced maximum output will be available for patients with a low defibrillation threshold. Efforts to develop better lead configurations38,46 –51 and waveforms46,52–54 to improve defibrillation efficacy will continue. Future ICDs might automatically alter the waveforms based on measured defibrillation impedance. Further improvements might be achieved if the timing of energy delivery is optimized.55,56 Energies needed for cardioversion might be substantially reduced if the ICD distinguishes between ventricular fibrillation and VT57 and delivers a different waveform for each.58 The battery longevity of today’s ICDs is short in comparison with that of pacemakers.59 Device replacements are expensive and expose the patient to a significant risk of infection. To increase device longevity, energy consumption has to be minimized. Ventricular demand (VVI) pacing significantly reduces battery longevity. In comparison with pacing leads, ICD leads show a poor performance of the acute and chronic pacing thresholds.60 Improved designs of the lead tip, including the steroid diluting tip, will be used within the next year. In the future, monitoring circuits might employ improved low-current components. Monitoring circuits cannot be used in parallel, but instead must be used in hierarchical order to avoid high current drains from the battery. Additional monitoring functions should be started only when the rate criterion of the ventricles is fulfilled. Recent reports on long-term stability of transvenous-subcutaneous defibrillation leads have shown high failure rates and the need for operative revisions.61– 63 Lead designs have already been changed to reduce lead fractures and insulation failures. Further design changes will be made to reduce lead diameter to as low as 5Fr.64,65 The inclusion of pacing modes, such as biventricular pacing,66,67 designed to amelio-

rate congestive heart failure, might further expand the benefit from implantable devices. The present generation of ICDs has a high number of programmable variables. Therapy histories retrieved from the memory of the device might cover hundreds of episodes with thousands of RR intervals and include .1 minute of electrograms from the most recent episodes. Thus, dealing with these ICDs is demanding and time consuming. Newer models, which will have hemodynamic sensors,68 will decide which therapy to use based on information on left ventricular function and hemodynamic tolerance of VTs. Based on success or acceleration rates, the therapies may be modified automatically.

ANTIARRHYTHMIC DRUGS: IS THERE A FUTURE? The past decade has seen a remarkable change in the approach to treating arrhythmias. The role of antiarrhythmic drugs, once defined with confidence, is now marked by uncertainty and apprehension. Until the results of the Cardiac Arrhythmia Suppression Trial (CAST) were reported,1 the prevailing view was that arrhythmias could be controlled by slowing conduction or suppressing automaticity, goals met well by the sodium-channel blocking (class I) drugs. CAST showed an increase in mortality associated with encainide, flecainide, and moricizine. As a result of this trial, emphasis shifted toward antiarrhythmic agents that cause selective prolongation of repolarization without any slowing of conduction. However, the development of these so-called pure class III antiarrhythmic drugs was stopped by most pharmaceutical companies after the results of the Survival With Oral d-Sotalol (SWORD) study became available.2 This trial intended to show that a pure potassium-channel blocking action reduces all-cause mortality in patients with previous myocardial infarction and left ventricular dysfunction. The study was prematurely terminated when an interim analysis showed increased mortality among patients assigned to d-sotalol. The hypothesis that implantable defibrillators may be superior to the most potent antiarrhythmic drugs currently available, d,l-sotalol69 and amiodarone,70,71 has been or is being tested in several randomized trials: the Antiarrhythmics Versus Implantable Defibrillators (AVID) study72 (see Addenda to articles by Reiffel73 and Haverkamp,74 in this supplement), the Cardiac Arrest Study Hamburg (CASH),75 and the Canadian Implantable Defibrillator Study (CIDS).76 However, as knowledge about arrhythmogenesis increases, antiarrhythmic strategies are likely to change profoundly. Arrhythmias will probably be managed with a broader, multidimensional approach, including treatment or reversal of arrhythmia conditioning and triggering factors as well as direct suppression of the arrhythmia. Specific ion channels77,78 and signal pathways that contribute to the genesis of arrhythmias are being identified, which may enable arrhythmia therapy to target these sites directly to reverse their dysfunction. An understanding of spatial differences among ion channels in atrial and ventricular myocarA SYMPOSIUM: CLASS III ANTIARRHYTHMIC AGENTS

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dium will become important for selection of antiarrhythmic agents. Some channels, such as the acetylcholine-sensitive potassium channel,79,80 are present predominantly in the atria, and therefore, drugs that target them would be good for the treatment of supraventricular arrhythmias without the potential to induce ventricular proarrhythmias. New drugs for treatment or prevention of ventricular fibrillation should significantly prolong the action potential duration and effective refractory period at the high heart rates seen during fibrillation but should have no effect at slower rates. A multidimensional approach to arrhythmia treatment might include therapies that focus on autonomic or neurohumoral factors as well as factors associated with electrical or structural remodeling. It is known that at zones bordering infarct scars, particularly those zones that are especially prone to reentry arrhythmia, there is marked disruption of the usual ordered distribution pattern of gap junctions. Investigations of the regulation of gap junctions in the peri-infarct zone as well as in myocardium distant from the infarct might lead to an understanding of the genesis of reentry arrhythmias and influence their treatment.81– 83 Scarring and fibrosis are additional factors that increase the likelihood of potentially fatal arrhythmias. b blockers or angiotensin-converting enzyme inhibitors that may prevent or reverse remodeling by targeting biochemical intermediaries of this process could be used for the treatment of arrhythmias arising from degenerative processes. In the setting of myocardial infarction, the broader approach to arrhythmia therapy includes prevention of scar formation during the acute stage of infarction (e.g., thrombolysis, revascularization), as well as prevention of mechanical overload and application of drugs that affect secondary hypertrophy in the peri-infarction interval. The long-term administration of lipid-lowering drugs might decrease the susceptibility to arrhythmias by reversing atherosclerosis, thus preventing transient myocardial ischemia. Clarifying the role of platelet activating factor and other mediators that are liberated during ischemia might influence the treatment of arrhythmias during the acute and subacute stage of myocardial infarction.84 – 86 Besides ischemia, there are a number of other mechanisms that might alter the electrophysiologic properties of the heart. These mechanisms include neurocardiac interactions occurring both at the local receptor level and the central nervous system level, as well as mechanoelectrical interactions87,88 (e.g., stretch-activated channels) caused by transient hemodynamic changes. In recent years interest has grown concerning the genetic background of the long-QT syndrome, which is associated with frequent occurrences of life-threatening torsades de pointes. Linkage analysis has associated this arrhythmia with genetic factors responsible for mutations in cardiac potassium or sodium channels, on 5 different chromosomes.89 –94 Future antiarrhythmic drug therapy will take into account the various forms of long-QT syndrome that can be identified on a genetic level. For example, in vivo experiments 102G THE AMERICAN JOURNAL OF CARDIOLOGYT

indicate that abnormal late sodium channel openings in the LQT3 form of the syndrome can be corrected by mexiletine95 or other sodium-channel blockers. Thus, these agents might be curative in LQT3 but not in other types of long-QT syndrome. The identification of specific molecular and genetic lesions might result in lesion-specific antiarrhythmic therapies, not only for the long-QT syndrome, but possibly also for early atrial fibrillation, hypertrophic cardiomyopathy,96 right-ventricular outflow tract tachycardia, or other types of arrhythmias.97

CONCLUSIONS The advances in technology that promoted nonpharmacologic therapy of arrhythmia during the last decade are likely to continue. The treatment of supraventricular tachycardias and of tachycardias involving accessory AV pathways will probably remain the domain of catheter ablation. Many patients can be cured using the available techniques of radiofrequency catheter ablation, and with promising new techniques under investigation, the spectrum of supraventricular arrhythmias that can be cured is likely to be expanded to include atrial fibrillation. However, the efficacy/ safety profile of newer techniques must be compared with the favorable, gold-standard efficacy/safety profile of existing techniques. Treatment of life-threatening ventricular tachyarrhythmias will probably remain the domain of the ICD in the foreseeable future. After completion of ongoing trials,75,76 the role of ICD therapy with respect to prolongation of life will be defined more clearly and will probably be expanded to include primary prophylaxis of sudden death in high-risk populations, as was studied in the Multicenter Automatic Defibrillatory Implantation (MADIT) trial.71 Antiarrhythmic drugs and catheter ablation are likely to be used to complement ICD therapy and reduce the number of interventions by the device, thereby improving quality of life. With the safety net of the ICD in place, new antiarrhythmic drugs or other forms of antiarrhythmic therapy with a favorable efficacy/safety profile can be developed and tested. 1. Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991;324:781–788. 2. Waldo AL, Camm AJ, deRuyter H, Friedman PL, MacNeil DJ, Pauls JF, Pitt B, Pratt CM, Schwartz PJ, Veltri EP, for the SWORD Investigators. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet 1996;348:7–12. 3. Budde T, Breithardt G, Borggrefe M, Podczek A, Langwasser J. Initial experiences with high-frequency electric ablation of the AV conduction system in the human. Z Kardiol 1987;76:204 –210. 4. Borggrefe M, Budde T, Podczeck A, Breithardt G. High frequency alternating current ablation of an accessory pathway in humans. J Am Coll Cardiol 1987; 10:576 –582. 5. Lavergne T, Guize L, Le Heuzey JY, Carcone P, Geslin J, Cousin MT. Closed-chest atrioventricular junction ablation by high-frequency energy transcatheter desiccation [letter]. Lancet 1986;2:858 – 859. 6. Calkins H, Sousa J, el-Atassi R, Rosenheck S, de Buitleir M, Kou WH, Kadish AH, Langberg JJ, Morady F. Diagnosis and cure of the Wolff-Parkinson-White syndrome or paroxysmal supraventricular tachycardias during a single electrophysiologic test. N Engl J Med 1991;324:1612–1618. 7. Jackman WM, Wang XZ, Friday KJ, Roman CA, Moulton KP, Beckman KJ, McClelland JH, Twidale N, Hazlitt HA, Prior MI, et al. Catheter ablation of

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