Evaluation of antiarrhythmic drug efficacy in patients with an ICD: unlimited potential or replete with complexity and problems?

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.

Evaluation of antiarrhythmic drug efficacy in patients with an ICD. Unlimited potential or replete with complexity and problems?

A report from a Study group, proposed by A. J. Camm, London, of the Working Groups on Arrhythmias and Cardiac Pacing of the European Society of Cardiology; co-sponsored by the North American Society of Pacing and Electrophysiology. The Study Group was convened on 29 August 1997 at Saltsjöbaden, near Stockholm. The meeting was chaired by A. J. Camm, London, and C. M. Pratt, Houston. Based on the presentation and discussions, a first draft of the documents was prepared by C. Pratt and J. Camm which was then circulated to all members three times for their review. All members of the Study Group approved the final manuscript. This report represents the opinion of the members of this Study Group and does not necessarily reflect the official position of either society.The meeting of the Study Group was made possible by unrestricted educational grants from Medtronic, Guidant, Proctor & Gamble, Berlex and Sanofi.Also, presented, in part, at the Cardio-Renal Drugs Advisory Board meeting of the Food and Drug Administration, Bethesda, Maryland, on 30 April 1999.

Clinical progress after randomized on/off pacemaker treatment for hypertrophic obstructive cardiomyopathy. Pacing in Cardiomyopathy (PIC) Study Group.

BACKGROUND: The therapeutic options for hypertrophic obstructive cardiomyopathy (HOCM) classically include medical treatment with beta-blockers and calcium antagonists or myectomy-myotomy as a surgical possibility for refractory cases. The observation that pacemaker activation of the heart in HOCM reduces the subaortic gradient is well known but less well investigated. METHODS: Eighty-three patients (33 female and 50 male) mean age 53 (18-82) years, with symptoms refractory to drug treatment and a resting gradient above 30 mmHg, who responded favourably to temporary pacing, were included in this prospective study and had a pacemaker (DDD) implanted. After an initial double-blind crossover phase of 6 months, patients were reinvestigated at 12 months and followed for a mean of 36 months. RESULTS: As observed during a screening investigation, the obstruction was significantly reduced from 72 +/- 35 mmHg to 29 +/- 24 mmHg (P < 0.01) when the pacemaker was on, while no major effect was seen during the sham phase. The effect was persistent at 1 year with a remaining resting gradient of 28 +/- 24 mmHg. In parallel, we documented an improvement in functional capacity, according to the NYHA classification and by quality of life analysis, and a significant improvement in dyspnoea and angina. Exercise on treadmill improved only in patients with reduced initial tolerance (< 8 min). During the mean follow-up of 36 months, 65 patients remained on pacing alone, with eight patients having additional AV-node ablation and five patients finally having surgery. CONCLUSION: This controlled multicentre study shows that pacemaker treatment is an option for HOCM patients; it is inoffensive and does not exclude alternative methods, but satisfies 79% of patients beyond 3 years.

Multicenter low energy transvenous atrial defibrillation (XAD) trial results in different subsets of atrial fibrillation.

OBJECTIVES: This prospective, multicenter trial was aimed at defining efficacy and safety of low energy shocks during atrial fibrillation in a diverse cohort of patients. BACKGROUND: Experimental studies in sheep and preliminary data in humans have suggested that low energy internal shocks delivered between right atrial and coronary sinus electrode catheters may terminate atrial fibrillation. METHODS: Biphasic 3/3-ms R wave synchronous shocks were delivered between two electrode catheters in the right atrium and coronary sinus. The defibrillation protocol started with a test shock of 20 V, and shocks increased in 40-V steps until restoration of sinus rhythm or a maximum of 400 V. Shock delivery was withheld after short RR intervals. In 141 patients with atrial fibrillation, the protocol was carried out under sedation in case the shock was associated with discomfort. The atrial arrhythmia was paroxysmal (< or = 7 days) in 50 patients, chronic (> 30 days) in 53, intermediate (> 7 days, < or = 30 days) in 18 and induced in 20. Underlying heart disease was present in 88 patients (62%). RESULTS: Paroxysmal atrial fibrillation was successfully terminated in 46 (92%) of 50 patients, chronic atrial fibrillation in 37 (70%) of 53, intermediate in 16 (89%) of 18 and induced in 16 (80%) of 20. Mean conversion threshold was 1.8 J (213 V) in the induced group, 2.0 J (229 V) in the paroxysmal group, 2.8 J (272 V) in the intermediate group and 3.6 J (311 V) in the chronic group. The conversion voltage was significantly (p < 0.001) higher in the chronic group than in the other groups of atrial fibrillation and increased significantly with the duration of atrial fibrillation and with left atrial size (p < 0.05). Of 1,779 R wave synchronized shocks delivered with a mean (+/-SD) preceding RR interval of 676 +/- 149 ms, no ventricular arrhythmia was induced. The latter may occur after unsynchronized shocks. CONCLUSIONS: Low energy transvenous shocks in patients with atrial fibrillation are effective and safe, provided that shocks are properly synchronized to R waves with preceding RR intervals that meet appropriate cycle length criteria. This study provides data that may be useful in the development of an implanted atrial defibrillator.

Technical improvements in sensors for rate adaptive pacemakers.

Many types of sensors have been developed and applied clinically during recent years. Technical improvements can be achieved through greater sensitivity and especially through more specificity for various physical or preferably physiologic signals. However, to date no single sensor properly reflects metabolic demands under all circumstances. In a manner analogous to the normal sinus node, the input from different sources will have to be considered. This leads to the development of dual-sensor or eventually multisensor pacemakers in which the rate is a computed result of blended and cross-checked information on the various parameters that are analyzed.

Rate responsive dual chamber pacing.

We report about a new pacemaker, which simultaneously offers dual chamber pacing in DDD Mode and activity controlled rate response. The system also uses activity-sensing to differentiate true sinus tachycardia from ectopic atrial activity or atrial fibrillation and therefore prevents pacemaker mediated arrhythmias. The clinical experience proves appropriate functioning of all technical aspects of the device. Preliminary noninvasive hemodynamic assessments confirm improvement in cardiac function with AV synchronous pacing mode and demonstrate the ouporiority of rate-responsive dual chamber versus single ventricular pacing.

Evaluation of flecainide acetate in rapid atrial fibrillation complicating Wolff-Parkinson-White syndrome.

Flecainide is reported to be effective in patients with paroxysmal tachycardias, but its effect on rapid ventricular response over accessory atrioventricular pathway during atrial fibrillation is not known. The influence of flecainide on various electrophysiological properties of the accessory pathway with special emphasis on ventricular rate during atrial fibrillation was investigated in 9 patients with severe symptomatic Wolff-Parkinson-White syndrome. The shortest ventricular response during atrial fibrillation increased from 218 (190-270) to 320 (240-block) ms. In 4 patients sustained rapid atrial fibrillation converted to sinus rhythm. The rate of circus movement tachycardia decreased from 166/min to 130/min after flecainide, due to a lengthening of retrograde ventriculoatrial conduction time over the accessory pathway. Flecainide caused a significant prolongation of the effective refractory period of the accessory pathway in our subgroup with extremely fast AV conduction during atrial fibrillation and induced a depressant effect on retrograde accessory pathway conduction. This makes the drug very promising for the emergency treatment of dangerous rapid tachyarrhythias complicating this syndrome.

Efficacy of amiodarone in the Wolff-Parkinson-White syndrome with rapid ventricular response via accessory pathway during atrial fibrillation.

Sudden death in Wolff-Parkinson-White syndrome (WPW) is related to a very fast ventricular response to spontaneous atrial fibrillation (AF) conducted via accessory pathway (AP). The effect of oral amiodarone was studied in 12 patients with WPW syndrome and life-threatening rapid ventricular response via an AP during spontaneous AF. The effective refractory period of the AP in the anterograde direction was 280 ms or less during control study in all patients. After amiodarone therapy, the effective refractory period remained 280 ms or less in 7 of the 12 patients. During incremental atrial pacing, the longest atrial pacing cycle length that produced block over an AP ranged from 200 to 310 ms (mean 261 +/- 42) during the control period and 240 to 980 ms (mean 377 +/- 198) after amiodarone therapy. During AF the shortest ventricular response via the AP could be measured in 10 of 12 of the patients both before and after amiodarone treatment and ranged from 200 to 290 ms (234 +/- 30) and 250 to 500 (mean 302 +/- 75), respectively (p less than 0.01). The average RR interval during AF before and after the drug ranged from 200 to 390 ms (mean 280 +/- 55) and 280 to 650 ms (mean 396 +/- 116), respectively (p less than 0.01). Thus, the safety of amiodarone in the WPW syndrome should be established by electrophysiologic studies and induction of AF, because amiodarone is not protective in all patients with WPW.