Introduction: Miles to go

MAY 22, 1978

The American

Journal

of CARDIOLOGY@’ VOLUME 41 NUMBER 6

SYMPOSIUM ON NEW ASPECTS OF ANTIARRHYTHMIC THERAPY Douglas P. Zipes, MD, FACC, Guest Editor

Introduction: Miles To Go

DOUGLAS P. ZIPES, MD, FACC Indianapolis,

Indiana

It is of interest to reflect that, just 15 years ago, when a patient presented with an acute myocardial infarction, he was placed in a regular hospital room, occasionally one located close to the nurses’ station, given an analgesic agent for pain, an anticoagulant drug and, sometimes, an oral antiarrhythmic agent. Concepts of coronary care monitoring and therapy, effective cardiopulmonary resuscitative techniques and electrical cardioversion were in their infancy. Embryonic in the early 1960’s, these three concepts have matured to provide the foundation for many of the clinical advances achieved in control of cardiac rhythm disturbances in the last one and one half decades. In this minisymposium, it was not possible to recapitulate all the recent progress made in the therapy of cardiac arrhythmias. Rather, the approach has been to obtain selected reviews from several prominent investigators who have made original, important contributions in the area of patient care and to the understanding, as well as management, of cardiac rhythm disturbances. These investigators provide a reflective review of the current state of the art in their special area From the Indiana University School of Medicine, Indianapolis, Indiana. Address for reprints: Douglas P. Zipes, MD, Indiana University School of Medicine, 1100 W. Michigan Street, Indianapolis, Indiana 46202.

of interest and expertise. Lown and DeSilva present observations linking the psyche with the heart and the role of the autonomic nervous system in preventing, permitting or precipitating the development of cardiac arrhythmias. Woosley and Shand review the present understanding of pharmacokinetic principles, necessary for correct use of antiarrhythmic agents. Harrison and associates, intimately acquainted with the role of long-term recordings of the cardiac rhythm in ambulatory patients, discuss the use of this technique in arrhythmia management. Our contribution is a review of some of the newer antiarrhythmic agents that we have used and that may become approved for clinical use in the United States sometime in the future. The last two topics, the application of pacing techniques, by Wellens et al. and the use of surgery, by Gallagher et al., represent innovative therapeutic approaches to the treatment of cardiac rhythm disturbances not responding to conventional measures. Many topics not discussed, in which progress has been gained in understanding or treating cardiac arrhythmias, include out-of-hospital ventricular fibrillation, its cause, treatment and prevention; mechanisms of arrhythmogenesis and drug therapy in patients with tachyarrhythmias associated with the Wolff-Parkinson-white syndrome; mechanisms responsible for supraventricular and, in some instances, ventricular

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tachyarrhythmias; use of new recording techniques such as body surface mapping, signal averaging and intracardiac methodology. The entire area of basic cardiac electrophysiology, which serves as the wellspring for much of our clinical knowledge, is not considered. These topics and others could easily fill several more symposia. As expected, in spite of the progress achieved, more questions remain unanswered than answered. We still do not fully understand the electrophysiologic mechanisms of many tachyarrhythmias in man, particularly those arising in the ventricles, and, even when we do, we are unable to predict with accuracy which drug will effectively control which specific arrhythmia. Particularly when treating ventricular tachyarrhythmias, control of each patient’s rhythm disturbance remains an individual pharmacologic experiment, the results of which are learned by empiric trial and error. Arrhythmias, almost capriciously, may respond to only one of two drugs with similar actions, for example, to quinidine but not to procainamide. Anecdotes about cases in which a particular drug suppressed a ventricular tachycardia refractory to all other agents exist for virtually every antiarrhythmic drug. As an example, one of our patients recently received a trial of 10 different antiarrhythmic agents until a drug was found that successfully suppressed his life-threatening ventricular tachycardia. Multiple drug regimens often must be tried for some patients until a successful combination of drugs is found. Perhaps acute drug testing, advocated by Lown, represents an initial approach to solving this problem by providing rapid screening methods, somewhat analogous to testing the sensitivity of an organism to an antibiotic drug. Complicating this approach, however, is the fact that the tachyarrhythmia to be suppressed is not always present when therapy is being evaluated. We need reliable methods of initiating the tachycardia, such as stress testing or premature electrical stimulation of the heart, as well as reliable methods for evaluating the patient’s response to therapy, such as attempts to reinitiate the tachycardia or the use of ambulatory recordings after therapy has been started. It is important to recall that the usual electrocardiogram, on which many physicians base the need for, as well as the response to, therapy represents approximately l/1,440 of a patient’s day. As pointed out by Harrison, significant variability occurs throughout the day in the frequency of many arrhythmias, and therapeutic decisions based only on the 12 lead electrocardiogram may lead to errors in judgment. Present status of antiarrhythmic therapy: It may be as naive to think that one antiarrhythmic drug will be effective for all patients as it is to think that one antibiotic agent will cure all infections. Therefore, we need to be able to choose from a wide selection of antiarrhythmic agents that have widely different electrophysiologic properties. No ideal universally effective antiarrhythmic agent exists. If it did, such questions as whom to treat and with what drug would not occur. Virtually all of the available antiarrhythmic agents have significant side effects, and, because of this, therapy

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should be looked on as substituting one disease for another. One must constantly appraise whether the “disease” (antiarrhythmic agent) given to the patient carries more risk than the disease (arrhythmia) being treated. The present state of antiarrhythmic therapy basically involves administering a drug potentially toxic to the myocardium to treat an abnormal condition. Correcting the abnormal state, rather than creating another, but different one, intuitively seems more appropriate, but such an approach can be used in only selected instances. One hopes that in the future, understanding the metabolic or cell changes associated with the genesis of arrhythmias may provide insight into therapy that actually reverses basic defects rather than simply suppresses them. Until that time, however, clinicians must continue to use wisely the existing forms of therapy, constantly evaluating the benefit to risk ratio. As is the requirement when administering investigational drugs, physicians using conventional drugs should inform patients of potential side effects before initiating therapy. It is important to realize that the pathophysiologic basis of cardiac arrhythmias may be a changing event. Particularly during the evolution of a myocardial infarction, the electrophysiologic mechanisms responsible for ventricular arrhythmias may change with time. Within minutes of occluding the coronary artery in dogs, the initial ventricular arrhythmias probably result from reentry occurring in ischemic myocardium; ventricular arrhythmias present 12 to 24 hours later may be due to abnormally enhanced automaticity, possibly arising in or near injured, but surviving Purkinje fibers; after 2 to 3 days, ventricular arrhythmias can again be elicited that may be caused by reentry excitation. Differences in the type of the infarction, transmural or subendocardial, also may create a different pathologic substrate establishing different electrophysiologic events. Therefore, it should not be surprising that the same drug may suppress arrhythmias in one patient with an acute myocardial infarction, but not in another patient, or at one time during the evolution of an infarction in one patient, and not at another time in the same patient. This point is easily documented in the laboratory. In our canine experiments, aprindine given before coronary occlusion, increases the spontaneous development of ventricular fibrillation, but given to dogs experiencing ventricular tachycardia 24 hours after coronary occlusion, aprindine is profoundly antiarrhythmic. Thus, in the dog, the same drug can be arrhythmogenic or antiarrhythmic, depending on the time it is given in relation to the coronary occlusion. It is our belief that any antiarrhythmic agent that significantly slows conduction, particularly in the acutely ischemic myocardium, which may be more sensitive to such slowing effects than is the normal myocardium, is capable of enhancing the potential for developing areas of unidirectional block conducive to reentry excitation. Conversely, drugs that improve conduction in the ischemic myocardium may be antiarrhythmic. It would appear to be an oversimplification to think that an antiarrhythmic agent with a negative dromotropic effect converts a single area with unidirectional block to one exhibiting bidirectional

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block, thus preventing reentry from occurring. The myocardium is a complex three-dimensional syncytium and, particularly when ischemia results in heterogeneous effects, many islets with different functional properties probably exist. Antiarrhythmic agents cannot affect the entire area uniformly and may abolish the propensity to develop reentry in one area but create it in another. Tacit to this reasoning is the assumption that the antiarrhythmic agent actually reaches the site of origin of the arrhythmia, which may not be so if a vessel is totally occluded, without collateral vessels to the ischemic or infarcted area. Patients already receiving an antiarrhythmic agent at the time of their infarction may represent an entirely different “model” than the patient who has already had an infarction and is then given an antiarrhythmic drug in the coronary care unit. The first clinical situation may be more similar to when an experimental animal is given a drug before coronary occlusion, and the second situation to when the drug is given after coronary occlusion. Role of experimental efficacy: The adequacy

models

for testing

drug

of experimental models in which to test the efficacy of an antiarrhythmic approach must be considered. Information regarding the effects of various agents on the electrophysiologic properties of isolated Purkinje fibers or cardiac muscle must be obtained from “sick” as well as healthy tissue preparations. After all, most situations of antiarrhythmic therapy involve patients with “sick” hearts. The response to drugs, to autonomic nervous system manipulation or to other interventions, of arrhythmias induced in various animal models by aconitine, digitalis, catecholamines, electrolyte changes, ischemia or hypoxia provides important information. However, in the final analysis, determination of whether an approach will suppress arrhythmias in man cannot be obtained by even the most elegant in vivo or in vitro studies in animals, but must be established by critical clinical studies in man himself. This consideration in no way invalidates or even minimizes the importance of experimental animal studies, which provide insight into understanding mechanisms of arrhythmia development and of the action of antiarrhythmic agents and which often suggest new areas for future research. Communication between the laboratory and the bedside must be fluid and bidirectional. Clinicians capitalized on the observation by Moe that a supraventricular tachycardia in a dog could be started or stopped by premature stimulation. Conversely, many laboratory experiments have been conducted to confirm the elegant concepts gleaned from the surface electrocardiogram by Katz, Pick and Langendorf. Role of clinical drug testing: Drug studies in man must be carefully designed and even more carefully interpreted; they must take into consideration the nature of the patient’s illness and arrhythmia. For example, in patients with stable recurrent premature ventricular complexes, it seems relatively easy to test the efficacy of an antiarrhythmic agent by comparing data obtained during an adequate control period with similar

data obtained during a treatment period. Studies can be single or double-blinded with a placebo control. Long-term drug therapy may be discontinued periodically during the patient’s course to be certain that the arrhythmia has not spontaneously ceased. When comparing the efficacy of one drug with another, parallel studies in matched populations or a blinded cross-over study using a placebo control, with an adequate washout period in between drug testing, may be used. However, clinical studies of these types raise certain issues, such as the duration of an adequate control period. A single 24 hour recording interval is often used, but some data suggest it may not be sufficient. A more important question involves the meaning of the results derived from such studies. What can be concluded regarding efficacy, if the drug achieves a 75 or even 90 percent reduction in the number of premature ventricular complexes in a stable, asymtomatic population? Obviously, therapy is a failure if it has suppressed 90 percent of the premature ventricular complexes but fails to prevent a single episode of ventricular fibrillation. Because such studies are generally performed in patients who have nonlife-threatening ventricular arrhythmias that do not produce symptoms and who may not need any treatment, the results obtained may not necessarily be applicable to patients with recurrent ventricular tachycardia or ventricular fibrillation that produces syncope and presyncope. Controlled studies in this latter group are complicated by the life-threatening nature of the ventricular arrhythmia. For example, a patient who has required electrical termination of ventricular fibrillation on multiple occasions in the preceding 24 hours in spite of conventional antiarrhythmic therapy cannot be treated with a placebo to establish a control period before he receives an investigational drug. Similarly, if the ventricular arrhythmia is related to a long-term problem, and has recurred over a period of time, it is difficult to justify discontinuing what appears to be effective therapy at some future time to establish whether the propensity to ventricular fibrillation is still present. If the drug is stopped, it must be done in the hospital, while the patient is monitored. Then, if the ventricular fibrillation does not recur, how long does one wait before restarting therapy to be certain the ventricular fibrillation will not return in the future? Although it may be more difficult to apply rigorous scientific methodology to investigations in this group of patients, it is for this very group with lifethreatening, recurrent ventricular tachyarrhythmias that effective antiarrhythmic therapy is needed. Whether 90 percent suppression of premature ventricular complexes alters morbidity or mortality remains to be established. In summary, the intention of this short symposium is to review progress made in selected areas of therapy of cardiac arrhythmias and to consider some aspects in which efforts must be concentrated. New knowledge about arrhythmias occurring in patients with mitral valve prolapse or prolonged Q-T interval, or in patients with a clinically normal heart, is intriguing but it remains incomplete. We still do not know whether sup-

May 22, 1978

The American

Journal of CARDIOLOGY

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41

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INTRODUCTION TO SYMPOSIUM-ZIPES

pression of ventricular ectopy in patients with coronary artery disease will affect sudden death, which is one of the most pressing questions to be answered in contemporary clinical cardiology. Are the premature ventricular complexes an independent marker or a precipitating force, or both? What creates the electrical instability leading to a ventricular fibrillation in patients who, after resuscitation, do not manifest a myocardial infarction, and why are these patients so prone to a recurrence? Does reperfusion of a previously occluded coronary artery, due to dislodgment of platelet thrombi or relaxation of spasm, play a role in these patients? Will premature stimulation of the ventricle expose patients prone to have life-threatening ventricular arrhythmias and sudden death? In this regard, we recently studied a patient who had been resuscitated from three episodes of ventricular fibrillation that had recurred over a 6 week period in spite of conventional drug therapy and were not associated with acute myocardial infarction. Between episodes, the patient demonstrated only occasional isolated or pairs of premature ventricular complexes, even after exercise (treadmill) stress testing. Premature stimulation of the right ventricle with single

and double stimuli, delivered at the earliest moment in diastole, at several cycle lengths and at different endocardial sites failed to elicit a single spontaneous repetitive ventricular complex in this patient. Perhaps, premature left ventricular stimulation would have been more revealing. Or perhaps, if ventricular fibrillation is an “electrical accident” resulting from evanescent electrical instability, such testing may not be predictive at all, because factors causing the electrical instability are not present at the time of testing, even though the anatomic substrate is abnormal. Finally, if such a test is useful, does it measure the “overall” propensity to fibrillate or only that triggered by an R on T event? It is clear that we have made great strides in recent years, but much remains to be done: The woods are lovely, dark and deep But I have promises to keep And miles to go before I sleep And miles to go before I sleep. -Robert

Frost

Stopping by Woods on a Snowy Evening”

From ‘Stopping by Woods on a Snowy Evening” from The Poetry of Robert Frost edited by Edward Connery Lathem. Copyright 1923, @ 1969 by Holt, Rinehart and Winston Copyright 1951 by Robert Frost. Reprinted by permission of Holt, Rinehart and Winston, Publishers and Jonathan Cape, Ltd. l

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May 22,1979

The American Jcurnal of CARDIOLOGY

Volume 41