Arrhythmogenesisof Antiarrhythmic Drugs PEDRO BRUGADA, MD, and HEIN J.J. WELLENS, MD
ntiarrhythmic drugs are administered to terminate an arrhythmia or to prevent its recurrence. Some of these drugs, like calcium antagonists, ,&blocking agents or amiodarone may also be given for other purposes, such as control of angina pectoris, or hypertension. Whereas the purpose of antiarrhythmic drugs is to abolish cardiac arrhythmias, they may occasionally worsen an arrhythmia or create new 0nes.l These unwanted effects of antiarrhythmic drugs take place in approximately 1 out of 10 patients1-3 and the possibility of a drug-induced arrhythmic death worries the physician. As recently discussed in a supplement to the Journa1,2s4attempts have been made to recognize patients who may develop this “arrhythmogenesis” or “arrhythmia aggravation.” The presently used criteria to recognize the occurrence of arrhythmia aggravation are not perfect. Because rather arbitrary criteria have been selected to discontinue potentially helpful drugs,2p4 let use examine them against the background of some of the pathophysiologic mechanisms involved in arrhythmogenesis. Arrhythmogenesis is best understood by considering the model proposed by Coume15 and shown in Figure 1. Three factors are involved in the spontaneous initiation atid perpetuation of tachycardias. They are the substrate, the trigger and the modulating factors. An arrhythmia can spontaneously occur only in the presence of a substrate (for instance, a reentry circuit], appropriate triggers (extrasystoles or changes in Sinus rate) and a modulating factor (like the autonomic nervous system] to provide the appropriate environment for the triggers and substrate to adequately interact in order to initiate and perpetuate tachycardia. The correct balance between these 3 factors has to be present, although it can easily be disrupted by a number of factors-including the administration of antiar-
rhythmic agents-and result ih the prevention or, on the contrary, a worsening of arrhythmias. We do not have, at the present time, a technique that can give us the necessary information about the tippropriate or inappropriate balance between the 3 factors required for spontaneous arrhythmia initiation and perpetuation. Programmed electric stimtxlation of the heart deals with the substrate of tachycardia by artificially providing the triggers. Long-term electrocardiographic monitoririg deals with some of the triggers (extrasjrstoles, changes in spontaneous rhythm] tind, in 6 very limited way, with the modulating factors of tbchycardias, such as changes in sinus rate as a marker of autonomic balance. Although exercise results in major changes in the autonomic balance, an exercise electrocardiogram usually fails to reproduce spontaneously occurring arrhythmias uriless they are related to exercise. None of the presently available techniques in arrhythmia management looks at the delicate balance between substrate, triggers and modulating factors.
Presently Used Criteria
From the Department
of Cardiology, Academic Hospital of Maastricht, University of Limburg. Maastricht, the Netherlands. Manuscript received October 29, 1987; revised manuscript received and accepted January 26, 1988. Address for reprints: Pedro Brugada, MD, University of Limburg, Clinical Electrophysiology Laboratory, Department of Cardiology, Maastricht, the Netherlands. 1108
Criteria used in noninvasive studies to detect potential arrhythmogenesis of antiatrhythmic drugs ii+ elude an increase in spontaneous ectopic activity or the first occurrence of a sustained or non&stained tachycardia during treatfient with an antiarrhythmic drug.2 During invasive studies,3s4 initiation of an arrhythmia by a lesser number of premature stimuli, a change from a nonsustained to a sustained tachycardia or a faster rate of the induced tachycardia during treatment have been considered indicators of an arrhythmic yesponse. The value of these proposed criteria for recognition of arrhythmogenesis has not yet been assessed with an appropriate study design. A careful study of possible arrhythmia aggravation requires continuation of the drug with or without presently used noninvasive and invasive ctiteria for arrhythmogenesis. Follow-up will show absence or occurrence of a spontaneous arrhythmogenic response. While the first occurrence of a sustained ventricular tachycardia (VT] during treatment with an antiarrhythmic drug is a clear-cut example of a troublesome, true arrhythmogenic response (particularly if that VT is rapid or of the torsade de pointes
May 1, 1988
type], the value of other currently used criteria of arrhythmogenesis may not be clinically relevant.
What Is an Arrhythmogenic Response? Two different responses should be considered as clinically troublesome problems during treatment of arrhythmias. The first one is the appearance of a new, clinically significant arrhythmia after initiation of treatment with an antiarrhythmic drug. As will be discussed later, that can occur because of 2 different pathophysiologic mechanisms: 11) the creation of a new arrhythmia mechanism by an antiarrhythmic drug (for example, torsade de pointes, possibly based upon early postdepolarizations or digitalis-induced arrhythmias caused by delayed postdepolarizations] or 12) the unmasking of a latent arrhythmia substrate. The second problem is an increase in incidence, duration or rate of a previously present arrhythmia after an antiarrhythmic drug has been given (facilitation of spontaneous arrhythmias]. The clinical significance of these responses depends upon the arrhythmia or possible arrhythmia being treated. In the patient with a documented sustained VT, an increase in asymptomatic ectopic activity after an antiarrhythmic drug which has successfully prevented sustained VT does not represent a clinically troublesome problem. However, some investigators have considered this to be an “arrhythmogenic” response and have discontinued the drug.3,4 A very different situation occurs when that same patient demonstrates complete suppression of both the sustained monomorphic VT and the previously present type of ectopic activity, but develops episodes of torsade de pointes during treatment. Discontinuation of the drug is mandatory in this case. The situation is also completely different when a patient with symptomatic ectopic activity, but no VT, receives an antiarrhythmic drug and develops for the first time episodes of sustained monomorphic VT. If variability in spontaneously occurring arrhythmias can be ruled out, the physician must decide between increasing the dose of the antiarrhythmic drug to suppress VT and discontinuing the drug if that undesired effect cannot be controlled. Although antiarrhythmic drugs may unmask a latent substrate at a certain dose, they may suppress the occurrence of arrhythmias using that substrate at a higher dose. The reasons for this will be discussed later. During invasive studies the situation is still more complex. The outcome of programmed electric stimulation of the heart is highly reproducible in patients with supraventricular tachycardia having a single substrate [such as the reentry circuit in a patient with an accessory atrioventricular pathway). In patients with an old myocardial infarction, however, there are multiple potential reentrant pathways for abnormal conduction and VT. Depending upon the stimulation protocol, the site of stimulation and a number of uncontrollable factors, such as the autonomic balance of the patient at the time of study and the stamina of the investigator, multiple morphologies of VT and a large variety of rates can be induced in the patient otherwise having a single morphology and rate during the spon-
True arrhythmogenesis. Creation of a new arrhythmia mechanism by an antiarrhythmic drug. Facilitation of spontaneous arrhythmias. Increase in the clinical severity of the same arrhythmia after a drug is given. Unmasking of a latent substrate. First spontaneous occurrence of an arrhythmia based upon a preexistent but latent substrate after giving an antiarrhythmic drug.
taneously occurring VTe6 The reproducibility of the clinically manifest arrhythmia is therefore less than perfect. Once an antiarrhythmic drug has been given, new morphologies of VT can be induced by artificially providing the triggers (extrastimuli). Because there is no reliable relation between the VT induced during programmed stimulation and the spontaneously occurring one, arrhythmogenesis cannot be predicted by programmed stimulation.6 Arrhythmogenic responses after drug administration are spontaneously occurring arrhythmias based upon the creation of a new arrhythmia substrate or the unmasking of a latent one by a drug, or the worsening of an already manifest and serious arrhythmia.
A Pathophysiologic Point of View Changes in the spontaneous behavior of arrhythmias can occur not only because of modifications in any of the 3 factors playing a role in the spontaneous initiation and perpetuation of tachycardias-the substrate, the triggers and the modulating factors-but also because of changes in the balance between them (possibly the most common situation]. We like to classify arrhythmogenesis after antiarrhythmic drug therapy (Table I) as follows: (1) “true arrhythmogenesis” or the creation of a new arrhythmia mechanism; (2) “facilitation” of the already manifest arrhythmia. The increase in incidence or clinical significance of spontaneously occurring arrhythmias is caused by drug-induced changes in the substrate of the tachycardia, the triggers, the modulating factors or their combination; (3) “unmasking of a latent substrate” leading to the occurrence of a new arrhythmia. REENTRY
TRIGGERS c---------) (EXTRASYSTOLES, CHANGES IN SPONTANEOUS RHYTHM)
MOOIJLATING FACTORS (AUTONOMIC NERVOUS SYSTEM, ELECTROLYTES, ISCHEMIA HORMONAL FACTORS ETC.)
FIGURE 1. A spontaneous tachycardla Is only posslblo when a substrate for the arrhythmia Is present, the necessary trlggers of the arrhythmla occur and the modulatlng factors provide the approprlate envlronment for the triggers and substrate to Interact approprlately and thus Initiate and perpetuate the tachycardla. The antlarrhythmic drugs have effects on all of these 3 factors and may suppress or facllltate the tachycardla depending upon their effect on the balance between the 3 factors.
TABLE II Steps to Reduce Incidence and Risks of ProArrhythmic Effects of Antlarrhythmlc Drugs Ask yourself if antiarrhythmic therapy is needed. Correct (when possiblel) additional ischemla and abnormalities in pump functlon. Be aware that torsade de pointes occurs most commonly with drugs prolonging the refractory period of the ventricle, such as class IA and III drugs. Correct electrolyte abnormalities especially hypokalemla. Be aware of risks of potassium-losing diuretics. Start antlarrhythmlc therapy for ventricular arrhythmia in hospital. Instruct patients to report Immediately an Increased occurrence of arrhythmias or development of dizziness and syncope.
The drug induces changes in preexistent but latent substrate, spontaneous triggers, modulating factors or the balance of these 3 factors. Such a classification takes the pathophysiologic mechanisms of arrhythmogenesis in consideration and might help in selecting the appropriate therapeutic action. “True arrhythmogenesis”: This effect occurs when an antiarrhythmic agent given to terminate or prevent a certain arrhythmia leads to a new arrhythmia because of the creation of a new arrhythmia mechanism. The most dramatic examples of “true arrhythmogenesis” are ventricular fibrillation or torsade de pointes induced by antiarrhythmic drugs. Many antiarrhythmic drugs, especially those that prolong the refractory period of the ventricle (e.g., class IA and III drugs), can cause the acquired long-QT syndrome and torsade de pointes. Although the exact mechanism of torsade de pointes is still poorly understood, experimental and clinical studies suggest that it might be caused by drug-induced early after-depolarizations.‘J An example of “true arrhythmogenesis” is the patient with the Wolff-Parkinson-White syndrome who receives quinidine to prevent circus movement tachycardia. After a few doses of quinidine the patient develops marked QT prolongation and episodes of torsade de pointes. Thus, quinidine has resulted in the development of spontaneous episodes of a new arrhythmia because of a new arrhythmia mechanism [early after-depolarizations?). While discontinuation of drug administration is mandatory in quinidine-induced torsade de pointes because the arrhythmia is not dose-related,9 true arrhythmogenesis as defined above may also occur as in digitalis intoxication when a certain toxic level is reached. Under such circumstances, a dose reduction is sufficient to abolish the arrhythmia (for example, atria1 tachycardia resulting from a toxic dose of digitalis will disappear when the drug level is lowered). “Facilitation”: The facilitation of spontaneously occurring arrhythmias by antiarrhythmic drugs is caused by drug-induced changes in the electrophysiologic properties of the tachycardia substrate, the type or number of trigger(s) or the modulating factors. This leads to worsening of the spontaneously occurring arrhythmia. A combination of these factors seems usually to play a role. Changes induced by antiarrhythmic drugs may result in more frequent, longer-lasting or faster sponta-
neous arrhythmias. In contrast to “true arrhythmogenesis,” the arrhythmia substrate and mechanism remain the same. A typical example is the patient with a reentry circuit in whom the occurrence of unidirectional block and a proper revolution time in the circuit determine the initiation and perpetuation of the arrhythmia. Changes in refractory period duration and conduction velocity may facilitate the initiation and perpetuation of the arrhythmia. A worsening of spontaneously occurring arrhythmias, as opposed to “true arrhythmogenesis,” does not always mandate discontinuation or lowering of the antiarrhythmic drug. Sometimes a dose increase may be required to control the worsening of spontaneous arrhythmias. This decision has to be made while considering many factors, such as the dose of the antiarrhythmic drug the patient is receiving at that time, the presence of side effects and the possibility of “true arrhythmogenesis” [for example digitalis intoxication) if the dose of the drug is increased. “Unmasking of a latent substrate”: The same mechanisms leading to facilitation of spontaneous arrhythmias by antiarrhythmic drugs may result in the unmasking of an already present but “quiet” arrhythmia substrate. In this situation, the arrhythmia occurs for the first time when an antiarrhythmic drug is given. This arrhythmia is, however, not based on the creation of a new arrhythmia mechanism, as is the case with “true arrhythmogenesis.” Administration of quinidine because of a short anterograde refractory period of the accessory pathway in an asymptomatic patient with the Wolff-Parkinson-White syndrome may result in a prolongation of the anterograde refractory period of the accessory pathway. Under these circumstances, a spontaneously occurring atria1 extrasystole or an exercise-induced sinus tachycardia may result in anterograde block in the accessory pathway, a condition necessary for reentry to occur. If the conduction characteristics within the circuit are appropriate, circus movement tachycardia may occur for the first time during treatment with quinidine in this previously asymptomatic patient. The substrate for circus movement tachycardia (the accessory pathway) has always been present. The electrophysiologic properties had to be changed by quinidine into the appropriate ones for a tachycardia to occur. Thus, the substrate for tachycardia was “unmasked” by quinidine. The clinical implications are clear: either the dose of quinidine is increased to control this unwanted effect or the physician has to reconsider the wisdom of giving quinidine to that asymptomatic patient with Wolff-ParkinsonWhite syndrome. Extrapolation of these concepts: Patients with the Wolff-Parkinson-White syndrome represent a unique model of reentry in the human heart. The combination of endocavitary recordings and programmed stimulation of the heart in these patients allows for a careful study of the properties of the components of the reentry circuit and the evaluation of changes induced by antiarrhythmic drugs. Unfortunately, this is not the case in most of the other arrhythmias, such as atrial, AV nodal or ventricular tachycardia. Although evidence suggesting reentry as the most common mechanism of human paroxysmal arrhythmias has been in-
creasing, definitive proof is still lacking. The behavior of these paroxysmal arrhythmias during electric stimulation and the effect of drugs, however, do support the reentry hypothesis. lo When “arrhythmogenesis” of antiarrhythmic drugs is considered, each of the 3 different types of arrhythmogenesis may occur in any reentrant arrhythmia regardless of the location of the reentrant pathway. When treating patients with supraventricular or ventricular arrhythmias, one should always consider the possibility of the development of a new arrhythmia mechanism, facilitation of the already occurring arrhythmia or the unmasking of a preexistent substrate.
Practical Considerations Arrhythmogenesis does exist. We have our reservations, however, that risk of arrhythmogenesis can be predicted by using preselected criteria during invasive studies which artificially provide the trigger for a tachycardia. After using noninvasive methods to study arrhythmias one may document that the first sustained arrhythmia results from worsening of a spontaneous nonsustained arrhythmia, the creation of a new arrhythmia mechanism by the drug or from unmasking of a latent substrate. The practical implications of such findings can only be assessed by considering the clinical situation before drug administration and the type of drug given. To reduce the incidence and risks of arrhythmogenesis by antiarrhythmic drugs we follow the steps listed in Table II. QT prolongation accompanied by torsade de pointes usually occurs early after the initiation of drug therapy because it is an idiosyncratic event not related to a toxic dose,g although its occurrence is favored by electrolyte abnormalities such as hypokalemia and hypomagnesemia. This should be realized when the patient given an antiarrhythmic drug is also receiving a potassium-losing diuretic. In general, an antiarrhythmic drug therapy for a serious arrhythmia should be initiated in the hospital under electrocardiographic monitoring. Once out of the hospital, the patients should be instructed to report any increase in incidence or severity of palpitations or complaints like dizziness or syncope. Plasma levels of antiarrhythmic drugs are of little value in reducing
arrhythmogenesis. Not only do most instances of torsade de pointes occur at “normal” plasma levels but also individual drug requirements (and therefore plasma levels) differ considerably in patients with reentrant arrhythmias depending upon the circuit size and the electrophysiologic properties within the circuit. Arrhythmogenesis is an expected effect of antiarrhythmic drugs. When arrhythmogenesis occurs the physician should try to understand the mechanisms and take the appropriate therapeutic action. “True arrhythmogenesis” requires either immediate drug discontinuation (as in quinidine-induced torsade de pointes) or dose reduction (as in digitalis intoxication]. On the contrary, “facilitation of spontaneous arrhythmias” may require a dose increase. The “unmasking of a latent substrate” demands a careful consideration of the wisdom of giving that drug. The presently used criteria to predict potential arrhythmogenesis need to to be evaluated prospectively to establish their value. The criteria should not be preselected and, to assess their relevance, patients should continue receiving their respective drugs.
References 1. Velebit V, Podrid P, Lown B, Cohen BH, Graboys TB. Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs. Circulation 1982;65:886-894. 2. Bigger JT, Sahar DI. Clinical types of proarrhythmic response to antiarrhythmic drugs. Am J Cordial 1987;59:2E-9E. 3. Horowitz LN, Greenspan AM, Rae AP, Kay HR, Speilman SR. Proarrhythmic responses during electrophysiologic testing. Am J Cardiol 1987;59:45E48E. 4. Horowitz LN. Zipes DP, Bigger JT, Campbell RWE, Podrid PJ, Rosen MR. Woosley RL. Proarrhythmia, arrhythmogenesis or aggravation of arrhythmia. A status report, 1987. Am J Cardiol 1987;59:54E-56E. 5. Coumel P. The management of clinical arrhythmias. An overview on invasive versus non-invasive electrophysiology. Em Heart J 1987;8:92-99. 6. Brugada P, Lemery R. Della Bella P, Talajic M, Wellens HJJ. Treatment of patients with ventricular tachycardia or ventricular fibrillation. First lessons from the “parallel study.” In: Brugada P. Wellens HJJ. eds. Cardiac Arrhythmias. Where to Go from Here? New York: Futura Publishing, 1987:435-436. 7. Brachmann J. Scherlag BJ. Rosentraukh LV. Lazzara R. Brady-cardiadependent triggered activity. Relevance to drug-induced multiform ventricular tachycardia. Circulation 1983;68:846-856. 8. Brugada P, Wellens HJJ. The role of triggered activity in clinical ventricular arrhythmias. PACE 1984:7:260-271. 9. Koster R, Wellens HJJ. Quinidine induced ventricular flutter and fibrillation without digitalis therapy. Am J Cardiol 1976;38:519-523. 10. Wellens HJJ. Value and limitations of programmed electrical stimulation of the heart in the study and treatment of tachycardia. Circulation 1978; 57:845-853.