216 JACC Vol . 14, No . I July 18 216-7 Editorial Comment Proarrhythmia and Primum Before all of their conclusions can be accepted, several methodologic problems bear closer scrutiny . The diagnosis Non Nocere*t of the proarrhythmic event was made on the basis of spontaneous arrhythmias on a telemetered unit . The diagno- sis of repetitive nonsustained ventricular tachycardia is MELVIN M . SCHEINMAN, MD, FACC never clearly defined as a proarrhythmic event because the San Francisco, California comparative frequency of this arrhythmia before and after drug administration is not given . In addition, initiation of ventricular tachycardia that required immediate termination Antiarrhythmic agents are used to suppress symptoms due might not be a true proarrhythmic effect but an example of to cardiac arrhythmias and, it is hoped, to prevent sudden drug inefficacy with recurrence of ventricular tachycardia death . In fact, however, these agents may promote cardiac under the influence of the negative inotropic effects of a arrhythmias (1-3) . Moreover, it has proved difficult to sep- given drug . arate true proarrhythmic effects of a drug from the natural Comparison with previous reports . In contrast to other history of the cardiac arrhythmia treated . In their report, reports (,10), Stanton et al . (8) found no clear-cut relation Velebit et al . (4) set out to define proarrhythmia largely (but between left ventricular size or ejection fraction and proar- not exclusively) on the basis of changes in frequency of rhythmic effects (an increased incidence of abnormal frac- premature ventricular complexes after drug therapy . This tional shortening was found in the proarrhythmic group) . type of analysis is complicated by the enormous spontane- This was perhaps related to a bias against using several of ous variation in such frequency (5), particularly over long- the more proarrhythmic agents in patients with more im- term electrocardiographic monitoring (6) . In addition, paired left ventricular function . The absence of reported changes in premature ventricular complex density relate to polymorphic ventricular tachycardia for patients treated one adverse effect of antiarrhythmic therapy, namely, pos- with type IA drugs is somewhat surprising . Prior prospective sible exacerbation of symptoms owing to increased fre- reports (11) have shown that the incidence of proarrhythmia quency of these complexes . Apart from the issue of fre- for this patient group may be as high as 5% . Were type IA quency are the electrophysiologic effects of these agents in drugs terminated during monitoring if marked prolongation patients with sustained ventricular tachycardia or ventricu- of the QT interval was observed? The incidence of acute lar fibrillation . It is conceivable, for example, that a drug proarrhythmic effects after amiodarone appears somewhat may not affect or increase premature ventricular complex higher than in some prior reports (12,13) . In our experience density but may still prevent sudden death by exerting (13), for example, we estimated that the incidence of serious use-dependent (7) blocking effects on reentrant pathways or proarrhythmic effects after initiation of amiodarone appears by raising the ventricular fibrillation threshold . to be <1% . Patients treated with amiodarone may have Present study . Stanton et al . (8), in this issue of the bursts of tachycardia that appear to disappear with further Journal, present important and interesting data concerning therapy . proarrhythmic effects of antiarrhythmic drugs . Their defini- Conclusions . The best approach to avoidance of serious tion of proarrhythmia was eminently reasonable and based proarrhythmic effects is avoidance of high risk situations on the development of a new spontaneous arrhythmic dis- where such effects become manifest . Prior reports describe turbance (i .e ., nonsustained, sustained or incessant ventric- patients at higher risk, namely, those with organic cardiac ular tachycardia, polymorphic ventricular tachycardia or disease with seriously impaired ventricular function . Several ventricular fibrillation) consonant with initiation of a given additional findings from the report by Stanton et al . (8) drug . The findings of Stanton et al . are of paramount clinical deserve emphasis. For example, serious proarrhythmic importance in documenting the frequency of severe proar- events may occur unassociated with significant lengthening rhythmic effects of commonly used antiarrhythmic agents . of either the QRS or the QT interval . The clinician must, therefore, not be lulled into complacency when no significant *First, do no harm . changes are found in these intervals after initiation of drug (Editorials published in Journal of the American College of Cardiology therapy . Moreover, the finding that patients with nonsus- reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology . tained ventricular tachycardia are at substantial risk for From the Department of Medicine and the Cardiovascular Research development of proarrhythmic effects is equally important . Institute, University of California, San Francisco, California. For patients with nonsustained ventricular tachycardia, in Address for reprints ~ Melvin M . Scheinman, MD, Room 312, Mothtt Hospital, University of California San Francisco, San Francisco, California particular, the clinician must carefully weigh risk versus the 4143-0214 . projected benefits of initiating antiarrhythmic drug therapy . ©18 by the American College of Cardiology 0735-107/8/$3 .50 JACC Vol . 14, No . I SCHEINMAN 217 July 18 ~ 2 1 6 -7 EDITORIAL COMMENT Stanton et al . (8) found the highest incidence of proar- 5 . Winkle RA. Antiarrhythmic drug effect mimicked by spontaneous vari- ability of ventricular ectopy . Circulation 178 ;57 1116-21 rhythmic events to be associated with use of the class IC . antiarrhythmic drugs . Our own experience (14), weighing the 6 . Pratt CM . Delclos G, Wierman AM, et al . The changing baseline of complex ventricular arrhythmias a new consideration in assessing long- evidence of efficacy versus adverse effects, leads us to term antiarrhythmic drug therapy . N Engl J Med 185 313 1444- . conclude that type IC drugs should not be used in the 7 . Hondeghem LM, Katzung BG . Antiarrhythmic agents the modulated management of patients with severe organic cardiac disease receptor mechanism of action of sodium and calcium channel blocking and a history of sustained ventricular tachycardia or ventric- drugs . Ann Rev Pharmacol Toxicol 184 ;24 387-425 . ular fibrillation . To avoid infliction of harm, the clinician is 8, Stanton MS . Prystowsky EN, Fineberg NS, Miles WM, Zipes DP, Heger advised to execute caution in deciding whether antiarrhyth- JJ . Arrhythmogenic effects of antiarrhythmic drugs a study of 506 patients treated for ventricular tachycardia or fibrillation . J Am Coll mic drugs should be used as well as knowledge of specific Cardiol 1814 20-15 . drug effects for specific clinical situations . ~ . Mahmarian JJ . Verani MS . Hohmann T, et al . The hemodynamic effects of sotalol and quinidine analysis by use of rest and exercise gated radionuclide angiography . Circulation 187 76324-31 . References 10 . Morganroth J . Anderson JL, Gentzkow GD . Classification by type of ventricular arrhythmia predicts frequency of adverse cardiac events from I . Selzer A, Wray HW . Quinidine syncope paroxysmal ventricular fibrilla- flecainide . J Am Coll Cardiol 18611 381-5 . tion occurring during treatment of chronic atrial arrhythmias . Circulation 16430 17-26 . 11 . Ejvinsson G . Orinius E . Prodromal ventricular premature beats preceded by a diastolic wave . Acta Med Scand 180 ;208 445-50 . 2 . Kerr WJ, Bender WL . Paroxysmal ventricular fibrillation with cardiac recovery in a case of auricular fibrillation and complete heart-block while 12 . Harris L . McKenna WJ, Rowland E, et al . Side effects of long-term under quinidine sulphate therapy . Heart 122 ~~26-81 . amiodarone therapy . Circulation 183 67 45-51 . 3 . Sclarovsky S, Strasberg B, Lewin RF, Agmon J . Polymorphous ventric- 13 . Nguyen PT, Scheinman MM . Seger J . Polymorphous ventricular tachy- ular tachycardia clinical features and treatment . Am J Cardiol 17 44 ~ cardia clinical characterization, therapy and the QT interval . Circulation 33-44 . 186 74340- . 4 . Velebit V . Podrid P, Lown B, Cohen BH, Graboys TB . Aggravation and 14 . Herre JM . Titus C . Franz MR . et al . Inefficacy and proarrhythmia of provocation of ventricular arrhythmias by antiarrhythmic drugs . Circula- flecainide and encainidein patients with sustained ventricular tachycardia tion 182 ;65 886-4 . (abstr) . Circulation 188 78(suppl 11) 11-61 ..