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The proarrhythmic effects of antiarrhythmic drugs
Volume 114
St. Jude
Number 2
9. Stein P, Collins JJ, Kantrowitz A. Antithrombotic therapy in mechanical and biological heart valves and saphenous vein bypass grafts. Chest 1986;89(suppl):46S53S. 10. Levine NM, Raskob G, Hirsh J. Hemorrhagic complications of long-term anticoagulant therapy. Chest 1986;89(suppl): 16S-25s. 11. Chesebro JH, Fuster V, Elveback LR, McGoon DC, Pluth JR, Puga FJ, Wallace RB, Danielson GK, Orzulak TA, Piehler JM, Schaff HV. Trial of combined warfarin plus dipyridamole or aspirin therapy in prosthetic valve replacement: danger of aspirin compared with dipyridamole. Am J Cardiol 1983;51:1537-41. 12 Sullivan JM, Harken DE, Gorlin R. Pharmacologic control of thromboembolic complications of cardiac valve replacement. N Engl J Med 1971;284:1391-4. 13. Borkon AM, Soul L, Reitz BA, Gorr VL, Gardner TJ. Five-year follow-up after valve replacement with the St. Jude medical valve in infants and child. Circulation 1986;74(suppl l):llO-5. 14. Pass HI, Sade RM, Crawford FA, Hohn AR. Cardiac valve prosthesis in children without anticoagulation. J Thorac Cardiovasc Surg 1984;87:832-35.
The proarrhythmic drugs
valve
15. Donahoo JS, Gardner TJ. St. Jude medical cardiac valve prosthesis in infants and children: early and intermediate experience. South Med J 1982;75:1538-40. 16. Schaffer MS, Clarke DR, Campbell DN, Madigan CK, Wiggins JW, Wolfe RR. The St. Jude medical cardiac valve in infants and children: role of anticoagulant therapy. J Co11 Cardiol 1987;%235-9. 17. Czer LSC, Weiss M, Bateman TM, Pfaff JM, DeRobertis MA, Eigler N, Vas R, Matloff JM, Gray RJ. Fibrinolytic therapy of St. Jude valve thrombosis under guidance of digital cinefluoroscopy. J Am Co11 Cardiol 1985;5:1244-9. 18. Kurzrok S, Singh AK, Most AS, Williams DO. Thrombolytic therapy for prosthetic cardiac valve thrombosis. J Am Co11 Cardiol 1987;%592-8. 19. Moreno-Cabral RJ, McNamara JJ, Mamiya RT, Brainard SC, Chung GKT. Acute thrombotic obstruction with BjorkShiley valves. Diagnostic and surgical considerations. J Thorat Cardiovasc Surg 197&75:321-30. 20. Kontos GJ, Schaff HV. Thrombotic occlusion of a prosthetic heart valve: diagnosis and management. Mayo Clinic Proc 1985;6@118-22.
effects of antiarrhythmic
J. E. Creamer, M.B., Ch.B., A. W. Nathan, London, England
M.D.,*
The contemporary physician has a considerable range of drugs that can be effective for the treatment of arrhythmias. However, with the increasing use of such agents, it has become apparent that they may also induce or exacerbate cardiac arrhythmias (Fig. 1). Bradyarrhythmias may be produced by these drugs because of suppression of conduction and automaticity in the specialized conducting system. Such effects are usually dose-dependent and may be seen as a feature of toxicity.lzz Similarly, in atria1 tachyarrhythmias with functional atrioventricular block, acceleration of the ventricular response due to anticholinergic effects on the atrioventricular node3 and/or to slowing of the tachycardia4 may also be From the Department of Cardiology, St. Bartholomew’s Hospital. Received for publication Feb. 23, 1987; accepted Apr. I, 1987. Reprint requests: Dr. J. E. Creamer, Dept. of Cardiology, St. Bartholomew’s Hospital, West Smithfield, London EClA 7BE, Englsnd. *Drs. Nathan and Camm were supported by the British Hesrt Foundation.
and A. J. Camm, M.D.*
anticipated. However, most attention has focused on the occurrence of new or increased ventricular tachyarrhythmias during antiarrhythmic drug therapy, or the acceleration or degeneration of a ventricular arrhythmia being treated. Unlike the bradyarrhythmias, these are less predictable, are usually intermittent, and are more difficult to document. More importantly, they may resemble the original tachycardia and thus be attributed simply to failure of treatment, thus prompting an increase in the drug dose with potentially disastrous results. Systematic study of this problem is hindered by the lack of a universally-accepted definition of a proarrhythmic effect. Table I lists the criteria used in some of the major studies.5-io All the definitions proposed have in common “the appearance of new or more malignant arrhythmias after treatment with antiarrhythmic drugs.” However, in those studies where provocation testing was employed, the ease of induction of ventricular arrhythmias is also considered. There has been much discussion about the increased frequency of ventricular premature beats 397
August
398
Creamer, bagman, and Canm
American
1967
Heart Jownsi
1. Proarrhythmic effect of flecainide. A, ECG of patient with mitral valve disease and paroxysmal atria1 fibrillation prior to prophylactic treatment with flecainide. ECG of same patient after 1 week of oral flecainide, 100 mg twice daily. Fig.
as a proarrhythmic effect. Their inclusion asa factor in any formal de~ition is ~omplica~d by underlying baselinevariability, and workers have suggested different mathematical formulas to define the minimal increasesnecessaryto justify inchmion.20 However, in practice, increasedfrequency of ventricular premature beats is probably not as important as the more malignant or sustained ventricular arrhythmias. Most of the evidence for the provocation of arrhythmias by antiarrhythmic drugsis basedon the temporal relationship between dose and effect, because rechallenge is usually considered unethic&.6,6However, rechallengeunder controlled conditions has been undertaken oc~ion~y as a means
of avoiding unnecessaryand potentially harmful ~ti~rh~hmic drug treatment8 Many case reports have appeared implicating virtually all ant&rhythmic drugs in the provocation of ~h~~~. Qu~id~ne syncope,due to unheralded ventricular tachyarrhythmias, often in patients being treated for supraventricular arrhythmias, is usually regardedas the prototype of druginduced arrhythmia and, although it was originally reported in patients who were also taking digoxin,ll this was not always the case-l2Rlood levels at the time of theseepisodeshaveusually beenwell within the therapeutic range.lsn l4 In 1952Read16reported a caseof fatal ventricular ~bri~tion following the intravenous ad~nistration
Volume 114
Proarrhythmic
Number 2
Table
I. Definitions
Winkle et al. (198lY Velebit et al. (198Z16 et al. (1982)’
Ruskin et al. 1983Y
Poser et al. (1983j9
Morganroth
399
of proarrhythmia detection
Rinkenberger
drugs
et al. (lSS41’0
Occurrence of new, or more malignant ventricular arrhythmias Marked exacerbation of arrhythmia Quadruple increase in VPBs Repetitive forms, couplets, VT (new, or lo-fold increase) Induction of sustained VT on drug when only nonsustained VT induced previously Spontaneous occurrence of ventricular arrhythmia during drug therapy and inducible ventricular arrhythmia absent without drugs but present on rechallenge Provocation of arrhythmia with fewer extrastimuli than in control study Sustained ~~ when only nonsus~ined VT during control Sustained VT at faster rate than during control Presence of new ventricular tachyarrhythmia &hange in previous ventricular arrhythmia Increased VPB frequency X3-10 Increased VT rate Change in ease of termination
of pro~~n~ide. Pol~orphi~ ventricular tachycardia due to both intravenous and oral procainamide was linked to concomitant QT interval prolongation in seven cases reported by Strasberg et all6 In two of these patients it degenerated to fatal ventricular fibrillation. Disopyramide therapy has been associated with similar arrhythmias occurring in the presence of prolonged ventricular repol~ization.1’-19 Cases of disopyramide toxicity associated with uniform and polymorphic ventricular tachycardia show widening of the QRS complex in addition to QTc prolongation.m*z1 Polymorphic ventricular tachycardia in the absence of significant QRS or QTc prolongation has been reported with mexiletine?2 and ventricular fibrillation has been induced by another Vaughan-Williams class Ib drug, tocainide.z3 Flecainide-associated ventricular tachycardia and ventricular flutter have been recorded in the presence of both therapeutic and toxic serum levels and with QT prolongation due entirely to QRS widening, the JT interval being unchanged.* The class III agents, amiodarone and sotalol, both prolong the QT interval.“sz5 Amiodarone has been associated with polymorphic ventricular tachycardia, both in combination with disopyramide ,% digoxin and metoprolol,2’ and alone.m A number of cases of sotalol intoxication have been reported showing marked increases in QT=*=’ and QTcs’ intervals, and with ventricular tachycardias in addition to atrioventricular block. Syncope and ventricular arrhythmias have also been
method
ECG telemetry %-hour ECG Maximal exercise ECG Programed
electrical stimulation
Programmed
electrical stimulation
Programmed
electrical stimulation
Programmed electrical stimulation Ambulatory ECG monitoring
reported in patients given large, but therapeutic doses of sotalol?2 and with normal therapeutic doses when combined with diuretic drugs, associated with low serum potassium levels or with other QTlengthening agents?3 Although reserved for the treatment of refractory ventricular arrhythmias, bretylium tosylate has itself been implicated in the provocation of more malignant ventricular tachycardias and fibrillation.M The incidence of proarrhythmic effects in practice is not well documented. This reflects the intermittent nature of the arrhythmias, which reduces the diagnostic yield from conventional monitoring techniques unless they are applied for extended periods. Such extensive monitoring is not always performed. Estimates may be obtained from studies on the survivors of “out of hospital” cardiac arrest due to ventricular tachyarrhythmias. Among these patients there is a high rate of recurrence of ventricular fibrillation and sudden death despite empirical antiarrhythmic therapy.35*B Furthermore, in two series, 30% to 69% of patients resuscitated from “out of hospital” cardiac arrest were taking antiarrhythmic drugs at the time of their cardiac arrest?7*s 0f 98 survivors of a cardiac arrest not associated with acute myocardial infarction, Ruskin et al.* found 25 in whom no ~h~hrni~ could be provoked by programmed ventricular stimulation. Six of these had been taking antiarrhythmic drugs at the time of their cardiac arrest and, when these drugs were
400
Creamer,
Nathan,
and Camm
tat NON-INVASIVE
ASSESSMENT *
Proarrh ivthmic effects 1%)
2. The incidence of proarrhythmic effects with individual antiarrhythmic drugs. A, Noninvasive assessment (Data from Velebit updated by Podrid,‘O with additional data* from Nathan et aL4 and Winkle et a1.r). B, Invasive assessment (Data from Poser updated by Podrid,“’ with additional data* from Nathan et al.’ and Winkle et al.5).
Fig.
reintroduced
and programmed
electrical stimulation
was repeated, ventricular arrhythmias were induced in four patients and high-grade atrioventricular block with spontaneous ventricular fibrillation occurred in one other.8 In a collected series,3D quinidine syncope has been reported in 0.5% to 4.4% of patients receiving the drug and was fatal in 11.5%. Velebit et al6 used a systematic program of antiarrhythmic drug testing, involving 24-hour ECG monitoring and maximum symptom-limited exercise testing, and observed a worsening of arrhythmia in 80 out of 722 (11% ) drug tests in 53 of 155 (34 % ) patients referred for treatment of refractory ventricular tachyarrhythmiss. Drug-induced arrhythmias varied from an increase in the frequency of ventric-
ular premature
beats to the occurrence of sustained
ventricular tachycardia. Fig. 2, A shows the incidence of proarrhythmic effects from the individual agents. The data are drawn from the work of Velebit et al. updated by Podrid,m with additional figures by other workers. The result-a are biased by the disproportionate use of the investigational drug, encainide. Nathan et al4 found proarrhythmic e@ects in 7 of 152 (4%) patients given flecainide, and of these five (3 % ) developed ventricular tachycardia or fibrillation.
Encainide-sssociated
ventricular
tachyar-
rhythmias occurred in up to 13% of patients with a previous history of sustained ventricular tachycardia or fibrillation? With the use of programmed intracardiac stimu-
volume 114 Number 2
lation for serial drug testing, Rinkenberger et al? found that in 11 out of 83 patients (13%) the administration of disopyramide, amiodarone, encainide, or quinidine converted inducible nonsustained ventricular ~~hy~ardia to sustained ventricular tachycardia. The incidence of proarrhythmic effects with individual agents as detected by invasive electrophysiologic testing is shown in Fig. 2, B, and is based on the work of Poser et aL9, updated by Podrid.& It is interesting to note that the frequency of these effects is greater with invasive than with noninvasive testing, suggesting that the former may be a more sensitive method of testing. The clinical effect of an anti~rh~~ic drug results from the specific electrophysiologic changes it produces imposed on the unique arrhythmia substrate in each patient. While a superficial knowledge of both aspects may be possible, the unique details at the microscopic and biochemical level cannot be ascertained for each individual. That both aspects must be considered in the production of drug-induced arrhythmias is suggested by those cases where individuals have had a similar proarrhythmic response to two different drugs with similar electrophysiologic characteristics, such as quinidine and disopyramide,l’ or lorcainide and encainide.5 The importance of the arrhythmia substrate in the occurrence of pro~rh~hmic effects is highlighted by the studies on encainide.5 A total of 180 patients were studied. No ventricular tachyarrhythmias were induced at electrophysiologic study in 32 patients who had had no previous spont~eous arrhythmia, nor in 13 patients who had previous supraventricular arrhythmias. However, inducible ventricular tachyarrhythmia was seen in 1 out of 45 patients (2.2%) given the drug for complex ventricular ectopy and in 12 out of 90 patients (13.3%) with prior sustained ventricular tachycardia.5 In a report summarizing the experience with flecainide in 558 patients from a number of different centers,lO it was noted that the group suffering proarrhythmic effects had a greater frequency of coronary artery disease, myocardial infarction, ventricular tachycardia, and cardiac failure. A combination of previous ventricular tachycardia and cardiac failure was seen in 52% of those who experienced proarrhythmic effects but in only 3% of those who did not. However, no significant difference in underlying diagnosis or severity of cardiac failure was noted in those patients experiencing proarrhythmic effects from encainide compared with those who did not.5 In addition to the electrophysiologic effects of the drugs themselves and the arrhythmia substrates, the
Proarrhythmic
Table
drugs
401
Il. Possible mechanisms of drug-induced arrhyth-
mias 1. 2. 3. 4. 5. 6. I. 6. 9.
Non-nniformity of repolarization Changes in conduction time Increased automaticity and triggered activity Fibrillation threshold Pacing threshold Effects on sinoatrial function Effects on atrioventricular conduction Autonomic effects Negative inotropic effects
p~ition is further complicated by the variety of autonomic states that an individual may experience and by changes in these autonomic effecti during daily living. The effects of such influences are difficult to evaluate systematically and little attention has been paid to this in the major studies except indirectly by the use of exercise testing.6 In many of the case reports, patients were noted to be taking more than one drug when proarrhythmic effects occurred. In these cases the phenomenon was usually attributed to the last drug to be introduced. However, the possibility of proarrhythmic effects being due to the combination of antiarrhythmic drugs has not been formally addressed. Amiodarone,*l verapamil,ht and quinid~e~ may all raise serum digoxin levels and potentially precipitate toxicity, but the mechanisms of other potential interactions are not known. Disturbances of potassium, calcium, and magnesium balance may also interact to provoke drug-induced arrhythmias, possibly through direct membrane effects. MECHANISMS
OF DRUG-INDUCED
ARRHYTHMIAS
mechanisms have been proposed to explain the proarrhythmic potential of antiarrhythmic drugs (Table II) that are based on their main properties. Nonuniformity of repolarization. Prolongation of the QRS, QT, and JT intervals is often seen in association with ventricular arrhythmias provoked by many of the Vaughan-Williams class I and class III agents. Overall prolongation of repolarization may be associated with temporal dispersion of refractory periods and nonuniform recovery of fiberst4 which may in turn lead to the occurrence of reentry circuits and the conditions for “reflection” of impulses- Differences in ventricular refractory periods at different sites within the ventricle have been demonstrated following amiodarone administration? Changes in conduction time. Agents such as flecainide and encainide do not prolong the JT interval,
402
Greamer, Nathan, and Gamm
although both may prolong the QT interval due to QRS widening. It has been proposed that slowing of intraventricular conduction may be their predominant proarrhythmic mechanism.4s5 Such conduction slowing may be nonuniform and thus may give rise to new reentry circuits or may sustain a circuit that was already present but previously nons~~ned. This is consistent with the occurrence of sustained ventricular tachycardia at a slower rate after drug administration, as noted by Rinkenberger et aL7 Paradoxical acceleration of ventricular tachycardia may occur where impulses from an ectopic tachycardia focus are limited by exit block. Slowing of the tachycardia rate by antiarrhythmic drugs may overcome the block and allow a one-to-one response. The rapid development of intraventric~ar conduction delay has been postulated as a mechanism underlying the occurrence of ventricular fibrillation after atropine, although this was based on observations of a single case with coronary artery disease and left ventricular failure? hxreased
automatkity
and
triggered
activity.
Abnormal automaticity has been invoked to explain the production of ventricular arrhythmias by some drugs. Cellular studies of digoxin toxicity suggest that delayed afterdepolarizations are responsiblet7 whereas early afterdepolarizations may be induced by N-acetylprocainamide administration.48 Def~br~liation threshold. In some instances of drugassociated ventricular ~brillation, electrical defibrillation has been unduly difficult or impossible.4~1’~1z It is likely that changes in defibrillation threshold reflect the effects of drugs on the fibrillation threshold. Studies in dogs have shown that lidocaine increases the threshold for transthoracic defibrillation.4s Bretylium either has no effect or decreases the threshold. The increasing clinical use of the automatic implantable cardioverter/defibrillator provides an opport~ity for similar observations in man. Amiodarone has been shown to increase the threshold for defibrillation by the device, tbus reducing its safety margin. 50,51No statistically significant effect was noted with digoxin and the Vaughan-Willies class I drugs as a group, and there are insufficient data to draw conclusions for the individual agents.51 Pacing threshold. Flecainide has been shown to increase the endocardial pacing t~eshold,52 and this has the potential for provoking arrhythmias due to pacing failure. Both bradycardias and bradycardiadependent tachycardias may be induced. Increases in acute and chronic pacing threshold have also been shown with the Vaughan-Willies class Ia drugs,
procainamide and quinidineF3 but the class Ib drugs, lidocaine and phenytoin, had little or no effect.“,~ By contrast, the class II agents, propranolol and oxprenolol, and the class IV agent, verapamil, have been shown to increase the pacing threshold by up to 40 76 when given intravenously,“, 57~ 5* although this is not a consistent finding.~g Effects on sinoatrial function. The influence of antiarrhythmic drugs on the sinus node may be direct or may occur through autonomic mechanisms. The most frequent result is simple sinus bradycardia, as seen with the beta-adrenergic blocking drugs, and amiodarone, which has both antiadrenergic and direct effects on the sinus node.m Sinus arrest may also occur, and occasionally bradyarrhythmias are severe enough to require pacinga61 Quinidine reduces sinoatrial conduction and may lead to exit block, although its effects in vivo may vary according to autonomic modulation.61a Procainamide has no effect on the sinus node in normal individuals, but may prolong the corrected sinus node recovery time after rapid atrial pacing in patients with the sick sinus syndrome.62 Lidocaine and mexiletine may reduce sinus node automaticity and conduction in patients with sinus node dysf~ction.~ The intravenous administration of verapamil to patients taking beta-blocking drugs may produce dramatic depression of the sinus node and lower escape pacemakers producing asystole.% By contrast, transient sinus tachycardia may be produced by bretylium by the initial release of stored catecholamines.65 Disopyramide, by its anticholinergic effects, may also cause sinus tachycardia, especially when high vagal tone is present.& Effects on atrioventricuiar conductton. As previously mentioned, antiarrhythmic drugs have the potential for proarrhythmic effects by their direct or indirect effects on the atrioventricular node. These may occur in the treatment of atria1 tachy~h~hmias associated with some degree of atrioventricular block. The anticholinergic effects of drugs such as disopyramide may paradoxically increase the ventricular response prior t,o termination of the arrhythmia.3 A similar increase in ventricular rate may be seen when a drug, such as flecainide, increases the cycle length of atria1 flutter so that it exceeds the refractory period of the atrioventricu1a.r node and allows a one-to-one ventricular response.* In patients with ventricular preexcitation, antiarrhythmic drugs may have deleterious effects on arrhythmias due to their effects on the accessory pathway. Digitalis may shorten the refractory period
Volume 114 Number 2
Fig. 3. The arrhythmogenic termination of atrioventricular maneuver.
Proarrhythmic
drugs
403
effect of autonomic changes. Ventricular arrhythmia occurring during reentrant tachycardia at the end of stage II (arrow) of the VaIsaIva
of the accessory pathwaf7 and may increase the ventricular response in some patients with the Wolff-Parkinson-White syndrome and atrial fibrillation.@ Lidocaine and verapamil have also been reported to speed the ventricular response to atria1 fibrillation in such patients.6ge7o In patients who suffer from atrioventricular reentrant tachycardia, drugs such as flecainide, which prolong conduction in the accessory pathways, may convert a paroxysmal arrhythmia into an incessant one if such conduction is not completely abolished. Autonomic effects. In addition to the modulating effects on the behavior of the sinoatrial node and atrioventricular junction, autonomic influences may be arrhythmogenic in other ways, for example, during a Valsalva maneuver, salvos of ventricular premature beats may occur during the transition from phase II (sympathetic predominant) to phase IV (parasympathetic predominant). In Fig. 3 a Valsalva maneuver performed during atrioventricular reentrant tachycardia induced a salvo of ventricular premature beats associated with termination of the tachycardia. Many antiarrhythmic drugs have autonomic effects and may provoke arrhythmias through this mechanism. The early onset of sustained ventricular tachycardia and ventricular ~brillation after bretylium administration may be related to local catecholamine release prior to neuronal depletion. In one such case, ventricular fibrillation occurred in the context of an increase in ventricular ectopic activity that could be controlled by propranolol?4 Negative inotropic effects. Other indirect mechanisms include the negative inotropic effect of most antiarrhythmic agents, which may exacerbate cardiac failure and associated ventricular arrh~hmi~. Such deleterious hemodynamic effects may also prejudice recovery from ventricular fibrillation.71
Table
Ill. Management of drug-induced arrhythmias 1. Emergency treatment (DC cardioversion, pacing) 2. Appropriate moni~ring (clinical, PEG, serum drug levels) 3. Correct contributory factors (bradycardia, electrolyte disturbance, heart failure, &hernia, other drugs) 4. Change antiarrhythmic drug therapy Reduce dose Change to another drug Stop all antiarrhythmic drugs Add another drug Consider another type of treatment Pacing Defibriilator Surgery
DETECTKJN
OF DOUG-INDUCED
A~~HY~~IAS
The possible occurrence of drug-induced ventricular arrhythmias in individual patients is not easily predicted from a consideration of clinical factors. It has been suggested that with certain drugs monitoring serial ECGs for QT prolongation would identify those patients at risk who should be followed more closely or perhaps have the drug withdrawn. The sensitivity, specificity, and “cut-ofI” point of disproportionate prolongation under these circumstances is not known. The monitoring of serum levels may be wise in those patients with renal or hepatic failure where accumulation is likely to occur, but its value in predicting arrhythmogenic effects is doubtful, since these effects often occur in the presence of “therapeutic” levels. 13s14 A recent study7z could not predict which patients would be susceptible to drug-induced aggravation of arrhythmia by using clinical criteria, ECG changes, or the pharmacolsmetics of antiarrhythmic drugs. Proarrhythmic effects were, howev-
404
Creamer, Nathan, and Camm
er, found more frequently in those with a history of malignant ventricular arrhythmias, suggesting that caution should be used in treating such patients. Most authors recommend some form of testing to monitor the efficacy of antiarrhythmic drug therapy but, with the appreciation of the importance of arrhythmogenic side effects of these drugs, a new dimension has been added to the significance and emphasis of such testing. Programs of antiarrhythmic drug testing include prolonged ambulatory ECG monitoring and exercise stress testing, or programmed intracardiac electrical stimulation, but the relative roles of these techniques, especially with reference to the identification of proarrhythmic effects, are still not established. MANAGEMENTOF
DRUG-INDUCEDARRHYTHMIAS
As the arrhythmogenic potential of antiarrhythmic drugs may be life-threatening and is not entirely predictable, the use of these drugs should be critically examined in each case and reserved for those with firm indications for treatment. Adequate assessment of their efficacy and arrhythmogenic potential should be attempted by means of ambulatory ECG monitoring and/or provocative testing by exercise or programmed electrical stimulation, as appropriate or available. The possibility of proarrhythmic effects should be borne in mind in the event of any unexpected exacerbation of the arrhythmia being treated or the occurrence of new arrhythmias; the need for antiarrhythmic drug therapy should be reassessed at this stage, and an appropriate treatment strategy should be selected. When drug-induced arrhythmias occur, there are a number of possible management strategies, as shown in Table III. These include reducing the drug dose (perhaps guided by serum levels), changing to an alternative drug, stopping the offending drug and reassessing whether any antiarrhythmic drug is needed at all (which is often the safest course), or adding another drug. The last of these strategies is probably the most dangerous and confusing. In those cases where multiple drug regimens have been employed, the most appropriate strategy is often to stop all antiarrhythmic drugs under appropriate observation in hospital, where facilities for immediate electrical cardioversion and temporary pacing are available. The assessment and treatment of aggravating factors such as heart failure, electrolyte disturbances, inappropriate bradycardia, and cardiac ischemia, should be attended to initially. Next, the arrhythmia itself should be assessed by means of appropriate monitoring and provocation testing, and on the basis of this assess-
American
August IQ87 Heart Journal
ment, an appropriate alternative specific treatment should be selected. This may involve the use of alternative drugs or combinations of drugs, implantable devices, or surgery. Finally, the specific treatment chosen should be assessed, both for efficacy and for proarrhythmic potential. While such a management strategy is time-consuming and the treatment options may be limited outside special centers, the process rm& be employed in difficult cases if such arrhythmias are to be treated safely and effectively. In conclusion, the occurrence of proarrhythmic effects during antiarrhythmic drug therapy is a significant problem that must be recognized. This occurrence is not easily predicted, but should be actively sought and appropriately managed by those who use such drugs. Antiarrhythmic agents are often effective but are also potentially dangerous and should be treated with respect. SUMMARY
Although antiarrhythmic drugs are effective for controlling cardiac arrhythmias, they may also induce or exacerbate them. Case reports have appeared implicating all classes of antiarrhythmic drugs. It is difficult to assess the size of the problem in practice, as it varies with difIerent subgroups of patients, but rates of up to 13% have been found where proarrhythmic effects were actively sought. Their occurrence is aBected both by the electrophysiologic characteristics of the drugs and by the arrhythmia substrate. Mechanisms of proarrhythmic effects may be classified according to the electrophysiologic and hemodynamic effects of the drugs. Detection of drug-induced arrhythmias depends on appreciation of the problem by physicians and, although there are few clear predictors, some form of monitoring of antiarrhythmic drug treatment is recommended. Management of such arrhythmias when they occur involves withdrawal of the offending agent, correcting contributory factors, and reassessing the initial arrhythmia and the strategy for its management. REFERENCES
1. Orr GM, Bodansky HJ, Dymond DS, Taylor M. Fatal verapamil overdose. Lancet 1982;2:1218-9. 2, Fach WA, Mai BV, Preusler W, Becker HJ. Flecanidintoxication. Innere Medizin 198411:27-31. 3. Birkhead JS, Vaughan-Williams EM. DuaI effect of disopyramide on atriaI and atrio-ventricuIar conduction and refractorv ueriods. Br Heart J 1977:3S%7-660. 4. Nab-ran AW, HeIIestrand KJ, Bextcn RS, Banim SO, Spurrell RAJ, Camm AJ. Proarrhythmic effects of the new antiarrhythmic agent flecainide acetate. AM HEART J 1984$0?2228.
volume 114 Number 2
5. Winkle RA, Mason JW, Griffin JC, Ross D. Malignant ventricular tachyarrhythmias associated with the use of encainide. & &ART J 1981;162:857-64. 6. Velebit V, Podrid P, Lown B, Cohen BH, Graboys TB. Aggravation and provocation of ventricular arrhythmias by antiarrh~~ic durgs. Circulation 198&65z%%6-94. 7. Rinkenberger RL, Prystowsky EN, Jackman WM, Naccarelli GV, Heger JJ, Zipes DP. Conversion of non-sustained ventricular tachycardia to sustained ventricular tachycardia during serial electrophysiologic studies: Identification of drugs that exaccerbate tachycardia and potential mechanisms. h HEART J 19%~103zl77-84. 8. Ruskin JN, McGovern B, Garan H, DiMarco JP, Kelly E. Antiarrhythmic drugs: A possible cause of out-of-hospital cardiac arrest. N Enel J Med 19%3:309:1302-6, 9. Poser R, Lombardi F, Podrid PJ,’ Lown B, Aggravation of arrhythmia during electrophysiologic testing (abstr). J Am Co11 Cardiol 198&!:708. J, Horowitz LN. Flecainide: Its pro~rh~hmic 10. Morg~roth effect and expected changes on the surface electrocardio” gram. Am J Cardiol 19%453;89B-94B. 11. Seizer A, Wray HW. Quinidine syncope: Paroxysmal ventricular fibrillation occurring during treatment of chronic atria1 arrhythmias. Circulation 19ti,3&17-26. ventricular 12 Koster RW, Wellens HJJ. Quinidine-educed flutter and fibrillation without digitalis therapy. Am J Cardiol 1976;38519-23. 13, Jenzer HR, Hagemeyer F. Quinidine syncope: Torsade de pointes with iow quinidine plasma concentrations. Eur J Cardiol 1976;&447-51. 14. Bauman JL, Bauernfeind RA, Hoff JV? Strasberg B, Swiryn S, Rosen KM. Torsades de pointes due to quinidine: Observations in 31 patients. AM HEARTJ 19%4;107:425-30. 15, Read JM. Fatal ventricular fibrillation following procainamide hydrochloride therapy. JAMA 1952;149:139&1. 16. Strasberg B, Sclarovsky S, Erdberg A, Duffy CE, Lam W, Swiryn S, Agmon J, Rosen KM. Pr~in~ide-induced polymorphous ventricular tachycardia. Am J Cardiol 1981; 47:1309-14. 17. Dhurandhar RW, Nademanee K, Goldman AM. Ventricular tachycardia-flutter associated disopyramide therapy: A report of three cases. Heart Lung 197&?783-7. 18. Chia BL. Disop~amide induced atypical ventric~ar tachycardia. Au& NZ J Med 198O$h665-8. 19. Nicholson WJ, Martin CE, Gracey JG, Knoch HR. Disopyramide-induced ventricular fibrillation. Am J Cardiol 1979; 43;1053-5. 20. Lo KS, Gantz KB, Stetson PL, Lucchesi BR, Pitt B. Disopyramide-induced ventricular tachvcardia. Arch Intern Med i980$4&413*4. 21. Meltzer RS, Robert EW, McMorrow M, Martin RP. Atypical ventricular tachycardia as a manifestation of disopyramide toxicitv. Am J Cardiol 197&42:1049-53. 22. Cocco G, Strozzi C, Chu D, Pansini R. Torsades de pointes as a manifes~tion of mexiletine toxicity. AM HEARTJ 19%
102222-8.
23. Eugler RL, LeWinter M. Tocainide induced ventricular fibrillation. AM HEART J 1981;101:494-6. 24. Debbas NMG, DuCailar C, Bexton RS, Demaille J, Camm AJ. Puech P. The QT interval A predictor of the plasma and mvocardia1 concentrations of imiodarone. Br Heart J lQ-8$51:316-20. 25. Nathan AW, Hellestrand KJ, Bexton RS, Ward DE, Spurrell RAJ. Camm AJ, Electronhysiological effects of sotalol-just another beta blocker? Br Heart J 19%2;4?515-20. 26. Westveer DC, Gadowski GA, Gordon S, Timmis GC. Amiodarone-induced ventricular tachycardia. Ann Intern Med 198% 92561-2. 27. McComb JM, Logan KR, Khan MM, Geddes JS, Adgey AAJ. Amiodarone-induced ventricular fibrillation. Eur J Cardiol 19%&11:381-5.
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drugs
405
2%. Veglia L, Scanditlio T, Guerricchio G. “Torsioni di puma” e amiodarone. G Ral Cardiol 197%&1025-9. 29. Desoutter P, Medioni J, Lerasle S, Haiat R. Bloc auriculoventriculaire et torsades de pointe apres sur dosage par le sotalol. Nouv Presse Med 1983523855. 30. Neuvonen PJ, Elonen E, Vuorenmaa T, Laakso M. Prolonged QT interval and severe ~chy~rh~i~. Common features of sotalol intoxication. Eur J Clin Pharmacol 1981;2&85-9. 31. Belton P, Sheridan J, Mulcahy R. A case of sotalol poisoning. Ir J Med Sci 19%2;151;126-7. 32. Laakso M, Pentikainen PJ, Pyorala K, Neuvonen PJ. Prolongation of the Q-T interval caused by sotalol-possible association with ventricular ~chy~rh~hmi~. Eur Heart J 1981;2%353-%. 33. McKibbin JK, Pocock WA, Barlow JB, Scott Millar RN, Obell IWP. Sotalol, hypokalaemia, syncope and torsade de nointes. Br Heart J 1984:51:157-62. 34. Anderson JL, Popat KD, Pitt B. Paradoxical ventricular tachycardia and fibriIlation after intravenous bretylium therapy. Report of two cases. Arch Intern Med 1981;141:801-2. 35. Lithbertson RR, Nagel EL, Hirschman JC, Nussenfeld SR. Prehospital ventricular defibrillation: Prognosis and followup course. N Engl J Med 197*291:317-21. 36. Cobb LA, Baum RS, Alvarez H, Schaffer WA. Resuscitation from out-of-hospi~l ventricuiar fibrillation: 4 years followup. Circulation 197&51 and 5Z(suppl IID:223-8. 37. Moss AJ, De Camilla J, Davis H. Cardiac death in the first six months after myocardial infarction: Potential for mortality reduction in the early post hospital period. Am J Cardiol 197%3Qz816-20. 38. Vismara LA, Vera Z, Foerster JM, Amsterdam EA, Mason DT. Identification of sudden death risk factors in acute and chronic artery disease. Am J Cardiol 1977;3Qz%21-8. 39. Reynolds EW, Vander Ark CR. Quinidine syncope and the delayed repolarization syndromes. Mod Concepts Cardiovasc Dis 197645117-22. 40. Podrid P. Aggravation of arrhythmia-a drug-induced complication. Drugs 1985;29(suppl4):33-44. 41. Moysey JO, Jaggarao NSV, Grundy EN, et al. Amiodarone increases plasma digoxin concentration. Br Med J 1981; 282272. 42. Kiein HO, Lang of verapamil -. R, Weiss E, et al. The-. influence . on serum digoxin concentration. ~1rcuIation 19%~6~9981003. 43. Ejvinsson G. Effect of quinidine on plasma concentrations of digoxin. Br Med J 1978;1:279-80. 44. Han J, Goel BG. Electrophysiological precursors of ventricular tachyarrhythmias. Arch Intern Med 1972$29:749-55. 45. Ezri MD, Huang SK, Messer JV, Denes P. Ele~ronhvsiolo~c observations of concealed ventricular depolarizations due-to amiodarone. AM HEARTJ 19%2;104:l69-72. 46. Santinelli V, Chiarello M, Condorelli M, Rapid increase of intraventricular conduction delay in the genesis of ventricular fibrillation after atropine. Int J Cardiol 19%$%109-11. 47. Rosen MR. Cellular machanisms of cardiac arrh~hmi~. In: Harrison DC, editor. Cardiac arrhythmias, a decade of progress. Boston:GK Hall Medical Publishers, 1981:25-38. 48. Dangman K, Hoffman BF. Effects of N-acetylprocainamide on cardiac Purkinje fibers (abstr). The pharmacologist 197&2&150. 49. Kerber RE, Pandian NG, Jensen SR, Cons~ntin L, Kieso RA, Melton J, Hunt M. Effects of lidocaine and bretylium on energy requirements for transthoracic defibrillation: Experimental studies. J Am Co11 Cardiol 1986;7:397-405. 50. Fogoros RN. Amiodarone-induced refractoriness to cardioversion. Ann Intern Med 1984$6Oz699-700. 51. Troup PJ, Chapman PD, Olinger GN, Kleinman LH. The implanted defibrillator: Relation of deflbrillating lead conflguration and clinical variables to defibrillation threshold. J Am Co11 Cardiol 1985$X315-21. 52. Hellestrand KJ, Burnett PJ, Milne JR, Bexton RS, Nathan
406
53. 54.
55.
56.
Creamer,
Nathan,
and Camm
AW, Camm AJ. Effect of t,he antiarrhythmic agent flecainide acetate on acute and chronic pacing thresholds. PACE 1983;&892-9. Singh BN, Hauswirth 0. Comparative mechanism of action of antiarrhythmic drugs. AM HURT J 197%87:367-82. Young MW, Meia H, Furman S, et al. Effects of lidocaine and ouabain on myocardial threshold to pacer stimuli (abstr). Circulation 197&4l:iII-209. Bigger JT, Weinberg DI, Kovalik ATW, et al. Effects of diphenylhydantoin on excitability and automaticity in the canine heart. Circ Res 1970;26:1. Preston TA, Fletcher RD, Lucchesi BR, et al. Changes in myocardial threshold. Physiologic an pharmacologic factors in patients with implanted pacemakers. AM HEART J
JT Jr. Electrophysiologic effects of procainamide on sinus node function in patients with and without sinus node disease. AM HEART J 1982;103z75-9. 63. Heger JJ, Prystowsky EN, Zipes DP. Clinical choice of antiarrhythmic drugs. In: Josephson ME, editor. Ventricular tachycardia: Mechanisms and management. Mt. Kisko, N.Y.: Futura Publishing Co., 1982: 195-235. 64. Benaim ME. Asystole after verapamil. Br Med J 197$2:169-
1967;74:235-42.
66.
Doenecke P, Flothner R, Rettig G, et al. Studies of short- and long-term threshold changes. In: Schaldach M, Furman S, ediiors. Advances in pa&maker technology. Berlin-Heidelberg-New York &ringer-Verlaz. 1975283-96. 58. Kuiler W, Sowto; E. influence-&f beta-blockade on myocardial threshold in patients with pacemakers. Lancet 1970;
70. 65.
51.
67,
68.
2:67-B.
Singh BN, Collett JT, Chew CYC. New perspectives in pharmacologic therapy of cardiac arrhythmias. Progr Cardiovast Dis 198@222z243-301. 60. Heger JJ, Prystowsky EN, Jackman WM, Naccarelli GV, Narfel KA. Rinkenbereer RL. Ziues DP. Amiodarone: Clinical efficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardia. N Engl J Med 1981;305:539-45. 61. Bigger JT Jr. Management of arrhythmias. In: Braunwald E, editor Heart disease: A textbook of cardiovascular medicine. Philadelphia: W.B, Saunders Co., 1980:717. 61a. Zipes DP. Specific arrhythmias: Diagnosis and treatment. In: Braunwald E, editor. Heart disease: A textbook of cardiovascular medicine. Philadelphia: W. B. Saunders Co., 1984:691. 62. Goldberg D, Reiffel JA, Davis JC, Gang E, Livelli F, Bigger
59.
69.
70.
Anderson JL, Patterson E, Wagner JG, Johnson TA, Lucchesi BR, Pitt B. CIinical pharmacokinetics of intravenous and oral bretylium tosylate in survivors of ventricular tachycardia or fibrillation: Clinical application of a new assay for bretylium. J Cardiovasc Pharmacol 1981;3:485-99. Danilo F Jr, Rosen MR. Cardiac effects of disopvamide. AM HEART J 1976;92:532-6. Wellens HJJ, Durrer D. Effect of digitalis on atrioventricular conduction and circus movement tachycardias in patients with Wolff-Parkinson-White syndrome. Circulation 1973; 47:129-33. Sellers TD, Bashore TM, Gallagher JJ. Digitalis in the preexicitation syndrome: Analysis during atria1 fibrillation. Circulation 1977;56:260-7. Akhtar M, Gilbert CJ, Shenasa M. Effect of lidocaine on atrioventricular response via the accessory pathway in patients with the Wolff-Parkinson-White syndrome. Circulation 1981;63:435-41. Gulamhusein S, Ko P, Carruthres SG, Klein GJ. Acceleration of the ventricular response during atria1 fibrillation in the Wolff-Parkinson-White syndrome. Circulation 1982;65:34854.
Euler DE, Zeman TW, Wallock ME, Scanlon PJ. Deleterious effects of bretylium on haemodynamic recovery from ventricular fibrillation (abstr). J Am Co11 Cardiol 19867:25OA. 72. Slater W, Podrid P, Lampert S, Lown B. Are there clinical predictors for arrhythmia aggravation? (abstr) J Am Co11 Cardiol 1986:7:158A. 71.
St. Jude
Number 2
9. Stein P, Collins JJ, Kantrowitz A. Antithrombotic therapy in mechanical and biological heart valves and saphenous vein bypass grafts. Chest 1986;89(suppl):46S53S. 10. Levine NM, Raskob G, Hirsh J. Hemorrhagic complications of long-term anticoagulant therapy. Chest 1986;89(suppl): 16S-25s. 11. Chesebro JH, Fuster V, Elveback LR, McGoon DC, Pluth JR, Puga FJ, Wallace RB, Danielson GK, Orzulak TA, Piehler JM, Schaff HV. Trial of combined warfarin plus dipyridamole or aspirin therapy in prosthetic valve replacement: danger of aspirin compared with dipyridamole. Am J Cardiol 1983;51:1537-41. 12 Sullivan JM, Harken DE, Gorlin R. Pharmacologic control of thromboembolic complications of cardiac valve replacement. N Engl J Med 1971;284:1391-4. 13. Borkon AM, Soul L, Reitz BA, Gorr VL, Gardner TJ. Five-year follow-up after valve replacement with the St. Jude medical valve in infants and child. Circulation 1986;74(suppl l):llO-5. 14. Pass HI, Sade RM, Crawford FA, Hohn AR. Cardiac valve prosthesis in children without anticoagulation. J Thorac Cardiovasc Surg 1984;87:832-35.
The proarrhythmic drugs
valve
15. Donahoo JS, Gardner TJ. St. Jude medical cardiac valve prosthesis in infants and children: early and intermediate experience. South Med J 1982;75:1538-40. 16. Schaffer MS, Clarke DR, Campbell DN, Madigan CK, Wiggins JW, Wolfe RR. The St. Jude medical cardiac valve in infants and children: role of anticoagulant therapy. J Co11 Cardiol 1987;%235-9. 17. Czer LSC, Weiss M, Bateman TM, Pfaff JM, DeRobertis MA, Eigler N, Vas R, Matloff JM, Gray RJ. Fibrinolytic therapy of St. Jude valve thrombosis under guidance of digital cinefluoroscopy. J Am Co11 Cardiol 1985;5:1244-9. 18. Kurzrok S, Singh AK, Most AS, Williams DO. Thrombolytic therapy for prosthetic cardiac valve thrombosis. J Am Co11 Cardiol 1987;%592-8. 19. Moreno-Cabral RJ, McNamara JJ, Mamiya RT, Brainard SC, Chung GKT. Acute thrombotic obstruction with BjorkShiley valves. Diagnostic and surgical considerations. J Thorat Cardiovasc Surg 197&75:321-30. 20. Kontos GJ, Schaff HV. Thrombotic occlusion of a prosthetic heart valve: diagnosis and management. Mayo Clinic Proc 1985;6@118-22.
effects of antiarrhythmic
J. E. Creamer, M.B., Ch.B., A. W. Nathan, London, England
M.D.,*
The contemporary physician has a considerable range of drugs that can be effective for the treatment of arrhythmias. However, with the increasing use of such agents, it has become apparent that they may also induce or exacerbate cardiac arrhythmias (Fig. 1). Bradyarrhythmias may be produced by these drugs because of suppression of conduction and automaticity in the specialized conducting system. Such effects are usually dose-dependent and may be seen as a feature of toxicity.lzz Similarly, in atria1 tachyarrhythmias with functional atrioventricular block, acceleration of the ventricular response due to anticholinergic effects on the atrioventricular node3 and/or to slowing of the tachycardia4 may also be From the Department of Cardiology, St. Bartholomew’s Hospital. Received for publication Feb. 23, 1987; accepted Apr. I, 1987. Reprint requests: Dr. J. E. Creamer, Dept. of Cardiology, St. Bartholomew’s Hospital, West Smithfield, London EClA 7BE, Englsnd. *Drs. Nathan and Camm were supported by the British Hesrt Foundation.
and A. J. Camm, M.D.*
anticipated. However, most attention has focused on the occurrence of new or increased ventricular tachyarrhythmias during antiarrhythmic drug therapy, or the acceleration or degeneration of a ventricular arrhythmia being treated. Unlike the bradyarrhythmias, these are less predictable, are usually intermittent, and are more difficult to document. More importantly, they may resemble the original tachycardia and thus be attributed simply to failure of treatment, thus prompting an increase in the drug dose with potentially disastrous results. Systematic study of this problem is hindered by the lack of a universally-accepted definition of a proarrhythmic effect. Table I lists the criteria used in some of the major studies.5-io All the definitions proposed have in common “the appearance of new or more malignant arrhythmias after treatment with antiarrhythmic drugs.” However, in those studies where provocation testing was employed, the ease of induction of ventricular arrhythmias is also considered. There has been much discussion about the increased frequency of ventricular premature beats 397
August
398
Creamer, bagman, and Canm
American
1967
Heart Jownsi
1. Proarrhythmic effect of flecainide. A, ECG of patient with mitral valve disease and paroxysmal atria1 fibrillation prior to prophylactic treatment with flecainide. ECG of same patient after 1 week of oral flecainide, 100 mg twice daily. Fig.
as a proarrhythmic effect. Their inclusion asa factor in any formal de~ition is ~omplica~d by underlying baselinevariability, and workers have suggested different mathematical formulas to define the minimal increasesnecessaryto justify inchmion.20 However, in practice, increasedfrequency of ventricular premature beats is probably not as important as the more malignant or sustained ventricular arrhythmias. Most of the evidence for the provocation of arrhythmias by antiarrhythmic drugsis basedon the temporal relationship between dose and effect, because rechallenge is usually considered unethic&.6,6However, rechallengeunder controlled conditions has been undertaken oc~ion~y as a means
of avoiding unnecessaryand potentially harmful ~ti~rh~hmic drug treatment8 Many case reports have appeared implicating virtually all ant&rhythmic drugs in the provocation of ~h~~~. Qu~id~ne syncope,due to unheralded ventricular tachyarrhythmias, often in patients being treated for supraventricular arrhythmias, is usually regardedas the prototype of druginduced arrhythmia and, although it was originally reported in patients who were also taking digoxin,ll this was not always the case-l2Rlood levels at the time of theseepisodeshaveusually beenwell within the therapeutic range.lsn l4 In 1952Read16reported a caseof fatal ventricular ~bri~tion following the intravenous ad~nistration
Volume 114
Proarrhythmic
Number 2
Table
I. Definitions
Winkle et al. (198lY Velebit et al. (198Z16 et al. (1982)’
Ruskin et al. 1983Y
Poser et al. (1983j9
Morganroth
399
of proarrhythmia detection
Rinkenberger
drugs
et al. (lSS41’0
Occurrence of new, or more malignant ventricular arrhythmias Marked exacerbation of arrhythmia Quadruple increase in VPBs Repetitive forms, couplets, VT (new, or lo-fold increase) Induction of sustained VT on drug when only nonsustained VT induced previously Spontaneous occurrence of ventricular arrhythmia during drug therapy and inducible ventricular arrhythmia absent without drugs but present on rechallenge Provocation of arrhythmia with fewer extrastimuli than in control study Sustained ~~ when only nonsus~ined VT during control Sustained VT at faster rate than during control Presence of new ventricular tachyarrhythmia &hange in previous ventricular arrhythmia Increased VPB frequency X3-10 Increased VT rate Change in ease of termination
of pro~~n~ide. Pol~orphi~ ventricular tachycardia due to both intravenous and oral procainamide was linked to concomitant QT interval prolongation in seven cases reported by Strasberg et all6 In two of these patients it degenerated to fatal ventricular fibrillation. Disopyramide therapy has been associated with similar arrhythmias occurring in the presence of prolonged ventricular repol~ization.1’-19 Cases of disopyramide toxicity associated with uniform and polymorphic ventricular tachycardia show widening of the QRS complex in addition to QTc prolongation.m*z1 Polymorphic ventricular tachycardia in the absence of significant QRS or QTc prolongation has been reported with mexiletine?2 and ventricular fibrillation has been induced by another Vaughan-Williams class Ib drug, tocainide.z3 Flecainide-associated ventricular tachycardia and ventricular flutter have been recorded in the presence of both therapeutic and toxic serum levels and with QT prolongation due entirely to QRS widening, the JT interval being unchanged.* The class III agents, amiodarone and sotalol, both prolong the QT interval.“sz5 Amiodarone has been associated with polymorphic ventricular tachycardia, both in combination with disopyramide ,% digoxin and metoprolol,2’ and alone.m A number of cases of sotalol intoxication have been reported showing marked increases in QT=*=’ and QTcs’ intervals, and with ventricular tachycardias in addition to atrioventricular block. Syncope and ventricular arrhythmias have also been
method
ECG telemetry %-hour ECG Maximal exercise ECG Programed
electrical stimulation
Programmed
electrical stimulation
Programmed
electrical stimulation
Programmed electrical stimulation Ambulatory ECG monitoring
reported in patients given large, but therapeutic doses of sotalol?2 and with normal therapeutic doses when combined with diuretic drugs, associated with low serum potassium levels or with other QTlengthening agents?3 Although reserved for the treatment of refractory ventricular arrhythmias, bretylium tosylate has itself been implicated in the provocation of more malignant ventricular tachycardias and fibrillation.M The incidence of proarrhythmic effects in practice is not well documented. This reflects the intermittent nature of the arrhythmias, which reduces the diagnostic yield from conventional monitoring techniques unless they are applied for extended periods. Such extensive monitoring is not always performed. Estimates may be obtained from studies on the survivors of “out of hospital” cardiac arrest due to ventricular tachyarrhythmias. Among these patients there is a high rate of recurrence of ventricular fibrillation and sudden death despite empirical antiarrhythmic therapy.35*B Furthermore, in two series, 30% to 69% of patients resuscitated from “out of hospital” cardiac arrest were taking antiarrhythmic drugs at the time of their cardiac arrest?7*s 0f 98 survivors of a cardiac arrest not associated with acute myocardial infarction, Ruskin et al.* found 25 in whom no ~h~hrni~ could be provoked by programmed ventricular stimulation. Six of these had been taking antiarrhythmic drugs at the time of their cardiac arrest and, when these drugs were
400
Creamer,
Nathan,
and Camm
tat NON-INVASIVE
ASSESSMENT *
Proarrh ivthmic effects 1%)
2. The incidence of proarrhythmic effects with individual antiarrhythmic drugs. A, Noninvasive assessment (Data from Velebit updated by Podrid,‘O with additional data* from Nathan et aL4 and Winkle et a1.r). B, Invasive assessment (Data from Poser updated by Podrid,“’ with additional data* from Nathan et al.’ and Winkle et al.5).
Fig.
reintroduced
and programmed
electrical stimulation
was repeated, ventricular arrhythmias were induced in four patients and high-grade atrioventricular block with spontaneous ventricular fibrillation occurred in one other.8 In a collected series,3D quinidine syncope has been reported in 0.5% to 4.4% of patients receiving the drug and was fatal in 11.5%. Velebit et al6 used a systematic program of antiarrhythmic drug testing, involving 24-hour ECG monitoring and maximum symptom-limited exercise testing, and observed a worsening of arrhythmia in 80 out of 722 (11% ) drug tests in 53 of 155 (34 % ) patients referred for treatment of refractory ventricular tachyarrhythmiss. Drug-induced arrhythmias varied from an increase in the frequency of ventric-
ular premature
beats to the occurrence of sustained
ventricular tachycardia. Fig. 2, A shows the incidence of proarrhythmic effects from the individual agents. The data are drawn from the work of Velebit et al. updated by Podrid,m with additional figures by other workers. The result-a are biased by the disproportionate use of the investigational drug, encainide. Nathan et al4 found proarrhythmic e@ects in 7 of 152 (4%) patients given flecainide, and of these five (3 % ) developed ventricular tachycardia or fibrillation.
Encainide-sssociated
ventricular
tachyar-
rhythmias occurred in up to 13% of patients with a previous history of sustained ventricular tachycardia or fibrillation? With the use of programmed intracardiac stimu-
volume 114 Number 2
lation for serial drug testing, Rinkenberger et al? found that in 11 out of 83 patients (13%) the administration of disopyramide, amiodarone, encainide, or quinidine converted inducible nonsustained ventricular ~~hy~ardia to sustained ventricular tachycardia. The incidence of proarrhythmic effects with individual agents as detected by invasive electrophysiologic testing is shown in Fig. 2, B, and is based on the work of Poser et aL9, updated by Podrid.& It is interesting to note that the frequency of these effects is greater with invasive than with noninvasive testing, suggesting that the former may be a more sensitive method of testing. The clinical effect of an anti~rh~~ic drug results from the specific electrophysiologic changes it produces imposed on the unique arrhythmia substrate in each patient. While a superficial knowledge of both aspects may be possible, the unique details at the microscopic and biochemical level cannot be ascertained for each individual. That both aspects must be considered in the production of drug-induced arrhythmias is suggested by those cases where individuals have had a similar proarrhythmic response to two different drugs with similar electrophysiologic characteristics, such as quinidine and disopyramide,l’ or lorcainide and encainide.5 The importance of the arrhythmia substrate in the occurrence of pro~rh~hmic effects is highlighted by the studies on encainide.5 A total of 180 patients were studied. No ventricular tachyarrhythmias were induced at electrophysiologic study in 32 patients who had had no previous spont~eous arrhythmia, nor in 13 patients who had previous supraventricular arrhythmias. However, inducible ventricular tachyarrhythmia was seen in 1 out of 45 patients (2.2%) given the drug for complex ventricular ectopy and in 12 out of 90 patients (13.3%) with prior sustained ventricular tachycardia.5 In a report summarizing the experience with flecainide in 558 patients from a number of different centers,lO it was noted that the group suffering proarrhythmic effects had a greater frequency of coronary artery disease, myocardial infarction, ventricular tachycardia, and cardiac failure. A combination of previous ventricular tachycardia and cardiac failure was seen in 52% of those who experienced proarrhythmic effects but in only 3% of those who did not. However, no significant difference in underlying diagnosis or severity of cardiac failure was noted in those patients experiencing proarrhythmic effects from encainide compared with those who did not.5 In addition to the electrophysiologic effects of the drugs themselves and the arrhythmia substrates, the
Proarrhythmic
Table
drugs
401
Il. Possible mechanisms of drug-induced arrhyth-
mias 1. 2. 3. 4. 5. 6. I. 6. 9.
Non-nniformity of repolarization Changes in conduction time Increased automaticity and triggered activity Fibrillation threshold Pacing threshold Effects on sinoatrial function Effects on atrioventricular conduction Autonomic effects Negative inotropic effects
p~ition is further complicated by the variety of autonomic states that an individual may experience and by changes in these autonomic effecti during daily living. The effects of such influences are difficult to evaluate systematically and little attention has been paid to this in the major studies except indirectly by the use of exercise testing.6 In many of the case reports, patients were noted to be taking more than one drug when proarrhythmic effects occurred. In these cases the phenomenon was usually attributed to the last drug to be introduced. However, the possibility of proarrhythmic effects being due to the combination of antiarrhythmic drugs has not been formally addressed. Amiodarone,*l verapamil,ht and quinid~e~ may all raise serum digoxin levels and potentially precipitate toxicity, but the mechanisms of other potential interactions are not known. Disturbances of potassium, calcium, and magnesium balance may also interact to provoke drug-induced arrhythmias, possibly through direct membrane effects. MECHANISMS
OF DRUG-INDUCED
ARRHYTHMIAS
mechanisms have been proposed to explain the proarrhythmic potential of antiarrhythmic drugs (Table II) that are based on their main properties. Nonuniformity of repolarization. Prolongation of the QRS, QT, and JT intervals is often seen in association with ventricular arrhythmias provoked by many of the Vaughan-Williams class I and class III agents. Overall prolongation of repolarization may be associated with temporal dispersion of refractory periods and nonuniform recovery of fiberst4 which may in turn lead to the occurrence of reentry circuits and the conditions for “reflection” of impulses- Differences in ventricular refractory periods at different sites within the ventricle have been demonstrated following amiodarone administration? Changes in conduction time. Agents such as flecainide and encainide do not prolong the JT interval,
402
Greamer, Nathan, and Gamm
although both may prolong the QT interval due to QRS widening. It has been proposed that slowing of intraventricular conduction may be their predominant proarrhythmic mechanism.4s5 Such conduction slowing may be nonuniform and thus may give rise to new reentry circuits or may sustain a circuit that was already present but previously nons~~ned. This is consistent with the occurrence of sustained ventricular tachycardia at a slower rate after drug administration, as noted by Rinkenberger et aL7 Paradoxical acceleration of ventricular tachycardia may occur where impulses from an ectopic tachycardia focus are limited by exit block. Slowing of the tachycardia rate by antiarrhythmic drugs may overcome the block and allow a one-to-one response. The rapid development of intraventric~ar conduction delay has been postulated as a mechanism underlying the occurrence of ventricular fibrillation after atropine, although this was based on observations of a single case with coronary artery disease and left ventricular failure? hxreased
automatkity
and
triggered
activity.
Abnormal automaticity has been invoked to explain the production of ventricular arrhythmias by some drugs. Cellular studies of digoxin toxicity suggest that delayed afterdepolarizations are responsiblet7 whereas early afterdepolarizations may be induced by N-acetylprocainamide administration.48 Def~br~liation threshold. In some instances of drugassociated ventricular ~brillation, electrical defibrillation has been unduly difficult or impossible.4~1’~1z It is likely that changes in defibrillation threshold reflect the effects of drugs on the fibrillation threshold. Studies in dogs have shown that lidocaine increases the threshold for transthoracic defibrillation.4s Bretylium either has no effect or decreases the threshold. The increasing clinical use of the automatic implantable cardioverter/defibrillator provides an opport~ity for similar observations in man. Amiodarone has been shown to increase the threshold for defibrillation by the device, tbus reducing its safety margin. 50,51No statistically significant effect was noted with digoxin and the Vaughan-Willies class I drugs as a group, and there are insufficient data to draw conclusions for the individual agents.51 Pacing threshold. Flecainide has been shown to increase the endocardial pacing t~eshold,52 and this has the potential for provoking arrhythmias due to pacing failure. Both bradycardias and bradycardiadependent tachycardias may be induced. Increases in acute and chronic pacing threshold have also been shown with the Vaughan-Willies class Ia drugs,
procainamide and quinidineF3 but the class Ib drugs, lidocaine and phenytoin, had little or no effect.“,~ By contrast, the class II agents, propranolol and oxprenolol, and the class IV agent, verapamil, have been shown to increase the pacing threshold by up to 40 76 when given intravenously,“, 57~ 5* although this is not a consistent finding.~g Effects on sinoatrial function. The influence of antiarrhythmic drugs on the sinus node may be direct or may occur through autonomic mechanisms. The most frequent result is simple sinus bradycardia, as seen with the beta-adrenergic blocking drugs, and amiodarone, which has both antiadrenergic and direct effects on the sinus node.m Sinus arrest may also occur, and occasionally bradyarrhythmias are severe enough to require pacinga61 Quinidine reduces sinoatrial conduction and may lead to exit block, although its effects in vivo may vary according to autonomic modulation.61a Procainamide has no effect on the sinus node in normal individuals, but may prolong the corrected sinus node recovery time after rapid atrial pacing in patients with the sick sinus syndrome.62 Lidocaine and mexiletine may reduce sinus node automaticity and conduction in patients with sinus node dysf~ction.~ The intravenous administration of verapamil to patients taking beta-blocking drugs may produce dramatic depression of the sinus node and lower escape pacemakers producing asystole.% By contrast, transient sinus tachycardia may be produced by bretylium by the initial release of stored catecholamines.65 Disopyramide, by its anticholinergic effects, may also cause sinus tachycardia, especially when high vagal tone is present.& Effects on atrioventricuiar conductton. As previously mentioned, antiarrhythmic drugs have the potential for proarrhythmic effects by their direct or indirect effects on the atrioventricular node. These may occur in the treatment of atria1 tachy~h~hmias associated with some degree of atrioventricular block. The anticholinergic effects of drugs such as disopyramide may paradoxically increase the ventricular response prior t,o termination of the arrhythmia.3 A similar increase in ventricular rate may be seen when a drug, such as flecainide, increases the cycle length of atria1 flutter so that it exceeds the refractory period of the atrioventricu1a.r node and allows a one-to-one ventricular response.* In patients with ventricular preexcitation, antiarrhythmic drugs may have deleterious effects on arrhythmias due to their effects on the accessory pathway. Digitalis may shorten the refractory period
Volume 114 Number 2
Fig. 3. The arrhythmogenic termination of atrioventricular maneuver.
Proarrhythmic
drugs
403
effect of autonomic changes. Ventricular arrhythmia occurring during reentrant tachycardia at the end of stage II (arrow) of the VaIsaIva
of the accessory pathwaf7 and may increase the ventricular response in some patients with the Wolff-Parkinson-White syndrome and atrial fibrillation.@ Lidocaine and verapamil have also been reported to speed the ventricular response to atria1 fibrillation in such patients.6ge7o In patients who suffer from atrioventricular reentrant tachycardia, drugs such as flecainide, which prolong conduction in the accessory pathways, may convert a paroxysmal arrhythmia into an incessant one if such conduction is not completely abolished. Autonomic effects. In addition to the modulating effects on the behavior of the sinoatrial node and atrioventricular junction, autonomic influences may be arrhythmogenic in other ways, for example, during a Valsalva maneuver, salvos of ventricular premature beats may occur during the transition from phase II (sympathetic predominant) to phase IV (parasympathetic predominant). In Fig. 3 a Valsalva maneuver performed during atrioventricular reentrant tachycardia induced a salvo of ventricular premature beats associated with termination of the tachycardia. Many antiarrhythmic drugs have autonomic effects and may provoke arrhythmias through this mechanism. The early onset of sustained ventricular tachycardia and ventricular ~brillation after bretylium administration may be related to local catecholamine release prior to neuronal depletion. In one such case, ventricular fibrillation occurred in the context of an increase in ventricular ectopic activity that could be controlled by propranolol?4 Negative inotropic effects. Other indirect mechanisms include the negative inotropic effect of most antiarrhythmic agents, which may exacerbate cardiac failure and associated ventricular arrh~hmi~. Such deleterious hemodynamic effects may also prejudice recovery from ventricular fibrillation.71
Table
Ill. Management of drug-induced arrhythmias 1. Emergency treatment (DC cardioversion, pacing) 2. Appropriate moni~ring (clinical, PEG, serum drug levels) 3. Correct contributory factors (bradycardia, electrolyte disturbance, heart failure, &hernia, other drugs) 4. Change antiarrhythmic drug therapy Reduce dose Change to another drug Stop all antiarrhythmic drugs Add another drug Consider another type of treatment Pacing Defibriilator Surgery
DETECTKJN
OF DOUG-INDUCED
A~~HY~~IAS
The possible occurrence of drug-induced ventricular arrhythmias in individual patients is not easily predicted from a consideration of clinical factors. It has been suggested that with certain drugs monitoring serial ECGs for QT prolongation would identify those patients at risk who should be followed more closely or perhaps have the drug withdrawn. The sensitivity, specificity, and “cut-ofI” point of disproportionate prolongation under these circumstances is not known. The monitoring of serum levels may be wise in those patients with renal or hepatic failure where accumulation is likely to occur, but its value in predicting arrhythmogenic effects is doubtful, since these effects often occur in the presence of “therapeutic” levels. 13s14 A recent study7z could not predict which patients would be susceptible to drug-induced aggravation of arrhythmia by using clinical criteria, ECG changes, or the pharmacolsmetics of antiarrhythmic drugs. Proarrhythmic effects were, howev-
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Creamer, Nathan, and Camm
er, found more frequently in those with a history of malignant ventricular arrhythmias, suggesting that caution should be used in treating such patients. Most authors recommend some form of testing to monitor the efficacy of antiarrhythmic drug therapy but, with the appreciation of the importance of arrhythmogenic side effects of these drugs, a new dimension has been added to the significance and emphasis of such testing. Programs of antiarrhythmic drug testing include prolonged ambulatory ECG monitoring and exercise stress testing, or programmed intracardiac electrical stimulation, but the relative roles of these techniques, especially with reference to the identification of proarrhythmic effects, are still not established. MANAGEMENTOF
DRUG-INDUCEDARRHYTHMIAS
As the arrhythmogenic potential of antiarrhythmic drugs may be life-threatening and is not entirely predictable, the use of these drugs should be critically examined in each case and reserved for those with firm indications for treatment. Adequate assessment of their efficacy and arrhythmogenic potential should be attempted by means of ambulatory ECG monitoring and/or provocative testing by exercise or programmed electrical stimulation, as appropriate or available. The possibility of proarrhythmic effects should be borne in mind in the event of any unexpected exacerbation of the arrhythmia being treated or the occurrence of new arrhythmias; the need for antiarrhythmic drug therapy should be reassessed at this stage, and an appropriate treatment strategy should be selected. When drug-induced arrhythmias occur, there are a number of possible management strategies, as shown in Table III. These include reducing the drug dose (perhaps guided by serum levels), changing to an alternative drug, stopping the offending drug and reassessing whether any antiarrhythmic drug is needed at all (which is often the safest course), or adding another drug. The last of these strategies is probably the most dangerous and confusing. In those cases where multiple drug regimens have been employed, the most appropriate strategy is often to stop all antiarrhythmic drugs under appropriate observation in hospital, where facilities for immediate electrical cardioversion and temporary pacing are available. The assessment and treatment of aggravating factors such as heart failure, electrolyte disturbances, inappropriate bradycardia, and cardiac ischemia, should be attended to initially. Next, the arrhythmia itself should be assessed by means of appropriate monitoring and provocation testing, and on the basis of this assess-
American
August IQ87 Heart Journal
ment, an appropriate alternative specific treatment should be selected. This may involve the use of alternative drugs or combinations of drugs, implantable devices, or surgery. Finally, the specific treatment chosen should be assessed, both for efficacy and for proarrhythmic potential. While such a management strategy is time-consuming and the treatment options may be limited outside special centers, the process rm& be employed in difficult cases if such arrhythmias are to be treated safely and effectively. In conclusion, the occurrence of proarrhythmic effects during antiarrhythmic drug therapy is a significant problem that must be recognized. This occurrence is not easily predicted, but should be actively sought and appropriately managed by those who use such drugs. Antiarrhythmic agents are often effective but are also potentially dangerous and should be treated with respect. SUMMARY
Although antiarrhythmic drugs are effective for controlling cardiac arrhythmias, they may also induce or exacerbate them. Case reports have appeared implicating all classes of antiarrhythmic drugs. It is difficult to assess the size of the problem in practice, as it varies with difIerent subgroups of patients, but rates of up to 13% have been found where proarrhythmic effects were actively sought. Their occurrence is aBected both by the electrophysiologic characteristics of the drugs and by the arrhythmia substrate. Mechanisms of proarrhythmic effects may be classified according to the electrophysiologic and hemodynamic effects of the drugs. Detection of drug-induced arrhythmias depends on appreciation of the problem by physicians and, although there are few clear predictors, some form of monitoring of antiarrhythmic drug treatment is recommended. Management of such arrhythmias when they occur involves withdrawal of the offending agent, correcting contributory factors, and reassessing the initial arrhythmia and the strategy for its management. REFERENCES
1. Orr GM, Bodansky HJ, Dymond DS, Taylor M. Fatal verapamil overdose. Lancet 1982;2:1218-9. 2, Fach WA, Mai BV, Preusler W, Becker HJ. Flecanidintoxication. Innere Medizin 198411:27-31. 3. Birkhead JS, Vaughan-Williams EM. DuaI effect of disopyramide on atriaI and atrio-ventricuIar conduction and refractorv ueriods. Br Heart J 1977:3S%7-660. 4. Nab-ran AW, HeIIestrand KJ, Bextcn RS, Banim SO, Spurrell RAJ, Camm AJ. Proarrhythmic effects of the new antiarrhythmic agent flecainide acetate. AM HEART J 1984$0?2228.
volume 114 Number 2
5. Winkle RA, Mason JW, Griffin JC, Ross D. Malignant ventricular tachyarrhythmias associated with the use of encainide. & &ART J 1981;162:857-64. 6. Velebit V, Podrid P, Lown B, Cohen BH, Graboys TB. Aggravation and provocation of ventricular arrhythmias by antiarrh~~ic durgs. Circulation 198&65z%%6-94. 7. Rinkenberger RL, Prystowsky EN, Jackman WM, Naccarelli GV, Heger JJ, Zipes DP. Conversion of non-sustained ventricular tachycardia to sustained ventricular tachycardia during serial electrophysiologic studies: Identification of drugs that exaccerbate tachycardia and potential mechanisms. h HEART J 19%~103zl77-84. 8. Ruskin JN, McGovern B, Garan H, DiMarco JP, Kelly E. Antiarrhythmic drugs: A possible cause of out-of-hospital cardiac arrest. N Enel J Med 19%3:309:1302-6, 9. Poser R, Lombardi F, Podrid PJ,’ Lown B, Aggravation of arrhythmia during electrophysiologic testing (abstr). J Am Co11 Cardiol 198&!:708. J, Horowitz LN. Flecainide: Its pro~rh~hmic 10. Morg~roth effect and expected changes on the surface electrocardio” gram. Am J Cardiol 19%453;89B-94B. 11. Seizer A, Wray HW. Quinidine syncope: Paroxysmal ventricular fibrillation occurring during treatment of chronic atria1 arrhythmias. Circulation 19ti,3&17-26. ventricular 12 Koster RW, Wellens HJJ. Quinidine-educed flutter and fibrillation without digitalis therapy. Am J Cardiol 1976;38519-23. 13, Jenzer HR, Hagemeyer F. Quinidine syncope: Torsade de pointes with iow quinidine plasma concentrations. Eur J Cardiol 1976;&447-51. 14. Bauman JL, Bauernfeind RA, Hoff JV? Strasberg B, Swiryn S, Rosen KM. Torsades de pointes due to quinidine: Observations in 31 patients. AM HEARTJ 19%4;107:425-30. 15, Read JM. Fatal ventricular fibrillation following procainamide hydrochloride therapy. JAMA 1952;149:139&1. 16. Strasberg B, Sclarovsky S, Erdberg A, Duffy CE, Lam W, Swiryn S, Agmon J, Rosen KM. Pr~in~ide-induced polymorphous ventricular tachycardia. Am J Cardiol 1981; 47:1309-14. 17. Dhurandhar RW, Nademanee K, Goldman AM. Ventricular tachycardia-flutter associated disopyramide therapy: A report of three cases. Heart Lung 197&?783-7. 18. Chia BL. Disop~amide induced atypical ventric~ar tachycardia. Au& NZ J Med 198O$h665-8. 19. Nicholson WJ, Martin CE, Gracey JG, Knoch HR. Disopyramide-induced ventricular fibrillation. Am J Cardiol 1979; 43;1053-5. 20. Lo KS, Gantz KB, Stetson PL, Lucchesi BR, Pitt B. Disopyramide-induced ventricular tachvcardia. Arch Intern Med i980$4&413*4. 21. Meltzer RS, Robert EW, McMorrow M, Martin RP. Atypical ventricular tachycardia as a manifestation of disopyramide toxicitv. Am J Cardiol 197&42:1049-53. 22. Cocco G, Strozzi C, Chu D, Pansini R. Torsades de pointes as a manifes~tion of mexiletine toxicity. AM HEARTJ 19%
102222-8.
23. Eugler RL, LeWinter M. Tocainide induced ventricular fibrillation. AM HEART J 1981;101:494-6. 24. Debbas NMG, DuCailar C, Bexton RS, Demaille J, Camm AJ. Puech P. The QT interval A predictor of the plasma and mvocardia1 concentrations of imiodarone. Br Heart J lQ-8$51:316-20. 25. Nathan AW, Hellestrand KJ, Bexton RS, Ward DE, Spurrell RAJ. Camm AJ, Electronhysiological effects of sotalol-just another beta blocker? Br Heart J 19%2;4?515-20. 26. Westveer DC, Gadowski GA, Gordon S, Timmis GC. Amiodarone-induced ventricular tachycardia. Ann Intern Med 198% 92561-2. 27. McComb JM, Logan KR, Khan MM, Geddes JS, Adgey AAJ. Amiodarone-induced ventricular fibrillation. Eur J Cardiol 19%&11:381-5.
Proarrhythmic
drugs
405
2%. Veglia L, Scanditlio T, Guerricchio G. “Torsioni di puma” e amiodarone. G Ral Cardiol 197%&1025-9. 29. Desoutter P, Medioni J, Lerasle S, Haiat R. Bloc auriculoventriculaire et torsades de pointe apres sur dosage par le sotalol. Nouv Presse Med 1983523855. 30. Neuvonen PJ, Elonen E, Vuorenmaa T, Laakso M. Prolonged QT interval and severe ~chy~rh~i~. Common features of sotalol intoxication. Eur J Clin Pharmacol 1981;2&85-9. 31. Belton P, Sheridan J, Mulcahy R. A case of sotalol poisoning. Ir J Med Sci 19%2;151;126-7. 32. Laakso M, Pentikainen PJ, Pyorala K, Neuvonen PJ. Prolongation of the Q-T interval caused by sotalol-possible association with ventricular ~chy~rh~hmi~. Eur Heart J 1981;2%353-%. 33. McKibbin JK, Pocock WA, Barlow JB, Scott Millar RN, Obell IWP. Sotalol, hypokalaemia, syncope and torsade de nointes. Br Heart J 1984:51:157-62. 34. Anderson JL, Popat KD, Pitt B. Paradoxical ventricular tachycardia and fibriIlation after intravenous bretylium therapy. Report of two cases. Arch Intern Med 1981;141:801-2. 35. Lithbertson RR, Nagel EL, Hirschman JC, Nussenfeld SR. Prehospital ventricular defibrillation: Prognosis and followup course. N Engl J Med 197*291:317-21. 36. Cobb LA, Baum RS, Alvarez H, Schaffer WA. Resuscitation from out-of-hospi~l ventricuiar fibrillation: 4 years followup. Circulation 197&51 and 5Z(suppl IID:223-8. 37. Moss AJ, De Camilla J, Davis H. Cardiac death in the first six months after myocardial infarction: Potential for mortality reduction in the early post hospital period. Am J Cardiol 197%3Qz816-20. 38. Vismara LA, Vera Z, Foerster JM, Amsterdam EA, Mason DT. Identification of sudden death risk factors in acute and chronic artery disease. Am J Cardiol 1977;3Qz%21-8. 39. Reynolds EW, Vander Ark CR. Quinidine syncope and the delayed repolarization syndromes. Mod Concepts Cardiovasc Dis 197645117-22. 40. Podrid P. Aggravation of arrhythmia-a drug-induced complication. Drugs 1985;29(suppl4):33-44. 41. Moysey JO, Jaggarao NSV, Grundy EN, et al. Amiodarone increases plasma digoxin concentration. Br Med J 1981; 282272. 42. Kiein HO, Lang of verapamil -. R, Weiss E, et al. The-. influence . on serum digoxin concentration. ~1rcuIation 19%~6~9981003. 43. Ejvinsson G. Effect of quinidine on plasma concentrations of digoxin. Br Med J 1978;1:279-80. 44. Han J, Goel BG. Electrophysiological precursors of ventricular tachyarrhythmias. Arch Intern Med 1972$29:749-55. 45. Ezri MD, Huang SK, Messer JV, Denes P. Ele~ronhvsiolo~c observations of concealed ventricular depolarizations due-to amiodarone. AM HEARTJ 19%2;104:l69-72. 46. Santinelli V, Chiarello M, Condorelli M, Rapid increase of intraventricular conduction delay in the genesis of ventricular fibrillation after atropine. Int J Cardiol 19%$%109-11. 47. Rosen MR. Cellular machanisms of cardiac arrh~hmi~. In: Harrison DC, editor. Cardiac arrhythmias, a decade of progress. Boston:GK Hall Medical Publishers, 1981:25-38. 48. Dangman K, Hoffman BF. Effects of N-acetylprocainamide on cardiac Purkinje fibers (abstr). The pharmacologist 197&2&150. 49. Kerber RE, Pandian NG, Jensen SR, Cons~ntin L, Kieso RA, Melton J, Hunt M. Effects of lidocaine and bretylium on energy requirements for transthoracic defibrillation: Experimental studies. J Am Co11 Cardiol 1986;7:397-405. 50. Fogoros RN. Amiodarone-induced refractoriness to cardioversion. Ann Intern Med 1984$6Oz699-700. 51. Troup PJ, Chapman PD, Olinger GN, Kleinman LH. The implanted defibrillator: Relation of deflbrillating lead conflguration and clinical variables to defibrillation threshold. J Am Co11 Cardiol 1985$X315-21. 52. Hellestrand KJ, Burnett PJ, Milne JR, Bexton RS, Nathan
406
53. 54.
55.
56.
Creamer,
Nathan,
and Camm
AW, Camm AJ. Effect of t,he antiarrhythmic agent flecainide acetate on acute and chronic pacing thresholds. PACE 1983;&892-9. Singh BN, Hauswirth 0. Comparative mechanism of action of antiarrhythmic drugs. AM HURT J 197%87:367-82. Young MW, Meia H, Furman S, et al. Effects of lidocaine and ouabain on myocardial threshold to pacer stimuli (abstr). Circulation 197&4l:iII-209. Bigger JT, Weinberg DI, Kovalik ATW, et al. Effects of diphenylhydantoin on excitability and automaticity in the canine heart. Circ Res 1970;26:1. Preston TA, Fletcher RD, Lucchesi BR, et al. Changes in myocardial threshold. Physiologic an pharmacologic factors in patients with implanted pacemakers. AM HEART J
JT Jr. Electrophysiologic effects of procainamide on sinus node function in patients with and without sinus node disease. AM HEART J 1982;103z75-9. 63. Heger JJ, Prystowsky EN, Zipes DP. Clinical choice of antiarrhythmic drugs. In: Josephson ME, editor. Ventricular tachycardia: Mechanisms and management. Mt. Kisko, N.Y.: Futura Publishing Co., 1982: 195-235. 64. Benaim ME. Asystole after verapamil. Br Med J 197$2:169-
1967;74:235-42.
66.
Doenecke P, Flothner R, Rettig G, et al. Studies of short- and long-term threshold changes. In: Schaldach M, Furman S, ediiors. Advances in pa&maker technology. Berlin-Heidelberg-New York &ringer-Verlaz. 1975283-96. 58. Kuiler W, Sowto; E. influence-&f beta-blockade on myocardial threshold in patients with pacemakers. Lancet 1970;
70. 65.
51.
67,
68.
2:67-B.
Singh BN, Collett JT, Chew CYC. New perspectives in pharmacologic therapy of cardiac arrhythmias. Progr Cardiovast Dis 198@222z243-301. 60. Heger JJ, Prystowsky EN, Jackman WM, Naccarelli GV, Narfel KA. Rinkenbereer RL. Ziues DP. Amiodarone: Clinical efficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardia. N Engl J Med 1981;305:539-45. 61. Bigger JT Jr. Management of arrhythmias. In: Braunwald E, editor Heart disease: A textbook of cardiovascular medicine. Philadelphia: W.B, Saunders Co., 1980:717. 61a. Zipes DP. Specific arrhythmias: Diagnosis and treatment. In: Braunwald E, editor. Heart disease: A textbook of cardiovascular medicine. Philadelphia: W. B. Saunders Co., 1984:691. 62. Goldberg D, Reiffel JA, Davis JC, Gang E, Livelli F, Bigger
59.
69.
70.
Anderson JL, Patterson E, Wagner JG, Johnson TA, Lucchesi BR, Pitt B. CIinical pharmacokinetics of intravenous and oral bretylium tosylate in survivors of ventricular tachycardia or fibrillation: Clinical application of a new assay for bretylium. J Cardiovasc Pharmacol 1981;3:485-99. Danilo F Jr, Rosen MR. Cardiac effects of disopvamide. AM HEART J 1976;92:532-6. Wellens HJJ, Durrer D. Effect of digitalis on atrioventricular conduction and circus movement tachycardias in patients with Wolff-Parkinson-White syndrome. Circulation 1973; 47:129-33. Sellers TD, Bashore TM, Gallagher JJ. Digitalis in the preexicitation syndrome: Analysis during atria1 fibrillation. Circulation 1977;56:260-7. Akhtar M, Gilbert CJ, Shenasa M. Effect of lidocaine on atrioventricular response via the accessory pathway in patients with the Wolff-Parkinson-White syndrome. Circulation 1981;63:435-41. Gulamhusein S, Ko P, Carruthres SG, Klein GJ. Acceleration of the ventricular response during atria1 fibrillation in the Wolff-Parkinson-White syndrome. Circulation 1982;65:34854.
Euler DE, Zeman TW, Wallock ME, Scanlon PJ. Deleterious effects of bretylium on haemodynamic recovery from ventricular fibrillation (abstr). J Am Co11 Cardiol 19867:25OA. 72. Slater W, Podrid P, Lampert S, Lown B. Are there clinical predictors for arrhythmia aggravation? (abstr) J Am Co11 Cardiol 1986:7:158A. 71.