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Proarrhythmic responses during electrophysiologic testing
Proarrhythmic Responses During ElectrophysiologicTesting ALAN
LEONARD N. HOROWITZ, P. RAE, MB, MRCP, HAROLD
MD, ALLAN M. GREENSPAN, MD, R. KAY, MD, and SCOTT R. SPIELMAN,
Antiarrhythmic drugs may worsen ventricular arrhythmias in certain patients. This effect, termed proarrhythmia, aggravation or provocation of arrhythmia, can be investigated with either noninvasive or invasive techniques. Using electrophysiologic study, 160 patients with ventricular tachycardia or ventricular fibrillation were evaluated during treatment with 432 different antiarrhythmic regimens. Proarrhythmic responses were noted in 68 drug trials (16 % ), and at least 1 event was observed in 51 patients (32 % ). Nonsustained ventricular tachy-
MD
cardia was converted to sustained ventricular tachycardia in 17 % of these studies. Hemodynamically stable ventricular tachycardia was converted to an arrhythmia that required cardioversion for termination in 5% of the studies. Ventricular tachyrhythmia was more easily induced in 12% of trials. These proarrhythmic responses were not related to changes in QRS duration, QT interval or JT interval measured at baseline or to changes produced by antiarrhythmic drugs. (Am J Cardiol 1987;59:45E-48E)
A
ntiarrhythmic drugs may worsen existing ventricular arrhythmias or produce new ones. This effect, called aggravation and provocation of arrhythmia or proarrhythmia, has been known for 20 years. An association between antiarrhythmic drugs and syncope from polymorphic ventricular tachycardia (VT) was reported in 1964,l although it had been suspected much earlier.2 Subsequently, the proarrhythmic potential of antiarrhythmic drugs in general has been emphasized.3-10 Despite this documentation, only recently has proarrhythmia been studied systematically.l”-13 To date, studies have described the types of proarrhythmic response and their frequency with various antiarrhythmic agents. Few studies have been directed specifically toward the mechanism of these responses.
From the Division of Clinical Cardiac Electrophysiology and Computer Center of the Likoff Cardiovascular Institute, Hahnemann University Hospital, Philadelphia, Pennsylvania. Dr. Horowitz’s current address is the Philadelphia Heart Institute, Presbyterian-University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, Address for reprints: Leonard N. Horowitz, MD, Philadelphia Heart Institute, Presbyterian-University of Pennsylvania Medical Center, 39th and Market Streets, Philadelphia, Pennsylvania 19104. 45E
Even the terminology describing these adverse effects has not been standardized. Some prefer “aggravation and provocation” to indicate the ability of antiarrhythmic drugs to both worsen and create serious arrhythmia.‘OJl Others use the term “proarrhythmia.“12j14J5Proarrhythmic responses have been evaluated by both noninvasive and invasive techniques. This review will consider drug-induced proarrhythmic effects encountered during invasive electrophysiologic testing and programmed electrical stimulation.
Electrophysiologic Testingto Evaluate ProarrhythmicEffects Electrophysiologic evaluation was carried out in patients with documented ventricular arrhythmias after informed written consent was obtained from each. Baseline and on-drug evaluations were performed with the patient in the postabsorptive state, and either no sedation or light diazepam sedation was used. Before the baseline evaluation, all antiarrhythmic agents were discontinued for a minimum of 5 half-lives. Patients receiving digoxin, P-adrenergic blocking agents or nonantiarrhythmic calcium antagonists continued to take these agents at a stable dosage throughout the electrophysiologic studies. Multiple electrode catheters were inserted percutaneously using bupivacaine (0.25%) anesthesia and positioned with fluoroscopic guidance. Electrocardio-
46E
A SYMPOSIUM:
PERSPECTIVES
ON PROARRHYTHMIA
graphic leads I, aVF and V1 and intracardiac electrograms were displayed on an oscilloscope and recorded on magnetic analog tape. Real-time recordings were obtained using an ink-jet recorder, and measurements were made at paper speeds of 100 to 250 mm/s. All electrocardiographic recordings were measured at a paper speed of 100 mm/s with the patient supine. Programmed electrical stimulation was performed with an optically isolated constant-current stimulator. The stimuli were rectangular pulses of 1 ms at an amplitude twice the late diastolic threshold. In no patient was stimulation performed at an amplitude >2 mA. The protocol included single, double and triple ventricular extrastimuli delivered during sinus rhythm and ventricular drive pacing at cycle lengths of 600 and 450 ms. The protocol was performed at the right ventricular apex, and if no sustained arrhythmia was induced, stimulation was repeated at the right ventricular outflow tract. Left ventricular stimulation was not performed. In subsequent drug evaluations, the entire protocol was performed at both right ventricular sites until a sustained, reproducible arrhythmia was induced. The entire protocol was performed irrespective of the type of stimulation that initiated the baseline arrhythmia. Antiarrhythmic drugs were administered either intravenously or orally. The dose was titrated upward to maximum tolerance or the maximum dose allowed for investigational agents. Electrophysiologic testing was performed at steady-state plasma concentration of the agent(s). Individual regimens were selected after evaluation of the patient’s previous exposure to antiarrhythmic drugs. A history of hypersensitivity, allergy or proarrhythmic response to the drug precluded its use; however, history of clinical ineffectiveness did not prohibit drug evaluation by electrophysiologic study.
Definitionsof VentricularTachvcardia and VentricularFibrillation VT was considered sustained if it was >30 seconds long or produced cardiovascular collapse requiring termination in <3O seconds. VT was considered nonsustained if it lasted 16 complexes and <3O seconds. The initiated arrhythmia was considered nonsustained VT only if the entire stimulation protocol was completed and no sustained arrhythmia occurred. The initiated arrhythmia was defined as ventricular fibrillation if within 3 seconds of initiation of a sustained ventricular tachyrhythmia, electrocardiographic characteristics of tvnical ventricular fibrillation were seen in 3 surface leads.
Criteria for Proarrhythmia Criteria for proarrhythmia during electrophysiologic studies are empiric, but little in the way of clinical data corroborates the significance of these alterations. We have used the following definitions: 1. Initiation of a sustained ventricular tachyarrhythmia (VT or ventricular fibrillation) in a patient in whom only nonsustained VT was provoked by the complete stimulation protocol during baseline.
2. Conversion while on drug therapy of induced sustained VT that, during the baseline study, could be terminated by programmed stimulation to a sustained ventricular tachyarrhythmia (VT or ventricular fibrillation], requiring cardioversion for termination during the drug evaluation. 3. Initiation of sustained VT or ventricular fibrillation during drug evaluation by an induction mode less aggressive than that required to initiate the sustained arrhythmia during baseline. 4. Development of spontaneous sustained VT during drug evaluation in a patient who required programmed stimulation to initiate the arrhythmia during baseline.
ProarrhythmicResponses During Electrophysiologic Testing In a study of 160 patients with ventricular tachyarrhythmias associated with coronary artery disease, 432 trials of different antiarrhythmic regimens were assessed by electrophysiologic techniques for proarrhythmic effects. Programmed stimulation initiated sustained VT in 121 patients, ventricular fibrillation in 16 patients and symptomatic nonsustained VT in 23 patients. A proarrhythmic effect was noted in 68 of the 432 drug trials (16%). At least 1 proarrhythmic event was observed in 51 of 160 patients (32%).12
Conversionof InducedNonsustained VentricularTachycardiato Sustained VentricularTachycardia In 23 patients, nonsustained VT was the only arrhythmia initiated despite completion of the entire programmed electrical stimulation protocol during the baseline study. Fifty-nine antiarrhythmic regimens were evaluated in these patients. The antiarrhythmic regimen allowed initiation of sustained monomorphic VT or ventricular fibrillation in 10 of 59 studies (17%). Such an effect was noted in 6 of 23 patients i26% i26%j.j. Typically, the sustained stained VT had a longer cycle length than the arrhythmia lmia initiated during baseline. In 1 study, more re extrastimuli exrrastimuli were required to initiate the sustained ’VT rm +n than were required to induce the nonsustained VT VI’ m in the baseline state. In the other studies, ’ r of extrastimuli, or fewer, initiated the same number sustained ventricular tachyarrhythmia.
Conversionof Hemodynamically Stable VentricularTachycardiato One RequiringCardioversion VT was initiated in 121 natients during the baseline studies, and 325 antiarrhychmic regimen; were evaluated. Conversion of a previously stable arrhythmia to one requiring cardioversion for termination occurred in 15 of 325 studies (5%). This effect was noted at least once in 12 of 121 patients (10%) with sustained VT who underwent programmed electrical stimulation. The typical response was a VT with a shorter cycle length or with a longer cycle length but hemodynamic deterioration. Such a proarrhythmic effect was noted in patients whose ventricular cycle length was prolonged
April 30.1987
-and when the antiarrhythmic regimen made terminating VT by programmed stimulation more difficult, when the drug regimen facilitated acceleration of the programmed electrical stimulation-initiated tachycardia or when hemodynamic deterioration occurred despite the slower ventricular rate. Ventricular fibrillation was initiated in only 1 patient who had experienced monomorphic sustained VT during the baseline study.
SpontaneousDevelopment of Sustained VentricularTachycardia The spontaneous development of VT on drug is an uncommon proarrhythmic response during electrophysiologic testing; most VT is noted during oral drug administration and is not specifically related to programmed stimulation. This type of proarrhythmia is generally discovered by noninvasive techniques. Nonetheless, during intravenous administration of an antiarrhythmic drug in 3 drug trials, spontaneous VT occurred without programmed stimulation and was considered a proarrhythmic response during electrophysiologic testing.
ProarrhythmicResponsesProduced by IndividualRegimens In a study of 160 patients with coronary artery disease, the 2 most significant forms of proarrhythmic response-conversion of nonsustained to sustained VT and conversion of hemodynamically stable to hemodynamically unstable ventricular tachyarrhythmia-occurred in 4% to 13% of various drug trials. Of 144 patients with sustained VT, 18 (13%) received at least 1 drug regimen that produced a proarrhythmic effect during electrophysiologic testing. No significant difference in the incidence of proarrhythmic responses among various agents was uncovered (Table I). In another study,13 significant differences in the occurrence of proarrhythmic responses during electrophysiologic testing were reported during trials with amiodarone, flecainide, quinidine plus mexiletine and amiodarone plus procainamide when compared with quinidine. Whether such differences are clinically significant and whether they will be replicated in other large patient populations evaluated with electrophysiologic testing remain to be seen.
JOURNAL
OF CARDIOLOGY
Volume 59
47E
TABLE I Proarrhythmic Responses with Individual Antiarrhythmic Regimens Response/ Regimen
Study Drug Procainamide Quinidine Mexiletine Amiodarone Quinidine and mexiletine Procainamide and mexiletine Amiodarone and procainamide Other regimens
EasierInductionof SustainedTachyarrhythmia Sustained ventricular tachyarrhythmia was initiated during the baseline study in 137 patients in whom 373 antiarrhythmic regimens were evaluated. In 43 (12%) of these studies, fewer programmed extrastimuli were required to induce a sustained arrhythmia on drug compared with baseline. This form of proarrhythmia was observed at least once in 26 patients (19%). In 85% of trials demonstrating this form of proarrhythmia, sustained tachyarrhythmia was accomplished by reducing the number of extrastimuli by 1, e.g., triple extrastimuli required in the baseline state and double extrastimuli while the patient was receiving a drug.
THE AMERICAN
6184 3159 2140 5/87 3/35 2115 l/25 3/40
(7%) (5%) (5%) (6%) (9%) (13%) (4%) (8%)
Electrocardiographic Intervalsand ProarrhythmicResponsesDuring ProgrammedElectricalStimulation We have analyzed baseline and on-drug QRS duration, QT interval, QTc interval, JT interval and JTc interval in 314 patients who underwent electrophysiologic studies. No significant differences emerged between the baseline intervals or the changes from baseline [expressed as the absolute difference or the percentage of change] in any individual antiarrhythmic regimen and the development of any type or form of proarrhythmia. This suggests that the drug that produced the proarrhythmic response may exert a local effect not reflected by the global electrophysiologic changes.
Discussion Although the potential of antiarrhythmic drugs to provoke or worsen ventricular arrhythmias is being extensively studied, evaluating the mechanism of this adverse response is difficult. Its occurrence, not yet predictable, often leads to catastrophic results. Thus, its study by other than phenomenologic approaches has been minimal. Proarrhythmic responses produced by antiarrhythmic drugs during electrophysiologic studies have a reported occurrence of 13% to 24%.11.13,16~17 This variation undoubtedly reflects differences in methodology, definition of proarrhythmia and antiarrhythmic drug regimens. Some uniformity in the criteria for proarrhythmic response during electrophysiologic study has surfaced. Rinkenberger et aPa reported a conversion of nonsustained to sustained VT of 13% during electrophysiologic evaluation of antiarrhythmic regimens. Most investigators have included this event in their definition of proarrhythmic responses during electrophysiologic studies
11,12,15-18
Less uniformity is seen in definitions of worsening of sustained VT. Although all investigators agree that worsening of a VT is possible, some require merely that the VT cycle be shortened,11r16whereas others insist on hemodynamic deterioration not noted in the baseline state.12x13 These events [shorter cycles or hemodynamic deterioration or both] are more inclusive, and may reflect not only a change in the rate of ar-
48E
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ON PROARRHYTHMIA
rhythmia but also effects of the drug on myocardial performance. This latter consequence, in fact, may reflect not true proarrhythmia but rather a combination of adverse effects on both electrophysiologic and hemodynamic parameters. Instead of a requirement for cardioversion, the induction of sustained VT with a cycle shorter than during control studies has been suggested to denote a worsening of sustained VT.16 Although the cycle length of VT initiated during programmed electrical stimulation is typically reproducible in an individual patient, it would seem prudent to specify the shortening of cycle length (e.g., >2O%] to avoid incorrectly attributing the spontaneous variation in cycle length to an adverse drug effect. Many investigators have included a reduction in the number of extrastimuli required to initiate the arrhythmia as an indication of proarrhythmic response to an antiarrhythmic regimen.llJ3J6 This criterion requires that the ventricular tachyarrhythmias during programmed electrical stimulation be precisely reproducible from study to study. In fact, 2 groups have reported that the VT in a second baseline study required a different number of extrastimuli in many patients.*gJOIn 1 report of 2 baseline studies, fewer extrastimuli were required to initiate VT in 15% of regimens in the second study.20 This percentage is not dissimilar from the one for occurrence of proarrhythmia reportedly identified by more easy inducibility. This standard, in fact, may be the least conclusive. Poser et allI described this form of proarrhythmia as “possible” when only 1 less extrastimulus was needed during drug evaluation compared with baseline, and “definite” when 2 less extrastimuli were required. The validity of this criterion remains to be established. To date, studies of the provocation and worsening of ventricular arrhythmias during programmed electrical stimulation have not analyzed the clinical relevance of observations made in the electrophysiology laboratory. Whether changes in inducibility and type of arrhythmia reflect an increased potential for the spontaneous worsening of ventricular arrhythmias is not clear. In addition, study of the mechanisms of these proarrhythmic responses has been limited-undoubtedly because the reproducibility of such observations has not been confirmed. In addition, such responses remain highly unpredictable and are often life-threatening, rendering prolongation to allow study ethically indefensible. It has been suggested that at least some forms of proarrhythmia during electrophysiologic testing may be related to slowing of conduction within the reen-
trant circuit, short-circuiting of the reentrant circuit to produce a shorter revolution time or increased dispersion of refractoriness allowing establishment of reentrant circuits. Although these hypotheses are rational, no definitive evidence to support them has been presented to date. Undoubtedly, further study will provide a superior understanding of these phenomena and their clinical relevance.
References 1. Selzer A, Wray HW. Quinidine
syncope: paroxysmal
ventricular
fibrilla-
tion occurring during treatment of atriai arrhythmias. Circulation 1964;36: 17-26. 2. Schwartz SP. Hallinaer L. Imnerialli A. Transient ventricular fibrillation. IV. The effects oj procaynamide on patients with transient ventricularjibrillation during established auricuio-ventricular dissociation. Circulation 1952;6: 193-200.
-
3. McCord ML, Taguchi JT. A study of the effect of procainamide hydrochloride in sunraventricular arrhvthmio. Circulation 1951:4:387-393. 4. Meltzer RS, Robert EW, l&Morrow M, Martin RP. Atypical ventricular tachycardia as a manifestation of disopyramide toxicity. Am J Cardioi 1978;42:1049-1053.
5. Cocco G, Strozzi C. Chu D, Pansini R. Torsades de pointes as a manijestation of mexiletine therapy. Am Heart 1 1980:100:878-880. 6. Engler RL, LeWinter M. Tocainide induced ventricular fibrillation. Am Heart J 1981;101:494-496. 7. Sclarovsky S, Lewin RF, Kracoft 0, Strasberg B. Arditta A. Agmon J. Amiodorone-induced polymorphous ventricular tachycardia. Am Heart 1 1983:105:6-12.
8. Winkle RA, Mason JW. Griffen JC, Ross D. Malignant ventriculartachycardia associated with the use of encainide. Am Heart J 1981;102:857-864. 9. Reid PR, Griffith LSC, Platia EV, Ord SE. Evaluation of jiecainide acetate in the management of patients at high risk of sudden cardiac death. Am r Cardiol 1984;53:108&1118. 10. Velebit V, Podrid P, Lown B, Cohen BH. Graboys TB. Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs. Circulation 1982;65:886-894. 11. Poser R. Lombardi F, Podrid PJ, Lown B. Aggravation of arrhythmia induced with antiarrhythmic drugs during electrophysiologic testing. Am Heart j 1985;110:9-16. 12. Rae AP. Greenspan AM, Spielman SR, Sokoloff NM, Webb CR, Kay HR, Horowitz LN. Anti&rhythmic drug efficacy for ventricular tachyarrhythmios associated with coronary artery disease as assessed by electrophysiologic studies. Am J Cardiol 1985;55:1494-1499. 13. Rae AP, Greenspan AM, Spielman SR, Horowitz LN. Proarrhythmia daring electrophysiologic studies (abstr). Br Heart J. in press. 14. Goldstein RE. Tibbits PA, Oefgen WJ. Proarrhythmic effects of antiarrhvthmic drugs. Ann NY Acad Sci 1984:427:94-100. 15: MorganrGh J, Horowitz LN. Flecainide. Its proarrhythmic effect and expected changes on the surface electrocardiogram. Am J Cardiol 1984;53: 898-948. 16. Podrid PJ. Aggravation of ventricular arrhythmia. A drug-induced complication. Drugs 1985;29:33-44. 17. Torres V, Flowers D, Somberg JC. The arrhythmogenicity of antiarrhythmic agents. Am Heart J 1985;109:1090-1097. 18. Rinkenberger RL, Prystowsky EN, Jackman WM, Naccarelli GV, Heger JJ. Zipes DP. Drug conversion of nonsustained ventricular tachycardia to sustained ventricular tachycardia during serial eiectrophysiologic studies: identification of drugs that exacerbate tachycardia and potential mechanisms. Am Heart J 1982;193:177-184. 19. Livelli FD, Gang ES, Reiffel JA, Ferrick KJ, Gliklich JI, Bigger JT. Reproducibilitv of inducible ventricular tachvcardia labs&l. Circulation 1982;66:Ii-
146. ’ ’
20. McPherson CA, Rosenfeld LE, Batsford WP. Day-to-day reproducibility of responses to right ventricular programmed stimulation: implications for serial drug testing. Am J Cardioi 1985;55:689-695.
LEONARD N. HOROWITZ, P. RAE, MB, MRCP, HAROLD
MD, ALLAN M. GREENSPAN, MD, R. KAY, MD, and SCOTT R. SPIELMAN,
Antiarrhythmic drugs may worsen ventricular arrhythmias in certain patients. This effect, termed proarrhythmia, aggravation or provocation of arrhythmia, can be investigated with either noninvasive or invasive techniques. Using electrophysiologic study, 160 patients with ventricular tachycardia or ventricular fibrillation were evaluated during treatment with 432 different antiarrhythmic regimens. Proarrhythmic responses were noted in 68 drug trials (16 % ), and at least 1 event was observed in 51 patients (32 % ). Nonsustained ventricular tachy-
MD
cardia was converted to sustained ventricular tachycardia in 17 % of these studies. Hemodynamically stable ventricular tachycardia was converted to an arrhythmia that required cardioversion for termination in 5% of the studies. Ventricular tachyrhythmia was more easily induced in 12% of trials. These proarrhythmic responses were not related to changes in QRS duration, QT interval or JT interval measured at baseline or to changes produced by antiarrhythmic drugs. (Am J Cardiol 1987;59:45E-48E)
A
ntiarrhythmic drugs may worsen existing ventricular arrhythmias or produce new ones. This effect, called aggravation and provocation of arrhythmia or proarrhythmia, has been known for 20 years. An association between antiarrhythmic drugs and syncope from polymorphic ventricular tachycardia (VT) was reported in 1964,l although it had been suspected much earlier.2 Subsequently, the proarrhythmic potential of antiarrhythmic drugs in general has been emphasized.3-10 Despite this documentation, only recently has proarrhythmia been studied systematically.l”-13 To date, studies have described the types of proarrhythmic response and their frequency with various antiarrhythmic agents. Few studies have been directed specifically toward the mechanism of these responses.
From the Division of Clinical Cardiac Electrophysiology and Computer Center of the Likoff Cardiovascular Institute, Hahnemann University Hospital, Philadelphia, Pennsylvania. Dr. Horowitz’s current address is the Philadelphia Heart Institute, Presbyterian-University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, Address for reprints: Leonard N. Horowitz, MD, Philadelphia Heart Institute, Presbyterian-University of Pennsylvania Medical Center, 39th and Market Streets, Philadelphia, Pennsylvania 19104. 45E
Even the terminology describing these adverse effects has not been standardized. Some prefer “aggravation and provocation” to indicate the ability of antiarrhythmic drugs to both worsen and create serious arrhythmia.‘OJl Others use the term “proarrhythmia.“12j14J5Proarrhythmic responses have been evaluated by both noninvasive and invasive techniques. This review will consider drug-induced proarrhythmic effects encountered during invasive electrophysiologic testing and programmed electrical stimulation.
Electrophysiologic Testingto Evaluate ProarrhythmicEffects Electrophysiologic evaluation was carried out in patients with documented ventricular arrhythmias after informed written consent was obtained from each. Baseline and on-drug evaluations were performed with the patient in the postabsorptive state, and either no sedation or light diazepam sedation was used. Before the baseline evaluation, all antiarrhythmic agents were discontinued for a minimum of 5 half-lives. Patients receiving digoxin, P-adrenergic blocking agents or nonantiarrhythmic calcium antagonists continued to take these agents at a stable dosage throughout the electrophysiologic studies. Multiple electrode catheters were inserted percutaneously using bupivacaine (0.25%) anesthesia and positioned with fluoroscopic guidance. Electrocardio-
46E
A SYMPOSIUM:
PERSPECTIVES
ON PROARRHYTHMIA
graphic leads I, aVF and V1 and intracardiac electrograms were displayed on an oscilloscope and recorded on magnetic analog tape. Real-time recordings were obtained using an ink-jet recorder, and measurements were made at paper speeds of 100 to 250 mm/s. All electrocardiographic recordings were measured at a paper speed of 100 mm/s with the patient supine. Programmed electrical stimulation was performed with an optically isolated constant-current stimulator. The stimuli were rectangular pulses of 1 ms at an amplitude twice the late diastolic threshold. In no patient was stimulation performed at an amplitude >2 mA. The protocol included single, double and triple ventricular extrastimuli delivered during sinus rhythm and ventricular drive pacing at cycle lengths of 600 and 450 ms. The protocol was performed at the right ventricular apex, and if no sustained arrhythmia was induced, stimulation was repeated at the right ventricular outflow tract. Left ventricular stimulation was not performed. In subsequent drug evaluations, the entire protocol was performed at both right ventricular sites until a sustained, reproducible arrhythmia was induced. The entire protocol was performed irrespective of the type of stimulation that initiated the baseline arrhythmia. Antiarrhythmic drugs were administered either intravenously or orally. The dose was titrated upward to maximum tolerance or the maximum dose allowed for investigational agents. Electrophysiologic testing was performed at steady-state plasma concentration of the agent(s). Individual regimens were selected after evaluation of the patient’s previous exposure to antiarrhythmic drugs. A history of hypersensitivity, allergy or proarrhythmic response to the drug precluded its use; however, history of clinical ineffectiveness did not prohibit drug evaluation by electrophysiologic study.
Definitionsof VentricularTachvcardia and VentricularFibrillation VT was considered sustained if it was >30 seconds long or produced cardiovascular collapse requiring termination in <3O seconds. VT was considered nonsustained if it lasted 16 complexes and <3O seconds. The initiated arrhythmia was considered nonsustained VT only if the entire stimulation protocol was completed and no sustained arrhythmia occurred. The initiated arrhythmia was defined as ventricular fibrillation if within 3 seconds of initiation of a sustained ventricular tachyrhythmia, electrocardiographic characteristics of tvnical ventricular fibrillation were seen in 3 surface leads.
Criteria for Proarrhythmia Criteria for proarrhythmia during electrophysiologic studies are empiric, but little in the way of clinical data corroborates the significance of these alterations. We have used the following definitions: 1. Initiation of a sustained ventricular tachyarrhythmia (VT or ventricular fibrillation) in a patient in whom only nonsustained VT was provoked by the complete stimulation protocol during baseline.
2. Conversion while on drug therapy of induced sustained VT that, during the baseline study, could be terminated by programmed stimulation to a sustained ventricular tachyarrhythmia (VT or ventricular fibrillation], requiring cardioversion for termination during the drug evaluation. 3. Initiation of sustained VT or ventricular fibrillation during drug evaluation by an induction mode less aggressive than that required to initiate the sustained arrhythmia during baseline. 4. Development of spontaneous sustained VT during drug evaluation in a patient who required programmed stimulation to initiate the arrhythmia during baseline.
ProarrhythmicResponses During Electrophysiologic Testing In a study of 160 patients with ventricular tachyarrhythmias associated with coronary artery disease, 432 trials of different antiarrhythmic regimens were assessed by electrophysiologic techniques for proarrhythmic effects. Programmed stimulation initiated sustained VT in 121 patients, ventricular fibrillation in 16 patients and symptomatic nonsustained VT in 23 patients. A proarrhythmic effect was noted in 68 of the 432 drug trials (16%). At least 1 proarrhythmic event was observed in 51 of 160 patients (32%).12
Conversionof InducedNonsustained VentricularTachycardiato Sustained VentricularTachycardia In 23 patients, nonsustained VT was the only arrhythmia initiated despite completion of the entire programmed electrical stimulation protocol during the baseline study. Fifty-nine antiarrhythmic regimens were evaluated in these patients. The antiarrhythmic regimen allowed initiation of sustained monomorphic VT or ventricular fibrillation in 10 of 59 studies (17%). Such an effect was noted in 6 of 23 patients i26% i26%j.j. Typically, the sustained stained VT had a longer cycle length than the arrhythmia lmia initiated during baseline. In 1 study, more re extrastimuli exrrastimuli were required to initiate the sustained ’VT rm +n than were required to induce the nonsustained VT VI’ m in the baseline state. In the other studies, ’ r of extrastimuli, or fewer, initiated the same number sustained ventricular tachyarrhythmia.
Conversionof Hemodynamically Stable VentricularTachycardiato One RequiringCardioversion VT was initiated in 121 natients during the baseline studies, and 325 antiarrhychmic regimen; were evaluated. Conversion of a previously stable arrhythmia to one requiring cardioversion for termination occurred in 15 of 325 studies (5%). This effect was noted at least once in 12 of 121 patients (10%) with sustained VT who underwent programmed electrical stimulation. The typical response was a VT with a shorter cycle length or with a longer cycle length but hemodynamic deterioration. Such a proarrhythmic effect was noted in patients whose ventricular cycle length was prolonged
April 30.1987
-and when the antiarrhythmic regimen made terminating VT by programmed stimulation more difficult, when the drug regimen facilitated acceleration of the programmed electrical stimulation-initiated tachycardia or when hemodynamic deterioration occurred despite the slower ventricular rate. Ventricular fibrillation was initiated in only 1 patient who had experienced monomorphic sustained VT during the baseline study.
SpontaneousDevelopment of Sustained VentricularTachycardia The spontaneous development of VT on drug is an uncommon proarrhythmic response during electrophysiologic testing; most VT is noted during oral drug administration and is not specifically related to programmed stimulation. This type of proarrhythmia is generally discovered by noninvasive techniques. Nonetheless, during intravenous administration of an antiarrhythmic drug in 3 drug trials, spontaneous VT occurred without programmed stimulation and was considered a proarrhythmic response during electrophysiologic testing.
ProarrhythmicResponsesProduced by IndividualRegimens In a study of 160 patients with coronary artery disease, the 2 most significant forms of proarrhythmic response-conversion of nonsustained to sustained VT and conversion of hemodynamically stable to hemodynamically unstable ventricular tachyarrhythmia-occurred in 4% to 13% of various drug trials. Of 144 patients with sustained VT, 18 (13%) received at least 1 drug regimen that produced a proarrhythmic effect during electrophysiologic testing. No significant difference in the incidence of proarrhythmic responses among various agents was uncovered (Table I). In another study,13 significant differences in the occurrence of proarrhythmic responses during electrophysiologic testing were reported during trials with amiodarone, flecainide, quinidine plus mexiletine and amiodarone plus procainamide when compared with quinidine. Whether such differences are clinically significant and whether they will be replicated in other large patient populations evaluated with electrophysiologic testing remain to be seen.
JOURNAL
OF CARDIOLOGY
Volume 59
47E
TABLE I Proarrhythmic Responses with Individual Antiarrhythmic Regimens Response/ Regimen
Study Drug Procainamide Quinidine Mexiletine Amiodarone Quinidine and mexiletine Procainamide and mexiletine Amiodarone and procainamide Other regimens
EasierInductionof SustainedTachyarrhythmia Sustained ventricular tachyarrhythmia was initiated during the baseline study in 137 patients in whom 373 antiarrhythmic regimens were evaluated. In 43 (12%) of these studies, fewer programmed extrastimuli were required to induce a sustained arrhythmia on drug compared with baseline. This form of proarrhythmia was observed at least once in 26 patients (19%). In 85% of trials demonstrating this form of proarrhythmia, sustained tachyarrhythmia was accomplished by reducing the number of extrastimuli by 1, e.g., triple extrastimuli required in the baseline state and double extrastimuli while the patient was receiving a drug.
THE AMERICAN
6184 3159 2140 5/87 3/35 2115 l/25 3/40
(7%) (5%) (5%) (6%) (9%) (13%) (4%) (8%)
Electrocardiographic Intervalsand ProarrhythmicResponsesDuring ProgrammedElectricalStimulation We have analyzed baseline and on-drug QRS duration, QT interval, QTc interval, JT interval and JTc interval in 314 patients who underwent electrophysiologic studies. No significant differences emerged between the baseline intervals or the changes from baseline [expressed as the absolute difference or the percentage of change] in any individual antiarrhythmic regimen and the development of any type or form of proarrhythmia. This suggests that the drug that produced the proarrhythmic response may exert a local effect not reflected by the global electrophysiologic changes.
Discussion Although the potential of antiarrhythmic drugs to provoke or worsen ventricular arrhythmias is being extensively studied, evaluating the mechanism of this adverse response is difficult. Its occurrence, not yet predictable, often leads to catastrophic results. Thus, its study by other than phenomenologic approaches has been minimal. Proarrhythmic responses produced by antiarrhythmic drugs during electrophysiologic studies have a reported occurrence of 13% to 24%.11.13,16~17 This variation undoubtedly reflects differences in methodology, definition of proarrhythmia and antiarrhythmic drug regimens. Some uniformity in the criteria for proarrhythmic response during electrophysiologic study has surfaced. Rinkenberger et aPa reported a conversion of nonsustained to sustained VT of 13% during electrophysiologic evaluation of antiarrhythmic regimens. Most investigators have included this event in their definition of proarrhythmic responses during electrophysiologic studies
11,12,15-18
Less uniformity is seen in definitions of worsening of sustained VT. Although all investigators agree that worsening of a VT is possible, some require merely that the VT cycle be shortened,11r16whereas others insist on hemodynamic deterioration not noted in the baseline state.12x13 These events [shorter cycles or hemodynamic deterioration or both] are more inclusive, and may reflect not only a change in the rate of ar-
48E
A SYMPOSIUM:
PERSPECTIVES
ON PROARRHYTHMIA
rhythmia but also effects of the drug on myocardial performance. This latter consequence, in fact, may reflect not true proarrhythmia but rather a combination of adverse effects on both electrophysiologic and hemodynamic parameters. Instead of a requirement for cardioversion, the induction of sustained VT with a cycle shorter than during control studies has been suggested to denote a worsening of sustained VT.16 Although the cycle length of VT initiated during programmed electrical stimulation is typically reproducible in an individual patient, it would seem prudent to specify the shortening of cycle length (e.g., >2O%] to avoid incorrectly attributing the spontaneous variation in cycle length to an adverse drug effect. Many investigators have included a reduction in the number of extrastimuli required to initiate the arrhythmia as an indication of proarrhythmic response to an antiarrhythmic regimen.llJ3J6 This criterion requires that the ventricular tachyarrhythmias during programmed electrical stimulation be precisely reproducible from study to study. In fact, 2 groups have reported that the VT in a second baseline study required a different number of extrastimuli in many patients.*gJOIn 1 report of 2 baseline studies, fewer extrastimuli were required to initiate VT in 15% of regimens in the second study.20 This percentage is not dissimilar from the one for occurrence of proarrhythmia reportedly identified by more easy inducibility. This standard, in fact, may be the least conclusive. Poser et allI described this form of proarrhythmia as “possible” when only 1 less extrastimulus was needed during drug evaluation compared with baseline, and “definite” when 2 less extrastimuli were required. The validity of this criterion remains to be established. To date, studies of the provocation and worsening of ventricular arrhythmias during programmed electrical stimulation have not analyzed the clinical relevance of observations made in the electrophysiology laboratory. Whether changes in inducibility and type of arrhythmia reflect an increased potential for the spontaneous worsening of ventricular arrhythmias is not clear. In addition, study of the mechanisms of these proarrhythmic responses has been limited-undoubtedly because the reproducibility of such observations has not been confirmed. In addition, such responses remain highly unpredictable and are often life-threatening, rendering prolongation to allow study ethically indefensible. It has been suggested that at least some forms of proarrhythmia during electrophysiologic testing may be related to slowing of conduction within the reen-
trant circuit, short-circuiting of the reentrant circuit to produce a shorter revolution time or increased dispersion of refractoriness allowing establishment of reentrant circuits. Although these hypotheses are rational, no definitive evidence to support them has been presented to date. Undoubtedly, further study will provide a superior understanding of these phenomena and their clinical relevance.
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