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982 IACC Vol. 12, No . 4 0-be, 1950982-0

Prediction of Successful Suppression of Sustained Ventricular Tachyarrhythmias by Serial Drug Testing From Data Derived at the Initial Electrophysiologic Study

DENNIS L . KUCHAR, MD, FRACP, JEFFREY ROTTMAN, MD, ERIC BERGER, MD, CHARLES S . FREEMAN, RN, HASAN GARAN, MD, FACC, JEREMY N . RUSKIN, MD, FACC Boston, Massachusetts

This study investigated whether data available after the Subgroup analysis combining each of these variables Iden- initial electrophysldogie study in patients with sustained tified patients with a high, intermediate or low probability ventricular tachyarrhylhmiu could identify those patients of Ending a successful oral drug regimen . Patients whose in whom serial drug testing Is likely to be eficucious, One arrhythmia was suppressed by intravenous procainamlde hundred six patients with Inducible sustained ventricular had a 100% likelihood (If left ventricular ejection fraction tachyarrhythmla, whose initial study included short-term was ?40%) or an 87% likelihood (if ejection traction was drug testing with intravenous procainamWe, were evalu- <40%) of responding to an oral regimen. Patients whose ated, The baseline arrhythmia induced (in the absence of all arrhythmia was still lndaeibie after letravcwuos procaina- antiarrhythmic drugs) was monomorphic tachycardia with mide and had an ejection fraction ?40% had an interme- a cycle length >200 ms in 81 patients and ventricular Purer diate likelihood (46%) of oral drug response. Patients with or fibrillation in the remaining 25 patients. After intrave- persistent ventricular tachycardle after Intravenous pro- nous infusion of procafnamide (1,250 ± 300 mg), a ventric- cainamidc and an ejection fraction <40% had a low ular tachyarrhythada could still be induced in 80 patients probability (19%) of successful response to an oral aatl- during testing with up to three exlrastimuli . Serial drug arrhythndc regimen. testing with one to four trials of oral conventional and Hence, patients who are unlikely to benefit from serial investigational agents was then undertaken . drug testy can be identified with use of s simple algorithm Evaluation of 15 clinical, hemodywnic and eleelrophys- incorporating the left ventricular ejectleo fraction and the iologic variables by stepwise logistic regression identified response to intravenmus procalimmfde at the initial ehx• two independent predictors of successful response to oral trophvsidogic study. Early consideration often Implantable aatiarrhythmic drugs: 1) aonindocibility of ventricular device or arrhythmia surgery may be appropriate for such tachycardia after intravenous (p < 0 .001), patients . and 2) left ventricular ejection fraction a40% (p < 0 .05) . (J Am Coll Card '1 1988:12:982)

Suppression of sustained ventricular tachyarrhythmias by testing is low for currently used conventional agents as well antiarrhythmic drugs identified as efficacious by serial pro- as for more recently introduced experimental agents, with grammed ventricular stimulation studies is associated with a overall suppression rates of 15 to 52% (5-10) . In the remain- favorable outcome (1-4). However, the yield of serial drug ing patients, surgical and catheter ablation, implantable devices and empiric therapy with have become acceptable therapeutic options (11-14). Identification, early From the Cardiac Arrhythmia Service . Electrophysiology Laboratory . after their initial evaluation of those patients whose arrhyth- Massuchusclts General Hospital, Harvard Medical School. Boston, Mass- chusetts . Dr. Kuchar is an Overseas Fellow of the National Hess Foundation mia is unlikely to b .- suppressed by drugs could reduce the of Australia . Woden, Australian Capital Territory, Australia . Dr. Ganr is the period of hospitalization and provide more cost-effective recipient of an established investigalorship from the American Hem Associ . ation (No. 84 2m), Dallas. Texas . Dr. Rotloon is the recipient ore training management. Recent studies (5-7) have suggested that such cram from the National Institutes of Health . Bethesda, Maryland . patients can be identified on the basis of demographic and Manuscript received March 7, 1988: revised manuscript received May 5 . clinical data ; successful drug-induced arrhythmia suppres- 1985, accepted May 12 . 1908 . Address for rrnrims ; Dennis Kuchar. MD, 3 plowman Street, North sion was seen particularly in patients without coronary Bondi, New South Wales. Australia, 2026. artery disease, and especially in those without any structural

01951 by the American College or Cardiology 0735 .1097/951t3.50

JACC Vol. 12 . No. 4 KUCHAR ET AL . 983 October 1958952-R PREDICTORS OF ANTIARRHYTHMIC aRUG RESPONSE

cardiac disease. However, in clinical practice . the majority were discontinued for at least five half-lives before study . of patients referred for electrophysiologic studies have sus- The protocol for programmed ventricular stimulation in . tained ventricular tachycardia occurring in the setting of cluded introduction of up to three extrastimuli during vein chronic myocardial infarction . tricular pacing at two basic cycle lengths (600 and 400 ms) In our initial electrophysiologic evaluation of patients from the right ventricular apex. If ventricular tachycardia with induced sustained ventricular tachycardia, we routinely could not be induced with three extrastimuli from the apex, perform short-term drug testing with intravenous procaina- the catheter was moved to the right ventricular outflow tract mide infusion . It has been suggested (15,16) that a favorable and stimulation repeated at this site . Burst right ventricular response to this agent is associated with a high likelihood of pacing was not performed in this group. Sustained ventric- arrhythmia suppression with other oral class I antiarrhyth- ular tachycardia was defined as a ventricular tachyarrhyth- mic drugs . This study was undertaken in an attempt to mia lasting ?30 s or requiring active termination because of identify predictors of successful drug suppression in a series hemodynamic collapse (17). Arrhythmias were subclassified of patients who underwent serial electrophysiologic testing according to the cycle length of the induced arrhythmia and with a wide range of antiarrhythmic agents, from information the constancy of beat to beat QRS configuration . Ventricular available after the initial electrophysiologic study, including tachycardia was defined as monomorphic if successive QRS the response to intravenous procainamide . complexes had a similar configa-ation in all leads without a change in frontal or horizontal axis >30° from one beat to another : monomorphic ventricular tachycardia with a cycle Methods length <_200 ms was defined as ventricular flutter . Ventricu- Study patients. The study group comprised 106 patients lar fibrillation was defined as a sustained polymorphic who underwent comprehensive electrophysiologic testing arrhythmia, with marked beat to beat variation in configura- for evaluation of documented or suspected spontaneous tion and electrocardiographic (ECO) frontal and horizontal ventricular tachycardia or fibrillation unrelated to acute axes. The induced arrhythmia was classified as monomor- myocardial infarction . These patients all had inducible sus- phic if z If successive beats displayed uniform configuration tained ventricular tachyarrhythmias in the absence of anti- before degenerating to ventricular fibrillation . arrhythmic drugs . They constitute a subgroup of patients After induction of venlraTdar tachycardia or frbri/larion, who underwent evaluation of the response to programmed an infusion of inrraveamrs procainamide Was instituted . This ventricular stimulation before and after infusion of intrave- was administered as a loading dose of 16 mg/kg body weight nous procainamide at the initial study, among a consecutive over 20 min followed by a maintenance infusion of 3 mg/min . series of patients with inducible ventricular arrhythmias . The infusion dose was decreased if significant hypotension These patients represent a distinct study group from those (<90 mm Hg systolic) or marked QRS or QT prolongation described in a prior report from our laboratory (7) . occurred . Repeat programmed ventricular stimulation was There were 87 men and 19 women with a mean age of 61 performed approximately 30 min after initiation of the infu- years (range 27 to 79) . Based on clinical, echocardiographic, sion, and blood levels were drawn at the conclusion of the histologic and angiographic data, the primary cardiac diag- stimulation protocol. The end point of stimulation after noses included coronary artery disease (luminal stenosis intravenous drug testing was induction of a sustained ven- w50% in at least one major vessel) in 94 patients (81 with a tricular arrhythmia or completion of the protocol with deliv- history of prior myocardial infarction), congestive cardiomy- ery of three extrastimuli, regardless of The baseline charac- opathy in 6 patients, valvular heart disease in 2 and hyper- teristics of ventricular tachycardia induction . Arrhythmia trophic cardiomyopathy, repaired tetralogy of Fallot and suppression during intravenous procainamide thereafter was right ventricular dysplasia in I patient each. One patient had defined as inability to initiate ventricular tachycardia . In no evidence of structural heart disease with normal right and addition, we did not consider ventricular tachycardia to be left ventricular function and normal right ventricular biopsy suppressed by intravenous procainamide if a nonsustained findings. Mean left ventricular ejection fraction determined ventricular arrhythmia > 15 beats was induced . Stimulation from radionuclide ventriculogaphy was 35 ._ 15% (range 10 was performed at the right ventricular outflow tract only if to 70%). Indications for electrophysiologic study included baseline induction of ventricular tachycardia was attained at out of hospital cardiac arrest in 45 patients and sustained this site. monomorphic ventricular tachycardia in 45 patients ; the Oral antiurhythmic drug trials. Serial drug testing with remaining patients were studied because of syncope (9) or oral antiarrhythmic agents was then performed with the aim high grade ventricular ectopic activity (7). of achieving suppression of ventricular tachycardia in re- Eketrophysiologicstudy. Patientsunderwentelectrophys- sponse to programmed ventricular stimulation . No set order iologic evaluation in the postabsorplive slate after informed of administration of antiarrhythmic agents was used; drug written consent was obtained . All antiarrhythmic agents selection was determined on the basis of prior drug history, (excluding beta-adrenergic blocking agents and ) left ventricular function and patient tolerance . Testing in

984 KUCHARETAt, . tACC Vol. 12. No. 4 PREDICTORS OF ANTIARRHYTHMIC DRUG RESPONSE Octobor 1999:982-8

patients who showed a favorable response to intravenous Results procainamide usually began with an oral class I agent . In Electrophyalologle profile at initial electrophysiologic addition to conventional class Is agents, drug testing in- study. All 106 patients had sustained ventricular tachycardia cluded a combination of class Ia and lb agents, Ic agents or fibrillation induced at the initial electrophysiologic study . (, , lorcainide, indecainide and propafe- Monomorphic ventricular tachycardia (with a cycle length none) . . hepridil, and amiodarone . Many of >200 ms) was induced in 81 patients ; the remainder had the latter agents were administered as part of investigational rapid ventricular tachyarrhythmias (cycle length X200 ms) drug studies or on compassionate drug use protocols, fre- that were either monomorphic (ventricular flutter) or poly- quently in patients who had already undergone several drug morphic (ventricular fibrillation) . The arrhythmia was in- trials at other centers. duced in 6 patients with three extrastimuli and in 100 patients An effective response to an oral antiarrhythmic regimen with two extrastimuli ; in no patient was sustained ventricu- was defined by the inability to initiate a sustained ventricular lar tachycardia induced with only a single extrastimulus . arrhythmia with the same number of extrastimuli required at Electrophysiologic effect of intravenous procainamide. the baseline study, that is, the same level of stimulation at The mean dose of procainamide administered was 1,250 t the right ventricular site as that which induced the ventric- 300 mg (500 to 1,950 mg). A modest (10%) increase in right ular arrhythmia at the baseline study, with use of the ventricular effective refractory psaiud was seen (during the maximal number of extrastimuli of that study as the end 600 ms drive), that is, from 240 ± 23 ms at baseline to 266 ± point of the protocol . Responders were discharged on a 28 ms after administration of procainamide (p < 0 .001) . maintenance dose of the drug that led to tachycardia sup- Ventricular tachycardia (> 15 beats) could All be induced in . In patients whose arrhythmia was not suppressed pression 80 patients during short-term drug testing ; the mean cycle by antiarrhythmic agents alone (nonresponders), therapeutic length of ventricular tachycardia was increased from 246 ± options included therapy with amiodarone (n = 34), trans- 63 ms at baseline to 313 ± 81 ms after administration of catheter electrical ablation (n = 6) and map-guided endocar procainamide (p < 0.001). Fewer ventricular extrastimuli dial resection (n = 2). The remainder were treated with were required for induction of ventricular tachycardia in 16 that appeared to be beneficial by Halter ambu- patients and three extrastimuli were required after adminis- latory (ECU) analysis . An automatic implantable cardio- tration of procainamide in 20 patients in whom two extra- vetter-defibrillator was implanted in seven of the patients stimuli induced ventricular tachycardia at the baseline study. whose arrhythmia was not suppressed by oral antiarrhyth- In four of six patients their arrhythmia induced initially with mic therapy . triple extrastimuli was suppressed by intravenous procaina- Data analysis. Continuous data are presented as mean mide . A slower ventricular tachycardia was induced after I SD. Unpaired data were compared by two-tailed r test for procainamide in 55 patients and a faster arrhythmia was continuous variables and by chi-square analysis for compar- induced in 10 . ison of proportions . The clinical variables tested as univari- Table I compares the clinical and electrophysiologic ate predictors of oral drug response were age, gender, features of patients whose arrhythmia was suppressed by etiology of heart disease, prior myocardial infarction, history intravenous procainamide with the features of those whose of cardiac arrest and left ventricular ejection fraction (both arrhythmia was not suppressed . Univariate predictors of absolute and when dichotomized at a value of 40%) . The arrhythmia suppression were 1) the absence of coronary baseline electrophysiologic variables included in the univari- artery disease or prior myocardial infarction ; 2) the induc- ate analysis were the type of arrhythmia induced and the tion of ventricular flutter or fibrillation at the initial study ; number of extrastimuli required for induction at the initial and 3) the need to use three extmstimuh at that study to study and right ventricular effective refractory period . Also induce the ventricular arrhythmia. included were variables assessing the response to intrave- Results or serial drug testing . A total of 187 trials of oral nous procainamide : change in refractory period, suppres- antiarrhythmic agents was performed (mean 1 .7 per patient) . sion of tachycardia, mode of induction and cycle length of Patients in whom drug suppression was not successful persistently inducible tachycardia and dose and serum level underwent an average of 2 .1 drug trials per patient. Serial of procainamide. Univariate predictors with a p value <0 .10 drug testing identified 47 drug responders (44% of patients). were identified, stepwise logistic regression (18) was per- A class Is agent alone was successful in suppressing ventric- formed to construct a multivariate predictor function . This ular tachycardia in 18 (46%) of 39 cases and was found to analysis assigns a coefficient (b) that describes the statistical result in the best overall suppression rate in patients tested weight of variables selected to be independently significant on these agents (Table 2). predictors. Patients with missing values for particular vari- Predictors of successful oral drug suppression . 1) Uni- ables were excluded from univariate analysis of these vari- variate analysis. Clinical and electrophysiologic variables ables. identified at the time of initial evaluation are compared for JACC Vol. 12 . No. 4 KUCHAR ET AL . 985 October M :.- PREDICTORS OF ANTIARRHYTHMIC DRUG RESPONSE

T" 1. Clinical and Electrophysiologic Features of 106 Patients Table 3 . Clinical and Electrophysiologic Features of Responders According to Response to Intravenous Procainamide to Serial Drug Testing Group I Group II p ltcspomlers Nonresponders p In = 261 In = got Value (a = 47) In = 591 Value Age (yr) 60 2 12 60 2 13 NS Age lyrl 59 x 12 61 c 12 NS Gender ltnrNworeen1 2016 67113 NS Gender(malelfenulel 35112 52R NS Cardiac disease Cardiac disease Coronary artery disease 20 74 <5 .65 Coronary artery disease 37 57 NS Prior myocardial infarction 16 65 <0.115 Prior my-dial infarction 31 50 <0.05 Congestive eardiomyopathy 3 3 NS Congestive cardiomyopathy 6 0 <0.05 Cardiac arrhythmia Cardiac arrhythmia History of cardiac arrest 10 35 NS History of cardiac arrest 21 24 NS Induced VF/flutter 9 16 <0.05 Induced VF :flurter 17 8 <0 .01 CL of induced VT 244 < 87 247 2 62 NS Cycle length or VT 237 z 00 555 -- 58 NS LVEF (9n) 39 x 12 37±14 NS LVEF(9r1 41!14 34-12 <0.005 LVEF < 40% Is 57 NS LVEF < 407, 23 4a <0o01 Empiric AAD 2.5 2 1.1 2_ .6! 1 .3 NS EmpirK AAD 2.5 7 L2 2.6 ± 1.2 NS Triple extrastimuli 4 2 < 5.05 Triple extrastimuli 4 2 N:. Pracainamide Response to intravenous ERP after procainamide +31 ± 21 +24 ± 21 NS procainamide Dose administered Img) 1 .209 ± 274 1,292 2 273 NS No VT induced 27 0 <0.001 Serum drug level (µg/m0 10 .7 7 5 .9 9 .1 2 2 .9 NS VT harder to induce 7 13 NS No . of oral drugs tested 1 .3 ! 0.8 17 - 1 .0 NS Slower VT induced 16 38 NS Group I represents pollens wbose arrhythmia was suppressed by intra . Abbreviations as in Table 1 . venous procainamide ; Group 11 represents patients whose arrhythmia could still be induced after procainamide. Results are expressed as mcvn ^_ SD . AAD = antianhythmie drugs ; CL = cycle length : ERP = change in egeclive Among patients whose ventricular tachycardia was still refractory period from baseline ; LVEF= ten ventricular ejectionfractin r: NS = not sigrdficanR VF = ventricularfihrillalion ; VT = ventricular tachycardia. inducible after intravenous procainamide, there was no statistically significant difference in the outcome of serial drug testing between those whose arrhythmia was inducible responders and nonresponders in Table 3. Responders were with more extrastimuli compared with those in whom it characterized by higher left ventricular ejection fraction (p = was induced with the same number of extrastimuli (35 0 .0008) and suppression of ventricular tachycardia by pro- versus 23%, p = NS) or between those patients whose grammed ventricular stimulation after intravenous procaina- induced tachycardia was the same and those in whom it was . P = mide (p = 0.0005). In addition, induction of ventricular slower after intravenous procainamide (30 versus 20% flutter or fibrillation (in the absence of antiarrhythmic drugs) NS). was also associated with successful drug suppression during 2) Multivariate analysis. Stepwise logistic regression serial drug testing. analysis selected three variables as independently significant predictors of oral drug suppression : a) inability to induce ventricular tachycardia with three extrastimuli after intrave- Table 2. Oral Antiarrhythmic Agents Tested by Serial nous procainamide (b = 3.3, p = 0.0004), b) the absence of Electrophysiotogic Study coronary artery disease (b = 0 .9, p = 0.005), and c) a left Response During ventricular ejection fraction >40% (b = 0 .7, p = 0.013) . A Vaagban-Williams Seral Testing separate analysis was also performed in the group ofpatients Class a I<

986 NUCHAR ET AL . JACC Vol . 12, No. 4 PREDICTORS OF ANTIARRHYTHMIC DRUG RESPONSE October 1988:982-8

Ep . .0001 - artery disease and prior myocardial infarction ; recently reported suppression rates for individual antiarrhythmic agents have ranged between 10 and 45% (19-22), and overall suppression rates between 15 and 52% (5-7, 16) . In addition, U10- serial drug testing is time consuming, expensive and uncom- Wit fortable for patients, often requiring multiple invasive pro- 80 - rsg 13,15 cedures and defibrillations and exposure to potential adverse drug effects (23) . It would therefore be desirable to devise an

so - objective means of stratifying patients soon after their initial evaluation by their likelihood of benefit from this technique . I This retrospective study suggests that an assessment of 40- left ventricular function and the response to acute testing with intravenous procainamide during the initial electrophys- 20- iologic study together enable identification of patients with -2 high and low probabilities of responding to an oral anti-

0 arrhythmic drug regimen . swmoaiol M W NO YES YES Predictive value of response to intravenous procainamide . NOmrainamke Previous investigators (15,16) have shown that a beneficial LVEF

JACC Vol . 12. No. 4 KDCHAR ET AL. 987 0aober 1988:982-8 PREDICTORS OF .ANTIARRHYTHMIC DRUG RESPONSE

evaluation, might have been spared the discomfort and outcome. Therefore, it may he reasonable to progress to a expense of serial drug testing . In patients with inducible nonpharmacologic approach in such patients . ventricular tachycardia after intravenous procainamide and Our overall suppression rate of 44% is somewhat higher with only mild left ventricular dysfunction, serial drug test- than that reported by other groups . We have defined the end ing may still be of sufficient yield to justify its routine point of stimulation during serial drug testing as that number application. of extrastimuli required at the baseline study to initiate The reason for the strong predictive power of left ventric- ventricular tachycardia . This is based on the favorable ularfunction in predicting drug response is not immediately outcome noted in our patients when these criteria were apparent. Recent studies (5,6,16) have demonstrated the adopted (3 .7) . negative association of left ventricular aneurysm and coro- Limitations of study. The major limitation of this study is nary artery disease with suppression of ventricular tachycar- the lack of uniformity of drug treatment during serial testing . dia . Furthermore, patients with a low ejection fraction have resulting in an inability to make strong conclusions about the fewer drug options because, in many of them, the anti- comparative predictability of subsequent drug responses . A arrhythmic agents have significant negative inotropic and prospective study with a uniform protocol for drug testing proarrhythmic effects . Our data suggest that the degree of may allow a more meaningful comparison of drug response ; left ventricular dysfunction is a major determinant of drug however, because of the likelihood of drug intolerance and responsiveness ; in patients with coronary artery disease and consideration of patients with poor left ventricular function, prior myocardial infarction, the ejection fraction remained the drug regimens for each patient will always need to be an independent predictor of drug response. individualizes . In this retrospective study, there was a bias Alternatives to serial electrophysiologle-pharmacologic towl.rd use of a class la drug as the first agent if short-term testing. With consideration of these two variables, available intravenous testing with procainamide was successful in early in a patient's hospitalization, it may be possible to suppressing tachycardia. Conversely, in the interest of re- stratify patients into distinct groups with differing probabil- ducing the number of drug trials and the patient's hospital ities of a successful response to oral antiarrhythmic therapy . stay, a class la agent was usually omitted or combined with Swerdlow et al . (5) suggested that patients identified as a class lb agent as the first serial drug evaluation in patients having a low likelihood of suppression by oral drug therapy in whom intravenous procainamide was unsuccessful . based on electrophysiologic testing should be evaluated Patients with a ventricular tachycardia that was induced using another modality, such as the use of ambulatory ECG by three exirastimuti at the baseline study had a high rate (Hotter) monitoring. Recent data (26), however, suggest that (g0%) of suppression after intravenous procainamide . This only a small minority of patients presenting with spontane- may reflect a consequence of the stimulation protocol, which ous sustained ventricular tachycardia have sufficient ventric- involved stimulation during short-term drug testing to a ular ectopic activity recorded to enable an objective assess- maximum of three extrastimuli . The use of an additional ment of antiarrhythmic effect ; furthermore, suppression of extrastimulus could conceivably have led to a lower suppres- ectopic activity on Halter monitoring is associated with an sion rate . unacceptable rate of spontaneous arrhythmia recurrence Ideally, at least one drug from each class in addition to (27). In patients evaluated by Halter monitoring, a recur- combinations of these agents should be tested before a rence rate of ventricular tachycardia of 50% was observed patient's arrhythmia is deemed to be truly drug refractory . In over a follow-up period of up to 2 years compared with 20% our series of patients, the mean number of drug tests per in the group evaluated by electrophysiologic testing . Al- patient was relatively low. This is, at least in part, a though these results represent only a small population, reflection of the group of patients seen at a tertiary care further alternatives of management are limited . The empiric institution where numerous pharmacologic options had al- use of amiodarone has been advocated by some groups (14) ready been explored at another hospital before our eke- in the light of data demonstrating a lack of association trophysiologic evaluation. between outcome and the results of el° .trophysiologic test- Clinical implleatlo s. The results of this study suggest a ing . However, our data suggest that the suppression of new method for objectively classifying patients into groups induced ventricular tachycatdia by ?otravenous procaina- with a high and low likelihood of successful response to oral mide is predictive for anriodarone as well as for class I antiarrhythmic therapy on the basis of the initial ei, :trophys- agents, although testing within 10 to 14 days of initiating iologic testing. Such a classification could be useful in therapy may underestimate the clinical efficacy of this drug identifying patients unlikely to benefit from serial drug (28) . With respect to continuing the patient on treatment testing in whom an early decision to proceed with therapeu- with a conventional that does not tic alternatives such as implantation of a defibrillator or suppress ventricular tachycardia, data have overwhelmingly performacce of a map-guided ablative procedure could be °flown that this practice is associated with a poor long-term made soon after the initial electrophysiologic evaluation .

988 KUCHAR St AL IACC Vol . 12, No. 4 PREDICTORS OF ANTIARRHYTRMIC DROO RESPONSE Octaher 19AA :9A2-n

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