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391 lACC Vol. 17. No.2 February 1991:391-6 ELECTROPHYSIOLOGIC STUDIES Drug Therapy for Ventricular Tachyarrhythmias: How Many Electropharmacologic Trials Are Appropriate? KATHERINE M. KAVANAGH, MD, D. GEORGE WYSE, MD, PHD, FACC, HENRY J. DUFF, MD, ANNE M. GILLIS, MD, ROBERT S. SHELDON, MD, PHD, L. BRENT MITCHELL, MD Calgary, Alberta, Canada = To determine how many electropharmacologic drug trials should be performed to select therapy for patients with ventricular tachyarrhythmias, the outcome of 150 consecutive patients with inducible ventricular tachyarrhythmias undergoing serial electropharmacologic testing was examined. The probability of identifying predicted effective therapy (induction of fewer than five ventricular responses with three ventricular extrastimuli at three pacing cycle lengths) and the probability of that therapy preventing sustained ventricular tachyarrhythmia recurrences were determined as a function of the number of preceding trials. The probability (:t SE) of identifying predicted effective therapy by the first trial (0.23 :t 0.03) was significantly higher than that of the second (0.09 :t 0.04), third (0.08 :t 0.04) and fourth (0.05 :t 0.04) trials (p 0.001). No patient had predicted effective therapy identified by subsequent trials. The 2 year actuarial probability of freedom from sustained ventricular tachyarrhythmias on predicted effective therapy was higher for the first (0.79 :t 0.08), second (0.73 :t 0.13) and third (0.86 :t 0.13) trials than for the fourth (0.33 :t 0.27) trial (p = 0.02). Thus, the probability of selecting therapy with long-term efficacy was highest for the first trial (0.18), intermediate for the second (0.07) and third (0.07) trials and lowest for the fourth (0.02) and subsequent (0.00) trials. Accordingly, the electropharmacologic approach to therapy selection should be abandoned after three unsuccessful trials. (1 Am Coli CardioI1991;17:391-6) Natural history studies (1-5) have reported high mortality rates among patients who have had sustained ventricular tachyarrhythmias without a reversible cause. However, the prognosis of such patients is improved with individualized antiarrhythmic therapy. A recent randomized trial (6) supported the practice of selecting therapy for these patients using the electropharmacologic approach, which begins with induction of a patient's tachyarrhythmia by programmed stimulation. Antiarrhythmic drug therapy is then assessed by repeat programmed stimulation. The process is repeated until predicted effective therapy is found. Although precise end points vary, predicted effective therapy is defined as that which prevents reinduction of the ventricular tachyarrhythmia (7-17). Such effective therapy is found for <50% of patients (16-21), and previous studies (9,22-24) have suggested that the probability of finding a predicted effective therapy decreases after one unsuccessful electropharmacologic trial. Viable alternative therapies now exist for patients for whom no therapy is considered effective by the electropharmacologic approach, such as empiric amiodarone therapy (25), implantable device therapy (26) and ablative therapy (27,28). Accordingly, when a patient is undergoing electropharmacologic testing, a decision must be made as to how many trials are appropriate before alternative therapeutic approaches are considered. The purpose of this study was to determine the probability of identifying predicted effective antiarrhythmic drug therapy and the follow-up probability of such therapy preventing sustained ventricular tachyarrhythmia recurrences as a function of the number of preceding unsuccessful trials. Such information would determine the appropriate number of electropharmacologic trials in patients with inducible ventricular tachyarrhythmias. From the Departments of Medicine and Pharmacology and Therapeutics. Foothills General Hospital and University of Calgary, Calgary. Alberta, Canada. This study was supported by grants from the Alberta Heart and Stroke Foundation, Calgary. Alberta. Drs. Wyse, Duff and Mitchell are Scholars, Dr. Gillis is a Clinical Investigator and Dr. Kavanagh is a Fellow of the Alberta Heritage Foundation for Medical Research, Edmonton. Alberta. Manuscript received May 16, 1990; revised manuscript received August 14, 1990, accepted August 28, 1990. Address for reprints: L. Brent Mitchell, MD, Division of Cardiology, Foothills General Hospital, 1403 29th Street. NW, Calgary. Alberta, Canada T2N 2T9. ©1991 by the American College of Cardiology Methods Study patients and design. The study group consisted of 150 consecutive patients with hypotensive ventricular tachycardia or ventricular fibrillation in the absence of a reversible cause (electrolyte abnormality, proarrhythmic drug effect, acute myocardial infarction). These patients had their ther0735-1097/91/$3.50 392 KAVANAGH ET AL. DRUG TRIALS FOR VENTRICULAR ARRHYTHMIAS apy selected by the electropharmacologic approach between February 1983 and July 1989. After written informed consent was obtained, baseline studies were performed while the patient was not taking any antiarrhythmic drug. These studies included radionuclide angiograms and programmed stimulation studies. Patients were eligible for the electropharmacologic approach if stimulation reproducibly induced their ventricular tachyarrhythmia. Oral therapy was then initiated and programmed stimulation was repeated under steady state conditions (five half-lives later). Antiarrhythmic drugs were assessed until predicted effective therapy was found or a prescribed series of drug trials had been evaluated. The series included at least one class Ia agent (quinidine, disopyramide, procainamide), a class Ib agent (usually mexiletine) and a combination of class Ia and class Ib agents. If left ventricular function permitted, the series also included a class Ie agent (usually propafenone), a class II agent (usually propranolol) and a class III agent (usually sotalol). Other investigational agents and combinations of agents were used less frequently. Ventricular tachycardia was defined as five or more consecutive ventricular complexes at a rate> 120 beats/min and was considered sustained when it persisted for ;:::30 s or required termination because of hemodynamic collapse. Predicted effective therapy was defined as that which prevented the induction of five or more consecutive beats of ventricular tachycardia. Electrophysiologic studies. Transvenous electrode catheters were inserted by the Seldinger technique under local anesthesia (lidocaine 0.33%). Programmed stimulation was performed using standard techniques (29). Single, double and triple extrastimuli were introduced after eight beats of ventricular pacing at cycle lengths of 600, 500 and 400 ms. Subsequently, 5 and 15 beats of rapid ventricular pacing at cycle lengths of 300 to 240 ms (10 ms decrements) were applied. If ventricular tachycardia was not reproducibly induced at the right ventricular apex, the pacing protocol was repeated at the right ventricular outflow tract and, if necessary, from the left ventricle. The end point of stimulation was completion of the stimulation protocol or reproducible induction of sustained ventricular tachyarrhythmia. Drug evaluation studies were performed after reinstrumentation (30) by repeating the entire stimulation protocol at the site permitting reproducible ventricular tachyarrhythmia induction at baseline study. Statistical analysis. Continuous data (mean values ± I SD) were compared by using Student's unpaired t test. Proportional data were compared by using the chi-square test. Cumulative probabilities of identifying predicted effective therapy as a function of the number of drug trials and of freedom from sustained ventricular tachyarrhythmias and sudden death as a function of the follow-up duration were calculated by the Kaplan-Meier method (31) and are presented as mean values ± I SEE. These probabilities were compared with use of the generalized Wilcoxon test. The JACC Vol. 17. No.2 February 1991:391-6 Table 1. Characteristics of 150 Study Patients Predictive Effective Therapy No. of patients Age (yr) Male LVEF Heart disease None ASHD/MI Other All Patients Found Not Found 150 60 ± 12 128 (85) 0.38 ± 0.15 58 56 ± 15 49 (84) 0.43 ± 0.16 62 ± 10 79 (86) 0.35 ± 0.14 0.01 NS 0.001 9 (16) 38 (66) 11 (19) 1 (I) 86 (93) 5 (5) <0.001 <0.001 0.009 10 (7) 124 (83) 16 (II) p Value 92 Data are presented as mean ± 1 SD or number (%) of patients. ASHDI MI = atherosclerotic heart disease with remote myocardial infarction; LVEF = radionuclide left ventricular ejection fraction; p Value = comparison of effective therapy found versus no therapy found. null hypothesis was rejected when the two-tailed p value was <0.05. Results Study patients. The clinical features of the study patients are presented in Table I. A mean of 2.6 ± 1.5 different therapies were tested for each patient (median 3 trials, range 1 to 8). Patients for whom a predicted effective therapy was found were younger and had a higher left ventricular ejection fraction than were those for whom no predicted effective therapy could be identified. Likewise, those for whom a predicted effective therapy was found were less likely to have atherosclerotic heart disease with remote myocardial infarction and were more likely to have either no structural heart disease or structural heart disease other than atherosclerotic heart disease. Details of the presenting and induced tachyarrhythmias are shown in Table 2. The majority (79%) of the 150 patients Table 2. Presenting and Induced Ventricular Tachyarrhythmias in 150 Patients Predictive Effective Therapy No. of patients Presenting VT/VF Nonsust VT Sust VT VF Induced VT/VF Nonsust VT Sust VT VF All Patients Found Not Found 150 58 92 32 (21) 86 (57) 32 (21) 17 (29) 26 (45) 15 (26) 15 (16) 60 (65) 17 (18) 0.06 0.01 NS 25 (17) 118 (79) 7 (5) 16 (28) 39 (67) 3 (5) 9 (10) 79 (86) 4 (4) 0.004 0.007 NS p Value Data represent the number (%) of patients. Nonsust and Sust VT nonsustained and sustained ventricular tachycardia, respectively. VF ventricular fibrillation. = = February 199\ :391-6 W 0.50 lrl 0.40 > 1= U. U. ~~ 0.30 >-a: .... w ;Ii!: I~---------------------I r------' r----- >- j ···::i\·L 0.80 m 1 I a J II: 0- I I I --' 1 0.60 i i w ~ 0.20 u. m c( m ~ ;.. "1 L ----------- 2 iii c( I I w>- 393 KAVANAGH ET AL. DRUG TRIALS FOR VENTRICULAR ARRHYTHMIAS JACC Vol. 17, No.2 ! 0.40 L·-·-·-·-·_·_·_·_·_·-4 ~ Z oa: ~ w 0- 2 4 5 6 7 6 ELECTROPHARMACOLOGIC TRIAL NUMBER 0.20 0.00 L . - - L - - - ' -_ _->-- o 3 6 12 -'- 24 FOllOW-UP (Months) Figure 1. Incremental (bar graphs :t 1standard error of the estimate) and cumulative (dashed line) probability of finding a predicted effective antiarrhythmic drug therapy for inducible ventricular tachycardia for serial electropharmacologic drug trials I through 8. presented with sustained ventricular tachycardia or fibrillation. The others presented with hypotensive symptoms (syncope in 25 of the 32 patients) and had spontaneous nonsustained ventricular tachycardia documented at another time. Regardless of the presenting tachyarrhythmia. programmed stimulation at baseline study induced sustained ventricular tachycardia in most patients (79%). Patients for whom predicted effective therapy was found were more likely to have nonsustained and less likely to have sustained ventricular tachycardia than were those for whom no predicted effective therapy could be identified. In this regard. the induced tachyarrhythmia was more discriminating than was the presenting tachyarrhythmia. Identification of predicted effective therapy. The electropharmacologic approach identified a predicted effective therapy for 58 of the 150 study patients. Figure I presents the incremental and cumulative probability of finding a predicted effective therapy as a function of the number of trials undertaken. The probability of finding a predicted effective therapy was 0.23 ± 0.03 for the first. 0.09 ± 0.04 for the second, 0.08 ± 0.04 for the third and 0.05 ± 0.04 for the fourth trial. No patient had a predicted effective therapy found at a fifth or subsequent trial. The probability of finding such therapy at the first trial was significantly higher than at subsequent trials (p = 0.001). However. there were no significant differences among the probabilities of finding a predicted effective therapy at the second, third and fourth trials. The probability of a particular agent or class of agents being considered effective therapy also showed dependence on the electropharmacologic trial number. For example, the probability of a class I agent being considered effective therapy was 0.24 (29 of 123 trials) for the first trial and 0.06 (4 of68 trials)for the second, third and fourth trials combined (p = 0.002). No patient had a predicted effective therapy with a class I agent identified at the fifth or subsequent electropharmacologic trials. This trial dependence of the probability of finding a predicted effective therapy was not the result of differences in the trough Figure 2. Actuarial probability of remaining free of sustained ven· tricular tachycardia, ventricular fibrillation and sudden cardiac death during follow-up study among patients whose therapy was predicted to be effective by their first electropharmacologic (I:dotted line), second (2:dashed line), third (3:solid line) or fourth (4:dashed/ dotted line) trial. steady-state serum levels obtained. For example, there were no differences among the concentrations of quinidine (the most commonly used agent in this study) assessed as the first (9.7 ± 2.8p,molJliter), second (10.0 ± 3.6p,molJliter) or third trial (12.0 ± 0.5 p,molJliter) (p > OJ) (reference 6.2 to 15.4 p,molJliter). Only trials of orally administered drugs were included in this analysis. Nevertheless. 41 of the 150 patients had 1 to 5 trials (mean 2.7 ± 1.4) of intravenously administered drugs before the testing of oral agents. Comparing the 41 patients who had and the 109 patients who had not undergone trials using intravenously administered drug testing. there were no significant differences among the incremental probabilities of finding a predicted effective therapy at the first (0.22 ± 0.Q7 and 0.23 ± 0.04, respectively), second (0.08 ± 0.Q7 and 0.10 ± 0.05. respectively), third (0.12 ± 0.08 and 0.06 ± 0.05. respectively) or fourth (0.07 ± 0.09 and 0.04 ± 0.05, respectively) trial. Thus, intravenous testing did not increase the likelihood of identifying an effective oral drug therapy and did not reduce the number of oral drug trials. The cumulative probability offinding a predicted effective therapy was also a function of the ventricular tachyarrhyth· mia induced at baseline-higher for nonsustained ventricular tachycardia (0.68 ± 0.10) and ventricular fibrillation (0.64 ± 0.27) than for sustained ventricular tachycardia (0.38 ± 0.05) (p = 0.003). Nevertheless, the incremental probability of finding a predicted effective therapy for each category of inducible ventricular tachyarrhythmia showed similar dependence on the number of preceding unsuccessful electropharmacologic trials. Long-term efficacy of selected therapy. Follow-up probabilities of freedom from recurrent sustained ventricular tachyarrhythmias and sudden death on drug therapy as a function of the electropharmacologic trial predicting that therapy to be effective are shown in Figure 2. The probability of freedom from sustained ventricular tachyarrhythmias 394 KAVANAGH ET AL. DRUG TRIALS FOR VENTRICULAR ARRHYTHMIAS and sudden death after 2 years was comparable for drug therapy predicted effective by the first (0.79 ± 0.08; n = 34), second (0.73 ± 0.13; n = 12) and third (0.86 ± 0.13; n = 9) trials. However, the 2 year probability offreedom from these outcomes in patients receiving therapy predicted to be effective by the fourth trial was significantly lower (0,33 ± 0.27; n = 3) (p = 0.02). The long-term efficacy of a predicted effective therapy was also a function of the category of ventricular tachyarrhythmia induced at the baseline programmed stimulation study. The 2 year probability of freedom from sustained ventricular tachycardia or fibrillation tended to be higher for patients with inducible nonsustained ventricular tachycardia (0.94 ± 0.06) than for those with inducible sustained ventricular tachycardia (0.69 ± 0.08) or inducible ventricular fibrillation (0.67 ± 0.27) (p = 0.11). However, recurrences in patients with inducible sustained ventricular tachycardia were rarely fatal. Accordingly, the 2 year follow-up probability of freedom from sudden cardiac death was higher for patients with inducible nonsustained ventricular tachycardia (1.00) and those with inducible sustained ventricular tachycardia (0.89 ± 0.06) than for those with inducible ventricular fibrillation (0.67 ± 0.27) (p = 0.03). Identification of therapy with long-term efficacy. The probability of finding therapy with long-term efficacy at each trial was determined by the product of the probability of predicting a therapy to be effective and the probability of that therapy proving to be effective for the subsequent 2 years. Thus, the probability of finding therapy with longterm efficacy was 0.18 for the first, 0.07 for the second, 0.07 for the third and 0.02, for the fourth trial. No patient had therapy with long-term efficacy identified at subsequent trials. Discussion This study demonstrates that the probability of finding antiarrhythmic drug therapy with long-term efficacy by the electropharmacologic approach for patients with inducible ventricular tachyarrhythmias is a function of the number of preceding unsuccessful trials. The probabilities of identifying therapy with long-term efficacy are highest for the first (0.18), intermediate for the second (0.07) and third (0.07), and lowest for the fourth (0.02) and subsequent (0.00) trials. Identification of predicted effective therapy. The probability of finding predicted effective therapy for ventricular tachyarrhythmias is a function of the number of preceding failed electropharmacologic trials. The probability of success for the first trial is 0.23 and decreases for the second, third and fourth trials (0.09, 0.08, 0.05, respectively), whereas subsequent trials have a very low probability of success (0.00 in this study). Thus, the number of failed electropharmacologic trials should be considered one of the factors that determine the probability of the next trial being considered effective. IACC Vol. 17. No.2 February 1991:391-6 Patient variables. The patient variables that were predictors of a successful application of the electropharmacologic approach in this investigation included young age, good left ventricular function and absence of structural heart disease, particularly atherosclerotic heart disease. These observations are in keeping with other investigations (21,24,32) examining predictive values of patient variables for this purpose. One predictive factor noted by Swerdlow et al. (21) was fewer preceding unsuccessful empiric drug trials. This clinical observation is in keeping with our demonstration that the probability of identifying a predicted effective therapy is a function of the number of preceding unsuccessful electropharmacologic trials. Pharmacologic variables. Antiarrhythmic drugs differ in their ability to suppress ventricular tachyarrhythmia induction by programmed stimulation (24,33,34). Although the relative efficacy of each agent has not yet been examined in a randomized trial, there is agreement that the probability of a trial being considered effective by the electropharmacologic approach is highest for class Ia drugs, the combination of class Ia and Ib drugs and sotalol (24,33-36). Accordingly, these agents are usually evaluated first in clinical practice. The sequence of antiarrhythmic drug use in the present investigation mirrored this clinical practice. Furthermore, for the particular agents used extensively in this investigation, the probability of being considered effective therapy showed the same dependence on the number of preceding unsuccessful drug trials as did antiarrhythmic therapy in general. The observation that patients with inducible ventricular tachycardia who respond to therapy are most likely to respond to the first therapy assessed suggests that a trial of intravenous therapy at the time of the baseline electrophysiologic study may have predictive value for subsequent oral trials. Indeed, we (23) and others (9,22,24) previously reported that this is so. However, the data from the present study indicate that the practice of intravenous drug testing does not reduce the number of subsequent oral trials required to identify a predicted effective therapy. A potential rationale for this apparent inconsistency has been previously reported (22-24), that is, a patient's response to an intravenous trial predicts that patient's eventual response to some oral agent, but not necessarily to the oral form of the drug tested during intravenous administration. Long-term efficacy of selected therapy. The follow-up probability of freedom from sustained ventricular tachyarrhythmias and sudden death is also dependent on the electropharmacologic trial number predicting the therapy to be effective. When therapy was considered effective by the first, second or third trial, the event-free probability at 2 years was approximately 0.80. This degree of long-term efficacy is comparable with results published previously (14,19). However, the outcome of patients followed up on therapy predicted to be effective at the fourth trial was less acceptable. To our knowledge, this relation has not been reported previously. The explanation for this finding may KAVANAGH ET AL. DRUG TRIALS FOR VENTRICULAR ARRHYTHMIAS JACC Vol. 17, No.2 February 1991:391-6 reside in Bayes' theorem. As the prevalence of a condition decreases, the predictive value of an imperfect test deteriorates. In this circumstance, the condition is finding a predicted effective drug therapy and the imperfect test is electropharmacologic testing. After multiple trials, the probability of false prediction of efficacy exceeds that of true prediction of efficacy. Thus, if more than three electropharmacologic trials are needed to identify a predicted effective therapy, the probability of long-term ventricular tachyarrhythmia prophylaxis from that therapy is suspect. Conclusions. When patients are having a series of electropharmacologic trials to select therapy for their ventricular tachyarrhythmias, a decision must be made as to how many trials are appropriate before consideration of alternative therapeutic approaches. The data from this study provide direction in that regard. The first trial has the highest probability of identifying therapy with long-term efficacy (0.18). Thereafter, the probability of finding therapy with long-term efficacy decreases to an intermediate level for the second (0.07) and third (0.07) trials. Subsequent trials have a very low probability of identifying drug therapy with longterm efficacy. Thus, alternative therapeutic approaches should be considered for those patients who have not responded to therapy after three electropharmacologic trials. Although a case could be made for offering alternative therapeutic approaches to patients in whom even one electropharmacologic trial has been unsuccessful, this practice would result in approximately 14% of patients being denied effective electropharmacologic drug therapy. We acknowledge the important contributions of Claire Miller, RN. Darlene Ramadan, RN and the staff of Unit 92 and the Electrophysiologic Laboratory of the Foothills Medical Center, Calgary, Alberta, Canada. References I. Strauss MB. Paroxysmal ventricular tachycardia. Am J Med Sci 1930; 179:337-45. 2. 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