Reproducibility of programmed electrical stimulation responses in patients with ventricular tachycardia or fibrillation associated with coronary artery disease

Reproducibility of Programmed Electrical Stimulation Responses in Patients with Ventricular Tachycardia or Fibrillation Associated with Coronary Artery Disease Annabelle S. Volgman, MD, Terry A. Zheutlin, MD, Thomas A. Mattioni, MD, Michele A. Parker, RN, MS, and Richard F. Kehoe, MD Invasive electrophysiologk studies were performed in 102 patients with sustained ventricular tachycardia (VT) or ventrkutar fibrillation (VF) using an aggressive programmed efectrkal stimulatiqn (PES) protocol. The study was repeated after 2.0 f 2.9 days in atl patients with no intercurrent changes in antiarrhythmic therapy. Patients with coronary artery disease (n = 72) were identified and PES results of these patients were analyzed and compared with results of patients without coronary artery disease. Multiple cthtkal and ekctrophysiologic factors were analyzed to determine any association with concordance of PES responses. No sfgnifkant dtfference in concordance of PES responses was found in the 2 groups of patients. PES responses were grouped into 3 categories: (1) nonhtducible, (2) nonsustahted VT, and (3) sustained VT. Kappa values of PW responses of noninducible and sustained VT in both groups were higher and therefore the PES responses were more reproducible than nonsustained VT. The induction of sustained monomorphic VT was more reproducible than a PES response of nonsustained or sustained potymorphic VT. Inducible sustained VT with a rate of 1250 beats/min was less reproducfble than induction of sustained VT with a rate <250 beats/min. Induction of VT by 3 extrastimuli was less reproducible than with any other mode. This short-term variability may account for fake negatives associated with PES-directed antiarrhythmic therapy. Because of these findings, tt is recommended that nonsustalned VT and sustained polymorphic or rapid polymorphic VT should not be used as PES end points to guide antiarrhythmic therapy. (Am J Cardiol1992;70:75&763)

From the Illiiois Masonic Medical Center and Northwestern University Medical School, Chicago, Illinois. Manuscript received January 6, 1992; revised manuscript received and accepted May 20,1992. Address for reprints: Annabelle S. Volgman, MD, Rush-Presbyts rian-St. Luk>s Medical Center, 1653 W. Congress Parkway, Chicago, Illinois 60612.

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he use of programmed electrical stimulation studies (PES) has become widely accepted as a clinical tool in the management of patients with sustained ventricular tachycardia (VT) or ventricular tibrillation (VF). PI33 studies have been suggested to be better than the noninvasive approach in assessing risk and directing antiarrhythmic therapy in these patientsi The Electrophysiologic Study Versus Electrocardiographic Monitoring trial, a multicenter, randomized trial is underway to help elucidate this issue.2 With the advent of more effective antiarrhythmic therapy, including drugs and devices, it is even more crucial to understand the sensitivity, specificity, predictive accuracy and reproducibility of PES studies. PES studies have been shown to have >90% sensitivity in patients with recurrent sustained VT and >90% specificity in patients without cliical VT.3 When PES studies are used to predict suppression of arrhythmic recurrence with antiarrhythmic drugs, it has 85 to 100% accuracy.4-7 The sensitivity of PES is affected by clinical factors and presenting arrhythmia. Factors that influence the reproducibility of PES are still unclear. The immediate reproducibility of sustained VT induction has been found to be high (77 to 98%),8,9 whereas late reproducibility (i.e., weeks to months) was found to be variable in canine infarct modelsi and in patients with previous infarctions.“-l3 Since decisions regarding antiarrhythmic therapy for high-risk patients need to be made in a timely fashion, the therapy is usually based on 1 PES study. It is important to determine its reproducibility from day to day as well as its immediate reproducibility. Day-to-day reproducibility of PES response has a wider range (57 to 97%) than that of immediate reproducibility.3s14-18These findings may in part be due to the lack of uniformity in the definitions of the induced ventricular tachyarrhythmias as well as differences in the protocols used. These previous studies did not evaluate the factors that may influence concordance of PES re sponses. This study was undertaken to determine factors that may account for day-to-day variability and to identify subgroups that have more reproducible PES responses. METHODS Between June 1987 and September 1989, 110 consecutive patients with documented sustained VT or VF were evaluated. Patients with VT or VF related to acute infarction, electrolyte disturbance or drug intoxication were excluded. A total of 102 patients consented to adSEPTEMBER

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ditional PES studies to determine its reproducibility, and 25 of these patients underwent additional reproducibility studies while taking antiarrhythmic therapy resulting in a total of 127 PES studies. Seventy-two patients were identified as having coronary artery disease by coronary arteriogram. The studies were performed in the drug-free control state in 84 patients or while receiving prediiharge antiarrhythmic therapy in 43 patients. No changes were made in antiarrhythmic therapy in the 2 studies. All patients underwent PES studies on 2 separate days. Patients treated with an antiarrhythmic agent underwent their first PES study (PES-1) after achieving a steady-state level (treatment for at least 4 halflives of the medication). Patients treated with amiodarone (n = 14) had PES- 1 performed after 7 to 10 days of amiodarone therapy with a dose of 1,200 mg/day. No intravenous drug testing was performed in any of the patients. A drug washout period of 15 serum elimination half-lives was allowed before performance of PES-1. No patients previously taking amiodarone were included. The second PES study (PES-2) was performed 2.0 f 2.9 days after PES-1. Study pop&tMr Table I summarizes the characteristics of the study population. &CtliUIStIlMatiOslprototd:PES P-Ivd was performed in the postabsorptive state. Standard quadripolar electrode catheters were inserted percutaneously into femoral veins. Catheters were positioned at the right ventricular apex and outflow tract. Intracardiac recordings were displayed simultaneously with surface electrocardiographic leads I, aVF, Vr and V6 on a multichannel oscilloscope recorder (Gould Electronics) and recorded at paper speeds of 50 or 100 mm/s. Cardiac stimulation was performed using a programmable stimulator (Bloom Associates, Ltd.) delivering rectangular pulses with stimulation duration of 2 ms and twice the mid-diastolic threshold for current strength. The pacing catheters were removed at the conclusion of each study. A new pacing catheter was inserted for each sub sequent study. PES was performed with single and double extrastimuli using g-beat drive trains at 3 drive cycle lengths of 600, 500 and 400 ms. The premature stimulus was initially positioned 300 rns after the last stimulus. Effective refractory periods of the extrastimulus were achieved with decrements of 10 ms. Burst pacing of 4 to 8 consecutive beats was delivered from 300 to 240 ms or until 2:l capture was achieved. The stimulation protocol was first done at the right ventricular apex then at the right ventricular outflow tract. Triple extrastimuli were introduced at the same 3 drive cycle lengths. The study was terminated with the induction of a sustained ventricular tachyarrhythmia that required cardioversion, or with completion of the protocol. If a monomorphic VT was induced, hemodynamic compromise was assessed by blood pressure monitoring and consciousness. If the VT persisted after 30 seconds, overdrive pacing was attempted. If the patient was stable, efforts were made to reproduce the VT or induce other VTs. The characteristics of PES responses compared were: (1) inducibility, (2) sustainability, (3) morphology (monomorphic vs polymorphic), (4) mode of induc-

TABLE

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of Study

Population

Patient population (n = 102) Age (mean ? SD years) Men/women Organic heart disease Coronary artery disease RV dysplasia idiopathic dilated cardiomyopathy Mitral valve prolapse Other valvular disease Long PT syndrome Tetralogy of Fallot No detectable heart disease LVEF (mean 2 SD, n = 102) Presenting arrhythmia Sustained ventricular tachycardia fn = 61) Ventricular fibrillation (n = 41) No. of days between.studies (mean 2 SD) Distribution of PES studies Control drug-free state (n = 84) Predischarge antiarrhythmic therapy (n = 43) Total number of PES comparisons (n = 127) Treatment Surgical ablation (n = 7) Amiodarone (n = 14) Sotalol (n = 20) Verapamil (n = 1) Procainamide (n = 1) LVEF = left ventricular RV = right ventricular.

ejection fraction;

60 + 14 79123 72 11 5 6 2 1 4 37% * 14%

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tion, and (5) cycle length of the VT. Functional refractory periods were measured and compared for reproduo ibility. Definitiom: PROGRAMMED ELECTRICAL STIMULATION RESPONSE CATEGORIES: (1) noninducible = <7 ventricu-

lar beats; (2) nonsustained VT = 17 ventricular beats but <30 seconds, (3) sustained VT = 130 seconds in duration or required termination because of hemodynamic compromise. INDUCIBLE VENTRICULAR TACHYCARDIA: Either nonsustained or sustained VT (note: When I1 VT was induced, the longest one was reported as the PES response). MONOMORPPIC VENTRICULAR TACHYCARDIA: Identical beat&beat QRS morphology in all recorded surface leads. POLYMORPHIC VE~RICULARTACHYCARDIA: 12 different QRS morphologies in surface leads. FUNCTIONAL REFRACTORY PERIOD: The shortest achievable coupling interval for (1) VrV2 for 1 extrastimulus; (2) V2V3 for 2 extrastimuli; and (3) V3V4 for 3 extrastimuli. StatIstk Continuous data are expressed as mean f SD. Comparisons of differences between groups were evaluated using the 2 sample t test for continuous variables and chi-square or Fisher’s exact test for discrete variables. A p value <0.05 was considered statistically significant. The kappa statistic19 (a measure of reproducibility) and its 95% confidence interval were calculated for each category. A kappa value <0.40 indicates

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poor to fair reproducibility and 0.41 to 0.60 indicates moderate reproducibility. Kappa values >0.80 indicate excellent reproducibility.2o

monomorphic VT was the most reproducible VT, and nonsustained monomorphic VT was the second most reproducible response. Polymorphic VT, either sustained or nonsustained, was less reproducible in both patient RESULTS groups. Patlent popWWnr The 102 patients were divided Rate of induced ventriab tachycmdia: Figure 3 into 2 groups according to presence of coronary artery shows that in both patient groups, slow (<250 beats/ disease. Results of PES responses of the 72 patients min) sustained VT was more reproducible than fast with and the 30 patients without coronary artery disease (2250 beats/min) sustained VT. Induction of slow nonwere studied in detail and compared. No significant dii- sustained VT was also more reproducible than induction ference in concordance of PES responses was found in of fast nonsustained VT. Figure 4 shows that slow the 2 groups of patients. monomorphic VT was more reproducible than fast ProgrammedekKMcdstimumm~durmonomorphic VT, and both slow and fast polymorphic W PE!S responses were grouped into 3 cate VT. gories: (1) noninducible, (2) nonsustained VT, and (3) Mode of IndWionr Sustained, monomorphic and sustained VT. Results are listed in Figure 1. Response slow VTs induced by a mode other than 3 extrastimuli categories of noninducible or sustained VT were more were more reproducible than the other responses, with reproducible (kappa >0.40) than the response category kappa values >0.40. Monomorphic VT induced by any of nonsustained VT. Thus, a response of nonsustained mode other than 3 extrastimuli was the largest and VT is more likely to occur randomly in both patient most reproducible subset: kappa 0.47 in patients with groups. This wide 95% confidence interval reflects a and kappa 0.52 in patients without coronary artery dislack of reproducibility for thii end point. ease. FdWWSOfi~ vehkdar tad~ycmtk AnalyFtmctbd refractory @odsr Mean functional resis of the morphology and sustainability of induced VT fractory period differences were analyzed in both right is depicted in Figure 2. The induction of sustained ventricular sites, all stimulation modes and all drive cy0.7 .84

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cle lengths. Comparisons were made between patients in whom PPS responses were discordant versus those with concordant PES responses. There was no difference in the mean functional refractory periods between the 2 groups* Clinkal m No clinical factor influenced the reproducibility of PES responses. SpecitIcally age, left ventricular ejection fraction, presenting arrhythmia or antiarrhythmic therapy were found not to affect concordance of PES responses. DISCUSSION There have been previous studies on day-to-day variability of PES responses; however, it remains unclear which subgroup of patients and which factors significantly influence PPS reproducibility. This study is the first to suggest that PES in patients without coronary artery disease have similar reproducibility as that in patients with coronary artery disease. This needs to be validated by a study using a larger population. Unlike previous studies on reproducibility, our study analyzed the end points obtained by using 3 extrastimuli, a more aggressive stimulation protocol in patients with coronary artery disease. Our stimulation protocol is currently more widely used than those used in previous studies on

reproducibility. This study also analyzed in detail the different PPS responses. Thii study found 2 response subgroups that had good reproducibility based on the end point of the study: patients who were noninducible and patients whose response was sustained monomorphic VT. The response of nonsustained VT was less reproducible. Using nonsustained VT as a PES end point, Podrid et alzl showed a low recurrence rate after an average follow-up of 21 months in patients with VT or VF and syncope. However, we believe that in patients with a history of sustained ventricular tachyarrhythmia, 2 PES studies may be necessary to contirm lack of inducibility of a sustained ventricular tachyarrhythmia. We concur with other investigators14J5J7*22 who recommended that 2 PES studies should be performed in certain groups of patients because of day-to-day variability in PPS response in the drug-free state and in the steady state of an antiarrhythmic drug. It has been shown that patients in whom inducible sustained VT cannot be suppressed by antiarrhythmic drugs are at considerable risk for arrhythmic recurrence.7 Since effective alternate forms of therapy (e.g., implanted devices) are available in this patient population, it becomes essential to confirm that inducible VT has been

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effectively suppressed, However, because of the rising costs of medical care, repeating PFS studies to confirm results is not cost-effective. It is more reasonable to select patients who should have PES responses confirmed, such as patients with responses of nonsustained or polymorphic VT. Because a response of polymorphic VT is known to be more nonspecific and not reproducible, it should not be used as an end point to guide therapy. It has been shown that increasing the number of extrastimuli increases the sensitivity of PES.16*23-25However, specificity and reproducibility of PES may decrease with more extrastimuli.14T17’ This study shows that induction with 3 extrastimuli produces a less reliable PES response than the other modes used (kappa values all
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to be that way in order to study the reproducibility of electrophysiologic studies done in a typical electrophysiology laboratory. CI!nkaI knplsccltionr: Our study demonstrates that in patients with and without coronary artery disease there are certain PES responses that are more reproducible than others. Inducible sustained monomorphic VT and no inducible sustained VT were very reproducible. However, PES end points of nonsustained VT, polymorphic VT and rapid VT (rate 2250 beats/m@, were not very reproducible; these end points may not be adequate to guide therapy in thii high-risk population. The end point of sustained monomorphic VT, especially when slow (rate <250 beats/mm) is reproducible and can be used to guide antiarrhythmic therapy. Ackmwledgmmk We acknowledge the expert secretarial assistance of Sharon Hines.

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