- Email: [email protected]
Treatment of Ventricular Arrhythmia
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Treatment of Ventricular Arrhythmia* Applications and Limitations of Noninvasive vs Invasive Approach Philip]. Podrid, M.D., FCCP
most widely used approach for the suppression prevention of serious ventricular arrhythmia is Iy with antiarrhythmic drugs. There are many , , available or undergoing investigation which I,' .een demonstrated to be effective for suppressing ~ ~ cular arrhythmia; however, there exists no reliway to predict the effect of any drug in an idual patient. The electrophysiologic properties ( he drug, the nature and extent of the underlying h\..art disease, and the type of the presenting arrh' :hmia do not provide helpful guidelines for the s. ·tion ofan appropriate drug. Response to the agent c. ' Jnly be demonstrated by its administration to the patient for a period oftime in order to achieve a steadystate therapeutic level in the blood. Therapy is therefore empiric and demands a systematic approach to the use of these drugs. At the present time, there are two methods available for evaluating the efficacy of antiarrhythmic drugs. A noninvasive approach uses repeated ambulatory monitoring and exercise testing. Criteria for drug efficacy depend upon the suppression of spontaneously occurring arrhythmias. 1•2 Support for the use of such an approach is based on the observation that the presence ofcertain types ofventricular premature beats (specifically, repetitive forms or runs of ventricular tachycardia) enhances the risk for sudden cardiac death. 3.4 Moreover, their suppression with antiarrhythmic drugs prevents a recurrence of arrhythmia and improves survival. 5 The second approach involves invasive electrophysiologic testing using multiple extrastimuli sequentially added to a basic drive rhythm in an attempt to induce a nonsustained or sustained ventricular tachyarrhythmia which resembles the clinical episode. 6-8 The use ofthis technique is based on the observation that arrhythmia can be provoked in a ~
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*From the Cardiovascular Laboratories, Department of Nutrition, Harvard School of Public Health, and the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston. Supported in part by grant HL-07776 from the National Heart, Lung, and BlOod Institute and by the Rappaport International Program in Cardiology, Boston. Reprint requests: Dr. Podrid, 221 Longwood Avenue, Boston 02115
majority of patients who have experienced a malignant arrhythmia9 . 10 and that failure to induce the arrhythmia dUring drug therapy predicts freedom from recurrence. 11.12 Regardless of the approach used to judge the drug's efficacy, administration of the antiarrhythmic agent for several days is required before its antiarrhythmic effects can be determined. Since there currently exist no simple guidelines for selecting a drug and since complex arrhythmias are often refractory to many agents, a systematic approach is necessary. We have developed a standardized method for testing antiarrhythmic drugs in patients with serious arrhythmias who require therapy. This method can be readily applied to invasive or noninvasive techniques and simplifies the process of selecting a drug. There are four phases of study, 1.2 as listed in the following tabulation: Phase 0: Control period (baseline data collection) Phase 1: Short-term testing (rapid screening for drug effect) Phase 2: Short-term maintenance (confirmation of drug efficacy; determination of side effects) Phase 3: Long-term maintenance (long-term therapy with drug)
The evaluation ofa drug's effect during phases 1 and 2 is noninvasive, with monitoring and exercise testing, or invasive, using electrophysiologic techniques.
Phase 0 Phase 0 is a control period for establishing the baseline level of arrhythmia. Therapy with all antiarrhythmic drugs is discontinued for 24 to 48 hours, allowing for a washout. Thereafter, a period of 48 hours of continuous ambulatory monitoring is obtained to establish the type, density, and reproducibility of spontaneous ventricular ectopic activity. A maximal, symptom-limited exercise test on a motorized treadmill is performed in each patient. In patients unable to exercise on a treadmill, a bicycle ergometer is used. All arrhythmia is categorized by the following grading system of Lown and Wolf: 13 grade 0, no ventricular premature beats (VPBs); grade lA, less than 30 VPBs CHEST I 88 I 1 I JULY, 1985
121
Table I-Arrhythmia EquaOOna Interpretation
21918'71
Exercise Rest Exercise After exercise
1 hr of no VPBs 4 hr of <30 VPBs per hour and occasionally > lImin Frequent (>301hr) VPBs for 19 hr; total of 2,971 VPBs 5 hr during which multiform VPBs were present; maximum of 4 forms during any hour 16 hr of couplets, maximum of 4 episodes per hour Runs of ventricular tachycardia present for 7 hr. There were 3 runs per hour. Longest was 6 cycles in length and fastest at rate of ISO beats per min. Arrhythmia Duration (min)
5 7
10
~ ~4A44BI3(11O) ~4A54B34(1'70)
Interpretation Rest
34 VPBs occurred during 5-min period before exercise Exercise During 7 minutes of exercise, there were 48 VPBs, 4 couplets, and 2 runs of 3-beat ventricular tachycardia at rate of 170 After exercise During 10 min after exercise, there were 334 VPBs, 5 couplets, and 3 runs ofventricular tachycardia (longest was 4 beats and at rate of 170)
per hour and less than l/min; grade lB, less than 30 VPBs per hour and occasionally more than l/min; grade 2, 30 or more VPBs per hour; grade 3, multiform VPBs; grade 4A, repetitive VPBs (couplets); grade 4B, repetitive VPBs or runs of ventricular tachycardia (three or more VPBs in a row); and grade 5, early R-on-T VPBs. The arrhYthmia occurring during each 24-hour period of ambulatory monitoring or provoked during exercise testing is expressed as a simple equation which permits easy recognition ofthe type and density of arrhythmia present (Table 1). A similar equation is established during therapy, allowing for simple determination of the drug's effect. At the conclusion of these baseline studies, a decision is made about the approach to drug evaluation to be employed. When there is a high density of reprodUcible repetitive arrhythmia, noninvasive techniques are used. In the absence of such arrhythmia, invasive electrophysiologic testing is performed. The level of arrhythmia deemed adequate for noninvasive study includes (1) grade-2 VPBs for more than 50 percent of the hours during each monitoring period, (2) at least three hours of grade-4A or grade-4B VPBs 122
during each monitoring period, and (3) during exercise testing at least two VPBs per minute and the provocation of repetitive forms. Approximately 75 percent of the patients referred to our group have a density of arrhythmia adequate for noninvasive testing, while 25 percent require electrophysiologic testing because this level of spontaneous arrhythmia is absent.
Phase 1 Phase 1, or short-term testing, involves the oral administration ofa single large dose ofdrug, 1. as listed in the following tabulation: p-adrenergic blocker Atenolol Metoprolol Pindolol Prop~olol
Disopyramide Mexiletine Procainamide Propafenone Quinidine Tocainide
100mg 100mg 20mg SOmg 300mg 400mg 1,500 mg 450mg 600mg SOOmg
The dose used is approximately one-half of the usual daily maintenance dose. In our experience with sevPROPAFENONE ACUTE DRUG TEST 450 mg CONTROL
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FIGURE 2. 5hort-term testing (invasive). During control study, one extrastimulus (5J induces nonsustained ventricular tachycardia (N5VI') which is ten cycles in length. Mexiletine (400 mg) is administered, and two hours later, electrophysiologic testing is repeated. Addition ofthree extrastimuli (5., 52' and 53) fails to induce arrhythmia. Arrhythmia remains noninducible during long-term therapy with mexiletine therapy (300 mg every eight hours).
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eral hundred tests, a therapeutic level in the blood is achieved within two hours. The drugs tested in this way have no active metabolites, and the establishment of a therapeutic level in the blood within a short time permits a rapid assessment of effect. On the day of the test, patients undergoing noninvasive techniques are monitored continuously for a 30-minute control period before and for three hours after administration of the drug (Fig 1). Baseline exercise on a bicycle ergometer is also performed during the control period and each hour thereafter. A sample of blood for determining the level of drug and an electrocardiogram for measuring intervals are obtained hourly. When electrophysiologic testing is used, a study is performed two hours after the dose of drug is administered (Fig 2).
Phases 2 and 3 Once a number of phase-l short-term tests have been performed, the patient enters phase 2. The agent judged to be most effective is selected, and multiple doses are administered for 72 to 96 hours. At the end of this period, ambulatory monitoring and exercise testing (Fig 3) or electrophysiologic testing (Fig 2) are repeated. If the criteria for the drugs efficacy have been achieved, the patient is discharged on therapy with the drug with long-term follow-up, or phase 3. During long-term therapy, monitoring and exercise PROPAFENONE 300 mg Q8h I
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3. Maintenance therapy (noninvasive evaluation). During control studies, frequent runs of ventricular tachycardia are present. Exercise testing increases frequency and length of runs. Ambulatory monitoring shows frequent (more than 3O/hr) VPBs for 22 hours (222), couplets for 22 hours (4A22), and 21 hours ofventricular tachycardia. There were up to 30 runs, 13 cycles in length and at rates of160 (4B 2I30.13( ). During therapy with propafenone, arrhythmia is completely eliminated during exercise and monitoring (~). HR, heart rate. FIGURE
CHEST I 88 I 1 I JULY. 1985
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FIGURE 4. Disparity between noninvasive and invasive evaluation. During control exercise, frequent runs of ventricular tachycardia are induced. Ambulatory monitoring demonstrates frequent (more than 3O/hr) VPBs for 23 hours, 15 hours ofcouplets with up to 17/hr (4AlSI7), and 12 hours ofventricular tachycardia. There were three episodes per hour, six cycles in length at rates of220/min (4B123,6(220))' During electrophysiologic studies, two extrastimuli (51' 5J induce sustained ventricular tachycardia. Therapy with mexiletine and metoprolol eliminated arrhythmia during exercise testing. There were only infrequent (less than 301hr) VPBs during ambulatory monitoring (122); however, with electrophysiologic testing, ventricular tachycardia remains inducible. The rate and morphology are the same as control.
testing are routinely obtained to ensure continued suppression of arrhythmia. The criteria for drug efficacy which we use are as follows: noninvasive (monitoring and exercise testing) (1) total elimination of runs of ventricular tachycardia, (2) 90 percent or greater reduction in couplets, and (3) 50 percent or greater decrease in VPB frequency. The invasive criterion was the inability to provoke three or more repetitive ventricular complexes during sinus rhythm and ventricular pacing when using three extrastimuli at current strengths of twice and three times the mid-diastolic threshold. Regardless of the approach used, there have been a number of reports confirming that recurrence of arrhythmias is prevented and survival of patients improved when an effective drug is administered. 5.11.12 Thus, either a noninvasive approach aimed at suppressing spontaneous ectopy or an invasive approach guided by the inability to induce an arrhythmia are effective ways to select a drug. It is uncertain if one approach is better or preferred in an individual patient, as there are no studies that have compared the two techniques. Each method has limitations, and the approach used in any patient should be based on the 124
density and reproducibility of ambient ventricular arrhythmia. Limitation of Noninvasive Testing The limitations of noninvasive techniques are summarized in the following tabulation: 1. Only reliable when spontaneous arrhythmia present. 2. Cannot be used in those with wide daily variability in type and density ofVPBs. 3. Monitoring technology may not provide accurate counts of VPBs and may fail to recognize complex fOrms. 4. There is uncertainty about the significance of type and frequency ofVPBs in certain groups of patients (ie, which VPBs constitute risk). 5. End point of therapy not well established.
There are a number of reasons why noninvasive techniques are preferred. Exercise testing and ambulatory monitoring are widely available procedures that are easy to perform, without risk, and relatively inexpensive. They can be performed in most centers without the need to refer the patient to a specialized institution that has an electrophysiology laboratory. These tests can be repeated as frequently as the clinical situation warrants and can be performed in outpatients Treatment of Ventricular Arrhythmia (Philip J Podrld)
without the need for hospitalization. Therefore, when side effects necessitate adjustments of dosage or a change in medication, testing is readily and simply repeated, eliminating the need for repeat hospitalization; however, there are a number of limitations to invasive technology: 1. Monitoring and exercise testing can only be used in patients who have a high density of spontaneous ventricular arrhythmia, since the drug's effect is based on suppression of VPBs. In our experience, approximately 25 percent of patients referred do not have adequate levels of arrhythmia, but this may vary depending upon the pattern of referral. 2. In some patients, there is wide daily and hourly variability of the frequency of VPBS.1:5.16 Such spontaneous changes in the level of arrhythmia make the evaluation of the effect of an antiarrhythmic drug difficult, for it is impossible to distinguish the drug's effect from what can be attributed to random variability. However, it must be emphasized that these observations ofvariability are in patients with frequent asymptomatic VPBs without a history of sustained ventricular tachyarrhythmias. We have not observed variability in the 75 percent ofpatients with a history of malignant arrhythmia who have a high density ofVPBs (Table 2). Additionally, random variability is dependent upon the frequency of baseline arrhythmia. When VPBs are of low frequency, variability is greater, and thus monitoring for several days is required to determine if changes result from the drug's effect; 15 however, when the baseline level ofVPBs is greater, variability is less marked, and a shorter period of monitoring is necessary. Lastly, when the criteria for a drug's effect include not only reduction of VPBs, but also elimination of repetitive forms, variability is a less important concern; however, before beginning a noninvasive drug evaluation, the daily reproducibility of arrhythmia must be established for each patient. The reproducibility ofarrhythmia provoked by exerTable 2-Reproducibility of Arrhythmia· Data Monitoring Grade 2 (hr) Grade 4A (hr) No. of patients Grade 4B (hr) No. of patients Exercise VPBs (No.) 4A (No.) No. of patients 4B (No. ov runs) No. of patients
with 4A with 4B
with 4A with 4B
Day I
Day 2
2O.9±3.3t 19.1 ±5.0t 100 11.8± 7.2t 100
21.1±3.3t 19.0±4.9t 100 II. 7±6.9t 97
330t 29t 29 6t 21
297t 21t 29 9t 20
*Based on 100 consecutive patients with two control monitors and 29 consecutive patients with two control exercise tests. tDay I vs day 2, not Significant.
cise testing is also uncertain. It has been reported that in patients without a history of serious arrhythmia, the occurrence of VPBs during two sequential exercise tests may be highly variable;17 however, in our experience with patients who have had serious arrhythmia, the number of VPBs and the occurrence of repetitive forms are reproducible during two control tests (Table 2). 3. Current technology for automated ambulatory electrocardiographic monitoring may not provide accurate counts of premature beats. More importantly, the recognition of repetitive forms may be uncertain and inadequate. Such problems may be eliminated by the use of a semiautomated system which requires interaction with a technician and the implementation of quality control which requires hand counts ofVPBs and repetitive forms during randomly selected hours. 4. Ambulatory monitoring for extended periods combined with exercise testing will identify patients with VPBs and document their density, type, and reproducibility; however, for certain groups of patients, it is unclear what type ofVPBs place the patient at risk for ventricular tachycardia or ventricular fibrillation. Patients who have experienced malignant tachyarrhythmia have a greater incidence of repetitive VPBs, and they are considered markers of risk in this group, although the occurrence of such forms in the general population is probably unimportant. The presence of repetitive forms, especially runs of ventricular tachycardia, enhances the risk of sudden death in patients with cardiomyopathy18 and in those with coronary artery disease and a recent myocardial infarction;3,4 howevet; in the latter group ofpatients, there is a changing level of arrhythmia during the period after infarction, and documenting the presence of these arrhythmias may be difficult. 19 In some studies the frequency of VPBs imparts risk, while repetitive arrhythmia is less important. 20 It is possible that the density of repetitive VPBs is important and not their mere presence; however, it is the much larger group of patients with coronary artery disease but without a recent infarction who constitute the greatest challenge, for they represent the majority of patients seen by the physician. The prognostic importance of repetitive VPBs in these patients is uncleat: Lastly, the importance of these arrhythmias in those with normal hearts is unknown. Therefore, in some subsets of patients, monitoring and exercise testing provide only limited data. 5. The end-points for therapy with a drug are uncleat: In patients with a history of malignant arrhythmia, suppression of runs of ventricular tachycardia prevent recurrent arrhythmia,:5 but it is uncertain if complete abolition is essential. Moreover, it is unknown what percentage of reduction of other forms is important. Although repetitive forms enhance the CHEST I 88 I 1 I JULY. 1985
125
risk of sudden death in patients with a recent infarction, it remains uncertain iftheir suppression by a drug protects against serious arrhythmia. The importance of reduction in single VPBs is also uncertain. Definitions ofa drugs efficacy vary among investigators, and there are no uniform criteria generally applied to ambulatory monitoring and exercise testing. We have established criteria which require the elimination of ventricular tachycardia associated with a reduction of the frequency of couplets and VPBs as evaluated by both monitoring and exercise testing. Limitations of Electrophysiologic Testing The limitations of invasive techniques are summarized in the following tabulation: 1. 2. 3. 4. 5.
No uniformity in stimulation protocols. Controversy about the appropriate end-point of study. Uncertainty about criteria for a drugs effectiveness. Reproducibility of technique not established. Uncertainty about the meaning of nonclinical arrhythmia induced by testing. 6. Sensitivity and specificity of technique in different populations not established. 7. Predictive accuracy with certain drugs not established. 8. Electrophysiologic testing evaluates a drugs effect during one point in time and does not account for changes in levels of the drug, alterations in potassium level, effect of autonomic nervous system and circulating catecholamines, or effect of ischemia.
Invasive electrophysiologic testing has been considered a more precise method for selecting an effective antiarrhythmic drug in patients with serious ventricular arrhythmia. Its use eliminates concerns about variability of spontaneous arrhythmia, for arrhythmia is induced during testing. Electrophysiologic testing is necessary when spontaneous arrhythmia is absent or variable, but controversy exists about its use when monitoring and exercise testing exposes frequent arrhythmia. Although there are some advantages to its use, there are many limitations to be considered. 1. There is no consensus about the appropriate technique for programmed electrical stimulation, and protocols vary widely. There are no data about an optimal protocol, and there are controversies involving the following: (a) the type ofdrive rhythm (sinus, atrial, or ventricular paced) to be used and the rate ofpacing; (b) the use of multiple pacing rates; (c) the number of extrastimuli to be employed (most investigators use two or three, although the addition of up to six has been reported); (d) the optimal pulse width of the extrastimuli; (e) the current strength of the extrastimuli (most commonly used is twice the mid-diastolic threshold, which is defined as the least amount of energy resulting in a propagated response; howevet; a current strength of ten times the mid-diastolic threshold and, in some studies, up to 20 mAmp have been used); (f) the timing sequence ofthe extrastimuli; (g) the location and number ofright ventricular sites to be stimulated (most often used are the apex and 128
outflow tract, but additional areas may also be stimulated); (h) the use ofleft ventricular stimulation; (i) the usefulness of rapid ventricular burst pacing (the rate and the duration of the burst may vary); and 0) the use of isoproterenol infusion. There is uncertainty about the aggressiveness ofthe protocol used to induce arrhythmia. When a more rigorous protocol is used, it is uncertain if the arrhythmia induced is clinically important or an artifact. Further complicating this is the evaluation of antiarrhythmic drugs. It is uncertain how aggressive testing must be to establish a drug"s efficacy. If a drug prevents the induction of arrhythmia when the same protocol is used as control, it is unclear if more vigorous methods should be employed. The use of a more aggressive study will increase sensitivity but will reduce specificity.21 It is possible that the low incidence of drug efficacy which has been reported is due to the use of methods that are too sensitive. 3. There exists no consensus about the appropriate end-point for electrophysiologic testing. Both nonsustained and sustained ventricular tachycardia have been advocated. The definitions of these end-points are also unclear. Nonsustained ventricular tachycardia has been defined as more than 3, more than 5, more than 15, or more than 100 repetitive cycles or that which lasts less than 30 or less than 60 seconds. Sustained ventricular tachycardia has been defined by the duration or by the need for an intervention for termination. 3. Criteria for a drugs efficacy vary among investigators. In some studies the inability to induce nonsustained ventricular tachycardia constitutes drug efficacy, although the definition of nonsustained ventricular tachycardia is variable. Other investigators have deemed a drug effective if a previously induced sustained tachyarrhythmia is no longer provoked so that the provocation of a nonsustained episode is acceptable. In some studies a drug is considered effective if the arrhythmia is more difficult to induce, defined as that which requires more extrastimuli, occurs only when additional right or left ventricular pacing sites are used, or is induced when pacing rates faster than control are used. Still others would accept ventricular tachycardia induced at a slower rate and without symptoms as indicative of a drugs effect. 4. The daily reproducibility of electrophysiologic testing remains uncertain. There have been several reports that when an identical protocol is used on two different days, an end-point is reproducibly achieved in only 60 percent of the patients.22.13 The reproducibility increases when a more aggressive protocol is used, but this alters the sensitivity and specificity of the technique,21 making comparison between studies difficult and determination ofa drug"s effect questionable. In our experience with 43 patients who underwent lt8aIment of VentrIcular Arrhythmia (PIlip J. Podrld)
two control tests on successive days, only 25 (58 percent) had the same end-point during both tests. On the first day, 33 patients were inducible, while only 23 were still inducible on the following day. The failure to reinduce arrhythmia in these ten patients might have been ascribed to the drug's effect, rather than to a random change in inducibility.
5. An accepted end-point of study is the induction of a tachycardia which resembles the clinical arrhythmia; howevet; in the patient who has experienced ventricular fibrillation, such a comparison is not possible. In these patients, it is uncertain which induced arrhythmia is important. During electrophysiologic testing the provocation of nonclinical arrhythmia is common and its significance uncertain, especially if it occurs during therapy with a drug. It is uncertain ifthis is failure of the drug, the configuration of the tachycardia being altered by the drug, or a nonspecific and unimportant finding. Complicating this is the fact that polymorphic ventricular tachycardia or even ventricular fibrillation can be provoked in patients who have never experienced ventricular arrhythmia. 14 When nonclinical arrhythmia is induced during a control study, it is unclear if this is an adequate end-point for evaluating antiarrhythmic drugs. 6. The sensitivity and specificity of electrophysiologic testing in different subsets of patients are poorly defined. Although the rate of induction is high in patients with ventricular tachycardia, patients with ventricular fibrillation are less often inducible. 25 Relationship to type and extent of underlying heart disease remains uncertain. The rate of induction is lower in those with tachycardia unrelated to coronary artery disease16 and in patients with nonsustained ventricular tachycardia. J7
7. The predictive accuracy of electrophysiologic testing is uncertain, especially with the new antiarrhythmic drugs. It has been reported that during therapy with a drug, failure to induce a previously inducible arrhythmia predicts freedom from recurrence;1LlJ howevet; it is uncertain if continued inducibility when certain drugs are administered predicts recurrence, especially if there has been suppression of spontaneous arrhythmia (Fig 4). This disparity between clinical outcome and the results of electrophysiologic testing has been reported with amiodaroneJ8·· and propafenone. 30 8. Electrophysiologic testing evaluates the effect of a drug during only one point in time and while the patient is in a supine position in an electrophysiologic laboratory. It does not account for changes in the levels of drug in the blood, autonomic inputs and circulating catecholamines, alterations in potassium level, changes in baroreceptor tone, or transient ischemia which can alter susceptibility to arrhythmia.
Data Days in hospital No. of drugs tested No. of monitors Cost· No. of exercise tests Cost· No. of electrophysiologic tests Cost· Total cost
Noninvasive (n=24)
Invasive (n= 15)
21±7 4.1±O.9 4.8±1.6 $1,152 3.6±2.0 $576
22±7 4.5± 1.9 2.7±O.8
o o
$1,728
t648
2.0±O.8 $320 6.0±3.1
3000 13,968
·Based on $240 Per monitor, $160 per exercise test, $1,000 for initial electrophysiologic study, and $400 for subsequent studies.
Invasive vs Noninvasive Techniques Both electrophysiologic testing and noninvasive techniques are time-consuming and costly. In our experience, electrophysiologic testing does not decrease the time necessary for evaluating a drug. Similar to noninvasive methods, several days ofadministration of a drug are required before efficacy is evaluated. Since the selection ofa drug is empiric, either method may involve several trials of drugs before an effective and well-tolerated drug is identified. In fact, the rate of response to individual drugs is less with electrophysiologic testing than that reported when monitoring is used, suggesting that more studies of drugs might be necessary when invasive techniques are employed. Electrophysiologic tests are far more costly when compared with monitoring and exercise testing (Table 3). Moreovet; invasive testing does not eliminate the need for monitoring before and during drug therapy to ensure that the drug is effective for suppressing spontaneous arrhythmia. Monitoring is also essential to document potential aggravation of arrhythmia. 31 Since electrophysiologic testing cannot be routinely repeated, ambulatory monitoring and exercise testing become important methods for long-tenn follow-up, and therefore the baseline levels of arrhythmia must be established for comparative purposes. If reliance is placed on noninvasive techniques during follow-up, why not use them during in-hospital evaluation of a drug? Despite the limitations of both approaches, a drug deemed effective and selected for long-tenn therapy substantially improves survival in patients who have had malignant ventricular arrhythmia. If spontaneous repetitive arrhythmia is suppressed by a drug, as evaluated by monitoring and exercise testing, annual sudden death is less than 4 percent. 5.31 In our experience, when the selected drug prevents the induction of arrhythmia with electrophysiologic testing, the annual rate of sudden death is similaJ: e Using a different protocol and end point, Swerdlow and co-workersll reported mortality at two years to be 16 percent in CHEST I 88 I 1 I JULY. 1885
1rt
patients responding to a drug as evaluated with electrophysiologic techniques. In conclusion, noninvasive and invasive methods have become established approaches for the treatment of patients with serious ventricular arrhythmia. Both techniques are useful and necessary for guiding therapy. The method chosen should depend upon the patient and the density of baseline ventricular arrhythmia; however, both techniques have limitations which must be recognized. Nevertheless, when an effective drug is selected by either approach, survival is improved. Comparative studies between these two methods are necessary to further define their application. REFERENCES 1 Lawn B, Podrid PJ, DeSilva RA, Graboys TB. Sudden cardiac death: management of the patient at risk. Circ Frobl Cardiol 1980; 4:1-62 2 Podrid PJ, Lown B. Management of malignant ventricular arrhythmia: experience with lorcainide. Am J Cardiol 1984; 54:29B-36B 3 Ruberman ~ Weinblatt E, GoldbergJD, Frank CW, Chaudhary BS, Shapiro S. Ventricular premature beats and mortality after myocardial infarction. N Eng} J Med 1977; 297:750-57 4 Bigger JI: Weld FM, Rolnitzky LM. Prevalence, characteristics and significance of ventricular tachycardia (three or more complexes) detected with ambulatory monitoring in the late hospital phase of acute myocardial infarction. Am J Cardiol 1981; 48:815-23 5 Graboys TB, Lawn B, Podrid PJ, DeSilva R. Long term survival of patients with malignant ventricular arrhythmia treated with antiarrhythmic drugs. Am J Cardiol 1982; 50:437-43 6 Podrid PJ, Schoeneberger A, Lown B, Lampert S, Matos J, Porterfield J, et ale Use ofnonsustained ventricular tachycardia as a guide to antiarrhythmic drug therapy in patients with malignant ventricular ~hythmia. Am Heart J 1983; 105:181-88 7 Mason JW, Winkle RA. Electrode catheter arrhythmia induction in the selection and assessment of antiarrhythmic drug therapy for recurrent ventricular tachycardia. Circulation 1978; 58:971-85 8 Horowitz LN, Josephson ME, Farshidi A, Spielman S, Michelson EL, Greenspan AM. Recurrent sustained ventricular tachycardia: role of the electrophysiologic study in selection of antiarrhythmic regimens. Circulation 1978; 58:987-97 9 Josephson ME, Horowitz LN, Spielman JR, Greenspan AM. Electrophysiologic and hemodynamic studies in patients resuscitated from cardiac arrest. Am J Cardio11980; 46:948-56 10 Horowitz LN, Josephson ME, Kastor JA. Intracardiac electrophysiologic studies as a method for the optimization of drug therapy in chronic ventricular arrhythmias. Frog Cardiovasc Dis 1980; 23:81-98 11 Ruskin IN, DiMarco J, Garan H. Out of hospital cardiac arrest: electrophysiologic observation and selection of long term antiarrhythmic therapy. N Engl J Med 1980; 303:607-13 12 Mason JW, Winkle RR. Accuracy of the ventricular tachycardia induction study for predicting long term efficacy and inefficacy of antiarrhythmic drugs. N Eng} J Med 1980; 303:1073-77 13 Lawn B, Wolf M. Approaches to sudden death from coronary heart disease. Circulation 1971; 44:130-42 14 Gaughan CE, Lawn B, Lanigan J, Voukydis J, Besser W. Acute oral testing for determining antiarrhythmic drug efficacy. 1. quindine. Am J Cardio11976; 38:677-84 15 Morganroth J, Michelson EL, Horowitz LN, Josephson ME, 128
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29
30 31 32 33
Pearlman AS, Dunkman WB. Limitations of routine long term electrocardiographic monitoring to assess ventricular ectopic frequency. Circulation 1978; 58:408-15 Winkle RA. Spontaneous variability of ventricular ectopics frequently mimics antiarrhythmic drug effect. Circulation 1978; 57:1116-21 Sheps D, Ernst J, Briese FR, Lopez L~ Conde LA, Castellanos A, et ale Decreased frequency of exercise induced ventricular ectopic activity in the second of two consecutive exercise tests. Circulation 1977; 55:892-95 Follansbee WD, Michelson EL, Morganroth J. Unsustained ventricular tachycardia in ambulatory patients: characteristics associated with sudden cardiac death. Ann Intern Med 1980; 92:241-47 Kleiger R, Martin 1: Miller J~ Oliver GC. Ventricular tachycardia and ventricular extrasystoles during the late recovery phase of myocardial infarction. Am J Cardioll974; 33:149 Bigger JI: Heller CA, Wenger TL, Weld FM. Risk stratification after acute myocardial infarction. Am J Cardiol 1978; 42:202-10 Buxton AE, Waxman HL, Marchlinski FE, Untereker WJ, Waspe LE, Josephson ME. Role of triple extrastimuli during electrophysiologic study of patients with documented sustained ventricular tachyarrhythmias. Circulation 1984; 69:532-40 Livelli FD, Gang ES, Reiffel JA, Ferreck FJ, Gleklich J, Bigger J1: Reproducibility ofinducible ventricular tachycardia. Circulation 1982; 66:11-146 Schoenfeld MH, Garan H, McGovern B, Kelly E, Ruskin IN. Long term reproducibility of programmed stimulation in patients with recurrent ventricular tachyarrhythmias (abstract). Circulation 1982; 66:11-146 Brugada ~ Abdollah H, Heddle B, Wellens HJJ. Results of a ventricular stimulation protocol using a maximum of four premature stimuli in patients without documented or suspected ventricular arrhythmia. Am J Cardioll983; 52:1214-18 Schoenfeld MH, McGovern B, Garan H, Kelly E, Grant G, Ruskin IN. Influence of the presenting arrhythmia on the outcome ofelectrophysiologic study (abstract). Circulation 1983; 68:111-242 Naccarelli G~ Prystowsky EN, Jackman WM, Heger J1 Rahilly Gl: Zipes D~ Role of electrophysiologic testing in managing patients who have ventricular tachycardia unrelated to coronary artery disease. Am J Cardiol 1982; 50:165 Vende Pol CJ, Farshidi A, Spielman SR, Greenspan AM, Horowitz LN, Josephson ME. The incidence and clinical significance of induced ventricular tachycardia. Am J Cardiol 1980; 45:725-31 Hamer A~ Finerman WB, Peter 1: Mandel WJ. Disparity between the clinical and electrophysiologic effects ofamiodarone in the treatment of recurrent ventricular tachyarrhythmias. Am Heart J 1981; 102:992-99 Heger JJ, Prystowsky EN, Jackman WN, Narcarelli GV, Wartel FA, Rinkenberger RL, et ale Amiodarone: clinical efficacy and electrophysiology during long term therapy for recurrent ventricular tachycardia or fibrillation. N Eng} J Med 1981; 305:539-45 Kingman H, Brugada ~ Paulussen G, Wellens HJJ. Intravenous and oral propafenone in patients with ventricular tachycardia on fibrillation (abstract). Circulation 1984; 70:11-55 Velebit ~ Podrid PJ, Cohen B, Lown B, Graboys TB. Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs. Circulation 1982; 65:886-94 Stein J, Podrid PJ, Lampert S, Horowitz G, Lawn B. Long term mexiletine for ventricular arrhythmia. Am Heart J 1984; 107:1091-98 Swerdlow CD, Winkle RA, Mason JW. Determinants ofsurvi" ,," in patients with ventricular tachyarrhythmia. N Eng} J ,\ 1 1983; 308:1436-41 Treatment of Ventricular Arrhyttvnia (Philip J Poo, J
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Treatment of Ventricular Arrhythmia* Applications and Limitations of Noninvasive vs Invasive Approach Philip]. Podrid, M.D., FCCP
most widely used approach for the suppression prevention of serious ventricular arrhythmia is Iy with antiarrhythmic drugs. There are many , , available or undergoing investigation which I,' .een demonstrated to be effective for suppressing ~ ~ cular arrhythmia; however, there exists no reliway to predict the effect of any drug in an idual patient. The electrophysiologic properties ( he drug, the nature and extent of the underlying h\..art disease, and the type of the presenting arrh' :hmia do not provide helpful guidelines for the s. ·tion ofan appropriate drug. Response to the agent c. ' Jnly be demonstrated by its administration to the patient for a period oftime in order to achieve a steadystate therapeutic level in the blood. Therapy is therefore empiric and demands a systematic approach to the use of these drugs. At the present time, there are two methods available for evaluating the efficacy of antiarrhythmic drugs. A noninvasive approach uses repeated ambulatory monitoring and exercise testing. Criteria for drug efficacy depend upon the suppression of spontaneously occurring arrhythmias. 1•2 Support for the use of such an approach is based on the observation that the presence ofcertain types ofventricular premature beats (specifically, repetitive forms or runs of ventricular tachycardia) enhances the risk for sudden cardiac death. 3.4 Moreover, their suppression with antiarrhythmic drugs prevents a recurrence of arrhythmia and improves survival. 5 The second approach involves invasive electrophysiologic testing using multiple extrastimuli sequentially added to a basic drive rhythm in an attempt to induce a nonsustained or sustained ventricular tachyarrhythmia which resembles the clinical episode. 6-8 The use ofthis technique is based on the observation that arrhythmia can be provoked in a ~
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*From the Cardiovascular Laboratories, Department of Nutrition, Harvard School of Public Health, and the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston. Supported in part by grant HL-07776 from the National Heart, Lung, and BlOod Institute and by the Rappaport International Program in Cardiology, Boston. Reprint requests: Dr. Podrid, 221 Longwood Avenue, Boston 02115
majority of patients who have experienced a malignant arrhythmia9 . 10 and that failure to induce the arrhythmia dUring drug therapy predicts freedom from recurrence. 11.12 Regardless of the approach used to judge the drug's efficacy, administration of the antiarrhythmic agent for several days is required before its antiarrhythmic effects can be determined. Since there currently exist no simple guidelines for selecting a drug and since complex arrhythmias are often refractory to many agents, a systematic approach is necessary. We have developed a standardized method for testing antiarrhythmic drugs in patients with serious arrhythmias who require therapy. This method can be readily applied to invasive or noninvasive techniques and simplifies the process of selecting a drug. There are four phases of study, 1.2 as listed in the following tabulation: Phase 0: Control period (baseline data collection) Phase 1: Short-term testing (rapid screening for drug effect) Phase 2: Short-term maintenance (confirmation of drug efficacy; determination of side effects) Phase 3: Long-term maintenance (long-term therapy with drug)
The evaluation ofa drug's effect during phases 1 and 2 is noninvasive, with monitoring and exercise testing, or invasive, using electrophysiologic techniques.
Phase 0 Phase 0 is a control period for establishing the baseline level of arrhythmia. Therapy with all antiarrhythmic drugs is discontinued for 24 to 48 hours, allowing for a washout. Thereafter, a period of 48 hours of continuous ambulatory monitoring is obtained to establish the type, density, and reproducibility of spontaneous ventricular ectopic activity. A maximal, symptom-limited exercise test on a motorized treadmill is performed in each patient. In patients unable to exercise on a treadmill, a bicycle ergometer is used. All arrhythmia is categorized by the following grading system of Lown and Wolf: 13 grade 0, no ventricular premature beats (VPBs); grade lA, less than 30 VPBs CHEST I 88 I 1 I JULY, 1985
121
Table I-Arrhythmia EquaOOna Interpretation
21918'71
Exercise Rest Exercise After exercise
1 hr of no VPBs 4 hr of <30 VPBs per hour and occasionally > lImin Frequent (>301hr) VPBs for 19 hr; total of 2,971 VPBs 5 hr during which multiform VPBs were present; maximum of 4 forms during any hour 16 hr of couplets, maximum of 4 episodes per hour Runs of ventricular tachycardia present for 7 hr. There were 3 runs per hour. Longest was 6 cycles in length and fastest at rate of ISO beats per min. Arrhythmia Duration (min)
5 7
10
~ ~4A44BI3(11O) ~4A54B34(1'70)
Interpretation Rest
34 VPBs occurred during 5-min period before exercise Exercise During 7 minutes of exercise, there were 48 VPBs, 4 couplets, and 2 runs of 3-beat ventricular tachycardia at rate of 170 After exercise During 10 min after exercise, there were 334 VPBs, 5 couplets, and 3 runs ofventricular tachycardia (longest was 4 beats and at rate of 170)
per hour and less than l/min; grade lB, less than 30 VPBs per hour and occasionally more than l/min; grade 2, 30 or more VPBs per hour; grade 3, multiform VPBs; grade 4A, repetitive VPBs (couplets); grade 4B, repetitive VPBs or runs of ventricular tachycardia (three or more VPBs in a row); and grade 5, early R-on-T VPBs. The arrhYthmia occurring during each 24-hour period of ambulatory monitoring or provoked during exercise testing is expressed as a simple equation which permits easy recognition ofthe type and density of arrhythmia present (Table 1). A similar equation is established during therapy, allowing for simple determination of the drug's effect. At the conclusion of these baseline studies, a decision is made about the approach to drug evaluation to be employed. When there is a high density of reprodUcible repetitive arrhythmia, noninvasive techniques are used. In the absence of such arrhythmia, invasive electrophysiologic testing is performed. The level of arrhythmia deemed adequate for noninvasive study includes (1) grade-2 VPBs for more than 50 percent of the hours during each monitoring period, (2) at least three hours of grade-4A or grade-4B VPBs 122
during each monitoring period, and (3) during exercise testing at least two VPBs per minute and the provocation of repetitive forms. Approximately 75 percent of the patients referred to our group have a density of arrhythmia adequate for noninvasive testing, while 25 percent require electrophysiologic testing because this level of spontaneous arrhythmia is absent.
Phase 1 Phase 1, or short-term testing, involves the oral administration ofa single large dose ofdrug, 1. as listed in the following tabulation: p-adrenergic blocker Atenolol Metoprolol Pindolol Prop~olol
Disopyramide Mexiletine Procainamide Propafenone Quinidine Tocainide
100mg 100mg 20mg SOmg 300mg 400mg 1,500 mg 450mg 600mg SOOmg
The dose used is approximately one-half of the usual daily maintenance dose. In our experience with sevPROPAFENONE ACUTE DRUG TEST 450 mg CONTROL
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FIGURE 2. 5hort-term testing (invasive). During control study, one extrastimulus (5J induces nonsustained ventricular tachycardia (N5VI') which is ten cycles in length. Mexiletine (400 mg) is administered, and two hours later, electrophysiologic testing is repeated. Addition ofthree extrastimuli (5., 52' and 53) fails to induce arrhythmia. Arrhythmia remains noninducible during long-term therapy with mexiletine therapy (300 mg every eight hours).
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eral hundred tests, a therapeutic level in the blood is achieved within two hours. The drugs tested in this way have no active metabolites, and the establishment of a therapeutic level in the blood within a short time permits a rapid assessment of effect. On the day of the test, patients undergoing noninvasive techniques are monitored continuously for a 30-minute control period before and for three hours after administration of the drug (Fig 1). Baseline exercise on a bicycle ergometer is also performed during the control period and each hour thereafter. A sample of blood for determining the level of drug and an electrocardiogram for measuring intervals are obtained hourly. When electrophysiologic testing is used, a study is performed two hours after the dose of drug is administered (Fig 2).
Phases 2 and 3 Once a number of phase-l short-term tests have been performed, the patient enters phase 2. The agent judged to be most effective is selected, and multiple doses are administered for 72 to 96 hours. At the end of this period, ambulatory monitoring and exercise testing (Fig 3) or electrophysiologic testing (Fig 2) are repeated. If the criteria for the drugs efficacy have been achieved, the patient is discharged on therapy with the drug with long-term follow-up, or phase 3. During long-term therapy, monitoring and exercise PROPAFENONE 300 mg Q8h I
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3. Maintenance therapy (noninvasive evaluation). During control studies, frequent runs of ventricular tachycardia are present. Exercise testing increases frequency and length of runs. Ambulatory monitoring shows frequent (more than 3O/hr) VPBs for 22 hours (222), couplets for 22 hours (4A22), and 21 hours ofventricular tachycardia. There were up to 30 runs, 13 cycles in length and at rates of160 (4B 2I30.13( ). During therapy with propafenone, arrhythmia is completely eliminated during exercise and monitoring (~). HR, heart rate. FIGURE
CHEST I 88 I 1 I JULY. 1985
123
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FIGURE 4. Disparity between noninvasive and invasive evaluation. During control exercise, frequent runs of ventricular tachycardia are induced. Ambulatory monitoring demonstrates frequent (more than 3O/hr) VPBs for 23 hours, 15 hours ofcouplets with up to 17/hr (4AlSI7), and 12 hours ofventricular tachycardia. There were three episodes per hour, six cycles in length at rates of220/min (4B123,6(220))' During electrophysiologic studies, two extrastimuli (51' 5J induce sustained ventricular tachycardia. Therapy with mexiletine and metoprolol eliminated arrhythmia during exercise testing. There were only infrequent (less than 301hr) VPBs during ambulatory monitoring (122); however, with electrophysiologic testing, ventricular tachycardia remains inducible. The rate and morphology are the same as control.
testing are routinely obtained to ensure continued suppression of arrhythmia. The criteria for drug efficacy which we use are as follows: noninvasive (monitoring and exercise testing) (1) total elimination of runs of ventricular tachycardia, (2) 90 percent or greater reduction in couplets, and (3) 50 percent or greater decrease in VPB frequency. The invasive criterion was the inability to provoke three or more repetitive ventricular complexes during sinus rhythm and ventricular pacing when using three extrastimuli at current strengths of twice and three times the mid-diastolic threshold. Regardless of the approach used, there have been a number of reports confirming that recurrence of arrhythmias is prevented and survival of patients improved when an effective drug is administered. 5.11.12 Thus, either a noninvasive approach aimed at suppressing spontaneous ectopy or an invasive approach guided by the inability to induce an arrhythmia are effective ways to select a drug. It is uncertain if one approach is better or preferred in an individual patient, as there are no studies that have compared the two techniques. Each method has limitations, and the approach used in any patient should be based on the 124
density and reproducibility of ambient ventricular arrhythmia. Limitation of Noninvasive Testing The limitations of noninvasive techniques are summarized in the following tabulation: 1. Only reliable when spontaneous arrhythmia present. 2. Cannot be used in those with wide daily variability in type and density ofVPBs. 3. Monitoring technology may not provide accurate counts of VPBs and may fail to recognize complex fOrms. 4. There is uncertainty about the significance of type and frequency ofVPBs in certain groups of patients (ie, which VPBs constitute risk). 5. End point of therapy not well established.
There are a number of reasons why noninvasive techniques are preferred. Exercise testing and ambulatory monitoring are widely available procedures that are easy to perform, without risk, and relatively inexpensive. They can be performed in most centers without the need to refer the patient to a specialized institution that has an electrophysiology laboratory. These tests can be repeated as frequently as the clinical situation warrants and can be performed in outpatients Treatment of Ventricular Arrhythmia (Philip J Podrld)
without the need for hospitalization. Therefore, when side effects necessitate adjustments of dosage or a change in medication, testing is readily and simply repeated, eliminating the need for repeat hospitalization; however, there are a number of limitations to invasive technology: 1. Monitoring and exercise testing can only be used in patients who have a high density of spontaneous ventricular arrhythmia, since the drug's effect is based on suppression of VPBs. In our experience, approximately 25 percent of patients referred do not have adequate levels of arrhythmia, but this may vary depending upon the pattern of referral. 2. In some patients, there is wide daily and hourly variability of the frequency of VPBS.1:5.16 Such spontaneous changes in the level of arrhythmia make the evaluation of the effect of an antiarrhythmic drug difficult, for it is impossible to distinguish the drug's effect from what can be attributed to random variability. However, it must be emphasized that these observations ofvariability are in patients with frequent asymptomatic VPBs without a history of sustained ventricular tachyarrhythmias. We have not observed variability in the 75 percent ofpatients with a history of malignant arrhythmia who have a high density ofVPBs (Table 2). Additionally, random variability is dependent upon the frequency of baseline arrhythmia. When VPBs are of low frequency, variability is greater, and thus monitoring for several days is required to determine if changes result from the drug's effect; 15 however, when the baseline level ofVPBs is greater, variability is less marked, and a shorter period of monitoring is necessary. Lastly, when the criteria for a drug's effect include not only reduction of VPBs, but also elimination of repetitive forms, variability is a less important concern; however, before beginning a noninvasive drug evaluation, the daily reproducibility of arrhythmia must be established for each patient. The reproducibility ofarrhythmia provoked by exerTable 2-Reproducibility of Arrhythmia· Data Monitoring Grade 2 (hr) Grade 4A (hr) No. of patients Grade 4B (hr) No. of patients Exercise VPBs (No.) 4A (No.) No. of patients 4B (No. ov runs) No. of patients
with 4A with 4B
with 4A with 4B
Day I
Day 2
2O.9±3.3t 19.1 ±5.0t 100 11.8± 7.2t 100
21.1±3.3t 19.0±4.9t 100 II. 7±6.9t 97
330t 29t 29 6t 21
297t 21t 29 9t 20
*Based on 100 consecutive patients with two control monitors and 29 consecutive patients with two control exercise tests. tDay I vs day 2, not Significant.
cise testing is also uncertain. It has been reported that in patients without a history of serious arrhythmia, the occurrence of VPBs during two sequential exercise tests may be highly variable;17 however, in our experience with patients who have had serious arrhythmia, the number of VPBs and the occurrence of repetitive forms are reproducible during two control tests (Table 2). 3. Current technology for automated ambulatory electrocardiographic monitoring may not provide accurate counts of premature beats. More importantly, the recognition of repetitive forms may be uncertain and inadequate. Such problems may be eliminated by the use of a semiautomated system which requires interaction with a technician and the implementation of quality control which requires hand counts ofVPBs and repetitive forms during randomly selected hours. 4. Ambulatory monitoring for extended periods combined with exercise testing will identify patients with VPBs and document their density, type, and reproducibility; however, for certain groups of patients, it is unclear what type ofVPBs place the patient at risk for ventricular tachycardia or ventricular fibrillation. Patients who have experienced malignant tachyarrhythmia have a greater incidence of repetitive VPBs, and they are considered markers of risk in this group, although the occurrence of such forms in the general population is probably unimportant. The presence of repetitive forms, especially runs of ventricular tachycardia, enhances the risk of sudden death in patients with cardiomyopathy18 and in those with coronary artery disease and a recent myocardial infarction;3,4 howevet; in the latter group ofpatients, there is a changing level of arrhythmia during the period after infarction, and documenting the presence of these arrhythmias may be difficult. 19 In some studies the frequency of VPBs imparts risk, while repetitive arrhythmia is less important. 20 It is possible that the density of repetitive VPBs is important and not their mere presence; however, it is the much larger group of patients with coronary artery disease but without a recent infarction who constitute the greatest challenge, for they represent the majority of patients seen by the physician. The prognostic importance of repetitive VPBs in these patients is uncleat: Lastly, the importance of these arrhythmias in those with normal hearts is unknown. Therefore, in some subsets of patients, monitoring and exercise testing provide only limited data. 5. The end-points for therapy with a drug are uncleat: In patients with a history of malignant arrhythmia, suppression of runs of ventricular tachycardia prevent recurrent arrhythmia,:5 but it is uncertain if complete abolition is essential. Moreover, it is unknown what percentage of reduction of other forms is important. Although repetitive forms enhance the CHEST I 88 I 1 I JULY. 1985
125
risk of sudden death in patients with a recent infarction, it remains uncertain iftheir suppression by a drug protects against serious arrhythmia. The importance of reduction in single VPBs is also uncertain. Definitions ofa drugs efficacy vary among investigators, and there are no uniform criteria generally applied to ambulatory monitoring and exercise testing. We have established criteria which require the elimination of ventricular tachycardia associated with a reduction of the frequency of couplets and VPBs as evaluated by both monitoring and exercise testing. Limitations of Electrophysiologic Testing The limitations of invasive techniques are summarized in the following tabulation: 1. 2. 3. 4. 5.
No uniformity in stimulation protocols. Controversy about the appropriate end-point of study. Uncertainty about criteria for a drugs effectiveness. Reproducibility of technique not established. Uncertainty about the meaning of nonclinical arrhythmia induced by testing. 6. Sensitivity and specificity of technique in different populations not established. 7. Predictive accuracy with certain drugs not established. 8. Electrophysiologic testing evaluates a drugs effect during one point in time and does not account for changes in levels of the drug, alterations in potassium level, effect of autonomic nervous system and circulating catecholamines, or effect of ischemia.
Invasive electrophysiologic testing has been considered a more precise method for selecting an effective antiarrhythmic drug in patients with serious ventricular arrhythmia. Its use eliminates concerns about variability of spontaneous arrhythmia, for arrhythmia is induced during testing. Electrophysiologic testing is necessary when spontaneous arrhythmia is absent or variable, but controversy exists about its use when monitoring and exercise testing exposes frequent arrhythmia. Although there are some advantages to its use, there are many limitations to be considered. 1. There is no consensus about the appropriate technique for programmed electrical stimulation, and protocols vary widely. There are no data about an optimal protocol, and there are controversies involving the following: (a) the type ofdrive rhythm (sinus, atrial, or ventricular paced) to be used and the rate ofpacing; (b) the use of multiple pacing rates; (c) the number of extrastimuli to be employed (most investigators use two or three, although the addition of up to six has been reported); (d) the optimal pulse width of the extrastimuli; (e) the current strength of the extrastimuli (most commonly used is twice the mid-diastolic threshold, which is defined as the least amount of energy resulting in a propagated response; howevet; a current strength of ten times the mid-diastolic threshold and, in some studies, up to 20 mAmp have been used); (f) the timing sequence ofthe extrastimuli; (g) the location and number ofright ventricular sites to be stimulated (most often used are the apex and 128
outflow tract, but additional areas may also be stimulated); (h) the use ofleft ventricular stimulation; (i) the usefulness of rapid ventricular burst pacing (the rate and the duration of the burst may vary); and 0) the use of isoproterenol infusion. There is uncertainty about the aggressiveness ofthe protocol used to induce arrhythmia. When a more rigorous protocol is used, it is uncertain if the arrhythmia induced is clinically important or an artifact. Further complicating this is the evaluation of antiarrhythmic drugs. It is uncertain how aggressive testing must be to establish a drug"s efficacy. If a drug prevents the induction of arrhythmia when the same protocol is used as control, it is unclear if more vigorous methods should be employed. The use of a more aggressive study will increase sensitivity but will reduce specificity.21 It is possible that the low incidence of drug efficacy which has been reported is due to the use of methods that are too sensitive. 3. There exists no consensus about the appropriate end-point for electrophysiologic testing. Both nonsustained and sustained ventricular tachycardia have been advocated. The definitions of these end-points are also unclear. Nonsustained ventricular tachycardia has been defined as more than 3, more than 5, more than 15, or more than 100 repetitive cycles or that which lasts less than 30 or less than 60 seconds. Sustained ventricular tachycardia has been defined by the duration or by the need for an intervention for termination. 3. Criteria for a drugs efficacy vary among investigators. In some studies the inability to induce nonsustained ventricular tachycardia constitutes drug efficacy, although the definition of nonsustained ventricular tachycardia is variable. Other investigators have deemed a drug effective if a previously induced sustained tachyarrhythmia is no longer provoked so that the provocation of a nonsustained episode is acceptable. In some studies a drug is considered effective if the arrhythmia is more difficult to induce, defined as that which requires more extrastimuli, occurs only when additional right or left ventricular pacing sites are used, or is induced when pacing rates faster than control are used. Still others would accept ventricular tachycardia induced at a slower rate and without symptoms as indicative of a drugs effect. 4. The daily reproducibility of electrophysiologic testing remains uncertain. There have been several reports that when an identical protocol is used on two different days, an end-point is reproducibly achieved in only 60 percent of the patients.22.13 The reproducibility increases when a more aggressive protocol is used, but this alters the sensitivity and specificity of the technique,21 making comparison between studies difficult and determination ofa drug"s effect questionable. In our experience with 43 patients who underwent lt8aIment of VentrIcular Arrhythmia (PIlip J. Podrld)
two control tests on successive days, only 25 (58 percent) had the same end-point during both tests. On the first day, 33 patients were inducible, while only 23 were still inducible on the following day. The failure to reinduce arrhythmia in these ten patients might have been ascribed to the drug's effect, rather than to a random change in inducibility.
5. An accepted end-point of study is the induction of a tachycardia which resembles the clinical arrhythmia; howevet; in the patient who has experienced ventricular fibrillation, such a comparison is not possible. In these patients, it is uncertain which induced arrhythmia is important. During electrophysiologic testing the provocation of nonclinical arrhythmia is common and its significance uncertain, especially if it occurs during therapy with a drug. It is uncertain ifthis is failure of the drug, the configuration of the tachycardia being altered by the drug, or a nonspecific and unimportant finding. Complicating this is the fact that polymorphic ventricular tachycardia or even ventricular fibrillation can be provoked in patients who have never experienced ventricular arrhythmia. 14 When nonclinical arrhythmia is induced during a control study, it is unclear if this is an adequate end-point for evaluating antiarrhythmic drugs. 6. The sensitivity and specificity of electrophysiologic testing in different subsets of patients are poorly defined. Although the rate of induction is high in patients with ventricular tachycardia, patients with ventricular fibrillation are less often inducible. 25 Relationship to type and extent of underlying heart disease remains uncertain. The rate of induction is lower in those with tachycardia unrelated to coronary artery disease16 and in patients with nonsustained ventricular tachycardia. J7
7. The predictive accuracy of electrophysiologic testing is uncertain, especially with the new antiarrhythmic drugs. It has been reported that during therapy with a drug, failure to induce a previously inducible arrhythmia predicts freedom from recurrence;1LlJ howevet; it is uncertain if continued inducibility when certain drugs are administered predicts recurrence, especially if there has been suppression of spontaneous arrhythmia (Fig 4). This disparity between clinical outcome and the results of electrophysiologic testing has been reported with amiodaroneJ8·· and propafenone. 30 8. Electrophysiologic testing evaluates the effect of a drug during only one point in time and while the patient is in a supine position in an electrophysiologic laboratory. It does not account for changes in the levels of drug in the blood, autonomic inputs and circulating catecholamines, alterations in potassium level, changes in baroreceptor tone, or transient ischemia which can alter susceptibility to arrhythmia.
Data Days in hospital No. of drugs tested No. of monitors Cost· No. of exercise tests Cost· No. of electrophysiologic tests Cost· Total cost
Noninvasive (n=24)
Invasive (n= 15)
21±7 4.1±O.9 4.8±1.6 $1,152 3.6±2.0 $576
22±7 4.5± 1.9 2.7±O.8
o o
$1,728
t648
2.0±O.8 $320 6.0±3.1
3000 13,968
·Based on $240 Per monitor, $160 per exercise test, $1,000 for initial electrophysiologic study, and $400 for subsequent studies.
Invasive vs Noninvasive Techniques Both electrophysiologic testing and noninvasive techniques are time-consuming and costly. In our experience, electrophysiologic testing does not decrease the time necessary for evaluating a drug. Similar to noninvasive methods, several days ofadministration of a drug are required before efficacy is evaluated. Since the selection ofa drug is empiric, either method may involve several trials of drugs before an effective and well-tolerated drug is identified. In fact, the rate of response to individual drugs is less with electrophysiologic testing than that reported when monitoring is used, suggesting that more studies of drugs might be necessary when invasive techniques are employed. Electrophysiologic tests are far more costly when compared with monitoring and exercise testing (Table 3). Moreovet; invasive testing does not eliminate the need for monitoring before and during drug therapy to ensure that the drug is effective for suppressing spontaneous arrhythmia. Monitoring is also essential to document potential aggravation of arrhythmia. 31 Since electrophysiologic testing cannot be routinely repeated, ambulatory monitoring and exercise testing become important methods for long-tenn follow-up, and therefore the baseline levels of arrhythmia must be established for comparative purposes. If reliance is placed on noninvasive techniques during follow-up, why not use them during in-hospital evaluation of a drug? Despite the limitations of both approaches, a drug deemed effective and selected for long-tenn therapy substantially improves survival in patients who have had malignant ventricular arrhythmia. If spontaneous repetitive arrhythmia is suppressed by a drug, as evaluated by monitoring and exercise testing, annual sudden death is less than 4 percent. 5.31 In our experience, when the selected drug prevents the induction of arrhythmia with electrophysiologic testing, the annual rate of sudden death is similaJ: e Using a different protocol and end point, Swerdlow and co-workersll reported mortality at two years to be 16 percent in CHEST I 88 I 1 I JULY. 1885
1rt
patients responding to a drug as evaluated with electrophysiologic techniques. In conclusion, noninvasive and invasive methods have become established approaches for the treatment of patients with serious ventricular arrhythmia. Both techniques are useful and necessary for guiding therapy. The method chosen should depend upon the patient and the density of baseline ventricular arrhythmia; however, both techniques have limitations which must be recognized. Nevertheless, when an effective drug is selected by either approach, survival is improved. Comparative studies between these two methods are necessary to further define their application. REFERENCES 1 Lawn B, Podrid PJ, DeSilva RA, Graboys TB. Sudden cardiac death: management of the patient at risk. Circ Frobl Cardiol 1980; 4:1-62 2 Podrid PJ, Lown B. Management of malignant ventricular arrhythmia: experience with lorcainide. Am J Cardiol 1984; 54:29B-36B 3 Ruberman ~ Weinblatt E, GoldbergJD, Frank CW, Chaudhary BS, Shapiro S. Ventricular premature beats and mortality after myocardial infarction. N Eng} J Med 1977; 297:750-57 4 Bigger JI: Weld FM, Rolnitzky LM. Prevalence, characteristics and significance of ventricular tachycardia (three or more complexes) detected with ambulatory monitoring in the late hospital phase of acute myocardial infarction. Am J Cardiol 1981; 48:815-23 5 Graboys TB, Lawn B, Podrid PJ, DeSilva R. Long term survival of patients with malignant ventricular arrhythmia treated with antiarrhythmic drugs. Am J Cardiol 1982; 50:437-43 6 Podrid PJ, Schoeneberger A, Lown B, Lampert S, Matos J, Porterfield J, et ale Use ofnonsustained ventricular tachycardia as a guide to antiarrhythmic drug therapy in patients with malignant ventricular ~hythmia. Am Heart J 1983; 105:181-88 7 Mason JW, Winkle RA. Electrode catheter arrhythmia induction in the selection and assessment of antiarrhythmic drug therapy for recurrent ventricular tachycardia. Circulation 1978; 58:971-85 8 Horowitz LN, Josephson ME, Farshidi A, Spielman S, Michelson EL, Greenspan AM. Recurrent sustained ventricular tachycardia: role of the electrophysiologic study in selection of antiarrhythmic regimens. Circulation 1978; 58:987-97 9 Josephson ME, Horowitz LN, Spielman JR, Greenspan AM. Electrophysiologic and hemodynamic studies in patients resuscitated from cardiac arrest. Am J Cardio11980; 46:948-56 10 Horowitz LN, Josephson ME, Kastor JA. Intracardiac electrophysiologic studies as a method for the optimization of drug therapy in chronic ventricular arrhythmias. Frog Cardiovasc Dis 1980; 23:81-98 11 Ruskin IN, DiMarco J, Garan H. Out of hospital cardiac arrest: electrophysiologic observation and selection of long term antiarrhythmic therapy. N Engl J Med 1980; 303:607-13 12 Mason JW, Winkle RR. Accuracy of the ventricular tachycardia induction study for predicting long term efficacy and inefficacy of antiarrhythmic drugs. N Eng} J Med 1980; 303:1073-77 13 Lawn B, Wolf M. Approaches to sudden death from coronary heart disease. Circulation 1971; 44:130-42 14 Gaughan CE, Lawn B, Lanigan J, Voukydis J, Besser W. Acute oral testing for determining antiarrhythmic drug efficacy. 1. quindine. Am J Cardio11976; 38:677-84 15 Morganroth J, Michelson EL, Horowitz LN, Josephson ME, 128
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