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Electrophysiologic and clinical factors influencing response to class IA antiarrhythmic agents in patients with inducible sustained monomorphic ventricular tachycardia
Electrophysiologic and clinical factors influencing response to class IA antiarrhythmic agents in patients with inducible sustained monomorphic ventricular tachycardia Clinical and electrophysiologic data from 51 consecutive patients with sustained monomorphic ventricular tachycardia inducible during programmed ventricular stimulation were evaluated to determine what variables predict the response to intravenous class IA antiarrhythmic agents. All patients received acute drug testing in the electrophysiologic laboratory with either intravenous procainamide or intravenous quinidine. Ventricular tachycardia suppression was achieved in g out of 51 patients (18%). The age, gender, left ventricular ejection fraction, baseline right ventricular effective refractory period, baseline HV interval, and baseline ventricular tachycardia cycle length were not predictive of ventricular tachycardia suppression with intravenous procainamide or quinidine during programmed ventricular stimulation. The degree of prolongation of the right ventricular effective refractory period after drug administration did not predict success or failure to suppress inducible ventricular tachycardia. The degree of prolongation of the HV interval was also not predictive. In addition, the degree of prolongation of the right ventricular effective refractory period or the HV interval did not predict the change in the ventricular tachycardia cycle length after drug administration in patients who remained inducible. These data indicate that the response to class IA antiarrhythmic agents in patients with inducible sustained monomorphic ventricular tachycardia cannot be predicted on the basis of various clinical and electrophysiologic parameters. (AM HEART J 112:g, 1986.)
Robert L. Gold, M.D., Charles I. Haffajee, M.B., M.R.C.P., Joseph S. Alpert, M.D. Worcester, Muss.
Electrophysiologic testing utilizing programmed ventricular stimulation and serial drug testing has been found to be useful in treating patients with ventricular tachycardia.‘,’ Recent work3-5 has described various predictors of success or failure of medical therapy in treating patients with ventricular tachycardia. However, none of these reports examined the relationship between the effect an antiarrhythmic agent has on the effective refractory period of the right ventricle and successful suppression of inducible ventricular tachycardia. These reports also did not examine the relationship between the effects that these drugs have on conduction velocity as measured by the change in the HV interval and successful suppression of inducible From the Divisron of Cardiovascular setts Medxal Center. Received accepted
ior publicatim Dec. 4, 1985.
Aug.
Medicine, 12, 1985;
Reprint requests: Robert L. Gold. Medicine, University of Massachusetts North. Wmester, MA 01605.
revision
University received
of MassachuOct.
28, 1985;
M.D., Division of Cardiovascular Medical Center, 55 Lake Ave.
and
ventricular tachycardia. Although conduction velocity cannot be measured directly, the change in the HV interval is an indirect method of evaluating the change in the conduction velocity of the His-Purkinje system after drug administration. Examining these relationship could possibly aid in evaluating the mechanism by which some antiarrhythmic agents exert their suppressive effect on arrhythmias in man. The mechanism of action of antiarrhythmic agents remains basically unknown. Currently, the class 1A drugs (quinidine, procainamide, and disopyramide) are the antiarrhythmic agents most commonly used to treat ventricular arrhythmias in this country. These drugs reduce the maximum upstroke velocity of phase 0 (V,,,) of the cardiac action potential, prolong action potential duration, delay recovery of activation of the fast sodium channel, and decrease automaticity.6,’ These effects result in a decrease in the conduction velocity of the cardiac impulse and also an increase in the effective refractory period. Which of these effects might be impor-
July.
10
Gold,
Haffajee,
and
Alpert
American
Table I. Relationship of underlying cardiac diseaseand suppression of inducible ventricular tachycardia with intravenous procainamide or quinidine Underlying
heart
disease
Previousmyocardialinfarction Primary electricaldisease Cardiomyopathy Aortic st,enosis SIP AVR AVR
= aorticvalvereplacement; S/F’
Responders
7 (17%) 1(20%)
0 (0%) 1 (100%) = status
Nonresponders
34 4 4 0
post.
tant in the antiarrhythmic action of these agents is not fully understood, although it is often assumed that the prolongation of the effective refractory period plays a major role. To test this hypothesis, patients with sustained monomorphic ventricular tachycardia induced by programmed ventricular stimulation were evaluated to ascertain the relationship between the degree of change of the right ventricular effective refractory period and success or failure of class IA antiarrhythmic drugs to prevent induction of ventricular tachycardia. Other clinical and electrophysiologic factors were also evaluated to determine if they were predictive of success or failure during electrophysiologic testing in patients with inducible sustained monomorphic ventricular tachycardia treated with quinidine or procainamide. In addition, changes in the right ventricular effective refractory period and HV intervals post drug administration were evaluated in patients who remained inducible to determine if these changes could predict the effect of these drugs on the rate of the ventricular tachycardia. METHODS Patient population. The study population consistedof 51 consecutive patients with sustainedmonomorphic ventricular tachycardia that was inducible during programmed ventricular stimulation. There were 39 men and 12 women. Electrophysiology study protocol. All studies were performed in patients in the baseline state after all antiarrhythmic agents except digoxin were discontinued for at least 5 half-lives. The protocol for programmed electrical stimulation included up to three ventricular extrastimuli during two basic cycle lengths (600 or 500 msecand 400 msec)and bursts of rapid ventricular pacing to a cycle length of 200 msecfrom the right ventricular (RV) apex. If ventricular tachycardia wasnot induced, the stimulation protocol was repeated from the RV outflow tract. In the baseline state all patients had inducible sustained monomorphic ventricular tachycardia (greater than 30 seconds’duration and/or requiring intervention). The above protocol was then repeated after the administration of intravenous quinidine or procainamide.
Heart
1986
Journal
Patients were considered responders if repeat programmed ventricular stimulation resulted in less than 10 repetitive ventricular responsesafter drug administration. All other patients were considerednonresponders. Drug administration. All patients had acute drug testing with either intravenous quinidine (22 patients) or intravenous procainamide (29 patients). Quinidine was given at a doseof 10 mg/kg intravenously over 20 minutes and procainamide was given at a dose of up to 2 gm intravenously at a rate of 50 mglmin. In many patients the total dose of quinidine or procainamide was limited by signs of toxicity (hypotension, marked QT prolongation, marked HV prolongation). Serum drug levels were drawn at the completion of the study. Predictors of efficacy. The following variables were studied to determine if they might predict successor failure of quinidine or procainamide therapy: (1) baseline right ventricular effective refractory period (RVERP) determined at a cycle length of 400 msec;(2) the changein the RVERP following drug administration defined as the RVERP post drug administration minus the baseline RVERP (ARVERP) (the RVERP pre and post drug administration were determined at the sameright ventricular site at a basicpaced cycle length of 400 msec);(3) the baseline HV interval; (4) the change in the HV interval following drug administration defined as the HV interval post drug administration minus the baselineHV interval (AHV); (5) baselineventricular tachycardia cycle length (VTCL); (6) age; (7) gender; (8) left ventricular ejection fraction as determined by radionuclide ventriculography; and (9) underlying cardiac disease.Data were analyzed with the chi square test and the Student’s t test for unpaired data. Multivariate analysis wasthen performed with multiple logistic regression. The relationship VTCL post drug.
between
ARVERP
and change
in
Patients with ventricular tachycardia still inducible after the administration of either quinidine or procainamide were evaluated to determine if a relationship exists between the changein the effective refractory period after the administration of the antiarrhythmic agent and the percent changein the ventricular tachycardia cycle length (%AVTCL). The change in VTCL was analyzed only when the same ventricular tachycardia morphology (sameaxis and bundle branch morphology) could be induced both before and after drug administration.%AVTCL is defined as the VTCL post drug minus the VTCL at baseline divided by the VTCL at baseline times 100%. These data were analyzed with simplelinear correlation analysis.The relationship betweenAHV and the changein VTCL post drug was evaluated in a similar manner. RESULTS
Ventricular tachycardia suppression was achieved in 9 of 51 patients (18%). Ventricular tachycardia was suppressed in 3 of the 22 patients receiving quinidine and in 6 of the 29 patients receiving procainamide. The underlying cardiac disease was
Volume Number
Table
112 1
II. Comparison ____
of variables*
Variable
_I--_--
Baseline RVERP AERP Baseline VTCL Mean Age Mean LVEF Baseline HV AHV
in responders
and nonresponders Nonrrsponders
Responders 218 32.2 236 51.2 29.4% 50.0 9.4
+ k + 57 k k -t
16 msec 17.9 msec 36 msec 11.3 14.1 11.2 msec 6.2 msec
msec 252 t 55 msec
62.3 t 12.6 X.8', 'I 13.: 50.0 2 I 1.4 13.3 i 1 I.2
*All values are expressed as mean + SD. RVERP = right ventricular effective refractory period; SERP = prolongation of effective rei’ractory LVEF = left ventriwlar ejection fraction; HV = HV interval; AHV = prolongation of HV interval.
coronary artery disease in 41 patients, primary electrical disease in five patients, cardiomyopathy in four patients, and aortic stenosis status post aortic valve replacement in one patient. The relationship between underlying cardiac disease and ventricular tachycardia suppression is shown in Table I. The average dose of intravenous procainamide given to responders was 1.34 gm, compared to 1.63 gm for nonresponders. The average dose of intravenous quinidine given to responders was 525 mg, compared to 531 mg for nonresponders. Procainamide levels averaged 8.6 pg/ml for responders and 12.0 pg/ml for nonresponders. Quinidine levels averaged 2.9 pg/ml for responders and 3.0 fig/ml for nonresponders. Ventricular tachycardia suppression was seen in 18 % of men and in 17 % of women. The mean age for responders (57.2 years) was similar to that of nonresponders (62.3 years). The mean left ventricular ejection fraction was also similar in these two groups (29.4% for responders vs 32.8% for nonresponders). The mean baseline RVERP at a basic cycle length of 400 msec was similar for responders and nonresponders (218 vs 226 msec, respectively). The mean baseline VTCL tended to be shorter in responders (236 msec) compared to nonresponders (252 msec), but this difference was not statistically significant. The mean change in the RVERP after the administration of procainamide or quinidine was also similar for responders (32.2 msec) and nonresponders (30.5 msec). The mean baseline HV interval was 50.0 msec in both responders and nonresponders. The mean change in the HV interval post drug administration was also similar for responders and nonresponders (9.4 msec vs 13.3 msec, respectively) (Table II). Univariate and multivariate analysis failed to identify any of the above-mentioned variables as a predictor of drug response. In 4‘2 patients ventricular tachycardia was inducible after drug administration. In 29 of these patients the ventricular tachycardia morphology
!, -- N.5 !I- NS rl .- NS
“26 f 20 :30.5 t 14.5
', :>
‘) - 3s La NS
msec msec
per~wi: V’I’CI, = vfwtrlcular
N:: NS
t&l\.
.x~l~.i I bolt. lvn~th
was similar both before and after drug administration. The relationship between the change in the RVERP post drug and the percent change in the VTCL post drug can be seen in Fig. 1. There was no correlation between the degree of prolongation of the RVERP post drug and the change in the VTCL (correlation coefficient r = -0.11, p = 0.28). The relationship between the change in the HV interval post drug and the percent change in the VTCL post drug can be seen in Fig. 2. No correlation was seen between the degree of prolongation of the HV interval post drug and the change in the VTCL (correlation coefficient r = 0.02, p = 0.46). DISCUSSION
Quinidine and procainamide have been shown to have similar electrophysiologic characteristics.6 In addition, several reports have suggested that the response to one of these drugs during programmed ventricular stimulation predicts the response to the other.3,8 For these reasons, in our laboratory patients are usually treated with only one intravenous class 1A agent (either intravenous quinidine or procainamide). The success rate in this study for suppression of inducible sustained monomorphic ventricular tachycardia was only 18% with intravenous procainamide and quinidine. This rate is only slightly lower than that noted in previous reports,B-‘” but this should not be interpreted as a general statement on the efficacy of these drugs because of patient selection bias. Many of these patients were referred for electrophysiologic testing because of ventricular tachycardia that was refractory to conventional antiarrhythmic therapy. ARVERP and AHV. Ventricular tachycardia that is inducible by programmed ventricular stimulation is often assumed to be secondary to reentry.s.ll This implies a region of unidirectional block in the reentry circuit and is dependent upon a delicate balance between conduction velocity and refractoriness. Class IA antiarrhythmic agents can prevent reen-
12
Gold, Haffajee,
July,
and Alpert
American
. 40 % AVTCL
. t
20
: i I
.
807
r=-0.11 p= 0.28
.
%AVTCL
: .
.
40" 20-
1986
Journal
r=o.oz p=O.46
1
60-
Heart
* .
' 1
l l
.
! .
. 1 o-
’ .
-2o0
10
20
A RVERP
30
40 (msecs)
50
60
between the change in the right ventricular effective refractory period post drug administration (AR VERP) and the percent change in the ventricular tachycardia cycle length (% AV7YX) post drug administration. Fig.
I. 0
1. Relationship
trant arrhythmias either (1) by depressing conduction velocity in the area of unidirectional block such that bidirectional block is produced, or (2) by increasing refractoriness in the reentry circuit so that the wave front meets tissue that is no longer excitable, or (3) by a combination of 1 and 2. In this study, there was no relationship between the ARVERP or the AHV and suppression of ventricular tachycardia with quinidine or procainamide. There are several possible explanations for this finding. One is that prolongation of refractoriness and prolongation of conduction velocity (as measured by changes in the HV interval) are not the major electrophysiologic properties responsible for the antiarrhythmic action of these drugs. However, Giardina and Bigger12 suggested that slowing of conduction velocity in the depressed portion of a reentrant pathway is the prominent mechanism of action of procainamide. Another explanation is that refractory period prolongation is important, but that temporal dispersion of refractoriness may also be important. Quinidine has been shown to cause an increase in the temporal dispersion of refractoriness, l3 and this effect may be arrhythmogenic. It is possible that the refractory period prolongs in a more homogeneous manner in patients who are successfully treated with class 1A antiarrhythmic agents compared to those in whom these drugs have failed. The temporal dispersion of refractoriness was not measured in this study, and would have required multiple electrodes in the right and left ventricular before and after drug administration to see if the refractory period prolonged more in some areas than in others. A more likely explanation for our observations is that prolongation of the refractory period or
. I
10
20 AHV
30
40
1 50
[msecs]
2. Relationship between the change in the HV interval post drug administration (AHV) and the percent change in the ventricular tachycardia cycle length (%
Fig.
AVTCL)
post drug administration.
conduction velocity in the reentry circuit is important, but that it is not possible to measure these changes in the reentry circuit itself. This would suggest that there is a dissociation between changes in these electrophysiologic variables in normal myocardium as compared to the abnormal tissue in the area of the reentry circuit. This explanation is consistent with animal studies that have demonstrated a differential effect of procainamide on diseased myocardium as compared to normal tissue.14sl5 Relationship between ARVERP and % AVTCL, and between AHV and % AVTCL. The cycle length of an
arrhythmia secondary to reentry is determined by the conduction velocity and the length of the reentry circuit. Therefore, the slowing of ventricular tachycardia post quinidine or procainamide could be either secondary to a decrease in conduction velocity or to an increase in the length of the reentry circuit, or to both. The reentry circuit would lengthen post drug administration if the impulse encountered areas of refractoriness within the original reentry circuit, requiring it to travel in another pathway. In this study, there was no relationship between the ARVERP and the % AVTCL, and there was no relationship between the AHV and the % AVTCL. This suggests that the effects of these drugs on the conduction velocity and on the effective refractory period in the reentry circuit do not parallel the effects of these agents on other areas of the myocardium, as measured by the changes in the HV interval and the RVERP. This also would be consistent with the previously mentioned animal studies that demonstrated a differential effect of procainamide between normal and abnormal myocardium.
Volume
112
Number
1
Responseto classIA antiarrhvthrylk
The age, gender, left ventricular ejection fraction, baseline RVERP, and baseline VTCL in patients with inducible sustained monomorphic ventricular tachycardia were not predictive of ventricular tachycardia suppression with quinidine or procainamide during programmed ventricular stimulation. This is in agreement with the findings of Swiryn et al.,3 who were also not able to find any clinical or electrophysiologic predictors of ventricular tachycardia suppression in patients with ventricular tachycardia who were treated with class I antiarrhythmic agents. Other studies4,” have shown that factors such as age, gender, left ventricular ejection fraction, and the absence of organic heart disease are useful in predicting outcome during programmed ventricular stimulation in patients with ventricular tachycardia. These studies differ from ours in that many other antiarrhythmic agents in addition to class 1A agents were used during drug testing in these other studies. Also, the study populations differ, because our observations were made only in patients with sustained monomorphic ventricular tachycardia. Clinical implications. If it were established that patients with certain clinical or electrophysiologic characteristics were likely to respond to class IA drugs during programmed ventricular stimulation, it would enable physicians to select patients who would benefit most from electrophysiologic testing and aid in the selection of drugs to be tested during acute drug testing. However, no such parameters were found in this study. Also, if it were established that patients with either no or minimal change in RVERP or HV interval post quinidine or procainamide administration routinely failed these drugs, then programmed ventricular stimulation could be terminated after the determination of the RVERP or HV interval post drug administration in these patients and repeat ventricular tachycardia induction could be avoided. However, this study failed to show a relationship between the effect that a drug had on the RVERP or HV interval and its ability to suppress ventricular tachycardia. Therefore, completion of the entire stimulation protocol is necessary to determine if a drug will be effective. In addition, although quinidine and procainamide usually increase the VTCL, this cannot be predicted by the change in the RVERP or HV interval post drug, and therefore ventricular tachycardia induction remains necessary if it is desirable to determine if Other
possible
predictors
of efficacy.
ngwzt,s 13
the VTCL will be slower and therefore better tolerated hemodynamically after administration of these antiarrhythmic agents. We would analysis.
like to thank
Marc
Zive
for his hein
with
statistical
REFERENCES
1. Horowitz LN, .Josephson ME, Farshidi A, Ypielman SR, Michelson EL, Greenspan AM: Recurrent sustained ventricular tachycardia. 3. Role of the electrophysiology study in selection of antiarrhythmic regimens. Circulation 58:986. 1578. of the vet&icular tachycar2. Mason JW, Winkle RA: Accuracy dia-induction study for predicting long-term efficacy and inefficacy of antiarrhythmic drugs. N Engl .J -Med 303:107X 1580. S, Bauerfeind RA, Strasberg B, Palileo E, Iverson N, 3. Swiryn Levy PS, Rosen KM: Prediction of response to class I antiarrhythmic drugs during electrophysiologic study of ventricular tachycardia. AM HEART J 104:43, 1982. 4. Spielman SR, Schwartz JS, McCarthy DM, Horowitz LN, Greenspan AM. Sadowski LM, Josephson ME, Waxman HL: Predictors of the success or failure of medical therapy in patients with chronic recurrent sustained ventricular tachycardia: A discriminant analysis. -J Am (:oll Cardiol 1:401, 1983. 5. Swerdlow CD, Gong G, Echt DS, Winkle KA, Griffin JC, Ross DL, Mason dW: Clinical factors predicting successful electrophysiologic-pharmacologic study in patients with ventricular tachycardia. J Am Co11 Cardiol 1:409, 1983. 6. Rosen MR, Wit AL: Electropharmacology of’ antiarrhythmic drugs. AM HEART J 106:829, 1983. 7. Rosen MR, Gelband H, Hoffman BF: C’auine electrocardiographic and cardiac electrophvsiologic changes induced hv procainamide. Circulation 46:528, 1572. 8. Waxman HL. Buxton AE. Sadowski LM. Joseahson ME: The _ response to procainamide during electrophysiologic study for sustained ventricular tachyarrhythmias predicts the res,,onse to other medicat,ions. Circulation 67:X): lY8:j. 9. Wellens HJJ. Bar FWHM. Lie KI. Dureli DR. Dohmen HJ: Effect of procainamide, propranoloi. and verapamil on mechanisms of tachycardia in patients with chronic recurrent ventricular tachycardia. Am J Card&l 40:459, 1977. 10. DiMarco dP, Garan H, Puskin JW: Quinidine for ventricular arrhythmias: Value of electrophysiologic i.esting. Am J Cardiol 51:90, 1983. ME, Horowitz LN, Farshidi A. K&or JA: Recur11. ,losephson rent sustained ventricular tachycardia. 1. Mechanisms. Circulation 57:431, 1978. 12. Giardina EGV, Bigger JT: Procainamidr against reentrant ventricular arrhythmias. Lengthening R-V intervals of coupled ventricular premature depolarizations as an insight into the mechanism of action of procainamide Circulation 48:959, 1973. recover?’ ot’ excitability in 13. Han .I, Moe GK: Nonuniform ventricular muscle. Circ Res l&44. 1964. 14. Myerburg RJ, Bassett AL. Epstein K. Gaide MS, Kozlovokis P, Wong SS. Castellanos A. Gelband H: Electrophysiological effects of procainamide in acute and healed experimental ischemic injury of cat myocardium. Circ Res 50:386, 1982. 15. Michelson EL, Spear JF. Moore EN: E?Xects of procainamide on strength interval relations in normal and chronically infarcted canine myocardium. Am .T rar:iiol 47:1223. 19x1.
Robert L. Gold, M.D., Charles I. Haffajee, M.B., M.R.C.P., Joseph S. Alpert, M.D. Worcester, Muss.
Electrophysiologic testing utilizing programmed ventricular stimulation and serial drug testing has been found to be useful in treating patients with ventricular tachycardia.‘,’ Recent work3-5 has described various predictors of success or failure of medical therapy in treating patients with ventricular tachycardia. However, none of these reports examined the relationship between the effect an antiarrhythmic agent has on the effective refractory period of the right ventricle and successful suppression of inducible ventricular tachycardia. These reports also did not examine the relationship between the effects that these drugs have on conduction velocity as measured by the change in the HV interval and successful suppression of inducible From the Divisron of Cardiovascular setts Medxal Center. Received accepted
ior publicatim Dec. 4, 1985.
Aug.
Medicine, 12, 1985;
Reprint requests: Robert L. Gold. Medicine, University of Massachusetts North. Wmester, MA 01605.
revision
University received
of MassachuOct.
28, 1985;
M.D., Division of Cardiovascular Medical Center, 55 Lake Ave.
and
ventricular tachycardia. Although conduction velocity cannot be measured directly, the change in the HV interval is an indirect method of evaluating the change in the conduction velocity of the His-Purkinje system after drug administration. Examining these relationship could possibly aid in evaluating the mechanism by which some antiarrhythmic agents exert their suppressive effect on arrhythmias in man. The mechanism of action of antiarrhythmic agents remains basically unknown. Currently, the class 1A drugs (quinidine, procainamide, and disopyramide) are the antiarrhythmic agents most commonly used to treat ventricular arrhythmias in this country. These drugs reduce the maximum upstroke velocity of phase 0 (V,,,) of the cardiac action potential, prolong action potential duration, delay recovery of activation of the fast sodium channel, and decrease automaticity.6,’ These effects result in a decrease in the conduction velocity of the cardiac impulse and also an increase in the effective refractory period. Which of these effects might be impor-
July.
10
Gold,
Haffajee,
and
Alpert
American
Table I. Relationship of underlying cardiac diseaseand suppression of inducible ventricular tachycardia with intravenous procainamide or quinidine Underlying
heart
disease
Previousmyocardialinfarction Primary electricaldisease Cardiomyopathy Aortic st,enosis SIP AVR AVR
= aorticvalvereplacement; S/F’
Responders
7 (17%) 1(20%)
0 (0%) 1 (100%) = status
Nonresponders
34 4 4 0
post.
tant in the antiarrhythmic action of these agents is not fully understood, although it is often assumed that the prolongation of the effective refractory period plays a major role. To test this hypothesis, patients with sustained monomorphic ventricular tachycardia induced by programmed ventricular stimulation were evaluated to ascertain the relationship between the degree of change of the right ventricular effective refractory period and success or failure of class IA antiarrhythmic drugs to prevent induction of ventricular tachycardia. Other clinical and electrophysiologic factors were also evaluated to determine if they were predictive of success or failure during electrophysiologic testing in patients with inducible sustained monomorphic ventricular tachycardia treated with quinidine or procainamide. In addition, changes in the right ventricular effective refractory period and HV intervals post drug administration were evaluated in patients who remained inducible to determine if these changes could predict the effect of these drugs on the rate of the ventricular tachycardia. METHODS Patient population. The study population consistedof 51 consecutive patients with sustainedmonomorphic ventricular tachycardia that was inducible during programmed ventricular stimulation. There were 39 men and 12 women. Electrophysiology study protocol. All studies were performed in patients in the baseline state after all antiarrhythmic agents except digoxin were discontinued for at least 5 half-lives. The protocol for programmed electrical stimulation included up to three ventricular extrastimuli during two basic cycle lengths (600 or 500 msecand 400 msec)and bursts of rapid ventricular pacing to a cycle length of 200 msecfrom the right ventricular (RV) apex. If ventricular tachycardia wasnot induced, the stimulation protocol was repeated from the RV outflow tract. In the baseline state all patients had inducible sustained monomorphic ventricular tachycardia (greater than 30 seconds’duration and/or requiring intervention). The above protocol was then repeated after the administration of intravenous quinidine or procainamide.
Heart
1986
Journal
Patients were considered responders if repeat programmed ventricular stimulation resulted in less than 10 repetitive ventricular responsesafter drug administration. All other patients were considerednonresponders. Drug administration. All patients had acute drug testing with either intravenous quinidine (22 patients) or intravenous procainamide (29 patients). Quinidine was given at a doseof 10 mg/kg intravenously over 20 minutes and procainamide was given at a dose of up to 2 gm intravenously at a rate of 50 mglmin. In many patients the total dose of quinidine or procainamide was limited by signs of toxicity (hypotension, marked QT prolongation, marked HV prolongation). Serum drug levels were drawn at the completion of the study. Predictors of efficacy. The following variables were studied to determine if they might predict successor failure of quinidine or procainamide therapy: (1) baseline right ventricular effective refractory period (RVERP) determined at a cycle length of 400 msec;(2) the changein the RVERP following drug administration defined as the RVERP post drug administration minus the baseline RVERP (ARVERP) (the RVERP pre and post drug administration were determined at the sameright ventricular site at a basicpaced cycle length of 400 msec);(3) the baseline HV interval; (4) the change in the HV interval following drug administration defined as the HV interval post drug administration minus the baselineHV interval (AHV); (5) baselineventricular tachycardia cycle length (VTCL); (6) age; (7) gender; (8) left ventricular ejection fraction as determined by radionuclide ventriculography; and (9) underlying cardiac disease.Data were analyzed with the chi square test and the Student’s t test for unpaired data. Multivariate analysis wasthen performed with multiple logistic regression. The relationship VTCL post drug.
between
ARVERP
and change
in
Patients with ventricular tachycardia still inducible after the administration of either quinidine or procainamide were evaluated to determine if a relationship exists between the changein the effective refractory period after the administration of the antiarrhythmic agent and the percent changein the ventricular tachycardia cycle length (%AVTCL). The change in VTCL was analyzed only when the same ventricular tachycardia morphology (sameaxis and bundle branch morphology) could be induced both before and after drug administration.%AVTCL is defined as the VTCL post drug minus the VTCL at baseline divided by the VTCL at baseline times 100%. These data were analyzed with simplelinear correlation analysis.The relationship betweenAHV and the changein VTCL post drug was evaluated in a similar manner. RESULTS
Ventricular tachycardia suppression was achieved in 9 of 51 patients (18%). Ventricular tachycardia was suppressed in 3 of the 22 patients receiving quinidine and in 6 of the 29 patients receiving procainamide. The underlying cardiac disease was
Volume Number
Table
112 1
II. Comparison ____
of variables*
Variable
_I--_--
Baseline RVERP AERP Baseline VTCL Mean Age Mean LVEF Baseline HV AHV
in responders
and nonresponders Nonrrsponders
Responders 218 32.2 236 51.2 29.4% 50.0 9.4
+ k + 57 k k -t
16 msec 17.9 msec 36 msec 11.3 14.1 11.2 msec 6.2 msec
msec 252 t 55 msec
62.3 t 12.6 X.8', 'I 13.: 50.0 2 I 1.4 13.3 i 1 I.2
*All values are expressed as mean + SD. RVERP = right ventricular effective refractory period; SERP = prolongation of effective rei’ractory LVEF = left ventriwlar ejection fraction; HV = HV interval; AHV = prolongation of HV interval.
coronary artery disease in 41 patients, primary electrical disease in five patients, cardiomyopathy in four patients, and aortic stenosis status post aortic valve replacement in one patient. The relationship between underlying cardiac disease and ventricular tachycardia suppression is shown in Table I. The average dose of intravenous procainamide given to responders was 1.34 gm, compared to 1.63 gm for nonresponders. The average dose of intravenous quinidine given to responders was 525 mg, compared to 531 mg for nonresponders. Procainamide levels averaged 8.6 pg/ml for responders and 12.0 pg/ml for nonresponders. Quinidine levels averaged 2.9 pg/ml for responders and 3.0 fig/ml for nonresponders. Ventricular tachycardia suppression was seen in 18 % of men and in 17 % of women. The mean age for responders (57.2 years) was similar to that of nonresponders (62.3 years). The mean left ventricular ejection fraction was also similar in these two groups (29.4% for responders vs 32.8% for nonresponders). The mean baseline RVERP at a basic cycle length of 400 msec was similar for responders and nonresponders (218 vs 226 msec, respectively). The mean baseline VTCL tended to be shorter in responders (236 msec) compared to nonresponders (252 msec), but this difference was not statistically significant. The mean change in the RVERP after the administration of procainamide or quinidine was also similar for responders (32.2 msec) and nonresponders (30.5 msec). The mean baseline HV interval was 50.0 msec in both responders and nonresponders. The mean change in the HV interval post drug administration was also similar for responders and nonresponders (9.4 msec vs 13.3 msec, respectively) (Table II). Univariate and multivariate analysis failed to identify any of the above-mentioned variables as a predictor of drug response. In 4‘2 patients ventricular tachycardia was inducible after drug administration. In 29 of these patients the ventricular tachycardia morphology
!, -- N.5 !I- NS rl .- NS
“26 f 20 :30.5 t 14.5
', :>
‘) - 3s La NS
msec msec
per~wi: V’I’CI, = vfwtrlcular
N:: NS
t&l\.
.x~l~.i I bolt. lvn~th
was similar both before and after drug administration. The relationship between the change in the RVERP post drug and the percent change in the VTCL post drug can be seen in Fig. 1. There was no correlation between the degree of prolongation of the RVERP post drug and the change in the VTCL (correlation coefficient r = -0.11, p = 0.28). The relationship between the change in the HV interval post drug and the percent change in the VTCL post drug can be seen in Fig. 2. No correlation was seen between the degree of prolongation of the HV interval post drug and the change in the VTCL (correlation coefficient r = 0.02, p = 0.46). DISCUSSION
Quinidine and procainamide have been shown to have similar electrophysiologic characteristics.6 In addition, several reports have suggested that the response to one of these drugs during programmed ventricular stimulation predicts the response to the other.3,8 For these reasons, in our laboratory patients are usually treated with only one intravenous class 1A agent (either intravenous quinidine or procainamide). The success rate in this study for suppression of inducible sustained monomorphic ventricular tachycardia was only 18% with intravenous procainamide and quinidine. This rate is only slightly lower than that noted in previous reports,B-‘” but this should not be interpreted as a general statement on the efficacy of these drugs because of patient selection bias. Many of these patients were referred for electrophysiologic testing because of ventricular tachycardia that was refractory to conventional antiarrhythmic therapy. ARVERP and AHV. Ventricular tachycardia that is inducible by programmed ventricular stimulation is often assumed to be secondary to reentry.s.ll This implies a region of unidirectional block in the reentry circuit and is dependent upon a delicate balance between conduction velocity and refractoriness. Class IA antiarrhythmic agents can prevent reen-
12
Gold, Haffajee,
July,
and Alpert
American
. 40 % AVTCL
. t
20
: i I
.
807
r=-0.11 p= 0.28
.
%AVTCL
: .
.
40" 20-
1986
Journal
r=o.oz p=O.46
1
60-
Heart
* .
' 1
l l
.
! .
. 1 o-
’ .
-2o0
10
20
A RVERP
30
40 (msecs)
50
60
between the change in the right ventricular effective refractory period post drug administration (AR VERP) and the percent change in the ventricular tachycardia cycle length (% AV7YX) post drug administration. Fig.
I. 0
1. Relationship
trant arrhythmias either (1) by depressing conduction velocity in the area of unidirectional block such that bidirectional block is produced, or (2) by increasing refractoriness in the reentry circuit so that the wave front meets tissue that is no longer excitable, or (3) by a combination of 1 and 2. In this study, there was no relationship between the ARVERP or the AHV and suppression of ventricular tachycardia with quinidine or procainamide. There are several possible explanations for this finding. One is that prolongation of refractoriness and prolongation of conduction velocity (as measured by changes in the HV interval) are not the major electrophysiologic properties responsible for the antiarrhythmic action of these drugs. However, Giardina and Bigger12 suggested that slowing of conduction velocity in the depressed portion of a reentrant pathway is the prominent mechanism of action of procainamide. Another explanation is that refractory period prolongation is important, but that temporal dispersion of refractoriness may also be important. Quinidine has been shown to cause an increase in the temporal dispersion of refractoriness, l3 and this effect may be arrhythmogenic. It is possible that the refractory period prolongs in a more homogeneous manner in patients who are successfully treated with class 1A antiarrhythmic agents compared to those in whom these drugs have failed. The temporal dispersion of refractoriness was not measured in this study, and would have required multiple electrodes in the right and left ventricular before and after drug administration to see if the refractory period prolonged more in some areas than in others. A more likely explanation for our observations is that prolongation of the refractory period or
. I
10
20 AHV
30
40
1 50
[msecs]
2. Relationship between the change in the HV interval post drug administration (AHV) and the percent change in the ventricular tachycardia cycle length (%
Fig.
AVTCL)
post drug administration.
conduction velocity in the reentry circuit is important, but that it is not possible to measure these changes in the reentry circuit itself. This would suggest that there is a dissociation between changes in these electrophysiologic variables in normal myocardium as compared to the abnormal tissue in the area of the reentry circuit. This explanation is consistent with animal studies that have demonstrated a differential effect of procainamide on diseased myocardium as compared to normal tissue.14sl5 Relationship between ARVERP and % AVTCL, and between AHV and % AVTCL. The cycle length of an
arrhythmia secondary to reentry is determined by the conduction velocity and the length of the reentry circuit. Therefore, the slowing of ventricular tachycardia post quinidine or procainamide could be either secondary to a decrease in conduction velocity or to an increase in the length of the reentry circuit, or to both. The reentry circuit would lengthen post drug administration if the impulse encountered areas of refractoriness within the original reentry circuit, requiring it to travel in another pathway. In this study, there was no relationship between the ARVERP and the % AVTCL, and there was no relationship between the AHV and the % AVTCL. This suggests that the effects of these drugs on the conduction velocity and on the effective refractory period in the reentry circuit do not parallel the effects of these agents on other areas of the myocardium, as measured by the changes in the HV interval and the RVERP. This also would be consistent with the previously mentioned animal studies that demonstrated a differential effect of procainamide between normal and abnormal myocardium.
Volume
112
Number
1
Responseto classIA antiarrhvthrylk
The age, gender, left ventricular ejection fraction, baseline RVERP, and baseline VTCL in patients with inducible sustained monomorphic ventricular tachycardia were not predictive of ventricular tachycardia suppression with quinidine or procainamide during programmed ventricular stimulation. This is in agreement with the findings of Swiryn et al.,3 who were also not able to find any clinical or electrophysiologic predictors of ventricular tachycardia suppression in patients with ventricular tachycardia who were treated with class I antiarrhythmic agents. Other studies4,” have shown that factors such as age, gender, left ventricular ejection fraction, and the absence of organic heart disease are useful in predicting outcome during programmed ventricular stimulation in patients with ventricular tachycardia. These studies differ from ours in that many other antiarrhythmic agents in addition to class 1A agents were used during drug testing in these other studies. Also, the study populations differ, because our observations were made only in patients with sustained monomorphic ventricular tachycardia. Clinical implications. If it were established that patients with certain clinical or electrophysiologic characteristics were likely to respond to class IA drugs during programmed ventricular stimulation, it would enable physicians to select patients who would benefit most from electrophysiologic testing and aid in the selection of drugs to be tested during acute drug testing. However, no such parameters were found in this study. Also, if it were established that patients with either no or minimal change in RVERP or HV interval post quinidine or procainamide administration routinely failed these drugs, then programmed ventricular stimulation could be terminated after the determination of the RVERP or HV interval post drug administration in these patients and repeat ventricular tachycardia induction could be avoided. However, this study failed to show a relationship between the effect that a drug had on the RVERP or HV interval and its ability to suppress ventricular tachycardia. Therefore, completion of the entire stimulation protocol is necessary to determine if a drug will be effective. In addition, although quinidine and procainamide usually increase the VTCL, this cannot be predicted by the change in the RVERP or HV interval post drug, and therefore ventricular tachycardia induction remains necessary if it is desirable to determine if Other
possible
predictors
of efficacy.
ngwzt,s 13
the VTCL will be slower and therefore better tolerated hemodynamically after administration of these antiarrhythmic agents. We would analysis.
like to thank
Marc
Zive
for his hein
with
statistical
REFERENCES
1. Horowitz LN, .Josephson ME, Farshidi A, Ypielman SR, Michelson EL, Greenspan AM: Recurrent sustained ventricular tachycardia. 3. Role of the electrophysiology study in selection of antiarrhythmic regimens. Circulation 58:986. 1578. of the vet&icular tachycar2. Mason JW, Winkle RA: Accuracy dia-induction study for predicting long-term efficacy and inefficacy of antiarrhythmic drugs. N Engl .J -Med 303:107X 1580. S, Bauerfeind RA, Strasberg B, Palileo E, Iverson N, 3. Swiryn Levy PS, Rosen KM: Prediction of response to class I antiarrhythmic drugs during electrophysiologic study of ventricular tachycardia. AM HEART J 104:43, 1982. 4. Spielman SR, Schwartz JS, McCarthy DM, Horowitz LN, Greenspan AM. Sadowski LM, Josephson ME, Waxman HL: Predictors of the success or failure of medical therapy in patients with chronic recurrent sustained ventricular tachycardia: A discriminant analysis. -J Am (:oll Cardiol 1:401, 1983. 5. Swerdlow CD, Gong G, Echt DS, Winkle KA, Griffin JC, Ross DL, Mason dW: Clinical factors predicting successful electrophysiologic-pharmacologic study in patients with ventricular tachycardia. J Am Co11 Cardiol 1:409, 1983. 6. Rosen MR, Wit AL: Electropharmacology of’ antiarrhythmic drugs. AM HEART J 106:829, 1983. 7. Rosen MR, Gelband H, Hoffman BF: C’auine electrocardiographic and cardiac electrophvsiologic changes induced hv procainamide. Circulation 46:528, 1572. 8. Waxman HL. Buxton AE. Sadowski LM. Joseahson ME: The _ response to procainamide during electrophysiologic study for sustained ventricular tachyarrhythmias predicts the res,,onse to other medicat,ions. Circulation 67:X): lY8:j. 9. Wellens HJJ. Bar FWHM. Lie KI. Dureli DR. Dohmen HJ: Effect of procainamide, propranoloi. and verapamil on mechanisms of tachycardia in patients with chronic recurrent ventricular tachycardia. Am J Card&l 40:459, 1977. 10. DiMarco dP, Garan H, Puskin JW: Quinidine for ventricular arrhythmias: Value of electrophysiologic i.esting. Am J Cardiol 51:90, 1983. ME, Horowitz LN, Farshidi A. K&or JA: Recur11. ,losephson rent sustained ventricular tachycardia. 1. Mechanisms. Circulation 57:431, 1978. 12. Giardina EGV, Bigger JT: Procainamidr against reentrant ventricular arrhythmias. Lengthening R-V intervals of coupled ventricular premature depolarizations as an insight into the mechanism of action of procainamide Circulation 48:959, 1973. recover?’ ot’ excitability in 13. Han .I, Moe GK: Nonuniform ventricular muscle. Circ Res l&44. 1964. 14. Myerburg RJ, Bassett AL. Epstein K. Gaide MS, Kozlovokis P, Wong SS. Castellanos A. Gelband H: Electrophysiological effects of procainamide in acute and healed experimental ischemic injury of cat myocardium. Circ Res 50:386, 1982. 15. Michelson EL, Spear JF. Moore EN: E?Xects of procainamide on strength interval relations in normal and chronically infarcted canine myocardium. Am .T rar:iiol 47:1223. 19x1.