September
630
Brodsky
et al.
American
O-L-
-t-
wa. 300 msec were rendered noninducible with combination therapy, Table
I. Clinical characteristics of all patients Number
Age
(yr)
Sex Heart disease LVEF (5) Clinical rhythm Induced rhythm No. of unsuccessful LVEF, Left DCM, dilated ventricular
19
drugs
62 i- 12 (range, 30 to 79) 89”;’ M, 11% F 955 CAD, 5’:’ DCM 34 L 11 (18-63) 74? VT,, 16’;s VF, 10°F VT,,, 100? VT,/Monomorphic 2.8 I!I 1.1 (l-6)
ventricular ejection fraction; CAD, coronary artery disease; cardiomyopathy; VT,?, sustained ventricular tachycardia: VF, fibrillation: VT,,?, nonsustained ventricular tachycardia.
tricular tachycardia at baseline frequently remain inducible despite serial drug testing. Unless these patients can be rendered noninducible by antiarrhythmic drug therapy, their prognosis is po0r.l Although these patients may be candidates for an implantable defibrillator, patients with these devices often require antiarrhythmic drug therapy in addition to minimize arrhythmic events.2 Results of previous studies have suggested that
P-blockers may enhance the effectiveness of class I antiarrhythmic drugs when the two are combined.3-e Evaluation of ventricular arrhythmia by noninvasive testing (ambulatory ECG monitoring and exercise testing) showed /3-blockers to have a beneficial effect in reducing the frequency of arrhythmias.3l 4 Friehling et a1.5used programmed stimulation to prove the beneficial effects of adding propranolol to class I drug therapy in patients with ventricular tachycardia.5 Previous data from our laboratory, in which noninvasive techniques were utilized, support these findings.6)i We retrospectively reviewed our invasive data and now specifically report on the effect of the combination of metoprolol and class I antiarrhythmic drugs in patients with inducible sustained monomorphic ventricular tachycardia. METHODS Patient
population. Of 95 consecutive patients evaluated for clinically significant ventricular tachyarrhythmias, 69 had inducible ventricular tachycardia. Of the inducible patients, nine underwent no further testing because they refused or had limiting concurrent medical problems. The remaining 60 patients were serially tested
Volume Number
124 3
Adjuvant
metoprolol
for inducible
VT
631
Fig.
2. Changein inducibility of ventricular tachycardia (VT) . Comparedwith baseline(BL), therapy with classI drugs made six patients more difficult to induce, causedno changein eight, and made five patients easierto induce. In comparisonwith classI drug therapy, the addition of the P-blocker (BB) metoprolol resulted in 13 patients being harder to induce, three with no change,and three being easierto induce. During therapy with a combination of classI drugs and the @-blockermetoprolol, 16 patients were harder to induce and three were easierto induce than during baselinestudy.
with classI antiarrhythmic drugs and 17 were rendered noninducible. Therefore 43 patients remainedpersistently inducible despiteevaluation with quinidine, procainamide, mexiletine, tocainide, flecainide, propafenone, or a combination of these drugs. Twenty-four of these patients were not given further consideration ascandidatesfor adjuvant metoprolol becausethey either had contraindications to p-blocker therapy or were being treated with amiodarone. The 19 remaining patients constitute the basisof this report. The clinical characteristicsof the 19patients are detailed in Table I. They all had clinical ventricular tachycardia and baselineinducible sustained monomorphic ventricular tachycardia and were persistently inducible despite therapy with at least one classI antiarrhythmic drug. These patients were all subsequently studied with the combination of metoprolol and the most effective classI therapy. Invasive cardiac electrophysiologic evaluation. All 19 patients underwent invasive cardiac electrophysiologic study in the fasting, nonsedatedstate in the absenceof any antiarrhythmic drugs. All previous classI antiarrhythmic therapy had been discontinued for at least five half-lives before the baselinestudy. No patient received amiodarone before the baselinestudy or at any time during the investigation. None of the patients had taken a p-blocker, verapamil, or diltiazem for at least five half-lives before this study aswell. Many of the patients were receiving therapy
for congestive heart failure including digoxin, diuretics, and afterload-reducing agents. Someof the patients were receiving therapy for ischemicheart diseaseincluding nitrates and nifedipine. Programmed stimulation was performed with a constant-current stimulator (Bloom Ltd., Reading, Pa.). All patients were tested with rectangular pulsesof 2 msecduration at 2.5 times middiastolic threshold. Programmed stimulation involved the introduction of up to three ventricular extrastimuli during ventricular pacing at two basicdrive cycle lengths (600, 500, and/or 400 msec).Ventricular extrastimuli were started in mid diastole and were decrementally advancedto refractoriness (with the exception of Sq, which was not decremented to less than 200 msec).Programmedstimulation wasinitially performed at the right ventricular apex, and if ventricular tachycardia was not induced the protocol was repeated at the right ventricular outflow tract. The induced ventricular tachycardia matched the clinical ventricular tachycardia morphology in all patients. Each patient was subjectedto serial drug testing evaluating class I antiarrhythmic drugs. Quinidine, procainamide, mexiletine, tocainide, flecainide,propafenone,and/or a combination of these agents were tested. The dosageof antiarrhythmic agentswas determined by blood levels of quinidine and procainamide. The dosage of the other agents was determined on the basis of standard dosing
632
Brodsky et al.
American
September 1992 Heart Journal
Fig. 3. Group 1 effective refractory periods. Ventricular effective refractory periodswere evaluated under three separate conditions in patients eventually rendered noninducible with a combination of class I drugs
and metoprolol therapy. Overall there was a significant difference with regard to ventricular effective refractory periods when comparing combination therapy.
baseline
with combination
regimens, ECG parameters, and/or side effects. Once patients were given a loading dose of antiarrhythmic therapy, they were subjected to repeat programmed stimulation.
Patients werethen maintained on the best classI drug, that is, the agent that made the tachycardia most difficult to induce and led to the slowest rate. All 19 patients were persistently inducible despite a range of one to six (mean 2.8) class I antiarrhythmic drugs before additional testing with adjuvant metoprolol. After the last electrophysiologic test on class I therapy, patients were tested on the combination of metoprolol and class I therapy within 1 day (13 patients), within 6 days (5 patients), and after more than 6 days (1 patient). The variation in metoprolol administration, dosing, and intervals between retesting was due to clinical and administrative considerations. All patients were clinically stable and exhibited adequate P-blockade at the time of testing of the combination therapy. Adjuvant metoprolol therapy. In considering patients for metoprolol therapy, exclusion criteria were a history of bronchospastic pulmonary disease, symptomatic peripheral vascular disease, insulin-dependent diabetes mellitus, recurrent pulmonary edema, second-degree atrioventricular block, and resting heart rate less than 40 beats/min. Metoprolol was given to 15 patients as oral therapy at a dosage of between 50 and 150 mg/day or as intravenous therapy in four patients at a dosage of approximately 0.1
therapy and between
solitary
class I drugs and
mg/kg. Patients were then tested 15 minutes after intravenous metoprolol or between 2 and 6 hours after oral therapy to allow for appropriate P-blocking effects asevidenced by heart rate. RESULTS
Each of the 19 patients who met the inclusion criteria was subjected to electrophysiologic testing with the combination of their most effective class I drug therapy and metoprolol. Eight patients were rendered noninducible (group l), whereas 11 remained persistently inducible (group 2). There was no significant difference between the groups with regard to age, sex, presenting rhythm, underlying heart disease, and left ventricular ejection fraction. Additionally, there were no differences in baseline electrophysiologic parameters including R-R interval, ventricular effective refractory period, or number of extrastimuli required to induce sustained ventricular tachycardia. There was a significant difference between groups with regard to the baseline induced ventricular tachycardia cycle length. Patients in group 1 had a significantly shorter induced cycle length (259 f 27 msec) than patients in group 2
Volume Number
124 3
Adjuvant
metoprolol
for
inducible
VT
633
4. Group 2 effective refractory periods. Ventricular effective refractory periodswere evaluated under three separateconditions in patients persistently inducible despite a combination of classI drugsand metoprolol therapy. Overall the only significant difference wasbetween baselineand combination therapy.
Fig.
(305 + 53 msec). When analyzed in a different way, no patient with a baseline induced ventricular tachycardia cycle length >300 msec was rendered noninducible with adjuvant metoprolol therapy (Fig. 1). On the other hand, if a patient had a baseline induced ventricular tachycardia cycle length 1300 msec, there was a 62% chance of successful therapy. For all patients sinus cycle length, ventricular effective refractory period, ventricular tachycardia cycle length, and the number of extrastimuli required to induce ventricular tachycardia were measured under three conditions: baseline, during the most effective class I drug therapy, and during combination class I drug and metoprolol therapy. There were no significant changes in sinus cycle length until the addition of metoprolol in both groups. The ventricular tachycardia cycle length was lengthened significantly with the addition of class I drug therapy as compared with the baseline value in both groups. In group 2 there was no significant prolongation of the ventric-
ular tachycardia cycle length with the addition of metoprolol to class I drug therapy. When all 19 patients were combined, there was a significant difference with regard to the inducibility of ventricular tachycardia (Fig. 2). When comparing combination
metoprolol and class I drug therapy with class I drug therapy alone, 68% of the patients were more diffi-
cult to induce. When comparing combination metopro101 and class I therapy with the baseline state, 84% of patients were more difficult to induce (p < 0.05). Eight of 19 patients (42%) became noninducible with the addition of metoprolol to class I drug therapy. The effect of adding metoprolol on the ventricular effective refractory period is illustrated in Figs. 3 and 4. Patients in group 1 required the addition of metopro101 to have a significant difference in the ventricular effective refractory period as compared with baseline or class I drug therapy. Patients in group 2 had differences only between baseline and combination therapy. Follow-up. Each patient in group I was discharged on a regimen of combination therapy. Only one patient was unable to tolerate combination therapy and metoprolol was discontinued. Within 1 year he had sudden cardiac death. None of the other patients in group 1 had recurrent tachyarrhythmia or sudden cardiac death. Six of the 11 patients in group 2 had
recurrent ventricular tachycardia had sudden cardiac death.
and one patient
634
Brodsky
et al.
DISCUSSION
In the current study adjuvant therapy with the P-blocker metoprolol had a number of significant electrophysiologic effects. The sinus cycle length was prolonged and the ventricular effective refractory period was lengthened significantly, proving that patients were affected by metoprolol. In addition, adjuvant metoprolol made ventricular tachycardia significantly more difficult to induce and rendered 42 7; of selected patients noninducible. This beneficial effect was predictable from baseline data obtained in a drug-free state. Patients with inducible ventricular tachycardia cycle lengths 1300 msec were more likely to benefit from adjuvant metoprolol therapy. This beneficial effect was corroborated during longterm follow-up. Mechanism. P-Blockers effectively control a variety of different ventricular arrhythmias including isolated ventricular premature depolarizations and ventricular tachyarrhythmias related to ischemia or alterations in adrenergic tone.8-10 Their efficacy in preventing inducible sustained monomorphic ventricular tachycardia has been reported to be limited.llB l2 Data from our laboratory support this claim, inasmuch as only 27% of patients with inducible sustained monomorphic ventricular tachycardia were rendered noninducible.13 Because of a low incidence of efficacy and general safety, we elected not to evaluate patients in this study with solitary P-blocker therapy (before initiating class I drug therapy). Some P-blockers possess membrane-stabilizing activity, but the plasma levels needed to produce an antiarrhythmic effect in humans are much lower than the drug concentration necessary to produce direct effects on cell membranes.14 The beneficial antiarrhythmic effects of these drugs are therefore related mostly to /?-adrenergic blockade.lj P-Blockers should reverse all of the detrimental effects of catecholamines. Catecholamines have no effect on resting membrane potential, rate of upstroke of the action potential, membrane responsiveness, or conduction velocity in normal cardiac fibers. In contrast, in abnormal fibers, catecholamines may act to increase the rate of rise of the phase 0 action potential amplitude, increase conduction velocity, and shorten the refractory period. These effects could create triggered activity and enhance the tendency toward reentrant arrhythmias.15 Furthermore, catecholamines could accelerate the rate of ventricular tachycardia. In this study patients with a more rapid rate of ventricular tachycardia were more responsive to adjuvant @blocker therapy. Class I drugs and ,&blockers may act in a synergistic fashion. P-Blockers may mitigate against the ad-
American
September 1992 Heart Journal
verse effects of catecholamine stimulation. Previous investigators have shown that catecholamine stimulation with either isoproterenol or epinephrine can reverse the protective effects of class I antiarrhythmic drugs. 16-i8 It is possible that the addition of P-blockers to class I drug therapy prevents elevated catecholamine levels from shortening the ventricular refractory period and increasing conduction velocity as would be expected in patients with diseased hearts. The effective combination of class I drugs and metoprolol suggests a possible synergism between membrane effects and P-receptor blockade. Combination therapy. Previous investigators have shown that P-blockers used in combination with class I drug therapy are effective in reducing ventricular arrhythmias. By use of 24-hour ambulatory ECG monitors and exercise tests to measure the frequency of arrhythmias, Hirsowitz et a1.4 found that adjuvant P-blocker therapy significantly decreased the incidence of ventricular tachycardia and couplets in a general population of 54 patients with clinical arrhythmias. In patients with left ventricular dysfunction and ventricular tachycardia, a 64 ?;, success rate was reported for combination class I drug and P-blocker therapy when evaluated with electrophysiologic monitoring, exercise testing, and invasive electrophysiologic study.6 Friehling et al.” used invasive testing to evaluate the role of propranolol as adjuvant therapy to class I drugs. Of 23 patients who remained inducible despite class I drug therapy, seven (30 %) became noninducible on a regimen of combination propranolol and class I drug therapy. The addition of propranolol to class I drug therapy significantly increased the ventricular effective refractory period. In addition, the combination therapy prolonged the cycle length of the ventricular tachycardia in the patients who were persistently inducible. In the present study we specifically analyzed the efficacy of metoprolol as adjuvant b-blocker therapy. There are several clinical advantages to using metopro101 instead of propranolol. Metoprolol is Pi-selective and has been shown to be well tolerated in patients with left ventricular dysfunction, a group of patients with a high potential for ventricular tachycardia.5* l7 Another benefit is that metoprolol has a longer half-life than propranolol. The current study is limited by the fact that this is a retrospective analysis. Furthermore, only a select population was evaluated. Of 95 patients initially considered, only 19 were eventual candidates for combination therapy. The results of this study confirm the beneficial effects of adjuvant metoprolol therapy in selected patients with ventricular tachycardia.
Volume Number
124 3
Adjuvant
REFERENCES 1. Wilber
2.
3.
4.
5.
6.
I.
8.
9. 10.
DJ,
Garan H, Finkelstein D, Kelly E, Newell J, McGovern B, Ruskin JN. Out of hospital cardiac arrest: use of electrophysiologic testing in the prediction of long term outcome. N Engl J Med 1988;318:19-24. Echt DA, Armstrong K, Schmidt P, Oyer PE, Stinson EB, Winkle RA. Clinical experience, complications, and survival in 70 patients with the automatic implantable cardioverter/ defibrillator. Circulation 1985;71:2&39-96. Leahev EB, Heissenbuttel RH, Giardina EG, Bigger JT. Combined mexiletine and propranolol treatment of refractory ventricular tachycardia. Br Med J 1980;281:357-8. Hirsowitz G, Podrid PJ, Lampert S, Stein J, Lown B. The role of beta blocking agents as adjunct therapy to membrane stabilizing drugs in malignant ventricular arrhythmia. AM HEART J 1986;.111:852-60. Friehline TD. Linshutz H. Marinchak RA. Stohler JL. Kowev PR. E&ctivene& of propranolol added to a type I’ antiarrhythmic agent for sustained ventricular tachycardia secondary to coronary artery disease. Am J Cardiol 1990;65:1328-33. Brodskv MA. Allen BJ. Bessen M. Luckett CR. Siddiai R. Henry WL. Beta-blocked therapy in patients with ventricula; tachyarrhythmias in the setting of left ventricular dysfunction. AM HEART J 1988;115:799-808. Brodsky MA, Allen BJ, Luckett C, Thomas R: Antiarrhythmic drug therapy for patients with ventricular tachyarrhythmia in the setting of left ventricular dysfunction: 1. The role of propafenone. 2. The role of adjunct beta-blockers. In: Beamish RE, Panagia V, Dhalla NS, eds. Pharmacological aspects of heart disease. Boston/Dordrecht/Lancaster: Martinus Nijhoff, 1987:45-57. Woosley RL, Kornhauser D, Smith R, Reele S, Higgins SB, Nies AS, Shand DG, Oates JA. Suppression of chronic ventricular arrhythmias with propranolol. Circulation 1979; 60:819-27. Vlay SC. Catecholamine-sensitive ventricular tachycardia. AM HEART J 1987;114:455-61. Ryden L, Ariniego R, Arnman K, Herlitz J, Hjalmarson A, Holmherg S, Reyes C, Smedgard P, Svedberg K, Vedin A,
11.
12.
13.
14.
15.
16.
17.
18.
19.
metoprolol
for inducible
VT
635
Waagstein F, Waldenstrom A, Wilhelmsson C, Wedel H, Yamamoto M. A double-blind trial of metoprolol in acute myocardial infarction: effects on ventricular tachyarrhythmias. N Engl J Med 1983;308:614-8. Horowitz LN, Josephson ME, Kastor JA. Intracardiac electrophysiologic studies as a method for the optimization of drug therapy in chronic ventricular arrhythmia. Prog Cardiovasc Dis 1980;23:81-98. Duff HJ, Mitchell B, Wyse G. Arrhythmia efficacy of propranolo1 comparison of low and high serum concentrations. J Am Co11 Cardiol 1986:8:959-65. Brodsky MA, Allen BJ, Luckett CR, Capparelli EV, Wolff LJ, Henry WL. Antiarrhythmic efficacy of solitary beta-adrenergic blockade for patients with sustained ventricular tachyarrhythmias. AM HEART J 1989;118:272-80. Anderson JL, Rodier HE, Green LS. Comparative effects of beta-adrenergic blocking drugs on experimental ventricular fibrillation threshold. Am J Cardiol 1983;51:1196-1202. Wit AL, Hoffman BF, Rosen MR. Electrophysiology and pharmacology of cardiac arrhythmias. IX. Cardiac electrophysiologic effects of beta adrenergic receptor stimulation and blockade. Parts A,B,C. AM HEART J 1975;90:521-33, 665.75, 795-803. Morady F, Kou WH, Kadish AH, Nelson SD, Toivonen LK, Kushner JA, Schmalz S, de Buitleir M. Antagonism of quinidine’s electrophysiologic effects by epinephrine in patients with ventricular tachycardia. J Am Co11 Cardiol 1988;12:38894. Jazayeri MR, Van Wyhe G, Avitall B, McKinnie J, Tchou P, Akhtar M. Isoproterenol reversal of antiarrhythmic effects in patients with inducible sustained ventricular tachvarrhvth_ ” &as. J Am Co11 Cardiol 1989;14:705-11. DiCarlo LA. Susser F. Winston SA. The role of beta blockade therapy for ventricular tachycardia induced with isoproterenol: a prospective analysis. AM HEART J 1990;120:1347-55. Swedberg K, Hjalmarson A, Waagstein F, Wallentin I. Prolongation of survival in congestive cardiomyopathy by betareceptor blockade. Lancet 1979;1:1374-85.
630
Brodsky
et al.
American
O-L-
-t-
wa. 300 msec were rendered noninducible with combination therapy, Table
I. Clinical characteristics of all patients Number
Age
(yr)
Sex Heart disease LVEF (5) Clinical rhythm Induced rhythm No. of unsuccessful LVEF, Left DCM, dilated ventricular
19
drugs
62 i- 12 (range, 30 to 79) 89”;’ M, 11% F 955 CAD, 5’:’ DCM 34 L 11 (18-63) 74? VT,, 16’;s VF, 10°F VT,,, 100? VT,/Monomorphic 2.8 I!I 1.1 (l-6)
ventricular ejection fraction; CAD, coronary artery disease; cardiomyopathy; VT,?, sustained ventricular tachycardia: VF, fibrillation: VT,,?, nonsustained ventricular tachycardia.
tricular tachycardia at baseline frequently remain inducible despite serial drug testing. Unless these patients can be rendered noninducible by antiarrhythmic drug therapy, their prognosis is po0r.l Although these patients may be candidates for an implantable defibrillator, patients with these devices often require antiarrhythmic drug therapy in addition to minimize arrhythmic events.2 Results of previous studies have suggested that
P-blockers may enhance the effectiveness of class I antiarrhythmic drugs when the two are combined.3-e Evaluation of ventricular arrhythmia by noninvasive testing (ambulatory ECG monitoring and exercise testing) showed /3-blockers to have a beneficial effect in reducing the frequency of arrhythmias.3l 4 Friehling et a1.5used programmed stimulation to prove the beneficial effects of adding propranolol to class I drug therapy in patients with ventricular tachycardia.5 Previous data from our laboratory, in which noninvasive techniques were utilized, support these findings.6)i We retrospectively reviewed our invasive data and now specifically report on the effect of the combination of metoprolol and class I antiarrhythmic drugs in patients with inducible sustained monomorphic ventricular tachycardia. METHODS Patient
population. Of 95 consecutive patients evaluated for clinically significant ventricular tachyarrhythmias, 69 had inducible ventricular tachycardia. Of the inducible patients, nine underwent no further testing because they refused or had limiting concurrent medical problems. The remaining 60 patients were serially tested
Volume Number
124 3
Adjuvant
metoprolol
for inducible
VT
631
Fig.
2. Changein inducibility of ventricular tachycardia (VT) . Comparedwith baseline(BL), therapy with classI drugs made six patients more difficult to induce, causedno changein eight, and made five patients easierto induce. In comparisonwith classI drug therapy, the addition of the P-blocker (BB) metoprolol resulted in 13 patients being harder to induce, three with no change,and three being easierto induce. During therapy with a combination of classI drugs and the @-blockermetoprolol, 16 patients were harder to induce and three were easierto induce than during baselinestudy.
with classI antiarrhythmic drugs and 17 were rendered noninducible. Therefore 43 patients remainedpersistently inducible despiteevaluation with quinidine, procainamide, mexiletine, tocainide, flecainide, propafenone, or a combination of these drugs. Twenty-four of these patients were not given further consideration ascandidatesfor adjuvant metoprolol becausethey either had contraindications to p-blocker therapy or were being treated with amiodarone. The 19 remaining patients constitute the basisof this report. The clinical characteristicsof the 19patients are detailed in Table I. They all had clinical ventricular tachycardia and baselineinducible sustained monomorphic ventricular tachycardia and were persistently inducible despite therapy with at least one classI antiarrhythmic drug. These patients were all subsequently studied with the combination of metoprolol and the most effective classI therapy. Invasive cardiac electrophysiologic evaluation. All 19 patients underwent invasive cardiac electrophysiologic study in the fasting, nonsedatedstate in the absenceof any antiarrhythmic drugs. All previous classI antiarrhythmic therapy had been discontinued for at least five half-lives before the baselinestudy. No patient received amiodarone before the baselinestudy or at any time during the investigation. None of the patients had taken a p-blocker, verapamil, or diltiazem for at least five half-lives before this study aswell. Many of the patients were receiving therapy
for congestive heart failure including digoxin, diuretics, and afterload-reducing agents. Someof the patients were receiving therapy for ischemicheart diseaseincluding nitrates and nifedipine. Programmed stimulation was performed with a constant-current stimulator (Bloom Ltd., Reading, Pa.). All patients were tested with rectangular pulsesof 2 msecduration at 2.5 times middiastolic threshold. Programmed stimulation involved the introduction of up to three ventricular extrastimuli during ventricular pacing at two basicdrive cycle lengths (600, 500, and/or 400 msec).Ventricular extrastimuli were started in mid diastole and were decrementally advancedto refractoriness (with the exception of Sq, which was not decremented to less than 200 msec).Programmedstimulation wasinitially performed at the right ventricular apex, and if ventricular tachycardia was not induced the protocol was repeated at the right ventricular outflow tract. The induced ventricular tachycardia matched the clinical ventricular tachycardia morphology in all patients. Each patient was subjectedto serial drug testing evaluating class I antiarrhythmic drugs. Quinidine, procainamide, mexiletine, tocainide, flecainide,propafenone,and/or a combination of these agents were tested. The dosageof antiarrhythmic agentswas determined by blood levels of quinidine and procainamide. The dosage of the other agents was determined on the basis of standard dosing
632
Brodsky et al.
American
September 1992 Heart Journal
Fig. 3. Group 1 effective refractory periods. Ventricular effective refractory periodswere evaluated under three separate conditions in patients eventually rendered noninducible with a combination of class I drugs
and metoprolol therapy. Overall there was a significant difference with regard to ventricular effective refractory periods when comparing combination therapy.
baseline
with combination
regimens, ECG parameters, and/or side effects. Once patients were given a loading dose of antiarrhythmic therapy, they were subjected to repeat programmed stimulation.
Patients werethen maintained on the best classI drug, that is, the agent that made the tachycardia most difficult to induce and led to the slowest rate. All 19 patients were persistently inducible despite a range of one to six (mean 2.8) class I antiarrhythmic drugs before additional testing with adjuvant metoprolol. After the last electrophysiologic test on class I therapy, patients were tested on the combination of metoprolol and class I therapy within 1 day (13 patients), within 6 days (5 patients), and after more than 6 days (1 patient). The variation in metoprolol administration, dosing, and intervals between retesting was due to clinical and administrative considerations. All patients were clinically stable and exhibited adequate P-blockade at the time of testing of the combination therapy. Adjuvant metoprolol therapy. In considering patients for metoprolol therapy, exclusion criteria were a history of bronchospastic pulmonary disease, symptomatic peripheral vascular disease, insulin-dependent diabetes mellitus, recurrent pulmonary edema, second-degree atrioventricular block, and resting heart rate less than 40 beats/min. Metoprolol was given to 15 patients as oral therapy at a dosage of between 50 and 150 mg/day or as intravenous therapy in four patients at a dosage of approximately 0.1
therapy and between
solitary
class I drugs and
mg/kg. Patients were then tested 15 minutes after intravenous metoprolol or between 2 and 6 hours after oral therapy to allow for appropriate P-blocking effects asevidenced by heart rate. RESULTS
Each of the 19 patients who met the inclusion criteria was subjected to electrophysiologic testing with the combination of their most effective class I drug therapy and metoprolol. Eight patients were rendered noninducible (group l), whereas 11 remained persistently inducible (group 2). There was no significant difference between the groups with regard to age, sex, presenting rhythm, underlying heart disease, and left ventricular ejection fraction. Additionally, there were no differences in baseline electrophysiologic parameters including R-R interval, ventricular effective refractory period, or number of extrastimuli required to induce sustained ventricular tachycardia. There was a significant difference between groups with regard to the baseline induced ventricular tachycardia cycle length. Patients in group 1 had a significantly shorter induced cycle length (259 f 27 msec) than patients in group 2
Volume Number
124 3
Adjuvant
metoprolol
for
inducible
VT
633
4. Group 2 effective refractory periods. Ventricular effective refractory periodswere evaluated under three separateconditions in patients persistently inducible despite a combination of classI drugsand metoprolol therapy. Overall the only significant difference wasbetween baselineand combination therapy.
Fig.
(305 + 53 msec). When analyzed in a different way, no patient with a baseline induced ventricular tachycardia cycle length >300 msec was rendered noninducible with adjuvant metoprolol therapy (Fig. 1). On the other hand, if a patient had a baseline induced ventricular tachycardia cycle length 1300 msec, there was a 62% chance of successful therapy. For all patients sinus cycle length, ventricular effective refractory period, ventricular tachycardia cycle length, and the number of extrastimuli required to induce ventricular tachycardia were measured under three conditions: baseline, during the most effective class I drug therapy, and during combination class I drug and metoprolol therapy. There were no significant changes in sinus cycle length until the addition of metoprolol in both groups. The ventricular tachycardia cycle length was lengthened significantly with the addition of class I drug therapy as compared with the baseline value in both groups. In group 2 there was no significant prolongation of the ventric-
ular tachycardia cycle length with the addition of metoprolol to class I drug therapy. When all 19 patients were combined, there was a significant difference with regard to the inducibility of ventricular tachycardia (Fig. 2). When comparing combination
metoprolol and class I drug therapy with class I drug therapy alone, 68% of the patients were more diffi-
cult to induce. When comparing combination metopro101 and class I therapy with the baseline state, 84% of patients were more difficult to induce (p < 0.05). Eight of 19 patients (42%) became noninducible with the addition of metoprolol to class I drug therapy. The effect of adding metoprolol on the ventricular effective refractory period is illustrated in Figs. 3 and 4. Patients in group 1 required the addition of metopro101 to have a significant difference in the ventricular effective refractory period as compared with baseline or class I drug therapy. Patients in group 2 had differences only between baseline and combination therapy. Follow-up. Each patient in group I was discharged on a regimen of combination therapy. Only one patient was unable to tolerate combination therapy and metoprolol was discontinued. Within 1 year he had sudden cardiac death. None of the other patients in group 1 had recurrent tachyarrhythmia or sudden cardiac death. Six of the 11 patients in group 2 had
recurrent ventricular tachycardia had sudden cardiac death.
and one patient
634
Brodsky
et al.
DISCUSSION
In the current study adjuvant therapy with the P-blocker metoprolol had a number of significant electrophysiologic effects. The sinus cycle length was prolonged and the ventricular effective refractory period was lengthened significantly, proving that patients were affected by metoprolol. In addition, adjuvant metoprolol made ventricular tachycardia significantly more difficult to induce and rendered 42 7; of selected patients noninducible. This beneficial effect was predictable from baseline data obtained in a drug-free state. Patients with inducible ventricular tachycardia cycle lengths 1300 msec were more likely to benefit from adjuvant metoprolol therapy. This beneficial effect was corroborated during longterm follow-up. Mechanism. P-Blockers effectively control a variety of different ventricular arrhythmias including isolated ventricular premature depolarizations and ventricular tachyarrhythmias related to ischemia or alterations in adrenergic tone.8-10 Their efficacy in preventing inducible sustained monomorphic ventricular tachycardia has been reported to be limited.llB l2 Data from our laboratory support this claim, inasmuch as only 27% of patients with inducible sustained monomorphic ventricular tachycardia were rendered noninducible.13 Because of a low incidence of efficacy and general safety, we elected not to evaluate patients in this study with solitary P-blocker therapy (before initiating class I drug therapy). Some P-blockers possess membrane-stabilizing activity, but the plasma levels needed to produce an antiarrhythmic effect in humans are much lower than the drug concentration necessary to produce direct effects on cell membranes.14 The beneficial antiarrhythmic effects of these drugs are therefore related mostly to /?-adrenergic blockade.lj P-Blockers should reverse all of the detrimental effects of catecholamines. Catecholamines have no effect on resting membrane potential, rate of upstroke of the action potential, membrane responsiveness, or conduction velocity in normal cardiac fibers. In contrast, in abnormal fibers, catecholamines may act to increase the rate of rise of the phase 0 action potential amplitude, increase conduction velocity, and shorten the refractory period. These effects could create triggered activity and enhance the tendency toward reentrant arrhythmias.15 Furthermore, catecholamines could accelerate the rate of ventricular tachycardia. In this study patients with a more rapid rate of ventricular tachycardia were more responsive to adjuvant @blocker therapy. Class I drugs and ,&blockers may act in a synergistic fashion. P-Blockers may mitigate against the ad-
American
September 1992 Heart Journal
verse effects of catecholamine stimulation. Previous investigators have shown that catecholamine stimulation with either isoproterenol or epinephrine can reverse the protective effects of class I antiarrhythmic drugs. 16-i8 It is possible that the addition of P-blockers to class I drug therapy prevents elevated catecholamine levels from shortening the ventricular refractory period and increasing conduction velocity as would be expected in patients with diseased hearts. The effective combination of class I drugs and metoprolol suggests a possible synergism between membrane effects and P-receptor blockade. Combination therapy. Previous investigators have shown that P-blockers used in combination with class I drug therapy are effective in reducing ventricular arrhythmias. By use of 24-hour ambulatory ECG monitors and exercise tests to measure the frequency of arrhythmias, Hirsowitz et a1.4 found that adjuvant P-blocker therapy significantly decreased the incidence of ventricular tachycardia and couplets in a general population of 54 patients with clinical arrhythmias. In patients with left ventricular dysfunction and ventricular tachycardia, a 64 ?;, success rate was reported for combination class I drug and P-blocker therapy when evaluated with electrophysiologic monitoring, exercise testing, and invasive electrophysiologic study.6 Friehling et al.” used invasive testing to evaluate the role of propranolol as adjuvant therapy to class I drugs. Of 23 patients who remained inducible despite class I drug therapy, seven (30 %) became noninducible on a regimen of combination propranolol and class I drug therapy. The addition of propranolol to class I drug therapy significantly increased the ventricular effective refractory period. In addition, the combination therapy prolonged the cycle length of the ventricular tachycardia in the patients who were persistently inducible. In the present study we specifically analyzed the efficacy of metoprolol as adjuvant b-blocker therapy. There are several clinical advantages to using metopro101 instead of propranolol. Metoprolol is Pi-selective and has been shown to be well tolerated in patients with left ventricular dysfunction, a group of patients with a high potential for ventricular tachycardia.5* l7 Another benefit is that metoprolol has a longer half-life than propranolol. The current study is limited by the fact that this is a retrospective analysis. Furthermore, only a select population was evaluated. Of 95 patients initially considered, only 19 were eventual candidates for combination therapy. The results of this study confirm the beneficial effects of adjuvant metoprolol therapy in selected patients with ventricular tachycardia.
Volume Number
124 3
Adjuvant
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