The electrophysiologic effects of enoximone in patients with preexisting ventricular tachyarrhythmias

The electrophysiologic effects of enoximone patients with preexisting ventricular tachyarrhythmias

in

Electrophysiologic and hemodynamic effects of intravenous enoximone were studied in 15 male patients, mean age 62.2 years, with New York Heart Association classes II to IV congestive heart failure (coronary artery disease in 10 and idiopathic dilated cardiomyopathy in five patients; mean ejection fraction, 0.19). All patients had spontsneous ventricular tachyarrhythmias; eight had sustained ventricular tachycardia (VT), one had ventricular fibrillation, and six had nonsustained VT. Hemodynamic and electrophysloiogic parameters including VT induction were determined before and during an intravenous infusion of enoximone. The cardiac index increased (2.49 + 0.69 to 2.96 + 0.76), and the pulmonary capillary wedge pressure decreased (22.4 + 13.2 to 10.0 + 9.0) after enoximone par predefined protocol endpoints. There was a significant decrease in spontaneous sinus cycle length, corrected sinus nodal recovery time, AH interval during atrial pacing, shortest cycle length at which 1:l atrioventriculsr nodal conduction occurred, and refractory periods of the atrium, ventricle, and atrioventriculsr node. Enoximone did not alter the cycle length of induced VT, and there was no consistent change in the number of extrastimuli required for VT induction. A baselkre Pehour ECG recordlng was obtsined on 14 patients (while receiving a long-term antiarrhythmic dfUQ regimen, if needed) and repeated after 1 week and 1 month of oral enoximone therapy. There was no slgnificsnt increase in the number of premature ventricular complexes per hour or VT episodes per 24 hours after 1 week or 1 month of therapy with enoximone. However, if four patients who received smiodarone and may not yet have reached steady state were excluded from analysis, there was a significant increase in the frequency of premature ventricular complexes per hour 1 month after initiation of enoximone. We conclude that intravenous enoximone reduces pulmonary capillary wedge pressure and increases cardiac output in most patients. Intravenous enoximone in doses sufficient to have hemodynamic effects shortens atrisl, ventricular, and atrioventricuiar nodal refractoriness and decreases AV nodal conduction time but has no consistent effect on VT induction or VT cycle length. The frequency of spontaneous ventricular ectopy may Increase in some patients after oral enoximone, but its clinical significance is undefined. Enoximone may be administered cautiously to patients with congestive heart failure and preexisting ventricu~sr tachyarrhythmias. (AM HEART J 1969; 117: 112.)

William M. Miles, MD, James J. Heger, MD, Joseph D. Minardo, MD, Lawrence S. Klein, MD, Eric N. Prystowsky, MD, and Douglas P. Zipes, MD. Indianapolis, Ind.

Enoximone is a nonglycoside, noncatecholamine, imidazolone derivative that has positive inotropic and arteriolar vasodilating properties.‘-* Its mecha-

From the Krannert Institute of Cardiology, Indiana University School of Medicine, Administration Medical Center.

the Department of Medicine, and the Roudebush Veterans

Supported in part by the Herman C. Krannert Fund, by grants HL-06308 and HL-07182 from the National Heart, Lung, and Blood Institute of the National Institutes of Health, the Attorney General of Indiana Public Health Trust, the Roudebueh Veterans Administration Medical Center, and the Merrell-Dow Research Institute. Received

for publication

July

5, 1988;

accepted

Reprint requests: William M. Miles, MD, Krannert 1001 W. 10th St., Indianapolis, IN 46202.

112

Aug. 22, 1988. Institute

of Cardiology,

nism of action probably involves inhibition of cardiac phosphodiesterase. l, 5 Previous studies have demonstrated a short-term increase in cardiac output and a decrease in left ventricular filling pressures in patients with severe congestive heart failure after administration of enoximone.3v4,6-15 Improvement in cardiac status with long-term oral enoximone administration has been reported by many79 8*I1913,“-I8 but not allgr12 investigators. Patients with severe congestive heart failure commonly have ventricular tachyarrhythmias,1g-21 and the safety of enoximone and the inotrope-vasodilator bipyridine derivatives, amrinone= and milrinone,% in patients with ventricular tachycardia (VT) has not been established.

Volume Number

117 1

Therefore the purpose of this study was to determine the electrophysiologic effects of enoximone in patients with cardiac failure and preexisting ventricular tachyarrhythmias. METHODS

After written and oral informed consent was obtained, 15 patients underwent hemodynamic and electrophysiologic evaluation before and after intravenous enoximone; 14 of the 15 patients subsequently received oral enoximone. All patients had congestive heart failure with symptoms of New York Heart Association functional classesII through IV. Sustained or nonsustainedVT had occurred spontaneously in all patients. No patient who had a seriouscomplicating illness or in whom immediate survival was not expected was entered into the study. Arterial vasodilators and antiarrhythmic drug therapy was discontinued at least five half-lives before hemodynamiclelectrophysiologic study. However, patients who already received amiodaronecontinued their stable longterm doseat the time of electrophysiologic study sincethe elimination half-life of amiodaroneprecluded drug washout. Digitalis wasdiscontinued before study unless(1) the patient had chronic or paroxysmal atria1 fibrillation requiring digitalis for rate control (n = 6), or (2) the patient received digitoxin, the long half-life of which precluded complete elimination before study (n = 2). Electrophysiologic and hemodynamic study. Patients were brought to the laboratory in the nonsedated,postabsorptive state. After local lidocaine anesthesia,two or three 6F multipolar electrode catheters (USCI, C.R. Bard, Inc., Berkeley Heights, N.J.) were introduced into the femoral vein and positioned under fluoroscopic guidance in the high right atrium, right ventricle, and acrossthe tricuspid valve in the region of the His bundle. A 7F balloon-guided pulmonary artery catheter (American Edwards, Santa Ana, Calif.) was introduced via the femoral or right internal jugular vein and positioned in the pulmonary artery. Baselinethermodilution cardiac output (using the mean of three determinations after the initial one was discarded) and pulmonary arterial, pulmonary capillary wedge, and right atrial pressureswere determined. Brachial arterial pressurewas measuredwith an arm cuff. ECG leads I, II, III, and V, were displayed simultaneously with intracardiac electrograms (filtered at 30 to 500 Hz) and pressure waveforms on a multichannel recorder (Electronics for Medicine/Honeywell Inc., PPG Biomedical Systems, Pleasantville, N.Y., VR-16) and recorded using paper speedsof 50 to 150 mm/set. Bipolar pacing was performed with rectangular stimuli of 2 msec duration and twice late diastolic threshold using a custom built programmablestimulator (Krannert Electrical Engineering, Indianapolis, Ind.). Baseline electrophysiologic parameters were obtained before enoximone administration, and included spontaneouscycle length, AH interval during sinus rhythm and atrial pacing, and HV interval. The longest sinus nodal recovery time obtained after 30 secondsof atria1 pacing at cycle lengths 350 to 700 msec

Electrophysiology

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113

was corrected by subtracting the spontaneoussinuscycle length (corrected sinusnodal recovery time). The shortest atrial pacing cycle length maintaining 1:l atrioventricular (AV) nodal conduction was determined with atrial pacing at progressively shorter cycle lengths. Atrial, AV nodal, and ventricular effective and functional refractory periods were determined by standard extrastimulus techniquesz4 VT induction wasattempted from one right ventricular apical site by introducing one and two ventricular extrastimuli during sinus rhythm, followed by one, two, and three ventricular extrastimuli during pacing at cycle lengths of 600,500, and 400 msec.2s For both spontaneous or induced episodes,sustained VT was defined as that lasting at least 30 secondsor requiring termination before 30secondsbecauseof hemodynamiccompromise.Nonsustained VT was defined asthat of at least three premature ventricular complexesin a row but lessthan 30 secondsin duration. Intravenous enoximone. After baseline hemodynamic and electrophysiologic parameters were determined, intravenous enoximone was administered at a doseof 90 &kg/min.% Hemodynamic values were obtained every 10 minutes until (1) the cardiac output increasedby 3096, (2) the pulmonary capillary wedge pressuredecreasedby 5 mm Hg, (3) the systolic blood pressuredecreasedby 20%) or (4) 50 minutes of intravenous loading infusion had been given. Blood was drawn for determination of plasma concentration of enoximone and its sulfoxide metabolitez7 eachtime hemodynamicvalues were measured.When one of these hemodynamic endpoints was reached, a maintenance intravenous infusion of enoximone was established for 15 minutes per a nomogrambasedon weight and time to endpoint response.At the end of 15 minutes, hemodynamic measurementswere repeated and all electrophysiologic parameters were again determined. If an external countershockfor VT termination wasrequired at any time during the study, no further electrophysiologic data were obtained until at least 15 minutes had elapsed.28The ventricular pacing catheter was not moved between programmed ventricular stimulation performed at baseline and during enoximone.administration. Once electrophysiologic parameters were determined, final hemodynamic values were measured and the enoximone infusion was discontinued. Oral enoximone. After the electrophysiologic study, nine patients were given an antiarrhythmic drug regimen for long-term arrhythmia control; six patients received no antiarrhythmic drug therapy. When steady state for the antiarrhythmic drug had been achieved (or 1 week of 800 mg, twice daily, for amiodarone in four patients), a baseline quantitative 24-hour ECG recording was performed with a commercially available service (Cardio Data Systems,Haddonfield, N.J.). Oral enoximone,75 mg three times a day (50 mg three times a day in one patient) was then administered, and 24-hour ECG recording was repeated after 1 week. After 1 week the doseof enoximone was increasedin selectedpatients to 150 mg three times a day (depending on clinical symptoms of heart failure or drug tolerance), and a 24-hour ECG recording was re-

114

Miles et al.

Table

1. Patient population and hemodynamics

American

--~_---.___--_~--..-

January 1989 Heart Journal

~_.. -~ .~ -.-_--. ._ _ _ _. Induced arrhythmia

Pt. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Mean + SD

Age (YF)

Sex

Heart disease

62 58 67 52 70 51 50 69 63 68 66 73 52 61 71

M M M M M M M M M M M M M M M

CAD CAD CAD CAD CAD DCM DCM DCM DCM CAD CAD CAD CAD DCM CAD

NYHA class III III III IV IV II III IV II IV III III IV III IV

Ejection fraction

0.19 0.35 0.19 0.25 0.12 0.21 0.14 0.13 0.25 0.11 0.31 0.21 0.16 0.18 0.11 0.19 i- 0.07

Clinical arrhythmia VT-NS VT-S VT-S VT-NS VT-S VT-NS VT-S VT-S VT-NS VT-S VT-NS VF VT-S VT-NS VT-S

c VT-S VT-S VT-S VT-NS VT-NS 0 VT-NS VT-S VT-S VT-S VT-S VT-S VT-S 0 0

E VT-NS VT-S VT-S VT-S VT-S 0 VT-S VT-S VT-S VT-S VT-NS VT-NS VT-S 0 0

M, male; CAD, coronary artery disease; DCM, dilated cardiomyopathy; NYHA, New York Heart Association; VT-N& nonsustained ventricular tachycardia; VT-S, sustained ventricular tachycardia; VF, ventricular fibrillation; 0, no arrhythmia; C, control; E, intravenous enoximone; PCW, pulmonary capillary wedge pressure; BP, systemic blood pressure. *Receiving amiodarone at the time of intravenous enoximone electrophysiologic study.

peated at 1 month. One patient (No. 6) elected not to receive oral drug therapy after receiving intravenous enoximone at electrophysiologic study. Patients 2 and 5 died, and patient 7 discontinued the drug because of nausea before the l-month ECG recording; patient 15 refused the l-month ECG recording. Statistkal analysis. Data are expressed as mean +- 1 standard deviation. Electrophysiologic data before and after intravenous enoximone administration were compared with paired t tests if distribution wasnormal or with the Wilcoxon signed-rank test if distribution was not

normal. Ambulatory ECG data for premature ventricular complexes(PVCs) per hour and VT episodesper day were compared before and after oral enoximone by means of the Wilcoxon signed-rank test. The change in arterial

pressure before and after enoximone was correlated with

sustained VT had sustained VT induced at electrophysiologic study. Two patients fit New York Heart Association functional class II, seven patients were class III, and six patients were class IV. The functional class for the group was 3.3 -+ 0.7. The radio-

nuclide ejection fraction was 0.19 ? 0.07 (range, 0.11 to 0.35). Eight patients received digitalis, and four patients received long-term amiodarone therapy at the time of electrophysiologic testing. Intravenous enoximone: Hemodynamic effects (Table I). The mean cardiac index increased 19% (2.49 to 2.96 L/min/m2), mean pulmonary capillary wedge pressure decreased 55% (22.4 to 10.0 mm Hg), and the mean blood pressure decreased 9% (96.7 to 68.4 mm Hg) during the administration of enoximone. Statistical tests were not performed on hemodynamic data since these were used as endpoints for drug

changesin all electrophysiologicparametersby meansof a Spearman rank correlation. A p value of X0.05 was consideredsignificant.

administration.

RESULTS

loading infusion of enoximone was the cardiac output or pulmonary capillary wedge pressure criterion

Patient popuiation (Table I). All 15 patients were men with a mean age of 62.2 years (range, 50 to 71 years). Ten patients had coronary artery disease and five patients had an idiopathic dilated cardiomyopathy. Eight patients had sustained VT as the spontaneous clinical arrhythmia, one patient had ventricular fibrillation, and six patients had nonsustamed VT (one of whom had sustained VT while receiving tocainide). Four of the patients with non-

The end point for the intravenous

in 13 of the 15 patients. The mean increase in

cardiac index was less than the criterion

of 30%

because some patients met other endpoint criteria

before increasing the cardiac index by 30 % . A blood pressure decrease or heart rate increase was the endpoint in two patients, one of whom (patient 9) initially had a low pulmonary capillary wedge pressure. In the other (patient 10) who had a low cardiac index at baseline and high filling pressure, the drug

Volume Number

117 1

Electrophysiology

PCW (mm f&9

Cardiac index (Lfminfmz) E

C

E

1.56

2.31 3.19 2.40 2.89 2.86 4.45 2.82 2.08 3.29 1.52 4.26 2.79 3.87 2.78 2.85 2.96 f 0.78

30 22 12 39 10 20 28 7 2 20 16 22 19 52 37 22.4 + 13.2

5 18 1 8 4 3 25 0 0 20 4 9 13 13 27 10.0 * 9.0

had no measurable hemodynamic effect. The mean infusion time required to reach one of the endpoints was 19.3 minutes (range, 10 to 50 minutes), and nine of the 15 patients reached the endpoint at the first lo-minute determination of hemodynamic values. The mean maintenance dose was 7.6 rg/kg/min with, a range of 4.5 to 14.8. The mean enoximone plasma level after 15 minutes of maintenance infusion was 1235 -+ 647 rig/ml (range, 377 to 2371), and the mean enoximone sulfoxide metabolite level was 1474 k 777 rig/ml (range, 680 to 2933). No patient experienced any adverse effects from the intravenous enoximone. Intravenous

enoximone:

Electrophysiologic

enoximone

115

Mean BP (mm W

c 1.92 2.33 2.33 2.04 4.93 1.99 1.62 3.16 1.85 3.29 3.48 2.14 2.53 2.13 2.49 + 0.89

of

effects.

Fig. 1 illustrates the effects of enoximone on spontaneous sinus cycle length and corrected sinus nodal recovery time. Spontaneous cycle length decreased significantly from 752 f 174 to 691 -+ 153 msec after enoximone. The mean corrected sinus nodal recovery time decreased from 480 + 655 to 285 rfi 159 msec after enoximone. Only one value was abnormal and decreased from 2530 to 700 msec after enoximone. Fig. 2 illustrates the effects of enoximone on the AH and HV intervals. To normalize the AH interval for the change in spontaneous cycle length, AH intervals were compared for each patient at the same atrial pacing cycle length both before and after enoximone (mean, 577 + 81 msec). AH intervals could not be measured in two patients with atrial fibrillation, and an HV interval was not obtained in one patient with complete infra-His block who was

c 97 91 86 108 87 95 92 92 77 76 96 110 91 138 114 96.7 k 15.7

E 81 90 76 107 77 71 83 86 67 64 94 95 97 122 116 88.4 f 17.1

Chronic therapy None Procainamide Amiodarone* Amiodarone* Amiodarone* None Amiodarone* quinidine Amiodarone None Amiodarone None Amiodarone Amiodarone None None

pacemaker dependent. There was no change in the AH or HV interval recorded during spontaneous sinus rhythm after enoximone (including four patients with abnormally prolonged HV intervals of 60 to 80 msec), but the AH interval during a constant atrial pacing cycle length decreased significantly from 129 f 39 to 113 + 44 msec. Thus the lack of change in the AH interval during sinus rhythm after enoximone was most likely because of the concurrent decrease in spontaneous sinus cycle length. In two patients with acceleration-dependent right bundle-branch block, enoximone eliminated the bundle-branch block in one and shortened the atrial pacing cycle length required to obtain bundlebranch block from 830 to 690 msec in the other. Fig. 3 illustrates the electrophysiologic effects of enoximone on atria1 and AV nodal properties. AV nodal refractory periods were not obtained in six patients because the atrial functional refractory period exceeded the AV nodal effective refractory period. The decrease in atrial effective refractory period from 275 + 55 to 257 f 67 msec after enoximone was not statistically significant. However, the decrease in atrial functional refractory period from 320 + 59 to 296 + 73 msec was significant. The shortest atrial pacing cycle length maintaining 1:l AV nodal conduction shortened significantly from 461 + 123 to 427 * 127 msec, as did the AV nodal effective refractory period (421 + 96 to 357 + 104 msec) and the AV nodal functional refractory period (489 +- 100 to 439 f 108 msec). Fig. 4 illustrates the effects of enoximone on

116

Miles

et al.

American

7-

*

* ?-

la q* pco.05 control

El

control

p-J

enoximone

,T$z enoximone . .._...

**

January 1989 Heart Journal

*

p-zo.05

p-Co.001

“>

E

75 50 n AH

paced n=l3

n =13

n=15

n=12

Fig. 1. Spontaneous cycle length (SCL) and corrected sinus nodal recovery time (CSNRT) are illustrated at control (hatched bars) and during intravenous enoximone infusion (stippled bars). For this and subsequentfigures the mean and 1 standard deviation are plotted.

electrophysiologic parameters obtained from the ventricle. There was a small but significant shortening of both effective (242 + 29 to 232 + 28 msec) and functional (269 r 34 to 262 + 38 msec) ventricular refractory periods after enoximone. Atrial, AV nodal, and ventricular effective refractory periods were compared in each patient at a pacing cycle length between 400 and 700 msec that was obtained both before and after enoximone administration. For the atria, that cycle length was 579 + 66 msec; for the AV node, 571 + 107 msec; and for the ventricle 480 + 41 msec. There was no correlation between the degree of blood pressure decrease induced by enoximone in each patient and the degree of shortening of atrial, ventricular, or AV nodal refractoriness or AV nodal conduction time. Intravenous enoximone: Arrhythmia Induction. In the eight patients who had VT of comparable morphology and at least 10 complexes in duration induced before and after enoximone, there was no difference in VT cycle length (240 ~fi 62 vs 241 f 60 msec) (Fig. 4). The VT cycle length did not change by more than 10 msec after enoximone administration in any patient, and enoximone had no effect on hemodynamic stability of the induced VT. Fig. 5 illustrates methods required for VT induction at control study and after intravenous enoximone. Three patients had no inducible VT before or after enoximone administration. Three patients with nonsustained

AH

HV n=14

Fig. 2. AH interval during sinusrhythm (AH), AH interval during atrial pacing (paced AH), and the HV interval are illustrated at control and during intravenous enoximone infusion.

VT induced at control study had sustained VT induced after enoximone, all three with three ventricular extrastimuli. Three patients with sustained VT at control had only nonsustained VT induced after enoximone. One patient with sustained VT induced with three ventricular extrastimuli at control had sustained VT induced with two extrastimuli after enoximone. The remaining five patients had sustained VT induced with the same induction technique before and after enoximone. In all, enoximone made no consistent change in VT induction. Oral enoximone:

Follow-up

ambulatofy

ECG recqrd-

(Table II). Quantitative 24-hour ambulatory ECG recording was performed before enoximone therapy (but during antiarrhythmic drug therapy, if any, Table I) and 1 week and 1 month after initiation of enoximone therapy. The mean dose of enoximone at 1 week was 220 mg/day (75 mg three times a day in 13 patients and 50 mg three times a day in one patient) and the mean dose at 1 month was 315 mg/day (75 mg three times a day in seven patients and 150 mg three times a day in three patients). One patient elected not to receive oral therapy after undergoing the intravenous portion of this study. Two patients died between the 1 week and 1 month study (one suddenly), and two patients discontinued the drug between the 1 week and 1 month study because of side effects. When all patients were included, there was no significant increase in the number of PVCs ‘per hour or VT episodes per 24 hours between the baseliie and 1 week or 1 month studies (Table II). However, when the four patients ing

Volume Number

117 1

Electrophysiology

@I 1

of

enoximone

117

control

6oo

f!J

enoximone

*

**

** T

p-zo.05

**

1T

pco.02

500

T

I

T

i

Atrial

ERP

Atrial

n=12

FRP

n-12

AVN 1:l conduction

AVN ERP

n=13

AVN FRP

n=7

n=7

Fig. 3. Atrial effective (ERP) and functional (FRP) refractory periods, the shortest atrial pacing cycle length maintaining 1: 1 AV nodal (AVN) conduction, and AV nodal effective and functional refractory periods are illustrated at control and during intravenous enoximone infusion.

Ei

control

/Tgj enoximone

0

V-ERP

* **

V-FRP

pco.05 P~O.001

VT cycle length

n =15

n=15

n=a

4. Ventricular effective (V-ERP) and functional (V-FRP) refractory periods and cycle length of induced VT are displayed at control and after intravenous enoximone infusion.

Fig.

who had received amiodarone for only 1 week (and therefore possibly not at steady state) at the time of baseline 24-hour ECG recording were excluded from analysis, the number of PVCs per hour (but not VT episodes) increased significantly from baseline to 1 month of oral enoximone therapy (median, 31.3 to 140.4 PVCsh Fig. 6). No patient had sustained VT documented while receiving enoximone. When evaluated individually after 1 month of oral

enoximone therapy, five of the 10 patients (Nos. 3,4, 12, 13, and 14) had a fourfold increase in PVC frequency compared with baseline 24-hour ECG recording; however, because of the relatively low PVC frequency at baseline recording (four of the five patients received amiodarone), only patients 4 and 14 met criteria for proarrhythmia. Patient 10, in whom amiodarone had recently been initiated, was the only patient with more than a fourfold

January

118

Miles

et al

American

Heart

1999 Journal

1000

v2v3

100

. VT-S 0 VT-NS 5 2 ;j

IO

ii

No VT

X7 :: control

x enoximone

1.0

Fig. 5. VT induction data are displayed at control (left) and during enoximone infusion (right) for each of the 15 patients. Filled circles represent sustained VT (VT-S) and unfilled circles nonsustainedVT (VT-NS). Ventricu-

lar tachycardia was induced after a ventricular-paced drive train with either one (V,), two (V,VJ, or three (V,V,V,) ventricular extrastimuli. X indicates that no VT was induced. Table

Median

Range

N

PVCs/hr Baseline One week One month VT episodes/24 hr Baseline 1 wk 1 mo

31.3

0.22-425

73.9

0.09-323 1.01-499

24.8

:“,I

10

I baseline

I 1 week

enoxinome

p = 0.028

I 1 month enoxinome

Fig. 6. Number of PVCs per hour on a 24-hour ECG recording are plotted by meansof a logarithmic scale at baseline,1 week, and 1 month of oral enoximone therapy, excluding the four patients who recently began amiodarone therapy. Filled circles represent individual patients, and unfilled circles the median PVC frequency at each determination. Mean enoximonedosewas220mglday at 1 week and 315 mg/day at 1 month.

II. Follow-up ambulatory ECG recording

ECG recoding

+

0.1

p=NS

I

monly have ventricular tachyarrhythmias,1g-21 which presumably are responsible for the high risk of o-34 10 II sudden death. Therefore we elected to examine the electrophysiologic properties of enoximone in patients with severe congestive heart failure and preexisting ventricular tachyarrhythmias, including reduction in PVC frequency. Patient two, who died sustained VT, because potential arrhythmia aggrasuddenly 2 weeks after the initiation of enoximone, vation by newer inotropic agents may be most had no VT recorded at baseline but had a 23 beat evident and clinically important in this subset of episode of nonsustained VT documented after 1 week of oral enoximone therapy. high-risk patients. Electrophysiologic effects of enoximone. Our findDISCUSSION ings that enoximone shortened spontaneous sinus cycle length, sinus nodal recovery time, atrial refracTherapy for patients with congestive heart failure toriness, AV nodal refractoriness, and AV nodal must relieve symptoms without shortening life conduction time are similar to the observations of expectancy, and ideally it should prolong survival. a However, their patients did not have Both short-term3s *, 6-15 and longer-term79 8,11*13,15-18 Pop et al. studies have demonstrated the efficacy of enoxicongestive heart failure or ventricular tachyarrhythmone in improving hemodynamic parameters and miss and did not represent the patient group to relieving symptoms of congestive heart failure. whom enoximone will be administered. In addition, we extended their observations to include shortenPatients with severe congestive heart failure com0 1 0

O-60

o-131

14 14

p=NS

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ing of ventricular refractory periods and lack of effects on induced VT. Even though an increase in PVC frequency is difficult to interpret in individual patients because of spontaneous variability, changes in PVC frequency demonstrated in a group of patients may be clinically relevant. When the four patients in whom amiodarone was recently begun were excluded from analysis, enoximone therapy was associated with a significant increase in PVC frequency at 1 month of treatment. The excluded amiodarone-treated patients received 1 week of amiodarone before the preenoximone baseline 24-hour ECG recording, and since drug accumulation and antiarrhythmic effects are not fully achieved until several weeks or longer,31r32 it seemed reasonable to exclude these patients from the analysis of PVC frequency. Other studies have not shown a significant increase in the frequency of spontaneous ventricular ectopy during enoximone therapy in small patient populations without serious underlying arrhythmias,*6-1* although in one study a tendency toward increased ectopy was evident. l8 Although enoximone appears safe in patients in this study, these patients had particular attention to VT control, and the effect on long-term survival is unknown. Large, long-term studies will be required to determine whether enoximone has a beneficial effect on long-term mortality or sudden death comparable with that of noninotrope vasodilators,33t34 or whether survival is adversely effected. Comparison with electrophysiologic properties of amrinone and milrinone. The electrophysiologic prop-

erties of amrinone35 and milrinone,36 two bipyridine derivatives with inotropic and vasodilating properties similar to enoximone, have been studied in patients with congestive heart failure. The patient population in these two studies was similar with respect to New York Heart Association functional class and mean ejection fraction to that of our study, and a 30% increase in cardiac output was obtained in both studies. However, patients with sustained ventricular tachyarrhythmias, those at highest risk of arrhythmia exacerbation, were excluded from both studies. Milrinone decreased AV nodal conduction time, although atrial, AV nodal, and ventricular refractoriness were unchanged. The number of patients who had electrically inducible VT decreased after milrinone administration but spontaneous frequency of VT episodes increased. Amrinone decreased the atria1 effective refractory period, the AV nodal functional refractory period, and AV nodal conduction time. The frequency of electrically inducible VT was unchanged. There was no change

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in the frequency of spontaneous PVCs or VT, but the frequency of ventricular couplets increased. Thus drugs similar to enoximone have been found to shorten atrial and AV nodal refractoriness and AV nodal conduction time but not as consistently as enoximone in our study or that of Pop et al.% Amrinone and milrinone did not shorten ventricular refractoriness as did enoximone in our study. A greater percentage of patients in our study had electrically inducible VT at baseline (probably because we required patients to have spontaneous VT for inclusion), but enoximone did not consistently alter the frequency or mode of VT induction. At least one measure of spontaneous ventricular arrhythmia frequency increased in each study; ventricular pairs with amrinoneZ5 VT with milrinone,36 and PVCs per hour in our study with enoximone. Thus there is a trend with all three drugs to higher arrhythmia frequency in these studies and others,37-3g although the relationship between increased PVC frequency and clinical events is unclear. Ludmer et a1.3g reported no increase in sudden cardiac death, even in a subgroup of patients who had an increase in complex ventricular arrhythmias during milrinone therapy. Mechanism of electrophysiologic effects. One could hypothesize that the mechanism responsible for decreased refractory periods and decreased AV nodal conduction time by enoximone may be related to baroreflex sympathetic activation from the decrease in arterial blood pressure. The degree of shortening of electrophysiologic parameters did not correlate with the degree of blood pressure decrease in the group as a whole, which suggests that reflex sympathetic stimulation did not account for the electrophysiologic changes in this study. However, because individual patients may differ in their degree of sympathetic response to a given decrease in blood pressure, the lack of overall correlation does not exclude the possibility that individual patients may have had some degree of reflex sympathetic stimulation. Other investigators have shown that plasma catecholamine levels did not increase after doses of enoximone sufficient to increase cardiac index by 28% to 67%.‘“*“.‘3*14 As with the phosphodiesterase inhibitors, @adrenergic agonists increase the intracellular concentration of cyclic adenosine monophosphate (AMP), a substance thought to mediate many of the pharmacologic actions of these agents.40 Therefore it is reasonable to assume that enoximone may have effects mediated by an increase in cyclic AMP on refractoriness, spontaneous cycle length, and AV nodal conduction time similar to those of isoproter-

January

120 Miles

et al.

eno1.41 Theophylline, another drug that increases cyclic AMP, likewise decreases sinus cycle length, sinus nodal recovery time, AV nodal refractoriness, and AV nodal conduction time.42 Limitations. Electrophysiologic results obtained during acute intravenous enoximone administration may not necessarily reflect long-term electrophysiologic effects from long-term oral enoximone administration. Induction of VT at electrophysiologic study determines the effect of a medication on the VT substrate but does not necessarily reflect whether the drug will prevent or exacerbate spontaneous ventricular tachyarrhythmias during clinical followup. In addition, the implications of small increases in the frequency of spontaneous ventricular ectopy with respect to the subsequent occurrence of sustained arrhythmias are unclear. Although concomitant antiarrhythmic drug administration complicated the oral enoximone protocol, the purpose of this study was to examine the effects of enoximone in patients with preexisting VT, many of whom require antiarrhythmic drugs in addition to therapy for congestive heart failure. From this study, one cannot totally exclude the possibilities that the changes in electrophysiologic parameters during intravenous enoximone are caused by increased catecholamine levels or improvement in hemodynamics (i.e., a decrease in myocardial stretch). Clinical implications. Enoximone should be used cautiously but appears to be safe in patients with severe congestive heart failure and preexisting sustained or nonsustained ventricular tachyarrhythmias, even if antiarrhythmic drug therapy is required. However, since the prevalence of spontaneous ventricular ectopy may increase in some patients, ECG monitoring should be obtained periodically during drug administration and follow-up. Enoximone should be administered carefully to patients with atria1 fibrillation, since it can decrease AV nodal conduction time and may increase the ventricular rate. Enoximone can be used safely in patients with intraventricular conduction delays and prolonged HV intervals.

American

3.

4.

5. 6.

7.

8.

9.

10.

11.

12. 13.

14.

15. 16.

We thank Naomi Fineberg, PhD, for help with the statistical analyses, and Sue Hennigar for secretarial assistance. REFERENCES

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