CLINICAL TRIALS AND THERAPEUTICS Effect of indecainide in patients with left ventricular dysfunction Indecainide, a new antiarrhythmic agent classified as type Ic was evaluated in 11 patients with heart disease who had ventricular premature complexes /hour, moderate-to-marked left ventricular dysfunction, and mean ejection fraction 34% -± 8%. Patients received indecainide, 50 mg by mouth, every 6 hours and the dose was increased until - 80% suppression was noted, adverse effects occurred, or a maximum dose of 100 mg indecainide was given every 6 hours. Ventricular premature complexes were suppressed . _80% in nine patients < 0.05) and ventricular tachycardia episodes were completely suppressed in five of eight patients. The effective or maximal mean daily indecainide dose was 191 -± 32 mg; half of the responders achieved efficacy at serum drug concentration .600 ng/ml. Serum drug concentration was directly related to gender (r = 0.78, p < 0.04) and inversely related to creatinine clearance (r = 0.74, p < 0.05) and ejection fraction (r = 0.71, p < 0.02). Indecainide prolonged mean PR and QRS intervals (p < 0.05) but not QT or QTc. There was a linear relation between percent change in PR (r = 0.80, p < 0.001) and QRS (r = 0.66, p < 0.001) intervals and serum drug concentration. After starting or increasing the dose, careful observation of patients with decreased renal function or reduced ejection fraction should be exercised because they attain higher drug concentration than normal subjects. (CLIN PHARMACOL THER 1990;48:582-9.)
Elsa-Grace V. Giardina, MD, Alan L. Saroff, MD, and Miriam Schneider, AB New York, N.Y. Indecainide hydrochloride is a new antiarrhythmic agent approved by the U.S. Food and Drug Administration in 1989 against malignant ventricular arrhythmias." Its predominant electrophysiologic effects are attributed to class Ic effects' that is, to decrease the maximal rate of rise of phase 0 (VrnaJ and conduction velocity. In humans, indecainide prolongs the AH and HV intervals and increases intraventricular conduction time without significantly affecting atrial or ventricular refractoriness.' Indecainide undergoes minor hepatic metabolism with formation of a metabolite, desisopropylindecainide, accounting for less than 10% of a dose." Preliminary pharmacokinetic data indicate creatinine clearance and indecainide clearance are coneFrom the Department of Medicine, College of Physicians and Surgeons, Columbia University. Supported in part by grant RR-00645 from the Research Resources Administration, Bethesda, Md., grant HL-07406 from the Department of Health and Human Services, Bethesda, Md., and Eli Lilly Research Laboratories, Indianapolis, Ind. Received for publication April 20, 1990; accepted July 27, 1990. Reprint requests: Elsa-Grace V. Giardina, MD, Columbia University, 630 West 168 St., New York, NY 10032.
13/1/24191
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lated and renal impairment significantly increases indecainide concentration. '° For an antiarrhythmic agent such as indecainide, which does not undergo significant metabolism, the parent compound measured in the plasma can be useful in managing patients if a relation between drug concentration and effect exists. For example, prolongation of the coupling interval observed with procainamide" or quinidine-mexiletine and atrioventricular or intraventricular conduction delay with flecainide" are useful surrogates to estimate therapeutic myocardial drug concentrations. We theorized that if indecainide is the major active compound accounting for its cardiac effects, then measurement of serum indecainide might be helpful in clinical management. To test whether a relation exists between serum drug concentration and the effect of indecainide on ventricular premature complexes and the electrocardiogram (ECG), the serum drug concentration was monitored in patients with heart disease treated in a dose-ranging protocol.
METHODS Study design. The trial was approved by the Institutional Review Board of the Health Sciences Campus,
VOLUME 48 NUMBER 5
Indecainide in heart failure 583
Table I. Clinical characteristics of patients Patient No.
Age
1
71
2
40
3
59 66
4 5
6 7 8
9 10 11
Mean ± SD
Coronary artery disease* Cardiomyopathy Cardiomyopathy Cardiomyopathy Hypertensive* Cornary artery disease Primary electrical abnormality Coronary artery disease* Coronary artery disease Coronary artery disease Hypertensive, chronic obstructive pulmonary*
70 59 36 70 40 63 64
58±
Heart disease
Sex
13
Ejection fraction (%) 24 28 37 46
Creatinine (mg I dl)
Cretinine clearance
(ml/min/1.73
1.4
31
1.1
59 99 66 88 66
42 37 24 44
1.2 1.2 1.9
71 71 35
1.1
66
38 25
1.2 1.0
71 73
34 ± 8
1.2 ± 0.27
70 ± 16
0.9 1.1
1.0
m2)
M, Male; F, female. *Patient was receiving digoxin.
Columbia University (New York, N.Y.). Patients who were candidates for the study were from 21 to 75 years of age, were hemodynamically stable, and had at least 30 ventricular premature complexes per hour. Exclusion criteria included the following: (1) history of malignant ventricular arrhythmias, (2) second- or third-degree atrioventricular conduction block, unless protected by a pacemaker, (3) PR interval a0.24 second or QRS interval a0.12 second, (4) decompensated congestive heart failure, (5) systolic pressure _90 mm Hg, (6) heart rate 1s50 beats/ min, (7) myocardial infarction within 3 weeks of study, and (8) clinically significant renal or hepatic disease. Other antiarrhythmic drugs were discontinued 5 half-lives before entry into the -
study. During dose ranging, patients were hospitalized and a physical examination, complete blood count, blood chemistries, blood and urine for creatinine clearance, a standard ECG and two continuous 24-hour ECGs were performed within a 2-day drug-free period. Baseline frequency of ventricular premature complexes was computed as the mean of the frequencies measured on the two drug-free recordings. A prestudy left ventricular ejection fraction was obtained before the active drug was started, and it was determined by radionuclide angiography (10 patients) or cardiac catheterization (1 patient). Research medication was provided by Eli Lilly Research Laboratories (Indianapolis, Ind.). Doses started with indecainide, 50 mg by mouth, given every 6 hours and were increased by 100 mg /day every 3 days if there was :5-80% suppression of ventricular premature complexes,'4"5 if treatment was tolerated, or if
a maximum daily dose of 400 mg indecainide was given. After at least 4 days on a dose, two consecutive 24-hour ECGs were monitored to test for an antiarrhythmic effect. At that time, physical examination, laboratory tests, and two 12-lead ECGs were also obtained. Serum was obtained before the morning dose and 3 to 4 hours after a dose on days when the 12-lead and 24-hour ECGs were recorded to measure indecainide and its metabolite. The trough serum indecainide concentration was used for data analysis. Samples collected 3 to 4 hours after a dose were determined to ensure drug absorption and to verify a change compared to trough concentrations. Patients were monitored while they were receiving the effective dose and were seen as outpatients at 1, 2, and 4 weeks and every 8 weeks when a brief history, physical examination, ECG, and blood for laboratory tests and drug concentration were determined for each subject. Criteria for discontinuing drug administration were as follows: (1) aggravation of arrhythmia as described by the Cardiac Antiarrhythmic Pilot Study (CAPS) investigators;16 (2) prolongation of electrocardiographic intervals: PR 0.30 second, QRS a 0.16 second, or QTc a- 0.48 second; (3) drug intolerance; or (4) request of the patient. Electrocardiographic intervals. Electrocardiograms were obtained on each of the 2 days when the 24-hour ambulatory ECG was monitored, that is, two during the drug-free period and two after each dose. Electrocardiographic intervals (RR, PR, QRS, QT) were measured 3 to 4 hours after a dose at 50 mm/ second. One investigator, who was blinded to the treatment phase,
a
CLIN PHARMACOL THER NOVEMBER 1990
Giardina, Saroff, and Schneider
584
Table II. Effect of indecainide on arrhythmia Ventricular premature complexes
Patient No.
Indecainide (per hr)
Baseline (per hr) 159 32 82
1
2 3
Ventricular tachycardia Efficacy (%) 95 22 100
8
25 0
1496
641
9
6 7
202 60 1157 1024
8
119
9 10
60
4 0
147
10
11
468
2
85 96 88 97 100 93 99
4 5
49 119
Mean ± SD 319 ± 400 147 Median
157
Baseline (episodes)
± 446
Efficacy (%)
(ng I ml)
100 100
505 255* 665 350 720 545 400 875 520 520 885
100
567 ± 203 512
1
106
10,500
3
3
0
0
0
0 24 0 0 0 0 0
1
0
4
0
2 0 9 11
6
3
95
10
Indecainide concentration
Indecainide (episodes)
± 4
12
1,100 100 100 100
± 32 0
4
*Patient No. 2 was not at steady state.
Table III. Maximal change of PR and QRS intervals QRS interval
PR interval
Patient No. 1
2 3* 5
6 7 8
Indecainide
Change
(msec)
(%)
33
80 120
100 120
25
11
260 200
63 43
100 100
160 160 320 160 140 240
14 14
80 80 100 80 80 80
120 120 120 80 120 80 80 100
20 20 50 0 20 0 0 25
lndecainde
Change
(msec)
(msec)
(%)
180 180
240 200
160 140 140 140
200 140 140 160
9 10 11
Mean ± SD
Baseline (msec)
Baseline
158
± 22
178 ±
60 14
0 50
69t
30
±-
23
90
-± 14
104
-±
0
18t
16
±
16
*Patient No. 3 had an electronic pacemaker that precluded measurement of PR or QRS. tp < 0.05 compared with baseline.
measured at least five of each of the intervals and determined the average. The QT interval was corrected for heart rate (QTc) by use of Bazett's formula. Ambulatory electrocardiographic monitoring. Continuous ECGs were recorded with an Avionics 445 twochannel recorder (Avionics Biomedical Instrumentation, Irvine, Calif.), scanned by one investigator, and analyzed by Cardiodata Systems (Haddonfield, N.J.) by use of a complete computer-generated report. 'J8 Drug assay. Indecainide was measured by a modi-
fication of a liquid chromatographic method afer extraction by ethylacetate-hexane.8 Data analysis. Statistical analysis was determined by use of the BMDP software package, 1983 edition. '9 For paired comparisons a paired t test was used; the Wilcoxon signed-rank test was used to evaluate arrhythmia frequency before and after drug administration. Isolated ventricular premature complexes and complex features were analyzed after a log transformation of the data. The Pearson correlation coefficient was used to test a
VOLUME 48 NUMBER 5
linear relation between dependent and independent variables. A probability (p) value less than 0.05 was considered significant. Data are presented as mean values ± SD and median.
RESULTS Patient population. Eleven patients, six men and five women, ranging in age from 36 to 71 years (mean age, 58 ± 13 years) enrolled in the study (Table I). Five patients had coronary artery disease, three had cardiomyopathy, one had hypertensive heart disease, one had hypertensive and chronic obstructive pulmonary disease, and one had a primary electrical abnormality. The mean ejection fraction was 34% ± 8% (range, 24% to 46%). Left ventricular failure requiring treatment was present in six patients; after treatment nine of the 11 were classified as functional class I or II and two as class III or IV of the New York Heart Association. Six patients were taking one or more cardiac medications including digoxin (four), diuretic agents (three), vasodilators (three), afterload reducing agents (three), 0blocker (one), and aspirin (one). The mean creatinine clearance was 70 ± 16 ml/ min/1.73 m2 (range, 35 to 99 ml/min/1.73m2). Effect on arrhythmia. The baseline frequency of ventricular premature complexes averaged 319 -± 400 per hour (range, 32 to 1157; median, 147; Table II). Total ventricular premature complexes per hour after indecainide averaged 157 ± 446 per hour (range, 0 to 1496; median, 10; Table II). Nine of 11 patients had suppression compared with baseline (p < . 80% 0.05). There was no difference in suppression of ventricular premature complexes for patients with ejection fraction .40% compared with those who had an ejection fraction >40%; however, the groups were small. Episodes of nonsustained ventricular tachycardia at baseline were observed in eight patients (mean, 3 ± 4; range, 1 to 11; median, 4; Table II). Mean frequency of episodes of ventricular tachycardia after indecainide was 12 ± 32 (range, 0 to 106; median, 0). There was complete suppression of episodes of ventricular tachycardia for five of eight patients; one patient had no change; and two patients had episodes increase. Electrocardiographic intervals. Before receiving indecainide, the mean PR interval was 158 ± 22 msec (range, 140 to 200 msec) and increased to a maximum PR interval of 178 ± 69 msec (range, 140 to 320 msec; mean percentage change, 30% ± 23%; Table III). Indecainide increased the PR interval in nine of 10 patients with sinus rhythm (p < 0.05; Table III). In four patients the PR interval prolonged to more than 200 msec (mean, 265 ± 38 msec; range, 240 to 320 msec); _.
Indecainide in heart failure
585
100
tv,
80
0
ct. 60 a+
t
Cc a)
40
(-V
a" 20 I
300 400 500
I
800
1100
SERUM INDECAINIDE CONCENTRATION
(ng/ml) Fig. 1. Linear log concentration-response relation for patients taking indecainide who had 80% suppression of ventricular premature complexes. Concentration on the abscissa represents data collected on the first (_.-80% suppression) effective 24-hour ECG. Eight patients were taking 200 mg indecainide and 1 was taking 100 mg indecainide daily. From the curve, the serum concentration at which 50% respond approximates _
600 ng/ml.
in these patients the mean percentage change was 52% ±- 14%. Four patients were taking digoxin (Table I). In these four patients, the baseline PR interval was longer (170 ± 26 msec), than the baseline PR interval in those not taking digoxin (150 ± 17 msec, not significant). In addition, the percentage increase after indecainide was significantly longer (47% ± 11% versus 19% ± 22%, p < 0.05). These findings suggest that digoxin plus indecainide have more profound effects on the PR interval than indecainide alone; however, our study sample is small. No patient developed second- or
third-degree atrioventricular block. Before the patients received indecainide, the mean QRS interval was 90 ± 14 msec (range, 80 to 120 msec) and increased to a maximum QRS of 104 -± 18 msec (range, 80 to 120 msec, p < 0.05; mean percentage change, 16% ± 16%; Table III). Indecainide increased the QRS interval in six of 10 patients; one patient had an electronic pacemaker and did not have QRS duration determined. New intraventricular con120 msec) occurred in four paduction delay (QRS tients whose mean QRS interval increased to 120 ± 11 msec (mean percentage change, 28% ± 15%). The
586
CLIN PHARMACOL THER NOVEMBER 1990
Giardina, Saroff, and Schneider
160
0
M 14 0
140
0 120 20
r
=
0.80 a_
p< 0,001
cc
0 100
A
I
I
200
600
11 1000
1
00 1
1400
B
o
INDECAINIDE CONCENTRATION
200
600
1000
1400
(ng/ml)
Fig. 2. The relation between PR interval (percentage of control, A) and QRS interval (percentage of control, B) and trough serum indecainide concentration (in nanograms per milliliter) in 10 patients with sinus rhythm. Data were collected on each of the 2 days when the 12-lead ECGs were monitored. There is interindividual variability in rate of change of ECG intervals related to drug concentration: PR (p
Elsa-Grace V. Giardina, MD, Alan L. Saroff, MD, and Miriam Schneider, AB New York, N.Y. Indecainide hydrochloride is a new antiarrhythmic agent approved by the U.S. Food and Drug Administration in 1989 against malignant ventricular arrhythmias." Its predominant electrophysiologic effects are attributed to class Ic effects' that is, to decrease the maximal rate of rise of phase 0 (VrnaJ and conduction velocity. In humans, indecainide prolongs the AH and HV intervals and increases intraventricular conduction time without significantly affecting atrial or ventricular refractoriness.' Indecainide undergoes minor hepatic metabolism with formation of a metabolite, desisopropylindecainide, accounting for less than 10% of a dose." Preliminary pharmacokinetic data indicate creatinine clearance and indecainide clearance are coneFrom the Department of Medicine, College of Physicians and Surgeons, Columbia University. Supported in part by grant RR-00645 from the Research Resources Administration, Bethesda, Md., grant HL-07406 from the Department of Health and Human Services, Bethesda, Md., and Eli Lilly Research Laboratories, Indianapolis, Ind. Received for publication April 20, 1990; accepted July 27, 1990. Reprint requests: Elsa-Grace V. Giardina, MD, Columbia University, 630 West 168 St., New York, NY 10032.
13/1/24191
582
lated and renal impairment significantly increases indecainide concentration. '° For an antiarrhythmic agent such as indecainide, which does not undergo significant metabolism, the parent compound measured in the plasma can be useful in managing patients if a relation between drug concentration and effect exists. For example, prolongation of the coupling interval observed with procainamide" or quinidine-mexiletine and atrioventricular or intraventricular conduction delay with flecainide" are useful surrogates to estimate therapeutic myocardial drug concentrations. We theorized that if indecainide is the major active compound accounting for its cardiac effects, then measurement of serum indecainide might be helpful in clinical management. To test whether a relation exists between serum drug concentration and the effect of indecainide on ventricular premature complexes and the electrocardiogram (ECG), the serum drug concentration was monitored in patients with heart disease treated in a dose-ranging protocol.
METHODS Study design. The trial was approved by the Institutional Review Board of the Health Sciences Campus,
VOLUME 48 NUMBER 5
Indecainide in heart failure 583
Table I. Clinical characteristics of patients Patient No.
Age
1
71
2
40
3
59 66
4 5
6 7 8
9 10 11
Mean ± SD
Coronary artery disease* Cardiomyopathy Cardiomyopathy Cardiomyopathy Hypertensive* Cornary artery disease Primary electrical abnormality Coronary artery disease* Coronary artery disease Coronary artery disease Hypertensive, chronic obstructive pulmonary*
70 59 36 70 40 63 64
58±
Heart disease
Sex
13
Ejection fraction (%) 24 28 37 46
Creatinine (mg I dl)
Cretinine clearance
(ml/min/1.73
1.4
31
1.1
59 99 66 88 66
42 37 24 44
1.2 1.2 1.9
71 71 35
1.1
66
38 25
1.2 1.0
71 73
34 ± 8
1.2 ± 0.27
70 ± 16
0.9 1.1
1.0
m2)
M, Male; F, female. *Patient was receiving digoxin.
Columbia University (New York, N.Y.). Patients who were candidates for the study were from 21 to 75 years of age, were hemodynamically stable, and had at least 30 ventricular premature complexes per hour. Exclusion criteria included the following: (1) history of malignant ventricular arrhythmias, (2) second- or third-degree atrioventricular conduction block, unless protected by a pacemaker, (3) PR interval a0.24 second or QRS interval a0.12 second, (4) decompensated congestive heart failure, (5) systolic pressure _90 mm Hg, (6) heart rate 1s50 beats/ min, (7) myocardial infarction within 3 weeks of study, and (8) clinically significant renal or hepatic disease. Other antiarrhythmic drugs were discontinued 5 half-lives before entry into the -
study. During dose ranging, patients were hospitalized and a physical examination, complete blood count, blood chemistries, blood and urine for creatinine clearance, a standard ECG and two continuous 24-hour ECGs were performed within a 2-day drug-free period. Baseline frequency of ventricular premature complexes was computed as the mean of the frequencies measured on the two drug-free recordings. A prestudy left ventricular ejection fraction was obtained before the active drug was started, and it was determined by radionuclide angiography (10 patients) or cardiac catheterization (1 patient). Research medication was provided by Eli Lilly Research Laboratories (Indianapolis, Ind.). Doses started with indecainide, 50 mg by mouth, given every 6 hours and were increased by 100 mg /day every 3 days if there was :5-80% suppression of ventricular premature complexes,'4"5 if treatment was tolerated, or if
a maximum daily dose of 400 mg indecainide was given. After at least 4 days on a dose, two consecutive 24-hour ECGs were monitored to test for an antiarrhythmic effect. At that time, physical examination, laboratory tests, and two 12-lead ECGs were also obtained. Serum was obtained before the morning dose and 3 to 4 hours after a dose on days when the 12-lead and 24-hour ECGs were recorded to measure indecainide and its metabolite. The trough serum indecainide concentration was used for data analysis. Samples collected 3 to 4 hours after a dose were determined to ensure drug absorption and to verify a change compared to trough concentrations. Patients were monitored while they were receiving the effective dose and were seen as outpatients at 1, 2, and 4 weeks and every 8 weeks when a brief history, physical examination, ECG, and blood for laboratory tests and drug concentration were determined for each subject. Criteria for discontinuing drug administration were as follows: (1) aggravation of arrhythmia as described by the Cardiac Antiarrhythmic Pilot Study (CAPS) investigators;16 (2) prolongation of electrocardiographic intervals: PR 0.30 second, QRS a 0.16 second, or QTc a- 0.48 second; (3) drug intolerance; or (4) request of the patient. Electrocardiographic intervals. Electrocardiograms were obtained on each of the 2 days when the 24-hour ambulatory ECG was monitored, that is, two during the drug-free period and two after each dose. Electrocardiographic intervals (RR, PR, QRS, QT) were measured 3 to 4 hours after a dose at 50 mm/ second. One investigator, who was blinded to the treatment phase,
a
CLIN PHARMACOL THER NOVEMBER 1990
Giardina, Saroff, and Schneider
584
Table II. Effect of indecainide on arrhythmia Ventricular premature complexes
Patient No.
Indecainide (per hr)
Baseline (per hr) 159 32 82
1
2 3
Ventricular tachycardia Efficacy (%) 95 22 100
8
25 0
1496
641
9
6 7
202 60 1157 1024
8
119
9 10
60
4 0
147
10
11
468
2
85 96 88 97 100 93 99
4 5
49 119
Mean ± SD 319 ± 400 147 Median
157
Baseline (episodes)
± 446
Efficacy (%)
(ng I ml)
100 100
505 255* 665 350 720 545 400 875 520 520 885
100
567 ± 203 512
1
106
10,500
3
3
0
0
0
0 24 0 0 0 0 0
1
0
4
0
2 0 9 11
6
3
95
10
Indecainide concentration
Indecainide (episodes)
± 4
12
1,100 100 100 100
± 32 0
4
*Patient No. 2 was not at steady state.
Table III. Maximal change of PR and QRS intervals QRS interval
PR interval
Patient No. 1
2 3* 5
6 7 8
Indecainide
Change
(msec)
(%)
33
80 120
100 120
25
11
260 200
63 43
100 100
160 160 320 160 140 240
14 14
80 80 100 80 80 80
120 120 120 80 120 80 80 100
20 20 50 0 20 0 0 25
lndecainde
Change
(msec)
(msec)
(%)
180 180
240 200
160 140 140 140
200 140 140 160
9 10 11
Mean ± SD
Baseline (msec)
Baseline
158
± 22
178 ±
60 14
0 50
69t
30
±-
23
90
-± 14
104
-±
0
18t
16
±
16
*Patient No. 3 had an electronic pacemaker that precluded measurement of PR or QRS. tp < 0.05 compared with baseline.
measured at least five of each of the intervals and determined the average. The QT interval was corrected for heart rate (QTc) by use of Bazett's formula. Ambulatory electrocardiographic monitoring. Continuous ECGs were recorded with an Avionics 445 twochannel recorder (Avionics Biomedical Instrumentation, Irvine, Calif.), scanned by one investigator, and analyzed by Cardiodata Systems (Haddonfield, N.J.) by use of a complete computer-generated report. 'J8 Drug assay. Indecainide was measured by a modi-
fication of a liquid chromatographic method afer extraction by ethylacetate-hexane.8 Data analysis. Statistical analysis was determined by use of the BMDP software package, 1983 edition. '9 For paired comparisons a paired t test was used; the Wilcoxon signed-rank test was used to evaluate arrhythmia frequency before and after drug administration. Isolated ventricular premature complexes and complex features were analyzed after a log transformation of the data. The Pearson correlation coefficient was used to test a
VOLUME 48 NUMBER 5
linear relation between dependent and independent variables. A probability (p) value less than 0.05 was considered significant. Data are presented as mean values ± SD and median.
RESULTS Patient population. Eleven patients, six men and five women, ranging in age from 36 to 71 years (mean age, 58 ± 13 years) enrolled in the study (Table I). Five patients had coronary artery disease, three had cardiomyopathy, one had hypertensive heart disease, one had hypertensive and chronic obstructive pulmonary disease, and one had a primary electrical abnormality. The mean ejection fraction was 34% ± 8% (range, 24% to 46%). Left ventricular failure requiring treatment was present in six patients; after treatment nine of the 11 were classified as functional class I or II and two as class III or IV of the New York Heart Association. Six patients were taking one or more cardiac medications including digoxin (four), diuretic agents (three), vasodilators (three), afterload reducing agents (three), 0blocker (one), and aspirin (one). The mean creatinine clearance was 70 ± 16 ml/ min/1.73 m2 (range, 35 to 99 ml/min/1.73m2). Effect on arrhythmia. The baseline frequency of ventricular premature complexes averaged 319 -± 400 per hour (range, 32 to 1157; median, 147; Table II). Total ventricular premature complexes per hour after indecainide averaged 157 ± 446 per hour (range, 0 to 1496; median, 10; Table II). Nine of 11 patients had suppression compared with baseline (p < . 80% 0.05). There was no difference in suppression of ventricular premature complexes for patients with ejection fraction .40% compared with those who had an ejection fraction >40%; however, the groups were small. Episodes of nonsustained ventricular tachycardia at baseline were observed in eight patients (mean, 3 ± 4; range, 1 to 11; median, 4; Table II). Mean frequency of episodes of ventricular tachycardia after indecainide was 12 ± 32 (range, 0 to 106; median, 0). There was complete suppression of episodes of ventricular tachycardia for five of eight patients; one patient had no change; and two patients had episodes increase. Electrocardiographic intervals. Before receiving indecainide, the mean PR interval was 158 ± 22 msec (range, 140 to 200 msec) and increased to a maximum PR interval of 178 ± 69 msec (range, 140 to 320 msec; mean percentage change, 30% ± 23%; Table III). Indecainide increased the PR interval in nine of 10 patients with sinus rhythm (p < 0.05; Table III). In four patients the PR interval prolonged to more than 200 msec (mean, 265 ± 38 msec; range, 240 to 320 msec); _.
Indecainide in heart failure
585
100
tv,
80
0
ct. 60 a+
t
Cc a)
40
(-V
a" 20 I
300 400 500
I
800
1100
SERUM INDECAINIDE CONCENTRATION
(ng/ml) Fig. 1. Linear log concentration-response relation for patients taking indecainide who had 80% suppression of ventricular premature complexes. Concentration on the abscissa represents data collected on the first (_.-80% suppression) effective 24-hour ECG. Eight patients were taking 200 mg indecainide and 1 was taking 100 mg indecainide daily. From the curve, the serum concentration at which 50% respond approximates _
600 ng/ml.
in these patients the mean percentage change was 52% ±- 14%. Four patients were taking digoxin (Table I). In these four patients, the baseline PR interval was longer (170 ± 26 msec), than the baseline PR interval in those not taking digoxin (150 ± 17 msec, not significant). In addition, the percentage increase after indecainide was significantly longer (47% ± 11% versus 19% ± 22%, p < 0.05). These findings suggest that digoxin plus indecainide have more profound effects on the PR interval than indecainide alone; however, our study sample is small. No patient developed second- or
third-degree atrioventricular block. Before the patients received indecainide, the mean QRS interval was 90 ± 14 msec (range, 80 to 120 msec) and increased to a maximum QRS of 104 -± 18 msec (range, 80 to 120 msec, p < 0.05; mean percentage change, 16% ± 16%; Table III). Indecainide increased the QRS interval in six of 10 patients; one patient had an electronic pacemaker and did not have QRS duration determined. New intraventricular con120 msec) occurred in four paduction delay (QRS tients whose mean QRS interval increased to 120 ± 11 msec (mean percentage change, 28% ± 15%). The
586
CLIN PHARMACOL THER NOVEMBER 1990
Giardina, Saroff, and Schneider
160
0
M 14 0
140
0 120 20
r
=
0.80 a_
p< 0,001
cc
0 100
A
I
I
200
600
11 1000
1
00 1
1400
B
o
INDECAINIDE CONCENTRATION
200
600
1000
1400
(ng/ml)
Fig. 2. The relation between PR interval (percentage of control, A) and QRS interval (percentage of control, B) and trough serum indecainide concentration (in nanograms per milliliter) in 10 patients with sinus rhythm. Data were collected on each of the 2 days when the 12-lead ECGs were monitored. There is interindividual variability in rate of change of ECG intervals related to drug concentration: PR (p
