Effects of Enoximone on Exercise Tolerance in Patients with Mild to Moderate Heart Failure Haruki Itoh, MD, Koichi Taniguchi, MD, Mayumi Doi, MD, Akira Koike, MD, and Akira Sakuma, PhD
To evaluate the efficacy of enoximone on exercise tolerance in patients with mild to moderate heart failure, 33 patients underwent cardiopulmonary exercise tests before and 3 hours after placebo or after receiving 25 or 100 mg of enoximone administered randomly in a double-blind manner. The electrocardiogram was monitored and blood pressure measured every minute throughout cycle ergometer exercise testing with a ramp protocol in which the work rate increased 1 W every 6 seconds after a 4-minute 26-W warm-up. Minute ventilation, oxygen uptake ( j102), and carbon dioxide output were measured every 10 seconds in order to determine anaerobic threshokl (AT) and peak irOz. Five patients were excluded from evaluation before breaking the double-blind key because of insufficient data. Heart rate increased and systolic blood pressure decreased throughout the testing only in the group taking 100 mg (n = 10). Significant increases in AT (14.4 to 16.2 ml/min/kg) and peak irO2 (29.8 to 22.9 ml/min/kg) were observed in the group taking 100 mg. The increases in AT showed a dose response, namely +0.7% in the placebo (n = 9), +6.9% in the 25mg (n = 9) and 12.5% in the 199. mg group. The work rates at the AT point increased in the 25- and 199-mg groups. These results lndlcate that a single oral administration of enoximone improves exercise tolerance in patients with mild to moderate heart failure. (AmJCardiol1991;9&390-394)
From the Second Department of Internal Medicine, Tokyo Medical and Dental University, Bunkyo-Ku, Tokyo, Japan. This study was supported by a grant from Marion Merrell Dow K.K., Tokyo, Japan. Manuscript received October 15,199O; revised manuscript received and accepted March 28, 1991. Address for reprints: Haruki Itoh, MD, the Cardiovascular Institute, 7-3-10 Roppongi, Minato-Ku, Tokyo 106, Japan.
360
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
68
he acute effects of phosphodiesterase inhibitors such as enoximone, amrinone and milrinone on severe congestive heart failure are wellknown*-3 and include improvement of hemodynamics and exercise capacity.4 It is still unclear whether these drugs are beneficial for patients with milder heart failure. One of the main goals of treatment for chronic heart failure without severe congestion is to improve exercise capacity, with a consequent improvement in daily activity. There have been few well-controlled studies of the acute effects of enoximone on exercise capacity in patients with mild to moderate heart failure. We conducted this study to evaluate the acute effects of oral enoximone on exercise capacity by measuring anaerobic threshold (AT) in patients with mild to moderate heart failure.
T
METHODS Patients: Thirty-three patients (22 men and 11 women, mean age f standard deviation 61 f 8 years [range 48 to 751) with chronic heart failure were enrolled in the study. No patient had severe congestion on chest x-ray or physical examination. Thirty-one patients were in New York Heart Association functional class II and 2 were in class III. The underlying diseases were regurgitant valvular heart disease in 12 patients, ischemic heart disease in 12, hypertensive heart disease in 5, dilated cardiomyopathy in 2, and other diseases in 2. Patients with stenotic valvular heart disease, hypertrophic obstructive cardiomyopathy, possible episode of angina pectoris, severe arrhythmias and anemia were excluded. Protocol: The patients were randomly allocated in a double-blind manner into 3 treatment groups: placebo, and 25 and 100 mg of eno.ximone. Cardiopulmonary exercise tests were performed before and 3 hours after administering the drug. All vasodilators and inotropes were withdrawn at least 1 week before exercise testing with the exception of digitalis and diuretic drugs, which were given after the second exercise test on the test day. Method of exercise testing: We used the ramploading technique for the cardiopulmonary exercise test with an electromagnetically controlled cycle ergometer (Siemens-Elema 930B with ramp slope controller). The work rate was increased 1 W every 6 seconds from a 4minute 20-W, 60 rpm warming-up stage up to the AUGUST
1, 1991
ratio (R; VCOz /iTOl) were computed simultaneously and displayed with 90, on a monitor during measurement using personal computer (NEC PC-9801, Foxboro, Massachusetts) with software developed in our laboratory. Determination of anaerobic threshold: The AT point was determined visually by 4 experienced reviewers before opening the key code of randomization. The criteria used for determination of AT were5@ (1) The vE/vOz curve, which was either flat or decreasing, begins to rise as the ~E/~COZ curve remains constant or decreases. (2) Gas exchange ratio, which was flat or gently rising, changes to a steeper slope. To determine
point of patient exhaustion. The patient was monitored throughout by a 1Z-lead electrocardiogram (Stress Test System ML-8000, Fukuda Denshi, Tokyo, Japan), and cuff blood pressure was measured every minute (Stress Test Blood Pressure Monitor STPD-680F, CoUin Denshi, Aichi, Japan). At the same time, expired gas analysis was performed throughout the exercise using an Aerobics Processor 391 (Nihon De&i San-ei, Tokyo, Japan). The system was carefully calibrated before each study, and oxygen uptake (VOI), carbon dioxide output (VCO?) and minute ventilation (VE) were measured every 10 seconds. The ventilatory equivalent for O2 (qE/vO& CO2 (\iE/vCOz) and gas exchange TABLE
I Background
of Patients
and
Exercise
Parameters
Before
and
After
Therapy
AT
in Each
Group*
Peak Exercise
CO2
WR
Pt. No.
Age(yr) & Sex
Weight (kg)
Height (cm)
Causeof Diseases
NYHA
Pre
2 6 a 11 14 19 21 25 31 Mean *SD p Value
61F 64F 59F 57M 65M 63M 56M 62F 63F 61.1 23.1
49 51 53 58 65 62 57.5 45 49 55.1 16.8
151 148 148 158 161 164 165 140 151 154 28.5
ASR/MSR MS/AR IHD MR HHD tiR DCM MSR OMI
II II II II II Ill II II II
18.0 19.3 12.1 10.4 14.2 14.0 14.2 16.4 14.4 14.1 13.3 14.9 18.6 16.8 17.9 19.1 11.9 10.7 15.0 15.1 k2.6 k3.2 p = 0.80
Post
GO2
Pre
Post
Pre
WR Post
Blood
Pre
Post
Concentration
Enoximone
MDL-19,438
Placebo 53 38 51 50 56 63 60 56 46 52.6 +7.5
51 40 50 63 65 68 60 65 41 55.9 k10.7 p = 0.14
21.6 26.5 20.0 17.6 21.7 20.4 27.8 26.9 31.2 26.9 18.4 17.7 26.7 23.0 24.8 21.0 14.8 14.0 23.0 21.6 25.1 24.6 p = 0.16
73 80 78 80 84 82 134 133 141 135 99 96 105 93 82 85 58 58 94.9 93.6 527.8 225.3 p = 0.49
0 0 0 0 0 0 0 0 0 0 -+O
13.6 19.7 20.6 25.9 20.3 22.6 19.0 19.7 19.5 20.1 53.2
53 60 98 96 82 84 110 112 127 123 80 79 88 90 77 76 123 129 93.1 94.3 ~23.8 a23 p = 0.34
32 32 32 24 26 48 112 82 35 47 z30
18 229 228 341 191 323 280 657 194 273 2172
102 125 108 123 80 86 106 138 90 53 101.1 224.9
155 541 478 133 168 278 87 207 210 366 262 &152
897 752 1,463 650 111 793 491 761 705 1,194 782 2366
0 0 0 0 0 0 0 0 0 0 t0
25mg 5 9 12 13 16 24 26 28 32 Mean ?SD p Value
59F 58M 63 F 66M 65M 75M 63M 63F 59M 63.4 25.2
42 65 46.5 52.5 73 51 56 51 66 55.9 210.1
144 165 144 165 159 147 166 147 171 156.4 k10.9
MSR OMI OMI AR OMI OMI MS/AR HHD MSR/AR
II II II II II II II II II
9.2 7.9 12.5 12.4 13.7 16.0 17.8 17.6 11.9 13.4 14.7 15.5 12.9 14.0 12.2 11.9 12.5 16.0 13.0 13.9 -+2.3 k2.9 p = 0.13
30 45 36 58 58 50 53 45 76 50.1 +13.5
38 56 48 70 63 46 58 41 81 55.7 +14.1 p = 0.027
11.9 22.8 24.3 24.2 21.6 21.5 18.2 19.8 23.7 20.9 23.9 p = 0.35
100mg 1 3 10 15 17 22 23 27 29 33 Mean -+SD p Value
64M 58M 64M 62M 48M 64F 61M 34M 54M 55F 56.4 29.5
65 60 67 74 50 54 58 65 61 47.5 60.2 +8.1
*There was no significant and after the drug, Student’s AR = aatiic regurgitation: heat disease; MR = mitral myocardial infarction; SD =
154 176 170 168 162 153 155 164 156 159 161.7 17.7
IHD IHD OMI HHD MR OMI HHD MS/AR OMI MSRiTR
II II II II II II II II II II
13.1 16.4 13.5 12.5 14.2 20.3 16.8 14.3 12.7 10.3 14.4 22.8
12.5 17.5 14.1 14.0 17.0 22.1 21.6 16.7 12.9 13.2 16.2 k3.5 p = 0.0058
60 65 60 61 43 60 55 65 56 40 56.5 +8.6
58 70 70 70 53 68 56 75 59 43 62.2 210.0 p = 0.0024
18.6 28.0 19.3 19.6 17.6 23.1 27.4 20.3 17.8 15.8 20.8 24.1 p =
19.5 26.7 19.6 22.3 25.4 24.4 27.4 24.1 21.4 17.7 22.9 +-3.3
0.029
106 123 112 132 91 87 94 127 102 61 103.5 ~21.5
p = 0.40
difference in the age and cardiothoracic ratio (U test), and the characteristics of the patients (chl-square test) amongthese 3 groups. To compare data before paired I test was used. Patients 4, 7! l&20 and 30 were excluded before opening the key code because of inwfhcient data or protocol violation. ASR = aortlc stenosis and regurgltabon; AT = anaerobic threshold: DCM = dilated cardiomyopathy; HHD = hypertensive heart disease: IHD = ischemic regurgitabon; MS = mitral stenosis; MSR = mitral stenosis and regurgitation; NYHA = New York Heart AssGclabon functional classification; OMI = old standard devlatian; TR = tricuspid regurgitation: VOz = oxygen uptake Iml/m~n.lkg!; WR = work (WI.
rate
EFFECTSOF
ENOXIMONEON
EXERCISETOLERANCE
361
\jO2 at AT point, measured regression line and the value taken as vO2 at AT value. the average 90~ of the last
vO2 was fitted to a linear corresponding to AT was Peak 90, was defined as 30 seconds of exercise. Blood concentration of the drug: The blood sample was obtained 3 hours after administration of the drug in order to measure enoximone and its active metabolite, MDL-19,438, concentration. Statistical analysis: Statistical analysis was performed using the Student paired t test to compare baseline and measurements after drug administration, the chi-square test to compare patient characteristics in each group, and the U test for patients’ background data. Statistical significance was at p
To evaluate the efficacy of enoximone on exercise tolerance in patients with mild to moderate heart failure, 33 patients underwent cardiopulmonary exercise tests before and 3 hours after placebo or after receiving 25 or 100 mg of enoximone administered randomly in a double-blind manner. The electrocardiogram was monitored and blood pressure measured every minute throughout cycle ergometer exercise testing with a ramp protocol in which the work rate increased 1 W every 6 seconds after a 4-minute 26-W warm-up. Minute ventilation, oxygen uptake ( j102), and carbon dioxide output were measured every 10 seconds in order to determine anaerobic threshokl (AT) and peak irOz. Five patients were excluded from evaluation before breaking the double-blind key because of insufficient data. Heart rate increased and systolic blood pressure decreased throughout the testing only in the group taking 100 mg (n = 10). Significant increases in AT (14.4 to 16.2 ml/min/kg) and peak irO2 (29.8 to 22.9 ml/min/kg) were observed in the group taking 100 mg. The increases in AT showed a dose response, namely +0.7% in the placebo (n = 9), +6.9% in the 25mg (n = 9) and 12.5% in the 199. mg group. The work rates at the AT point increased in the 25- and 199-mg groups. These results lndlcate that a single oral administration of enoximone improves exercise tolerance in patients with mild to moderate heart failure. (AmJCardiol1991;9&390-394)
From the Second Department of Internal Medicine, Tokyo Medical and Dental University, Bunkyo-Ku, Tokyo, Japan. This study was supported by a grant from Marion Merrell Dow K.K., Tokyo, Japan. Manuscript received October 15,199O; revised manuscript received and accepted March 28, 1991. Address for reprints: Haruki Itoh, MD, the Cardiovascular Institute, 7-3-10 Roppongi, Minato-Ku, Tokyo 106, Japan.
360
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
68
he acute effects of phosphodiesterase inhibitors such as enoximone, amrinone and milrinone on severe congestive heart failure are wellknown*-3 and include improvement of hemodynamics and exercise capacity.4 It is still unclear whether these drugs are beneficial for patients with milder heart failure. One of the main goals of treatment for chronic heart failure without severe congestion is to improve exercise capacity, with a consequent improvement in daily activity. There have been few well-controlled studies of the acute effects of enoximone on exercise capacity in patients with mild to moderate heart failure. We conducted this study to evaluate the acute effects of oral enoximone on exercise capacity by measuring anaerobic threshold (AT) in patients with mild to moderate heart failure.
T
METHODS Patients: Thirty-three patients (22 men and 11 women, mean age f standard deviation 61 f 8 years [range 48 to 751) with chronic heart failure were enrolled in the study. No patient had severe congestion on chest x-ray or physical examination. Thirty-one patients were in New York Heart Association functional class II and 2 were in class III. The underlying diseases were regurgitant valvular heart disease in 12 patients, ischemic heart disease in 12, hypertensive heart disease in 5, dilated cardiomyopathy in 2, and other diseases in 2. Patients with stenotic valvular heart disease, hypertrophic obstructive cardiomyopathy, possible episode of angina pectoris, severe arrhythmias and anemia were excluded. Protocol: The patients were randomly allocated in a double-blind manner into 3 treatment groups: placebo, and 25 and 100 mg of eno.ximone. Cardiopulmonary exercise tests were performed before and 3 hours after administering the drug. All vasodilators and inotropes were withdrawn at least 1 week before exercise testing with the exception of digitalis and diuretic drugs, which were given after the second exercise test on the test day. Method of exercise testing: We used the ramploading technique for the cardiopulmonary exercise test with an electromagnetically controlled cycle ergometer (Siemens-Elema 930B with ramp slope controller). The work rate was increased 1 W every 6 seconds from a 4minute 20-W, 60 rpm warming-up stage up to the AUGUST
1, 1991
ratio (R; VCOz /iTOl) were computed simultaneously and displayed with 90, on a monitor during measurement using personal computer (NEC PC-9801, Foxboro, Massachusetts) with software developed in our laboratory. Determination of anaerobic threshold: The AT point was determined visually by 4 experienced reviewers before opening the key code of randomization. The criteria used for determination of AT were5@ (1) The vE/vOz curve, which was either flat or decreasing, begins to rise as the ~E/~COZ curve remains constant or decreases. (2) Gas exchange ratio, which was flat or gently rising, changes to a steeper slope. To determine
point of patient exhaustion. The patient was monitored throughout by a 1Z-lead electrocardiogram (Stress Test System ML-8000, Fukuda Denshi, Tokyo, Japan), and cuff blood pressure was measured every minute (Stress Test Blood Pressure Monitor STPD-680F, CoUin Denshi, Aichi, Japan). At the same time, expired gas analysis was performed throughout the exercise using an Aerobics Processor 391 (Nihon De&i San-ei, Tokyo, Japan). The system was carefully calibrated before each study, and oxygen uptake (VOI), carbon dioxide output (VCO?) and minute ventilation (VE) were measured every 10 seconds. The ventilatory equivalent for O2 (qE/vO& CO2 (\iE/vCOz) and gas exchange TABLE
I Background
of Patients
and
Exercise
Parameters
Before
and
After
Therapy
AT
in Each
Group*
Peak Exercise
CO2
WR
Pt. No.
Age(yr) & Sex
Weight (kg)
Height (cm)
Causeof Diseases
NYHA
Pre
2 6 a 11 14 19 21 25 31 Mean *SD p Value
61F 64F 59F 57M 65M 63M 56M 62F 63F 61.1 23.1
49 51 53 58 65 62 57.5 45 49 55.1 16.8
151 148 148 158 161 164 165 140 151 154 28.5
ASR/MSR MS/AR IHD MR HHD tiR DCM MSR OMI
II II II II II Ill II II II
18.0 19.3 12.1 10.4 14.2 14.0 14.2 16.4 14.4 14.1 13.3 14.9 18.6 16.8 17.9 19.1 11.9 10.7 15.0 15.1 k2.6 k3.2 p = 0.80
Post
GO2
Pre
Post
Pre
WR Post
Blood
Pre
Post
Concentration
Enoximone
MDL-19,438
Placebo 53 38 51 50 56 63 60 56 46 52.6 +7.5
51 40 50 63 65 68 60 65 41 55.9 k10.7 p = 0.14
21.6 26.5 20.0 17.6 21.7 20.4 27.8 26.9 31.2 26.9 18.4 17.7 26.7 23.0 24.8 21.0 14.8 14.0 23.0 21.6 25.1 24.6 p = 0.16
73 80 78 80 84 82 134 133 141 135 99 96 105 93 82 85 58 58 94.9 93.6 527.8 225.3 p = 0.49
0 0 0 0 0 0 0 0 0 0 -+O
13.6 19.7 20.6 25.9 20.3 22.6 19.0 19.7 19.5 20.1 53.2
53 60 98 96 82 84 110 112 127 123 80 79 88 90 77 76 123 129 93.1 94.3 ~23.8 a23 p = 0.34
32 32 32 24 26 48 112 82 35 47 z30
18 229 228 341 191 323 280 657 194 273 2172
102 125 108 123 80 86 106 138 90 53 101.1 224.9
155 541 478 133 168 278 87 207 210 366 262 &152
897 752 1,463 650 111 793 491 761 705 1,194 782 2366
0 0 0 0 0 0 0 0 0 0 t0
25mg 5 9 12 13 16 24 26 28 32 Mean ?SD p Value
59F 58M 63 F 66M 65M 75M 63M 63F 59M 63.4 25.2
42 65 46.5 52.5 73 51 56 51 66 55.9 210.1
144 165 144 165 159 147 166 147 171 156.4 k10.9
MSR OMI OMI AR OMI OMI MS/AR HHD MSR/AR
II II II II II II II II II
9.2 7.9 12.5 12.4 13.7 16.0 17.8 17.6 11.9 13.4 14.7 15.5 12.9 14.0 12.2 11.9 12.5 16.0 13.0 13.9 -+2.3 k2.9 p = 0.13
30 45 36 58 58 50 53 45 76 50.1 +13.5
38 56 48 70 63 46 58 41 81 55.7 +14.1 p = 0.027
11.9 22.8 24.3 24.2 21.6 21.5 18.2 19.8 23.7 20.9 23.9 p = 0.35
100mg 1 3 10 15 17 22 23 27 29 33 Mean -+SD p Value
64M 58M 64M 62M 48M 64F 61M 34M 54M 55F 56.4 29.5
65 60 67 74 50 54 58 65 61 47.5 60.2 +8.1
*There was no significant and after the drug, Student’s AR = aatiic regurgitation: heat disease; MR = mitral myocardial infarction; SD =
154 176 170 168 162 153 155 164 156 159 161.7 17.7
IHD IHD OMI HHD MR OMI HHD MS/AR OMI MSRiTR
II II II II II II II II II II
13.1 16.4 13.5 12.5 14.2 20.3 16.8 14.3 12.7 10.3 14.4 22.8
12.5 17.5 14.1 14.0 17.0 22.1 21.6 16.7 12.9 13.2 16.2 k3.5 p = 0.0058
60 65 60 61 43 60 55 65 56 40 56.5 +8.6
58 70 70 70 53 68 56 75 59 43 62.2 210.0 p = 0.0024
18.6 28.0 19.3 19.6 17.6 23.1 27.4 20.3 17.8 15.8 20.8 24.1 p =
19.5 26.7 19.6 22.3 25.4 24.4 27.4 24.1 21.4 17.7 22.9 +-3.3
0.029
106 123 112 132 91 87 94 127 102 61 103.5 ~21.5
p = 0.40
difference in the age and cardiothoracic ratio (U test), and the characteristics of the patients (chl-square test) amongthese 3 groups. To compare data before paired I test was used. Patients 4, 7! l&20 and 30 were excluded before opening the key code because of inwfhcient data or protocol violation. ASR = aortlc stenosis and regurgltabon; AT = anaerobic threshold: DCM = dilated cardiomyopathy; HHD = hypertensive heart disease: IHD = ischemic regurgitabon; MS = mitral stenosis; MSR = mitral stenosis and regurgitation; NYHA = New York Heart AssGclabon functional classification; OMI = old standard devlatian; TR = tricuspid regurgitation: VOz = oxygen uptake Iml/m~n.lkg!; WR = work (WI.
rate
EFFECTSOF
ENOXIMONEON
EXERCISETOLERANCE
361
\jO2 at AT point, measured regression line and the value taken as vO2 at AT value. the average 90~ of the last
vO2 was fitted to a linear corresponding to AT was Peak 90, was defined as 30 seconds of exercise. Blood concentration of the drug: The blood sample was obtained 3 hours after administration of the drug in order to measure enoximone and its active metabolite, MDL-19,438, concentration. Statistical analysis: Statistical analysis was performed using the Student paired t test to compare baseline and measurements after drug administration, the chi-square test to compare patient characteristics in each group, and the U test for patients’ background data. Statistical significance was at p
