International Elsevier
CARD10
S33
Journal of Cardrologv. 28 (1990) S33-S43
01126
Placebo-controlled trial of oral enoximone in end-stage congestive heart failure refractory to optimal treatment 0. Dubourg,’
G. Delorme,’
A. Hardy,’
A. Beauchet,‘A.
Tarral’
and J.P. Bourdariasi
’ Department of Cardiologr: FacultP de M6decine Paris-Ouest, H6pital Ambroise Park. Boulogne, France; .’ Medical Research Unit. Merrell-Dow
France SA, Strashour&
France
Dubourg D, Delorme G, Hardy A, Beauchet A, Tarral A, Bourdarias JP. Placebo-controlled enoximone in end-stage congestive heart failure refractory to optimal treatment. Int J Cardiol l):S33-s43.
trial of oral 1990:28(Suppl
A double-blind, randomized, concurrent trial of enoximone vs placebo was undertaken to assess the efficacy and safety of enoximone, 100 mg t.d.s. added to optimal therapy in 30 patients (mean age, 66.4 f 14 years) with severe congestive heart failure. Before inclusion, all patients remained markedly symptomatic despite treatment with diuretics, digitalis, vasodilators and angiotensin converting enzyme inhibitors. Symptoms and quality of life were evaluated at inclusion, and at days 4 and 31; 24-hour electrocardiography and Doppler echocardiography were performed at inclusion and at day 31. Clinical and echocardiographic baseline characteristics were similar in the two groups. During the study, 10 patients dropped out: 3 in the enoximone group (1 death) and 7 in the placebo group (3 deaths). At day 4, symptoms were improved in 13 enoximone-treated patients and in 8 patients on placebo (P < 0.05). At day 31, symptoms were still improving in 10 of 12 patients on enoximone and in 6 of 8 patients on placebo (NS). No serious clinical side-effects were reported, and no statistically significant difference in the frequency of premature ventricular contractions between the two groups was apparent on Holter monitoring. Peak acceleration of ascending aortic blood flow at entry was 17 i- 6 m/second’ in the enoximone group and 18 f 5 m/second’ in the placebo group (NS). At day 31, the change in peak acceleration was + 20% in the enoximone group vs -6% in the placebo group (P < 0.05). Cardiac index increased by 18% in the enoximone group (from 2.17 f 0.7 litres/minute/m2 to 2.4 f 1.0 litres/minute/m2 (NS). This study demonstrated that oral enoximone improves functional class, quality of life and left ventricular function in patients with congestive heart failure refractory to optimal therapy and may be used as a pharmacological bridge to cardiac transplantation. Key words:
Enoximone;
Congestive
heart failure;
Aortic
Introduction Patients with severe heart failure have a limited response to digoxin, diuretics and vasodilators [ 11.
Correspondence to: Dr. 0. Dubourg, Department Cardiology, Hapital Ambroise Park, 9 avenue Charles Gaulle, 92100 Boulogne, France.
016?-5273/90/$03.50
0 1990 Elsevier Science
Publishers
of de
flow acceleration;
Pharmacological
bridge
Vasodilator therapy is now accepted in the treatment of congestive heart failure, but it may fail to control symptoms in the most severe cases [2]. In these patients, combinations of vasodilators and positive inotropic drugs might be of interest. Enoximone is a new phosphodiesterase inhibitor which has both vasodilator and positive inotropic activities [3].
B.V. (Biomedical
Division)
S34
Enoximone, administered either intravenously [4,5] or orally has undergone extensive clinical evaluation in both open [1,6-81 and controlled studies [2,9-121. Marked symptomatic and haemodynamic improvement suggests that enoximone may have a role in the short-term [1,6,7] and the long-term management of heart failure [7,12] though the latter appears more controversial. The present authors hypothesized that enoximone would improve the haemodynamic state, clinical course and quality of life of patients with severe heart failure refractory to maximal therapy. This study was designed to compare the effects of enoximone and placebo over a period of 4 weeks, in a randomized double-blind trial using non-invasive methods.
Patients and Methods In all, 30 patients (24 men, 6 women), ranging in age from 36 to 88 years (mean, 66.4 & 14 years) were selected for the study. Their NYHA functional class was a mean of 3.6 f 0.5. All of them had severe congestive heart failure for a mean duration of 42.9 months (range, 6-156 months), and remained markedly symptomatic despite frusemide, digitalis and vasodilators, which included angiotensin converting enzyme inhibitors (25 patients), nitrates (22 patients), and prazosin (12 patients). All the patients had received angiotensin converting enzyme inhibitors for a mean duration of 12 months (range, l-48 months), except for 5 in whom this therapy had to be withdrawn due to adverse effects. Twenty patients were in sinus rhythm and 10 had atria1 fibrillation controlled by digitalis; 20 patients were given amiodarone for documented ventricular arrhythmias. Congestive heart failure was secondary to ischaemic heart disease (16 patients), dilated cardiomyopathy (10 patients) or valvular heart disease (4 patients). One patient had chronic mitral incompetence, and 2 had aortic incompetence. In the remaining patient, who had undergone aortic and mitral valve replacements several years before, heart failure was due to poor left ventricular function.
TABLE
1
Demographic tion.
and clinical
characteristics
Age (years) Sex Duration of symptoms (months) NYHA functional class Aetiology Ischaemic heart disease Dilated cardiomyopathy Valvular heart disease
of the study
popula-
Placebo (n =15)
Enoximone (n =15)
64+_16 12M/3F 32+24 III : 5 IV:10
69ill 12M/3F 53.5 +45 III : I IV:8
9 4 2
I 6 2
The demographic and clinical characteristics of the study population are presented in Table 1. Exclusion criteria were the presence of restrictive or hypertrophic cardiomyopathy, stenotic valvular disease, uncontrolled ventricular dysrhythmias, myocardial infarction within 3 months, major disease of any other organ system (chronic pulmonary, hepatic, haematological or neurological disease) and renal insufficiency (serum creatinine > 300 pmol/litre). Patients gave informed consent and the study protocol was approved by the hospital ethics committee.
Study protocol During the initial in-patient period, baseline investigations consisted of a full clinical examination with evaluation of quality of life, using a questionnaire consisting of three sets of five questions each (total score of 15). Resting 12-lead electrocardiography, 24-hour Holter monitoring, chest radiography, and a complete Doppler echocardiographic study were performed. The patients underwent serial laboratory examinations, including electrolytes, liver and renal function tests, and haematological profile with platelet count. After the control period, patients entered the treatment period and were randomly assigned to receive either enoximone, 100 mg t.d.s. or placebo, 1 capsule t.d.s. for 4 weeks, in addition to their initial treatment which remained unchanged during the study. At day 4, when discharged from
s35
hospital, all patients underwent another clinical examination, evaluation of NYHA functional class and quality of life, as well as laboratory screening. At this time, if the clinical condition of a patient had deteriorated or had not improved, the patient was withdrawn from the study. Thereafter, patients enrolled in the placebo group were given enoximone, 100 mg t.d.s. In those assigned to the active drug, the enoximone dose was increased to 150 mg t.d.s. Patients were readmitted after 4 weeks for further clinical, biological, radiological and echocardiographic assessment. A second 24hour Holter monitoring was performed at this time. Ventricular arrhythmias were classified according to Myerburg et al. [13]. At the end of the 4-week study period, all patients were put on or maintained on enoximone, whether or not they were initially assigned to placebo or enoximone.
Left ventricular and right ventricular areas were computed from the tracing of the end-systolic and end-diastolic endocardial surface of five consecutive cardiac cycles using a personal computer interfaced with a digitizing tablet and custom-developed software. Right ventricular fractional area contraction was computed as: RVDA
-
RVSA x lOO/RVDA
where RVDA is the right ventricular diastolic area, RVSA the right ventricular systolic area. Left ventricular end-diastolic and end-systolic volumes were calculated using the area-length method [19]. Finally, right and left atria1 areas were measured on the view displaying end systole of each ventricle. Doppler studies
Echocardiographic
and Doppler studies
Using standard techniques, ultrasonic studies were performed with a commercially available sector scanner (Diasonics CV 400) interfaced with a mechanical transducer (3.5 MHz) for two-dimensional and M-mode echocardiography and with a Pedoff transducer (Vingmed 2.25 MHz) for Doppler echocardiography. All studies were recorded on videotape for subsequent real-time playback analysis. Measurements on M-mode echocardiographs were performed as recommended by the American Society of Echocardiography [14]. Left ventricular mass was calculated according to the Penn convention measurements by the formula of Devereux [15] and normalized for body surface area. End-diastolic and end-systolic volumes were derived from end-diastolic and end-systolic dimensions according to the cubic model of Teichholz et al. [16]. Mean velocity of circumferential fibre shortening was calculated according to the usual formula [17]. Left ventricular ejection time was measured on the Doppler transaortic velocity recording. Left ventricular diastolic thickness-toradius ratio was computed as reported by Mathews et al. [18]. Finally, the aortic annulus surface area was measured in each patient from the parasternal two-dimensional view.
After a complete pulsed Doppler echocardiographic study, a continuous wave Doppler recording was obtained according to the method of Chan et al. [20] in order to measure the right ventricular systolic pressure. Aortic flow velocity was recorded from the apical view and aortic acceleration was calculated from the maximal spectral envelope. The transducer was applied on the apical window and the ultrasonic beam was oriented parallel to the aortic flow and guided by audiographic signals to obtain maximum Doppler shift. with velocity envelopes having distinct borders. The spectral output was recorded on a video-strip chart recorder at the speed of 50 mm/second. Peak velocity, time to peak velocity. mean acceleration (peak velocity/time to peak velocity) and velocity-time integral were measured on 20 consecutive beats and averaged by two independent observers. Beats with a poor signal-to-noise ratio. as well as extrasystolic and post-extrasystolic beats, were rejected. The analogue signal of the maximal envelope was recorded on a video-strip chart recorder and digitized with the computer. A personal program was used to measure peak flow acceleration on the aortic Doppler waveform. The aortic flow envelope was divided into time intervals of 1 ms (dt). For each time interval, the difference be-
S36
tween velocities at the beginning and the end of this interval (du) was measured and the acceleration (du/dt) was computed; this value was then averaged with the value of the previous and the following interval (moving average method). Stroke volume was calculated from the product of the velocity-time integral and the aortic annulus area. To determine whether values of peak acceleration were comparable with those reported in the literature, peak velocity and accleration were measured in 24 normal volunteers (16 men and 8 women ranging in age from 30 to 78 years, mean age, 52 * 15 years).
parametric data and small size samples. Contingency tables were examined with a &i-squared or Fisher exact test. Values are expressed as means f 1 standard deviation. Results At inclusion, all clinical characteristics (Tables 1 and 2) and echocardiographic measurements (Tables 3 and 4) were similar for the placebo and enoximone groups. In the enoximone group, patients received 1.5 + 0.19 mg/kg t.d.s. Enoximone did not significantly affect heart rate or blood pressure when compared to placebo. NYHA functional class was improved by at least one class in 13 patients after 4 days of treatment with enoximone (Fig. 1). A similar improvement was observed in 8 patients on placebo (Fig. 2). A total of 9 patients was withdrawn from the study at day 4: 2 patients in the enoximone group and 6 in the placebo group did not improve, and 1 patient on placebo died before the day 4 evaluation. After discharge, congestive heart failure relapsed in 2 patients from the enoximone group and in 4 pa-
Statistical analysis Differences among groups were examined using Student’s t-test and analysis of variance. When variances were different, the Mann-Whitney test, and the Welch approximation were used. Contingency tables were analysed with a &i-square or Fisher exact test. Differences between periods within a group were examined with Student’s t-test for paired data and the Wilcoxon test for non-
TABLE Evolution
2 of clinical
and cardiovascular Placebo
(mm Hg f SD) Diastolic blood pressure (mm Hg + SD) NYHA functional class (mean f SD) Distribution of NYHA functional class Quality of life score (x/15) *SD a P i 0.05 vs placebo;
in the placebo
and enoximone
Day 4 (n = 14)
89
*lO
84
116
+24
116
71
*11
71
13.7 + 0.5 0 II 5 III 10 IV
0.69 + 0.14
groups.
Enoximone
( n = 15)
Baseline (n = 15) Heart rate (beats/mm f SD) Systolic blood pressure
parameters
Week 4 (n=8)
82
+lO
83
*21
116
+22
113
*15
71
+18
74
+9
3.0 f 3 II 8 III 3 IV
0.7
0.46 + 0.15 ’
b P < 0.05 vs baseline;
(n = 15)
Baseline (n = 15)
kll
Week 4 (n = 12)
85
*16
89
+12
+25
113
*14
115
*12
*13
67
+lO
72
+8
2.75 &- 0.9 4 II 2 III 2 IV
3.5 * 0 II 7 III 8 IV
0.53 rt 0.23 b
0.64 + 0.17
’ P < 0.001 vs baseline.
Day 4 (n = 15)
0.5
2.4 &0.6 += 10 II 4 III 1 IV
2.33 + 0.65 ’ 9 II 2 III 1 IV
0.40 + 0.19 c
0.37 + 0.19 =
s31 TABLE
3
Echocardiographic
findings
at pretreatment
baseline
Normal adults (n=24) Aortic
and at 4 weeks of initial
therapy.
Baseline (means f SD)
4 weeks (means i SD)
Placebo (?I = 15)
Placebo (n = 8)
Enoximone (n = 15)
Enoximone (il=Zl)
annulus 20 51 31 39
(nun) LVIDd (mm) LVIDs (mm) FS (g) Vcf (circumferences/
1.5 126 66 48 0.43
second) LM mass (g/m2 ) LVEF (Teichholz) (%) RVFAS (‘%) t/r
20 68 58 14.5
+2 +5 +5 +6
*1 58 +8 * 5
0.6 219 27 28 0.31
+ 0.3 *20 +6 +I * 0.1
19 12 62 13.8
f 0.2 +71 + 0.9 511 + 0.6
0.6 232 26 24 0.30
+1 *9 rtl0 f 4
+ 0.2 *51 + 0.7 +lO f 0.05
19 68 58 15.1
0.6 237 29 30 0.34
19 il 70 i6 59 il 14.9 i 4
+7 i9 k8 f 5
0.7 221 29 27 0.31
i 0.2 * 71 i_ 0.1 *13 i 0.06
LVIDd = left ventricular internal diameter in diastole; LVIDs = left ventricular internal diameter in systole; shortening; Vcf = mean circumferential fibre shortening; LVEF = left ventricular ejection fraction; FSR = fractional RVFAS = right ventricular fractional area shortening; t/r = thickness to radius ratio.
tients from the placebo group; 2 patients in the placebo group died at home, and 1 in the enoximone group was excluded because of poor compliance with treatment. The quality of life score improved (Table 2) as did the NYHA classification (P < 0.001). At 4 weeks, there was still an improvement in the quality of life in both
TABLE Aortic
FS = fractional shortening rate;
groups, but this improvement was more marked and sustained in the enoximone group, while in the placebo group a downward trend was apparent. In the enoximone group, 3 patients experienced transient side-effects: nausea (1 patient), headache (1 patient), diarrhoea (1 patient). In the placebo
4 Doppler
findings
Ejection time (millisec) Peak velocity (m/=) Peak acceleration (m/sec2) Mean acceleration (m/sec2) Velocity-time integral (cm) Cardiac index (litres/min/m2) Data
* 0.2 +40 i 0.1 +ll f 0.04
are presented
at baseline
and at 4 weeks of initial
therapy.
Normal adults (n = 24)
Baseline Placebo (n = 15)
Enoximone (n = 15)
Placebo (n=8)
Enoximone (n = 12)
263
236
232
245
229
kO.01
1.2 + 0.2 35
*8
20
+7
23
F4
3.5 i 0.04
as means f SD;
Week 4
k30
1.1 f
0.3
18 f (n = 11 * (n = 16 * (n = 2.5 f (n =
5 14) 3 14) 4 14) 0.6 14)
+39
1.0 + 0.4 17
+6
11
*3
16
*6
2.17 f
a P < 0.05 vs placebo;
0.7
Percentage- change_
&39
1.2 * 17 f (n=7) 12 * (n=7) 15 * (n=7) 1.9 i (n=7)
0.5
f33
1.1 f
0.3
21
k
3
14
+ 4
5
17
f
b P < 0.01 vs baseline.
2.4*
Enoximone (n=12)
0
4
0.05
Placebo (n = 8)
6
7 1
0.15 -6 (n = 7) +4 (n = 7) -6 (n = 7) -17 (n=7)
0 +13 + 2,o a.h + 20 a.h +18 +I8
S38
Da; 31
Da; 4
D&O Fig. 1. Time course
of functional status patients.
in enoximone-treated
group, 1 patient had scleral bleeding due to anticoagulation and another experienced insomnia and therefore dropped out of the study. Laboratory findings No changes haematological
were seen in blood chemistry and variables throughout the study.
Holter monitoring There was no statistically significant difference in the frequency of premature ventricular contractions between the two groups. The mean frequency of premature ventricular contractions in the enoximone group was 86/hour (range, 0-300/hour) and in the placebo group, 26/hour (range, lThe premature ventricular contraction
I
.
Day 0
Fig.
2. Time
course
Day 31
Day 4 Placebo
treatment
of functional patients.
status
time in placebo-treated
forms were stable or tended to become less multiform in all but 3 of the patients who completed the study on day 31. In 2 patients of the enoximone group, the premature ventricular contraction form was modified, changing from uniform to multiform (1 patient) and from uniform to repetitive (1 patient). In one patient of the placebo group, the premature ventricular contraction form changed from uniform to repetitive. Ten patients did not complete the study: 3 were on enoximone, and 7 on placebo. In the enoximone group, 2 patients had moderate ventricular ectopic activity (class I and II, form A and B) and 1 patient had severe ventricular ectopic activity (class IV, form C) but dropped out of the study for poor compliance to treatment. Among these three patients withdrawn from the enoximone group, only one died from intractable heart failure (class II, form B). Among the 7 patients withdrawn from the placebo group, 2 patients had a qualitative (class A and B) and quantitative (class 0 and I) moderate ventricular ectopic activity: one dropped out for relapse of congestive heart failure and the other died at day 21. Five patients had severe ventricular activity both quantitatively (i.e. class III (n = 2) or class IV (n = 3)) and qualitatively (i.e. class B (n = 3), class C (n = 1) and class D (n = 1)); 2 of them died (class III B and class IV C). Ekhocardiographic
studies
In both groups, a slight but statistically nonsignificant decrease in left ventricular end-diastolic and end-systolic internal diameters was observed at week 4 (Table 3). Short-axis percentage fractional shortening, shortening rate and left ventricular ejection fraction slightly increased on enoximone, but this change did not reach statistical significance. Bight ventricular fractional area contraction showed a similar trend. In the placebo group, a patient with severe aortic regurgitation was excluded from Doppler analysis because of potential alteration in the flow of the ascending aorta. Ejection time remained unchanged in both groups. Peak velocity and velocity-time integral both increased on enoximone and did not change or decrease on
s39
30 F;
1
-20-1
I m
*
Placebo
p < 0.05 vs placebo
* * p < 0.01 vs baseline
Enoximone
Peak velocity
Cardiac index
Velocity-time integral Fig. 3. Doppler
echocardiographic
placebo. However, these changes did not reach statistical significance (Table 4). As shown in Fig. 3, peak aortic acceleration increased by 20% on enoximone and decreased by 6% on placebo (P < 0.01). Mean aortic flow acceleration also increased by 20% (P < 0.01) on enoximone and by 4% on placebo. Cardiac index increased by 18% in the enoximone group and this change was mainly mediated through an increase in stroke index (14%); cardiac index decreased by 17% in the placebo group, due to a decrease in stroke index (-12%).
Follow-up study After completion of this 4-week study, all survivors (25 patients) were given enoximone, loo-150 mg t.d.s. Five patients had a heart transplantation within 2-9 months, and 11 patients were still alive and receiving enoximone at 12 months. At that time, 4 of them were still on the waiting list. Thus, mortality in the patients who received enoximone for up to 12 months was 45%.
Discussion The purpose of this study was to determine whether the addition of enoximone, 100 mg t.d.s., could be of some benefit to patients with end-stage congestive heart failure refractory to optimal therapy. The treatment of patients whose heart failure
Peak aortic acceleration
Mean aortic acceleration
studies.
is not controlled by a combination of digitalis, diuretics and vasodilators (including angiotensin converting enzyme inhibitors) represents a therapeutic challenge. In the authors’ study, which included patients with advanced heart failure as demonstrated by NYHA functional classification and severe left ventricular dysfunction. oral administration of enoximone was associated with an improvement in functional class by at least one grade, and this was maintained over 4 weeks. In addition, an increase in quality of life score was observed which persisted throughout the study period. These findings are consistent with the results reported by other investigators [2,11,12]. Leier et al. [9] and Shah et al. [6] also noted beneficial results at 4 weeks. This improvement was transient, however, and at 16 weeks no difference in comparison to the placebo-treated group was found [9]. The early clinical benefits seen in the present study were associated with an improvement in objective measures of left ventricular performance. In enoximone-treated patients, cardiac index increased by 18%, which contrasted with a 17% decrease in the placebo group. Determination of cardiac output from the velocity-time integral has been questioned because the area through which flow occurs varies greatly between individuals [21]. In the present study, this drawback was avoided by measuring the aortic annulus area in each patient, as suggested by Sagar et al. [22]. Short-axis
MO
fractional shortening, mean circumferential shortening rate and left ventricular dimensions improved slightly, but these changes did not reach statistical significance. Echocardiographic studies have been advocated to monitor the course of chronic congestive heart failure [8]. However, it has been shown that the changes that can be expected in these patients with severe left ventricular dilatation are too small for detection with echocardiography and remain within the range of intrinsic variability of the method [23]. This lack of sensitivity may explain the discrepancy between our results and those reported by Tresse et al. [8], who found a decrease in M-mode left ventricular dimensions after oral administration of another phosphodiesterase inhibitor. Continuous-wave Doppler measurements of blood flow velocity and acceleration have yielded excellent correlations with electromagnetic measurements both in animals [22] and humans [24,25]. Experimentally, peak and mean acceleration corre lated with peak left ventricular dp/dt [22]. In addition, it has been demonstrated that the loading conditions of the left ventricle have little effect on peak acceleration, whereas an increase in the inotropic state produces a significant increase in peak acceleration [26] and little or no change in the velocity-time integral [24,26]. Ascending aortic blood flow peak acceleration has been reported to be highly predictive of left ventricular performance [27,28]. Peak acceleration shows a close correlation with left ventricular ejection fraction [29] and can detect improvement in left ventricular function in patients with congestive heart failure [30]. Using a commercially available continuouswave Doppler system, peak acceleration was obtained semi-automatically by external differentiation and not by internal differentiation as in the previous studies [22,29]. Our normal values are higher than those reported by previous investigators [22,25,28,29]. It is very likely that this resulted from a different technical approach, namely that aortic flow velocity was recorded from the apical view instead of the suprasternal view, and aortic flow acceleration was computed from the maximal spectral envelope and not from instantaneous modal velocity. In our study, although measure-
ment of the maximal spectral envelope yielded higher values than those previously reported, mean blood flow acceleration showed the same trend as peak acceleration, that is, it increased in enoximone-treated patients by 20% and decreased by 6% in patients on placebo. Sagar et al. [22] have demonstrated that Doppler-derived modal and peak velocity, peak and mean acceleration were closely correlated. The velocity-time interval increased by 18% on enoximone and decreased by 6% on placebo. Although this change was not significant, it is consistent with the finding of an increased stroke volume in enoximone-treated patients, as the systolic velocity-time integral has been shown to provide a reliable assessment of changes in stroke volume [22,31,32]. Like all other drugs that elevate the cellular levels of cyclic adenosine monophosphate, enoximone is potentially arrhythmogenic, and these effects appear to be dose-related. An increase in ventricular ectopic activity has been reported with high doses of enoximone in the range 1.7-19.0 mg/kg [6]. Ventricular ectopic beats and short runs of ventricular tachycardia are common in patients with severe heart failure and approximately half of the patients die suddenly [33,34]. In this respect, evaluation of the potential arrhythmogenic effect of enoximone is particularly relevant. Holter monitoring revealed no significant difference in the incidence of ventricular arrhythmias in enoximone-treated patients compared to placebo-treated patients. Individual results were highly variable, however, and no clearcut pattern was seen. Malignant arrhythmias were not observed at any time on enoximone. It might be argued that amiodarone could have exerted a prophylactic antiarrhythmic effect. However, patients receiving amiodarone were equally distributed in the two groups (10 in each group). Other investigators have also reported that the incidence of ventricular ectopic activity did not change significantly with enoximone administered orally at a daily dose of 150 mg t.d.s. [2,11]. Other side-effects were quite uncommon in the present study. Uretsky et al. [4] have reported a high incidence of side-effects, usually of gastrointestinal origin, when large initial doses of enoximone (3-6 mg/kg) were
s41
used; however, doses of 1-2 mg/kg, as used in this study, were well tolerated according to several investigators [1,9,35]. Limitations
of the study
Of the 30 patients who entered the study, only 20 completed it (12 on enoximone and 8 on placebo). In addition, the results of this study should be interpreted in the light of the doses used. The dose of angiotensin converting enzyme inhibitor was the one used in common clinical practice [36] and that of enoximone was selected according to the previously established therapeutic range [4,9-111. Enoximone blood levels were not determined, as available data suggest that enoximone plasma concentration does not reflect its concentration at the sites at which this agent is active [7]. On the basis of a time to peak concentration of oral enoximone averaging 1.6 f 1.2 hours, however, Doppler echocardiographic studies were always performed 2 hours after administration of a dose. This short-term study did not allow assessment of the effect of enoximone on eventual survival. However, over 6-12 months of follow-up, 19 patients continued to receive enoximone and 5 patients had heart transplantation within 2-9 months. Mortality in these patients with end-stage heart failure was 45%, similar to that usually reported in this subgroup of patients [6,37,38]. It has been argued that patients with advanced heart failure have such extensive myocardial disease that no important prolongation of life by any medical treatment can be expected. Palliative therapy may stabilize a rapidly deteriorating process, however, and therefore may reduce mortality at least for a limited period of time. In addition, in patients with end-stage congestive heart failure, improvement in quality of life is an appropriate end point 1391. In conclusion, in comparison to placebo, enoximone improved functional status, quality of life and left ventricular function in patients with congestive heart failure refractory to optimal therapy (including angiotensin converting enzyme inhibitors). Oral enoximone may be a useful adjunct to stabilize very ill patients who would otherwise
be treated intermittently by inotropes administered intravenously. In addition, in candidates for cardiac transplantation, inotropic support is often necessary during the waiting period. Since these patients are hospital-bound and maintained on intravenous inotropes, oral enoximone may be used as a ‘pharmacological bridge’ to cardiac transplantation.
References 1 Weber KT, Janicki JS, Jain MC. Enoximone (MDL17.043). a phosphodiesterase inhibitor, in the treatment of advanced, unstable chronic heart failure. J Heart Transplant 1986; 5: 105-112. 2 Choraria SK, Taylor D. Pilcher J. Double-blind crossover comparison of enoximone and placebo in patients with congestive heart failure. Circulation 1987: 76: 1307-1311. 3 Leier CV. Lima JJ, Meiler Sel, Unverferth DV. Central and regional hemodynamic effects of oral enoximone in congestive heart failure: a double-blind, placebo-controlled study. Am Heart J 1988; 115: 1051-1059. 4 Uretsky BF, Generalovich T, Reddy PS, et al. Acute hemodynamic effect of oral MDL 17.043 in severe congestive heart failure. Am J Cardiol 1984: 54: 357-362. 5 Rigaud M, Delorme G, Dubourg 0, Bourdarias JP. Effets comparatifs de l’enoximone et de la trinitrine sur la performance ventriculaire gauche chez le coronarien en insuffisance cardiaque. Rean Soins Intens Med Urg 1989: 5: 139-143. 6 Shah PK, Amin DK, Hulse S, Shellock F. Swan HJC. Inotropic therapy for refractory congestive heart failure with oral enoximone (MDL-17.043): poor long-term results despite early hemodynamic and clinical improvement. Circulation 1985; 71: 326-331. 7 Uretsky BF. Valdes AM, Reddy PS. Positive inotropic therapy for short-term support and long-term management of patients with congestive heart failure: hemodynamic effects and clinical efficacy of MDL 17.043. Circulation 1986; 73 (Suppl 2): 219-229. 8 Tresse N, Erbel R, Pilcher J, et al. Long-term treatment with oral enoximone for chronic congestive heart failure: the European experience. Am J Cardioll987; 60: 85C-90C. 9 Leier CV, Binkley PF, Starling RC, Huss-Randolph P. Disparity between improvement in left ventricular function and changes in clinical status and exercise capacity during chronic enoximone therapy. Am Heart J 1989; 117: 10921098. 10 Striven AJI. Lipkin DP, Anand IS. Sutton GC, Poole-Wilson PA. A comparison of hemodynamic effects of onemonth oral captopril and enoximone treatment for severe congestive heart failure. Am J Cardiol 1987; 60: 68C-71C. 11 Zipperle G. Butzer F, Dieterich HA. Heinrich F. A double-blind dose response comparison of oral enoximone and placebo for congestive heart failure. Am J Cardiol 1987: 60: 72C-74C.
S42 12 Khalife K, Zannad F, Brunotte F. et al. Placebo-controlled study of oral enoximone in congestive heart failure with initial and final intravenous hemodynamic evaluation. Am J Cardiol 1987; 60: 75C-79C. 13 Myerburg RJ, Kessler KM, Luceri RM. et al. Classification of ventricular arrhythmias based on parallel hierarchies of frequency and form. Am J Cardiol 1984; 54: 1355-1358. 14 Sahn DJ, DeMaria A, Kiss10 J, et al. The committee on M-mode standardization of the American Society of Echocardiography. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978; 58: 10721083. 15 Devereux RB. Alonso DR, Lutas EM, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986; 57: 450-458. 16 Teichholz LE. Kreulen T, Herman MV, Gorlin R. Problems in echocardiographic volume determinations: echocardiographic-angiographic correlations in the presence or absence of asynergy. Am J Cardiol 1976: 37: 7-11. evaluation 17 Ghafour AS, Gutgesell HP. Echocardiographic of left ventricular function in children with congestive cardiomyopathy. Am J Cardiol 1979; 44: 1332-1338. 18 Mathews EC Jr, Gardin JM, Henry WL, et al. Echocardiographic abnormalities in chronic alcoholics with and without overt congestive heart failure. Am J Cardiol 1981; 47: 570-578. 19 Folland ED, Parisi AF, Moynihan PF, Jones DR, Feldman CL. Tow DE. Assessment of left ventricular ejection fraction and volumes by real-time, two-dimensional echocardiography. Circulation 1979; 60: 760-766. 20 Chan KL, Currie PJ, Seward JB, Hagler DJ, Mair DD. Tajik AJ. Comparison of three Doppler ultrasound methods in the prediction of pulmonary artery pressure. J Am Co11 Cardiol 1987; 9: 549-554. L, lhlen H. Cardiac output. In: 21 Skjaerpe T, Hegrenaes Hatle L, Angelsen B, eds. Doppler ultrasound in cardiology: physical principles and clinical applications. Second edition. Philadelphia: Lea and Febiger 1985; 306-320. of peak 22 Sagar KB. Wann S, Boerboom L, et al. Comparison and modal aortic blood flow velocities with invasive measures of left ventricular performance. J Am Sot Echocardiol 1988; 3: 194-200. therapy 23 Haq A, Rakowski H. Baigrie R. et al. Vasodilator in refractory congestive heart failure: a comparative analysis of hemodynamic and noninvasive studies. Am J Cardiol 1982; 49: 439-444. 24 Metha N, Bennett DE. Impaired left ventricular function in acute myocardial infarction assessed by Doppler measurement of ascending aortic blood velocity and maximum acceleration. Am J Cardiol 1986; 57: 1052-1058. 25 Mehta N, Bennett D, Mannering D, Dawkins K, Ward DE. Usefulness of noninvasive Doppler measurement of ascending aortic blood velocity and acceleration in detecting im-
26
27
28
29
30
31
32
33
34
35
36
37 38
39
pairment of the left ventricular functional response to exercise three weeks after acute myocardial infarction. Am J Cardiol 1986; 58: 879-884. Bennett ED. Barclay SA, Davis AL, Mannering D, Mehta N. Ascending aortic blood velocity and acceleration using Doppler ultrasound in the assessment of left ventricular function. Cardiovasc Res 1984; 18: 632-638. Kezdi P. Stanley EL, Marshall WJ Jr, Kordenat RK. Aortic flow velocity and acceleration as an index of ventricular performance during myocardial infarction. Am J Med Sci 1969: 257: 61-71. Lazarus M, Dang T-Y. Gardin JM, Allfie A, Henry WL. Evaluation of age, gender, heart rate and blood presure changes and exercise conditioning on Doppler measured aortic blood flow acceleration and velocity during upright treadmill testing. Am J Cardiol 1988; 62: 4399443. Sabbah HN, Khaja F. Brymer JF, et al. Noninvasive evaluation of left ventricular performance based on peak aortic blood acceleration measured with a continuous-wave Doppler velocity meter. Circulation 1986; 74: 323-329. Sabbah HN, Gheorghiade M, Smith ST, Frank DM, Stein PD. Serial evaluation of left ventricular function in congestive heart failure by measurement of peak aortic blood acceleration. Am J Cardiol 1988; 61: 367-370. Elkayam U, Gardin JM, Berkley R, Hughes CA, Henry WL. The use of Doppler flow velocity measurement to assess the hemodynamic response to vasodilators in patients with heart failure. Circulation 1983; 67: 377-383. Wallmeyer K. Wann S, Sagar KB, Kalbfleisch J, Klopfenstein HS. The influence of preload and heart rate on Doppler echocardiographic indexes of left ventricular performance: comparison with invasive indexes in an experimental preparation. Circulation 1986; 74: 181-186. Wilson JR, Schwartz JS, Sutton MS, et al. Prognosis in severe heart failure: relation to hemodynamic measurements and ventricular ectopic activity. J Am Co11 Cardiol 1983; 2: 403-410. Bigger JT Jr. Why patients with congestive heart failure die: arrhythmias and sudden cardiac death. Circulation 1987; 75 (Suppl 4): 28-35. Leier CV, Huss P, Magorien RD. Unverferth DV. Improved exercise capacity and differing arterial and venous tolerance during chronic isosorbide dinitrate therapy for congestive heart failure. Circulation 1983: 67: 817-822. Captopril Multicenter Research Group. A placebo-controlled trial of captopril in refractory chronic congestive heart failure. J Am Co11 Cardiol 1983; 4: 755-763. Braunwald E, Colucci WS. Evaluating the efficacy of new inotropic agents. J Am Co11 Cardiol 1984; 6: 1570-1574. Keriakes D, Chatterjee K, Parmley WW, et al. Intravenous and oral MDL 17,043 (a new inotrope-vasodilator agent) in congestive heart failure: hemodynamic and clinical evaluation in 38 patients. J Am Co11 Cardiol 1984; 4: 884-889. Parmley WN. Medical treatment of congestive heart failure, where are we now? Circulation 1987: 75 (Suppl 4): 4-5.
s43
Discussion Question: What is your explanation for the differential effects on the peak flow velocity and the peak and mean acceleration with enoximone? 0. Dubourg: I have no explanation for the results; I merely observed the effects. I do not think there is any relationship between the peak velocity and the mean acceleration. The peak acceleration is perhaps a more sensitive index of left ventricular function than the peak velocity.
Question: Did you follow the renal function of these patients during the 4 weeks of the study? 0. Dubourg: Yes; there were no problems of renal function with enoximone. Question: How about diuresis? Did you measure creatinine clearance? 0. Dubourg: No; we did not measure creatinine clearance.
CARD10
S33
Journal of Cardrologv. 28 (1990) S33-S43
01126
Placebo-controlled trial of oral enoximone in end-stage congestive heart failure refractory to optimal treatment 0. Dubourg,’
G. Delorme,’
A. Hardy,’
A. Beauchet,‘A.
Tarral’
and J.P. Bourdariasi
’ Department of Cardiologr: FacultP de M6decine Paris-Ouest, H6pital Ambroise Park. Boulogne, France; .’ Medical Research Unit. Merrell-Dow
France SA, Strashour&
France
Dubourg D, Delorme G, Hardy A, Beauchet A, Tarral A, Bourdarias JP. Placebo-controlled enoximone in end-stage congestive heart failure refractory to optimal treatment. Int J Cardiol l):S33-s43.
trial of oral 1990:28(Suppl
A double-blind, randomized, concurrent trial of enoximone vs placebo was undertaken to assess the efficacy and safety of enoximone, 100 mg t.d.s. added to optimal therapy in 30 patients (mean age, 66.4 f 14 years) with severe congestive heart failure. Before inclusion, all patients remained markedly symptomatic despite treatment with diuretics, digitalis, vasodilators and angiotensin converting enzyme inhibitors. Symptoms and quality of life were evaluated at inclusion, and at days 4 and 31; 24-hour electrocardiography and Doppler echocardiography were performed at inclusion and at day 31. Clinical and echocardiographic baseline characteristics were similar in the two groups. During the study, 10 patients dropped out: 3 in the enoximone group (1 death) and 7 in the placebo group (3 deaths). At day 4, symptoms were improved in 13 enoximone-treated patients and in 8 patients on placebo (P < 0.05). At day 31, symptoms were still improving in 10 of 12 patients on enoximone and in 6 of 8 patients on placebo (NS). No serious clinical side-effects were reported, and no statistically significant difference in the frequency of premature ventricular contractions between the two groups was apparent on Holter monitoring. Peak acceleration of ascending aortic blood flow at entry was 17 i- 6 m/second’ in the enoximone group and 18 f 5 m/second’ in the placebo group (NS). At day 31, the change in peak acceleration was + 20% in the enoximone group vs -6% in the placebo group (P < 0.05). Cardiac index increased by 18% in the enoximone group (from 2.17 f 0.7 litres/minute/m2 to 2.4 f 1.0 litres/minute/m2 (NS). This study demonstrated that oral enoximone improves functional class, quality of life and left ventricular function in patients with congestive heart failure refractory to optimal therapy and may be used as a pharmacological bridge to cardiac transplantation. Key words:
Enoximone;
Congestive
heart failure;
Aortic
Introduction Patients with severe heart failure have a limited response to digoxin, diuretics and vasodilators [ 11.
Correspondence to: Dr. 0. Dubourg, Department Cardiology, Hapital Ambroise Park, 9 avenue Charles Gaulle, 92100 Boulogne, France.
016?-5273/90/$03.50
0 1990 Elsevier Science
Publishers
of de
flow acceleration;
Pharmacological
bridge
Vasodilator therapy is now accepted in the treatment of congestive heart failure, but it may fail to control symptoms in the most severe cases [2]. In these patients, combinations of vasodilators and positive inotropic drugs might be of interest. Enoximone is a new phosphodiesterase inhibitor which has both vasodilator and positive inotropic activities [3].
B.V. (Biomedical
Division)
S34
Enoximone, administered either intravenously [4,5] or orally has undergone extensive clinical evaluation in both open [1,6-81 and controlled studies [2,9-121. Marked symptomatic and haemodynamic improvement suggests that enoximone may have a role in the short-term [1,6,7] and the long-term management of heart failure [7,12] though the latter appears more controversial. The present authors hypothesized that enoximone would improve the haemodynamic state, clinical course and quality of life of patients with severe heart failure refractory to maximal therapy. This study was designed to compare the effects of enoximone and placebo over a period of 4 weeks, in a randomized double-blind trial using non-invasive methods.
Patients and Methods In all, 30 patients (24 men, 6 women), ranging in age from 36 to 88 years (mean, 66.4 & 14 years) were selected for the study. Their NYHA functional class was a mean of 3.6 f 0.5. All of them had severe congestive heart failure for a mean duration of 42.9 months (range, 6-156 months), and remained markedly symptomatic despite frusemide, digitalis and vasodilators, which included angiotensin converting enzyme inhibitors (25 patients), nitrates (22 patients), and prazosin (12 patients). All the patients had received angiotensin converting enzyme inhibitors for a mean duration of 12 months (range, l-48 months), except for 5 in whom this therapy had to be withdrawn due to adverse effects. Twenty patients were in sinus rhythm and 10 had atria1 fibrillation controlled by digitalis; 20 patients were given amiodarone for documented ventricular arrhythmias. Congestive heart failure was secondary to ischaemic heart disease (16 patients), dilated cardiomyopathy (10 patients) or valvular heart disease (4 patients). One patient had chronic mitral incompetence, and 2 had aortic incompetence. In the remaining patient, who had undergone aortic and mitral valve replacements several years before, heart failure was due to poor left ventricular function.
TABLE
1
Demographic tion.
and clinical
characteristics
Age (years) Sex Duration of symptoms (months) NYHA functional class Aetiology Ischaemic heart disease Dilated cardiomyopathy Valvular heart disease
of the study
popula-
Placebo (n =15)
Enoximone (n =15)
64+_16 12M/3F 32+24 III : 5 IV:10
69ill 12M/3F 53.5 +45 III : I IV:8
9 4 2
I 6 2
The demographic and clinical characteristics of the study population are presented in Table 1. Exclusion criteria were the presence of restrictive or hypertrophic cardiomyopathy, stenotic valvular disease, uncontrolled ventricular dysrhythmias, myocardial infarction within 3 months, major disease of any other organ system (chronic pulmonary, hepatic, haematological or neurological disease) and renal insufficiency (serum creatinine > 300 pmol/litre). Patients gave informed consent and the study protocol was approved by the hospital ethics committee.
Study protocol During the initial in-patient period, baseline investigations consisted of a full clinical examination with evaluation of quality of life, using a questionnaire consisting of three sets of five questions each (total score of 15). Resting 12-lead electrocardiography, 24-hour Holter monitoring, chest radiography, and a complete Doppler echocardiographic study were performed. The patients underwent serial laboratory examinations, including electrolytes, liver and renal function tests, and haematological profile with platelet count. After the control period, patients entered the treatment period and were randomly assigned to receive either enoximone, 100 mg t.d.s. or placebo, 1 capsule t.d.s. for 4 weeks, in addition to their initial treatment which remained unchanged during the study. At day 4, when discharged from
s35
hospital, all patients underwent another clinical examination, evaluation of NYHA functional class and quality of life, as well as laboratory screening. At this time, if the clinical condition of a patient had deteriorated or had not improved, the patient was withdrawn from the study. Thereafter, patients enrolled in the placebo group were given enoximone, 100 mg t.d.s. In those assigned to the active drug, the enoximone dose was increased to 150 mg t.d.s. Patients were readmitted after 4 weeks for further clinical, biological, radiological and echocardiographic assessment. A second 24hour Holter monitoring was performed at this time. Ventricular arrhythmias were classified according to Myerburg et al. [13]. At the end of the 4-week study period, all patients were put on or maintained on enoximone, whether or not they were initially assigned to placebo or enoximone.
Left ventricular and right ventricular areas were computed from the tracing of the end-systolic and end-diastolic endocardial surface of five consecutive cardiac cycles using a personal computer interfaced with a digitizing tablet and custom-developed software. Right ventricular fractional area contraction was computed as: RVDA
-
RVSA x lOO/RVDA
where RVDA is the right ventricular diastolic area, RVSA the right ventricular systolic area. Left ventricular end-diastolic and end-systolic volumes were calculated using the area-length method [19]. Finally, right and left atria1 areas were measured on the view displaying end systole of each ventricle. Doppler studies
Echocardiographic
and Doppler studies
Using standard techniques, ultrasonic studies were performed with a commercially available sector scanner (Diasonics CV 400) interfaced with a mechanical transducer (3.5 MHz) for two-dimensional and M-mode echocardiography and with a Pedoff transducer (Vingmed 2.25 MHz) for Doppler echocardiography. All studies were recorded on videotape for subsequent real-time playback analysis. Measurements on M-mode echocardiographs were performed as recommended by the American Society of Echocardiography [14]. Left ventricular mass was calculated according to the Penn convention measurements by the formula of Devereux [15] and normalized for body surface area. End-diastolic and end-systolic volumes were derived from end-diastolic and end-systolic dimensions according to the cubic model of Teichholz et al. [16]. Mean velocity of circumferential fibre shortening was calculated according to the usual formula [17]. Left ventricular ejection time was measured on the Doppler transaortic velocity recording. Left ventricular diastolic thickness-toradius ratio was computed as reported by Mathews et al. [18]. Finally, the aortic annulus surface area was measured in each patient from the parasternal two-dimensional view.
After a complete pulsed Doppler echocardiographic study, a continuous wave Doppler recording was obtained according to the method of Chan et al. [20] in order to measure the right ventricular systolic pressure. Aortic flow velocity was recorded from the apical view and aortic acceleration was calculated from the maximal spectral envelope. The transducer was applied on the apical window and the ultrasonic beam was oriented parallel to the aortic flow and guided by audiographic signals to obtain maximum Doppler shift. with velocity envelopes having distinct borders. The spectral output was recorded on a video-strip chart recorder at the speed of 50 mm/second. Peak velocity, time to peak velocity. mean acceleration (peak velocity/time to peak velocity) and velocity-time integral were measured on 20 consecutive beats and averaged by two independent observers. Beats with a poor signal-to-noise ratio. as well as extrasystolic and post-extrasystolic beats, were rejected. The analogue signal of the maximal envelope was recorded on a video-strip chart recorder and digitized with the computer. A personal program was used to measure peak flow acceleration on the aortic Doppler waveform. The aortic flow envelope was divided into time intervals of 1 ms (dt). For each time interval, the difference be-
S36
tween velocities at the beginning and the end of this interval (du) was measured and the acceleration (du/dt) was computed; this value was then averaged with the value of the previous and the following interval (moving average method). Stroke volume was calculated from the product of the velocity-time integral and the aortic annulus area. To determine whether values of peak acceleration were comparable with those reported in the literature, peak velocity and accleration were measured in 24 normal volunteers (16 men and 8 women ranging in age from 30 to 78 years, mean age, 52 * 15 years).
parametric data and small size samples. Contingency tables were examined with a &i-squared or Fisher exact test. Values are expressed as means f 1 standard deviation. Results At inclusion, all clinical characteristics (Tables 1 and 2) and echocardiographic measurements (Tables 3 and 4) were similar for the placebo and enoximone groups. In the enoximone group, patients received 1.5 + 0.19 mg/kg t.d.s. Enoximone did not significantly affect heart rate or blood pressure when compared to placebo. NYHA functional class was improved by at least one class in 13 patients after 4 days of treatment with enoximone (Fig. 1). A similar improvement was observed in 8 patients on placebo (Fig. 2). A total of 9 patients was withdrawn from the study at day 4: 2 patients in the enoximone group and 6 in the placebo group did not improve, and 1 patient on placebo died before the day 4 evaluation. After discharge, congestive heart failure relapsed in 2 patients from the enoximone group and in 4 pa-
Statistical analysis Differences among groups were examined using Student’s t-test and analysis of variance. When variances were different, the Mann-Whitney test, and the Welch approximation were used. Contingency tables were analysed with a &i-square or Fisher exact test. Differences between periods within a group were examined with Student’s t-test for paired data and the Wilcoxon test for non-
TABLE Evolution
2 of clinical
and cardiovascular Placebo
(mm Hg f SD) Diastolic blood pressure (mm Hg + SD) NYHA functional class (mean f SD) Distribution of NYHA functional class Quality of life score (x/15) *SD a P i 0.05 vs placebo;
in the placebo
and enoximone
Day 4 (n = 14)
89
*lO
84
116
+24
116
71
*11
71
13.7 + 0.5 0 II 5 III 10 IV
0.69 + 0.14
groups.
Enoximone
( n = 15)
Baseline (n = 15) Heart rate (beats/mm f SD) Systolic blood pressure
parameters
Week 4 (n=8)
82
+lO
83
*21
116
+22
113
*15
71
+18
74
+9
3.0 f 3 II 8 III 3 IV
0.7
0.46 + 0.15 ’
b P < 0.05 vs baseline;
(n = 15)
Baseline (n = 15)
kll
Week 4 (n = 12)
85
*16
89
+12
+25
113
*14
115
*12
*13
67
+lO
72
+8
2.75 &- 0.9 4 II 2 III 2 IV
3.5 * 0 II 7 III 8 IV
0.53 rt 0.23 b
0.64 + 0.17
’ P < 0.001 vs baseline.
Day 4 (n = 15)
0.5
2.4 &0.6 += 10 II 4 III 1 IV
2.33 + 0.65 ’ 9 II 2 III 1 IV
0.40 + 0.19 c
0.37 + 0.19 =
s31 TABLE
3
Echocardiographic
findings
at pretreatment
baseline
Normal adults (n=24) Aortic
and at 4 weeks of initial
therapy.
Baseline (means f SD)
4 weeks (means i SD)
Placebo (?I = 15)
Placebo (n = 8)
Enoximone (n = 15)
Enoximone (il=Zl)
annulus 20 51 31 39
(nun) LVIDd (mm) LVIDs (mm) FS (g) Vcf (circumferences/
1.5 126 66 48 0.43
second) LM mass (g/m2 ) LVEF (Teichholz) (%) RVFAS (‘%) t/r
20 68 58 14.5
+2 +5 +5 +6
*1 58 +8 * 5
0.6 219 27 28 0.31
+ 0.3 *20 +6 +I * 0.1
19 12 62 13.8
f 0.2 +71 + 0.9 511 + 0.6
0.6 232 26 24 0.30
+1 *9 rtl0 f 4
+ 0.2 *51 + 0.7 +lO f 0.05
19 68 58 15.1
0.6 237 29 30 0.34
19 il 70 i6 59 il 14.9 i 4
+7 i9 k8 f 5
0.7 221 29 27 0.31
i 0.2 * 71 i_ 0.1 *13 i 0.06
LVIDd = left ventricular internal diameter in diastole; LVIDs = left ventricular internal diameter in systole; shortening; Vcf = mean circumferential fibre shortening; LVEF = left ventricular ejection fraction; FSR = fractional RVFAS = right ventricular fractional area shortening; t/r = thickness to radius ratio.
tients from the placebo group; 2 patients in the placebo group died at home, and 1 in the enoximone group was excluded because of poor compliance with treatment. The quality of life score improved (Table 2) as did the NYHA classification (P < 0.001). At 4 weeks, there was still an improvement in the quality of life in both
TABLE Aortic
FS = fractional shortening rate;
groups, but this improvement was more marked and sustained in the enoximone group, while in the placebo group a downward trend was apparent. In the enoximone group, 3 patients experienced transient side-effects: nausea (1 patient), headache (1 patient), diarrhoea (1 patient). In the placebo
4 Doppler
findings
Ejection time (millisec) Peak velocity (m/=) Peak acceleration (m/sec2) Mean acceleration (m/sec2) Velocity-time integral (cm) Cardiac index (litres/min/m2) Data
* 0.2 +40 i 0.1 +ll f 0.04
are presented
at baseline
and at 4 weeks of initial
therapy.
Normal adults (n = 24)
Baseline Placebo (n = 15)
Enoximone (n = 15)
Placebo (n=8)
Enoximone (n = 12)
263
236
232
245
229
kO.01
1.2 + 0.2 35
*8
20
+7
23
F4
3.5 i 0.04
as means f SD;
Week 4
k30
1.1 f
0.3
18 f (n = 11 * (n = 16 * (n = 2.5 f (n =
5 14) 3 14) 4 14) 0.6 14)
+39
1.0 + 0.4 17
+6
11
*3
16
*6
2.17 f
a P < 0.05 vs placebo;
0.7
Percentage- change_
&39
1.2 * 17 f (n=7) 12 * (n=7) 15 * (n=7) 1.9 i (n=7)
0.5
f33
1.1 f
0.3
21
k
3
14
+ 4
5
17
f
b P < 0.01 vs baseline.
2.4*
Enoximone (n=12)
0
4
0.05
Placebo (n = 8)
6
7 1
0.15 -6 (n = 7) +4 (n = 7) -6 (n = 7) -17 (n=7)
0 +13 + 2,o a.h + 20 a.h +18 +I8
S38
Da; 31
Da; 4
D&O Fig. 1. Time course
of functional status patients.
in enoximone-treated
group, 1 patient had scleral bleeding due to anticoagulation and another experienced insomnia and therefore dropped out of the study. Laboratory findings No changes haematological
were seen in blood chemistry and variables throughout the study.
Holter monitoring There was no statistically significant difference in the frequency of premature ventricular contractions between the two groups. The mean frequency of premature ventricular contractions in the enoximone group was 86/hour (range, 0-300/hour) and in the placebo group, 26/hour (range, lThe premature ventricular contraction
I
.
Day 0
Fig.
2. Time
course
Day 31
Day 4 Placebo
treatment
of functional patients.
status
time in placebo-treated
forms were stable or tended to become less multiform in all but 3 of the patients who completed the study on day 31. In 2 patients of the enoximone group, the premature ventricular contraction form was modified, changing from uniform to multiform (1 patient) and from uniform to repetitive (1 patient). In one patient of the placebo group, the premature ventricular contraction form changed from uniform to repetitive. Ten patients did not complete the study: 3 were on enoximone, and 7 on placebo. In the enoximone group, 2 patients had moderate ventricular ectopic activity (class I and II, form A and B) and 1 patient had severe ventricular ectopic activity (class IV, form C) but dropped out of the study for poor compliance to treatment. Among these three patients withdrawn from the enoximone group, only one died from intractable heart failure (class II, form B). Among the 7 patients withdrawn from the placebo group, 2 patients had a qualitative (class A and B) and quantitative (class 0 and I) moderate ventricular ectopic activity: one dropped out for relapse of congestive heart failure and the other died at day 21. Five patients had severe ventricular activity both quantitatively (i.e. class III (n = 2) or class IV (n = 3)) and qualitatively (i.e. class B (n = 3), class C (n = 1) and class D (n = 1)); 2 of them died (class III B and class IV C). Ekhocardiographic
studies
In both groups, a slight but statistically nonsignificant decrease in left ventricular end-diastolic and end-systolic internal diameters was observed at week 4 (Table 3). Short-axis percentage fractional shortening, shortening rate and left ventricular ejection fraction slightly increased on enoximone, but this change did not reach statistical significance. Bight ventricular fractional area contraction showed a similar trend. In the placebo group, a patient with severe aortic regurgitation was excluded from Doppler analysis because of potential alteration in the flow of the ascending aorta. Ejection time remained unchanged in both groups. Peak velocity and velocity-time integral both increased on enoximone and did not change or decrease on
s39
30 F;
1
-20-1
I m
*
Placebo
p < 0.05 vs placebo
* * p < 0.01 vs baseline
Enoximone
Peak velocity
Cardiac index
Velocity-time integral Fig. 3. Doppler
echocardiographic
placebo. However, these changes did not reach statistical significance (Table 4). As shown in Fig. 3, peak aortic acceleration increased by 20% on enoximone and decreased by 6% on placebo (P < 0.01). Mean aortic flow acceleration also increased by 20% (P < 0.01) on enoximone and by 4% on placebo. Cardiac index increased by 18% in the enoximone group and this change was mainly mediated through an increase in stroke index (14%); cardiac index decreased by 17% in the placebo group, due to a decrease in stroke index (-12%).
Follow-up study After completion of this 4-week study, all survivors (25 patients) were given enoximone, loo-150 mg t.d.s. Five patients had a heart transplantation within 2-9 months, and 11 patients were still alive and receiving enoximone at 12 months. At that time, 4 of them were still on the waiting list. Thus, mortality in the patients who received enoximone for up to 12 months was 45%.
Discussion The purpose of this study was to determine whether the addition of enoximone, 100 mg t.d.s., could be of some benefit to patients with end-stage congestive heart failure refractory to optimal therapy. The treatment of patients whose heart failure
Peak aortic acceleration
Mean aortic acceleration
studies.
is not controlled by a combination of digitalis, diuretics and vasodilators (including angiotensin converting enzyme inhibitors) represents a therapeutic challenge. In the authors’ study, which included patients with advanced heart failure as demonstrated by NYHA functional classification and severe left ventricular dysfunction. oral administration of enoximone was associated with an improvement in functional class by at least one grade, and this was maintained over 4 weeks. In addition, an increase in quality of life score was observed which persisted throughout the study period. These findings are consistent with the results reported by other investigators [2,11,12]. Leier et al. [9] and Shah et al. [6] also noted beneficial results at 4 weeks. This improvement was transient, however, and at 16 weeks no difference in comparison to the placebo-treated group was found [9]. The early clinical benefits seen in the present study were associated with an improvement in objective measures of left ventricular performance. In enoximone-treated patients, cardiac index increased by 18%, which contrasted with a 17% decrease in the placebo group. Determination of cardiac output from the velocity-time integral has been questioned because the area through which flow occurs varies greatly between individuals [21]. In the present study, this drawback was avoided by measuring the aortic annulus area in each patient, as suggested by Sagar et al. [22]. Short-axis
MO
fractional shortening, mean circumferential shortening rate and left ventricular dimensions improved slightly, but these changes did not reach statistical significance. Echocardiographic studies have been advocated to monitor the course of chronic congestive heart failure [8]. However, it has been shown that the changes that can be expected in these patients with severe left ventricular dilatation are too small for detection with echocardiography and remain within the range of intrinsic variability of the method [23]. This lack of sensitivity may explain the discrepancy between our results and those reported by Tresse et al. [8], who found a decrease in M-mode left ventricular dimensions after oral administration of another phosphodiesterase inhibitor. Continuous-wave Doppler measurements of blood flow velocity and acceleration have yielded excellent correlations with electromagnetic measurements both in animals [22] and humans [24,25]. Experimentally, peak and mean acceleration corre lated with peak left ventricular dp/dt [22]. In addition, it has been demonstrated that the loading conditions of the left ventricle have little effect on peak acceleration, whereas an increase in the inotropic state produces a significant increase in peak acceleration [26] and little or no change in the velocity-time integral [24,26]. Ascending aortic blood flow peak acceleration has been reported to be highly predictive of left ventricular performance [27,28]. Peak acceleration shows a close correlation with left ventricular ejection fraction [29] and can detect improvement in left ventricular function in patients with congestive heart failure [30]. Using a commercially available continuouswave Doppler system, peak acceleration was obtained semi-automatically by external differentiation and not by internal differentiation as in the previous studies [22,29]. Our normal values are higher than those reported by previous investigators [22,25,28,29]. It is very likely that this resulted from a different technical approach, namely that aortic flow velocity was recorded from the apical view instead of the suprasternal view, and aortic flow acceleration was computed from the maximal spectral envelope and not from instantaneous modal velocity. In our study, although measure-
ment of the maximal spectral envelope yielded higher values than those previously reported, mean blood flow acceleration showed the same trend as peak acceleration, that is, it increased in enoximone-treated patients by 20% and decreased by 6% in patients on placebo. Sagar et al. [22] have demonstrated that Doppler-derived modal and peak velocity, peak and mean acceleration were closely correlated. The velocity-time interval increased by 18% on enoximone and decreased by 6% on placebo. Although this change was not significant, it is consistent with the finding of an increased stroke volume in enoximone-treated patients, as the systolic velocity-time integral has been shown to provide a reliable assessment of changes in stroke volume [22,31,32]. Like all other drugs that elevate the cellular levels of cyclic adenosine monophosphate, enoximone is potentially arrhythmogenic, and these effects appear to be dose-related. An increase in ventricular ectopic activity has been reported with high doses of enoximone in the range 1.7-19.0 mg/kg [6]. Ventricular ectopic beats and short runs of ventricular tachycardia are common in patients with severe heart failure and approximately half of the patients die suddenly [33,34]. In this respect, evaluation of the potential arrhythmogenic effect of enoximone is particularly relevant. Holter monitoring revealed no significant difference in the incidence of ventricular arrhythmias in enoximone-treated patients compared to placebo-treated patients. Individual results were highly variable, however, and no clearcut pattern was seen. Malignant arrhythmias were not observed at any time on enoximone. It might be argued that amiodarone could have exerted a prophylactic antiarrhythmic effect. However, patients receiving amiodarone were equally distributed in the two groups (10 in each group). Other investigators have also reported that the incidence of ventricular ectopic activity did not change significantly with enoximone administered orally at a daily dose of 150 mg t.d.s. [2,11]. Other side-effects were quite uncommon in the present study. Uretsky et al. [4] have reported a high incidence of side-effects, usually of gastrointestinal origin, when large initial doses of enoximone (3-6 mg/kg) were
s41
used; however, doses of 1-2 mg/kg, as used in this study, were well tolerated according to several investigators [1,9,35]. Limitations
of the study
Of the 30 patients who entered the study, only 20 completed it (12 on enoximone and 8 on placebo). In addition, the results of this study should be interpreted in the light of the doses used. The dose of angiotensin converting enzyme inhibitor was the one used in common clinical practice [36] and that of enoximone was selected according to the previously established therapeutic range [4,9-111. Enoximone blood levels were not determined, as available data suggest that enoximone plasma concentration does not reflect its concentration at the sites at which this agent is active [7]. On the basis of a time to peak concentration of oral enoximone averaging 1.6 f 1.2 hours, however, Doppler echocardiographic studies were always performed 2 hours after administration of a dose. This short-term study did not allow assessment of the effect of enoximone on eventual survival. However, over 6-12 months of follow-up, 19 patients continued to receive enoximone and 5 patients had heart transplantation within 2-9 months. Mortality in these patients with end-stage heart failure was 45%, similar to that usually reported in this subgroup of patients [6,37,38]. It has been argued that patients with advanced heart failure have such extensive myocardial disease that no important prolongation of life by any medical treatment can be expected. Palliative therapy may stabilize a rapidly deteriorating process, however, and therefore may reduce mortality at least for a limited period of time. In addition, in patients with end-stage congestive heart failure, improvement in quality of life is an appropriate end point 1391. In conclusion, in comparison to placebo, enoximone improved functional status, quality of life and left ventricular function in patients with congestive heart failure refractory to optimal therapy (including angiotensin converting enzyme inhibitors). Oral enoximone may be a useful adjunct to stabilize very ill patients who would otherwise
be treated intermittently by inotropes administered intravenously. In addition, in candidates for cardiac transplantation, inotropic support is often necessary during the waiting period. Since these patients are hospital-bound and maintained on intravenous inotropes, oral enoximone may be used as a ‘pharmacological bridge’ to cardiac transplantation.
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Discussion Question: What is your explanation for the differential effects on the peak flow velocity and the peak and mean acceleration with enoximone? 0. Dubourg: I have no explanation for the results; I merely observed the effects. I do not think there is any relationship between the peak velocity and the mean acceleration. The peak acceleration is perhaps a more sensitive index of left ventricular function than the peak velocity.
Question: Did you follow the renal function of these patients during the 4 weeks of the study? 0. Dubourg: Yes; there were no problems of renal function with enoximone. Question: How about diuresis? Did you measure creatinine clearance? 0. Dubourg: No; we did not measure creatinine clearance.
