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Comparison of the safety and efficacy of delapril with enalapril in patients with congestive heart failure
Comparison of the Safev and Efficacy of Delapril with Enalapril In Patients with Congestowe Heart Failure Franc0 Ren o, MD, Domenico Antonio Nice Bino, MD, Costantino
Acanfora, Picone,
MD, Giuseppe Furgi, MD, Antimo Papa, MD, MD, Dino Franc0 Vitale, MD, Carlo Rengo, MD
To evaluate safety and efficacy of delapril versus enalapril in patients with congest’nre heart failure (CHF), New York Heart Association (NWA) class II and III, 198 patients were enrolled in a study in 13 centers involving a double-blind parallel group design. After completing a 2-week run-in period on placebo, patients were randomized to receive delapril 7.5 mg twice daily or enalapril 2.5 mg twice daily for 2 weeks. The dose was then doubled for the remaining 6 weeks. In this phase, 1 patient in each group experienced orthostatic hypotension; the dose was then reduced to the initial dose for study completion. A total of 195 patients received active treatment (96 delapril, 99 enalapril). After 8 weeks’ treatment, bicycle ergometry demonstrated a significant increase in exercise duration (p ~0.01)
and workload (p ~0.01). Echo Doppler investigations showed a significant reduction (p ~0.01) in left ventricular end-systolic volume associated with a significant increase (p ~0.01) in eiection fraction and cardiac output. No clinically significant changes in blood pressure, heart rate, electrocardiogram, or biochemical and hematologic tests were found. There were no significant differences between treatment groups. Three patients in each group experienced adverse reactions requiring withdrawal of 1 patient in each group. Delapril 15 mg twice daily, like enalapril 5 mg twice daily, was effective in improving signs and symptoms of CHF and was well tolerated. (Am J Cardioll995;75:25F-28F)
A
sion (World Health Organization stages I and II), exhibited a significant reduction in blood pressure.5,6 The aim of the study was to compare the safety and efficacy of delapril 15 mg twice daily with enalapril 5 mg twice daily given orally for an g-week period to patients with NYHA class II or III CHF. Enalapril is a known effective treatment for CHF.7-9
ngiotensin-converting enzyme (ACE) inhibitor drugs act on the renin-angiotensin ystem to produce vasodilation and a reduction of the arteriolar resistance as well as decreasing the fluid retention caused by aldosterone in patients with congestive heart failure (CHF).l ACE inhibitors also have a significant impact on the quality of life of patients with CHF and can prolong it in the medium term, particularly if treatment is started when signs and symptoms of ventricular dysfunction are not yet evident.2 Delapril (CV3317) is a new short-acting ACE inhibitor. After oral administration, it is rapidly converted to 2 active metabolites, CV3317-COOH and CV3317-(SOH)-COOH, with more potent antihypertensive effects and a half-life of <4 hours.3 As an ACE inhibitor, delapril is essentially equivalent to enalapril and superior to captopril.4 After 8 weeks of treatment with delapril, 70% of patients, with mild-to-moderate essential hyperten-
From the Clinica del Lavaro Foundation, Institute of Care and Scientific Research Medical Center of Campoli del Monte Taburna (BN), Italy (F.R., D.A., G.F., A.P., A.N., C.P.); and Institute of Internal Medicine, Cardiology and Cardiovascular Surgen/, Chair of Geriatrics, Federico II University, School of Medicine, Naples, Italy (F.R., D.F.V., CR.). Address for reprints: Franc0 Rengo, MD, lstituto di Medicina Inferno, Cardiologia e Chirurgia Cardiovascolare, Cattedra di Geriatria, Universita degli Studi Federico II, Facoltb di Medicina e Chirurgia, Via S. Pansini, 5,80131 Napoli, Italy.
PATIENTS AND METHODS Study design: The study took the form of a multicenter, randomized, double-blind, parallel group design. After a 2-week run-in period on placebo (1 capsule in the morning and 1 in the evening) during which nonpermitted concomitant treatments were withdrawn, patients were randomly assigned to receive delapril 7.5 mg twice daily or enalapril 2.5 mg twice daily for 2 weeks. The dose was then doubled for the remaining 6 weeks’ treatment. If any signs or symptoms of orthostatic hypotension occurred, the code was broken and the patient completed the study at the low dose. The study treatment tablets were encapsulated to maintain the double-blind conditions. Patient selection criteria: Patients of both sexes were included if they fulfilled the following criteria: between 25 and 70 years of age; able to exercise for 3-12 minutes on a bicycle ergometer; signs and symptoms of NYHA class II or III CHF, for at least A SYMPOSIUM:
NEW
ACE
INHIBITOR
25F
TABLE
I Patient
No.
%
63 36
64 36
Delopril
Enolopril
(n = 99)
(n = 99)
Mean
2 SD
No.
%
70 29
71 29
Mean
k SD
Sex Mole FWlole Age (vd Range Duration
60.5
+- 8.33 34-70
59.2
k 8.37 31-70
of disease
(4 SBP (mm Hg) DBP (mm Hg) HR (beats/min) NYHA Class II Class III Etiologic factor Cardiomyopathy Coronary artery disease Hypertension Digitalis therapy
10.1 1394 84.5 76.3
A + + -c
9.47 19.15 10.96 11.54
9.9 140.5 84.4 77.4
81
a2
18
18
79 20
80 20
34
34
33
33
41 24 32
41 24 32
45 21 33
46 21 33
DBP = diastolic blood pressure; HR = heart Assoc~at,on; SBP = systchc blood pressure
rate; NYHA
k 9.00 + 21.19 + 11.70 r
11.58
= New York Heart
3 months; if on digitalis, stabilized for at least 3 months; and a diagnosis of ischemic, dilatative, or hypertensive cardiomyopathy. Patients were excluded if they had acute heart failure or myocardial infarction in the previous 3 months, stroke in the previous 6 months, hypotension (systolic blood pressure <90 mm Hg or diastolic blood pressure ~60 mm Hg), resting angina or exercise angina (Canadian class > I), an exercise test in which the results might have been affected by various symptoms of CHF (intermittent claudication, symptomatic pulmonary disease, and severe neurologic or muscular disease), valvular disease likely to require surgery, severe mitral or aortic stenosis, acute myocarditis, pericarditis, hypertrophic cardiomyopathy (obstructive and nonobstructive), arrhythmias or conduction problems not controlled by therapy or pacemakers, hyperaldosteronism, renal artery stenosis, hemodialysis or only one functional kidney, renal or hepatic failure, unstable diabetes mellitus, collagen disease, hypokalemia or hyperkalemia (potassium < 3.0 or > 5.0 mmol/liter), severe allergic diathesis, or a family history of angioneurotic edema. Patients being treated with positive inotropic drug (excluding digitalis), diuretic, allopurinol, cytostatic, immunosuppressant, p blocker, calcium antagonist, vasodilator, or another ACE inhibitor were excluded. Patients gave their informed consent to participate.
26F
THE
AMERICAN
Efficacy was evaluated at the start (baseline) and end of the study treatment (final) by bicycle ergometry, echo Doppler, sitting systolic and diastolic blood pressures (mercury sphygmomanometer), and heart rate. BICYCLE ERGOMETRY TEST: An initial load of20 W increased by 10 Wlmin was used. Exercise duration (minutes), maximum workload (watts), oxygen consumption (systolic blood pressure times heart rate product), systolic and diastolic blood pressures and heart rate at maximum exercise, and the reasons for stopping the test were recorded. ECHO DOPPLER: Ultrasonic studies were performed immediately after a lo-minute rest period. Systolic volume, cardiac output, ejection fraction, left ventricular end-diastolic diameter, left ventricular end-systolic diameter, intraventricular septum thickness, and posterior wall thickness were calculated. Safety was evaluated by the reporting of adverse reactions, baseline and final electrocardiograms, and biochemical, hematologic, and urine laboratory tests. The electrocardiogram was obtained using the standard 12 leads with the patient supine after a 5-minute rest. PQ and QT intervals and heart rate were monitored. Compliance with administration of the study treatment was assessed by making a residual capsule count. Statistical analysis: Statistical analysis was performed by means of the following tests: analysis of variance for repeated measures for quantitative continuous variables; chi-square test or Fisher’s exact test for frequency variables; and Student’s t test for quantitative continuous variables. The comparability of the treatment groups was investigated using the chi-square test for categorial and the unpaired t test for continuous variables. In addition, at baseline and after 8 weeks’ treatment (final), possible interactions between bicycle ergometric and echo Doppler parameters with concomitant digitalis therapy and the study treatment were investigated. Interaction was evaluated by means of multivariate analysis. A significance level of 0.05 (2-tailed test) was used. The number of patients exhibiting values outside the normal ranges for the laboratory test parameters was analyzed using the McNemar test, always using a level of significance of 0.05. The chi-square test was used for the analysis of frequencies between treatment groups. Study procedures:
Characteristics
JOURNAL
OF
CARDIOLOGY
VOLUME
75
JUNE
16.
1995
RESULTS A total of 198 patients were enrolled in the 13 study centers (Table I), of which 195 patients (96 delapril, 99 enalapril) were included in the analysis. Three patients were withdrawn prior to starting the active study treatment: 1 due to reinfarction, 1 lost to follow-up, and 1 declined to participate further. Analysis of the homogeneity of the 2 treatment groups with respect to age, gender, and disease characteristics failed to show any difference. Analysis of the homogeneity of the 2 treatment groups in terms of the efficacy parameters also failed to show any significant difference. Only 1 patient in each treatment group exhibited signs or symptoms of orthostatic hypotension during the study that resulted in the dose being reduced to the low dose for the remainder of the study. One patient in the delapril group was withdrawn due to left ventricular failure. Efficacy evaluation: BICYCLE ERGOMETRY: A statistically significant (p < 0.01) increase was seen in exercise duration, 19% in the delapril group and 22% in the enalapril group. No significant difference between the groups was found (Table II). At the end of the 8 weeks’ treatment period, there was a statistically significant (p 20% of patients. This increased to > 50% at the end of treatment in both treatment groups. ECHO DOPPLER: There was no difference between the groups for systolic volume. Cardiac output, however, significantly (p < 0.01) increased at the end of treatment in the delapril group (5.3 ? 2.09 liters/min vs 4.9 ? 2.16 liters/min), but there was no increase in the enalapril group (Table III). There was a significant (p
1 TABLE II Bicycle
I
Ergometry
Results
Parameter
Delapril
Exercise duration (min) Baseline Final Workload (w) Baseline Final Oxygen consumption* Baseline Final SBP Baseline Final DBP
Enalopril
5.6 e 1.66 6.6 r 1.7 66.1 76.0
+ 16.44 f 17.62
21,774.l 22,467.l
BOSelIne
Final
5.7 k 1.79 6.8 2 2.04 66.5 77.3
k 5405.29 f 4957.08
22,268.a 22,676.1
+ 17.92 + 20.69 f 5955.12 -t 5396.91
176.6 176.2
+ 27.29 + 22.35
181.8 179.1
+ 29.72 + 24.95
95.5 94.7
f 11 .a4 2 11.36
96.6 94.0
2 12.98 2 13.27t
122.0 126.0
2 18.51 2 18.46$
HR Baseline Final
i 22.8 126.6
+ 22.58 + 21 .OO$
*Systolic blood pressure times heart rote product tP < 0.05 vs baseline. $P < 0.01 vs baseline. Values are mew z SD; abbnwotions os in Table I.
TABLE Ill Echo
Doppler
Results
Parameter SV (ml/beat/m*) Baseline Final CO (liters/min) Baseline Final EF (%) Baseline FlllOl LVEDD (cm) Baseline Final LVESD (cm) Baseline Final IVS (cm) Baseline Final PW (cm) Baseline Final
Delapril
60.1 60.9
Enclopril
+ 19.12 e 18.35
63.9 64.3
4.9 -+ 2.16 5.3 + 2.09’ 45.0 48.6
2 23.09 + 20.57
5.2 f 2.15 5.4 f 2.09’
+ 11.76 2 12.35*
45.4 48.8
+ 12.36 t 12.41’
5.7 f 1.07 5.7 2 0.92
5.7 k 0.98 5.7 k 0.83
4.3 f 0.98 4.2 k 1 .Olt
4.4 2 0.94 4.3 2 0.94t
1 .O 2 0.24 1 .o + 0.20
1.0 + 0.21 1 .o f 0.21
1.0 -t 0.16 1 .o IT 0.20
1 .O + 0.16 1.0 + 0.14
*p < 0.01 vs bar&e. tp < 0.05 vs baseline. CO = cardiac output; EF = election froctlon; IVS = lntraventr~culor septum thickness; LVEDD = left ventricular end-diostollc diameter; LVESD = left ventricular end-systolic diameter; PW = posterior wall thickness; SV = systolic volume.
sion was significantly (p
A SYMPOSIUM:
NEW
ACE
INHIBITOR
27F
DISCUSSION After 8 weeks’ treatment with delapril or enalapril, the clinical symptoms of CHF were improved, reflected by a significant increase in the exercise period (19% in the delapril group and 22% in the enalapril group) and a significant increase in the load tolerated (16% in the delapril group and 18% in the enalapril group). There was no significant difference between the treatment groups. These results were confirmed also by the improvement in myocardial function: ejection fraction and cardiac output were significantly increased whereas left ventricular end-systolic dimension was significantly reduced in both treatment groups. In addition, no clinically relevant changes in blood pressure were evidenced. This result is important, as the signs and symptoms of hypotension are the most common reasons for suspending treatment with ACE inhibitors.8 Delapril and enalapril were equally well tolerated, few patients experienced adverse reactions, and no clinically or statistically significant changes in the electrocardiogram were seen. Delapri115 mg twice daily like enalapril 5 mg twice daily, was effective in improving signs and symptoms of CHF and was well tolerated.
FIGURE 1. Percent change (A%) in echo Doppler pammeten for both treatment groups. CO = cardiac output; EF = eiection fraction; IVS = intraventricular septum; LVEDD = left ventricular end-diastolic dimension; LVESD = left ventricular end-systolic dimension; PW = posterior wall.
1. Creager MA, Faxon DP, Cutler SS, Kohhnann 0, Ryan TJ, Gavras H. Contribution of vasopressin to vasoconstriction in patients with congestive heart failure. Comparison with the renin angiotensin system and sympathetic nervous system. I Am Cd Card01 1986;7:75&765. 2. Todd PA, Heel RC. Enalapril; review of its phamwcdynamic and phamw cokinetic properties and therapeutic use in hypertension and congestive heart failure. Dnrgs 1986;31:19&248. 3. Ogihara T, Nakamaru M, Higaki J. Effect of CV3317, an orally active converting enzyme inhibitor, in normal volunteers (phase I study). Jpn Phannaco1 Thm 1983,11:4663. 4. Comparison of the ACE inhibitors delapril and enalapril in mild to moderate essential hypertension. Takeda Pharma KF3317/04. Data on lile. 5. Miyakawa T, Minamisawa K, Yamada Y, Sasaki 0, Fujiki Y, Tochikubo 0, Ishii M. A study of the effects of delapril, a new angiotensin converting enzyme inhibitor, on the diurnal variation of arterial pressure in patients with essential hypertension using indirect and direct arterial pressure monitoring methods. Am J @p&eru 1991;4(suppl 1):2S-29s. 6. Portioli I. Phamwokinetic and pharmacodynamic study of delapril in elderly hypertensive patients. Chiesi Farmaceutici S.p.A. 1989. Data on file. 7. Fitzpatrick D, Nicholls MG, Ikram H, Espiner EA. Acute hemodynamic, hormonal and electrolyte effects and short-term clinical response to enalapril in heart failure. .I &r&ens 1983;l(suppl 1):147-153. 8. Sharpe DN, Murphy J, C&m R, Hannan SF. Enalapril in patients with chronic heart failure: a placebc-controlled, randomized, double-blind study. Cimhion 1984;70:221. 9. Cody RJ. Clinical and hemodynamic ezqxrience with enalapril in congestive heart failure. Am J Cnrdiol1985;55:36A4OA.
Three patients in each treatment group reported adverse reactions. In the delapril group, 1 patient reported vertigo, for which treatment was withdrawn, 1 patient who had nephrolithiasis reported left renal pain and spasm and another patient had diarrhea and asthenia. In the enalapril group, 1 patient reported severe pulmonary edema, for which treatment was withdrawn, 1 patient reported a cough, and another patient had headaches. There were no significant changes in the electrocardiographic parameters from baseline in either treatment group, nor between groups. There was no difference in the number of values outside the normal range for the biochemical, hematologic, and urine parameters within or between groups. All patients had >90% compliance with the study treatment administration. Safely evaluation:
28F
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
75
JUNE
16, 1995
Acanfora, Picone,
MD, Giuseppe Furgi, MD, Antimo Papa, MD, MD, Dino Franc0 Vitale, MD, Carlo Rengo, MD
To evaluate safety and efficacy of delapril versus enalapril in patients with congest’nre heart failure (CHF), New York Heart Association (NWA) class II and III, 198 patients were enrolled in a study in 13 centers involving a double-blind parallel group design. After completing a 2-week run-in period on placebo, patients were randomized to receive delapril 7.5 mg twice daily or enalapril 2.5 mg twice daily for 2 weeks. The dose was then doubled for the remaining 6 weeks. In this phase, 1 patient in each group experienced orthostatic hypotension; the dose was then reduced to the initial dose for study completion. A total of 195 patients received active treatment (96 delapril, 99 enalapril). After 8 weeks’ treatment, bicycle ergometry demonstrated a significant increase in exercise duration (p ~0.01)
and workload (p ~0.01). Echo Doppler investigations showed a significant reduction (p ~0.01) in left ventricular end-systolic volume associated with a significant increase (p ~0.01) in eiection fraction and cardiac output. No clinically significant changes in blood pressure, heart rate, electrocardiogram, or biochemical and hematologic tests were found. There were no significant differences between treatment groups. Three patients in each group experienced adverse reactions requiring withdrawal of 1 patient in each group. Delapril 15 mg twice daily, like enalapril 5 mg twice daily, was effective in improving signs and symptoms of CHF and was well tolerated. (Am J Cardioll995;75:25F-28F)
A
sion (World Health Organization stages I and II), exhibited a significant reduction in blood pressure.5,6 The aim of the study was to compare the safety and efficacy of delapril 15 mg twice daily with enalapril 5 mg twice daily given orally for an g-week period to patients with NYHA class II or III CHF. Enalapril is a known effective treatment for CHF.7-9
ngiotensin-converting enzyme (ACE) inhibitor drugs act on the renin-angiotensin ystem to produce vasodilation and a reduction of the arteriolar resistance as well as decreasing the fluid retention caused by aldosterone in patients with congestive heart failure (CHF).l ACE inhibitors also have a significant impact on the quality of life of patients with CHF and can prolong it in the medium term, particularly if treatment is started when signs and symptoms of ventricular dysfunction are not yet evident.2 Delapril (CV3317) is a new short-acting ACE inhibitor. After oral administration, it is rapidly converted to 2 active metabolites, CV3317-COOH and CV3317-(SOH)-COOH, with more potent antihypertensive effects and a half-life of <4 hours.3 As an ACE inhibitor, delapril is essentially equivalent to enalapril and superior to captopril.4 After 8 weeks of treatment with delapril, 70% of patients, with mild-to-moderate essential hyperten-
From the Clinica del Lavaro Foundation, Institute of Care and Scientific Research Medical Center of Campoli del Monte Taburna (BN), Italy (F.R., D.A., G.F., A.P., A.N., C.P.); and Institute of Internal Medicine, Cardiology and Cardiovascular Surgen/, Chair of Geriatrics, Federico II University, School of Medicine, Naples, Italy (F.R., D.F.V., CR.). Address for reprints: Franc0 Rengo, MD, lstituto di Medicina Inferno, Cardiologia e Chirurgia Cardiovascolare, Cattedra di Geriatria, Universita degli Studi Federico II, Facoltb di Medicina e Chirurgia, Via S. Pansini, 5,80131 Napoli, Italy.
PATIENTS AND METHODS Study design: The study took the form of a multicenter, randomized, double-blind, parallel group design. After a 2-week run-in period on placebo (1 capsule in the morning and 1 in the evening) during which nonpermitted concomitant treatments were withdrawn, patients were randomly assigned to receive delapril 7.5 mg twice daily or enalapril 2.5 mg twice daily for 2 weeks. The dose was then doubled for the remaining 6 weeks’ treatment. If any signs or symptoms of orthostatic hypotension occurred, the code was broken and the patient completed the study at the low dose. The study treatment tablets were encapsulated to maintain the double-blind conditions. Patient selection criteria: Patients of both sexes were included if they fulfilled the following criteria: between 25 and 70 years of age; able to exercise for 3-12 minutes on a bicycle ergometer; signs and symptoms of NYHA class II or III CHF, for at least A SYMPOSIUM:
NEW
ACE
INHIBITOR
25F
TABLE
I Patient
No.
%
63 36
64 36
Delopril
Enolopril
(n = 99)
(n = 99)
Mean
2 SD
No.
%
70 29
71 29
Mean
k SD
Sex Mole FWlole Age (vd Range Duration
60.5
+- 8.33 34-70
59.2
k 8.37 31-70
of disease
(4 SBP (mm Hg) DBP (mm Hg) HR (beats/min) NYHA Class II Class III Etiologic factor Cardiomyopathy Coronary artery disease Hypertension Digitalis therapy
10.1 1394 84.5 76.3
A + + -c
9.47 19.15 10.96 11.54
9.9 140.5 84.4 77.4
81
a2
18
18
79 20
80 20
34
34
33
33
41 24 32
41 24 32
45 21 33
46 21 33
DBP = diastolic blood pressure; HR = heart Assoc~at,on; SBP = systchc blood pressure
rate; NYHA
k 9.00 + 21.19 + 11.70 r
11.58
= New York Heart
3 months; if on digitalis, stabilized for at least 3 months; and a diagnosis of ischemic, dilatative, or hypertensive cardiomyopathy. Patients were excluded if they had acute heart failure or myocardial infarction in the previous 3 months, stroke in the previous 6 months, hypotension (systolic blood pressure <90 mm Hg or diastolic blood pressure ~60 mm Hg), resting angina or exercise angina (Canadian class > I), an exercise test in which the results might have been affected by various symptoms of CHF (intermittent claudication, symptomatic pulmonary disease, and severe neurologic or muscular disease), valvular disease likely to require surgery, severe mitral or aortic stenosis, acute myocarditis, pericarditis, hypertrophic cardiomyopathy (obstructive and nonobstructive), arrhythmias or conduction problems not controlled by therapy or pacemakers, hyperaldosteronism, renal artery stenosis, hemodialysis or only one functional kidney, renal or hepatic failure, unstable diabetes mellitus, collagen disease, hypokalemia or hyperkalemia (potassium < 3.0 or > 5.0 mmol/liter), severe allergic diathesis, or a family history of angioneurotic edema. Patients being treated with positive inotropic drug (excluding digitalis), diuretic, allopurinol, cytostatic, immunosuppressant, p blocker, calcium antagonist, vasodilator, or another ACE inhibitor were excluded. Patients gave their informed consent to participate.
26F
THE
AMERICAN
Efficacy was evaluated at the start (baseline) and end of the study treatment (final) by bicycle ergometry, echo Doppler, sitting systolic and diastolic blood pressures (mercury sphygmomanometer), and heart rate. BICYCLE ERGOMETRY TEST: An initial load of20 W increased by 10 Wlmin was used. Exercise duration (minutes), maximum workload (watts), oxygen consumption (systolic blood pressure times heart rate product), systolic and diastolic blood pressures and heart rate at maximum exercise, and the reasons for stopping the test were recorded. ECHO DOPPLER: Ultrasonic studies were performed immediately after a lo-minute rest period. Systolic volume, cardiac output, ejection fraction, left ventricular end-diastolic diameter, left ventricular end-systolic diameter, intraventricular septum thickness, and posterior wall thickness were calculated. Safety was evaluated by the reporting of adverse reactions, baseline and final electrocardiograms, and biochemical, hematologic, and urine laboratory tests. The electrocardiogram was obtained using the standard 12 leads with the patient supine after a 5-minute rest. PQ and QT intervals and heart rate were monitored. Compliance with administration of the study treatment was assessed by making a residual capsule count. Statistical analysis: Statistical analysis was performed by means of the following tests: analysis of variance for repeated measures for quantitative continuous variables; chi-square test or Fisher’s exact test for frequency variables; and Student’s t test for quantitative continuous variables. The comparability of the treatment groups was investigated using the chi-square test for categorial and the unpaired t test for continuous variables. In addition, at baseline and after 8 weeks’ treatment (final), possible interactions between bicycle ergometric and echo Doppler parameters with concomitant digitalis therapy and the study treatment were investigated. Interaction was evaluated by means of multivariate analysis. A significance level of 0.05 (2-tailed test) was used. The number of patients exhibiting values outside the normal ranges for the laboratory test parameters was analyzed using the McNemar test, always using a level of significance of 0.05. The chi-square test was used for the analysis of frequencies between treatment groups. Study procedures:
Characteristics
JOURNAL
OF
CARDIOLOGY
VOLUME
75
JUNE
16.
1995
RESULTS A total of 198 patients were enrolled in the 13 study centers (Table I), of which 195 patients (96 delapril, 99 enalapril) were included in the analysis. Three patients were withdrawn prior to starting the active study treatment: 1 due to reinfarction, 1 lost to follow-up, and 1 declined to participate further. Analysis of the homogeneity of the 2 treatment groups with respect to age, gender, and disease characteristics failed to show any difference. Analysis of the homogeneity of the 2 treatment groups in terms of the efficacy parameters also failed to show any significant difference. Only 1 patient in each treatment group exhibited signs or symptoms of orthostatic hypotension during the study that resulted in the dose being reduced to the low dose for the remainder of the study. One patient in the delapril group was withdrawn due to left ventricular failure. Efficacy evaluation: BICYCLE ERGOMETRY: A statistically significant (p < 0.01) increase was seen in exercise duration, 19% in the delapril group and 22% in the enalapril group. No significant difference between the groups was found (Table II). At the end of the 8 weeks’ treatment period, there was a statistically significant (p
1 TABLE II Bicycle
I
Ergometry
Results
Parameter
Delapril
Exercise duration (min) Baseline Final Workload (w) Baseline Final Oxygen consumption* Baseline Final SBP Baseline Final DBP
Enalopril
5.6 e 1.66 6.6 r 1.7 66.1 76.0
+ 16.44 f 17.62
21,774.l 22,467.l
BOSelIne
Final
5.7 k 1.79 6.8 2 2.04 66.5 77.3
k 5405.29 f 4957.08
22,268.a 22,676.1
+ 17.92 + 20.69 f 5955.12 -t 5396.91
176.6 176.2
+ 27.29 + 22.35
181.8 179.1
+ 29.72 + 24.95
95.5 94.7
f 11 .a4 2 11.36
96.6 94.0
2 12.98 2 13.27t
122.0 126.0
2 18.51 2 18.46$
HR Baseline Final
i 22.8 126.6
+ 22.58 + 21 .OO$
*Systolic blood pressure times heart rote product tP < 0.05 vs baseline. $P < 0.01 vs baseline. Values are mew z SD; abbnwotions os in Table I.
TABLE Ill Echo
Doppler
Results
Parameter SV (ml/beat/m*) Baseline Final CO (liters/min) Baseline Final EF (%) Baseline FlllOl LVEDD (cm) Baseline Final LVESD (cm) Baseline Final IVS (cm) Baseline Final PW (cm) Baseline Final
Delapril
60.1 60.9
Enclopril
+ 19.12 e 18.35
63.9 64.3
4.9 -+ 2.16 5.3 + 2.09’ 45.0 48.6
2 23.09 + 20.57
5.2 f 2.15 5.4 f 2.09’
+ 11.76 2 12.35*
45.4 48.8
+ 12.36 t 12.41’
5.7 f 1.07 5.7 2 0.92
5.7 k 0.98 5.7 k 0.83
4.3 f 0.98 4.2 k 1 .Olt
4.4 2 0.94 4.3 2 0.94t
1 .O 2 0.24 1 .o + 0.20
1.0 + 0.21 1 .o f 0.21
1.0 -t 0.16 1 .o IT 0.20
1 .O + 0.16 1.0 + 0.14
*p < 0.01 vs bar&e. tp < 0.05 vs baseline. CO = cardiac output; EF = election froctlon; IVS = lntraventr~culor septum thickness; LVEDD = left ventricular end-diostollc diameter; LVESD = left ventricular end-systolic diameter; PW = posterior wall thickness; SV = systolic volume.
sion was significantly (p
A SYMPOSIUM:
NEW
ACE
INHIBITOR
27F
DISCUSSION After 8 weeks’ treatment with delapril or enalapril, the clinical symptoms of CHF were improved, reflected by a significant increase in the exercise period (19% in the delapril group and 22% in the enalapril group) and a significant increase in the load tolerated (16% in the delapril group and 18% in the enalapril group). There was no significant difference between the treatment groups. These results were confirmed also by the improvement in myocardial function: ejection fraction and cardiac output were significantly increased whereas left ventricular end-systolic dimension was significantly reduced in both treatment groups. In addition, no clinically relevant changes in blood pressure were evidenced. This result is important, as the signs and symptoms of hypotension are the most common reasons for suspending treatment with ACE inhibitors.8 Delapril and enalapril were equally well tolerated, few patients experienced adverse reactions, and no clinically or statistically significant changes in the electrocardiogram were seen. Delapri115 mg twice daily like enalapril 5 mg twice daily, was effective in improving signs and symptoms of CHF and was well tolerated.
FIGURE 1. Percent change (A%) in echo Doppler pammeten for both treatment groups. CO = cardiac output; EF = eiection fraction; IVS = intraventricular septum; LVEDD = left ventricular end-diastolic dimension; LVESD = left ventricular end-systolic dimension; PW = posterior wall.
1. Creager MA, Faxon DP, Cutler SS, Kohhnann 0, Ryan TJ, Gavras H. Contribution of vasopressin to vasoconstriction in patients with congestive heart failure. Comparison with the renin angiotensin system and sympathetic nervous system. I Am Cd Card01 1986;7:75&765. 2. Todd PA, Heel RC. Enalapril; review of its phamwcdynamic and phamw cokinetic properties and therapeutic use in hypertension and congestive heart failure. Dnrgs 1986;31:19&248. 3. Ogihara T, Nakamaru M, Higaki J. Effect of CV3317, an orally active converting enzyme inhibitor, in normal volunteers (phase I study). Jpn Phannaco1 Thm 1983,11:4663. 4. Comparison of the ACE inhibitors delapril and enalapril in mild to moderate essential hypertension. Takeda Pharma KF3317/04. Data on lile. 5. Miyakawa T, Minamisawa K, Yamada Y, Sasaki 0, Fujiki Y, Tochikubo 0, Ishii M. A study of the effects of delapril, a new angiotensin converting enzyme inhibitor, on the diurnal variation of arterial pressure in patients with essential hypertension using indirect and direct arterial pressure monitoring methods. Am J @p&eru 1991;4(suppl 1):2S-29s. 6. Portioli I. Phamwokinetic and pharmacodynamic study of delapril in elderly hypertensive patients. Chiesi Farmaceutici S.p.A. 1989. Data on file. 7. Fitzpatrick D, Nicholls MG, Ikram H, Espiner EA. Acute hemodynamic, hormonal and electrolyte effects and short-term clinical response to enalapril in heart failure. .I &r&ens 1983;l(suppl 1):147-153. 8. Sharpe DN, Murphy J, C&m R, Hannan SF. Enalapril in patients with chronic heart failure: a placebc-controlled, randomized, double-blind study. Cimhion 1984;70:221. 9. Cody RJ. Clinical and hemodynamic ezqxrience with enalapril in congestive heart failure. Am J Cnrdiol1985;55:36A4OA.
Three patients in each treatment group reported adverse reactions. In the delapril group, 1 patient reported vertigo, for which treatment was withdrawn, 1 patient who had nephrolithiasis reported left renal pain and spasm and another patient had diarrhea and asthenia. In the enalapril group, 1 patient reported severe pulmonary edema, for which treatment was withdrawn, 1 patient reported a cough, and another patient had headaches. There were no significant changes in the electrocardiographic parameters from baseline in either treatment group, nor between groups. There was no difference in the number of values outside the normal range for the biochemical, hematologic, and urine parameters within or between groups. All patients had >90% compliance with the study treatment administration. Safely evaluation:
28F
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
75
JUNE
16, 1995