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Comparison of the antihypertensive effect of imidapril and enalapril in the treatment of mild to moderate essential hypertension: a randomized, double-blind, parallel-group study
VOL. 62, No. 6, JUNE 2001
Comparison of the Antihypertensive Effect of lmidapril and Enalapril in the Treatment of Mild to Moderate Essential Hypertension: A Randomized, Double-Blind, Parallel-Group Study Reinhard van der Does, MD,’ and Rolf Euler, PhD2 ‘/ST CmbH, Mannheim, Darmstadt, Germany
and *Therapeutic Area Cardiovascular, Merck KGaA,
ABSTRACT
Budgmund: Imidapril is a novel angiotensin-converting enzyme (ACE) inhibitor that has been shown to be effective in the treatment of mild to moderate hypertension at doses ranging from 5 to 40 mg. 06je&ve: The purpose of this study was to compare the antihypertensive efficacy of imidapril (5-10 mg daily) with that of the ACE inhibitor enalapril (5-10 mg daily) in patients with essential hypertension. Metro& After a 4-week, single-blind, placebo run-in phase, patients were randomized to receive imidapril 5 to 10 mg daily or enalapril 5 to 10 mg daily for 12 weeks. The dose of medication could be doubled if mean sitting diastolic blood pressure @BP) remained >90 mm Hg after 4 weeks of treatment. Response was defined as sitting DBP 190 mm Hg or a reduction in sitting DBP of 210 mm Hg compared with baseline. Efficacy and safety were evaluated in the intent-to-treat population. Redts: A total of 353 patients from 24 centers were randomized to treatment (176 imidapril; 177 enalapril); 341 completed the trial. One patient did not receive study medication; the intent-to-treat population therefore consisted of 352 patients. There was no difference between groups in the proportion of patients who responded favorably to treatment with imidapril (131/175 [ 74.9%]) or enalapril (131/l 77 [ 74.0%]). Clinically relevant reductions in sitting and standing DBP and systolic blood pressure were apparent after 2 weeks of treatment, and there was a trend toward further reductions for the remainder of the study period in both treatment groups. There was no significant difference in the numbers of patients with rl adverse event between the imidapril group (76/175 [43.4%]) and the enalapril group (86/177 [48.6%]). In both treatment groups, the most common adverse events (occurring in >5% of patients) were headache, bronchitis, cough, and upper respiratory tract infections. Accepted for publication April 4, 200 1. Printed in the USA. Reproduction in whole or part is not permitted.
0011-393x/01/$1
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There was no difference between groups in the incidence of treatment-related adverse events. Conclusions: The results of this study suggest that imidapril and enalapril are equally effective and well tolerated in patients with mild to moderate essential hypertension. The dose range of 5 to 10 mg for imidapril was appropriate for the treatment of patients with essential hypertension. Key wonis: imidapril, essential hypertension, antihypertensive, enalapril. (Gun- Ther Res Clin Exp. 2001;62:437-450)
INTRODUCTION
Because of their efficacy and tolerability, angiotensinconverting enzyme (ACE) inhibitors are well established in the treatment of mild to moderate hypertension.’ lmidapril is a novel ACE inhibitor that does not contain a sulfhydryl moiety; it is a prodrug that is converted to its active metabolite imidaprilat mainly in the liver.* A placebo-controlled, dose-finding study3 of imidapril5 to 40 mg once daily reported that although imidapri15 mg was more effective than placebo, the difference was not significant; however, imidapril at doses ranging from 10 to 40 mg was more effective than placebo and imidapril5 mg. There was no significant difference in the antihypertensive effects of imidapril in the range of 10 to 40 mg.3 An S-week, double-blind, dose-titration study4 concluded that at dosages between 5 and 20 mg daily, imidapril is more effective than placebo. Based on these results, imidapril5 mg appears to be an appropriate initial dose. If optimum control of blood pressure is not achieved after 3 weeks of treatment, the daily dose should be increased to 10 mg, which has been determined to be the most effective daily dose. Enalapril is an ACE inhibitor widely used in the treatment of hypertension. The primary objective of this study was to evaluate the antihypertensive efficacy of imidapri15 to 10 mg once daily versus enalapri15 to 10 mg once daily in patients with mild to moderate essential hypertension. Each regimen was individually titrated to effect. Secondary objectives were to compare the effects of the 2 agents on heart rate, physical examination findings, electrocardiogram (ECG) recordings, and laboratory values, and to compare the incidence of adverse events associated with the 2 agents. PATiENTS AND METHODS Patients
Patients aged 18 to 75 years with mild to moderate essential hypertension (mean sitting diastolic blood pressure [DBP] 295 and 1115 mm Hg) were eligible for the study. Exclusion criteria were severe hypertension @BP >115 mm Hg or systolic blood pressure [SBP] >240 mm Hg); malignant or secondary hypertension; myocardial infarction within the past 3 months; severe cardiac disease, unstable angina pectoris, Prinzmetal’s angina, cerebro-
438
R. van der Does and R. Euler
vascular accident, or transient ischemic attack within the past 6 months; cardiac arrhythmias requiring therapy; reduced renal or liver function; proteinuria; abnormal serum potassium values; unstable or poorly controlled diabetes; or clinically relevant endocrine or hematopoietic disorders. Concomitant use of other antihypertensive drugs, antiarrhythmic agents, nonsteroidal antiinflammatory agents (with the exception of aspirin), immunosuppressants, oral contraceptives, and drugs likely to affect gastrointestinal absorption was not permitted. The study was approved by local ethics committees and conducted in accordance with the principles of the Declaration of Helsinki. All patients provided written informed consent for study participation. Study Design
This was a controlled, multicenter (24 centers), randomized, double-blind, double-dummy, comparative dose-titration study with 2 parallel treatment groups. The study consisted of a 4-week, single-blind, placebo run-in period followed by a 12-week, double-blind, active-treatment period (Figure 1). Before the placebo period, a medical history was obtained and physical examination was performed for all patients. Patients were randomized to receive either imidapril5 to 10 mg once daily or enalapri15 to 10 mg once daily. After 4 weeks of active treatment, the dose of study medication could be doubled if mean sitting DBP remained >90 mm Hg (Figure 1). Methods
Blood pressure was measured at each visit using a standard mercury sphygmomanometer 24 f 3 hours after the last dose of study medication at the end of each week of the placebo run-in period and the activetreatment period.
Dose increase if mean sitting diastolic blood ~t~~~;90 mm Hg
lmidapril
10 mg/d
lmidaprll5
mg/d
Placebo
I Enalapril 5 mg/d Enalapril 10 mg/d +
Placebo run-in period a I
Week-4 Visit 1
Figure
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1. Study
I
Week-l Visit 3
Active-treatment I I
Week0 vlslt 4
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Week 2 Visit 5
I
Week4 Visit 6
period -1 I
Week6 Vlsit 7
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Week8 Visit 8
Week 12 vlslt 9
design.
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Measurements were taken over a period of 3 minutes, with the patient in the sitting position after 5 minutes of rest. To detect any orthostatic hypotensive reactions, a single blood pressure measurement was taken with the patient in the standing position 2 minutes after standing up. Heart rate was determined at each visit by counting the radial pulse over 30 seconds immediately after the blood pressure measurements. Urine samples-were collected at week 3 of the placebo run-in period and at week 12 of the active-treatment period. Blood samples for hematology and biochemistry evaluations were drawn at week 3 of the placebo run-in period, and at weeks 2 and 12 of the active-treatment period. Hematology evaluations included hemoglobin, hematocrit, red blood cell count, white blood cell count, platelet count, and erythrocyte sedimentation rate. Biochemistry evaluations included measurements of sodium, potassium, creatinine, calcium, urea, uric acid, glucose, lipids (triglycerides, total cholesterol, high-density and low-density lipoprotein cholesterol), and liver enzymes (alanine aminotransferase, aspartate aminotransferase, y-glutamyltransferase, alkaline phosphatase, and total bilirubin). ECG recordings were made at week 0 and week 12 of the treatment period, or on the day of premature discontinuation. Compliance was assessed by tablet counts at each visit. Statistical Analysis
The primary efficacy variable was the response rate after 12 weeks of treatment (last observation carried forward). Response was defined as a DBP reading of 590 mm Hg or a reduction in sitting DBP of 210 mm Hg compared with baseline. Secondary efficacy variables were the differences in sitting/standing DBP and SBP compared with baseline values. Safety variables evaluated were adverse events, physical examination findings, ECG recordings, heart rate, and laboratory parameters. The safety and intent-to-treat populations included all randomized patients who had taken 5: 1 dose of study drug. The per-protocol population included all patients who were treated according to the protocol. The primary analysis of efficacy was performed on the intent-to-treat population, and a supportive analysis was made on the per-protocol population. Differences in response rates between the treatment groups were assessed using the Fisher exact test (confirmatory analysis), and 2-way analysis of variance was performed for the secondary variables with respect to the parallelgroup design (descriptive analysis). The 95% Cls were calculated for the differences between the 2 treatment groups, and mean differences between measurements at various time points within each treatment group were computed with 95% Cls. If the Cf did not include zero, the mean differences were interpreted as statistically significant (paired t test, 2-sided, descriptive analysis). Significance was set at the 5% level. All other variables, including safety, were analyzed descriptively.
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R. van der Does and R. Euler
RESULTS A total of 353 patients were randomized to treatment with imidapril (n = 176) or enalapril (n = 177); 341 patients completed the trial. All randomized patients, except 1 who received no study medication and withdrew from the study immediately after randomization for personal reasons, were included in the intent-to-treat analysis for efficacy and safety. The per-protocol analysis included 300 patientsm154 in the imidapril group and 146 in the enalapril group. The treatment groups were well matched in both the per-protocol and intent-to-treat populations with respect to sex, age, b o d y weight, blood pressure, and heart rate (Table I). All patients were white, and there were no differences between treatment groups in the mean duration of hypertension, previous and concomitant medication use, medical history, concomitant diseases, height, and ECG results. Efficacy There was no difference in response rates (mean sitting DBP <-90 mm Hg or reduction of >10 mm Hg) between groups treated with imidapril (131/175 [74.9%]) and enalapril (131/177 [74.0%]) (P = 0.90; 95% CI, -0.088-0.106). Blood pressure was normalized in 69.7% (122/175) of imidapril-treated patients and 67.8% (120/177) of enalapril-treated patients (Table II). At the end of the study period, 85 of 175 patients (48.6%) in the imidapril group were receiving 5 mg and 90 patients (51.4%) were receiving 10 mg. In the enalapril group, 79 of 177 patients (44.6%) were receiving 5 mg and 98 patients
Table I.
Baseline patient characteristics. Intent-to-Treat Population
Sex, no. (%) Male Female Age, y, mean _ SD Body weight, kg, mean _ SD Sitting SBP, m m Hg, mean ± SEM Sitting DBP, m m Hg, mean ± SEM Heart rate, bpm, mean ± SEM
Per-Protocol Population
Imidapril (n = 175)
Enalapril (n = 177)
Imidapril (n = 154)
Enalapril (n = 146)
86 (49.1) 89 (50.9) 58.4 _ 10.1
76 (42.9) 101 (57.1) 57.8 _ 10.0
74 (48.1) 80 (51.9) 58.4 ± 10.4
60 (41.1) 86 (58.9) 58.1 ± 9.4
76.84 _ 11.0
77.28 _ 10.2
76.2 ± 10.8
76.8 _ 10.1
166.2 ± 1.1
164.9 ± 1.1
166.3 ± 1.2
165.1 ± 1.2
101.8 ± 0.3
102.2 ± 0.4
101.7 ± 0.4
102.3 ± 0.4
74.2 ± 0.7
74.1 ± 0.6
73.8 ± 0.7
74.3 ± 0.7
SBP = systolic blood pressure; DBP = diastolic blood pressure.
441
53 (29.9) 69 (39.0)
82 (46.9)
89 (50.3)
88 (50.3)
96 (54.2)
6
97 (54.8)
97 (55.4)
108 (61 .O)
106 (60.6)
117 (66.1)
116 (66.3)
Week
DBP = diastolic blood pressure. *Response was defined as a DBP reading 590 mm Hg or a reduction in DBP of ~10 mm Hg.
Enalapril
68 (38.9)
78 (44.1)
DBP 190 mm Hg lmidapril
69 (39.4)
Enalapril
mm Hg
DBP decrease lmidapril
210
85 (48.6) 84 (47.5)
Enalapril
Week 4
(n = 177).
8
114 (64.4)
116 (66.3)
118 (66.7)
126 (72.0)
132 (74.6)
132 (75.4)
Week
No. (%) of Patients (All Doses)
(n = 175) or enalapril
97 (55.4)
with imidapril
Week 2
II. Response rates to treatment
Response* lmidapril
Table
12
117 (66.1)
122 (69.7)
120 (67.8)
117 (66.9)
128 (72.3)
130 (74.3)
Week
120 (67.8)
122 (69.7)
123 (69.5)
118 (67.4)
131 (74.0)
131 (74.9)
Final
R. van der Does and R. Euler
(55.4%)were receiving
10 mg. Mean doses at the end of the study period were 7.6 mg in the imidapril group and 7.8 mg in the enalapril group. When response rates were evaluated according to the dose of study medication (high dose vs low dose), we found that response rates increased in patients switched from low to high doses in both treatment groups. However, response rates continued to be lower in the high-dose subgroups compared with patients receiving lower doses. In the per-protocol population, response rates tended to be higher than in the intent-to-treat population, and again there was no difference between the 2 treatment groups. Clinically relevant reductions in sitting and standing SBP and DBP occurred in both treatment groups after 2 weeks of active treatment, and there was a trend toward further decreases in sitting SBP and DBP during the course of the study (Table 111and Figure 2). There were no further reductions in blood pressure in patients continuing with low-dose treatment after 4 weeks of active therapy, but DBP continued to decrease in those patients who had been switched to higher doses at week 4 (Figure 3). Heart rate remained constant throughout the study period. The results were similar in the intent-to-treat and the per-protocol populations. Safety Adverse Events
Serious adverse events were reported in 6 patients (2 in the imidapril group and 4 in the enalapril group) during the active-treatment period, and these were considered to be unrelated or remotely related to the study medication. In the imidapril group, the serious adverse events were malignant neoplasm of the tongue and mouth and rupture of an ovarian cyst. In the enalapril group, the serious adverse events were necrotic appendicitis, hypertensive crisis, recurrence of a squamous cell bladder carcinoma, and recurrence of a malignant breast neoplasm. Three of these adverse events, all in the enalapril group, led to patient withdrawal from the study. There were no additional withdrawals due to adverse events during active treatment. The number of patients with 21 adverse event was lower in the imidapril group (76/175 [43.4%]) than in the enalapril group (86/177 [48.6%]). The most common adverse events (~5%) were headache, bronchitis, cough, and upper respiratory tract infections in both groups. Musculoskeletal pain at various sites occurred with an incidence >5% only in the imidapril group. Adverse events occurring in >2% of patients were lumbar disorders, neck pain, and dizziness in both groups; nausea and conjunctival disorders in the imidapril group; and gastritis, pharyngitis, and skin disorders in the enalapril group. In general, the adverse-event profiles of imidapril and enalapril were similar. There were no differences between treatment groups in the incidence of adverse events that were judged to be possibly, probably, or highly probably related to the study medication (Table IV). Adverse events such as headache,
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upper respiratory tract infection, and bronchitis were also reported placebo run-in period, although only 1 patient reported cough.
during the
Laboratoory Values and Other Variables No changes in hematology or serum biochemistry
values were observed during active treatment. One case of leukopenia in the imidapril group resolved when treatment was discontinued. In the enalapril group, 1 patient had increased serum creatinine levels. Neither imidapril nor enalapril appeared likely to be associated with an elevated risk of orthostatic hypotension. There were no relevant changes in resting ECG measurements during active treatment, and no trends in body weight changes were noted. Patient compliance ranged from 98.0% to 99.3% in the 2 treatment groups. DISCUSSION
The long-acting ACE inhibitor imidapril, which was first developed in Japan,2 has been evaluated for efficacy and safety in the treatment of essential hypertension in clinical studies in Japan and Europe.S’o Results from those studies have shown that imidapril is effective and well tolerated in patients with hypertension. The present study was designed to compare the efficacy and safety of imidapril 5 to 10 mg once daily with enalapril 5 to 10 mg once daily in the treatment of essential hypertension. Both ACE inhibitors significantly lowered blood pressure, and there was no difference in response rates between the 2 treatment groups (imidapril, 74.9%; enalapril, 74.0%). The mean reductions tn
445
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R. van der Does and R. Euler
Table IV. Number (%) of patients experiencing adverse events possibly, probably, or highly probably related (according to investigator’s judgment) to study medication. No. (96) of Patients
Adverse Event
lmidapril (n = 175)
Enalapril (n = 177)
Total Headache Cough Dizziness Nausea Diarrhea Giddiness Bronchitis Dry nose and throat Palpitation Tachycardia Leg cramps Cephalgia Fainting Skin tingling Hypertensive crisis Castralgia Vomiting Stretching sensation in skin Speech disorder Dyspnea Tiredness
21 9 5 4 3 2 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0
25 10 7 4 2 0 2 0 0 0 1 1 1 1 1 1 1 1 1 1 1 1
(12.0) (5.1) (2.9) (2.3) (1.7) (1 .l) (0.6) (0.6) (0.6) (0.6) (0.6) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0)
(14.1) (5.6) (4.0) (2.3) (1 .l) (0.0) (1 .l) (0.0) (0.0) (0.0) (0.6) (0.6) (0.6) (0.6) (0.6) (0.6) (0.6) (0.6) (0.6) (0.6) (0.6) (0.6)
sitting DBP (-12.9 mm Hg in the imidapril group and -13.2 mm Hg in the enalapril group) and SBP (-16.6 mm Hg and -15.8 mm Hg, respectively) were similar in the 2 groups. Clinically relevant decreases in standing SBP and DBP occurred in both treatment groups. Heart rate values remained constant in both treatment groups. Similar results were obtained in the per-protocol population. More than half of the study patients had their medication dose titrated upward after 4 weeks of active treatment. Among patients who continued taking low doses throughout the study period, there was a marked reduction in sitting DBP within the first 4 weeks of treatment, and no further clinically relevant changes occurred after week 4. In the high-dose cohorts, there was a modest decrease in sitting DBP during the first 2 weeks of active treatment with no changes between weeks 2 and 4. After increasing the dose at week 4, there was a marked reduction in blood pressure during the next 2 weeks. Response rates, however, continued to be lower in the high-dose subgroups; thus, patients who
447
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were switched to the higher doses may have been more refractory to antihypertensive treatment. Response rates in the per-protocol population were higher than those in the intent-to-treat population, although there was no difference between treatment groups. These findings suggest that treatment with imidapril should be initiated at a dose of 5 mg once daily. If optimum control of blood pressure has not been achieved within 4 weeks of initiating treatment, the daily dose should be increased to 10 mg. Overall, the magnitude of the antihypertensive effect and the response rates seen with both treatment groups were comparable to those noted in previous studies with enalapril and other ACE inhibitors. l1 The antihypertensive effects of enalapril were as expected; thus, from the point of efficacy, the comparison appears to be a valid one, despite the lack of a placebo control. Moreover, the safety data were obtained in a patient population that was being adequately treated. All patients enrolled in the present study were white; therefore, our results are applicable to this group of patients and cannot be generalized. Monotherapy with ACE inhibitors has been shown to be less effective in African Americans; however, the addition of diuretics may markedly improve the response in these patients.12 There was no significant difference between treatment groups in the proportion of patients with ~1 adverse event. It should be noted, however, that the study was not powered to demonstrate equivalence between the 2 treatments. The incidence of adverse events classified as at least possibly related to the test drug was comparable in the 2 treatment groups; these adverse events included headache, cough, and dizziness. Many of the adverse events were also observed during the placebo run-in period. Overall, there were no unexpected or previously unknown adverse events, and their distribution was similar in the imidapril and enalapril groups. The overall safety profile of both drugs was comparable to previously reported data for enalapril,13 and for ACE inhibitors in general.14 The proportion of patients with cough, an adverse event specific to ACE inhibitors, was also comparable in the 2 treatment groups. However, a comparative study in Japan that assessed the incidence of cough associated with ACE inhibitors showed that the incidence was significantly lower with imidapril than with enalapril. l5 Additional studies focusing on cough incidence in patients receiving imidapril versus other ACE inhibitors are warranted. The present study enrolled mainly patients with uncomplicated hypertension who had or had not received previous antihypertensive therapy. It should be noted that according to the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure,12 beta-blockers and diuretics should be considered as initial drug choices in patients with uncomplicated hypertension. The use of ACE inhibitors is recommended for patients who do not respond adequately to initial therapy or pa-
R. van der Does and R. Euler
tients with certain comorbidities, such as heart failure, diabetes, and renal insufficiency. CONCLUSIONS
There was no statistically significant difference between the imidapril and enalapril treatment groups in terms of antihypertensive response. Both imidapril and enalapril reduced elevated blood pressure levels effectively, and the dose range of 5 to 10 mg for both ACE inhibitors was appropriate for the treatment of patients with essential hypertension. Both treatments were well tolerated, and the safety profile in this study was in agreement with data from other trials of ACE inhibitors. There were no unexpected adverse events considered to be causally related to the study medication. ACKNOWLEDGMENTS
This study was sponsored by Merck KGaA, Darmstadt, Germany. We thank all the investigators who took part in the study. REFERENCES 1. Unger T, Gohlke P. Converting enzyme inhibitors in cardiovascular therapy: Current status and future potential. Cardiovasc Res. 1994;28:146-158. 2. Kubo M, Kato J, Ishida R, et al. Pharmacological studies on (4S)-l-methyl-3[(2S)-2{N-((lS)-l-ethoxycarbonyl-3-phenylpropyl)amino}propionyl]-2-oxo-imidazoline-4carboxylic acid hydrochloride (TA6366), a new ACE inhibitor: I. ACE inhibitory and antihypertensive activities. Jpn J fhamacol. 1990;53:201-210. 3. Vandenburg MJ, Mackay EM, Dews I, et al. Dose finding studies with imidapril-a new ACE inhibitor. Br J Chin Pharrnacol. 1994;37:265-272. dose titration 4. Vandenburg M, Mackay E, Pullan T, et al. An 8 week placebocontrolled study of imidapril in the treatment of mild to moderate essential hypertension. Br J Clin Pharmacol. 1995;39:93P. Abstract. 5. Pinto YM, van Veldhuisen DJ, Tjon-Ka-Jie RT, et al. Dose-finding study of imidapril, a novel angiotensin converting enzyme inhibitor, in patients with stable chronic heart failure. Eur J Clin Phannacol. 1996;50:265-268. 6. Saruta T, Omae T, Yoshinaga K, et al. Effect of ACE/TA-6366 (imidapril hydrochlo ride), angiotensin-converting enzyme inhibitor, on diurnal blood pressure change in essential hypertension. J Clin Ther Med. 1991;7:2205-2219. 7. Saruta T, Omae T, Yoshinaga K, et al. Efficacy and safety of imidapril (ACE/TA-6366), angiotensin I converting enzyme inhibitor, in monotherapy on essential hypertension-multiclinic open trial. J Clin Ther Med. 1991:7:24&G2504. 8. Saruta T, Omae T, Yoshinaga K, et al. Efficacy and safety of imidapril hydrochloride (ACE/TA-6366), angiotensin converting enzyme inhibitor, on essential hypertension in the long-term treatment. J C’lin 77zel:Med. 1991;7:2715-2735. 9. Suzuki N, Mori M, Kusano S. Circadian variation in blood pressure and pharmacokinetics following single and consecutive doses of angiotensinconverting enzyme
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11. 12.
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inhibitor ACE/TA-6366 (imidapril hydrochloride) in patients with essential hypertension. Jpn J Clin Exp Med. 1992;69:320-332. Saruta T, Omae T, Kuramochi M, et al. Imidapril hydrochloride in essential hypertension: A double-blind comparative study using enalapril maleate as a control. J Hyperfens. 1995;13 (Suppl 3):S23-S30. Frampton JE, Peters DH. Ramipril. An updated review of its therapeutic use in essential hypertension and heart failure. Drugs. 1995;49:440-466. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Bethesda, Md: National Institutes of Health; 1997. Publication No. 98-4080. Todd PA, Goa KL. Enalapril. A reappraisal of its pharmacology and therapeutic use in hypertension. Drugs. 1992;43:346-381. Parish RC, Miller LJ. Adverse effects of angiotensinconverting enzyme (ACE) inhibitors. An update. Drug Saf. 1992;7:14-31. Saruta T, Arakawa K, Iimura 0, et al. Difference in the incidence of cough induced by angiotensin converting enzyme inhibitors: A comparative study using imidapril hydrochloride and enalapril maleate. Hyperfens Res C/in Exp. 1999;22:197-202.
Address correspondence to: Reinhard van der Does, MD
IST GmbH Kruegerstrasse 7-l 1 D862 19 Mannheim Germany Email: [email protected]
450
Comparison of the Antihypertensive Effect of lmidapril and Enalapril in the Treatment of Mild to Moderate Essential Hypertension: A Randomized, Double-Blind, Parallel-Group Study Reinhard van der Does, MD,’ and Rolf Euler, PhD2 ‘/ST CmbH, Mannheim, Darmstadt, Germany
and *Therapeutic Area Cardiovascular, Merck KGaA,
ABSTRACT
Budgmund: Imidapril is a novel angiotensin-converting enzyme (ACE) inhibitor that has been shown to be effective in the treatment of mild to moderate hypertension at doses ranging from 5 to 40 mg. 06je&ve: The purpose of this study was to compare the antihypertensive efficacy of imidapril (5-10 mg daily) with that of the ACE inhibitor enalapril (5-10 mg daily) in patients with essential hypertension. Metro& After a 4-week, single-blind, placebo run-in phase, patients were randomized to receive imidapril 5 to 10 mg daily or enalapril 5 to 10 mg daily for 12 weeks. The dose of medication could be doubled if mean sitting diastolic blood pressure @BP) remained >90 mm Hg after 4 weeks of treatment. Response was defined as sitting DBP 190 mm Hg or a reduction in sitting DBP of 210 mm Hg compared with baseline. Efficacy and safety were evaluated in the intent-to-treat population. Redts: A total of 353 patients from 24 centers were randomized to treatment (176 imidapril; 177 enalapril); 341 completed the trial. One patient did not receive study medication; the intent-to-treat population therefore consisted of 352 patients. There was no difference between groups in the proportion of patients who responded favorably to treatment with imidapril (131/175 [ 74.9%]) or enalapril (131/l 77 [ 74.0%]). Clinically relevant reductions in sitting and standing DBP and systolic blood pressure were apparent after 2 weeks of treatment, and there was a trend toward further reductions for the remainder of the study period in both treatment groups. There was no significant difference in the numbers of patients with rl adverse event between the imidapril group (76/175 [43.4%]) and the enalapril group (86/177 [48.6%]). In both treatment groups, the most common adverse events (occurring in >5% of patients) were headache, bronchitis, cough, and upper respiratory tract infections. Accepted for publication April 4, 200 1. Printed in the USA. Reproduction in whole or part is not permitted.
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There was no difference between groups in the incidence of treatment-related adverse events. Conclusions: The results of this study suggest that imidapril and enalapril are equally effective and well tolerated in patients with mild to moderate essential hypertension. The dose range of 5 to 10 mg for imidapril was appropriate for the treatment of patients with essential hypertension. Key wonis: imidapril, essential hypertension, antihypertensive, enalapril. (Gun- Ther Res Clin Exp. 2001;62:437-450)
INTRODUCTION
Because of their efficacy and tolerability, angiotensinconverting enzyme (ACE) inhibitors are well established in the treatment of mild to moderate hypertension.’ lmidapril is a novel ACE inhibitor that does not contain a sulfhydryl moiety; it is a prodrug that is converted to its active metabolite imidaprilat mainly in the liver.* A placebo-controlled, dose-finding study3 of imidapril5 to 40 mg once daily reported that although imidapri15 mg was more effective than placebo, the difference was not significant; however, imidapril at doses ranging from 10 to 40 mg was more effective than placebo and imidapril5 mg. There was no significant difference in the antihypertensive effects of imidapril in the range of 10 to 40 mg.3 An S-week, double-blind, dose-titration study4 concluded that at dosages between 5 and 20 mg daily, imidapril is more effective than placebo. Based on these results, imidapril5 mg appears to be an appropriate initial dose. If optimum control of blood pressure is not achieved after 3 weeks of treatment, the daily dose should be increased to 10 mg, which has been determined to be the most effective daily dose. Enalapril is an ACE inhibitor widely used in the treatment of hypertension. The primary objective of this study was to evaluate the antihypertensive efficacy of imidapri15 to 10 mg once daily versus enalapri15 to 10 mg once daily in patients with mild to moderate essential hypertension. Each regimen was individually titrated to effect. Secondary objectives were to compare the effects of the 2 agents on heart rate, physical examination findings, electrocardiogram (ECG) recordings, and laboratory values, and to compare the incidence of adverse events associated with the 2 agents. PATiENTS AND METHODS Patients
Patients aged 18 to 75 years with mild to moderate essential hypertension (mean sitting diastolic blood pressure [DBP] 295 and 1115 mm Hg) were eligible for the study. Exclusion criteria were severe hypertension @BP >115 mm Hg or systolic blood pressure [SBP] >240 mm Hg); malignant or secondary hypertension; myocardial infarction within the past 3 months; severe cardiac disease, unstable angina pectoris, Prinzmetal’s angina, cerebro-
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R. van der Does and R. Euler
vascular accident, or transient ischemic attack within the past 6 months; cardiac arrhythmias requiring therapy; reduced renal or liver function; proteinuria; abnormal serum potassium values; unstable or poorly controlled diabetes; or clinically relevant endocrine or hematopoietic disorders. Concomitant use of other antihypertensive drugs, antiarrhythmic agents, nonsteroidal antiinflammatory agents (with the exception of aspirin), immunosuppressants, oral contraceptives, and drugs likely to affect gastrointestinal absorption was not permitted. The study was approved by local ethics committees and conducted in accordance with the principles of the Declaration of Helsinki. All patients provided written informed consent for study participation. Study Design
This was a controlled, multicenter (24 centers), randomized, double-blind, double-dummy, comparative dose-titration study with 2 parallel treatment groups. The study consisted of a 4-week, single-blind, placebo run-in period followed by a 12-week, double-blind, active-treatment period (Figure 1). Before the placebo period, a medical history was obtained and physical examination was performed for all patients. Patients were randomized to receive either imidapril5 to 10 mg once daily or enalapri15 to 10 mg once daily. After 4 weeks of active treatment, the dose of study medication could be doubled if mean sitting DBP remained >90 mm Hg (Figure 1). Methods
Blood pressure was measured at each visit using a standard mercury sphygmomanometer 24 f 3 hours after the last dose of study medication at the end of each week of the placebo run-in period and the activetreatment period.
Dose increase if mean sitting diastolic blood ~t~~~;90 mm Hg
lmidapril
10 mg/d
lmidaprll5
mg/d
Placebo
I Enalapril 5 mg/d Enalapril 10 mg/d +
Placebo run-in period a I
Week-4 Visit 1
Figure
Week-2 visit 2
1. Study
I
Week-l Visit 3
Active-treatment I I
Week0 vlslt 4
I
Week 2 Visit 5
I
Week4 Visit 6
period -1 I
Week6 Vlsit 7
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Week8 Visit 8
Week 12 vlslt 9
design.
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Measurements were taken over a period of 3 minutes, with the patient in the sitting position after 5 minutes of rest. To detect any orthostatic hypotensive reactions, a single blood pressure measurement was taken with the patient in the standing position 2 minutes after standing up. Heart rate was determined at each visit by counting the radial pulse over 30 seconds immediately after the blood pressure measurements. Urine samples-were collected at week 3 of the placebo run-in period and at week 12 of the active-treatment period. Blood samples for hematology and biochemistry evaluations were drawn at week 3 of the placebo run-in period, and at weeks 2 and 12 of the active-treatment period. Hematology evaluations included hemoglobin, hematocrit, red blood cell count, white blood cell count, platelet count, and erythrocyte sedimentation rate. Biochemistry evaluations included measurements of sodium, potassium, creatinine, calcium, urea, uric acid, glucose, lipids (triglycerides, total cholesterol, high-density and low-density lipoprotein cholesterol), and liver enzymes (alanine aminotransferase, aspartate aminotransferase, y-glutamyltransferase, alkaline phosphatase, and total bilirubin). ECG recordings were made at week 0 and week 12 of the treatment period, or on the day of premature discontinuation. Compliance was assessed by tablet counts at each visit. Statistical Analysis
The primary efficacy variable was the response rate after 12 weeks of treatment (last observation carried forward). Response was defined as a DBP reading of 590 mm Hg or a reduction in sitting DBP of 210 mm Hg compared with baseline. Secondary efficacy variables were the differences in sitting/standing DBP and SBP compared with baseline values. Safety variables evaluated were adverse events, physical examination findings, ECG recordings, heart rate, and laboratory parameters. The safety and intent-to-treat populations included all randomized patients who had taken 5: 1 dose of study drug. The per-protocol population included all patients who were treated according to the protocol. The primary analysis of efficacy was performed on the intent-to-treat population, and a supportive analysis was made on the per-protocol population. Differences in response rates between the treatment groups were assessed using the Fisher exact test (confirmatory analysis), and 2-way analysis of variance was performed for the secondary variables with respect to the parallelgroup design (descriptive analysis). The 95% Cls were calculated for the differences between the 2 treatment groups, and mean differences between measurements at various time points within each treatment group were computed with 95% Cls. If the Cf did not include zero, the mean differences were interpreted as statistically significant (paired t test, 2-sided, descriptive analysis). Significance was set at the 5% level. All other variables, including safety, were analyzed descriptively.
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RESULTS A total of 353 patients were randomized to treatment with imidapril (n = 176) or enalapril (n = 177); 341 patients completed the trial. All randomized patients, except 1 who received no study medication and withdrew from the study immediately after randomization for personal reasons, were included in the intent-to-treat analysis for efficacy and safety. The per-protocol analysis included 300 patientsm154 in the imidapril group and 146 in the enalapril group. The treatment groups were well matched in both the per-protocol and intent-to-treat populations with respect to sex, age, b o d y weight, blood pressure, and heart rate (Table I). All patients were white, and there were no differences between treatment groups in the mean duration of hypertension, previous and concomitant medication use, medical history, concomitant diseases, height, and ECG results. Efficacy There was no difference in response rates (mean sitting DBP <-90 mm Hg or reduction of >10 mm Hg) between groups treated with imidapril (131/175 [74.9%]) and enalapril (131/177 [74.0%]) (P = 0.90; 95% CI, -0.088-0.106). Blood pressure was normalized in 69.7% (122/175) of imidapril-treated patients and 67.8% (120/177) of enalapril-treated patients (Table II). At the end of the study period, 85 of 175 patients (48.6%) in the imidapril group were receiving 5 mg and 90 patients (51.4%) were receiving 10 mg. In the enalapril group, 79 of 177 patients (44.6%) were receiving 5 mg and 98 patients
Table I.
Baseline patient characteristics. Intent-to-Treat Population
Sex, no. (%) Male Female Age, y, mean _ SD Body weight, kg, mean _ SD Sitting SBP, m m Hg, mean ± SEM Sitting DBP, m m Hg, mean ± SEM Heart rate, bpm, mean ± SEM
Per-Protocol Population
Imidapril (n = 175)
Enalapril (n = 177)
Imidapril (n = 154)
Enalapril (n = 146)
86 (49.1) 89 (50.9) 58.4 _ 10.1
76 (42.9) 101 (57.1) 57.8 _ 10.0
74 (48.1) 80 (51.9) 58.4 ± 10.4
60 (41.1) 86 (58.9) 58.1 ± 9.4
76.84 _ 11.0
77.28 _ 10.2
76.2 ± 10.8
76.8 _ 10.1
166.2 ± 1.1
164.9 ± 1.1
166.3 ± 1.2
165.1 ± 1.2
101.8 ± 0.3
102.2 ± 0.4
101.7 ± 0.4
102.3 ± 0.4
74.2 ± 0.7
74.1 ± 0.6
73.8 ± 0.7
74.3 ± 0.7
SBP = systolic blood pressure; DBP = diastolic blood pressure.
441
53 (29.9) 69 (39.0)
82 (46.9)
89 (50.3)
88 (50.3)
96 (54.2)
6
97 (54.8)
97 (55.4)
108 (61 .O)
106 (60.6)
117 (66.1)
116 (66.3)
Week
DBP = diastolic blood pressure. *Response was defined as a DBP reading 590 mm Hg or a reduction in DBP of ~10 mm Hg.
Enalapril
68 (38.9)
78 (44.1)
DBP 190 mm Hg lmidapril
69 (39.4)
Enalapril
mm Hg
DBP decrease lmidapril
210
85 (48.6) 84 (47.5)
Enalapril
Week 4
(n = 177).
8
114 (64.4)
116 (66.3)
118 (66.7)
126 (72.0)
132 (74.6)
132 (75.4)
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No. (%) of Patients (All Doses)
(n = 175) or enalapril
97 (55.4)
with imidapril
Week 2
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Response* lmidapril
Table
12
117 (66.1)
122 (69.7)
120 (67.8)
117 (66.9)
128 (72.3)
130 (74.3)
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120 (67.8)
122 (69.7)
123 (69.5)
118 (67.4)
131 (74.0)
131 (74.9)
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R. van der Does and R. Euler
(55.4%)were receiving
10 mg. Mean doses at the end of the study period were 7.6 mg in the imidapril group and 7.8 mg in the enalapril group. When response rates were evaluated according to the dose of study medication (high dose vs low dose), we found that response rates increased in patients switched from low to high doses in both treatment groups. However, response rates continued to be lower in the high-dose subgroups compared with patients receiving lower doses. In the per-protocol population, response rates tended to be higher than in the intent-to-treat population, and again there was no difference between the 2 treatment groups. Clinically relevant reductions in sitting and standing SBP and DBP occurred in both treatment groups after 2 weeks of active treatment, and there was a trend toward further decreases in sitting SBP and DBP during the course of the study (Table 111and Figure 2). There were no further reductions in blood pressure in patients continuing with low-dose treatment after 4 weeks of active therapy, but DBP continued to decrease in those patients who had been switched to higher doses at week 4 (Figure 3). Heart rate remained constant throughout the study period. The results were similar in the intent-to-treat and the per-protocol populations. Safety Adverse Events
Serious adverse events were reported in 6 patients (2 in the imidapril group and 4 in the enalapril group) during the active-treatment period, and these were considered to be unrelated or remotely related to the study medication. In the imidapril group, the serious adverse events were malignant neoplasm of the tongue and mouth and rupture of an ovarian cyst. In the enalapril group, the serious adverse events were necrotic appendicitis, hypertensive crisis, recurrence of a squamous cell bladder carcinoma, and recurrence of a malignant breast neoplasm. Three of these adverse events, all in the enalapril group, led to patient withdrawal from the study. There were no additional withdrawals due to adverse events during active treatment. The number of patients with 21 adverse event was lower in the imidapril group (76/175 [43.4%]) than in the enalapril group (86/177 [48.6%]). The most common adverse events (~5%) were headache, bronchitis, cough, and upper respiratory tract infections in both groups. Musculoskeletal pain at various sites occurred with an incidence >5% only in the imidapril group. Adverse events occurring in >2% of patients were lumbar disorders, neck pain, and dizziness in both groups; nausea and conjunctival disorders in the imidapril group; and gastritis, pharyngitis, and skin disorders in the enalapril group. In general, the adverse-event profiles of imidapril and enalapril were similar. There were no differences between treatment groups in the incidence of adverse events that were judged to be possibly, probably, or highly probably related to the study medication (Table IV). Adverse events such as headache,
443
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upper respiratory tract infection, and bronchitis were also reported placebo run-in period, although only 1 patient reported cough.
during the
Laboratoory Values and Other Variables No changes in hematology or serum biochemistry
values were observed during active treatment. One case of leukopenia in the imidapril group resolved when treatment was discontinued. In the enalapril group, 1 patient had increased serum creatinine levels. Neither imidapril nor enalapril appeared likely to be associated with an elevated risk of orthostatic hypotension. There were no relevant changes in resting ECG measurements during active treatment, and no trends in body weight changes were noted. Patient compliance ranged from 98.0% to 99.3% in the 2 treatment groups. DISCUSSION
The long-acting ACE inhibitor imidapril, which was first developed in Japan,2 has been evaluated for efficacy and safety in the treatment of essential hypertension in clinical studies in Japan and Europe.S’o Results from those studies have shown that imidapril is effective and well tolerated in patients with hypertension. The present study was designed to compare the efficacy and safety of imidapril 5 to 10 mg once daily with enalapril 5 to 10 mg once daily in the treatment of essential hypertension. Both ACE inhibitors significantly lowered blood pressure, and there was no difference in response rates between the 2 treatment groups (imidapril, 74.9%; enalapril, 74.0%). The mean reductions tn
445
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R. van der Does and R. Euler
Table IV. Number (%) of patients experiencing adverse events possibly, probably, or highly probably related (according to investigator’s judgment) to study medication. No. (96) of Patients
Adverse Event
lmidapril (n = 175)
Enalapril (n = 177)
Total Headache Cough Dizziness Nausea Diarrhea Giddiness Bronchitis Dry nose and throat Palpitation Tachycardia Leg cramps Cephalgia Fainting Skin tingling Hypertensive crisis Castralgia Vomiting Stretching sensation in skin Speech disorder Dyspnea Tiredness
21 9 5 4 3 2 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0
25 10 7 4 2 0 2 0 0 0 1 1 1 1 1 1 1 1 1 1 1 1
(12.0) (5.1) (2.9) (2.3) (1.7) (1 .l) (0.6) (0.6) (0.6) (0.6) (0.6) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0)
(14.1) (5.6) (4.0) (2.3) (1 .l) (0.0) (1 .l) (0.0) (0.0) (0.0) (0.6) (0.6) (0.6) (0.6) (0.6) (0.6) (0.6) (0.6) (0.6) (0.6) (0.6) (0.6)
sitting DBP (-12.9 mm Hg in the imidapril group and -13.2 mm Hg in the enalapril group) and SBP (-16.6 mm Hg and -15.8 mm Hg, respectively) were similar in the 2 groups. Clinically relevant decreases in standing SBP and DBP occurred in both treatment groups. Heart rate values remained constant in both treatment groups. Similar results were obtained in the per-protocol population. More than half of the study patients had their medication dose titrated upward after 4 weeks of active treatment. Among patients who continued taking low doses throughout the study period, there was a marked reduction in sitting DBP within the first 4 weeks of treatment, and no further clinically relevant changes occurred after week 4. In the high-dose cohorts, there was a modest decrease in sitting DBP during the first 2 weeks of active treatment with no changes between weeks 2 and 4. After increasing the dose at week 4, there was a marked reduction in blood pressure during the next 2 weeks. Response rates, however, continued to be lower in the high-dose subgroups; thus, patients who
447
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were switched to the higher doses may have been more refractory to antihypertensive treatment. Response rates in the per-protocol population were higher than those in the intent-to-treat population, although there was no difference between treatment groups. These findings suggest that treatment with imidapril should be initiated at a dose of 5 mg once daily. If optimum control of blood pressure has not been achieved within 4 weeks of initiating treatment, the daily dose should be increased to 10 mg. Overall, the magnitude of the antihypertensive effect and the response rates seen with both treatment groups were comparable to those noted in previous studies with enalapril and other ACE inhibitors. l1 The antihypertensive effects of enalapril were as expected; thus, from the point of efficacy, the comparison appears to be a valid one, despite the lack of a placebo control. Moreover, the safety data were obtained in a patient population that was being adequately treated. All patients enrolled in the present study were white; therefore, our results are applicable to this group of patients and cannot be generalized. Monotherapy with ACE inhibitors has been shown to be less effective in African Americans; however, the addition of diuretics may markedly improve the response in these patients.12 There was no significant difference between treatment groups in the proportion of patients with ~1 adverse event. It should be noted, however, that the study was not powered to demonstrate equivalence between the 2 treatments. The incidence of adverse events classified as at least possibly related to the test drug was comparable in the 2 treatment groups; these adverse events included headache, cough, and dizziness. Many of the adverse events were also observed during the placebo run-in period. Overall, there were no unexpected or previously unknown adverse events, and their distribution was similar in the imidapril and enalapril groups. The overall safety profile of both drugs was comparable to previously reported data for enalapril,13 and for ACE inhibitors in general.14 The proportion of patients with cough, an adverse event specific to ACE inhibitors, was also comparable in the 2 treatment groups. However, a comparative study in Japan that assessed the incidence of cough associated with ACE inhibitors showed that the incidence was significantly lower with imidapril than with enalapril. l5 Additional studies focusing on cough incidence in patients receiving imidapril versus other ACE inhibitors are warranted. The present study enrolled mainly patients with uncomplicated hypertension who had or had not received previous antihypertensive therapy. It should be noted that according to the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure,12 beta-blockers and diuretics should be considered as initial drug choices in patients with uncomplicated hypertension. The use of ACE inhibitors is recommended for patients who do not respond adequately to initial therapy or pa-
R. van der Does and R. Euler
tients with certain comorbidities, such as heart failure, diabetes, and renal insufficiency. CONCLUSIONS
There was no statistically significant difference between the imidapril and enalapril treatment groups in terms of antihypertensive response. Both imidapril and enalapril reduced elevated blood pressure levels effectively, and the dose range of 5 to 10 mg for both ACE inhibitors was appropriate for the treatment of patients with essential hypertension. Both treatments were well tolerated, and the safety profile in this study was in agreement with data from other trials of ACE inhibitors. There were no unexpected adverse events considered to be causally related to the study medication. ACKNOWLEDGMENTS
This study was sponsored by Merck KGaA, Darmstadt, Germany. We thank all the investigators who took part in the study. REFERENCES 1. Unger T, Gohlke P. Converting enzyme inhibitors in cardiovascular therapy: Current status and future potential. Cardiovasc Res. 1994;28:146-158. 2. Kubo M, Kato J, Ishida R, et al. Pharmacological studies on (4S)-l-methyl-3[(2S)-2{N-((lS)-l-ethoxycarbonyl-3-phenylpropyl)amino}propionyl]-2-oxo-imidazoline-4carboxylic acid hydrochloride (TA6366), a new ACE inhibitor: I. ACE inhibitory and antihypertensive activities. Jpn J fhamacol. 1990;53:201-210. 3. Vandenburg MJ, Mackay EM, Dews I, et al. Dose finding studies with imidapril-a new ACE inhibitor. Br J Chin Pharrnacol. 1994;37:265-272. dose titration 4. Vandenburg M, Mackay E, Pullan T, et al. An 8 week placebocontrolled study of imidapril in the treatment of mild to moderate essential hypertension. Br J Clin Pharmacol. 1995;39:93P. Abstract. 5. Pinto YM, van Veldhuisen DJ, Tjon-Ka-Jie RT, et al. Dose-finding study of imidapril, a novel angiotensin converting enzyme inhibitor, in patients with stable chronic heart failure. Eur J Clin Phannacol. 1996;50:265-268. 6. Saruta T, Omae T, Yoshinaga K, et al. Effect of ACE/TA-6366 (imidapril hydrochlo ride), angiotensin-converting enzyme inhibitor, on diurnal blood pressure change in essential hypertension. J Clin Ther Med. 1991;7:2205-2219. 7. Saruta T, Omae T, Yoshinaga K, et al. Efficacy and safety of imidapril (ACE/TA-6366), angiotensin I converting enzyme inhibitor, in monotherapy on essential hypertension-multiclinic open trial. J Clin Ther Med. 1991:7:24&G2504. 8. Saruta T, Omae T, Yoshinaga K, et al. Efficacy and safety of imidapril hydrochloride (ACE/TA-6366), angiotensin converting enzyme inhibitor, on essential hypertension in the long-term treatment. J C’lin 77zel:Med. 1991;7:2715-2735. 9. Suzuki N, Mori M, Kusano S. Circadian variation in blood pressure and pharmacokinetics following single and consecutive doses of angiotensinconverting enzyme
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Address correspondence to: Reinhard van der Does, MD
IST GmbH Kruegerstrasse 7-l 1 D862 19 Mannheim Germany Email: [email protected]
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