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Moexipril Versus Captopril in Patients with Mild to Moderate Hypertension

Stimpel, Michael; Koch, Brigitte; Jansen, Thomas; Fox, Alanna; Loh, Irving*

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Journal of Cardiovascular Pharmacology: December 1996 - Volume 28 - Issue 6 - p 769-773
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Maintaining uniform blood pressure control over a 24-h period seems to be a desirable goal in the treatment of patients with hypertension. This can be achieved with long-acting antihypertensive drugs administered once daily.

Moexipril is a prodrug of a new long-acting, non-peptide, nonsulfhydryl, angiotensin-converting enzyme (ACE) inhibitor. After hepatic cleavage to its active metabolite moexiprilat, it has been shown to be an orally active antihypertensive agent in animal and human pharmacology models. Administered once daily at doses of 7.5, 15, or 30 mg, moexipril demonstrates potent and specific competitive inhibition of the converting enzyme that is responsible for the cleavage of angiotensin I to angiotensin II. Maximum blood pressure reductions could be seen within 3-6 h after administration of moexipril, with an antihypertensive effect persisting for up to 24 h. The maximum effect of a once-daily dose of moexipril is reached after 4 weeks of treatment (1-4).

The objective of this study was to compare the efficacy, safety, and tolerability of moexipril with that of captopril-the prototype of ACE inhibitors-in the treatment of patients with mild to moderate hypertension during a 12-week double-blind period.



Nonhospitalized male and female patients who provided written informed consent and were older than 18 but younger than 76 years with uncomplicated essential hypertension constituted the study population. Patients were eligible if the prestudy examination and the patient's history did not show evidence of significant disease other than hypertension. Excluded from the study were patients with chronic systolic blood pressure ≥200 mm Hg, known secondary hypertension, chronic heart or renal disease, cancer, active substance abuse, or psychotic illness. Additionally, all those conditions were exclusionary, which could increase the risk to the patient or decrease the chance of obtaining satisfactory data to achieve the study objectives. Concomitant antihypertensive therapy other than the study medications was not permitted.

Course of the study

After a 4-week single-blind placebo period, patients with a seated diastolic blood pressure (SDBP) of 95-114 mm Hg, inclusive, and a difference in SDBP ≤10 mm Hg at the last two consecutive visits, were randomized in a 2:1 ratio to receive moexipril, 7.5 mg, once daily or captopril, 25 mg twice daily. During the 12-week treatment period, patients were seen at 2-week intervals. If a patients' SDBP remained ≥90 mm Hg after 6 weeks of therapy, the dose was increased to 15 mg moexipril once daily or to 50 mg captopril twice daily. The study medication was blinded by a double-dummy technique, and patients had to self-administer one moexipril capsule and one captopril tablet or matching placebos each morning and one captopril tablet or matching placebo each evening, 10-14 h after the morning dose.

Blood pressure and pulse measurements

Investigators were asked to see patients at approximately the same time of day throughout the study, 22-26 h after the previous morning dose and 10-14 h after the last intake of captopril. Blood pressure and pulse measurements were obtained at the screening visit and at each later visit. Furthermore, blood pressure was taken at 1 and 2 h postdose at the baseline visit and the visit on which the patient's dose was increased, if applicable. Three blood pressure readings, taken 1 min apart, were obtained after the patient had been sitting quietly for ≥5 min. The average of these three measurements at any visit for an individual patient is referred to as sitting systolic blood pressure (SSBP) and SDBP. Pulse was counted for 30 s after the third blood pressure measurement. On completion of the sitting readings, the patient was to stand, and an immediate measurement of pressures and pulse rate was obtained. After the patient had been standing for ≥2 min, pressures were measured again. Two readings taken 1 min apart were obtained.

Laboratory values

Laboratory tests including hemoglobin, hematocrit, white blood cell count, differential platelet count, urinalysis, blood chemistries, and lipid profiles were performed at the prestudy screening visit and before dosing at study week 0, 4, 8, and 12. Laboratory specimens were obtained after blood pressure and pulse determinations and analyzed at a central laboratory.


A 12-lead resting electrocardiogram was obtained at the prestudy visit and repeated before dosing at weeks 0 and 12.

Adverse events

Adverse events were assessed at each visit by questioning in a general way. The adverse events were graded by the investigator as “serious” or “nonserious,” as “mild,” “moderate,” or “severe,” and their relation to the study medication was characterized as “none,” “unlikely,” “possible,” “probable,” or “highly probable.”

Statistical analysis

Based on prior studies with moexipril, a sample size of 150 patients (100 in the moexipril and 50 in the captopril group) was determined to be sufficient to detect a 5-mm Hg difference between the two groups in mean SDBP change from baseline with >90% power (at the 5% significance level by using a two-tailed alternative).

Comparability of the two treatment groups with respect to demographics and baseline blood pressure and pulse variables was assessed by using two-way analysis of variance (ANOVA) with treatment and investigator as factors for the continuous variables (e.g., age) and by the Cochran-Mantel-Haenszel (CMH) test, stratified by investigator for the categoric variables (e.g., sex). The general association form of the CMH statistic was used. Comparisons between treatment groups with respect to change from baseline in blood pressure were made by using two-way analysis of covariance (ANCOVA) with treatment and investigator as factor and the baseline measurements as the covariant.


One hundred ninety-three patients entered the single-blind period of this study. Of these, 159 patients were randomized in a 2:1 ratio to receive moexipril or captopril for a 12-week period. The moexipril group and the captopril group consisted of 105 and 54 patients, respectively; both were comparable with respect to demographics and baseline characteristics. Refer to Table 1 for the baseline demographics and disease characteristics of the study population.

At study endpoint (the 12-week endpoint reading is the calculation of the “Intent to Treat Analysis” with the last observation carried forward for those patients who dropped out during the study. This 12-week endpoint is the last predose blood pressure measurement during double-blind period for each patient), 51% of the patients in the moexipril group and 56% of the patients in the captopril group were receiving a doubled dose of study medication.

Sitting diastolic blood pressure

As shown in Table 1, SDBP means at baseline were nearly identical: 101.5 and 101.4 mm Hg, in the moexipril and captopril groups, respectively. Two hours after the initial dose of study medication, mean SDBP decreased to 92.8 mm Hg in the moexipril group and 89.9 mm Hg in the captopril group. During the first 6 weeks of the double-blind period, substantial reductions from baseline in mean SDBP were exhibited at the predose time points in both treatment groups, although means remained >90 mm Hg (92.2 mm Hg in the moexipril group and 94.7 mm Hg in the captopril group). During the following 6 weeks of the double-blind period, additional reductions in mean SDBP values were observed. At the study endpoint, SDBP means were 91.5 and 92.5 mm Hg in the moexipril and captopril groups, respectively. As shown in Table 2, the adjusted mean reductions in SDBP calculated at the 6-week and 12-week study endpoint were -9.0 and -9.8 mm Hg in the moexipril group versus -6.6 and -8.7 mm Hg in the captopril group.

As shown in Table 3, the percentages of patients with an excellent (SDBP <90 mm Hg) or good (SDBP ≥90 mm Hg, but a reduction of ≥10 mm Hg from baseline) response to treatment at the 12-week endpoint were 65 and 60% in the moexipril and captopril groups, respectively.

For patients who remained on the initial dose of study medication, the percentages of good or excellent responders at the study endpoint were 76% in the moexipril group and 54% in the captopril group.

Sitting systolic blood pressure

Adjusted mean changes from baseline in SSBP at each evaluated double-blind time point are presented in Table 4. The results for SSBP exhibited a similar trend to the results for SDBP. Differences between the two groups achieved statistical significance at the 6-week endpoint and the study end point. At the 6-week end point, adjusted mean SSBP reductions were -7.9 mm Hg in the moexipril group and -3.5 mm Hg in the captopril group. After 12 weeks' treatment, moexipril and captopril reduced systolic blood pressure by -10.3 and -5.6 mm Hg, respectively.

Standing blood pressure

The results for standing blood pressure showed a similar trend to the results for sitting blood pressure. It was noticed, however, that adjusted mean reductions from baseline in standing DBP were slightly but consistently smaller than those for sitting DBP.

Analysis of subgroups

Data on the efficacy of moexipril and captopril as related to gender and age are summarized in Table 5.

Safety results

The number and percentage of patients in each treatment group reporting one or more clinical adverse experiences are presented in Table 6. Moexipril and captopril were generally well tolerated. The overall percentage of patients who had one or more clinical adverse events during the 12-week double-blind period, regardless of relation to study medication, was 62% in the moexipril group and 59% in the captopril group. There were no statistically significant differences between the two groups with respect to the proportions of patients reporting any individual adverse experience. The most frequently reported clinical adverse experiences during the double-blind period were headache (12% in the moexipril group and 15% in the captopril group), dizziness (8% in the moexipril group and 13% in the captopril group) and upper respiratory infection (9% in both groups).


The principal finding of this study was that the new ACE inhibitor moexipril-given once daily-is as efficacious and safe as twice daily captopril in reducing blood pressure in patients with mild to moderate hypertension. Diastolic blood pressure reductions observed with moexipril after 6 and 12 weeks of treatment were -9.0 and -9.8 mm Hg, respectively, compared with -6.6 and -8.7 mm Hg in the captopril group. Overall these results are comparable to the degree of blood pressure-reducing activity demonstrated in several other short-term studies with moexipril and seen with other ACE inibitors as well (5-7). Percentages of patients with a good or excellent response to treatment with moexipril and captopril were 65% and 59%, respectively.

By demonstrating that once-daily moexipril is as efficacious as twice-daily captopril in treating patients with mild to moderate hypertension, this study confirms that moexipril is an effective long-acting antihypertensive agent. This is in accordance with former results showing that moexipril is capable of maintaining uniform blood pressure control for 24 h, as confirmed by ambulatory blood pressure monitoring in patients treated once daily (8). The prolonged action of moexipril-which is an important request for increasing patient compliance-is attributable to the pharmacokinetic profile of its active metabolite, moexiprilat (9).

Subanalyses of blood pressure reduction in men and women, younger and older patients, as well as in mild and moderate hypertensives, showed only few group-specific differences. A small tendency could be seen for the older patients of both treatment groups to exhibit slightly larger mean reductions from baseline SDBP than the younger patients. Additionally, in contrast to captopril, low doses of moexipril (7.5 mg) seemed to be more effective in older than in younger patients. This observation is consistent with findings of a study comparing the pharmacokinetics of moexiprilat in elderly (65-80 years) and young (18-39 years) healthy male volunteers. This study shows that after once-daily administration of moexipril, the pharmacokinetic parameter AUC (area under the curve) for moexiprilat was ≈30% higher for the elderly than for the younger control group (10). However, the degree of blood pressure reduction in this study is the same as that obtained with other ACE inhibitors in elderly patients (11,12). As it is possible that compensatory mechanisms of blood pressure reduction might be impaired in this subgroup, gentle treatment with moexipril is recommended.

Given once daily in doses of 7.5 or 15 mg, moexipril was as safe as captopril in doses of 25 and 50 mg given as a twice-daily regimen. Moexipril and captopril were generally well tolerated. The most frequently reported clinical adverse experiences during the double-blind period were headache (12% in the moexipril group and 13% in the captopril group), dizziness (7% in the moexipril group and 13% in the captopril group), and upper respiratory infection (9% in both groups). The prevalence of these three kinds of adverse experiences was similar to that observed in other ACE inhibitor studies (13-16).

In conclusion, the data indicate that moexipril in dosages of 7.5 and 15 mg once daily is as efficacious as captopril twice daily in reducing blood pressure in patients with mild to moderate hypertension. It is as safe and effective in men as in women, in elderly patients as in younger patients, and in all degrees of hypertension. When 24-h blood pressure control combined with a good safety profile are imperative requirements for a new antihypertensive drug, moexipril has proved to be a good alternative in the treatment of hypertension.

Note: Principal Investigators in this study were Dr. Anthony Bennett, Little Rock, AR; Dr. James Burnell, Seattle, WA; Dr. Michael Davidov, Falls Church, VA; Dr. David J. DiPette, Galveston, TX; Dr. James Doherty, Little Rock, AR; Dr. James M. Ferguson, Salt Lake City, UT; Dr. William J. Hisgen, Madison, WI; Dr. James E. Lewis, Sunnyvale, CA; Dr. Irving K. Loh, Thousands Oaks, CA; Dr. F. Gilbert McMahon, New Orleans, LA; Dr. David T. Nash, Syracuse, NY; Dr. Robert Remmler, Savannah, GA; Dr. Jon Ruckle, Tacoma, WA; Dr. William B. Smith, New Orleans, LA; Dr. Michael Sullivan, San Diego, CA.

Acknowledgment: We thank Mrs. Marion Berger and Mrs. Renate Bosbach for their excellent secretarial assistance.


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Moexipril; Captopril; Hypertension

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