ORIGINAL ARTICLE

An evaluation of the initial and long-term antihypertensive efficacy ofzofenopril compared with enalapril in mild to moderate hypertension

JEAN-MICHEL MALLION

Service de Cardiologie et hypertension arterielle, CHU, Grenoble, France

AbstractAngiotensin-converting enzyme inhibitors (ACEIs) are used in the management of a range of cardiovascular disorders andare well established in primary as well as secondary cardiovascular prevention programmes. Over the years, several second-and third-generation ACEIs have been introduced into the clinic. In a comparative study in patients with mild to moderatehypertension, the efficacy and safety of zofenopril 30 mg od (with an up-titration to 60 mg od after 4 weeks in non-responder patients) was compared with enalapril 20 mg od (with an up-titration to 40 mg od after 4 weeks in non-responders) during 12 weeks of treatment. Both treatments significantly reduced systolic (SBP) and diastolic blood pressure(DBP). BP reduction was significantly greater with zofenopril (30 mg/day) during the initial 4 weeks of treatment comparedwith enalapril (20 mg/day). A larger proportion of patients needed dose up-titration with enalapril compared with zofenoprilto reach preset BP goals. After 12 weeks of treatment and after appropriate dose up-titration, SBP and DBPs were loweredto similar extent in the two treatment groups, resulting in no differences between the groups in terms of response andcontrol rates. A similar number of patients reported adverse events in the two study groups. However, the severity of adverseevents were significantly milder with zofenopril compared with enalapril. In mild to moderate hypertensive patients,zofenopril treatment results in a more pronounced lowering of BP compared with enalapril at recommended dose levels.Additionally, at clinical and comparative antihypertensive doses, zofenopril presents a more beneficial adverse event profilecompared with enalapril.

Key Words: Hypertension, zofenopril, enalapril, dose titration, adverse events

Introduction

The clinical benefits of the angiotensin-converting

enzyme inhibitors (ACEI) have been clearly defined

in cardiovascular conditions such as in hypertension,

chronic heart failure, asymptomatic left ventricular

dysfunction, acute myocardial infarction and dia-

betic nephropathy, as well as in patients at high risk

of cardiovascular events (1,2).

Because of the range of preventive effects, ACEIs

are established first-line drugs in mild to moderate

hypertension and generally considered suitable for

initial medication, particularly in patients with

diabetes. When used as a single therapy, they achieve

adequate antihypertensive control in about 40–50%

of patients, and in those not reaching target pressures,

a combination of an ACEI and calcium antagonist or

a diuretic or is usually employed (1). In hyperten-

sive patients, ACEIs reduce mortality and most

cardiovascular outcomes at to an extent that is similar

to that achieved with diuretics and beta-blockers (2).

Today, a large number of outcome trials in

patients with hypertension and related cardiovascu-

lar risks have shown survival and other significant

therapeutic benefits of ACEIs (ESH/ESC, 2003).

Within the group of agents, the relative therapeutic

advantage of one particular ACEI over the other in

such populations is, however, still largely unknown,

since only a few comparisons based on small studies

are available. Moreover, since the potential benefits

of auxiliary properties other than the ACE inhibition

itself, e.g. kinin activation, NO upgrading, antiox-

idative properties and other effects, can only be

speculated upon, it is feasible that any clinical

relevant differences that may exist between the

agents of the ACEI class may be related to onset

and/or extent of antihypertensive action as well as

the relative incidence and severity of side-effects.

Correspondence: J.-M. Mallion, Service de Cardiologie et hypertension arterielle, CHU, Grenoble, France. E-mail: jmmallion@chu-grenoble.fr

Blood Pressure. 2007; 16 (Suppl 2): 13–18

ISSN 0803-8023 print/ISSN 1651-2480 online # 2007 Taylor & Francis

DOI: 10.1080/08038020701561703

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Within the range of available ACEIs, agents differ

in terms of antihypertensive dose-range, onset and

duration of blood pressure (BP) lowering effects as

well as therapeutic balance between cardiovascular

preventive effects and side-effects.

In the present study, the third-generation lipo-

philic ACEI zofenopril characterized by a high

degree of tissue penetration and long-term cardiac

ACE inhibition was assessed in comparison with the

second-generation agent enalapril, in terms of

efficacy and onset of antihypertensive action in a

patient cohort with mild to moderate hypertension.

Patients and methods

The study was conducted as a comparative parallel-

group double-blind randomized multi-centre study

in patients with mild to moderate hypertension

according to the declaration of Helsinki. The study

protocol was approved by the relevant ethics

committees at the participating study centres. In

all, 360 patients with mild to moderate hypertension

were enrolled, of which 323 patients met the

inclusion criteria and none of the exclusion criteria.

All included patients had a stable clinic hypertension

and were aged between 18 and 70 years. BP was

measured in the sitting position by standard mercury

sphygmomanometry after an appropriate period of

rest. At each clinic visit, the supine and standing

systolic (SBP) and diastolic blood pressure (DBP)

were measured. Subjects were included in the study

if they had stable diastolic hypertension, defined as

‘‘office’’ DBP between >95 mmHg and under

v115 mmHg assessed as the median of three

consecutive measurements at randomization.

Patients were randomly allocated to receive either

oral zofenopril 30 mg once daily (could be up-

titrated to 60 mg once daily) or oral enalapril 20 mg

once daily (could be up-titrated to 40 mg once

daily). In addition to the randomization visit,

patients were seen at clinic for two pre-randomiza-

tion visits as well as four post-randomization visits

(at weeks 2, 4, 8 and 12 after randomization). The

oral zofenopril or enalapril treatment regimens could

be up-titrated at week 4 if the DBP was w90 mmHg

and if the DBP reduction was less than 10 mmHg at

that visit. In addition to the BP measurements,

patients were asked for adverse events at each study

visit. Routine laboratory assessments were taken at

randomization and at the end of the study.

Male or female hypertensive patients with a history

of mild to moderate primary hypertension over at

least 6 months were selected for the study. Patients

with severe or secondary forms of hypertension were

excluded, as were patients with two antihypertensive

agents or more at the initial screening visit. Also,

patients with cardiovascular or renal complications as

well as subjects with insulin-dependent diabetes were

excluded. Patients taking concomitant medications

judged to interfere with the study drugs were not

allowed into the trial. The study treatment used,

zofenopril (Menarini) and enalapril (Renitec, MSD),

were both commercially available and given in

capsules in order to ensure proper blinding. Study

medications were given in the morning.

Patients were seen in the morning and all BP

readings were taken after 10 min of supine rest.

Sitting and standing BPs were taken after the supine

assessments. BP readings were measured by standard

mercury sphygmomanometry and the SBP was taken

at Korotkoff 1 and the DBP at Korotkoff 5. BP

readings were taken in the same arm and performed

by the same person at each of the clinic follow-up

visits. A standard 12-lead electrocardiogram was

obtained in relation to the standard physical exam-

ination in the beginning and the end of the study.

Adverse events were assessed during the study and

recorded in adverse event forms, and coded using the

dictionary terms from the MEDdra dictionary. The

events were classified into WHO sub-organ classes

and judged whether they were drug related. Adverse

events were also assessed in terms of severity.

After any previous antihypertensive treatment had

been washed out, the patients were entered in the

run-in phase and at the randomization visits, one of

the respective study drugs were given, either

zofenopril or enalapril. During the study, no other

antihypertensive medications than the study drugs

were allowed.

Statistical assessments were performed using the

SAS system after computing the original data from

the case record forms. The primary statistical

evaluation compared baseline data at randomization

with data after 12 weeks of treatment. Also, baseline

data were compared with data obtained 4 weeks

after monotherapy. All comparisons were made

using analysis of variance (ANOVA) and the

Mann–Whitney U-test relating to changes before

and after treatment. All efficacy analyses were

assessed according to intension to treat (ITT). The

ITT population, 308 patients, consisted of subjects

who took at least one dose of the study medication

and who did not violate the study protocol. The per

protocol (PP) population consisted of the subjects

who completed the 12-week study period, had valid

primary criteria data, had a medication compliance

w90% and no major deviation from the protocol.

Semi-quantitative data were analysed using the

14 J.-M. Mallion

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Rank-Sign test and all test were two-tailed at a50.05

significance level.

Results

The ITT study cohort of 308 males and females

ranged between 23 to 70 years of age and

approximately 40% were previously treated

(Table I). At the inclusion, the supine SBP and

DBP were 161¡12/101¡5 in the zofenopril group

(n5152) and 161¡13/101¡5 mmHg in the enala-

pril group (n5156). Supine heart rates were 74¡9

and 74¡10 beats/min in the two groups respectively

(Table I).

BP and response rates

After start of treatment, supine as well as standing

SBP and DBP dropped substantially both in the

zofenopril and enalapril groups (Tables II and III).

The BP reduction compared with the run in visit

was 17.5¡9.7/13.8¡8.0 mmHg after 2 weeks and

19.8¡10.0/15.6¡9.1 mmHg after 4 weeks of

treatment in the zofenopril group. In the enalapril

group, the corresponding 2 and 4 weeks’ BP

reductions were 14.2¡11.1/11.4¡8.0 and 17.0¡

11.9/13.8¡9.1 mmHg, respectively. The differences

at these scheduled visits, i.e. 3.3/2.4 and 2.7/

1.8 mmHg, respectively, were significant between

the treatments (Tables II and III). At the following 8-

and 12-week assessments, there were no differences

between the zofenopril and enalapril treatments in

respect to supine BPs.

Furthermore, at weeks 2 and 4 after initiation of

treatment, there were also significant differences in

standing SBP and DBP between the two treatments.

The BP reduction was more pronounced for

zofenopril compared with enalapril at week 2 (3.4/

3.9 mmHg) as well as after week 4 (3.4/3.1 mmHg)

(Tables II and III). In the standing positions, DBP

and SBP did not differ between the treatments at

week 8 and 12 (Tables II and III).

Heart rates in the supine as well as standing

positions did not differ between the treatments

throughout 12-week study period.

Table I. Demographics of the study patient cohort

Zofenopril Enalapril p-value

n 152 156

Gender (male/female) 73/79 76/80 0.946

Age (years) 52.0¡9.7 53.3¡10.3 0.236

Body mass index 28.1¡5.0 27.7¡4.5 0.430

Previously treated/untreated 57/95 65/91 0.483

Supine SBP/DBP (mmHg) 160.3¡9.7/101.0¡5.5 160.3¡9.7/100.8¡4.0 0.614/0.628

Supine HR (beats/min) 72.7¡8.3 73.6¡9.4 0.374

Race

Caucasian 142 (93%) 150 (96%) 0.342

Black 3 (2%) 3 (2%)

Oriental 4 (3%) 3 (2%)

Other 3 (2%) 0 (0%)

Shown are actual numbers or means¡SD. Statistical comparison by Student t-test or Fisher’s exact probability test. SBP, systolic blood

pressure; DBP, diastolic blood pressure; HR, heart rate.

Table II. Supine systolic (SBP) and diastolic blood pressures (DBP) in zofenopril- and enalapril-treated patients during 12 weeks of follow

up.

Zofenopril (SBP/DBP) Enalapril (SBP/DBP) p-value

Baseline 160.7¡12.1/101.3¡4.6 161.3¡12.5/101.1¡4.5

Week 2 143.1¡9.5/87.5¡6.2 147.0¡13.1/89.8¡8.4 0.006/0.005

Week 4 140.9¡9.2/85.7¡5.5 144.2¡13.5/87.4¡8.9 0.030/0.038

Week 8 140.5¡9.9/85.2¡7.0 141.7¡13.4/86.0¡9.1 0.621/0.296

Week 12 140.6¡10.5/84.6¡7.1 141.7¡12.5/85.7¡8.1 0.678/0.187

Shown are means¡SD of blood pressure values in mmHg from the 12 weeks intention-to-treat population (zofenopril 30–60 mg od5152;

enalapril 20–40 mg od5156).Dose up-titration was optional in non-responders at week 4. Statistical comparison between treatments

denotes baseline corrected differences between treatments by ANOVA. SBP and DBP reductions at weeks 4, 8 or 12 vs baseline value all

pv0.001.

Antihypertensive efficacy of zofenopril compared with enalapril 15

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Response rates

The response rate, defined as a DBP below

90 mmHg or DBP reduction >10 mmHg, did not

differ between the zofenopril and enalapril treat-

ments at 4 and 12 weeks after initiation of therapy.

At the 4-week treatment visit, 64% of patients were

classified as responders in the zofenopril group and

59% in the enalapril group. After 12 weeks, the

corresponding responder proportions were 71% in

the zofenopril and 69% in the enalapril groups.

None of these differences was statistically significant.

Safety and tolerance

Adverse events (AE) were reported by 67 zofenopril-

treated patients and 81 enalapril-treated patients. A

total of 383 AEs were reported, of which 143 were

mild, 162 moderate and 23 severe. Most were

transient and not judged to be related to the study

medication by the responsible investigator. Of the

142 total AEs reported by the 155 zofenopril

patients and the 186 AEs reported by the 168

enalapril-treated patients, there were significantly

more AEs that were possibly probably or definitely

drug related in the enalapril group (Table IV).

Discussion

In clinical practice, an ACEI may be used as initial

treatment all patients with hypertension, and such

therapy is particularly suitable in diabetic patients or

in patients with metabolic decompensation (3).

Notably, in the recent CAPPP study, ACEI therapy

was shown to be superior to the reference diuretic/

beta-blocker antihypertensive treatment regimen in

preventing cardiovascular events in hypertensive

diabetic patients, especially in those with metabolic

decompensation. Thus, in that study, the composite

primary end point (fatal and non-fatal myocardial

infarction and stroke, as well as other cardiovascular

deaths) was markedly lower in the ACEI group than

in the conventional therapy group (relative risk

[RR]50.59; p50.018). Also in CAPPP, an ACEI-

based antihypertensive treatment regimen was asso-

ciated with a lower risk of diabetes development

Table III. Standing systolic (SBP) and diastolic blood pressures (DBP) in zofenopril- and enalapril-treated patients during 12 weeks of

follow up.

Zofenopril (SBP/DBP) Enalapril (SBP/DBP) p-value

Baseline 159.6¡12.1/101.7¡5.8 160.6¡13.5/101.9¡8.2

Week 2 142.5¡9.5/87.7¡5.3 146.8¡13.8/91.9¡9.7 0.015/v0.001

Week 4 140.4¡9.2/85.8¡5.8 143.8¡14.1/89.2¡9.6 0.099/0.001

Week 8 140.3¡9.9/86.1¡6.5 141.6¡14.0/88.1¡9.8 0.771/0.075

Week 12 140.4¡10.5/85.9¡6.4 142.5¡14.1/87.3¡8.7 0.464/0.228

Shown are means¡SD of blood pressure values in mmHg from the 12 weeks intention-to-treat population (zofenopril 30–60 mg od5152;

enalapril 20–40 mg od5156). Dose up-titration was optional in non-responders at week 4. Statistical comparison between treatments

denotes baseline corrected differences between treatments by ANOVA. SBP and DBP reductions at weeks 4, 8 or 12 vs baseline value all

pv0.001.

Table IV. Adverse events during exposure to the study medications.

Zofenopril Enalapril p-value

n 155 168

Total AEs reported 142 186

Mild 78 65

Moderate 57 105

Severe 7 16

Subjects with AEs 67 81 0.369

Subjects with SAE 1 2

Subjects discontinued for an AE 6 5

AEs possibly, probably or definitely drug related 32 49

Mild 18 13

Moderate 13 31 0.008

Severe 1 5

Shown are actual numbers of subjects with events as well as number of events in zofenopril- and enalapril-treated patients over the course of

the trial. AEs, adverse event; SAE, severe adverse event. The SAEs experienced were not judged to be related to treatments. Statistical

comparison by Student t-test or Fisher’s exact probability test.

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(14%; p50.034), compared with conventional ther-

apy based on diuretics and/or beta-blockers (3–5).

Thus, in addition to the antihypertensive effect of

the ACEI, there is an additional positive metabolic

effect of ACEI, which is manifested as a lower

incidence of diabetes development (6).

As regards the antihypertensive effect of the two

treatments demonstrated in the present study,

zofenopril 30 mg od was shown to produce a more

rapid reduction of BP in comparison with enalapril

20 mg od. After initiation of therapy, there was a

gradual lowering of SBP as well as DBP by both

treatments over 2 and 4 weeks of therapy. The was,

however, a difference in the initial BP lowering

response over the first 4 weeks of treatment in favour

of zofenopril, which was approximately 4/2 mmHg

in the supine and 4/4 mmHg in the standing

position. After 4 weeks of treatment and the

possibility of dose up-titration in non-responding

patients, the difference between zofenopril and

enalapril treatments were no longer significant, but

still remained at an approximate 0.5–1/1–1.5 mmHg

difference between the two treatments.

Based on the results from the recent VALUE trial

(7), it might be speculated that such initial and long-

term BP differences between treatments may be of

relevance for long-term morbidity outcomes. In

VALUE, initial BP was reduced by both randomized

treatments, but the effects of amlodipine were

superior to the valsartan-based regimen, especially

in the early period (BP 4.0/2.1 mmHg lower in the

amlodipine than in the valsartan group after 1

month; 1.5/1.3 mmHg after 1 year; pv0.001).

Importantly in terms of study outcomes, this

difference in BP between treatments was associated

with a difference in the incidence of myocardial

infarction by 19% and stroke by 15%. Interestingly,

it was also seen in VALUE that BP control after 6

months and even after 1 month was a powerful

predictor of eventual outcome. Thus, seemingly

small differences in the antihypertensive response

between treatments may be deleterious over the long

run and clearly, the extent of the initial as well as

long-term BP reduction by antihypertensive regi-

mens seems to be of importance for long-term

cardiovascular outcomes.

The benefit of a good BP control for lowering

stroke incidence has also recently been demon-

strated by Arakawa and coworkers (8), who analysed

patients with hypertensive brain haemorrhage fol-

lowed up as outpatients for a mean of 2.8 years. BP

and other clinical features were compared between

the groups of patients with and without re-bleeding.

They found that a 6-mmHg difference in DBP

(88¡8 vs 82¡7 mmHg; p50.04) was associated

with a higher stroke recurrence. SBP and other

clinical variables were not different between the

groups. The stroke recurrence rate due to DBP

difference was 10.0% per patient-year in patients

with DBP w90 mmHg and v1.5% in those with

lower DBP ( pv0.001). No patients with DBP

v70 mmHg experienced a re-bleeding.

Thus, in the choice of an agent for initiating

antihypertensive treatment, not only is a predictable

and sizable BP reduction of importance, but there

should also be few initial side-effects and a high

degree of tolerability. In the present study, the

number and spectrum of possible and definitely

drug-related side-effects were similar, but zofenopril

was associated with a lower number of moderate to

severe reactions. Tentatively, this could be of

importance for concordance with therapy over the

long run and overall well-being (9).

In conclusion, the present study has demonstrated

that initiation of therapy using zofenopril in recom-

mended doses is associated with a more pronounced

antihypertensive effect than initiating treatment with

corresponding recommended doses of enalapril.

Although the differences were small and transient

over the first month of treatment, such changes in a

hypertensive population, however, may be asso-

ciated with a difference in the incidence of myocar-

dial infarction and stroke.

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Appendix

Principal investigator

A. Carre

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