ORIGINAL ARTICLE

Blood pressure control and response rates with zofenopril comparedwith amlodipine in hypertensive patients

CSABA FARSANG

First Department of Internal Medicine, Semmelweiss University, Budapest, Hungary

AbstractAngiotensin-converting enzyme inhibitors (ACEIs) and calcium antagonists are today extensively used as first-linemonotherapy as well as appropriate combination therapy in mild to moderate hypertension. In a parallel-group study, usingclinically recommended doses, the ACEI zofenopril was compared with the calcium antagonist amlodipine in respect oftheir antihypertensive properties. In the study, 303 hypertensive patients, aged 18–75 years, were compared in terms ofantihypertensive response and adverse effects after treatment with zofenopril, 30–60 mg once daily or amlodipine 5–10 mgod. After receiving the lower starting dose, up-titration was optional at 4 weeks to the higher dose if diastolic pressure (DBP)was 90 mmHg or more or if a decrease from base line of v10 mmHg was present. After 4 weeks and appropriate up-titration of dose in non-responder patients, there were significant and similar reductions of sitting DBP by 210.0 and29.9 mmHg and systolic blood pressure (SBP) by 213.0 and 213.2 mmHg the in the zofenopril and amlodipine groups,respectively. After 12 weeks of therapy, there were further reductions in blood pressure (BP) by the respective therapies.Thus, the higher zofenopril dose lowered SBP/DBP by 15.7/12.0 mmHg and the higher amlodipine dose by 17.1/12.2 mmHg (ns). Also, at the end of the study, the percentage of patients controlled (with sitting DBP v90 mmHg) was61.4% in the amlodipine and 62.2% in the zofenopril group and the percentage controlled (with sitting DBP v90 mmHgand/or a decrease of at least 10 mmHg) was 76.4 in the amlodipine and 70.1 in the zofenopril groups (both ns). Weconclude that SBP as well as DBP were substantially reduced in mild to moderate hypertensive patients over 12 weekstreatment with zofenopril or amlodipine in monotherapy. Thus, given the size of the BP reduction, such treatments arelikely to produce beneficial cardiovascular outcome effects in patients with mild to moderate hypertension.

Key Words: Blood pressure control, response rate, zofenopril, amlodipine

Introduction

Current recommendations for management of hyper-

tensive patients with intermediate to higher risk due

to additional risk factors or organ damage often

include an angiotensin-converting enzyme inhibitor

(ACEI) alone or in combination (1,2). ACEI treat-

ment is commonly considered as first-choice therapy

in patients with diabetes, previous myocardial infarc-

tion or stroke, heart failure, reduced systolic left

ventricular ejection fraction or and patients with high

coronary disease risk, based on the efficacy of these

drugs in such patient populations (3).

In fact, in the initial meta-analysis by the Blood

Pressure Lowering Treatment Trialists Collabora-

tion, the collected evidence from placebo-controlled

trials with an ACEI demonstrated substantial

reductions in stroke (30%), coronary heart disease

(20%) and major cardiovascular events (21%) (4,5).

A more recent analysis by the same group (6) of

major studies including 33,395 patients with dia-

betes and 125,314 without diabetes demonstrated

that any of the four major classes of antihypertensive

produced substantial reductions in short- to med-

ium-term risks for the leading causes of death and

disability. There was, however, some evidence that

patients with diabetes had a greater reduction in the

risk of total major cardiovascular events with

antihypertensive regimens that targeted lower BP

goals, and also evidence that patients with diabetes

had more protection against cardiovascular death

and total mortality with an ACEI-based regimen.

Further to that, ACEIs and angiotensin II type 1

antagonists (AT1As) have been shown to have

Correspondence: Csaba Farsang, First Department of Internal Medicine, Semmelweiss University, Koranyl S. u. 2/a, H-1083 Budapest, Hungary. E-mail:

farsang@bel1.sote.hu

Blood Pressure. 2007; 16 (Suppl 2): 19–24

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

DOI: 10.1080/08038020701561737

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specific renoprotective effects independent of the

level of BP or the extent of BP lowering, at least in

some subgroups of diabetic patients (7). Notably,

ACEIs and AT1As slow the progression to end-stage

renal disease (ESRD) by approximately 25% as

compared with other antihypertensive drugs in

hypertensive diabetic patients with macroalbuminuria

and renal insufficiency. Whether the independent

renoprotective effects of ACEIs and AT1As extend to

all patients with hypertension and diabetes or only to

those with albuminuria remains to be settled.

Thus, although some hypertensive patient groups

may experience specific BP-independent benefits

from ACEI therapy, it is important to establish the

BP lowering potential of this class vs well-established

antihypertensive agents. In particular, it is of interest

to evaluate the antihypertensive efficacy to a widely

used calcium antagonist such as amlodipine in

representative hypertensive cohorts.

In the present study, the antihypertensive efficacy

of the long-acting ACEI zofenopril was compared

with amlodipine in middle-aged patients with un-

complicated hypertension.

Patients and methods

The study was as a parallel-group double-blind

randomized multi-centre study in patients with mild

to moderate hypertension, randomizing patients to

either the ACEI zofenopril or to the calcium

antagonist amlodipine. The study was approved by

the human research ethics committees at the

different study sites. Taken together, 357 subjects

were enrolled in the run-in phase and 303 patients

with mild to moderate hypertension were rando-

mized after meeting the inclusion criteria and none

of the exclusion criteria. The intention-to-treat

(ITT) population at 4 weeks was 284 patients and

at 12 weeks 254 patients. Patients included were

subjects with mild to moderate hypertension and

aged between 18 and 75 years. Patients with severe

or secondary forms of hypertension were excluded as

well as patients with two antihypertensive agents or

more at the initial screening visit. Furthermore,

patients with cardiovascular renal complication as

well as subjects with insulin-dependent diabetes

were excluded. Also excluded were patients taking

concomitant medications known to interfere with

the study drugs. After a 2-week placebo run-in

period, patients were randomized to receive either

12 weeks of treatment with zofenopril (Menarini)

30 mg od (could be titrated to 60 mg) or amlodipine

5 mg od (could be titrated to 10 mg). Both study

treatments used were commercially available and

were given in the morning. During the study, no

other antihypertensive medications than the study

drugs were allowed.

The patient’s BP was measured in the clinic in the

sitting position by a standard mercury sphygmo-

manometer after appropriate rest. At each clinic

visit, the supine as well as the standing systolic (SBP)

and diastolic (DBP) were measured. Subjects were

included in the study if they had stable diastolic

hypertension, defined as ‘‘office’’ DBP between

>95 mmHg and v110 mmHg as assessed by the

median of three consecutive measurements at

randomization. Patients were scheduled to the clinic

for two pre-randomization visits, the randomization

visits, and five post-randomization visits (at weeks 2,

4, 6, 8 and 12 after randomization). The primary

end-point for evaluation of the BP changes was the

mean sitting DBP at 24 h after the last dose at 4

weeks. The initial dose of zofenopril or amlodipine

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. Apart from BP assessments,

adverse event recording were assessed at each study

visit and routine laboratory assessments were taken

at randomization and at the end of the study.

Patients were seen in the morning and BP read-

ings were taken by a standard mercury sphygmo-

manometer after 10 min of supine rest. All BP

readings were taken in the same arm and performed

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

Korotkoff 1 and Korotkoff 5 were taken as the SBP

and DBP readings, respectively.

Adverse events (AEs) were assessed during the

study and recorded in adverse event case record

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.

Statistical assessments were performed using the

SAS system after computing the original data from

the case record forms. After excluding subjects with

no follow-up data and protocol violators, the ITT

population (subjects who took at least one dose of the

study medication and who did not violate the study

protocol) at 4 weeks of treatment was 284 patients

and at 12 weeks, it was 254 patients. The primary

statistical evaluation compared baseline data at

randomization with data after 12 weeks of treatment.

Also, baseline data were compared with data obtained

after 4 weeks of monotherapy. All comparisons were

made using analysis of variance (ANOVA) and for

confirmation with the Mann–Whitney U-test relating

to changes before and after treatment. All efficacy

analysis was assessed according to ITT. Baseline

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corrected variables were compared statistically for

both treatment groups by using Student’s t-test or

ANOVA. Semi-quantitative variables were analysed

using the Cochran–Mantel–Haenszel test and for

categorical data, Fisher’s probability test was used.

All test were two-tailed at a50.05 significance level.

Results

The mean age of the study cohort was 55 years in the

zofenopril group and 57 years in the amlodipine

group; about half were females, and the two groups

did not differ in background variables in any respect

(Table I). After initiating active zofenopril or amlo-

dipine treatment, sitting SBP and DBP were gradu-

ally lowered to a similar extent in both groups to the 4

weeks dose up-titration (Table II). At 12 weeks, the

baseline sitting DBP was decreased by 212.2¡7.4

( pv0.001) and 212.3¡6.3 ( pv0.001) mmHg and

SBP by 214.6¡12.4 ( pv0.001) and 216.1¡12.5

( pv0.001) mmHg in the zofenopril and amlodipine

groups, respectively. Furthermore, at the 12-week

visit, the DBP was 88.6¡7.2 mmHg in the zofenopril

group and 88.3¡6.7 mmHg in the amlodipine

group, with a difference between groups that did

not exceed the predefined cut-off value of 5 mmHg

(Table II). The time course of the effect of the study

drugs on the sitting DBP and SBP did not differ

between treatments.

At the end of the study (at week 12), a total of

89 patients (70.1%) receiving zofenopril and 97

patients (76.4%) receiving amlodipine were classi-

fied as responders (sitting DBP v90 mmHg, and/or

decrease in sitting DBP by at least 10 mmHg from

baseline) and 79 (62.2%) and 78 (61.4%) were

controlled (sitting DBP v90 mmHg) by the respec-

tive treatments (ns).

Adverse events (AEs), possibly or probably related

to the study drug, were reported by 24 zofenopril

patients (79 events) and by 37 (127 events)

amlodipine patients (ns) (Table III). The most

frequent events were headache, oedema and cough.

In the zofenopril and amlodipine groups, there were

10 vs 15 events of headache (by three and eight

Table I. Patient demographics and characteristics.

Zofenopril Alodipine p-value

n 151 152

Gender (male/female) 76/75 76/76 0.954

Age (years) 54.9¡11.8 57.3¡10.3 0.071

Body mass index 27.6¡3.8 27.3¡3.5 0.542

Sitting SBP/DBP (mmHg) 160.2¡12.5/101.2¡4.4 159.8¡11.6/101.0¡4.4 0.892/0.802

Sitting HR (beats/min) 73.8¡8.3 74.0¡8.7 0.280

Additional CV risk factors

Obesity 46 34 0.110

Smoker 22 25 0.670

Hyperlipidemia 50 47 0.621

CHD 42 42 0.910

Diabetes 11 15 0.422

PAD 1 3 0.317

Shown are actual numbers or means¡SD. SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; CV, cardiovascular;

CHD, coronary heart disease; PAD, peripheral arterial disease. Statistical comparison by Student t-test or Fisher’s exact probability test.

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

follow-up.

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

Baseline 159.6¡12.6/100.8¡4.2 159.6¡10.9/100.6¡4.3

Week 2 148.7¡13.2/93.0¡7.5 147.8¡13.7/92.6¡6.8 0.473/0.872

Week 4 147.1¡14.2/91.1¡7.7 145.8¡12.7/90.6¡8.3 0.412/0.530

Week 6 143.7¡12.4/89.2¡6.8 143.3¡11.4/88.8¡6.6 0.995 /0.595

Week 8 143.9¡12.8/88.8¡7.2 142.5¡11.5/88.4¡6.2 0.470/0.772

Week 12 145.0¡12.0/88.6¡7.2 143.5¡12.6/88.3¡6.7 0.464/0.632

Shown are means¡SD of blood pressure values in mmHg from the 12 weeks intention-to-treat population (zofenopril 30–60 mg od5127;

amlodipine 5–10 mg od5127). 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 2, 4, 8, 6 or 12 vs baseline value

all pv0.001.

Zofenopril compared with amlodipine 21

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subjects, respectively), while 0 and 41 events of

oedema were reported by 0 and 19 patients,

respectively, in the zofenopril and amlodipine

groups. Cough was reported by five patients receiv-

ing zofenopril vs two receiving amlodipine. There

were no serious adverse events during the trial that

were causally related to any of the study drugs. All

together, including also AEs that were judged not to

be possibly or probably related to the study drug, a

total of 221 AEs were reported in the zofenopril

group, of which 115 were classified as mild, 96

moderate and 10 severe. In the amlodipine-treated

patients, altogether, a total of 271 AEs were

reported, of which 174 were mild, 86 moderate, 10

severe and one unclassified.

Discussion

Over the 3 months of treatment in this comparative

trial, DBP fell by approximately 12 mmHg in each

of the two groups. Such effects can be translated into

significant clinical benefits in terms of lowering of

cardiovascular events, since BP exhibits a contin-

uous relationship with the risk of cardiovascular

events across the usual hypertensive BP range in all

age groups (1). Importantly also, evidence from

large outcome trials have emphasized the impor-

tance of tight control of BP in patients, especially

those with high cardiovascular risk. This was

relevant in the present study where more than half

of the patient cohort has additional risk factors or

target organ damage, placing them in moderate- or

high-risk categories.

ACEIs such as zofenopril are particularly useful in

such cohorts of hypertensive patients with added

risks. ACEIs as well as AT1As have been shown to

reduce cardiovascular events in hypertensive diabetic

patients. For example, the PERSUADE (Perindopril

Substudy in Coronary Artery Disease and Diabetes),

the EUROPA (EUropean trial on Reduction Of

cardiac events with Perindopril in stable coronary

Artery) trial and the MICRO-HOPE (Micro-

albuminuria Cardiovascular Renal Outcomes, the

Heart Outcomes Prevention Evaluation substudy),

all compared ACEIs with placebo in high-risk

subjects, many of whom had hypertension (8–10).

Interestingly, these studies generally found a greater

reduction in cardiovascular end-points with ACEIs

than would have been expected through the achieved

BP lowering effect in mmHg.

Some of the shortfalls in cardiovascular outcome

observed in early hypertension trials were in part

attributed to metabolic disadvantages of the diure-

tics and beta-blockers used (1). Thus, for a given BP

reduction, it was suggested that ACEIs and calcium

antagonists would have advantages over diuretics

and beta-blockers. In particular, combination treat-

ment with beta-blockers and thiazide diuretics were

judged to exhibit disadvantages compared with an

ACEI or a calcium antagonist alone or in combina-

tion. ACEIs such as zofenopril may therefore have

some benefit beyond BP control in preventing

coronary disease and calcium antagonists such as

amlodipine may have a similar benefit in preventing

stroke.

In addition to effects of drugs on other risk factors

than high BP, there may be other reasons for

suboptimal risk factor management of hypertensive

patients. Such factors may include a failure to achieve

BP control, due to lack of awareness of hypertension,

suboptimal medical management, as well as poor

patient adherence to antihypertensive medication

regimens and lifestyle changes. Despite the focus on

the importance of maintaining BP below 140/

Table III. Adverse events (AEs) during exposure to the study medications.

Zofenopril Amlodipine p-value

n 151 152

Subjects with AEs 69 78 0.328

Number of AEs (all events) 221 271

Mild 115 174

Moderate 96 86

Severe 10 10

Subjects with AEs possibly, probably or definitely drug related 24 37 0.067

Number of AEs possibly, probably or definitely drug related 79 127

Mild 48 81

Moderate 31 42

Severe 0 4

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

of the trial. AEs, adverse event. Statistical comparison by Student t-test or Fisher’s exact probability test.

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90 mmHg in the general hypertensive population and

still lower in diabetics, hypertension control rates

remain a disappointing issue (11,12). Often, patient

non-adherence remains the main focus of attention in

treated hypertensive patients, even though a key

determinant of BP control is the clinicians’ knowl-

edge and attitudes regarding the importance of

achieving target BP goals (13). Although much

remains to be understood about the obstacles to

achieve adequate BP control in average risk as well as

high-risk hypertensive patients, earlier implementa-

tion of combination strategies as well as more

aggressive treatment with potent antihypertensive

drugs remain important issues.

Thus, use of potent antihypertensive agents

remains an important issue in bringing BP to

control. In the present study, initiation of zofenopril

or amlodipine monotherapy substantially reduced

SBP by 14–16 mmHg and DBP by about 12 mmHg

after appropriate up-titration in non-responding

patients, corresponding to response rates of 70–75%.

In addition to that, when starting with an ACEI or

a calcium antagonist, there is a possibility of using a

combination of drugs, either free or fixed, to further

lower BPs in order to obtain adequate BP control. In

recent guidelines (1), the use of combination

treatments may be implemented at start, a strategy

that possibility would contribute to improve BP

control because of the higher capacity of combina-

tion treatments to lower BP. In addition, such

combinations of low doses of two agents from

different classes could also help to avoid the

adverse-effect profiles commonly associated with

high-dose monotherapy (1).

In order to estimate the burden of the elevated risk

of all cause cardiovascular disease, Hansson and

coworkers (14) calculated the impact of uncontrolled

hypertension to each national healthcare system.

They estimated that 29 million adult people in the

five countries (13% population) had BP levels above

160/95 mmHg, and an additional 46 million people

(21% population) had BP values in the range of 140/

90–160/95 mmHg. Based on their model, a health-

care system cost of 1.26 billion euros could be

avoided if optimal hypertension management could

be implemented. With a similar aim, Loyd et al. (15),

in a descriptive epidemiological study, estimated the

cost and morbidity consequences of uncontrolled

hypertension in the UK. If all people with hyperten-

sion had BP treated to target levels, they estimated

that the number of major cardiovascular events and

acute hospital costs that could be avoided in the UK

was 58 000 major cardiovascular events per year.

This would correspond to a reduced cost to the NHS

of managing major cardiovascular events of 97.2

million GBP per year at 2000/01 prices.

In summary, the present study has demonstrated

that zofenopril as well as amlodipine effectively and

to a similar extent lower DBP. Thus, the clinical use

of either agent in monotherapy as well as in proper

combination would be expected to have a significant

impact on cardiovascular risk in patients with

hypertension and other associated cardiovascular

risk factors.

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Appendix

Principal investigators

F. Harrison,

W. I. C. Clark

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