Antihypertensive efficacy of zofenopril compared with atenolol in patients with mild to moderate hypertension

Abstract

Two first‐line antihypertensive therapies for initiating treatment in hypertension were compared, the angiotensin‐converting enzyme inhibitor (ACEI) zofenopril and the beta‐blocker atenolol. The study was multi‐centre and double‐blind, and included 304 middle‐aged to elderly patients with mild to moderate hypertension who were randomized to receive either zofenopril 30–60 mg once daily (od) or atenolol 50–100 mg od for 4 weeks with the possibility to an up‐titration in non‐responding patients. The higher dose level was then administered until 12 weeks after randomization. Blood pressures (BPs) were substantially reduced by either treatment, but after 4 weeks, the systolic and diastolic BP reductions were significantly greater (p<0.05) with zofenopril (−15.6/−13.5 mmHg) compared with atenolol (−13.1/−11.8 mmHg). After 12 weeks and the possibility of dose up‐titration, BP differences between treatments were no longer significant. However, control rates (sitting diastolic BP <90 mmHg) for zofenopril remained significantly higher compared with atenolol. The number of subjects with adverse drug reactions possibly or probably related to the study medication was 14 (9.1%) in the zofenopril group and 30 (20.8%) in the atenolol group (p = 0.008). It is concluded that zofenopril as well as atenolol induces substantial reductions of diastolic BP in middle‐aged to elderly patients with hypertension. However, the control rate when initiating antihypertensive therapy with zofenopril is higher than that for atenolol.

• First‐line therapy
• zofenopril
• atenolol
• blood pressure
• control rate
• hypertension

Introduction

In the aftermath of recent large hypertension morbidity and mortality trials and in relation to the presentation of updated meta‐analyses on the outcome effects of antihypertensive treatment, there has been a lively debate on the most optimal pharmacological therapy and which combination therapies to favour in low‐risk as well as high‐risk hypertensive patients. Over the past decades, diuretics and beta‐blockers have maintained their role as being appropriate drugs and first‐line alternatives for the initial treatment of uncomplicated hypertension, despite growing concerns that these agents may be associated with adverse metabolic effects [1]. However, while diuretics such as low doses of chlorthalidone have documented cardiovascular preventive effects (VA studies), there has never been any study showing a reduction in heart attacks, strokes or all‐cause mortality with a beta‐blocker‐based therapy in uncomplicated hypertension [2–4]. This has led several researchers to question the use of diuretics as well as beta‐blockers as main first‐choice treatments for hypertension [2–5].

For many patients, in particular those with associated clinical conditions or some forms of target organ disease, such as renal dysfunction and diabetes, an angiotensin‐converting enzyme inhibitor (ACEI) or an angiotensin II type 1 antagonist (AT1A) may be preferable [1],[5–8]. Also, ACEIs and AT1As may also be superior as initial therapy in patients with congestive heart failure as well as in patients with prior myocardial infarction or coronary artery disease [1].

Blockade of the renin–angiotensin system (RAS) has been evaluated vs beta‐blocker treatment in the LIFE trial as well as in the ASCOT trial [7,8]. In spite of the recent considerable criticism of beta‐blockers as first‐line agents in hypertension [4,5], atenolol and other beta‐blockers have been and will remain a cornerstone in the clinical management of cardiovascular disease. Several agents of the beta‐blocker class still remain invaluable treatments for coronary heart disease, congestive heart failure, and many forms of arrhythmias [1].

The efficacy and tolerability of the ACEI zofenopril in the treatment of essential hypertension have been evaluated against placebo and compared with the main classes of antihypertensive drugs [9–13].

In the present trial, zofenopril was compared with the beta‐blocker atenolol to study response and control rates over 12 weeks treatment in patients assigned to a zofenopril dose of 30–60 mg once daily (od) compared with atenolol in the dose steps 50–100 mg od.

Patients and methods

The study was conducted as a randomized comparative parallel‐group double‐blind multi‐centre study in patients with mild to moderate hypertension. The study was conducted according to the declaration of Helsinki after approval of the relevant ethics committees at the different study sites. In all, a total of 326 subjects were screened in the run‐in phase, 304 were randomized meeting the inclusion criteria and none of the exclusion criteria. Adult males and females with mild to moderate hypertension were included, aged between 18 and 75 years of age. The intention‐to‐treat (ITT) population at 4 weeks was 292 patients and at 12 weeks 287 patients.

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 or 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. The study treatments used, commercially available zofenopril and atenolol as well as placebo, were provided in indistinguishable capsules produced by Pharmakapsel GmbH to ensure proper blinding. The study medications were given in the morning.

Patients were seen in the morning, and sitting and standing BPs were measured after the supine assessments. BP readings were taken by a standard mercury sphygmomanometer; systolic BP (SBP) was taken at Korotkoff 1 and the diastolic (DBP) at Korotkoff 5. BP readings were measured in the same arm and performed by the same person at each clinic follow‐up. A standard 12‐lead electrocardiogram was taken in relation to the standard physical examination in the beginning and the end of the study. During the study, no other antihypertensive medications than the study drugs were allowed.

Inclusion BP was defined as “office” DBP between ⩾95 mmHg and <115 mmHg assessed as mean of three consecutive measurements at randomization. Patients were scheduled to the clinic for two pre‐randomization visits, the randomization visits and four post‐randomization visits (at weeks 2, 4, 8 and 12 after randomization). After the randomization visit, the study patients were randomly assigned to 12 weeks' treatment with zofenopril 30–60 mg od or atenolol 50–100 mg od, followed by 2 weeks' dose tapering for safety assessment.

Oral zofenopril or atenolol could be up‐titrated at 4 weeks after initiating treatment if the DBP was >90 mmHg and if the DBP reduction was less than 10 mmHg at that visit. Response rate was defined as a DBP below 90 mmHg or a reduction by at least 10 mmHg from the baseline BP value, and control was defined as a DBP <90 mmHg.

In addition to the BP assessments, adverse event recordings were made at each study visit, and routine laboratory assessments were taken at randomization and at the end of the study. Adverse events were assessed during the study by non‐leading questions and recorded in adverse event forms, and coded using the dictionary terms from the MEDdra dictionary. The events were assessed in terms of probable or possible relation to the study treatments as well as in terms of severity. All adverse event reports were classified into WHO sub‐organ classes.

Statistical assessments were performed using the SAS system (version 6.12) 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 efficacy analysis was assessed according to ITT. Semi‐quantitative data were analysed using the Rank‐Sign test and all test were two‐tailed at the α = 0.05 significance level. Efficacy variables were corrected for baseline. The baseline‐corrected variables were then compared statistically for both treatment groups using Student's t‐test or analysis of variance (ANOVA). Semi‐quantitative variables were compared statistically for both treatment groups by using Cochran–Mantel–Haenszel, whereas for categorical data, Fishers exact probability test was applied. Efficacy variables are generally presented as means and standard deviation (SD).

Results

Of the 304 patients randomized in the study, 292 were included in the final 4 weeks ITT analysis (147 were in the zofenopril group and 145 in the atenolol group) and 287 patients in the 12‐week analysis. Patients were young to middle‐aged; the mean age of the zofenopril study participants was 55 years and the atenolol participants 53 years. Females made up about half of the population. Patient demographics and characteristics were similar in all respects (Table I). Average mean sitting SBP/DBP at the end of the 2‐week run‐in period was 156/100 mmHg and 154/100 mmHg respectively in the zofnopril and atenolol groups, and heart rates were 75 beats/min in both groups. Zofenopril 30 mg or atenolol 50 mg were given for 4 weeks as initial therapy in both groups, and both treatments substantially lowered SBP and DBP by 11–15 mmHg (Table II). By 2 weeks after initiating treatment, mean SBP and DBP were significantly reduced (Table II) and after 4 weeks the SBP/DBP reductions were significantly greater (p<0.05) with zofenopril (−15.6/−13.5 mmHg) compared with atenolol (−13.1/−11.8 mmHg). The response rates were similar for the two treatments but the proportion of patients controlled was significantly higher (p = 0.015) in the zofenopril group after 4 weeks of treatment at the initial dose level (Table III).

Table I. Demographics of the study patient cohort.

	Zofenopril	Atenolol	p‐value
n	153	151
Gender (male/female)	68/85	78/73	0.208
Age (years)	55.0±9.8	53.2±11.9	0.153
Body mass index	26.2±2.1	26.5±2.3	0.242
Previously treated/untreated	143/10	136/15	0.281
Sitting SBP/DBP (mmHg)	156.1±10.4/100.4±3.5	154.3±11.1/100.4±3.5	0.144/0.904
Sitting HR (beats/min)	75.0±8.1	75.0±8.3	0.905

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. Sitting systolic (SBP) and diastolic blood pressures (DBP) in zofenopril and atenolol treated patients during 12 weeks of follow‐up.

	Zofenopril (SBP/DBP)	Atenolol (SBP/DBP)	p‐value
Baseline	156.0±10.4/100.5±3.5	154.6±11.1/100.5±3.8
Week 2	142.1±12.7/89.2±6.7	143.0±12.5/90.7±5.9	0.046/0.033
Week 4	140.4±11.7/87.0±6.6	141.5±12.2/88.7±6.3	0.035/0.024
Week 8	139.0±10.1/87.1±6.2	140.0±11.3/88.7±6.3	0.042/0.303
Week 12	140.1±11.9/86.5±4.8	139.9±11.9/88.8±5.7	0.329/0.689

Shown are means±SD of blood pressure values in mmHg from the 12 weeks intention‐to‐treat population (zofenopril 30–60 mg od = 127; atenolol 50–100 mg od = 127). 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 p<0.001.

Table III. Response rates (sitting diastolic blood pressure <90 mmHg, and/or decrease in sitting diastolic blood pressure by at least 10 mmHg from baseline) and control rates (sitting diastolic blood pressure <90 mmHg) after 12 weeks of treatment by zofenopril or atenolol.

	Zofenopril, n (%)	Atenolol, n (%)	p‐value
Responder	130 (90.9)	123 (85.4)	0.150
Non‐responder	13 (9.1)	21 (14.8)
Controlled	115 (80.4)	97 (67.4)	0.012
Non‐controlled	28 (19.6)	47 (32.6)

After the initial 4‐week dose period, the respective drug dosages could be doubled in non‐responders, i.e. if DBP was not reduced below 90 mmHg or if the reduction was less than 10 mmHg during the initial lower dose treatment period. In the zofenopril group, such patients received a dose increase from 30–60 mg od and the in atenolol group the dose increase was from 50–100 mg od. Such a dose increase after the 4‐week visit was implemented in 44 zofenopril and 68 atenolol patients. This further lowered the DBP from the 4‐week to the 12‐week visit in the zofenopril group from 94.8±4.5 to 88.3±5.0 mmHg and in the atenolol group from 93.6±4.9 to 89.5±4.9 mmHg.

After 12 weeks of treatment and appropriate dose up‐titration in non‐responders (Table III), BPs were reduced by 15.9±10.4/13.9±4.9 mmHg (p<0.001/p<0.001) in the zofenopril and by 14.7±9.8/13.8±5.9 mmHg (p<0.001/p<0.001) in the atenolol group. While the responder rates did not differ between treatments, the number and proportion of patients controlled were higher in the zofenopril group (Table III).

Possibly and probably drug‐related adverse events were reported in 14 patients treated with zofenopril and 30 treated with atenolol (p = 0.008). The severity tended to be more pronounced in the patients receiving the beta‐blocker (Table IV). Most frequently reported were liver enzyme abnormalities and dizziness for zofenopril, and bradycardia and fatigue for atenolol.

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

	Zofenopril	Atenolol	p‐value
n	153	151
Subjects with AEs	31	40	0.199
Subjects with AEs possibly, probably or definitely drug related	14	30	0.008
Severity of AEs (all events)			0.039
Mild	51	71
Moderate	5	23
Severe	2	7
Severity of AEs possibly, probably or definitely drug related			0.069
Mild	17	34
Moderate	1	17
Severe	2	6

Shown are actual numbers of subjects with events as well as number of events in zofenopril and atenolol treated patients over the course of the trial. Statistical comparison by chi‐squared test.

Discussion

The major benefit of antihypertensive therapy is generally considered to be related to the lowering of SBP as well as DBP per se. A reduction of BP to at least <140/90 mmHg is characteristically protective for the patient in terms of cardiovascular disease events. One of the most important findings of recent meta‐analyses [14,15] of BP lowering trials is that patients randomized to more compared with less intensive treatment have approximately a 20% lower rate of strokes and coronary heart disease events. In this trial, zofenopril as well as atenolol substantially lowered SBP and DBP by 10–15% and furthermore, the rate of controlled DBP was higher in the zofenopril group. Thus, administration of zofenopril in the 30–60‐mg dose range is likely to translate into a reduction of cardiovascular complications, that should be tested in future studies.

In a recent trial by Malacco et al. [16], zofenopril therapy was shown to lower 24‐h ambulatory BP compared with placebo in the dose ranges 7.5–60 mg daily. In their study, they evaluated the antihypertensive efficacy and safety of zofenopril in mild‐to‐moderate hypertension and showed substantial BP lowering effects. They concluded that zofenopril in a dose of 15 mg od or more was required for obtaining a clinically relevant reduction of DBP in mild‐to‐moderate hypertension. Interestingly, zofenopril showed a more marked dose‐response effect on mean sitting SBP and, to a lesser extent on DBP in the older age group (>50 years). Furthermore and interestingly, the 60 mg dose produced a greater trough effect and a more reliable SBP response in older patients.

In an early study, Lacourcière & Provencher [9] demonstrated that zofenopril was superior to diuretics in lowering daily working ambulatory BP compared with hydrochlorothiazide in patients with mild to moderate essential hypertension. Further, a fixed combination of zofenopril/hydrochlorothiazide (30/12.5 mg/day) was more effective in normalizing BP than each agent administered as monotherapy [17]. In particular, the zofenopril/hydrochlorothiazide fixed combination provided more optimal BP control in a larger proportion of patients than would be achievable with monotherapy, while maintaining the tolerability profile observed with each of the respective individual agents.

In the present study, the tolerability profile was higher for zofenopril compared with atenolol, since possibly or probably cause‐related adverse events were lower with zofenopril compared with atenolol. Also, adverse reactions tended to be milder with the ACEI compared with the beta‐blocker.

However, despite the fact that BP was lowered to a similar extent with beta‐blockers compared with other drug classes, the recent LIFE and ASCOT trials [7,8] have demonstrated the inefficacy of this drug class for the prevention of cardiovascular events in hypertensive patients. The reasons for this are not fully known, but it has been noted that the risk of developing diabetes appears to be increased by diuretics and beta‐blockers, whereas ACEIs and AT1As may decrease this risk [5]. Since approximately 85% of hypertensive patients are predisposed to develop diabetes, many clinicians may hesitate to prescribe a thiazide diuretic or a beta‐blocker as initial therapy to many patients, but argue that a thiazide diuretic should only be used in combination with an ACEI or an AT1A to mitigate possible adverse metabolic effects, in particular the negative influence on glucose metabolism. Thus, since diuretics and beta‐blockers, especially when used in combination, may enhance development of new‐onset diabetes [5], there may be obvious reasons to avoid of diuretics and beta‐blockers, at least in combination therapy in patients with the metabolic syndrome.

In addition to the concerns raised based on metabolic reasons, a recent meta‐analysis [18] has further questioned the efficacy of atenolol, in particular, in reducing stroke risk in hypertensive patients. In their meta‐analysis of randomized controlled trials, Lindholm et al. [18] found that the relative risk of stroke was 16% higher for beta‐blockers (95% CI 4–30%) than for other antihypertensive drugs, whereas there was no difference for myocardial infarction. When compared with placebo or no treatment, the relative risk of stroke was reduced by 19% for all beta‐blockers (7–29%), which is about half that expected from earlier placebo controlled or no treatment trials in mild to moderate hypertension. Based on their findings, Lindholm et al. [18] argued that beta‐blockers may in fact be inferior to other antihypertensive drugs in reducing stroke in hypertension, and for that reason, beta‐blockers should not remain first choice in the treatment of primary hypertension [19].

In summary, the results from this comparative trial of zofenopril and atenolol in mild to moderate hypertensive patients demonstrate that both agents substantially reduce SBP and DBP. However, the response rate was higher with zofenopril treatment and the adverse event profile milder.

Appendix

Principal investigator

F. Perlik

Co‐investigators

B. Krause

D. Kuzmanic

J. Vrany

J. Drazka

L. Pesl

M. Sabljar Matinovic

M. Vostradovska

O. Jerabek

T. Grodzicki

V. Mazac

V. Smejkalova

J. Bultas

O. Topolcan