Abstract
In a parallel double‐blind multicentre study, 375 hypertensive patients were enrolled and treated with either the angiotensin‐converting enzyme inhibitor (ACEI) zofenopril 30 mg once daily (titration 60 mg od) or the angiotensin II type 1 receptor (AT1) antagonist losartan 50 mg od (titration 100 mg od). Patients with mild to moderate hypertension, defined as a diastolic blood pressure (DBP) between 95 and 110 mmHg in the sitting position without other signs of cardiovascular disease were enrolled and treated for 12 weeks. BP was assessed in the clinic, and self‐measured by the patients at home during a working day and a holiday, as well as before and at the clinic follow‐ups. Systolic (SBP) and DBP were significantly reduced in both treatment groups to a similar extent at the end of the 12‐week study. However, the immediate or early reduction of DBP as well as DBP reduction over the first month was significantly greater with zofenopril (p = 0.01 and p = 0.003, respectively) compared with losartan treatment. After 3 months of treatment and dose up‐titration, clinic BP reductions were similar in both groups. However, more subjects with losartan had used a higher dose step (42.1%) compared with zofenopril (33.1%). Home BP assessments demonstrated that systolic and diastolic pressures were substantially lower than the BP measurements made by sphygmomanometer in the clinic. In particular, assessments 2–3 days before the clinic visits during working days and holidays were characteristically lower, while the measurements during the clinic visits were largely similar to the conventional BP measurements by the doctor. The number and the severity of adverse events, related to the study medications, were largely benign and similar in both groups. The present study demonstrates that zofenopril in clinically recommended doses is at least therapeutically equivalent to losartan treatment, when assessed by conventional sphygmomanometry at the doctor's office or at home by self‐measured BP assessments by the patients. Zofenopril however, induces a more rapid initial lowering of BP over the first month of therapy.
Introduction
Most antihypertensive drugs when administered to patients with mild to moderate hypertension reduce clinic blood pressure (BP) by 10–15% Citation[1,2]. Initial monotherapy is usually effective in inducing a substantial BP reduction in about 50% of unselected patients, while those with stage 2 or 3 hypertension often need more than one drug. Overall, in large trials, the efficacy of most antihypertensive agents in optimal doses are remarkably similar, although there may be a pronounced individual variation in responsiveness between classes as well as between specific antihypertensive drugs Citation[1–3]. Thus, the choice of therapy for the individual patient is usually based on a combined assessment of several characteristics of the patient, such as cardiovascular (CV) risk stratification, presence of coexisting conditions, age, race or ethnic group, the response to previously used drugs, as well as the previous experience of adverse reactions Citation[1,2].
For specific groups of patients, such as hypertensive diabetes mellitus patients with or without nephropathy, and patients at high risk of CV events, an angiotensin‐converting enzyme inhibitor (ACEI) or an angiotensin II type 1 antagonist (AT1A) is usually advocated as first‐line therapy Citation[1–4] based on the beneficial results of such therapy in metabolically compromised patients in recent outcome trials Citation[5–10].
The efficacy and tolerability of zofenopril in the treatment of essential hypertension is previously evaluated in monotherapy and combination therapy Citation[11,12]. In monotherapy, zofenopril is significantly more effective than placebo in reducing 24‐h ambulatory BP. In recent comparative studies Citation[13–15], zofenopril 30–60 mg/day once daily was at least as effective as atenolol 50–100 mg/day, amlodipine 5–10 mg/day or enalapril 20–40 mg/day when assessed by reductions in diastolic BP (DBP). Moreover, adverse effects reported for zofenopril are class specific and transient, and the incidence is similar or compares favourably with other first‐line or major classes of antihypertensive drugs Citation[11,12].
The results of the Survival of Myocardial Infarction Long‐term Evaluation (SMILE) trials Citation[16–19] demonstrate that the early administration of zofenopril to patients with acute myocardial infarction is associated with a significant reduction in the occurrence of major CV events (death and congestive heart failure) in high‐risk patients with anterior non‐thrombolysed myocardial infarction. Furthermore, the beneficial effect of zofenopril is more pronounced in some higher‐risk subgroups of patients, notably those with a history of diabetes mellitus or arterial hypertension.
Similar outcome benefits in hypertensive patient populations with added CV risk have been demonstrated for AT1As, such as losartan in the LIFE study Citation[9]. In particular, benefits were pronounced in the diabetic subgroup Citation[20], where losartan treatment was associated with a reduction of the primary composite endpoint of CV morbidity and mortality (CV death, stroke or myocardial infarction) by 24% and total mortality by 39%. In addition, substantial morbidity and mortality benefits in diabetic patients were reported in the SCOPE and VALUE trials Citation[21].
In the present study, zofenopril was compared with losartan, the prototype AT1A, in terms of antihypertensive efficacy during 12 weeks in mild to moderate hypertensive patients. In addition to conventional clinic BP assessments, BP measurements were performed by the patients themselves at home during work and leisure, as well as in the clinic prior to the scheduled visits.
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. The study was conducted according to the declaration of Helsinki after approval of the relevant ethics committees at the different study sites. In all, 360 patients with mild to moderate hypertension were enrolled, of which 327 patients met the inclusion criteria and none of the exclusion criteria. Patients included were subjects with mild to moderate hypertension, aged between 18 and 75 years. Patients demographics and characteristics are presented in . 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. Also patients with CV renal complication and subjects with insulin‐dependent diabetes were not allowed into the trial. Also excluded were patients taking concomitant medications known to interfere with the study drugs. The study treatment used zofenopril (Menarini) and losartan, both commercial available. Study medications were given in the morning and in a double‐dummy fashion to ensure proper blinding. BP was measured in the sitting position by a standard mercury sphygmomanometer after at least 20 min of rest. At each clinic visit, standing SBP and DBP were also measured. Subjects were included in the study if they had stable diastolic hypertension, defined as “office” DBP between ⩾95 mmHg and under <110 mmHg assessed as the median of three consecutive measurements at randomization. Patients were randomized to receive either oral zofenopril 30 mg once daily (could be up‐titrated to 60 mg once daily) or oral losartan 50 mg once daily (could be up‐titrated to 100 mg once daily). Patients were scheduled to the clinic for two pre‐randomization visits, the randomization visit and three post randomization visits (at weeks 4, 8 and 12 after randomization). Oral zofenopril or losartan could be up‐titrated at week 4 if the DBP was >90 mmHg and if the DBP reduction was less than 10 mmHg at that visit. Apart from BP assessments, adverse event recordings were made at each study visit and routine laboratory blood sampling was made at randomization and at the end of the study.
Table I. Patient demographics and characteristics.
Patients were seen in the morning and BP readings were taken after 10 min of supine rest. Sitting and standing BPs were taken after the supine assessments. BP readings were obtained by standard mercury sphygmomanometry and SBP was taken at Korotkoff 1 and the DBP at Korotkoff 5. BP measurements were made in the same arm and performed by the same person at each clinic follow‐up.
In addition to the conventional clinical BP measurements by sphygmomanometer performed by the physician, BP was also self‐measured at home (Omron, HEM‐705CP device). Measurements were performed at home by the patients during one working day and during one holiday. BPs were measured four times a day, assessing diastolic and systolic values. Additional measurements were also done by the patient 2–3 days before the clinic visit and also during the clinic visit. Assessments were done three times during the study: at the randomization visit, before the 4‐week visit and at the end of the 12‐week treatment period. 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.
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.
Statistics was performed by 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 for confirmed with the Mann–Whitney U‐test relating to changes before and after treatment. All efficacy analysis was assessed according to intension to treat (ITT). Semi‐quantitative data were analysed using the Rank‐Sign test and all test were two‐tailed at α = 0.05 significance level.
Results
Of the 327 patients were randomized in the study, 165 were in the zofenopril group and 162 in the losartan group. Patients were young to middle‐aged () with a mean SBP/DBP in the zofenopril group of 158/99 mmHg and in the losartan group of 158/99 mmHg. Zofenopril 30 mg and losartan 50 mg respectively were given for 4 weeks and after that period, the dose could be doubled in non‐responders, i.e. if reduction of DBP was less than 10 mmHg during the period.
During the initial 4‐week treatment period, SBP/DBP was reduced by 16.6±11.4/12.8±6.6 mmHg (p<0.001/p<0.001) in the zofenopril (n = 157) group and by 13.2±11.2/10.5±7.0 mmHg (p<0.001/p<0.001) in the losartan group (n = 145). At that visit, the SBP and DBP reductions by zofenopril was more pronounced than that for losartan (3.4/2.3 mmHg; p<0.01/p<0.003) (). There were no differences in heart rates between the two treatments. Furthermore, in terms of proportions of patients reaching DBP below 90 mmHg and/or DBP decrease of at least 10 mmHg, there were no differences between the two treatment alternatives.
Table II. Sitting systolic and diastolic blood pressures in zofenopril and losartan treated patients during 12 weeks of follow‐up.
After 4 weeks of treatment, at the 8‐ and 12‐week clinic visit respectively, BPs were only slightly further reduced by the zofenopril and losartan treatment. Dose up‐titrations were performed in 48 zofenopril‐treated patients and 58 losartan‐treated patients. The sitting SBP and DBP are shown in . In those patients who were non‐ responders, the DBP reduction was only about half of that seen in the responder populations on the two respective treatments ().
Table III. Diastolic blood pressures during the 12 weeks follow‐up after zofenopril and losartan treatment in responder and non‐responder patient groups.
Home SBP and DBP measurements by the Omron device were performed by the subjects 2–3 days before the clinic visit date as well as during a working day, holidays and on the day of the physician consultation. Results from the home BP measurements () demonstrate that the mean SBP and DBP measurements taken by the patients were markedly lower than the clinic sphygmomanometer measurements at the randomization visit. Moreover, substantial but slightly lower BP differences were seen after 4 and 12 weeks of treatment with either zofenopril or losartan, whether or not the measurements were taken at working days or holidays ().
Table IV. Comparisons of clinic blood pressure (BP) measurements by sphygmomanometry and home BP measurements (by the patient) using an Omron device at 12 weeks.
Adverse events classified according to the WHO adverse reaction dictionary were recorded at each scheduled visit by means of spontaneous reports and by non‐leading questions. The severity, onset, duration and resolution of events did not differ between the two treatments.
Discussion
ACEIs and AT1 antagonists both suppress cellular signalling of angiotensin II, however, by different mechanisms of action. Despite major differences in the mode of angiotensin II suppression and the modulation of other hormones and receptors, both classes of drugs are generally effective in attenuating the physiological and clinical manifestations of angiotensin II. In clinical use, ACEIs and AT1As are well‐tolerated antihypertensive drugs that are particularly useful in metabolically compromised diabetic patients as well as in hypertensive patient cohorts with multiple risks Citation[21,22]. In hypertension, after myocardial infarction and in stable coronary heart disease, ACEI and AT1A therapy has been shown to reduce mortality in a manner independent of haemodynamic alterations Citation[5–10]. Moreover, inhibition of the renin‐angiotensin system, with either ACEIs or AT1As, improves endothelial dysfunction, is associated with beneficial effects on insulin sensitivity and decreases oxidative stress in hypertensive patients Citation[22].
In the present study, both zofenopril and losartan significantly lowered SBP by 16.6 mmHg and 13.2 mmHg, respectively, after 4 weeks of treatment. At that point, a significant reduction of DBP was also seen by zofenopril (−12.8 mmHg) and losartan (−10.5 mmHg). The DBP reduction induced by zofenopril was statistically more pronounced than that of losartan. Also, dose up‐titration was more common in losartan‐treated patients (42.1%) compared with zofenopril‐treated patients (33,1%). Interestingly, also in the comparison between clinic and home BP measurements, there was a remaining “white coat” effect observed during the study follow‐up visits.
The clinical antihypertensive efficacy of ACEI has been compared with that of direct AT1As in several trials. In most of the studies, a similar BP lowering efficacy was demonstrated by the AT1As and the comparator ACEI Citation[23]. In the study by Tikkanen et al. Citation[23], the BP lowering efficacy as well as tolerability and safety of the AT1A losartan was compared with that of the ACEI enalapril in patients with mild to moderate essential hypertension. The results of their study showed that BP changes from baseline at trough (22–26 h after the dose) did not differ between the two groups and that response rates (DBP<90 mmHg or reduction in DBP of 10 mmHg), being 51% and 53%, were similar in the losartan and enalapril groups, respectively.
Today, guidelines Citation[1] recognize ACEI and AT1A as first‐line drugs in the management of hypertension. In particular, such drugs are recognized to have specific benefits in high‐risk patients, e.g. those with diabetic or chronic kidney disease Citation[1,2] and they are highly useful in combination therapy with a calcium antagonist or a diuretic. Moreover, guidelines do stress that effective BP therapy may be reached if patients are motivated to follow prescribed therapy and if drug‐related side‐effects are few. In the present study, both zofenopril and losartan were associated with a low degree of largely tolerable side‐effects, which confirms previous studies on the high degree tolerability of ACEIs and AT1 antagonists.
Taking the size of hypertension problem, which affects approximately 25% of adults worldwide, and the fact that only 30% or less of patients in developed and developing countries are adequately treated Citation[1], improvements are urgently needed. In addition to effective non‐pharmacological approaches, rational drug combination strategies have to be implemented more often in order to reach goals in a majority of hypertensive patients.
Thus, in the future, choices of treatment have to be improved in order to achieve not only effective mono‐ and combination therapies but also to implement cost‐effective regimens for the management of hypertensive populations at various degrees of future CV risk.
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Appendix
Principal investigators
J. L. Llisterri Caro
J. V. Lozano Vidal
Co‐investigators
D. Diaz Fernandez
R. Dura Belinchon
M. A. Crespo Galera
J. Barber Rubio
J. Ruiz Baixauli
T. Sanchez Ruiz
J. A. Herranz Martinez
L. Ramos Ramos
M. T. Amoros Barber
F. Sanchez Sanchez
F. Valls Roca
V. Valor Font
J. L. Lafuente Gutierrez
P. Navalon Gomez
P. Gimenez Roset
J. Martinez Manuel
E. Carsi Villalba
T. Fuster Bellido
E. Navio Engli
E. G. Tena
J. Nadal Oltra
J. Ballester Palanca