Abstract
Angiotensin‐converting enzyme inhibitors (ACEIs) are used in the management of a range of cardiovascular disorders and are 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 moderate hypertension, 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 compared with enalapril (20 mg/day). A larger proportion of patients needed dose up‐titration with enalapril compared with zofenopril to reach preset BP goals. After 12 weeks of treatment and after appropriate dose up‐titration, SBP and DBPs were lowered to similar extent in the two treatment groups, resulting in no differences between the groups in terms of response and control rates. A similar number of patients reported adverse events in the two study groups. However, the severity of adverse events 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 profile compared with enalapril.
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 diabetic nephropathy, as well as in patients at high risk of cardiovascular events Citation[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 Citation[1]. In hypertensive patients, ACEIs reduce mortality and most cardiovascular outcomes at to an extent that is similar to that achieved with diuretics and beta‐blockers Citation[2].
Today, a large number of outcome trials in patients with hypertension and related cardiovascular 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, antioxidative 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.
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 lipophilic 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 <115 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‐randomization 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 >90 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 examination 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 >90% and no major deviation from the protocol. Semi‐quantitative data were analysed using the Rank‐Sign test and all test were two‐tailed at α = 0.05 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 (). At the inclusion, the supine SBP and DBP were 161±12/101±5 in the zofenopril group (n = 152) and 161±13/101±5 mmHg in the enalapril group (n = 156). Supine heart rates were 74±9 and 74±10 beats/min in the two groups respectively ().
Table I. Demographics of the study patient cohort
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 and ). 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 and ). At the following 8‐ and 12‐week assessments, there were no differences between the zofenopril and enalapril treatments in respect to supine BPs.
Table II. Supine systolic (SBP) and diastolic blood pressures (DBP) in zofenopril‐ and enalapril‐treated patients during 12 weeks of follow up.
Table III. Standing systolic (SBP) and diastolic blood pressures (DBP) in zofenopril‐ and enalapril‐treated patients during 12 weeks of follow up.
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 and ). In the standing positions, DBP and SBP did not differ between the treatments at week 8 and 12 (Tables and ).
Heart rates in the supine as well as standing positions did not differ between the treatments throughout 12‐week study period.
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 treatments 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. Adverse events during exposure to the study medications.
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 Citation[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] = 0.59; p = 0.018). Also in CAPPP, an ACEI‐based antihypertensive treatment regimen was associated with a lower risk of diabetes development (14%; p = 0.034), compared with conventional therapy based on diuretics and/or beta‐blockers Citation[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 Citation[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 Citation[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; p<0.001).
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 regimens 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 demonstrated by Arakawa and coworkers Citation[8], who analysed patients with hypertensive brain haemorrhage followed 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; p = 0.04) 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 >90 mmHg and <1.5% in those with lower DBP (p<0.001). No patients with DBP <70 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 Citation[9].
In conclusion, the present study has demonstrated that initiation of therapy using zofenopril in recommended 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 associated with a difference in the incidence of myocardial infarction and stroke.
Related Research Data
References
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Appendix
Principal investigator
A. Carre