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

Abstract

Angiotensin‐converting enzyme inhibitors (ACEIs) and calcium antagonists are today extensively used as first‐line monotherapy as well as appropriate combination therapy in mild to moderate hypertension. In a parallel‐group study, using clinically recommended doses, the ACEI zofenopril was compared with the calcium antagonist amlodipine in respect of their antihypertensive properties. In the study, 303 hypertensive patients, aged 18–75 years, were compared in terms of antihypertensive response and adverse effects after treatment with zofenopril, 30–60 mg once daily or amlodipine 5–10 mg od. 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 <10 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 −10.0 and −9.9 mmHg and systolic blood pressure (SBP) by −13.0 and −13.2 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 <90 mmHg) was 61.4% in the amlodipine and 62.2% in the zofenopril group and the percentage controlled (with sitting DBP <90 mmHg and/or a decrease of at least 10 mmHg) was 76.4 in the amlodipine and 70.1 in the zofenopril groups (both ns). We conclude that SBP as well as DBP were substantially reduced in mild to moderate hypertensive patients over 12 weeks treatment with zofenopril or amlodipine in monotherapy. Thus, given the size of the BP reduction, such treatments are likely to produce beneficial cardiovascular outcome effects in patients with mild to moderate hypertension.

• Blood pressure control
• response rate
• zofenopril
• amlodipine

Introduction

Current recommendations for management of hypertensive 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 treatment is commonly considered as first‐choice therapy in patients with diabetes, previous myocardial infarction 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 Collaboration, 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 diabetes and 125,314 without diabetes demonstrated that any of the four major classes of antihypertensive produced substantial reductions in short‐ to medium‐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 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 uncomplicated 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 randomized 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 sphygmomanometer 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 <110 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 >90 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 readings were taken by a standard mercury sphygmomanometer 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 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 α = 0.05 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 amlodipine treatment, sitting SBP and DBP were gradually 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 −12.2±7.4 (p<0.001) and −12.3±6.3 (p<0.001) mmHg and SBP by −14.6±12.4 (p<0.001) and −16.1±12.5 (p<0.001) 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.

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 od = 127; amlodipine 5–10 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.

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 classified as responders (sitting DBP <90 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 <90 mmHg) by the respective 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 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 receiving 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.

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.

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 continuous 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 importance 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 (Microalbuminuria 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 diuretics 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 treatment with beta‐blockers and thiazide diuretics were judged to exhibit disadvantages compared with an ACEI or a calcium antagonist alone or in combination. 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 140/90 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' knowledge 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 implementation 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 combination 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 healthcare 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 hypertension 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.

Appendix

Principal investigators

F. Harrison,

W. I. C. Clark