0Current Therapeutic Research
Volume 69, Number 3, June 2008
Antihypertensive Effect of Zofenopril Plus Hydrochlorothiazide Versus Zofenopril Monotherapy in Patients with Essential Hypertension According to Their Cardiovascular Risk Level: A Post Hoc Analysis
Ettore Malacco, MD1; and Stefano Omboni, MD2; on behalf of the Study Group*
1Division of Internal Medicine III, L. Sacco Hospital, University of Milano, Milano, Italy; and 2Italian Institute of Telemedicine, Varese, Italy
ABSTRACT
BACKGROUND: International guidelines recommend the use of angiotensin-converting enzyme inhibitors, possibly in combination with other antihypertensive drugs, to treat hypertension with associated risk factors.
OBJECTIVE: The aim of this study was to compare the antihypertensive effect of the combination of zofenopril plus hydrochlorothiazide versus zofenopril monotherapy in patients with essential hypertension, according to their cardiovascular risk level.
METHODS: This was a post hoc analysis of a previously published efficacy and tolerability study. After a 4-week placebo washout, patients with mild to moderate essential hypertension (diastolic blood pressure [DBP] 95-115 mm Hg), aged 18 to 75 years, were randomized at a ratio of 2:1:1 to treatment with zofenopril 30 mg plus hydrochlorothiazide 12.5 mg or monotherapy with zofenopril 30 mg or hydrochlorothiazide 12.5 mg for 12 weeks in an international, multicenter, double-blind study. This period was followed by 24 weeks of open-label treatment. Systolic BP [SBP] and DBP were measured by mercury sphygmomanometry, and changes associated with treatment were calculated. Patients' cardiovascular risk was computed using the Heart Score algorithm. Patients were classified in quartiles according to distribution of cardiovascular risk level, and comparisons were limited to the zofenopril plus hydrochlorothiazide and zofenopril monotherapy treatment groups. The primary end point was change in office DBP.
RESULTS: Two hundred forty-six patients (139 men, 107 women; mean [SD} age, 54 [11] years) were included in the analysis. Mean baseline cardiovascular risk was similar in the zofenopril plus hydrochlorothiazide group and the zofenopril monotherapy group (7% vs 9%). DBP and SBP reductions with treatment were significantly greater (both, P < 0.01) with combination treatment than with monotherapy for each quartile of cardiovascular risk. Cardiovascular risk reduction at the end of the 12 weeks of double-blind treatment was greater in the zofenopril plus hydrochlorothiazide group than in the zofenopril monotherapy group (1.9% vs 0.2%; P < 0.01), particularly in the
*Participating investigators are listed in the Acknowledgments.
Accepted for publication February 22, 2008. doi:10.10l6/j.curtheres.2008.06.008
0 2008 Excerpta Medica Inc. All rights reserved. 0011-393X/I32.00
group of patients with the highest cardiovascular risk at baseline (5.2% vs 2.0%). At the end of the 24-week open-label treatment period, the mean reduction in cardiovascular risk was also significantly greater in the combination treatment group than in the monotherapy group (1.4% vs 0.5%; P < 0.01).
CONCLUSIONS: In these hypertensive patients, combination treatment with zofenopril plus hydrochlorothiazide was associated with a significantly greater decrease in BP compared with zofenopril monotherapy, regardless of the patient's cardiovascular risk. The difference between combination treatment and monotherapy was particularly evident for the group of patients at highest risk. (Curr Ther Res Clin Exp. 2008;69:232-242) © 2008 Excerpta Medica Inc.
KEY WORDS: essential hypertension, cardiovascular risk, zofenopril, hydrochlorothiazide.
INTRODUCTION
International guidelines1'2 recommend the use of angiotensin-converting enzyme (ACE) inhibitors, possibly in combination with other antihypertensive drugs, to treat hypertension with associated risk factors because of their renoprotective, vascular, and cardioprotective effects. In more than half of high-risk hypertensive patients adequate blood pressure (BP) control is difficult to achieve with a single antihypertensive drug.1-3
Zofenopril, a sulfhydryl ACE inhibitor, is characterized by high lipophilicity, sustained cardiac ACE inhibition, and promotional antioxidant and tissue-protective properties.4-7 Its selective, long-acting ACE inhibitory activity makes it effective and well-tolerated for the treatment of a number of cardiovascular diseases (eg, acute myocardial infarction,8-10 heart failure,11'12 and essential hypertension13-16). When combined with low-dose hydrochlorothiazide (12.5 mg), zofenopril 30 mg showed an additional 4- to 8-mm Hg antihypertensive effect with favorable tolerability, in line with that of other combinations of an ACE inhibitor and low-dose hydrochlorothiazide.17,18 Zofenopril plus hydrochlorothiazide might be particularly useful in high-risk patients, such as those with metabolic syndrome.19
The present paper reports the results of a post hoc analysis of a 12-week, doubleblind, randomized, parallel-group study with a 24-week, open-label follow-up phase. The main study18 found a significantly greater mean (SD) office diastolic BP (DBP) reduction (primary study objective) with the combination of zofenopril 30 mg plus hydrochlorothiazide 12.5 mg (14 [9] mm Hg) than with monotherapy with zofenopril 30 mg (10 [8] mm Hg) or hydrochlorothiazide 12.5 mg (10 [9] mm Hg) alone. The safety profile of zofenopril plus hydrochlorothiazide did not differ significantly from that obtained with the corresponding monotherapies (24% of patients with drug-related adverse events vs 20% with zofenopril alone and 17% with hydrochlorothiazide alone).
The aim of this post hoc analysis was to compare the antihypertensive effect of the combination of zofenopril plus hydrochlorothiazide versus zofenopril alone in patients with essential hypertension, some of whom had metabolic syndrome,19 according to their cardiovascular risk level using the Heart Score algorithm.20
PATIENTS AND METHODS
Study Population
Written informed consent was obtained from all patients prior to their inclusion in the study. The study was approved by the independent institutional review boards of the centers involved. The original study18 assessed consecutive outpatients of either gender with mild to moderate essential hypertension. No patient was compensated, reimbursed, or paid for treatment or for participation in the study. Patients were eligible for the study if they were aged 18 to 75 years and had an office sitting systolic blood pressure (SBP) of <240 mm Hg and DBP of 95 to 115 mm Hg after 4 weeks of placebo washout from previous antihypertensive treatment. Patients were excluded if they had any of the following: (1) a difference in office sitting DBP >10 mm Hg between the screening and randomization visits; (2) secondary or malignant hypertension; (3) clinically significant heart disease (cardiac valvular disease, cardiac arrest, unstable angina, or myocardial infarction in the previous 6 months); (4) cerebrovascular disease; (5) renal insufficiency (serum creatinine concentration >1.8 mg/dL); (6) known or suspected renovascular disease; (7) inadequately controlled type 1 or 2 diabetes mellitus; (8) a history of malignancy in the previous 5 years; (9) severe hepatic impairment; (10) a history of alcohol or drug abuse; or (11) known hypersensitivity to ACE inhibitors or thiazide diuretics. Pregnant or breast-feeding women and women of childbearing potential who were not practicing an effective method of birth control were also excluded. During the study, use of antihypertensive drugs other than the study drugs was not allowed.
Study Design
This was a post hoc analysis of an international (France, United Kingdom, The Netherlands, Belgium, and Poland), multicenter (58 centers), randomized, double-blind, parallel-group study. A 4-week placebo washout period, during which previous antihypertensive treatment had to be withdrawn, was followed by 12 weeks of randomized treatment with zofenopril 30 mg plus hydrochlorothiazide 12.5 mg or monotherapy with zofenopril 30 mg or hydrochlorothiazide 12.5 mg. Patients were randomized in a ratio of 2:1:1. Randomization was done by blocks and generated by a computer. The patient randomization numbers were allocated sequentially by center in the order in which the patients entered the study. Each investigator had an envelope containing the information needed to break the randomization code; the envelope was stored in a secure place and was to be opened in case of emergency. Blinding of the physicians and the patients was ensured using a double-dummy technique in which each dose consisted of 2 identical-looking pills. The drugs were administered QD between 9 am and
11 am. The initial 12-week treatment period was the efficacy phase of the study, which was followed by a 24-week period during which only tolerability was assessed.
At the screening visit, a medical history was collected and a full physical examination, 12-lead electrocardiogram (ECG), and informed consent were obtained. ECGs were assessed again at randomization and after 12 and 36 weeks of treatment. Hematology, biochemistry, and urinalysis were performed at screening, at randomization, and after
12 and 36 weeks of treatment. After 4 weeks of treatment, a reduced laboratory assessment (blood urea nitrogen and serum creatinine and electrolyte concentrations) was also
carried out. Patients were seen 4, 8, 12, 24, and 36 weeks after randomization. During these visits and at screening and at randomization, BP, heart rate, and adverse events (AEs) were assessed. Compliance to treatment was assessed at each study visit by counting returned pills.
Blood Pressure and Heart Rate Measurement
BP was measured in the clinic using a standard sphygmomanometer 24 hours after the last drug dose was administered. Three measurements taken at 2-minute intervals after 10 minutes of rest in the sitting position were averaged and used as the office BP reference value during the first 12 weeks of the study. During the 24-week tolerability phase, a single BP reading was collected at each visit. SBP and DBP values were taken at the first and fifth Korotkoff sounds, respectively. Heart rate was measured by palpating the radial artery pulse.
Statistical Analysis
The present study is a post hoc analysis of a main efficacy and safety trial18 performed in patients classified according to their cardiovascular risk level, computed using the Heart Score algorithm, which takes into account age, sex, total cholesterol levels, SBP, and patient's smoking status.20
We limited the analysis to a comparison of the zofenopril plus hydrochlorothiazide group with the zofenopril monotherapy group. The analysis was performed on patients who were valid according to the protocol (ie, all randomized patients who completed the 12-week study period plus the open-label follow-up without major protocol violations).
We used the same primary end point as that of the main study—change in office DBP. In this post hoc analysis we classified patients in quartiles of cardiovascular risk level (risk of developing a cardiovascular disease in the next 10 years; quartile 1 = lowest risk to quartile 4 = highest risk).20 At baseline and at the end of the 12-week treatment period, office sitting SBP and DBP and mean cardiovascular risk levels were computed. Changes in baseline office BP and cardiovascular risk level were determined after the 12-week treatment phase. The effect of drug treatment on cardiovascular risk was also assessed for the open-label period. No tolerability analysis was performed because of the post hoc nature of this study and the main study objective.
All variables were compared between treatments using analysis of variance, with analysis for repeated measures when comparison was made across quartiles. P < 0.05 was considered statistically significant. Data are reported as mean (SD).
RESULTS
Demographic and Clinical data
Three hundred fifty patients were randomized to zofenopril 30 mg plus hydrochlorothiazide 12.5 mg (n = 235) or to zofenopril 30 mg (n = 115). Of these patients, 256 (73.1%) completed the 12-week randomized phase plus the 24-week open-label phase without protocol violations and thus were included in the per protocol analysis. The main reason for premature study discontinuation was the occurrence of AEs (6% in the zofenopril plus hydrochlorothiazide group vs 9% in the zofenopril mono-
therapy group); data were not available to calculate cardiovascular risk for 10 patients, and thus the final per protocol population for this post hoc analysis comprised 246 patients (157 zofenopril plus hydrochlorothiazide and 89 zofenopril monotherapy; 139 men, 107 women; mean [SD] age, 54 [11} years).
All baseline demographic and clinical data were comparable between treatment groups (Table). The mean baseline risk for developing cardiovascular disease in the next 10 years was 0.5% for the first quartile, 2.2% for the second, 7.1% for the third, and 19.9% for the fourth, with no statistically significant difference between the 2 treatment groups in the percentage of risk.
office Blood pressure Changes
Office sitting DBP and SBP reductions after 12 weeks of double-blind treatment, according to quartiles of baseline cardiovascular risk, were significantly greater (all, P < 0.01) in the group receiving zofenopril plus hydrochlorothiazide than in the zofenopril monotherapy group (Figure 1). The difference between combination treatment and monotherapy was particularly evident for the group of patients at highest risk.
Cardiovascular Risk Level
Mean baseline cardiovascular risk was similar in the zofenopril plus hydrochlorothiazide group and the zofenopril monotherapy group (7% vs 9%). Cardiovascular risk reduction at the end of the 12 weeks of double-blind treatment was significantly greater in the zofenopril plus hydrochlorothiazide group than in the zofenopril monotherapy group (1.9% vs 0.2%; P < 0.01), particularly in the group of patients with the highest cardiovascular risk at baseline (5.2% vs 2.0%). At the end of the 24-week open-label
Table. Baseline demographic and clinical characteristics of the study patients randomized to zofenopril 30 mg plus hydrochlorothiazide 12.5 mg or zofenopril 30 mg monotherapy (N = 246).* Data are mean (SD) unless otherwise specified.
Characteristic Zofenopril + Hydrochlorothiazide (n = 157) Zofenopril Monotherapy (n = 89)
Age, y 53 (11) 54 (11)
Sex, no. (%)
Male 92 (59) 47 (53)
Female 65 (41) 42 (47)
DBP, mm Hg 101 (4) 101 (4)
SBP, mm Hg 161 (14) 158 (13)
HR, beats/min 74(9) 73 (9)
Cardiovascular risk level, % 7(7) 9 (12)
Low cardiovascular risk (<5%), no. (%) 88 (56) 43 (48)
High cardiovascular risk (>5%), no. (%) 69 (44) 46 (52)
DBP = diastolic blood pressure; SBP = systolic blood pressure; HR = heart rate. *No significant between-group differences were found.
■ Zofenopril 30 mg + hydrochlorothiazide 12.5 mg □ Zofenopril 30 mg
Quartile 1 (n = 61)
Quartile 2 (n = 61)
Quartile 3 (n = 63)
Quartile 4 (n = 61)
-14 (9) -14 (9)
Trend, P < 0.01
24 (13)
Trend, P < 0.01
Figure 1. Reductions In mean (SD) office (A) diastolic blood pressure (DBP) and (B) sitting systolic BP (SBP) after 12 weeks of treatment, by quartiles of cardiovascular risk level (quartile 1 = lowest risk to quartile 4 = highest risk), in patients treated with zofenopril 30 mg plus hydrochlorothiazide 12.5 mg (n = 157) and zofenopril 30 mg (n = 89). P refers to the statistical significance of the trend of the difference between combination treatment and monotherapy over the 4 quartiles as determined by analysis of variance.
treatment period, the mean reduction in cardiovascular risk was also significantly greater in the combination treatment group than in the monotherapy group (1.4% vs 0.5%; P < 0.01).
In patients treated with zofenopril plus hydrochlorothiazide, a significantly greater (P < 0.01) reduction in 10-year risk of cardiovascular disease was observed in patients in the higher-risk quartiles (Figure 2). Of the 44 patients at high cardiovascular risk (>5%) at baseline, 22 (50%) had their risk reduced to a low level (<5%) after 12 weeks of treatment. The change in risk after treatment was significantly different compared with baseline (P < 0.01).
DISCUSSION
In these patients with essential hypertension, combination treatment with zofenopril plus hydrochlorothiazide was associated with greater BP reduction than treatment with zofenopril alone. The drug combination was significantly better for different levels of cardiovascular risk, particularly for SBP. In patients with the highest level of cardiovascular risk, the between-treatment difference was greatest, suggesting that these patients may benefit more from combination treatment.
= 6 m ^
RRR (Treatment-baseline)
■ Baseline □ Week 12
Trend, P < 0.01
Quartile 1 -20%
Quartile 2 Quartile 3
-18% -19%
Figure 2. Mean cardiovascular risk at baseline and after 12 weeks of treatment, by quartiles of cardiovascular risk level (quartile 1 = lowest risk to quartile 4 = highest risk), in patients treated with zofenopril 30 mg plus hydrochlorothiazide 12.5 mg (n = 157). The relative risk reduction (RRR) after treatment compared to baseline (%) is shown below each quartile. P refers to the statistical significance of the trend of the difference between baseline and treatment over the 4 quartiles as determined by analysis of variance.
Previous studies21-23 have shown that hypertensive patients at highest risk have a greater chance of being resistant to monotherapy. Therefore, they require combination drug treatment to achieve adequate BP control and protection from cardiovascular events. For instance, in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study,21 which enrolled 15,245 treated and untreated hypertensive patients at high risk of cardiovascular events, a majority of patients (59%) were receiving treatment with >2 antihypertensive drugs at study end (including randomized treatment with valsartan or amlodipine). After a mean follow-up of 4.2 years, the overall mean SBP and DBP were 138 and 78 mm Hg, respectively (with a reduction of 10%—11 % and 9%-ll%), a cardiac morbidity of -8%, and a rate of cerebrovascular accident of 4%. In the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial,22 which enrolled 16,602 hypertensive patients with >1 additional risk factor for cardiovascular disease who were randomized to verapamil, atenolol, or hydrochlorothiazide, after a median follow-up of 3 years 80% of patients were taking combination treatment. The mean BP at the end of treatment was 137 mm Hg (systolic) and 79 mm Hg (diastolic) in all treatment groups, with a reduction of 9% and 8% to 9%, respectively, and a cardiovascular events rate of 9% to 10%. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study,23 33,357 patients with hypertension and Si other cardiovascular risk factor were treated for 4.9 years with chlorthalidone, amlodipine, or lisinopril, and -40% were receiving combination treatment. The BP achieved in all treatment groups at study end was 135 mm Hg (systolic) and 75 mm Hg (diastolic), with an 8% and 11% reduction, respectively, and with a rate of fatal and nonfatal cardiovascular events of 11% to 12%.
In the present study, patients administered combination treatment who had a comparable predicted risk of cardiovascular diseases (3rd and 4th quartiles) achieved SBP and relative reduction from baseline that were similar to those observed in the aforementioned studies (140 mm Hg and 14%, respectively), although DBP was numerically higher (87 mm Hg with a 14% reduction). This suggests that relatively short-term treatment with an ACE inhibitor and a diuretic, in patients classified as being at high risk according to the Heart Score algorithm,20 might yield advantages similar to those observed in long-term, outcome-based trials of high-risk hypertensive patients receiving multiple drug treatment. It also supports current international guidelines1 that identify the combination of an ACE inhibitor plus a diuretic as first-line treatment for higher-risk hypertensive patients in whom a more prompt and consistent antihypertensive effect is desirable.
Another finding of this study was the effect of combination therapy on cardiovascular risk level, which was reduced in high-risk patients, with half of the patients at high risk20 moving to the low-risk category after 12 weeks of treatment. The positive effect of the combination treatment and its significant effect versus monotherapy were maintained during the 24-week open-label period.
A possible explanation for the overall good antihypertensive effect of the combination of zofenopril plus hydrochlorothiazide in hypertensive patients at risk for cardiovascular diseases may be its sustained and consistent BP control over 24 hours14,17 and
zofenopril's antioxidant activity, which may reduce endothelial activation in hypertensive patients and thus may provide vascular and cardiac protection.4'24
This post hoc analysis is based on a subgroup of the patients in a published trial, and thus a specific sample size calculation was not made. Another limitation was a high patient dropout rate during the study, especially during the double-blind phase, mainly due to the occurrence of AEs. Finally, the sample size of the analysis was limited because only the per protocol population was included. All these limitations may have introduced potential bias in the interpretation of study results; therefore, a study with an adequate sample size should be conducted to confirm our findings.
CONCLUSIONS
In these hypertensive patients, combination treatment with zofenopril plus hydrochlorothiazide was associated with a significantly greater decrease in BP compared with zofenopril monotherapy, regardless of the patient's cardiovascular risk. In this relatively short period of time, the combination therapy appeared to be effective in reducing cardiovascular risk level in individuals with varying levels of cardiovascular risk at baseline, with larger reductions being observed in patients at highest risk for cardiovascular events.
ACKNOWLEDGMENTS
This article was written with financial assistance from Menarini Industrie Farmaceutiche Riunite (Firenze, Italy) and Istituto Lusofarmaco d'Italia S.p.A (Milano, Italy).
Drs. Malacco and Omboni have served as occasional consultants for Menarini Industrie Farmaceutiche Riunite and Istituto Lusofarmaco d'Italia. Dr. Omboni performed all of the statistical analyses; writing was done by both authors.
The study participants were as follows: Coordinators'. Drs. Becq (France), van Nes (The Netherlands), Zaleska (Poland), Blagden (United Kingdom); Belgium: Drs. Capiau, D'hoohhe, Debruyne, Haerens, Loos; United Kingdom: Drs. Baskaran, Bremner, Burton, Canning, Hosie, Hughes, Hutchison, Kansagra, Lane, Leak, Lee, Lee PS, Dauncey, Maksimczyk, Orpen, Pimm, Scott, Eavis, Walzer, Lightstone; Poland: Drs. Achremczyk, Burduk, Dabrowski, Wojciechowski, Gessek, Jaworska, Kawka-Urbanek, Kolodziej, Maciejewicz, Malinski, Marcinowska-Suchowierska, Nartowicz, Piotrowski, Ruminski, Smiciak-Korombel; The Netherlands: Drs. Bonanius, Burgers, Croughs, De Ruitter, Dikschei, Ferguson, Passage, Veerman; France: Drs. Beignol-Devalmont, Ripoll, Dumond, Rousset, Flosi, Dreyfus, Havy, Burguier, Béard, and Colombani.
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address correspondence to: Ettore Malacco, MD, Division of Internal Medicine, L. Sacco Hospital, Via G.B. Grassi 74, University of Milano, 20157 Milano, Italy. E-mail: ettore.malacco@tiscali.it
