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Zofenopril plus hydrochlorothiazide combination in the treatment of hypertension: an update Expert Rev. Cardiovasc. Ther. 12(9), 1055–1065 (2014)
Claudio Borghi*1 and Stefano Omboni2 1 Unit of Internal Medicine, Policlinico S.Orsola, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy 2 Clinical Research Unit, Italian Institute of Telemedicine, Varese, Italy *Author for correspondence: Tel.: +39 051 636 3243 Fax: +39 051 391 320 [email protected]
The fixed combination of zofenopril 30 mg plus hydrochlorothiazide 12.5 mg is indicated for the management of hypertensive patients whose blood pressure (BP) is not adequately controlled on zofenopril alone. In clinical trials, this combination therapy proved to be superior to monotherapy in reducing office and ambulatory BP. In this review, the authors have updated the current evidence on the efficacy of the zofenopril plus hydrochlorothiazide combination in light of the results of the recent ZODIAC study on previously monotherapy-treated uncontrolled hypertensive patients with associated cardiovascular risk factors. The trial documented a similar BP control under this combination and with irbesartan plus hydrochlorothiazide, but a larger reduction of high-sensitivity C-reactive protein, suggesting a potential protective effect against vascular inflammation. Thus, the fixed combination of zofenopril plus hydrochlorothiazide may have a particular place in the treatment of high-risk or monotherapy-treated uncontrolled hypertensive patients requiring a more prompt, intensive and sustained BP reduction, as recommended by the current guidelines. KEYWORDS: ambulatory blood pressure monitoring • essential hypertension • hydrochlorothiazide • office blood pressure • zofenopril
Large intervention trials have demonstrated that adequate blood pressure (BP) control and effective cardiovascular prevention is possible among majority of hypertensive patients if combinations of two or more antihypertensive medications are used for treatment [1,2]. This is particularly true for patients with associated cardiovascular risk factors or co-morbidities, conditions which may alter antihypertensive efficacy and require more intensive drug treatment [3–6]. Accordingly, European and American guidelines now advocate the use of two-drug combination when BP control with initial monotherapy treatment is inadequate or as an initial therapy for patients with grade 2 hypertension (systolic blood pressure [SBP] 160–179 mmHg and/or diastolic blood pressure [DBP] 100–109 mmHg) or for patients with grade 1 hypertension (SBP 140– 149 mmHg and/or DBP 90–99 mmHg) and concomitant diabetes mellitus, coronary disease or other associated clinical conditions which increase their cardiovascular risk [7,8]. informahealthcare.com
10.1586/14779072.2014.946405
The obvious advantage of starting treatment with a combination therapy rather than with a low-dose monotherapy with a stepwise up-titration is a prompter antihypertensive response and a larger chance of success in achieving the target BP. In this regard, a metaanalysis of factorial trials in which participants were randomly allocated to one drug alone, another drug alone, both drugs together or placebo has clearly documented that combining two agents from any two classes of antihypertensive drugs improves the BP reduction much more than increasing the dose of one agent [9]. In addition to the benefits attributable to possible synergistic pharmacological and physiological actions, the strategy of combining two different drug classes as the first choice in hypertensive patients or in patients not responding to a high-dose monotherapy may contribute to improve patient’s compliance and adherence, particularly when a fixed combination is used [10,11]. A therapeutic approach
2014 Informa UK Ltd
ISSN 1477-9072
1055
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Drug Profile
Borghi & Omboni
based on a fixed combination therapy may also cause fewer side effects compared to individual agents [12]. It is now widely accepted that an effective fixed-dose twodrug combination should have complementary mechanisms of action, an antihypertensive effect which is at least similar or superior to that of either agent administered singly or as a sequential combination, enhanced ability to offer end-organ protection and minimal adverse effects (including hemodynamic and metabolic effects) [7,8]. Selection of two-drug combinations which have been successfully used in outcome trials may be preferable. These combinations include an angiotensin-converting enzyme (ACE)-inhibitor or an angiotensin II receptor blocker (ARB) plus a thiazide diuretic or a dihydropyridine calcium channel blocker, and a beta-blocker plus a diuretic [3–6,13–20]. The only combination that cannot be recommended, at least in high-risk patients, following the results of the ONTARGET trial, is that between and an ACE-inhibitor and an ARB [21,22]. Given these premises, we reviewed the current evidence on the efficacy of a recommended ACE-inhibitor plus thiazide diuretic combination (zofenopril plus hydrochlorothiazide), specifically presenting and discussing the results of the recent ZODIAC study. In this trial, the efficacy of zofenopril plus hydrochlorothiazide combination was compared with that of an ARB plus a thiazide diuretic combination (irbesartan plus hydrochlorothiazide) in previously monotherapy-treated uncontrolled hypertensive patients with associated cardiovascular risk factors, following the indications of current guidelines. Combination treatment versus monotherapy
Irrespective of the drug employed, large intervention trials and meta-analyses have clearly documented that monotherapy can effectively reduce BP in only a limited number of hypertensive patients and that the ability of any agent to achieve target BP of 140/90 mmHg or below when given alone does not exceed 20–30% of the overall hypertensive population [9,10]. This means that most hypertensive patients require a combination of at least two drugs to achieve BP control, and that a two-drug regimen may be considered as an alternative to monotherapy as a first-choice therapeutic approach. Though the major disadvantage of initiating treatment with two drugs is that of potentially exposing the patient to an unnecessary agent, nonetheless, such a choice may bring several potential advantages. As a matter of fact, use of the combination treatment allows both drugs to be given in the low-dose range, reducing the risk of side effects compared to full-dose monotherapy. Additionally, the complementary mechanisms of action of the drugs in the combination may minimize their individual side effects. Combining two drugs may avoid the frustration of repetitively and vainly searching for effective monotherapies in patients with very high BP values and organ damage. Furthermore, if used as fixed low doses, the combination may be administered as a single tablet, simplifying the treatment regimen and optimizing compliance [23]. Finally, initiating treatment with a two-drug combination may allow BP targets to be reached earlier than with 1056
monotherapy, which is particularly important in high-risk hypertensive patients [7]. Combination therapy between an ACE-inhibitor & a thiazide diuretic
One of the most effective two-drug antihypertensive combinations is that between an ACE-inhibitor and a thiazide diuretic. The mechanism of action of such a combination involves a synergistic and opposite effect on the renin–angiotensin–aldosterone system (RAAS): the ACE-inhibitor antagonizes the counter-regulatory system activity triggered by the diuretic, thus improving the efficacy and tolerability of single drug components [24,25]. The thiazide diuretic therapy can initially reduce plasma volume with a consequent increase in plasma renin activity, aldosterone secretion and urinary potassium loss [24]. Conversely, ACE inhibition blocks the production of angiotensin II while counteracting the reactive hyperreninemia that may reduce the antihypertensive effect of the diuretic. Therefore, combination of the two drugs seems specifically designed to promote the maximal antihypertensive effect of both classes of drugs [24]. Additionally, the dosages of each agent needed to achieve adequate BP control are less than those required in monotherapy, and this may improve tolerability, reducing the adverse effects of single components, particularly the metabolic effects that are often associated with the use of high-dose diuretic therapy [7,8,24]. ACE-inhibitors are also known to counteract the tendency of thiazide diuretics to lower serum potassium levels. The combination between an ACE-inhibitor and a diuretic has shown to effectively reduce BP levels and prevent end-organ damage of hypertension, being particularly effective in reducing left ventricular hypertrophy [26]. Rationale for the fixed combination between zofenopril & hydrochlorothiazide
Zofenopril calcium, a prodrug of the active compound zofenoprilat, is chemically characterized by the presence of a sulfhydryl group, which is responsible for its high lipophilicity, the highest among all the ACE-inhibitors [27]. The sulfhydryl moiety of zofenopril is not associated with an increased rate of adverse events, as observed with another sulfhydryl-containing ACE-inhibitors such as captopril, while it confers the drug an effective and long-lasting tissue penetration [27–30]. Furthermore, zofenopril has a sustained activity on cardiac ACE inhibition, antioxidant properties and remarkable tissue protective effect, [31], and can improve the oxidative stress in patients with essential hypertension [32]. Hydrochlorothiazide is the 3,4-dihydro derivative of chlorothiazide. It affects the distal renal tubular mechanisms of electrolyte resorption, directly increasing the excretion of sodium and chloride in approximately equivalent amounts. Natriuresis is responsible for the diminished plasma volume and venous return, increased renin release, and reduced cardiac output whose net effect is a reduction in BP. The increase in plasma renin activity results in aldosterone secretion and urinary potassium loss, with a consequent decrease in serum potassium. Expert Rev. Cardiovasc. Ther. 12(9), (2014)
[37] 53* 44 64**
informahealthcare.com
DBP response: DBP £90 mmHg (£85 mmHg in the non-responder study) or reduction by ‡10 mmHg. SBP response: SBP £140 mmHg (£130 mmHg in the non-responder study) or reduction by ‡20 mmHg. *p < 0.005 and **p < 0.01 combination versus monotherapy. DBP: Diastolic blood pressure; SBP: Systolic blood pressure. Reproduced with permission from [36,37].
7* 8 369 Malacco (2005)
Mild-moderate essential hypertensive patients (DBP 90–110 mmHg) not responding to 4 weeks of single-blind treatment with zofenopril 30 mg
8
10**
5
57
[37] 67** 44 73** 11** 8 350 Malacco (2005)
Mild-moderate essential hypertension (DBP 95–115 mmHg)
12
16**
7
51
[36] 62 50 80 12 16 73 Parati (2006)
Mild-moderate essential hypertension (DBP 95–110 mmHg)
12
18
11
71
Combination
DBP response
Monotherapy Combination
SBP response
Monotherapy Combination
DBP reduction
Monotherapy Combination
SBP reduction
Monotherapy
Treatment duration (weeks) Patients’ characteristics Patients (n) Study (year)
Table 1. Efficacy of zofenopril 30 mg plus hydrochlorothiazide 12.5 mg combination versus zofenopril 30 monotherapy in three double-blind, randomized pivotal studies.
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Ref.
Zofenopril plus hydrochlorothiazide in hypertensive patients
Drug Profile
Other possible mechanisms by which hydrochlorothiazide chronically lowers BP include direct endothelial or vascular smooth muscle–mediated vasodilation [33]. Recent experimental models suggest that the synergistic and contrasting effects on the RAAS resulting from the concomitant administration of zofenopril and hydrochlorothiazide may differ from those resulting from the combination between hydrochlorothiazide and other ACE-inhibitors. Such differences may depend on the lipophilicity of the ACE-inhibitor. The volume depletion induced by hydrochlorothiazide in the rat increases the tissue levels of zofenoprilat but not those of lisinopril, a highly hydrophilic ACE-inhibitor [34]. Thus, hydrochlorothiazide could act as a ‘tissue levels enhancer’ by increasing the tissue concentrations of zofenopril and inducing a peculiar enhancement of the tissue activity of this lipophilic ACE-inhibitor [34]. Such an effect could contribute to the development of organprotective effects of ACE-inhibitor therapy. Therefore, a highly lipophilic ACE-inhibitor, such as zofenopril, would take advantage of co-administration with hydrochlorothiazide, in comparison to a hydrophilic ACEinhibitor, such as lisinopril, and potentially increases its cardiovascular therapeutic effects [34]. Such an effect seems to be peculiar of zofenopril and only marginally related to its lipophilic nature, since in animal models another lipophilic ACE-inhibitor, such as fosinopril, although exhibiting cardiac ACE inhibition potency similar to zofenopril, showed different anti-ischemic and cardioprotective effects [35]. Zofenopril plus hydrochlorothiazide combination in patients with essential hypertension
The fixed-dose combination of zofenopril 30 mg plus hydrochlorothiazide 12.5 mg once daily is approved in several European countries for the management of mild-moderate hypertension in patients whose BP is not adequately controlled on zofenopril alone. Such a combination has been shown to be effective for treating arterial hypertension in clinical studies and has also been shown to be superior to monotherapy with either agent. Overall, efficacy data from a total of approximately 800 patients with mild-moderate hypertension have been collected and compared. The larger efficacy of the zofenopril 30 mg plus hydrochlorothiazide 12.5 mg combination versus that of either zofenopril 30 mg or hydrochlorothiazide 12.5 mg was first demonstrated in a multifactorial study and confirmed in two parallel-group studies, the first one carried out in patients with mild-moderate essential hypertension and the second one in patients with hypertension not responding to previous zofenopril 30 mg monotherapy. Main results of such studies are summarized in TABLE 1 [36–38]. In the dose response study, not only office, but also 24-h and hourly changes in BP were 1057
Drug Profile
Metabolic syndrome (n = 198)
Borghi & Omboni
Elevated Atherogenic fasting glucose dyslipidemia (n = 34) (n = 111)
Moderately impaired renal function (n = 56)
Metabolic syndrome (n = 198)
0
Elevated fasting Atherogenic glucose dyslipidemia (n = 111) (n = 34)
Moderately impaired renal function (n = 56)
0
-5 -5
D Office DBP (mmHg)
D Office SBP (mmHg)
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-10
-15
-20
-25
-10
-15
-20
-30 -25
** *
**
-35 ** -40
** *
**
-30
Figure 1. Mean changes (D) ± SD in office systolic and diastolic blood pressure in different high-risk subgroups of patients treated with zofenopril 30 mg monotherapy (open bars) or zofenopril 30 mg plus hydrochlorothiazide 12.5 mg (full bars). Moderately impaired renal function is defined according to guidelines by a creatinine clearance between 30 and 59 ml/min. Asterisks refer to the statistical significance of the difference between the two treatment groups (*p < 0.05 and **p < 0.01). DBP: Diastolic blood pressure; SBP: Systolic blood pressure. Adapted with permission from [38,39].
greater with zofenopril 30 mg plus hydrochlorothiazide 12.5 mg combination treatment than with either agent administered singly. Furthermore, higher smoothness indices, evaluated by ambulatory BP monitoring, indicated that combination treatment with 30 mg zofenopril and 12.5 mg hydrochlorothiazide induced a smooth and homogeneous BP control over the dosing interval superior to that provided by the monotherapy [36]. Regarding the comparative studies, in the first one, the SBP and DBP reduction and the proportion of responders after 12 weeks of treatment were significantly greater with combination therapy than with zofenopril monotherapy [37]. In the second comparative study, significantly greater reduction in BP and higher response rates were observed at the end of the 8 weeks of treatment with the two-drug combination than with the monotherapy [37]. Furthermore, the reduction in BP plateaued at 6 weeks with zofenopril monotherapy, while the BP continued to decrease over the entire study period with combination treatment [37]. Further analyses of the first aforementioned comparative, double-blind, randomized parallel-group study were carried out in order to specifically evaluate the efficacy of zofenopril 30 mg plus hydrochlorothiazide 12.5 mg in subgroups of high-risk 1058
patients with hypertension, such as those with the metabolic syndrome, impaired fasting glucose, atherogenic dyslipidemia and altered renal function [38,39]. Also, in these high-risk patients, sitting office DBP and SBP reductions were larger in the group receiving zofenopril 30 mg plus hydrochlorothiazide 12.5 mg once daily than in the zofenopril 30 mg once-daily monotherapy group (FIGURE 1) [38,39]. Furthermore, the efficacy of the combination treatment was specifically assessed according to the patient’s overall cardiovascular risk level using the Heart Score algorithm, which determines the risk for developing a cardiovascular disease in the next 10 years, taking into account age, gender, total cholesterol levels, SBP and patient’s smoking status [40]. After 12 weeks of treatment, office BP reductions were greater in the combination treatment group than in the monotherapy group for each different quartile of baseline cardiovascular risk in which the subjects were grouped (FIGURE 2) [41]. Zofenopril plus hydrochlorothiazide versus irbesartan plus hydrochlorothiazide: the ZODIAC study
Thiazide diuretics are effective and recommended by guidelines in combination not only with an ACE-inhibitor, but more in Expert Rev. Cardiovasc. Ther. 12(9), (2014)
Zofenopril plus hydrochlorothiazide in hypertensive patients
Q1 0.5% (n = 61)
Q2 2.2% (n = 61)
Q3 7.1% (n = 63)
Q4 19.9% (n = 61)
Q1 0.5% (n = 61)
Q2 2.2% (n = 61)
Drug Profile
Q3 7.1% (n = 63)
Q4 19.9% (n = 61)
0
0
-5 -5
D Office DBP (mmHg)
D Office SBP (mmHg)
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-10
-15
-20
-25
-10
-15
-30 -20 -35
-40
p < 0.01 for trend
-25
p < 0.01 for trend
Figure 2. Mean changes (D) ± SD in office systolic and diastolic blood pressure according to quartiles (Q) of cardiovascular risk level in patients treated with zofenopril 30 mg monotherapy (open bars) or zofenopril 30 mg plus hydrochlorothiazide 12.5 mg (full bars). The p-value refers to the statistical significance of the trend of the difference between the treatment groups. DBP: Diastolic blood pressure; SBP: Systolic blood pressure. Adapted with permission from [40].
general with all RAAS blockers, thus including ARBs [7,8]. The results of several large prospective trials confirmed that a diuretic plus an ARB combination reduces BP further than monotherapies [41,42]. Among the ARB plus thiazide diuretic combinations, the most studied and most effective appears to be that between irbesartan and hydrochlorothiazide [43–50]. This combination was observed to be particularly effective in patients failing to achieve BP control with monotherapy, as documented by the COSIMA [49] and INCLUSIVE [50] studies. In such trials, a 2-month treatment with a combination of irbesartan 150 or 300 mg and hydrochlorothiazide 12.5 or 25 mg allowed to attain BP normalization in 50–70% of patients previously uncontrolled under monotherapy. Given the large use of RAAS inhibitors plus thiazide diuretic combination for treatment of hypertension and since direct comparative data on the antihypertensive efficacy and safety of the zofenopril plus hydrochlorothiazide versus that of an ARB and hydrochlorothiazide combination was lacking, a doubleblind, randomized comparative study was devised: the ZODIAC study [51]. Interestingly, in this study, the efficacy of the highest available dose of zofenopril (60 mg) plus hydrochlorothiazide was also tested and compared with that of the currently marketed one (30 mg). In order to comply with the informahealthcare.com
current recommendations, the patients targeted for treatment were those with an essential hypertension not controlled by a previous monotherapy, associated with one or more additional cardiovascular risk factors [7,8]. In the international multicenter, randomized, double-blind, parallel-group ZODIAC study, 353 patients were treated for 18 weeks with zofenopril 30 mg plus hydrochlorothiazide 12.5 mg or irbesartan 150 mg plus hydrochlorothiazide 12.5 mg. After the first 6 and 12 weeks, the dose of zofenopril or irbesartan had to be doubled to 60 and 300 mg, respectively, if office SBP was ‡140 mmHg or office DBP was ‡90 mmHg in non-diabetic patients and if office SBP was ‡130 mmHg or office DBP was ‡80 mmHg in diabetic patients. All subjects had to be previously treated and uncontrolled with a monotherapy and had at least one additional risk factor among the following: dyslipidemia, diabetes, abdominal obesity, family history for premature cardiovascular disease and current smoking. Active drug treatment was preceded by a 2-week single-blind run-in during which previous antihypertensive treatment was stopped. The study was a non-inferiority trial and the primary efficacy endpoint was the betweentreatment comparison in sitting office DBP changes from baseline to the end of treatment. A subgroup of 181 patients also 1059
Drug Profile
Borghi & Omboni
All subjects (n = 353) DBP
0 -5 -10 -15 -20 -25 -30
Lower drug dose (n = 124) D Office BP (mmHg)
SBP -5 -10 -15 -20 -25 -30 -35
DBP
* Higher drug dose (n = 229) SBP
D Office BP (mmHg)
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D Office BP (mmHg)
SBP
DBP
0 -5 -10 -15 -20 -25 -30
Figure 3. Baseline-adjusted office SBP and DBP mean changes (95% confidence intervals) from baseline after 18 weeks of treatment with zofenopril plus hydrochlorothiazide (open bars) or irbesartan plus hydrochlorothiazide (gray bars) in the whole study sample and by drug dose (lower drug dose: zofenopril 30 mg or irbesartan 150 mg; higher drug dose: zofenopril 60 mg or irbesartan 300 mg). Asterisk refers to the statistical significance of between-treatment differences (*p < 0.05). BP: Blood pressure; DBP: Diastolic blood pressure; SBP: Systolic blood pressure. Adapted with permission from [51].
underwent 24-h ambulatory BP monitoring and in 91 patients, the blood levels of high-sensitivity C-reactive protein (hs-CRP) were quantified. After 18 weeks of treatment, the office SBP and DBP reduction observed in patients treated with zofenopril 30 or 60 mg plus hydrochlorothiazide 12.5 mg once a day was similar to that observed in patients treated with irbesartan 150 or 300 mg plus hydrochlorothiazide 12.5 mg once a day (FIGURE 3). Additionally, sitting office BP normalization was achieved by the end of treatment by a similar proportion of subjects treated with zofenopril plus hydrochlorothiazide and irbesartan plus hydrochlorothiazide (80% for both, p = 0.973 between groups). Such results were attained with the higher drug dosage in a slightly, but not significantly (p = 0.183) larger proportion of subjects treated with zofenopril (69%) than with irbesartan (61%). This was probably due 1060
to the worse cardiovascular profile of patients randomized to zofenopril plus hydrochlorothiazide. In the subjects with valid ambulatory BP recordings, treatment-induced 24-h BP reductions under zofenopril plus hydrochlorothiazide did not differ from those under irbesartan plus hydrochlorothiazide (TABLE 2). Both drugs displayed a similarly smooth and long-lasting antihypertensive effect, ensuring good BP coverage also in the hours farthest from the last drug intake. Interestingly, the magnitude of the 24-h BP reduction yielded by zofenopril and irbesartan plus the diuretic in the ZODIAC study was comparable with that observed in previous studies based on ambulatory BP monitoring and making use of the same doses of the two drug combinations [36,50]. As shown in FIGURE 3, at the end of the study, office sitting SBP and DBP reductions were larger with the lower drug dose of zofenopril (30 mg) plus hydrochlorothiazide than with the lower drug dose of irbesartan (150 mg) plus hydrochlorothiazide, while they were similar when the subgroup treated with the higher drug doses was considered. In the subgroups of patients with mild hypertension and diabetes, both drugs yielded a similar office BP lowering effect (TABLE 3). Conversely, in patients with grade 2 hypertension, office DBP drops obtained under zofenopril were significantly larger than those under irbesartan (TABLE 3). However, the post-hoc nature of this analysis cannot exclude that our finding might be the result of chance. The fact that the BP lowering effect of both medications was well maintained also in diabetics, known to often display a reduced response to antihypertensive drug treatment, confirms that ACE-inhibitors or ARBs are among the most indicated first options in these high-risk patients [7,8,52]. The ZODIAC study also explored the possible positive effect of zofenopril and irbesartan on markers of vascular inflammation. Indeed, the results of epidemiological and clinical studies support a pivotal role for inflammation in all phases of atherosclerosis, from the endothelial cell dysfunction to the culmination in acute coronary syndrome [53]. In our hypertensive subjects, treatment with zofenopril plus hydrochlorothiazide reduced hs-CRP by 0.52 mg/l (95% confidence interval: -10.5; 0.01), while this was not the case for irbesartan-treated patients (0.97 [0.29; 1.65] mg/l, p = 0.001 between treatments). This finding confirms previous evidence derived from studies carried out in hypertensive individuals showing that treatment with zofenopril may be associated with a reduction of the oxidative stress, an improvement in the nitric oxide pathway and an antiinflammatory vasculoprotective effect [20,54,55]. Likely, the sulfhydryl ACE-inhibitor zofenopril, in addition to ensuring BP control, may contribute to slow down the development of atherosclerosis [56,57]. Tolerability of both treatment regimens was good and similar to that observed in previous studies, with a very limited number of drug-related adverse events recorded during the study (7.8% of zofenopril-treated patients vs 6.6% of irbesartan-treated patients) [58,59]. The combination containing zofenopril induced a slightly larger risk of cough, while dizziness or asthenia was more commonly reported by irbesartan-treated patients. Expert Rev. Cardiovasc. Ther. 12(9), (2014)
Zofenopril plus hydrochlorothiazide in hypertensive patients
Drug Profile
Table 2. Average 24-h ambulatory systolic and diastolic blood pressure at randomization and baseline-adjusted reductions after 18 weeks of treatment with zofenopril 30–60 mg + hydrochlorothiazide 12.5 mg or irbesartan 150–300 mg + hydrochlorothiazide 12.5 mg. Zofenopril 30–60 mg + HCTZ 12.5 mg (n = 95)
Irbesartan 150–300 mg + HCTZ 12.5 mg (n = 86)
Baseline
144.6 ± 14.0
142.2 ± 13.0
Reduction with treatment
11.7 (15.4, 8.0)
12.6 (17.2, 8.0)
Baseline
84.8 ± 8.0
86.1 ± 7.6
Reduction with treatment
6.7 (8.7, 4.6)
6.3 (8.8, 3.7)
p-value
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24-h SBP (mmHg)
0.758
24-h DBP (mmHg)
0.810
Data are reported as mean and 95% confidence interval. The p-value refers to the statistical significance of the between-treatment differences. DBP: Diastolic blood pressure; HCTZ: Hydrochlorothiazide; SBP: Systolic blood pressure. Reproduced with permission from [51].
Conclusions
Results of the double-blind, randomized studies based on zofenopril 30 mg plus hydrochlorothiazide 12.5 mg combination treatment confirm that in the majority of patients not responding to a monotherapy, such a combination treatment may substantially increase the chance of response. The recent ZODIAC study, which enrolled hypertensive patients not controlled by previous monotherapy and with one or more additional cardiovascular risk factors, also added new clinically relevant information to the existing one. Indeed, this study suggested that the combination of zofenopril and hydrochlorothiazide and that of irbesartan and hydrochlorothiazide may provide similarly effective, prolonged and well-tolerated control of BP. The ZODIAC study also demonstrated a reduction in hs-CRP in
zofenopril-treated patients, suggesting an additional beneficial effect of this combination therapy on vascular inflammation. According to the evidence collected so far, the combination of zofenopril and hydrochlorothiazide may be indicated among the first-line two-drug fixed-combination choices for treatment of high-risk hypertensive patients or for those not responding to a previous monotherapy. Expert commentary
Current guidelines recommend the use of two-drug combination when BP control with initial monotherapy treatment is inadequate or as an initial therapy for patients with grade 2 hypertension or for those with grade 1 hypertension and concomitant diabetes mellitus, coronary disease or other associated
Table 3. Baseline-adjusted systolic and diastolic blood pressure reductions after 18 weeks of treatment with zofenopril + hydrochlorothiazide or irbesartan + hydrochlorothiazide by hypertension grade (grade 1: systolic blood pressure 140–159 mmHg and/or diastolic blood pressure 90–99 mmHg; grade 2: systolic blood pressure ‡160 mmHg and/or diastolic blood pressure ‡100 mmHg) and diabetes. Zofenopril 30–60 mg + HCTZ 12.5 mg
Irbesartan 150–300 mg + HCTZ 12.5 mg
p-value
Grade 1 hypertension
n = 120
n = 126
SBP (mmHg)
15.9 (19.7, 12.1)
15.7 (20.1, 11.4)
0.959
DBP (mmHg)
14.5 (17.3, 11.7)
14.3 (17.2, 11.4)
0.902
Grade 2 hypertension
n = 55
n = 52
SBP (mmHg)
31.8 (37.2, 26.5)
28.4 (34.4, 22.5)
0.402
DBP (mmHg)
20.0 (23.3, 16.8)
14.7 (18.4, 10.9)
0.035
Diabetes mellitus
n = 34
n = 29
SBP (mmHg)
18.2 (21.8, 14.6)
22.0 (25.9, 18.1)
0.155
DBP (mmHg)
16.4 (18.6, 14.3)
15.0 (17.4, 12.6)
0.366
Data are reported as mean and 95% confidence interval. The p-value refers to the statistical significance of the between-treatment differences. DBP: Diastolic blood pressure; HCTZ: Hydrochlorothiazide; SBP: Systolic blood pressure.
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Drug Profile
Borghi & Omboni
clinical conditions that increase their cardiovascular risk. One of the most effective two-drug antihypertensive combinations is that between an ACE-inhibitor and a thiazide diuretic and among such combinations, the one between the ACE-inhibitor zofenopril and a thiazide diuretic (hydrochlorothiazide) may be particularly interesting for several reasons. First, the drug has proved to be more effective in reducing BP than zofenopril or hydrochlorothiazide alone in grade 1 and 2 essential hypertensive patients and also in patients previously uncontrolled by zofenopril monotherapy. The 30 mg zofenopril dose plus the 12.5 mg hydrochlorothiazide seems to be the ideal choice to achieve control in the majority of subjects. Second, the antihypertensive efficacy of the zofenopril plus hydrochlorothiazide combination was similar to that of the irbesartan plus hydrochlorothiazide combination in the recent ZODIAC study, suggesting that the former may represent a suitable alternative to the combination treatment between an ARB and a thiazide diuretic. Third, the lipophilic nature of zofenopril and the presence of a sulfhydryl group allow high tissue penetration and confer the drug specific anti-oxidative, anti-ischemic, antiinflammatory and anti-atherogenic effects, as demonstrated in experimental models in animals and humans. Such ancillary properties have been indirectly documented in the hypertensive subjects of the ZODIAC study treated with zofenopril plus hydrochlorothiazide by a significant reduction in the blood levels of hs-CRP. Thus, the data collected so far support the role of the zofenopril plus hydrochlorothiazide combination in the treatment of hypertensive patients uncontrolled by a monotherapy. The potential anti-inflammatory effects of zofenopril shown in the recently published ZODIAC study suggest that further clinical
trials need to be performed in the future to explore its possible ancillary anti-atherogenic properties. Five-year view
The evidence collected on the efficacy of the zofenopril plus hydrochlorothiazide combination in various double-blind randomized studies in hypertensive patients has relevance for the clinical practice because it indicates that this combination complies with the current recommendations. Zofenopril plus hydrochlorothiazide fixed combination may be indicated for the treatment of hypertensive patients at high risk, particularly in cases showing no response to a previous monotherapy, as shown in the ZODIAC study. The potential anti-atherogenic and target organ protective properties of zofenopril are currently under investigation in high-risk hypertensive patients in the ZENITH study. If such properties, previously documented in post-acute myocardial infarction patients, are confirmed also in patients with high BP, this may help to place the zofenopril plus hydrochlorothiazide combination among the preferable ACE-inhibitor plus thiazide diuretic combinations for treating arterial hypertension. Financial & competing interests disclosure
Both authors have occasionally received grants for lectures or scientific meeting attendance by Menarini International Operations Luxembourg S. A., manufacturer of zofenopril. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues • Three pivotal studies performed in almost 800 grade 1–2 hypertensive subjects, also including subjects previously not responding to zofenopril monotherapy, treated for 8–12 weeks with the zofenopril 30 mg plus hydrochlorothiazide 12.5 mg combination, clearly demonstrated the superiority of the combination over the monotherapies. • The combination treatment also induced a consistent, smooth and homogeneous blood pressure (BP) control over 24 h. • Post-hoc analyses of one of the three pivotal studies confirmed the good efficacy of the zofenopril 30 mg plus hydrochlorothiazide 12.5 mg combination also in high-risk patients with hypertension, such as those with the metabolic syndrome, impaired fasting glucose, atherogenic dyslipidemia and altered renal function. • In the ZODIAC study, 18 weeks of treatment with zofenopril 30 or 60 mg combined with hydrochlorothiazide of patients previously treated and uncontrolled with a monotherapy and with at least one additional cardiovascular risk factor resulted in BP responses similar to that of the combination between irbesartan 150 or 300 mg and hydrochlorothiazide 12.5 mg. • The ZODIAC study also documented a reduction of high-sensitivity C-reactive protein (hs-CRP) with zofenopril plus hydrochlorothiazide but not with irbesartan plus hydrochlorothiazide, suggesting that zofenopril, in addition to ensuring BP control, may contribute to slow down the development of atherosclerosis. • Due to the robust evidence collected so far, the fixed-dose combination of zofenopril 30 mg plus hydrochlorothiazide 12.5 mg once daily is now approved and recommended for the management of grade 1–2 essential hypertension in patients whose BP is not adequately controlled on zofenopril alone.
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Zofenopril plus hydrochlorothiazide in hypertensive patients
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Drug Profile
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1065
Drug Profile
Zofenopril plus hydrochlorothiazide combination in the treatment of hypertension: an update Expert Rev. Cardiovasc. Ther. 12(9), 1055–1065 (2014)
Claudio Borghi*1 and Stefano Omboni2 1 Unit of Internal Medicine, Policlinico S.Orsola, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy 2 Clinical Research Unit, Italian Institute of Telemedicine, Varese, Italy *Author for correspondence: Tel.: +39 051 636 3243 Fax: +39 051 391 320 [email protected]
The fixed combination of zofenopril 30 mg plus hydrochlorothiazide 12.5 mg is indicated for the management of hypertensive patients whose blood pressure (BP) is not adequately controlled on zofenopril alone. In clinical trials, this combination therapy proved to be superior to monotherapy in reducing office and ambulatory BP. In this review, the authors have updated the current evidence on the efficacy of the zofenopril plus hydrochlorothiazide combination in light of the results of the recent ZODIAC study on previously monotherapy-treated uncontrolled hypertensive patients with associated cardiovascular risk factors. The trial documented a similar BP control under this combination and with irbesartan plus hydrochlorothiazide, but a larger reduction of high-sensitivity C-reactive protein, suggesting a potential protective effect against vascular inflammation. Thus, the fixed combination of zofenopril plus hydrochlorothiazide may have a particular place in the treatment of high-risk or monotherapy-treated uncontrolled hypertensive patients requiring a more prompt, intensive and sustained BP reduction, as recommended by the current guidelines. KEYWORDS: ambulatory blood pressure monitoring • essential hypertension • hydrochlorothiazide • office blood pressure • zofenopril
Large intervention trials have demonstrated that adequate blood pressure (BP) control and effective cardiovascular prevention is possible among majority of hypertensive patients if combinations of two or more antihypertensive medications are used for treatment [1,2]. This is particularly true for patients with associated cardiovascular risk factors or co-morbidities, conditions which may alter antihypertensive efficacy and require more intensive drug treatment [3–6]. Accordingly, European and American guidelines now advocate the use of two-drug combination when BP control with initial monotherapy treatment is inadequate or as an initial therapy for patients with grade 2 hypertension (systolic blood pressure [SBP] 160–179 mmHg and/or diastolic blood pressure [DBP] 100–109 mmHg) or for patients with grade 1 hypertension (SBP 140– 149 mmHg and/or DBP 90–99 mmHg) and concomitant diabetes mellitus, coronary disease or other associated clinical conditions which increase their cardiovascular risk [7,8]. informahealthcare.com
10.1586/14779072.2014.946405
The obvious advantage of starting treatment with a combination therapy rather than with a low-dose monotherapy with a stepwise up-titration is a prompter antihypertensive response and a larger chance of success in achieving the target BP. In this regard, a metaanalysis of factorial trials in which participants were randomly allocated to one drug alone, another drug alone, both drugs together or placebo has clearly documented that combining two agents from any two classes of antihypertensive drugs improves the BP reduction much more than increasing the dose of one agent [9]. In addition to the benefits attributable to possible synergistic pharmacological and physiological actions, the strategy of combining two different drug classes as the first choice in hypertensive patients or in patients not responding to a high-dose monotherapy may contribute to improve patient’s compliance and adherence, particularly when a fixed combination is used [10,11]. A therapeutic approach
2014 Informa UK Ltd
ISSN 1477-9072
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Borghi & Omboni
based on a fixed combination therapy may also cause fewer side effects compared to individual agents [12]. It is now widely accepted that an effective fixed-dose twodrug combination should have complementary mechanisms of action, an antihypertensive effect which is at least similar or superior to that of either agent administered singly or as a sequential combination, enhanced ability to offer end-organ protection and minimal adverse effects (including hemodynamic and metabolic effects) [7,8]. Selection of two-drug combinations which have been successfully used in outcome trials may be preferable. These combinations include an angiotensin-converting enzyme (ACE)-inhibitor or an angiotensin II receptor blocker (ARB) plus a thiazide diuretic or a dihydropyridine calcium channel blocker, and a beta-blocker plus a diuretic [3–6,13–20]. The only combination that cannot be recommended, at least in high-risk patients, following the results of the ONTARGET trial, is that between and an ACE-inhibitor and an ARB [21,22]. Given these premises, we reviewed the current evidence on the efficacy of a recommended ACE-inhibitor plus thiazide diuretic combination (zofenopril plus hydrochlorothiazide), specifically presenting and discussing the results of the recent ZODIAC study. In this trial, the efficacy of zofenopril plus hydrochlorothiazide combination was compared with that of an ARB plus a thiazide diuretic combination (irbesartan plus hydrochlorothiazide) in previously monotherapy-treated uncontrolled hypertensive patients with associated cardiovascular risk factors, following the indications of current guidelines. Combination treatment versus monotherapy
Irrespective of the drug employed, large intervention trials and meta-analyses have clearly documented that monotherapy can effectively reduce BP in only a limited number of hypertensive patients and that the ability of any agent to achieve target BP of 140/90 mmHg or below when given alone does not exceed 20–30% of the overall hypertensive population [9,10]. This means that most hypertensive patients require a combination of at least two drugs to achieve BP control, and that a two-drug regimen may be considered as an alternative to monotherapy as a first-choice therapeutic approach. Though the major disadvantage of initiating treatment with two drugs is that of potentially exposing the patient to an unnecessary agent, nonetheless, such a choice may bring several potential advantages. As a matter of fact, use of the combination treatment allows both drugs to be given in the low-dose range, reducing the risk of side effects compared to full-dose monotherapy. Additionally, the complementary mechanisms of action of the drugs in the combination may minimize their individual side effects. Combining two drugs may avoid the frustration of repetitively and vainly searching for effective monotherapies in patients with very high BP values and organ damage. Furthermore, if used as fixed low doses, the combination may be administered as a single tablet, simplifying the treatment regimen and optimizing compliance [23]. Finally, initiating treatment with a two-drug combination may allow BP targets to be reached earlier than with 1056
monotherapy, which is particularly important in high-risk hypertensive patients [7]. Combination therapy between an ACE-inhibitor & a thiazide diuretic
One of the most effective two-drug antihypertensive combinations is that between an ACE-inhibitor and a thiazide diuretic. The mechanism of action of such a combination involves a synergistic and opposite effect on the renin–angiotensin–aldosterone system (RAAS): the ACE-inhibitor antagonizes the counter-regulatory system activity triggered by the diuretic, thus improving the efficacy and tolerability of single drug components [24,25]. The thiazide diuretic therapy can initially reduce plasma volume with a consequent increase in plasma renin activity, aldosterone secretion and urinary potassium loss [24]. Conversely, ACE inhibition blocks the production of angiotensin II while counteracting the reactive hyperreninemia that may reduce the antihypertensive effect of the diuretic. Therefore, combination of the two drugs seems specifically designed to promote the maximal antihypertensive effect of both classes of drugs [24]. Additionally, the dosages of each agent needed to achieve adequate BP control are less than those required in monotherapy, and this may improve tolerability, reducing the adverse effects of single components, particularly the metabolic effects that are often associated with the use of high-dose diuretic therapy [7,8,24]. ACE-inhibitors are also known to counteract the tendency of thiazide diuretics to lower serum potassium levels. The combination between an ACE-inhibitor and a diuretic has shown to effectively reduce BP levels and prevent end-organ damage of hypertension, being particularly effective in reducing left ventricular hypertrophy [26]. Rationale for the fixed combination between zofenopril & hydrochlorothiazide
Zofenopril calcium, a prodrug of the active compound zofenoprilat, is chemically characterized by the presence of a sulfhydryl group, which is responsible for its high lipophilicity, the highest among all the ACE-inhibitors [27]. The sulfhydryl moiety of zofenopril is not associated with an increased rate of adverse events, as observed with another sulfhydryl-containing ACE-inhibitors such as captopril, while it confers the drug an effective and long-lasting tissue penetration [27–30]. Furthermore, zofenopril has a sustained activity on cardiac ACE inhibition, antioxidant properties and remarkable tissue protective effect, [31], and can improve the oxidative stress in patients with essential hypertension [32]. Hydrochlorothiazide is the 3,4-dihydro derivative of chlorothiazide. It affects the distal renal tubular mechanisms of electrolyte resorption, directly increasing the excretion of sodium and chloride in approximately equivalent amounts. Natriuresis is responsible for the diminished plasma volume and venous return, increased renin release, and reduced cardiac output whose net effect is a reduction in BP. The increase in plasma renin activity results in aldosterone secretion and urinary potassium loss, with a consequent decrease in serum potassium. Expert Rev. Cardiovasc. Ther. 12(9), (2014)
[37] 53* 44 64**
informahealthcare.com
DBP response: DBP £90 mmHg (£85 mmHg in the non-responder study) or reduction by ‡10 mmHg. SBP response: SBP £140 mmHg (£130 mmHg in the non-responder study) or reduction by ‡20 mmHg. *p < 0.005 and **p < 0.01 combination versus monotherapy. DBP: Diastolic blood pressure; SBP: Systolic blood pressure. Reproduced with permission from [36,37].
7* 8 369 Malacco (2005)
Mild-moderate essential hypertensive patients (DBP 90–110 mmHg) not responding to 4 weeks of single-blind treatment with zofenopril 30 mg
8
10**
5
57
[37] 67** 44 73** 11** 8 350 Malacco (2005)
Mild-moderate essential hypertension (DBP 95–115 mmHg)
12
16**
7
51
[36] 62 50 80 12 16 73 Parati (2006)
Mild-moderate essential hypertension (DBP 95–110 mmHg)
12
18
11
71
Combination
DBP response
Monotherapy Combination
SBP response
Monotherapy Combination
DBP reduction
Monotherapy Combination
SBP reduction
Monotherapy
Treatment duration (weeks) Patients’ characteristics Patients (n) Study (year)
Table 1. Efficacy of zofenopril 30 mg plus hydrochlorothiazide 12.5 mg combination versus zofenopril 30 monotherapy in three double-blind, randomized pivotal studies.
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Ref.
Zofenopril plus hydrochlorothiazide in hypertensive patients
Drug Profile
Other possible mechanisms by which hydrochlorothiazide chronically lowers BP include direct endothelial or vascular smooth muscle–mediated vasodilation [33]. Recent experimental models suggest that the synergistic and contrasting effects on the RAAS resulting from the concomitant administration of zofenopril and hydrochlorothiazide may differ from those resulting from the combination between hydrochlorothiazide and other ACE-inhibitors. Such differences may depend on the lipophilicity of the ACE-inhibitor. The volume depletion induced by hydrochlorothiazide in the rat increases the tissue levels of zofenoprilat but not those of lisinopril, a highly hydrophilic ACE-inhibitor [34]. Thus, hydrochlorothiazide could act as a ‘tissue levels enhancer’ by increasing the tissue concentrations of zofenopril and inducing a peculiar enhancement of the tissue activity of this lipophilic ACE-inhibitor [34]. Such an effect could contribute to the development of organprotective effects of ACE-inhibitor therapy. Therefore, a highly lipophilic ACE-inhibitor, such as zofenopril, would take advantage of co-administration with hydrochlorothiazide, in comparison to a hydrophilic ACEinhibitor, such as lisinopril, and potentially increases its cardiovascular therapeutic effects [34]. Such an effect seems to be peculiar of zofenopril and only marginally related to its lipophilic nature, since in animal models another lipophilic ACE-inhibitor, such as fosinopril, although exhibiting cardiac ACE inhibition potency similar to zofenopril, showed different anti-ischemic and cardioprotective effects [35]. Zofenopril plus hydrochlorothiazide combination in patients with essential hypertension
The fixed-dose combination of zofenopril 30 mg plus hydrochlorothiazide 12.5 mg once daily is approved in several European countries for the management of mild-moderate hypertension in patients whose BP is not adequately controlled on zofenopril alone. Such a combination has been shown to be effective for treating arterial hypertension in clinical studies and has also been shown to be superior to monotherapy with either agent. Overall, efficacy data from a total of approximately 800 patients with mild-moderate hypertension have been collected and compared. The larger efficacy of the zofenopril 30 mg plus hydrochlorothiazide 12.5 mg combination versus that of either zofenopril 30 mg or hydrochlorothiazide 12.5 mg was first demonstrated in a multifactorial study and confirmed in two parallel-group studies, the first one carried out in patients with mild-moderate essential hypertension and the second one in patients with hypertension not responding to previous zofenopril 30 mg monotherapy. Main results of such studies are summarized in TABLE 1 [36–38]. In the dose response study, not only office, but also 24-h and hourly changes in BP were 1057
Drug Profile
Metabolic syndrome (n = 198)
Borghi & Omboni
Elevated Atherogenic fasting glucose dyslipidemia (n = 34) (n = 111)
Moderately impaired renal function (n = 56)
Metabolic syndrome (n = 198)
0
Elevated fasting Atherogenic glucose dyslipidemia (n = 111) (n = 34)
Moderately impaired renal function (n = 56)
0
-5 -5
D Office DBP (mmHg)
D Office SBP (mmHg)
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-10
-15
-20
-25
-10
-15
-20
-30 -25
** *
**
-35 ** -40
** *
**
-30
Figure 1. Mean changes (D) ± SD in office systolic and diastolic blood pressure in different high-risk subgroups of patients treated with zofenopril 30 mg monotherapy (open bars) or zofenopril 30 mg plus hydrochlorothiazide 12.5 mg (full bars). Moderately impaired renal function is defined according to guidelines by a creatinine clearance between 30 and 59 ml/min. Asterisks refer to the statistical significance of the difference between the two treatment groups (*p < 0.05 and **p < 0.01). DBP: Diastolic blood pressure; SBP: Systolic blood pressure. Adapted with permission from [38,39].
greater with zofenopril 30 mg plus hydrochlorothiazide 12.5 mg combination treatment than with either agent administered singly. Furthermore, higher smoothness indices, evaluated by ambulatory BP monitoring, indicated that combination treatment with 30 mg zofenopril and 12.5 mg hydrochlorothiazide induced a smooth and homogeneous BP control over the dosing interval superior to that provided by the monotherapy [36]. Regarding the comparative studies, in the first one, the SBP and DBP reduction and the proportion of responders after 12 weeks of treatment were significantly greater with combination therapy than with zofenopril monotherapy [37]. In the second comparative study, significantly greater reduction in BP and higher response rates were observed at the end of the 8 weeks of treatment with the two-drug combination than with the monotherapy [37]. Furthermore, the reduction in BP plateaued at 6 weeks with zofenopril monotherapy, while the BP continued to decrease over the entire study period with combination treatment [37]. Further analyses of the first aforementioned comparative, double-blind, randomized parallel-group study were carried out in order to specifically evaluate the efficacy of zofenopril 30 mg plus hydrochlorothiazide 12.5 mg in subgroups of high-risk 1058
patients with hypertension, such as those with the metabolic syndrome, impaired fasting glucose, atherogenic dyslipidemia and altered renal function [38,39]. Also, in these high-risk patients, sitting office DBP and SBP reductions were larger in the group receiving zofenopril 30 mg plus hydrochlorothiazide 12.5 mg once daily than in the zofenopril 30 mg once-daily monotherapy group (FIGURE 1) [38,39]. Furthermore, the efficacy of the combination treatment was specifically assessed according to the patient’s overall cardiovascular risk level using the Heart Score algorithm, which determines the risk for developing a cardiovascular disease in the next 10 years, taking into account age, gender, total cholesterol levels, SBP and patient’s smoking status [40]. After 12 weeks of treatment, office BP reductions were greater in the combination treatment group than in the monotherapy group for each different quartile of baseline cardiovascular risk in which the subjects were grouped (FIGURE 2) [41]. Zofenopril plus hydrochlorothiazide versus irbesartan plus hydrochlorothiazide: the ZODIAC study
Thiazide diuretics are effective and recommended by guidelines in combination not only with an ACE-inhibitor, but more in Expert Rev. Cardiovasc. Ther. 12(9), (2014)
Zofenopril plus hydrochlorothiazide in hypertensive patients
Q1 0.5% (n = 61)
Q2 2.2% (n = 61)
Q3 7.1% (n = 63)
Q4 19.9% (n = 61)
Q1 0.5% (n = 61)
Q2 2.2% (n = 61)
Drug Profile
Q3 7.1% (n = 63)
Q4 19.9% (n = 61)
0
0
-5 -5
D Office DBP (mmHg)
D Office SBP (mmHg)
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-10
-15
-20
-25
-10
-15
-30 -20 -35
-40
p < 0.01 for trend
-25
p < 0.01 for trend
Figure 2. Mean changes (D) ± SD in office systolic and diastolic blood pressure according to quartiles (Q) of cardiovascular risk level in patients treated with zofenopril 30 mg monotherapy (open bars) or zofenopril 30 mg plus hydrochlorothiazide 12.5 mg (full bars). The p-value refers to the statistical significance of the trend of the difference between the treatment groups. DBP: Diastolic blood pressure; SBP: Systolic blood pressure. Adapted with permission from [40].
general with all RAAS blockers, thus including ARBs [7,8]. The results of several large prospective trials confirmed that a diuretic plus an ARB combination reduces BP further than monotherapies [41,42]. Among the ARB plus thiazide diuretic combinations, the most studied and most effective appears to be that between irbesartan and hydrochlorothiazide [43–50]. This combination was observed to be particularly effective in patients failing to achieve BP control with monotherapy, as documented by the COSIMA [49] and INCLUSIVE [50] studies. In such trials, a 2-month treatment with a combination of irbesartan 150 or 300 mg and hydrochlorothiazide 12.5 or 25 mg allowed to attain BP normalization in 50–70% of patients previously uncontrolled under monotherapy. Given the large use of RAAS inhibitors plus thiazide diuretic combination for treatment of hypertension and since direct comparative data on the antihypertensive efficacy and safety of the zofenopril plus hydrochlorothiazide versus that of an ARB and hydrochlorothiazide combination was lacking, a doubleblind, randomized comparative study was devised: the ZODIAC study [51]. Interestingly, in this study, the efficacy of the highest available dose of zofenopril (60 mg) plus hydrochlorothiazide was also tested and compared with that of the currently marketed one (30 mg). In order to comply with the informahealthcare.com
current recommendations, the patients targeted for treatment were those with an essential hypertension not controlled by a previous monotherapy, associated with one or more additional cardiovascular risk factors [7,8]. In the international multicenter, randomized, double-blind, parallel-group ZODIAC study, 353 patients were treated for 18 weeks with zofenopril 30 mg plus hydrochlorothiazide 12.5 mg or irbesartan 150 mg plus hydrochlorothiazide 12.5 mg. After the first 6 and 12 weeks, the dose of zofenopril or irbesartan had to be doubled to 60 and 300 mg, respectively, if office SBP was ‡140 mmHg or office DBP was ‡90 mmHg in non-diabetic patients and if office SBP was ‡130 mmHg or office DBP was ‡80 mmHg in diabetic patients. All subjects had to be previously treated and uncontrolled with a monotherapy and had at least one additional risk factor among the following: dyslipidemia, diabetes, abdominal obesity, family history for premature cardiovascular disease and current smoking. Active drug treatment was preceded by a 2-week single-blind run-in during which previous antihypertensive treatment was stopped. The study was a non-inferiority trial and the primary efficacy endpoint was the betweentreatment comparison in sitting office DBP changes from baseline to the end of treatment. A subgroup of 181 patients also 1059
Drug Profile
Borghi & Omboni
All subjects (n = 353) DBP
0 -5 -10 -15 -20 -25 -30
Lower drug dose (n = 124) D Office BP (mmHg)
SBP -5 -10 -15 -20 -25 -30 -35
DBP
* Higher drug dose (n = 229) SBP
D Office BP (mmHg)
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D Office BP (mmHg)
SBP
DBP
0 -5 -10 -15 -20 -25 -30
Figure 3. Baseline-adjusted office SBP and DBP mean changes (95% confidence intervals) from baseline after 18 weeks of treatment with zofenopril plus hydrochlorothiazide (open bars) or irbesartan plus hydrochlorothiazide (gray bars) in the whole study sample and by drug dose (lower drug dose: zofenopril 30 mg or irbesartan 150 mg; higher drug dose: zofenopril 60 mg or irbesartan 300 mg). Asterisk refers to the statistical significance of between-treatment differences (*p < 0.05). BP: Blood pressure; DBP: Diastolic blood pressure; SBP: Systolic blood pressure. Adapted with permission from [51].
underwent 24-h ambulatory BP monitoring and in 91 patients, the blood levels of high-sensitivity C-reactive protein (hs-CRP) were quantified. After 18 weeks of treatment, the office SBP and DBP reduction observed in patients treated with zofenopril 30 or 60 mg plus hydrochlorothiazide 12.5 mg once a day was similar to that observed in patients treated with irbesartan 150 or 300 mg plus hydrochlorothiazide 12.5 mg once a day (FIGURE 3). Additionally, sitting office BP normalization was achieved by the end of treatment by a similar proportion of subjects treated with zofenopril plus hydrochlorothiazide and irbesartan plus hydrochlorothiazide (80% for both, p = 0.973 between groups). Such results were attained with the higher drug dosage in a slightly, but not significantly (p = 0.183) larger proportion of subjects treated with zofenopril (69%) than with irbesartan (61%). This was probably due 1060
to the worse cardiovascular profile of patients randomized to zofenopril plus hydrochlorothiazide. In the subjects with valid ambulatory BP recordings, treatment-induced 24-h BP reductions under zofenopril plus hydrochlorothiazide did not differ from those under irbesartan plus hydrochlorothiazide (TABLE 2). Both drugs displayed a similarly smooth and long-lasting antihypertensive effect, ensuring good BP coverage also in the hours farthest from the last drug intake. Interestingly, the magnitude of the 24-h BP reduction yielded by zofenopril and irbesartan plus the diuretic in the ZODIAC study was comparable with that observed in previous studies based on ambulatory BP monitoring and making use of the same doses of the two drug combinations [36,50]. As shown in FIGURE 3, at the end of the study, office sitting SBP and DBP reductions were larger with the lower drug dose of zofenopril (30 mg) plus hydrochlorothiazide than with the lower drug dose of irbesartan (150 mg) plus hydrochlorothiazide, while they were similar when the subgroup treated with the higher drug doses was considered. In the subgroups of patients with mild hypertension and diabetes, both drugs yielded a similar office BP lowering effect (TABLE 3). Conversely, in patients with grade 2 hypertension, office DBP drops obtained under zofenopril were significantly larger than those under irbesartan (TABLE 3). However, the post-hoc nature of this analysis cannot exclude that our finding might be the result of chance. The fact that the BP lowering effect of both medications was well maintained also in diabetics, known to often display a reduced response to antihypertensive drug treatment, confirms that ACE-inhibitors or ARBs are among the most indicated first options in these high-risk patients [7,8,52]. The ZODIAC study also explored the possible positive effect of zofenopril and irbesartan on markers of vascular inflammation. Indeed, the results of epidemiological and clinical studies support a pivotal role for inflammation in all phases of atherosclerosis, from the endothelial cell dysfunction to the culmination in acute coronary syndrome [53]. In our hypertensive subjects, treatment with zofenopril plus hydrochlorothiazide reduced hs-CRP by 0.52 mg/l (95% confidence interval: -10.5; 0.01), while this was not the case for irbesartan-treated patients (0.97 [0.29; 1.65] mg/l, p = 0.001 between treatments). This finding confirms previous evidence derived from studies carried out in hypertensive individuals showing that treatment with zofenopril may be associated with a reduction of the oxidative stress, an improvement in the nitric oxide pathway and an antiinflammatory vasculoprotective effect [20,54,55]. Likely, the sulfhydryl ACE-inhibitor zofenopril, in addition to ensuring BP control, may contribute to slow down the development of atherosclerosis [56,57]. Tolerability of both treatment regimens was good and similar to that observed in previous studies, with a very limited number of drug-related adverse events recorded during the study (7.8% of zofenopril-treated patients vs 6.6% of irbesartan-treated patients) [58,59]. The combination containing zofenopril induced a slightly larger risk of cough, while dizziness or asthenia was more commonly reported by irbesartan-treated patients. Expert Rev. Cardiovasc. Ther. 12(9), (2014)
Zofenopril plus hydrochlorothiazide in hypertensive patients
Drug Profile
Table 2. Average 24-h ambulatory systolic and diastolic blood pressure at randomization and baseline-adjusted reductions after 18 weeks of treatment with zofenopril 30–60 mg + hydrochlorothiazide 12.5 mg or irbesartan 150–300 mg + hydrochlorothiazide 12.5 mg. Zofenopril 30–60 mg + HCTZ 12.5 mg (n = 95)
Irbesartan 150–300 mg + HCTZ 12.5 mg (n = 86)
Baseline
144.6 ± 14.0
142.2 ± 13.0
Reduction with treatment
11.7 (15.4, 8.0)
12.6 (17.2, 8.0)
Baseline
84.8 ± 8.0
86.1 ± 7.6
Reduction with treatment
6.7 (8.7, 4.6)
6.3 (8.8, 3.7)
p-value
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24-h SBP (mmHg)
0.758
24-h DBP (mmHg)
0.810
Data are reported as mean and 95% confidence interval. The p-value refers to the statistical significance of the between-treatment differences. DBP: Diastolic blood pressure; HCTZ: Hydrochlorothiazide; SBP: Systolic blood pressure. Reproduced with permission from [51].
Conclusions
Results of the double-blind, randomized studies based on zofenopril 30 mg plus hydrochlorothiazide 12.5 mg combination treatment confirm that in the majority of patients not responding to a monotherapy, such a combination treatment may substantially increase the chance of response. The recent ZODIAC study, which enrolled hypertensive patients not controlled by previous monotherapy and with one or more additional cardiovascular risk factors, also added new clinically relevant information to the existing one. Indeed, this study suggested that the combination of zofenopril and hydrochlorothiazide and that of irbesartan and hydrochlorothiazide may provide similarly effective, prolonged and well-tolerated control of BP. The ZODIAC study also demonstrated a reduction in hs-CRP in
zofenopril-treated patients, suggesting an additional beneficial effect of this combination therapy on vascular inflammation. According to the evidence collected so far, the combination of zofenopril and hydrochlorothiazide may be indicated among the first-line two-drug fixed-combination choices for treatment of high-risk hypertensive patients or for those not responding to a previous monotherapy. Expert commentary
Current guidelines recommend the use of two-drug combination when BP control with initial monotherapy treatment is inadequate or as an initial therapy for patients with grade 2 hypertension or for those with grade 1 hypertension and concomitant diabetes mellitus, coronary disease or other associated
Table 3. Baseline-adjusted systolic and diastolic blood pressure reductions after 18 weeks of treatment with zofenopril + hydrochlorothiazide or irbesartan + hydrochlorothiazide by hypertension grade (grade 1: systolic blood pressure 140–159 mmHg and/or diastolic blood pressure 90–99 mmHg; grade 2: systolic blood pressure ‡160 mmHg and/or diastolic blood pressure ‡100 mmHg) and diabetes. Zofenopril 30–60 mg + HCTZ 12.5 mg
Irbesartan 150–300 mg + HCTZ 12.5 mg
p-value
Grade 1 hypertension
n = 120
n = 126
SBP (mmHg)
15.9 (19.7, 12.1)
15.7 (20.1, 11.4)
0.959
DBP (mmHg)
14.5 (17.3, 11.7)
14.3 (17.2, 11.4)
0.902
Grade 2 hypertension
n = 55
n = 52
SBP (mmHg)
31.8 (37.2, 26.5)
28.4 (34.4, 22.5)
0.402
DBP (mmHg)
20.0 (23.3, 16.8)
14.7 (18.4, 10.9)
0.035
Diabetes mellitus
n = 34
n = 29
SBP (mmHg)
18.2 (21.8, 14.6)
22.0 (25.9, 18.1)
0.155
DBP (mmHg)
16.4 (18.6, 14.3)
15.0 (17.4, 12.6)
0.366
Data are reported as mean and 95% confidence interval. The p-value refers to the statistical significance of the between-treatment differences. DBP: Diastolic blood pressure; HCTZ: Hydrochlorothiazide; SBP: Systolic blood pressure.
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Drug Profile
Borghi & Omboni
clinical conditions that increase their cardiovascular risk. One of the most effective two-drug antihypertensive combinations is that between an ACE-inhibitor and a thiazide diuretic and among such combinations, the one between the ACE-inhibitor zofenopril and a thiazide diuretic (hydrochlorothiazide) may be particularly interesting for several reasons. First, the drug has proved to be more effective in reducing BP than zofenopril or hydrochlorothiazide alone in grade 1 and 2 essential hypertensive patients and also in patients previously uncontrolled by zofenopril monotherapy. The 30 mg zofenopril dose plus the 12.5 mg hydrochlorothiazide seems to be the ideal choice to achieve control in the majority of subjects. Second, the antihypertensive efficacy of the zofenopril plus hydrochlorothiazide combination was similar to that of the irbesartan plus hydrochlorothiazide combination in the recent ZODIAC study, suggesting that the former may represent a suitable alternative to the combination treatment between an ARB and a thiazide diuretic. Third, the lipophilic nature of zofenopril and the presence of a sulfhydryl group allow high tissue penetration and confer the drug specific anti-oxidative, anti-ischemic, antiinflammatory and anti-atherogenic effects, as demonstrated in experimental models in animals and humans. Such ancillary properties have been indirectly documented in the hypertensive subjects of the ZODIAC study treated with zofenopril plus hydrochlorothiazide by a significant reduction in the blood levels of hs-CRP. Thus, the data collected so far support the role of the zofenopril plus hydrochlorothiazide combination in the treatment of hypertensive patients uncontrolled by a monotherapy. The potential anti-inflammatory effects of zofenopril shown in the recently published ZODIAC study suggest that further clinical
trials need to be performed in the future to explore its possible ancillary anti-atherogenic properties. Five-year view
The evidence collected on the efficacy of the zofenopril plus hydrochlorothiazide combination in various double-blind randomized studies in hypertensive patients has relevance for the clinical practice because it indicates that this combination complies with the current recommendations. Zofenopril plus hydrochlorothiazide fixed combination may be indicated for the treatment of hypertensive patients at high risk, particularly in cases showing no response to a previous monotherapy, as shown in the ZODIAC study. The potential anti-atherogenic and target organ protective properties of zofenopril are currently under investigation in high-risk hypertensive patients in the ZENITH study. If such properties, previously documented in post-acute myocardial infarction patients, are confirmed also in patients with high BP, this may help to place the zofenopril plus hydrochlorothiazide combination among the preferable ACE-inhibitor plus thiazide diuretic combinations for treating arterial hypertension. Financial & competing interests disclosure
Both authors have occasionally received grants for lectures or scientific meeting attendance by Menarini International Operations Luxembourg S. A., manufacturer of zofenopril. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues • Three pivotal studies performed in almost 800 grade 1–2 hypertensive subjects, also including subjects previously not responding to zofenopril monotherapy, treated for 8–12 weeks with the zofenopril 30 mg plus hydrochlorothiazide 12.5 mg combination, clearly demonstrated the superiority of the combination over the monotherapies. • The combination treatment also induced a consistent, smooth and homogeneous blood pressure (BP) control over 24 h. • Post-hoc analyses of one of the three pivotal studies confirmed the good efficacy of the zofenopril 30 mg plus hydrochlorothiazide 12.5 mg combination also in high-risk patients with hypertension, such as those with the metabolic syndrome, impaired fasting glucose, atherogenic dyslipidemia and altered renal function. • In the ZODIAC study, 18 weeks of treatment with zofenopril 30 or 60 mg combined with hydrochlorothiazide of patients previously treated and uncontrolled with a monotherapy and with at least one additional cardiovascular risk factor resulted in BP responses similar to that of the combination between irbesartan 150 or 300 mg and hydrochlorothiazide 12.5 mg. • The ZODIAC study also documented a reduction of high-sensitivity C-reactive protein (hs-CRP) with zofenopril plus hydrochlorothiazide but not with irbesartan plus hydrochlorothiazide, suggesting that zofenopril, in addition to ensuring BP control, may contribute to slow down the development of atherosclerosis. • Due to the robust evidence collected so far, the fixed-dose combination of zofenopril 30 mg plus hydrochlorothiazide 12.5 mg once daily is now approved and recommended for the management of grade 1–2 essential hypertension in patients whose BP is not adequately controlled on zofenopril alone.
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