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Efficacy Of Zofenopril Alone Or In Combination With Hydrochlorothiazide In

Patients With Kidney Dysfunction

Article · October 2018

DOI: 10.2174/1574884713666181025145404

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Current Clinical Pharmacology, 2018, 13, 1-11 1

REVIEW ARTICLE

Efficacy of Zofenopril Alone or in Combination with Hydrochlorothiazide

in Patients with Kidney Dysfunction

Stefano Omboni1,2,* and Claudio Borghi3

1
Clinical Research Unit, Italian Institute of Telemedicine, Varese, Italy; 2Scientific Research Department of Cardiology,
Science and Technology Park for Biomedicine, Sechenov First Moscow State Medical University, Moscow, Russian
Federation; 3Unit of Internal Medicine, Policlinico S. Orsola, University of Bologna, Bologna, Italy

A R T I C L E H I S T O R Y
  ministered for 12 weeks showed a similar blood pressure-lowering effect irrespective of the stage of
Received: June 26, 2018
Revised: September 24, 2018
Accepted: October 19, 2018
DOI:
10.2174/1574884713666181025145404
Abstract: Hypertension and kidney disease often coexist, further increasing the risk of future car-
diovascular events. Treatment of hypertensive adults with an angiotensin converting enzyme inhibi-
tor in case of concomitant kidney disease may slow disease progression. The third-generation
liphophilic angiotensin converting enzyme inhibitor zofenopril, administered alone or combined
with a thiazide diuretic, has proved to be effective in lowering blood pressure in hypertensive pa-
tients and to reduce the risk of fatal and non-fatal events in post-acute myocardial infarction and
heart failure. In almost three-hundred hypertensive patients with kidney impairment zofenopril ad-
the disease, with larger effects in combination with a thiazide diuretic, particularly in patients with
slightly or moderately impaired kidney function. In animal models, zofenopril produced a signifi-
cant and long-lasting inhibition of kidney angiotensin converting enzyme inhibitor and prevented
kidney morphological and functional alterations following kidney ischemia-reperfusion injury.
Treatment of hypertensive patients for 18 weeks with a combination of zofenopril 30 mg and hy-
drochlorothiazide 12.5 mg resulted in a reduction in albumin creatinine ratio of 8.4 mg/g (49.6%
reduction from baseline values) and no changes in glomerular filtration rate, variations in line with
those obtained in the control group treated with a combination of irbesartan 150 mg and hydro-
chlorothiazide 12.5 mg. Thus, some preliminary evidence exists to support that relatively long-term
treatment with the angiotensin converting enzyme inhibitor zofenopril alone or combined with hy-
drochlorothiazide is effective in controlling blood pressure and may confer some kidney protection
due to ACE inhibition properties.

Keywords: Arterial hypertension, kidney dysfunction, chronic kidney disease, angiotensin-converting enzyme inhibitors,
zofenopril, hydrochlorothiazide.

INTRODUCTION According to meta-analyses of observational and ran-

Hypertension is commonly associated with an impaired
kidney function and represents the most common comorbid-
ity affecting patients with chronic kidney disease (CKD) [1].
Both hypertension and CKD constitute very potent risk fac-
tors for cardiovascular (CV) disease and their coexistence
further increases the risk of future CV events, particularly
when proteinuria is detected [2].
It is well established that BP lowering is an effective
strategy for preventing CV and kidney events in people with
hypertension and CKD, also in case of mildly or moderately
reduced glomerular filtration rate [3].
*Address correspondence to this author at the Clinical Research Unit, Italian
Institute of Telemedicine, Via Colombera 29, 21048 Solbiate Arno (Varese),
Italy; Tel. +39 0331 984176; E-mail: stefano.omboni@iitelemed.org
domized controlled studies, due to their specific renoprotec-
tive effects, angiotensin converting enzyme (ACE) inhibitors
and angiotensin II receptors blockers (ARBs) represent the
ideal drugs to reduce the risk of kidney outcomes and im-
prove survival in people with a wide range of severity of
kidney impairment [4-9]. ACE inhibitors have been found
superior to ARBs for kidney failure, CV death and all-cause
mortality in patients with CKD, suggesting that they could
be the first choice for treatment in this population [9]. How-
ever, it must be recognized that BP reduction by antihyper-
tensive treatment and particularly with drugs acting on the
renin angiotensin system often leads to an acute deterioration
of renal function (increase in serum creatinine by as much as
20-30%) which has a functional basis and does not usually
reflect manifest renal injury, but its long-term clinical sig-
nificance is still unclear [10, 11]. Furthermore, it has been

1574-8847/18 $58.00+.00 © 2018 Bentham Science Publishers

2 Current Clinical Pharmacology, 2018, Vol. 13, No. 4
shown that treatment with a combination between two dif-
ferent blockers of the renin angiotensin system may be asso-
ciated with an increased risk of renal deterioration and dis-
ease [12].
According to the evidence collected so far, the most re-
cent hypertension guidelines recommend to treat all adults
with hypertension and kidney disease (CKD stage 3 or
higher or stage 1 or 2 with albuminuria) with an ACE inhibi-
tor (or an ARB if the ACE inhibitor is not tolerated) to a BP
goal of <130/80 mmHg, in order to slow kidney disease pro-
gression [13]. The ACE inhibitor or ARB can eventually be
combined with other drugs such as loop diuretics or dihy-
dropyridine calcium channel blockers, if target BP is not
achieved or no significant reduction in proteinuria is ob-
served.
The third-generation ACE inhibitor zofenopril is amongst
the recommended treatments for hypertensive patients, either
as a monotherapy or as a fixed combination with a thiazide
diuretic. In this review, we will present data of studies sup-
porting the potential specific renoprotective effects of the
drug and its clinical efficacy in hypertensive patients with
various degrees of kidney impairment.
THE PHARMACOLOGICAL PROFILE OF THE ACE
INHIBITOR ZOFENOPRIL
General Pharmacological Features of Zofenopril
Zofenopril calcium is a highly lipophilic third-generation
ACE inhibitor, characterized by a high degree of tissue pene-
tration, long-term cardiac ACE inhibition and ancillary anti-
oxidant and cardioprotective properties [14]. Lipophilicity
confers zofenopril a high ACE inhibitory potency [15, 16],
significant tissue selectivity (inhibition of cardiac ACE is
90% one h after administration and 45% after 24 h) [17],
rapid onset and long duration of action (in hypertensive pa-
Fig. (1). Inhibition of kidney angiotensin converting enzyme (ACE) activity in spontaneously hypertensive rats as a function of time (hours,
h) after administration of equivalent oral doses of six ACE inhibitors [Redrawn from 22 with permission].
Omboni and Borghi
tients the peak blood pressure reduction is achieved 2 h after
administration and 70% of the peak effect is still observed 24
h after the administration) [18].
The increased capacity of zofenopril to reach tissue ACE
as compared to other compounds of the same class, contrib-
utes to several pleiotrophic effects such as prevention of en-
dothelial dysfunction, reversal of nitrate tolerance (useful in
patients with ischemic heart disease), anti-ischemic, anti-
inflammatory and antiatherogenic effects, enhanced angio-
genesis and reversal of apoptosis [19]. The sulfhydryl moiety
of zofenopril is also responsible for a reduced rate of adverse
events, and in particular of cough [20].
Pharmacological Properties of Zofenopril and the Kidney
After oral administration zofenopril calcium is rapidly
and completely absorbed and undergoes nearly complete
metabolic thioester hydrolysis mainly in the liver, yielding
the free sulfhydryl active compound zofenoprilat, which
reaches peak blood levels after 1.5 h. Absorption is essen-
tially complete. According to in-vivo human studies zofeno-
prilat labelled with carbon-11 (11-C) mainly accumulates in
organs which express high levels of ACE, like lungs and
kidneys, and to a minor extent in the heart, where it can af-
ford organ protection [21]. Ex vivo studies in spontaneously
hypertensive rat tissues removed at different times after oral
dosing have shown that zofenopril, like lisinopril and enala-
pril, produces significant and long-lasting inhibition of kid-
ney ACE, whereas captopril, ramipril and fosinopril have
weaker effects, perhaps because of a different route of excre-
tion (Fig. 1) [17, 22].
The accumulation of zofenoprilat in the kidney and its
elevated ACE inhibitory activity at this site may be respon-
sible for specific organ protection. As a matter of fact, in
experimental animal models, zofenopril treatment prevented
kidney morphological and functional alterations following
Zofenopril in Kidney Dysfunction
kidney ischemia-reperfusion injury [23]. In the same model,
a more complete organ protection was observed with
zofenopril than enalapril and this was related to an activation
of endothelial nitric oxide synthase expression and to a nor-
malization of the oxidative stress parameters due to the inhi-
bition of angiotensin II [24].
The main elimination route of zofenoprilat is kidney (ap-
proximately 70-75%), whereas a small amount of the me-
tabolite can be found in the feces (15-25%) [25]. Metabolism
and body clearance of zofenopril may be modified in case of
kidney impairment or in patients in dialysis, as shown in two
separate studies.
A first study evaluated the pharmacokinetic of zofenopril
free sulfhydryl or zofenoprilat (the active drug resulted from
the thio-ester hydrolysis of zofenopril) after a single oral
dose of 30 mg of radiolabeled (14-C) zofenopril in normal
subjects (n=6, creatinine clearance >100 mL/min) and in
patients with mild (n=5, creatinine clearance 45 to 80
mL/min), moderate (n=6, creatinine clearance 20 to 44
mL/min) and severe (n=7, creatinine clearance <20 mL/min)
kidney impairment [26]. In this study, zofenoprilat was
eliminated from the body in patients with severe kidney im-
pairment at half the rate of patients with moderate impair-
ment or normal subjects. As a matter of fact, kidney clear-
ance of zofenoprilat was similar in the group with normal
kidney function (2.7±0.6 mL/min/kg) and in that with mild
kidney impairment (2.3±0.9 mL/min/kg), but dropped mark-
edly in the groups with moderate (0.4±0.1 mL/min/kg) and
severe (0.1±0.01 mL/min/kg) kidney impairment. Kidney
impairment did not affect the conversion of zofenopril to
zofenoprilat, which was metabolized more extensively in the
patients with moderate to severe kidney impairment. This
may be due to the peculiarity of zofenopril, of being elimi-
nated by both kidney and non-kidney routes, at variance with
other ACE inhibitors which are mainly eliminated through
the kidney.
In the above-mentioned study, the mild kidney impair-
ment and normal kidney function groups excreted similar
percentages of administered radioactivity in urine (70.0±5.6
and 75.2±1.8%) and feces (21.9±3.3 and 20.2±2.8%). As
kidney function worsened, the moderate and severe groups
excreted less radioactivity in urine (47.9±3.8 and 39.3±3.5%),
while fecal recoveries increased (29.1±4.2 and 37.2±6.1%).
These data suggest that biliary excretion partially offsets
decreased urinary elimination in patients with more pro-
nounced kidney impairment and that in the presence of kid-
ney or hepatic impairment there appears to be a compensa-
tory elimination by the alternate excretory route. This feature
would eliminate the need for complex dosage adjustments
when using zofenopril in patients with impaired kidney func-
tion, although appropriate adjustment still needs to be main-
tained for patients with end-stage kidney disease. In this
study, a relationship was not apparent between the degree of
kidney impairment and the binding of radioactivity to plasma
protein and the cellular elements of blood. These data indi-
cated that the dose level and once-daily regimen for zofeno-
pril employed for patients with normal kidney function is
appropriate for patients with mild kidney impairment. How-
ever, patients with moderate to severe impairment (creatinine
Current Clinical Pharmacology, 2018, Vol. 13, No. 4 3
clearance <45 mL/min) [27] should be given one-half the
usual starting dose of zofenopril recommended for patients
with normal kidney function, whereas the once-daily dosage
regimen does not require modification.
In end-stage kidney disease [28], the total body clearance
of zofenoprilat averaged 3.9 mL/min/kg in patients on
hemodialysis (n=6) and 2.7 mL/min/kg in patients on perito-
neal dialysis (n=6), and were about half that determined pre-
viously in patients with severe kidney impairment (8.5
mL/min/kg). These observations indicate that the starting
dose of zofenopril employed for patients requiring dialysis
should be one quarter that used in patients with normal kid-
ney function or one half the dose used for patients with se-
vere kidney impairment not dependent on dialysis. The
clearance of total radioactivity and zofenoprilat 14-C by
hemodialysis averaged 19% and 32% of the urea clearance,
respectively. The clearance of total radioactivity by perito-
neal dialysis averaged 25% of the urea clearance. The clear-
ances of zofenoprilat 14-C could not be determined because
levels of zofenoprilat 14-C were not detectable in the perito-
neal dialysate. These data indicate that dialysis contributes
modestly to the elimination of the drug and indicate that the
starting dose of zofenopril employed for patients requiring
dialysis should be one quarter that used in patients with nor-
mal kidney function or one half the dose used for patients
with severe kidney impairment not dependent on dialysis.
As shown in animals, the concomitant administration of
hydrochlorothiazide may affect the renal clearance of
zofenopril which tends to accumulate in tissue due to its
lipophilicity: this may have some clinical implications in
patients with renal impairment. In rats with myocardial in-
farction treated for 3 weeks with 50 mg/kg/day hydro-
chlorothiazide or control with concomitant lisinopril or
zofenopril in equipotent dosages (3.3 and 10 mg/kg/day,
respectively) in the last week of treatment, zofenopril but not
lisinopril levels were markedly increased in the kidney [29].
In contrast, plasma concentrations were unchanged for
zofenopril and significantly increased for lisinopril. The in-
crease in plasma levels of lisinopril could be fully explained
by a decreased renal function, as evidenced by an increase in
plasma creatinine levels (from 61±5 to 82±5 µM, p<0.001)
which was less pronounced under zofenopril (from 54±5 to
61±3 µM, p=0.150).
The pharmacokinetic studies in humans and animals
helped to determine the current drug label for zofenopril
alone or in combination with hydrochlorothiazide for renally
impaired patients [30, 31].
In hypertensive patients with mild impairment (creatinine
clearance >45 mL/min) the same dose level and once-daily
regimen of zofenopril or zofenopril plus hydrochlorothiazide
can be employed as for patients with normal renal function.
In patients with moderate to severe impairment (creatinine
clearance <45 mL/min) zofenopril should be employed at
half the therapeutic dose. The combination of zofenopril
with hydrochlorothiazide is not recommended in case of
moderate impairment and contraindicated in case of severe
renal impairment (creatinine clearance <30 mL/min). The
starting dose and the dosage regimen of zofenopril for hyper-
tensive patients maintained on dialysis should be one-quarter
4 Current Clinical Pharmacology, 2018, Vol. 13, No. 4
the dose used for patients with normal renal function,
whereas its use in combination with hydrochlorothiazide is
not recommended.
CURRENT EVIDENCE OF ZOFENOPRIL EFFICACY
IN PATIENTS WITH KIDNEY IMPAIRMENT
The clinical efficacy of zofenopril, alone or in combina-
tion with a thiazide diuretic, has been extensively studied in
patients with acute myocardial infarction (AMI) [32-35],
heart failure (HF) [36] and essential hypertension [19, 37-
39]. Few of these studies have also investigated the drug
efficacy in case of kidney impairment of various degrees and
a recent post-hoc analysis evaluated the impact of long-term
zofenopril treatment on kidney function in hypertensive pa-
tients. The overall evidence collected so far with zofenopril
and the one specially related to kidney patients will be sum-
marized and discussed in the next sections of the paper.
Overall Data of Zofenopril Efficacy in Post-AMI, HF and
Arterial Hypertension
In patients with AMI, HF or mild to severe arterial hyper-
tension treatment with zofenopril has been shown to be very
effective both in comparison to placebo and active treat-
ments (Table 1). In 3,630 post-AMI patients enrolled in the
four randomized controlled trials of the SMILE program
zofenopril at doses of 30 mg twice-daily reduced the risk of
combined occurrence of death or hospitalization for CV
causes, compared to placebo and, at least in the long term,
even compared to lisinopril and ramipril. The activity of
zofenopril was evident immediately after starting the treat-
ment and sustained over time: a 28% risk reduction was
achieved in the first 6 weeks [hazard ratio and 95% confi-
dence interval: 0.72 (0.54, 0.97), p=0.029], while a 40% re-
duction was reached after 1 year of follow-up [hazard ratio
and 95% confidence interval: 0.60 (0.49, 0.74), p=0.0001]
[40]. In one observational prospective study of 224 patients
with a NYHA I-III heart failure followed-up for an average
period of 6.1 years, zofenopril 15 to 30 mg/day and ramipril
5 to 10 mg/day appeared to be equivalent regarding the ef-
fects on cardiovascular mortality (45 deaths in the zofeno-
pril-treated group and 48 in the ramipril-treated group;
p=0.251) [36]. However, zofenopril was a significant predic-
tor of better survival in older patients (odds ratio and 95%
confidence interval: 0.56, 0.35 to 0.91), in men (0.57, 0.30 to
0.98), and in patients with a lower ejection fraction (0.52,
0.26 to 0.97). In spite of the evidence of the efficacy of
zofenopril in both post-AMI and HF failure patients, the
drug is currently indicated only for the treatment of AMI
patients, with or without signs and symptoms of HF.
The evidence of the efficacy of zofenopril alone or in
combination with hydrochlorothiazide in hypertensive pa-
tients comes from 25 double-blind randomized placebo or
actives controlled studies [18, 37-39]. All these studies
showed that zofenopril administered alone or in combination
with hydrochlorothiazide, exerts a consistent and sustained
antihypertensive effect with some ancillary features resulting
in positive effects on systemic inflammation, cardiac, kidney
and vascular damage of hypertension, arterial stiffness and
metabolic biochemical parameters (mainly blood lipids and
glucose). In all studies, the antihypertensive efficacy of
Omboni and Borghi
zofenopril was larger than that of placebo and similar to that
of active principles of other antihypertensive drug classes.
In hypertensive patients, the usual effective dose is 30
mg once-daily which can be increased up to a maximum of
60 mg daily administered in a single dose or in two divided
doses. In non-responder patients (BP not normalized or in-
sufficient BP reduction with treatment) the fixed combina-
tion of zofenopril 30 mg plus hydrochlorothiazide 12.5 mg
can be selected.
Dosage adjustments may be needed in the elderly or in
patients with kidney impairment or other pathophysiological
conditions as discussed above.
Evidence of BP-lowering Efficacy of Zofenopril in Early
Studies in Patients with Impaired Kidney Function
In an early study performed in USA, the efficacy of
zofenopril monotherapy was tested in comparison with that
of enalapril in mild-moderate hypertensive patients (sitting
office DBP between 95 and 110 mmHg) with kidney im-
pairment (serum creatinine 1.5 to 5.0 mg/dL) [41]. After a 4
to 6 weeks of placebo eligible patients were double-blind
randomized to 12 weeks of treatment with zofenopril 15 mg
(n=38) or enalapril 2.5 mg (n=35) once-daily. Drug doses
could be doubled if DBP was not controlled after 4 and 8
weeks of treatment, up to 60 mg for zofenopril and 10 mg
for enalapril. The primary indicator of efficacy in this study
was the change in sitting office DBP, whereas a favorable
response to treatment was defined as a sitting office DBP
≤90 mmHg or a reduction of ≥10% from baseline. At the end
of the 12 weeks of treatment mean office DBP significantly
(p<0.01) dropped from 101.6 mmHg to 87.6 mmHg in the
zofenopril group, and from 102.1 mmHg to 91.5 mmHg in
the enalapril group, with a statistically significant (p=0.043)
between-groups difference in favor of zofenopril (Fig. 2).
The response rate was similar between the two treatment
groups (Fig. 2).
A post-hoc analysis of a large parallel group randomized
study, evaluated the blood pressure-lowering effect of 12
weeks of treatment with zofenopril 30 mg monotherapy vs.
that of the combination of zofenopril 30 mg and hydro-
chlorothiazide 12.5 mg once-daily in 246 patients with mild-
moderate hypertension (DBP between 95 and 115 mmHg)
according to stages of kidney disease [37]. Presence of kid-
ney disease was determined on the basis of the level of
creatinine clearance as estimated via the Cockroft-Gault
formula [42], using serum creatinine, age, gender, and body
weight. Kidney disease was classified as follows: (a) Stage 1
or normal function (creatinine clearance ≥ 90 mL/min); (b)
Stage 2 or slightly impaired kidney function (creatinine
clearance 60–89 mL/min); (c) Stage 3 or moderately im-
paired kidney function (creatinine clearance 30–59 mL/min);
(d) Stage 4 or severely impaired kidney function (creatinine
clearance 15–29 mL/min); and (e) Stage 5 or end-stage kid-
ney failure (creatinine clearance < 15 mL/min or on dialysis)
[43]. Most of the patients (n=137, 56%) had a slightly im-
paired kidney function, and no patient had a severe impair-
ment of kidney function or end-stage kidney failure. In all
patients, BP dropped to a similar extent irrespective of the
stage of kidney disease. However, the BP reduction was
Zofenopril in Kidney Dysfunction Current Clinical Pharmacology, 2018, Vol. 13, No. 4 5

Table 1. Overview of the main studies based on zofenopril monotherapy or combination with hydrochlorothiazide, performed in
post-myocardial infarction, heart failure and hypertensive patients, and in patients with kidney impairment.

AMI and HF

Study, Study Population Number of Treatments Duration of Main Results

Author Design Subjects (Daily dose and Treatment
(Number of Number of
Studies) Subjects)

Borghi et al. Double- • Post-AMI patients 3,630 (4) • Placebo (951) 6-48 weeks • 40% reduction of 1 year com-
[40] blind, ran- • Mean age: 61±11 • Zofenopril 30-60 bined occurrence of death or
domized, years mg (1,808) hospitalization for CV causes
parallel vs. placebo (HR=0.60, 95% CI
• 76% males • Lisinopril 5-10
group 0.49 to 0.74; p=0.0001)
mg (520)
• 23% reduction of 1 year major
• Ramipril 10 mg
CV events vs. other ACE-
(351)
inhibitors (0.77, 0.63 to 0.95;
p=0.015)
• The benefit of zofenopril vs.
placebo was already evident af-
ter the first 6 weeks of treatment
(−28%; 0.72, 0.54 to 0.97;
p=0.029), while this was not the
case for the other ACE inhibi-
tors (−19%; 0.81, 0.57 to 1.17;
p=0.262)
• In the first 6 weeks of treatment
zofenopril showed a trend to-
wards a larger reduction in CV
events versus the other ACE-
inhibitors (−11%; 0.89, 0.69 to
1.15; p=0.372).

Borghi et al. Prospective, • HF patients 224 (1) Zofenopril 15-30 6.1 years • Zofenopril and ramipril were
[36] randomized, (NYHA class I-III) mg (102) equivalent regarding the effects
open, never treated with Ramipril 5-10 mg on cardiovascular mortality (45
blinded, end ACE-inhibitors or (73) vs.. 48 deaths; p=0.251)in the
point trial ARBs entire sample
(PROBE) • Mean age: 74±10 • Zofenopril was a significant
years predictor of better survival in
• 62% males older patients (OR=0.56, 95%
CI 0.35 to 0.91), in men (0.57,
0.30 to 0.98), and in patients
with a lower ejection fraction
(0.52, 0.26 to 0.97)

Arterial Hypertension

Study, Study De- Population Number of Treatments Duration of Main Results

Author sign Subjects (Daily Dose) Treatment
(Studies) (Weeks)

Studies Double- • Mild-moderate 1,670 (6) • Placebo (380) 6-8 weeks • All doses of zofenopril resulted
21,974-23, blind, ran- essential hyperten- • Zofenopril 7.5- in larger BP reduction than pla-
SQZ/02, domized, sive patients 60 mg (1,290) cebo
ZOF01MEN, parallel • A dose-response relationship
21,974-26, group was observed, with larger BP
21,974-11, reductions achieved with the 60
SQZ/05 [38] and 30 mg doses
(Table 1) contd….
6 Current Clinical Pharmacology, 2018, Vol. 13, No. 4 Omboni and Borghi

Arterial Hypertension

Study, Study Population Number of Treatments Duration of Main Results

Author Design Subjects (Daily Dose) Treatment
(Studies) (Weeks)

Omboni et al. Double- • Mild-moderate or 3,191 (12) • Zofenopril 15-60 8-12 weeks • Zofenopril showed an anti-
[37,38] blind, ran- moderate-severe mg (1,617) hypertensive efficacy on office
domized, essential hyperten- • HCTZ 25-50 mg BP similar to that of the com-
parallel sive patients (161) parators
group
• Atenolol 50-100
mg (338)
• Propranolol 40-80
mg (133)
• Enalapril 2.5-40
mg (376)
• Lisinopril 10-20
mg (90)
• Nifedipine SR 80
mg (40)
• Amlodipine 5-10
mg (152)
• Losartan 50-100
mg (162)
• Candesartan 8-16
mg (122)

Parati et al. Double- • Mild-moderate 353 (1) • Zofenopril 15-30- 12 weeks • Efficacy of the combination
[18] blind, ran- essential hyperten- 60 mg (106) was greater than that of individ-
domized, sive patients • HCTZ 12.5-25 mg ual treatments, with best results
parallel • Mean age: 57±2 (71) achieved under zofenopril 30
group years mg + HCTZ 12.5 mg
• Zofenopril 15-30-
• 56% males 60 mg + HCTZ • The efficacy was good also in
12.5-25 mg (176) ambulatory conditions, the
combination yielding a homo-
geneous and sustained BP con-
trol over the 24 hours

Omboni et al. Double- • Mild-moderate 719 (2) • Zofenopril 30 mg 8-12 weeks • Reduction of office BP and
[37] blind, ran- essential hyperten- (299) proportion of responders signifi-
domized, sive patients (± not • Zofenopril 30 mg cantly greater with the combina-
parallel responding to pre- + HCTZ 12.5 mg tion treatment than with the
group vious monotherapy (420) monotherapy
with zofenopril) • The superiority of the zofenopril
• Mean age: 52±12 + HCTZ combination was evi-
years dent also in high risk patients
• 58% males with the metabolic syndrome,
elevated fasting glucose, athero-
genic dyslipidemia and kidney
impairment
• BP response with the combina-
tion was good also in patients
with a high risk of developing
cardiovascular disease in the
next 10 years
(Table 1) contd….
Zofenopril in Kidney Dysfunction Current Clinical Pharmacology, 2018, Vol. 13, No. 4 7

Arterial Hypertension

Study, Study Population Number of Treatments Duration of Main Results

Author Design Subjects (Daily Dose) Treatment
(Studies) (Weeks)

Omboni et al. Double- • Hypertensive pa- 1,469 (4) • Zofenopril 30-60 18-24 weeks • Both treatments similarly re-
[39] blind, ran- tients uncontrolled mg + HCTZ 12.5 duced office and ambulatory BPs
domized, by a previous mg (726) • A larger reduction in hs-CRP
parallel monotherapy and • Irbesartan 150-300 was observed under zofenopril
group with ≥1 CV risk mg + HCTZ 12.5 (-0.52 vs. +0.97 mg/dL under
factor mg (743) irbesartan, p = 0.001), suggesting
• Mean age: 61±10 a potential protective effect
years against the development of
• 56% males atherosclerosis

• 44% diabetics • The rate of carotid plaque regres-

sion was significantly larger
under zofenopril (32% vs. 16%
irbesartan; p = 0.047)
• In diabetic patients no adverse
effects of treatments on blood
glucose and lipids as well as an
improvement of kidney function
were observed
• In patients with isolated systolic
hypertension a slight and similar
improvement in kidney function
and small reductions in PWV,
AI, and central systolic BP were
documented with both treatments

Kidney Impairment

Study, Study Population Number of Treatments Duration of Main Results

Author Design Subjects (Daily Dose) Treatment
(Studies) (Weeks)

Study Double- • Mild-moderate 73 (1) • Zofenopril 15-60 12 weeks • Both drugs reduced office BP to
21,974-28 blind, ran- essential hyperten- mg (38) a comparable degree and were
[41] domized, sion • Enalapril 2.5-10 equally well tolerated
parallel • Kidney impairment mg (35)
group (serum creatinine
15-5.0 mg/dL)

Omboni et al. Double- • Mild-moderate 246 (1) • Zofenopril 30 mg 12 weeks • BP was similarly reduced by
[44-46] blind, ran- essential hyperten- (157) treatment regardless of the stage
domized, sion • Zofenopril 30 mg of kidney disease
parallel • CKD stage 1-3 + HCTZ 12.5 mg • The BP reduction was larger
group (89) under combination treatment
than under monotherapy, par-
ticularly in patients with slightly
impaired or moderately impaired
kidney function

SMILE: AMI: Acute Myocardial Infarction; CV: Cardiovascular; HR: Hazard Ratio; CI: Confidence Interval; ACE: Angiotensin Converting Enzyme; PROBE: Prospective Random-
ized Open Blinded Endpoint; HF: Heart Failure; NYHA: New York Heart Association; ARB: Angiotensin II Receptor Blockers; OR: Odds Ratio; BP: Blood Pressure; HCTZ: Hydro-
chlorothiazide; hs-CRP: high sensitivity C Reactive Protein; PWV: Pulse Wave Velocity; AI: Augmentation Index; CKD: Chronic Kidney Disease.

larger under combination treatment than under monotherapy, Both the studies described above helped to confirm in a
particularly in patients with slightly impaired or moderately relatively large sample of hypertensive patients, that treatment
impaired kidney function (Fig. 3). with the ACE inhibitor zofenopril alone or in combination
8 Current Clinical Pharmacology, 2018, Vol. 13, No. 4 Omboni and Borghi

Fig. (2). Mean changes (and 95% confidence intervals) in office diastolic blood pressure (DBP) and DBP response (DBP ≤90 mmHg or re-
duction ≥10%) after 4, 8 or 12 weeks of treatment with zofenopril 15-60 mg once-daily (open bars) or enalapril 2.5-10 mg once-daily (full
bars). Values for mean change and standard deviation for DBP are reported at the bottom of each bar. P-values of the difference between the
two treatment groups are reported [41].

Fig. (3). Mean changes (and 95% confidence intervals) in office diastolic (DBP) and systolic blood pressure (SBP) according to the level of
creatinine clearance (CC) after 12 weeks of treatment with zofenopril 30 mg once-daily (open bars) or zofenopril 30 mg plus hydrochlorothi-
azide 12.5 mg once-daily (full bars). Values for mean change and standard deviation for both SBP and DBP are reported at the bottom of
each bar. P-values of the difference between the two treatment groups are reported [Redrawn from 37 with permission].

with a thiazide diuretic may effectively reduced BP also in could not provide information on any possible benefit of the
presence of kidney impairment. However, these studies drug on kidney function in hypertensive patients.
Zofenopril in Kidney Dysfunction Current Clinical Pharmacology, 2018, Vol. 13, No. 4 9

Effects of Zofenopril on Kidney Function
The impact of zofenopril in combination with a thiazide
diuretic on kidney function has been recently evaluated in a
post-hoc analysis of three double-blind randomized studies
[44-46]. Following a 2-week single blind placebo run-in, 287
patients with essential hypertension, not controlled by a pre-
vious monotherapy and with one or more additional cardio-
vascular risk factors, were randomized double-blind to
18 weeks of treatment with zofenopril 30 mg or irbesartan
150 mg, both given in combination with hydrochlorothiazide
12.5 mg.
In these studies no specific inclusion/exclusion criteria
regarding albumin-creatinine ratio (ACR) thresholds at en-
rolment were foreseen. At the end of treatment ACR was
significantly (p=0.0001) reduced by both zofenopril [base-
line-adjusted reduction of 8.4 (10.5, 6.4) mg/g] and irbesar-
tan [9.1 (10.8, 7.3) mg/g] combinations, with no between-
treatment difference (p=0.655) (Fig. 4). The proportion of
patients with abnormal ACR values (≥22 mg/g in males and
≥31 mg/g in females) [47] dropped from 12.9% at baseline to
6.5% at the end of treatment in the zofenopril-treated group
(corresponding to 49.6% reduction) and from 9.5% to 4.8%
in the irbesartan-treated group (49.5% redustion), with no
between-treatment statistically significant differences (p=0.792)
(Fig 4).
In the same patients we also evaluated the impact of ACE
inhibitor and ARB treatment in combination with the thiaz-
ide diuretic on creatinine clearance estimated through the
Cockroft-Gault formula. Baseline-adjusted changes with
treatment in creatinine clearance were negligible in both
zofenopril-treated [-1.7 (-16.2, +12.8) mL/min] and irbesar-
tan-treated patients [+7.6 (-4.6, +19.9) mL/min] and no sta-
tistically significant difference could be detected between the

Fig. (4). Baseline-adjusted mean changes (and 95% confidence intervals) in albumin creatinine ratio (ACR) after 18 weeks of treatment with
zofenopril 30 mg + hydrochlorothiazide (HCTZ) 12.5 mg once-daily (open bars) or irbesartan 150 mg + HCTZ 12.5 mg once-daily (full
bars) and frequency (%) of patients with abnormal ACR (≥22 mg/g in males and ≥31 mg/g in females) at baseline and after 18 weeks of
treatment. P-values of the difference between the two treatment groups are reported.

Fig. (5). Baseline-adjusted mean changes (and 95% confidence intervals) in creatinine clearance (CC) after 18 weeks of treatment with
zofenopril 30 mg + hydrochlorothiazide (HCTZ) 12.5 mg once-daily (open bars) or irbesartan 150 mg + HCTZ 12.5 mg once-daily (full
bars) and frequency (%) of patients with abnormal CC (<60 mL/min) values at baseline and after 18 weeks of treatment. P-values of the dif-
ference between the two treatment groups are reported.
10 Current Clinical Pharmacology, 2018, Vol. 13, No. 4
treatments (p=0.332) (Fig 5). Similarly the proportion of
patients with a reduced creatinine clearance (<60 mL/min)
was low and did not differ between baseline and end of
treatment and between the two treatment groups (Fig. 5).
CONCLUSIONS
Treatment with the ACE inhibitor zofenopril alone or in
combination with a thiazide diuretic is effective in control-
ling BP also in patients with hypertension and impaired kid-
ney function. The long-term administration of the zofenopril
plus hydrochlorothiazide combination in high-risk hyperten-
sive patients resulted in a slight improvement in urine pro-
tein excretion, which was similar to that observed for the
combination of an ARB (irbesartan) with a thiazide diuretic.
The pharmacological properties of zofenopril suggest poten-
tial renoprotective ancillary features of the drug, which need
to be confirmed in large randomized controlled studies spe-
cifically designed and performed in patients at various stages
of CKD.
INFORMED CONSENT
This article is based on previously conducted studies. In
case of studies involving humans, informed consent was
obtained from all individual participants.
FUNDING
The costs for the preparation of this manuscript were
funded by Menarini International Operations Luxembourg
S.A. The funding source did not influence or comment on
preparation, review, or approval of the manuscript, and deci-
sion to submit the manuscript for publication.
AUTHORSHIP
All named authors meet the International Committee of
Medical Journal Editors (ICMJE) criteria for authorship for
this manuscript, take responsibility for the integrity of the
work as a whole, and have given final approval to the ver-
sion to be published. Stefano Omboni devised the original
idea of the work, made the search of the literature and wrote
the manuscript. Claudio Borghi critically revised the paper.
DATA AVAILABILITY
The datasets generated during and/or analyzed during the
current study are not publicly available because they are
property of the Sponsor of the studies Menarini International
Operations Luxembourg S.A., but they are available from
the corresponding author on reasonable request.
HUMAN AND ANIMAL RIGHTS
This article is based on previously conducted studies, and
does not contain any new studies with human participants or
animals performed by any of the authors.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
Stefano Omboni has received honorarium from Menarini
International for manuscript preparation.
Omboni and Borghi
Claudio Borghi has occasionally received grants for lec-
tures or for scientific meeting attendance by the manufac-
turer of zofenopril.
ACKNOWLEDGEMENTS
Declared none.
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