REVIEW

Efficacy of Zofenopril vs. Irbesartan in Combinationwith a Thiazide Diuretic in Hypertensive Patientswith Multiple Risk Factors not Controlledby a Previous Monotherapy: A Review of theDouble-Blind, Randomized ‘‘Z’’ Studies

Stefano Omboni . Ettore Malacco . Claudio Napoli . Pietro Amedeo Modesti .

Athanasios Manolis . Gianfranco Parati . Enrico Agabiti-Rosei . Claudio Borghi

Received: December 21, 2016 / Published online: March 4, 2017� The Author(s) 2017. This article is published with open access at Springerlink.com

ABSTRACT

Combinations between an angiotensin con-verting enzyme (ACE) inhibitor or an angio-tensin II receptor blocker (ARB) andhydrochlorothiazide (HCTZ) are among therecommended treatments for hypertensivepatients uncontrolled by monotherapy. Fourrandomized, double-blind, parallel group

studies with a similar design, including 1469hypertensive patients uncontrolled by a previ-ous monotherapy and with C1 cardiovascularrisk factor, compared the efficacy of a combi-nation of a sulfhydryl ACE inhibitor (zofenoprilat 30 or 60 mg) or an ARB (irbesartan at 150 or300 mg) plus HCTZ 12.5 mg. The extent ofblood pressure (BP)-lowering was assessed in theoffice and over 24 h. Pleiotropic features of thetreatments were evaluated by studying theireffect on systemic inflammation, organ damage,arterial stiffness, and metabolic biochemicalparameters. Both treatments similarly reduced

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S. Omboni (&)Clinical Research Unit, Italian Institute ofTelemedicine, Varese, Italye-mail: stefano.omboni@iitelemed.org

E. MalaccoL. Sacco Hospital, Milan, Italy

C. NapoliDepartment of Internal Medicine and SpecialisticUnits, U.O.C. of Clinical Immunology,Immunohematology, Transfusion Medicine andOrgan Transplantation, Azienda OspedalieraUniversitaria (AOU), Second University of Naples,Naples, Italy

C. NapoliSDN Foundation and IRCCS, Naples, Italy

P. A. ModestiDepartment of Clinical and Experimental Medicine,Careggi Hospital, University of Florence, Florence,Italy

A. ManolisAsklepeion General Hospital of Voula, University ofAthens, Athens, Greece

G. ParatiDepartment of Cardiovascular, Neural andMetabolic Sciences, Istituto Auxologico Italiano,Milan, Italy

G. ParatiDepartment of Medicine and Surgery, University ofMilano-Bicocca, Milan, Italy

E. Agabiti-RoseiDivision of Medicine and Surgery, Spedali Civili andUniversity of Brescia, Brescia, Italy

C. BorghiDepartment of Internal Medicine, University ofBologna, Bologna, Italy

Adv Ther (2017) 34:784–798

DOI 10.1007/s12325-017-0497-8

office and ambulatory BPs after 18–24 weeks. Inthe ZODIAC study a larger reduction in highsensitivity C reactive protein (hs-CRP) wasobserved under zofenopril (-0.52 vs. ?0.97 mg/dL under irbesartan, p = 0.001), suggesting apotential protective effect against the develop-ment of atherosclerosis. In the ZENITH studythe rate of carotid plaque regression was signif-icantly larger under zofenopril (32% vs. 16%;p = 0.047). In the diabetic patients of theZAMES study, no adverse effects of treatmentson blood glucose and lipids as well as animprovement of renal function were observed.In patients with isolated systolic hypertensionof the ZEUS study, a slight and similarimprovement in renal function and smallreductions in pulse wave velocity (PWV), aug-mentation index (AI), and central systolic BPwere documented with both treatments. Thus,the fixed combination of zofenopril and HCTZmay have a relevant place in the treatment ofhigh-risk or monotherapy-treated uncontrolledhypertensive patients requiring a more prompt,intensive, and sustained BP reduction, in linewith the recommendations of currentguidelines.

Keywords: Ambulatory blood pressure;Angiotensin converting enzyme inhibitors;Angiotensin II receptor blockers; Essentialhypertension; Hydrochlorothiazide; Irbesartan;Office blood pressure; Thiazide diuretics;Zofenopril

INTRODUCTION

Large intervention trials have shown that themajority of hypertensive patients may need acombination of two or more antihypertensivemedications to achieve satisfactory blood pres-sure (BP) control and effective cardiovascular(CV) protection [1, 2]. This holds true particu-larly for patients at high risk for CV events, suchas older individuals, patients with diabetes orthe metabolic syndrome, co-existing CV dis-ease, or other associated clinical conditions[3, 4]. According to the evidence provided bymajor intervention trials, current guidelines for

the management of arterial hypertensionacknowledge and recommend the use of com-bination treatment, particularly when BP con-trol with initial monotherapy is inadequate[5–8].

Amongst the most effective two-drug anti-hypertensive combinations are those betweenan antagonist of the renin–angiotensin–aldos-terone system (RAAS), such as an angiotensinconverting enzyme (ACE) inhibitor or anangiotensin II receptor blocker (ARB), and athiazide diuretic. The mechanism of action ofsuch a combination implies a synergistic andopposite effect on the RAAS, in which the ACEinhibitor or the ARB antagonize the coun-ter-regulatory system activity triggered by thediuretic, thus improving the efficacy and toler-ability of single drug components [9–11].

Recently, we published four randomized,double-blind, parallel group, direct comparativestudies (also called ‘‘Z’’ studies, because of thecommon initial of their acronyms: ZODIAC,ZENITH, ZAMES, and ZEUS) which were plan-ned to gain a deeper insight into the mecha-nisms of the antihypertensive effects of atwo-drug fixed combination between a RAASantagonist and a thiazide diuretic [12–15]. Inthese non-inferiority trials, efficacy and safetyof the sulfhydryl ACE inhibitor zofenopril andof the ARB irbesartan both combined withhydrochlorothiazide (HCTZ) 12.5 mg were tes-ted in hypertensive patients with one or moreCV risk factors beyond hypertension (includingdiabetes, metabolic syndrome, and advancedage) and not responding to a previousmonotherapy. In all studies, zofenopril andirbesartan were started at a dose of 30 and150 mg, respectively, and were increased duringthe course of the follow-up to 60 and 300 mg, innon-responders, in order to check the effec-tiveness and tolerability of a highest dose of thedrugs. Efficacy was evaluated not only in theoffice but also over 24 h by ambulatory bloodpressure monitoring (ABPM). In addition,ancillary or pleiotropic features of the studydrugs were evaluated by studying their effect oninflammation, target organ damage, arterialstiffness, and metabolic biochemical parameters(blood glucose and lipids). A summary of thestudy designs and an overview of the number of

Adv Ther (2017) 34:784–798 785

Table1

Overviewof

thestudypopulation,design,andmainresults

ofthestudiesbasedon

zofenoprilplus

hydrochlorothiazide(H

CTZ)or

irbesartan

plus

HCTZ

inhypertensive

subjects(so-calledZstudies)

ZODIA

Cstud

y[12]

ZENIT

Hstud

y[13]

ZAMESstud

y[14]

ZEUSstud

y[15]

Maininclusioncriteria

Office

DBPC90

mmHg,

uncontrolledby

aprevious

monotherapy

withC1CV

risk

factor

Office

SBPC140and/or

C90

mmHg,un

controlled

byaprevious

monotherapy

withC1CVrisk

factor

Office

SBPC140and/or

C90

mmHg,un

controlled

byaprevious

monotherapy,

withdiabetes

andC1CV

risk

factor

formetabolic

synd

rome

Office

SBPC140andDBP

\90

mmHgplus

daytim

eSB

PC135mmHgand

daytim

eDBP\85

mmHg,

ageC65

years,un

treatedor

uncontrolledby

B2

medications

Studydesign

2weeks

ofsingle-blin

dplacebo

run-in,followed

by18

weeks

ofdouble-blin

dtreatm

ent

2weeks

ofrun-in

under

currentmonotherapy,

followed

by18

weeks

ofdouble-blin

dtreatm

ent

2weeks

ofrun-in

under

currentmonotherapy,

followed

by24

weeks

ofdouble-blin

dtreatm

ent

1-weeksingle-blin

drun-in

undercurrenttreatm

ent

followed

by18

weeks

ofdouble-blin

dtreatm

ent

Treatments

Zofenopril30

mgor

irbesartan

150mg(plusHCTZ

12.5mg)

up-titratedto

high

dose

(60and300mg)

after6

and12

weeks

innon-norm

alized

patients

(office

DBPC90

mmHg)

Zofenopril30

mgor

irbesartan

150mg(plus

HCTZ12.5mg)

up-titratedto

high

dose(60

and300mg)

after6and

12weeks

innon-norm

alized

patients

(office

DBPC90

mmHg)

Forced

up-titration

ofzofenopril(30to

60mg)

andirbesartan

(150–3

00mg)

plus

HCTZ

12.5mgafter8weeks

and

withdrawalifnot

norm

alized

after16

weeks

Zofenopril30

mgor

irbesartan

150mg(plus

HCTZ12.5mg)

up-titratedto

high

dose(60

and300mg)

after6and

12weeks

innon-norm

alized

patients

(plusadd-on

therapywith

nitrendipine

20mgin

non-respon

dersat

high

dose)

Extension

phase

14weeks

ofopen-label

follow-upin

patientstaking

high

dose

treatm

entat

study

end

30weeks

ofdouble-blin

dfollow-upin

patientstaking

high

dose

treatm

entat

studyend

None

None

Prim

aryefficacy

parameter

Office

DBPchangesafter

18weeks

Office

BPresponse

(\140/

90mmHgnon-diabetics,

\130/80

mmHgdiabetics,

orSB

P/DBPreduction

C20/C

10mmHg)

after

18weeks

Office

DBPchangesafter

24weeks

Meandaytim

eSB

Pchanges

after6-weeks

Second

aryefficacy

parameters

ABPM

,hs-CRP

Targetorgandamage

progression(cardiac,

vascular,and

renal),A

BPM

ABPM

,metabolic

parameters,renalfunction

Office

BP,

renalfunction,

arterialstiffness(PWVand

AIx)andcentralBP

786 Adv Ther (2017) 34:784–798

Table1

continued

ZODIA

Cstud

y[12]

ZENIT

Hstud

y[13]

ZAMESstud

y[14]

ZEUSstud

y[15]

Centers(n)

2734

4124

Countries

(n)

5(Europe)

1(Italy)

2(Europe)

3(Europe)

Typeof

treatm

ent

Zofenopril?

HCTZ

Irbesartan

?HCTZ

Zofenopril?

HCTZ

Irbesartan

?HCTZ

Zofenopril?

HCTZ

Irbesartan

?HCTZ

Zofenopril?

HCTZ

Irbesartan

?HCTZ

Num

berof

subjects

rand

omized

(n)

180

181

227

235

241

241

114

116

Num

berof

subjects

analyzed

(FAS)

(n)

175

178

213

221

231

235

107

109

Num

berof

subjects

subm

ittedto

ABPM

(n)

131

132

113

116

3534

107

109

Percentage

ofsubjects

underfulldrug

dose

(±add-on)(%

)

69.1

61.2

55.8

47.1

100.0

100.0

66.4

62.4

Meanage(years)

56±

1154

±11

56±

1156

±11

59±

1060

±9

73±

672

±6

Percentage

ofmales

(%)

64.0

55.6

58.2

54.3

55.0

51.1

55.1

56.0

Percentage

ofdiabetics(%

)19.4

16.3

10.8

10.4

100.0

100.0

36.4

33.9

Percentage

ofsubjects

withmultipleCV

risk

factorsor

(*)with

metabolicsynd

rome

81.7

72.5

92.5

92.3

46.8

(*)

40.0

(*)

80.4

(*)

66.0

(*)

Mainresults

Similarefficacyof

both

drugson

officeandam

bulatory

BP,

but

larger

effect

ofthezofenopril

combination

oninflammatory

markers(hs-CRP)

Rateof

officeandam

bulatory

BPresponse

andof

reductionin

cardiacand

renaldamagesimilar

betweenthetwotreatm

ent

groups,w

hereas

therate

ofcarotidplaque

regression

was

larger

underzofenopril

Treatmentwiththetwo-drug

combinationswas

associated

withcomparable

antihypertensive

and

metabolicresponse

The

daytim

eSB

Presponse

achieved

withthetwo

combination

swas

similar

andsustainedduring

the

study.Asm

allreductionin

arterialstiffnessandcentral

BPwas

also

observed

DBPdiastolic

bloodpressure,SB

Psystolic

bloodpressure,FA

Sfullanalysisset,CVcardiovascular,ABPM

ambulatory

bloodpressure

monitoring,hs-CRPhigh

sensitivityC

reactive

protein,

PWVpulse

wavevelocity,A

Ixaugm

entation

Index,BPbloodpressure

Adv Ther (2017) 34:784–798 787

patients included in each individual study andthe main patient features are reported inTable 1. In total, 1535 hypertensives wererecruited in 126 centers in six European coun-tries (Italy, Greece, Lithuania, Romania, Turkey,and Russia). Both drugs had a similar efficacy onoffice and ambulatory BP but some differencesbetween the study medications could beobserved for secondary efficacy endpoints. Inthe ZODIAC study, treatment with the zofeno-pril combination was associated with a larger(p = 0.001) reduction of hs-CRP (-0.52 mg/dL)than irbesartan (?0.97 mg/dL, p = 0.001), sug-gesting a potential protective effect againstvascular inflammation, a well-known promoterof atherosclerosis at all its stages, from theendothelial cell dysfunction to the culminationin acute coronary syndrome [16, 17]. In theZENITH study, both treatments had a similarpositive effect on regression of cardiac and renaldamage, whereas a larger proportion of patientsshowing carotid plaque regression was observedunder zofenopril (31.6% vs. 16.1%; p = 0.047),particularly in the subgroup of patients takingthe low dose of zofenopril (30 mg) plus HCTZ12.5 mg (4.7% vs 10.0% irbesartan 150 mg plusHCTZ 12.5 mg; p = 0.043). These findings fur-ther confirmed the potent antiatheroscleroticeffects of RAAS blockade and in particular ofzofenopril, which are mediated by its antihy-pertensive, anti-inflammatory, antiproliferative,and oxidative stress-lowering properties[18, 19]. In the ZAMES study, metabolicparameters and renal function were not alteredby treatments, except for albumin-to-creatinineratio (ACR), whose reduction with treatmentwas larger under irbesartan combined with thethiazide diuretics (-24.2 vs. -9.9 mg/g withzofenopril; p = 0.027). The metabolic neutralityof treatment documented in this large study isan important finding, given the relevant notionthat thiazide diuretics may induce metabolicabnormalities and that patients with metabolicsyndrome may be particularly susceptible tosuch effects [20]. Finally, in a subgroup of 93elderly hypertensive patients of the ZEUS study,treatment with zofenopril or irbesartan wasassociated with small reductions in central SBPand arterial stiffness indices (pulse wave veloc-ity or PWV and augmentation index or AI),

which were similar between the two study drugsat any time point of the study, including thefirst 6 weeks when all patients were treated withthe lowest dose of zofenopril or irbesartancombined with the thiazide diuretic. Thoughsuch improvements were not striking as a resultof the limited vascular impairments of thepatients, they are relevant, because arterialstiffness represents a late manifestation ofincrease elastic arterial stiffness [21], andbecause they are consistent with those observedin previous randomized studies with the sameclasses of antihypertensive agents [22–24].

Given these premises, in the next sections ofthis review we will briefly summarize and dis-cuss other results of the ‘‘Z’’ studies, which werenot presented in the original publications.These include outcomes based on low dosetreatment of both study medications, pooledindividual analysis of ABPM data and of safetydata. This article is based on previously con-ducted studies and does not involve any newstudies of human or animal subjects performedby any of the authors.

EFFICACY IN LOW DOSESUBGROUP

As expected on the basis of the study design andobjectives, most of the patients enrolled in the‘‘Z’’ studies took the high dose of zofenopril(75%) and the high dose of irbesartan (69%).

In three of the four ‘‘Z’’ studies, the efficacyof low dose zofenopril combination (30 mg)and low dose irbesartan combination (150 mg)was also assessed: this subanalysis was com-pelling because the zofenopril 30 mg plus HCTZ12.5 mg combination is at present the onlymarketed fixed-drug combination of zofenoprilwith a thiazide diuretic. Average office BPchanges with treatment under the low drugdoses in these studies are shown in Fig. 1. Nopatients were under low dose drug treatment atstudy end in the ZAMES study because onlypatients forcedly up-titrated to the high dosewere kept in that study.

In the ZODIAC study at the end of the18 weeks, office sitting DBP reductions weresignificantly larger (p = 0.022) with zofenopril

788 Adv Ther (2017) 34:784–798

30 mg plus HCTZ [n = 55; 19.8 (22.8, 16.8)mmHg] than with irbesartan 150 mg plus HCTZ[n = 69; 14.5 (17.9, 11.1) mmHg], whereas theywere similar for SBP [zofenopril: 25.8 (30.5,21.2) mmHg vs. irbesartan: 22.0 (27.1, 16.8)mmHg; p = 0.274] [25]. In the patients of theZENITH study taking the low drug doses atstudy end (n = 223), the proportion of respon-ders did not differ (p = 0.693) between zofeno-pril (76.4%) and irbesartan (78.9%), as well asthe office SBP and DBP reductions (Fig. 1) [13].Also in the subgroup of patients with moder-ate–severe hypertension (office BP C160 mmHgand DBP C100 mmHg) taking the lowest doseduring the study, the zofenopril combinationwas associated with an antihypertensiveresponse similar to that of the irbesartan com-bination (88.9% vs. 80.0%; p = 0.596).

In the patients of the ZEUS study maintain-ing the low drug doses throughout the study(n = 77), the magnitude of the daytime BPlowering was always slightly larger underzofenopril 30 mg plus HCTZ 12.5 mg thanunder irbesartan 150 mg plus HCTZ 12.5 mg[14]. In this study subgroup, a statistically

significant (p = 0.028) difference in favor ofzofenopril-treated patients was achieved atstudy end [16.2 (20.0, 12.5) mmHg vs. 11.2(14.4, 7.9) mmHg irbesartan-treated patients].For the low dose subgroup also the percentageof patients showing daytime SBP normalization(\135 mmHg) and daytime SBP response (SBP\135 mmHg or reduction C10 mmHg) at studyend was significantly larger under zofenopril(88.9% and 91.7%) than under irbesartan(73.2% and 78.0%; p = 0.017 and p = 0.024,respectively).

The high rate of BP control and the goodBP-lowering effect observed in the ‘‘Z’’ studieswith both RAAS antagonists at the lowest dosageconfirm recommendations of current guidelineswhich indicate a two-drug lowdose combinationof an ACE inhibitor or an ARB and a thiazidediuretic as a reasonable alternative to high dosemonotherapy in patients previously classified asnon-responders to monotherapy [6, 7]. It alsostrengthens the evidence from previous largerandomized studies in patients with mild–mod-erate hypertension, in which treatment with thelow dose of zofenopril (30 mg) combined with

-25.8

-19.8

-22.0

-14.5

-35

-30

-25

-20

-15

-10

-5SBP DBP

∆ 81

retfaP

Beciff

O-w

(mm

Hg)

Zofenopril + HCTZIrbesartan + HCTZ

ZODIAC (n=124)

-19.5

-12.7

-22.5

-15.2

-35

-30

-25

-20

-15

-10

-5SBP DBP

∆ O

ffice

BP

afte

r 18-

w (m

mH

g)

ZENITH (n=223)

-15.2-16.6 -16.2

-13.7 -12.9-11.2

-22

-18

-14

-10

-6

-2

6 weeks 12 weeks 18 weeks

ΔD

ay-ti

me

SB

P (m

mH

g)

ZEUS (n=77)

p<0.05

p<0.05

A B C

Fig. 1 Mean changes (D) with treatment (and 95%confidence interval) in office systolic blood pressure(SBP) and diastolic blood pressure (DBP) in the ZODIAC(a) and ZENITH study (b), and mean daytime SBP

changes in the ZEUS study (c), in the subgroup of patientsreceiving the low drug doses during the study. The p valuesrefer to the statistical significance of the between-treatmentdifference

Adv Ther (2017) 34:784–798 789

HCTZ 12.5 mg once-daily showed a greater effi-cacy than the monotherapy with either agent,with an increase in the response rate up to55–65% [26, 27].

EFFICACY OVER 24H

As detailed in the publications of the individual‘‘Z’’ studies, the good office BP control obtainedwith zofenopril and irbesartan was confirmedover 24 h by ABPM, which was available for53% of patients included in primary endpointanalysis. In order to better assess the antihy-pertensive effect of the drugs over 24 h, wepooled individual ABPM data of the ZODIAC,ZENITH, and ZAMES studies, namely the ‘‘Z’’studies with similar inclusion criteria (the ZEUSstudy included only isolated systolic hyperten-sion or ISH patients, and selection of patientsfor study entry was based not only on office butalso on ambulatory BP). In the 561 patients ofthe pooled ABPM data analysis, the 24-h anti-hypertensive effect was similar between the twodrugs, regardless of the dose employed: 24-hSBP was reduced by 7.6 (9.5, 5.7) mmHg underzofenopril and by 9.5 (11.2, 7.7) mmHg underirbesartan (p = 0.155), whereas DBP dropped by5.5 (6.6, 4.4) mmHg and by 6.6 (7.6, 5.5) mmHg(p = 0.170).

As shown in Fig. 2a, both drugs displayed asimilarly smooth and long-lasting antihyper-tensive effect, with similar smoothness indicesfor SBP [zofenopril: 0.57 (0.41, 0.73) vs. irbe-sartan: 0.76 (0.61, 0.91); p = 0.100] and DBP[0.50 (0.36, 0.63) vs. 0.61 (0.49, 0.74);p = 0.217]. Interestingly, the magnitude of the24-h BP reduction yielded by zofenopril andirbesartan in the ‘‘Z’’ studies was comparablewith that observed in previous studies based onABPM and making use of the same doses of thetwo drug combinations [28, 29].

The BP-lowering effect of the two testeddrugs was also similar in the low (n = 157, 28%of patients) and the high drug dose (n = 404;72%) subgroup, either over 24 h or in the last6 h from the last drug intake: in this subperiodthe BP reduction was still comparable betweenzofenopril and irbesartan and corresponded to75–85% of the overall 24-h effect (Fig. 3).

In the low drug dose subgroup BP waseffectively reduced both under zofenopril(30 mg) and irbesartan (150 mg) plus HCTZ12.5 mg for each hour of the 24 h (Fig. 2b).Twenty-four hour BP was also similarly reducedin subgroups of high risk patients such as males,aged persons (C55 years for males and C65 yearsfor females), smokers and alcohol drinkers,patients with diabetes or impaired fasting glu-cose, patients with a high or very high cardio-vascular risk, and patients with sustainedhypertension (namely those simultaneouslydisplaying elevated office and 24-h BP)(Table 2).

LONG-TERM EFFICACYOF THE COMBINATIONS

In the ZODIAC and ZENITH studies long-termfollow-up of patients treated with high dosecombination at study end was planned in orderto collect more information on study drug effi-cacy and safety. Both drugs ensured a consistentefficacy, together with a good tolerability (seenext section), also in the long-term follow-upobservation.

In the ZODIAC study at the end of the18 weeks of double-blind treatment, 229 patientsamong those receiving high dose combinationtreatment entered anopen-label extensionphaseandwere followed up for an additional 14 weeks.As shown in the upper panel of Fig. 4, both SBPandDBP reductionswerewellmaintained duringlong-term treatment and did not differ betweenthe two study arms.

In the 223 patients of the ZENITH studyreceiving drug dose up-titration at the end ofthe 18 weeks of treatment and continuing thedouble-blind treatment for additional 30 weeks,no difference was observed in office BP responsebetween the two treatment groups (28.6%zofenopril vs. 22.1% irbesartan; p = 0.178) [13].As shown in Fig. 4, in these patients, office and24-h BPs were similarly reduced under zofeno-pril and irbesartan combinations either at theend of the 18 weeks or at the end of the exten-sion phase. Likewise, the impact of treatmenton organ damage did not significantly differbetween the two study drugs.

790 Adv Ther (2017) 34:784–798

TOLERABILITY OF BOTH DRUGCOMBINATIONS

The overall tolerability profile of zofenopril andirbesartan in the ‘‘Z’’ studies was good andcomparable with that in previous reports

[26, 30]. The safety population consisted of1535 patients, of which 762 received thezofenopril and 773 the irbesartan combination(Table 3). Both drugs were well tolerated, with avery limited number of adverse events, whichwere well balanced between the two study arms

Fig. 2 Average hourly systolic blood pressure (SBP) anddiastolic blood pressure (DBP) values at baseline (B, dashedline) and at the end of the double-blind treatment (T,continuous line) in patients treated with zofenopril30–60 mg plus hydrochlorothiazide (HCTZ) 12.5 mg orirbesartan 150–300 mg plus hydrochlorothiazide 12.5 mg

in the whole 561 patients of the ZODIAC, ZENITH, andZAMES studies (a) and in those treated with the lowestdose of zofenopril (30 mg) or irbesartan (150 mg) (b) andwith a valid ambulatory blood pressure monitoring(ABPM)

Adv Ther (2017) 34:784–798 791

(25.2% of patients receiving zofenopril and21.9% receiving irbesartan; p = 0.715). Thepercentage of drug-related adverse events wasmuch smaller than that of overall adverseevents and still homogeneously distributedbetween the two groups (9.4% zofenopril vs.6.2% irbesartan; p = 0.273). In total, only 66patients (4.3%) were withdrawn from the stud-ies because of an adverse event, 38 in thezofenopril (4.9%) and 28 in the irbesartantreatment group (3.6%; p = 0.593). The mostcommon drug-related adverse event observedunder zofenopril was cough (1.8% of patients),whereas dizziness was the most prevalent drugadverse reaction in irbesartan-treated patients(1.4%). All these side effects could be expectedwith these classes of drugs. Interestingly, theprevalence of cough with zofenopril in the ‘‘Z’’studies (1.8%) was very close to that observed inprevious double-blind or open-label post-mar-keting studies including 5794 hypertensivepatients (2.4%) [31]. The relatively low inci-dence of cough in patients receiving zofenoprilmight be related to its limited ACE inhibitorpotency at the lung level, responsible for a lesseraccumulation of bradykinin and a reducedsynthesis of prostaglandins in this tissue, asfound in some experimental and animal studies[31].

In the ZODIAC and ZENITH studies safetywas also evaluated during a long-term follow-upunder high drug dose. In the ZODIAC study,6.3% of zofenopril-treated patients and 1.9% ofirbesartan-treated patients reported a drug-re-lated adverse event (p = 0.172) during the pro-longed follow-up. No patients treated withirbesartan were withdrawn from the study dur-ing the extension phase, whereas five patients(4.5%) dropped out in the zofenopril group(p = 0.060). In the extension phase of theZENITH study, 12.3% of patients under highdose zofenopril plus HCTZ and 11.4% underhigh dose irbesartan plus HCTZ reported anadverse event (p = 0.843). Treatment-relatedadverse events occurred in 3.8% and 3.5%of patients under the two study drugs(p = 0.859); of these patients four were defi-nitely withdrawn from the extension phase(three taking zofenopril vs. one taking irbesar-tan; p = 0.368) [13].

LIMITATIONS OF THIS REVIEW

A major limitation of this review is that itreports mixed information from previous orig-inal publications and from new pooled data orsubgroup analyses, particularly those based on

Pooled ABPM analysis (n=561)

-5.2

-6.3

-4.0

-4.5-5.7

-7.1

-3.9

-6.0

-12

-10

-8

-6

-4

-2

0

24-hhigh dose

24-hlow dose

Last 6-hhigh dose

Last 6-hlow dose

∆ A

mbu

lato

ry D

BP

(mm

Hg)

-7.3-8.1

-5.4

-6.3-7.9-8.9

-6.4

-8.4

-16

-12

-8

-4

0

24-hhigh dose

24-hlow dose

Last 6-hhigh dose

Last 6-hlow dose

∆ P

BS

yrotalubm

A(m

mH

g)

Zofenopril + HCTZIrbesartan + HCTZ

Fig. 3 24-h and last 6-h average systolic (SBP) anddiastolic blood pressure (DBP) reductions (D) withtreatment (and 95% confidence interval) in the 561patients of the ZODIAC, ZENITH, and ZAMES studies

with a valid ambulatory blood pressure monitoring(ABPM). Data are shown for the two subgroups receivinglow or high dose treatment at study end

792 Adv Ther (2017) 34:784–798

Table2

Adjustedmeanchanges(and

95%confi

denceintervals)for24-h

systolicbloodpressure

(SBP)

anddiastolic

bloodpressure

(DBP)

inpatientstreatedwith

thelowdoseof

zofenopril(30mg)plus

hydrochlorothiazide(H

CTZ)or

lowdoseof

irbesartan

(150

mg)plus

HCTZaccordingto

gend

er,age

atrisk

(age

C55

years

inmales

andageC65

yearsin

females),sm

okingandalcohold

rinking,diabetes,h

ighor

very

high

cardiovascular

risk,and

sustainedhypertension

(bothofficeand

24-h

BPelevated)

24-h

SBPchanges(m

mHg)

24-h

DBPchanges(m

mHg)

Zofenop

ril

30mg1

HCTZ

12.5

mg

Irbesartan

150mg1

HCTZ

12.5

mg

pvalue

Zofenop

ril

30mg1

HCTZ

12.5mg

Irbesartan

150mg1

HCTZ

12.5mg

pvalue

Males

(n=

44/38)

-10.3

(-13.2/-

7.4)

-9.5(-

13.6/-

5.4)

0.752

-7.8(-

10.2/-

5.5)

-7.7(-

11.1/-

4.2)

0.935

Age

atrisk

(n=

29/21)

-11.6

(-16.3/-

7.0)

-9.0(-

16.2/-

1.9)

0.550

-5.9(-

9.1/-2.7)

-6.7(-

11.6/-

1.9)

0.775

Smokers(n

=30/31)

-9.4(-

13.5/-

5.3)

-8.1(-

13.6/-

2.6)

0.708

-8.1(-

11.2/-

5.1)

-5.7(-

9.8/-1.6)

0.354

Alcohol

drinkers(n

=22/35)

-8.7(-

13.1/-

4.4)

-6.2(-

11.9/-

0.5)

0.507

-5.4(-

7.8/-3.0)

-7.4(-

10.4/-

4.4)

0.326

Diabetesor

impaired

fasting

glucose(n

=21/25)

-13.7

(-18.0/-

9.4)

-10.6

(-15.1/-

6.1)

0.336

-8.8(-

11.8/-

5.7)

-6.4(-

9.6/-3.2)

0.305

Highor

very

high

cardiovascular

risk

(n=

30/22)

-10.7

(-14.2/-

7.1)

-12.6

(-17.9/-

7.3)

0.549

-7.1(-

9.5/-4.8)

-5.6(-

9.1/-2.2)

0.470

Sustainedhypertension

(n=

49/

63)

-11.5

(-16.0/-

7.0)

-11.6

(-14.8/-

8.3)

0.978

-9.2(-

12.7/-

5.7)

-9.0(-

11.5/-

6.4)

0.937

pvalues

forbetween-treatm

entdifference

arealso

reported

Adv Ther (2017) 34:784–798 793

ABPM data. For this reason, it may be arguedthat it cannot be classified either as a review oran original paper. Indeed, in our review webriefly summarized the main results of thesingle studies, which helped introduce thereader to the secondary results which wereavailable at the time of the original publica-tions, but which were only outlined or evenomitted for reasons of space. The currentreview gave us the possibility to add thisinformation in order to provide a comprehen-sive presentation of all the available data of the‘‘Z’’ studies. We think that this review may helpcomplete the large amount of informationderiving from the ‘‘Z’’ studies, which standamongst the largest double-blind randomizedstudies comparing the effect of an ACE inhi-bitor and an ARB in hypertensive patients withmultiple risk factors not controlled by a pre-vious monotherapy.

CONCLUSIONS

In all the ‘‘Z’’ studies the combination betweenzofenopril and HCTZ was always similarlyeffective as that of irbesartan plus HCTZ, and itperformed well either at the lowest dose(30 mg), which is the currently marketed one,or at the highest (60 mg) dose. Zofenopril alsoshowed some ancillary features which suggestthat the fixed combination of this drug withHCTZ may have a particular place in the treat-ment of high-risk or monotherapy-treateduncontrolled hypertensive patients requiring amore prompt, intensive, and sustained BPreduction, in line with the recommendations ofcurrent guidelines [6, 7]. The effective BPreduction and the large proportion of respon-ders in both treatment arms in the ‘‘Z’’ studiesalso support the findings of previous studiesthat, in most patients not responding to a single

First phase ZENITH study (18-w) Extension phase ZENITH study (30-w)

-17.8

-11.7-7.6

-4.5

-21.2

-12.9

-7.2-5.9

-30

-25

-20

-15

-10

-5

0

OfficeSBP

OfficeDBP

24-hSBP

24-hDBP

∆ B

P 30

-w -

base

line

(mm

Hg)

-15.7

-8.6-6.4

-3.6

-19.3

-11.6 -9.2-7.0

-30

-25

-20

-15

-10

-5

0

OfficeSBP

OfficeDBP

24-hSBP

24-hDBP

∆ B

P 18

-w –

base

line

(mm

Hg)

Zofenopril 30-60 mg + HCTZ 12.5 mgIrbesartan 150-300 mg + HCTZ 12.5 mg

Office BP in the high-dose subgroup of the ZODIAC study (18-w + 14-w) (n=229)

65

85

105

125

145

165

0 6 12 18 25 32

Offi

ce B

P (m

mH

g)

weeks

Zofenopril + HCTZ Irbesartan + HCTZ

SBP

DBP

A

B

Fig. 4 Average office systolic (SBP) and diastolic bloodpressure (DBP) (±SD) in the whole 32 weeks of theZODIAC study, for patients treated with high dosezofenopril or irbesartan combination (a). Office and 24-h

SBP and DBP reductions (D) in the 48 weeks of treatment(and 95% confidence interval) in the high dose subgroupof the ZENITH study are reported in b

794 Adv Ther (2017) 34:784–798

Table3

Safety

profileof

thecombination

betweenzofenoprilandhydrochlorothiazide(H

CTZ)andirbesartan

plus

HCTZ

ZODIA

Cstud

y[12]

ZENIT

Hstud

y[13]

ZAMESstud

y[14]

ZEUSstud

y[15]

Allstud

ies

Zofenop

ril1

HCTZ

Irbesartan

1

HCTZ

Zofenop

ril1

HCTZ

Irbesartan

1

HCTZ

Zofenop

ril1

HCTZ

Irbesartan

1

HCTZ

Zofenop

ril1

HCTZ

Irbesartan

1

HCTZ

Zofenop

ril1

HCTZ

Irbesartan

1

HCTZ

Num

berof

patientsin

the

safety

analysis

(n)

180

181

227

235

241

241

114

116

762

773

Percentage

ofpatientswith

AEs(%

)

26.7

22.1

16.3

10.6

31.5

25.3

27.2

37.4

25.2

21.9

Percentage

ofpatientswith

drug-related

AEs(%

)

7.8

6.6

7.5

3.0

14.9

9.1

4.4

6.0

9.4

6.2

Percentage

ofpatients

withdrawnfor

AE(%

)

0.2

0.2

6.1

1.7

5.0

5.0

7.0

8.0

4.9

3.6

AEadverseevent

Adv Ther (2017) 34:784–798 795

antihypertensive medication, combinationtreatment with two drugs may substantiallyincrease the chance of response [32, 33]. Vas-cular protection afforded by the sulfhydryl ACEinhibitor zofenopril may be related to its directantiatherogenic effects [19, 34, 35], bothreduction of systemic oxidative stress[17, 19, 34–38] and nitric oxide deficiency[17, 19, 38, 39], and enhancement of circulatingendothelial progenitor cells [36] together withimproved vascular function [40, 41].

In conclusion, results of the large ‘‘Z’’ studiesconfirm that combination treatment between adrug acting on the RAAS and a thiazide diureticshould be among the preferred choices whenmonotherapies fail to lower BP to or below tar-get levels, particularly in patients displayingmultiple CV risk factors.

ACKNOWLEDGEMENTS

The ‘‘Z’’ studies were financially supported byMenarini International Operations Luxem-bourg S.A., through an unconditional andunrestricted grant. Article processing chargesand open access fee for the present paper werefunded by Menarini International OperationsLuxembourg S.A. Concerning the currentreview paper, the funding source did notinfluence or comment on planned methods,protocol, data analysis, and interpretation ofthe results, preparation, review, or approval ofthe manuscript, and decision to submit themanuscript for publication. All named authorsmeet the International Committee of MedicalJournal Editors (ICMJE) criteria for authorshipfor this manuscript, take responsibility for theintegrity of the work as a whole, and havegiven final approval to the version to bepublished.

Disclosures. Stefano Omboni has receivedhonorarium from Menarini International formanuscript preparation. Ettore Malacco hasoccasionally received grants for lectures or forscientific meeting attendance from MenariniInternational. Claudio Napoli has occasionallyreceived grants for lectures or for scientific

meeting attendance from Menarini Interna-tional. Pietro Amedeo Modesti has occasionallyreceived grants for lectures or for scientificmeeting attendance from Menarini Interna-tional. Athanasios Manolis has occasionallyreceived grants for lectures or for scientificmeeting attendance from Menarini Interna-tional. Gianfranco Parati has occasionallyreceived grants for lectures or for scientificmeeting attendance from Menarini Interna-tional. Enrico Agabiti-Rosei has occasionallyreceived grants for lectures or for scientificmeeting attendance from Menarini Interna-tional. Claudio Borghi has occasionally receivedgrants for lectures or for scientific meetingattendance from Menarini International.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesanddoesnot involve anynewstudiesof humanoranimal subjects performed by any of the authors.

Data Availability. The datasets generatedduring and/or analyzed during the currentstudy are not publicly available because they areproperty of the sponsor of the studies, MenariniInternational Operations Luxembourg S.A., butthey are available from the correspondingauthor on reasonable request.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

REFERENCES

1. Bakris G, Sarafidis P, Agarwal R, Ruilope L. Reviewof blood pressure control rates and outcomes. J AmSoc Hypertens. 2014;8:127–41.

2. Gorostidi M, de la Sierra A. Combination therapy inhypertension. Adv Ther. 2013;30:320–36.

796 Adv Ther (2017) 34:784–798

3. Thomopoulos C, Parati G, Zanchetti A. Effects ofblood pressure lowering on outcome incidence inhypertension: 3. Effects in patients at differentlevels of cardiovascular risk–overview andmeta-analyses of randomized trials. J Hypertens.2014;32:2305–14.

4. Collaboration Blood Pressure Lowering TreatmentTrialists’ Collaboration, Sundstrom J, Arima H, et al.Blood pressure-lowering treatment based on car-diovascular risk: a meta-analysis of individualpatient data. Lancet. 2014;384:591–8.

5. Piepoli MF, Hoes AW, Agewall S, et al. 2016 Euro-pean Guidelines on cardiovascular disease preven-tion in clinical practice: The Sixth Joint Task Forceof the European Society of Cardiology and OtherSocieties on Cardiovascular Disease Prevention inClinical Practice (constituted by representatives of10 societies and by invited experts): Developed withthe special contribution of the European Associa-tion for Cardiovascular Prevention and Rehabilita-tion (EACPR). Eur J Prev Cardiol.2016;23:NP1–NP96.

6. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC practice guidelines for the management ofarterial hypertension. Blood Press. 2014;23:3–16.

7. Weber MA, Schiffrin EL, White WB, et al. Clinicalpractice guidelines for the management of hyper-tension in the community: a statement by theAmerican Society of Hypertension and the Inter-national Society of Hypertension. J Clin Hypertens(Greenwich). 2014;16:14–26.

8. Kjeldsen S, Feldman RD, Lisheng L, et al. Updatednational and international hypertension guideli-nes: a review of current recommendations. Drugs.2014;74:2033–51.

9. Mercier K, Smith H, Biederman J. Renin-an-giotensin-aldosterone system inhibition: overviewof the therapeutic use of angiotensin-convertingenzyme inhibitors, angiotensin receptor blockers,mineralocorticoid receptor antagonists, and directrenin inhibitors. Prim Care. 2014;41:765–78.

10. Schmieder RE. The role of fixed-dose combinationtherapy with drugs that target the renin-an-giotensin system in the hypertension paradigm.Clin Exp Hypertens. 2010;32:35–42.

11. Waeber B, Feihl F, Ruilope LM. Fixed-dose combi-nations as initial therapy for hypertension: a reviewof approved agents and a guide to patient selection.Drugs. 2009;69:1761–76.

12. Agabiti-Rosei E, Manolis A, Zava D, Omboni S,ZODIAC Study Group. Zofenopril plushydrochlorothiazide and irbesartan plushydrochlorothiazide in previously treated and

uncontrolled diabetic and non-diabetic essentialhypertensive patients. Adv Ther. 2014;31:217–33.

13. Malacco E, Omboni S, Parati G. Blood pressureresponse to zofenopril or irbesartan each combinedwith hydrochlorothiazide in high-risk hyperten-sives uncontrolled by monotherapy: a randomized,double-blind, controlled, parallel group, noninferi-ority trial. Int J Hypertens. 2015;2015:139465.

14. Modesti PA, Omboni S, Taddei S, et al. Zofenopril orirbesartan plus hydrochlorothiazide in elderly patientswith isolated systolic hypertension untreated oruncontrolled by previous treatment: a double-blind,randomized study. J Hypertens. 2016;34:576–87.

15. Napoli C, Omboni S, Borghi C. Fixed-dose combi-nation of zofenopril plus hydrochlorothiazide vs.irbesartan plus hydrochlorothiazide in hyperten-sive patients with established metabolic syndromeuncontrolled by previous monotherapy. TheZAMES study. J Hypertens. 2016;34:2287–97.

16. Devaraj S, Singh U, Jialal I. The evolving role ofC-reactive protein in atherothrombosis. Clin Chem.2009;55:229–38.

17. Napoli C, Sica V, de Nigris F, et al. Sulfhydrylangiotensin-converting enzyme inhibition inducessustained reduction of systemic oxidative stress andimproves the nitric oxide pathway in patients withessential hypertension. Am Heart J. 2004;148:e5.

18. Schmieder RE, Hilgers KF, Schlaich MP, SchmidtBM. Renin-angiotensin system and cardiovascularrisk. Lancet. 2007;369:1208–19.

19. Napoli C, Bruzzese G, Ignarro LJ, et al. Long-termtreatment with sulfhydryl angiotensin-convertingenzyme inhibition reduces carotid intima-mediathickening and improves the nitric oxide/oxidativestress pathways in newly diagnosed patients withmild to moderate primary hypertension. Am HeartJ. 2008;156(1154):e1–8.

20. Musini VM, Nazer M, Bassett K, Wright JM. Bloodpressure-lowering efficacy of monotherapy withthiazide diuretics for primary hypertension.Cochrane Database Syst Rev. 2014;(5):CD003824.

21. McEniery CM, Wilkinson IB, Avolio AP. Age,hypertension and arterial function. Clin Exp Phar-macol Physiol. 2007;34:665–71.

22. Ong KT, Delerme S, Pannier B, et al. Aortic stiffnessis reduced beyond blood pressure lowering byshort-term and long-term antihypertensive treat-ment: a meta-analysis of individual data in 294patients. J Hypertens. 2011;29:1034–42.

23. Manisty CH, Hughes AD. Meta-analysis of thecomparative effects of different classes of

Adv Ther (2017) 34:784–798 797

antihypertensive agents on brachial and centralsystolic blood pressure, and augmentation index. BrJ Clin Pharmacol. 2013;75:79–92.

24. Omboni S. Do arterial stiffness and wave reflectionsimprove more with angiotensin receptor blockersthan with other antihypertensive drug classes?J Thorac Dis. 2016;8:1417–20.

25. Borghi C, Omboni S. Zofenopril plushydrochlorothiazide combination in the treatmentof hypertension: an update. Expert Rev CardiovascTher. 2014;12:1055–65.

26. Omboni S, Malacco E, Parati G. Zofenopril plushydrochlorothiazide fixed combination in thetreatment of hypertension and associated clinicalconditions. Cardiovasc Ther. 2009;27:275–88.

27. Zanchetti A, Parati G, Malacco E. Zofenopril plushydrochlorothiazide: combination therapy for thetreatment of mild to moderate hypertension.Drugs. 2006;66:1107–15.

28. Parati G, Omboni S, Malacco E. Antihypertensiveefficacy of zofenopril and hydrochlorothiazidecombination on ambulatory blood pressure. BloodPress. 2006;15(suppl. 1):7–17.

29. Neutel JM, Smith D. Ambulatory blood pressurecomparison of the anti-hypertensive efficacy offixed combinations of irbesartan/hydrochloroth-iazide and losartan/hydrochlorothiazide in patientswith mild-to-moderate hypertension. J Int Med Res.2005;33:620–31.

30. Bramlage P. Fixed combination of irbesartan andhydrochlorothiazide in the management of hyper-tension. Vasc Health Risk Manag. 2009;5:213–24.

31. Omboni S, Borghi C. Zofenopril and incidence ofcough: a review of published and unpublished data.Ther Clin Risk Manag. 2011;7:459–71.

32. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ.Combination therapy versus monotherapy in reduc-ing blood pressure: meta-analysis on 11,000 partici-pants from 42 trials. Am J Med. 2009;122:290–300.

33. Law MR, Wald NJ, Morris JK, Jordan RE. Value oflow dose combination treatment with blood

pressure lowering drugs: analysis of 354 randomisedtrials. BMJ. 2003;326:1427.

34. Napoli C, Cicala C, D’Armiento FP, et al. Beneficialeffects of ACE-inhibition with zofenopril on plaqueformation and low-density lipoprotein oxidation inwatanabe heritable hyperlipidemic rabbits. GenPharmacol. 1999;33:467–77.

35. de Nigris F, D’Armiento FP, Somma P, et al. Chronictreatment with sulfhydryl angiotensin-convertingenzyme inhibitors reduce susceptibility of plasmaLDL to in vitro oxidation, formation of oxida-tion-specific epitopes in the arterial wall, andatherogenesis in apolipoprotein E knockout mice.Int J Cardiol. 2001;81:107–15.

36. Cacciatore F, Bruzzese G, Vitale DF, et al. Effects ofACE inhibition on circulating endothelial progeni-tor cells, vascular damage, and oxidative stress inhypertensive patients. Eur J Clin Pharmacol.2011;67:877–83.

37. Sacco G, Mario B, Lopez G, Evangelista S, Manzini S,Maggi CA. ACE inhibition and protection fromdoxorubicin-induced cardiotoxicity in the rat.Vascul Pharmacol. 2009;50:166–70.

38. Scribner AW, Loscalzo J, Napoli C. The effect ofangiotensin-converting enzyme inhibition onendothelial function and oxidant stress. Eur JPharmacol. 2003;482:95–9.

39. Garcıa-Estan J, Ortiz MC, O’Valle F, et al. Effects ofangiotensin-converting-enzyme inhibitors in com-bination with diuretics on blood pressure and renalinjury in nitric oxide-deficiency-induced hyperten-sion in rats. Clin Sci (Lond). 2006;110:227–33.

40. Elijovich F, Laffer CL, Schiffrin EL. The effects ofatenolol and zofenopril on plasma atrial natriureticpeptide are due to their interactions with targetorgan damage of essential hypertensive patients.J Hum Hypertens. 1997;11:313–9.

41. Pasini AF, Garbin U, Nava MC, et al. Effect of sulf-hydryl and non-sulfhydryl angiotensin-convertingenzyme inhibitors on endothelial function inessential hypertensive patients. Am J Hypertens.2007;20:443–50.

798 Adv Ther (2017) 34:784–798