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Efficacy of Zofenopril Vs. Irbesartan in Combination with a Thiazide Diuretic in Hypertensive Patients with Multiple Risk Factor

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Efficacy of Zofenopril Vs. Irbesartan in Combination with a Thiazide Diuretic in Hypertensive Patients with Multiple Risk Factor Adv Ther DOI 10.1007/s12325-017-0497-8 REVIEW Efficacy of Zofenopril vs. Irbesartan in Combination with a Thiazide Diuretic in Hypertensive Patients with Multiple Risk Factors not Controlled by a Previous Monotherapy: A Review of the Double-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 Ó The Author(s) 2017. This article is published with open access at Springerlink.com ABSTRACT studies with a similar design, including 1469 hypertensive patients uncontrolled by a previ- Combinations between an angiotensin con- ous monotherapy and with C1 cardiovascular verting enzyme (ACE) inhibitor or an angio- risk factor, compared the efficacy of a combi- tensin II receptor blocker (ARB) and nation of a sulfhydryl ACE inhibitor (zofenopril hydrochlorothiazide (HCTZ) are among the at 30 or 60 mg) or an ARB (irbesartan at 150 or recommended treatments for hypertensive 300 mg) plus HCTZ 12.5 mg. The extent of patients uncontrolled by monotherapy. Four blood pressure (BP)-lowering was assessed in the randomized, double-blind, parallel group office and over 24 h. Pleiotropic features of the treatments were evaluated by studying their effect on systemic inflammation, organ damage, Enhanced content To view enhanced content for this arterial stiffness, and metabolic biochemical article go to http://www.medengine.com/Redeem/ 8097F06066FC0C29. parameters. Both treatments similarly reduced S. Omboni (&) A. Manolis Clinical Research Unit, Italian Institute of Asklepeion General Hospital of Voula, University of Telemedicine, Varese, Italy Athens, Athens, Greece e-mail: [email protected] G. Parati E. Malacco Department of Cardiovascular, Neural and L. Sacco Hospital, Milan, Italy Metabolic Sciences, Istituto Auxologico Italiano, Milan, Italy C. Napoli Department of Internal Medicine and Specialistic G. Parati Units, U.O.C. of Clinical Immunology, Department of Medicine and Surgery, University of Immunohematology, Transfusion Medicine and Milano-Bicocca, Milan, Italy Organ Transplantation, Azienda Ospedaliera Universitaria (AOU), Second University of Naples, E. Agabiti-Rosei Naples, Italy Division of Medicine and Surgery, Spedali Civili and University of Brescia, Brescia, Italy C. Napoli SDN Foundation and IRCCS, Naples, Italy C. Borghi Department of Internal Medicine, University of P. A. Modesti Bologna, Bologna, Italy Department of Clinical and Experimental Medicine, Careggi Hospital, University of Florence, Florence, Italy Adv Ther office and ambulatory BPs after 18–24 weeks. In the management of arterial hypertension the ZODIAC study a larger reduction in high acknowledge and recommend the use of com- sensitivity C reactive protein (hs-CRP) was bination treatment, particularly when BP con- observed under zofenopril (-0.52 vs. ?0.97 mg/ trol with initial monotherapy is inadequate dL under irbesartan, p = 0.001), suggesting a [5–8]. potential protective effect against the develop- Amongst the most effective two-drug anti- ment of atherosclerosis. In the ZENITH study hypertensive combinations are those between the rate of carotid plaque regression was signif- an antagonist of the renin–angiotensin–aldos- icantly larger under zofenopril (32% vs. 16%; terone system (RAAS), such as an angiotensin p = 0.047). In the diabetic patients of the converting enzyme (ACE) inhibitor or an ZAMES study, no adverse effects of treatments angiotensin II receptor blocker (ARB), and a on blood glucose and lipids as well as an thiazide diuretic. The mechanism of action of improvement of renal function were observed. such a combination implies a synergistic and In patients with isolated systolic hypertension opposite effect on the RAAS, in which the ACE of the ZEUS study, a slight and similar inhibitor or the ARB antagonize the coun- improvement in renal function and small ter-regulatory system activity triggered by the reductions in pulse wave velocity (PWV), aug- diuretic, thus improving the efficacy and toler- mentation index (AI), and central systolic BP ability of single drug components [9–11]. were documented with both treatments. Thus, Recently, we published four randomized, the fixed combination of zofenopril and HCTZ double-blind, parallel group, direct comparative may have a relevant place in the treatment of studies (also called ‘‘Z’’ studies, because of the high-risk or monotherapy-treated uncontrolled common initial of their acronyms: ZODIAC, hypertensive patients requiring a more prompt, ZENITH, ZAMES, and ZEUS) which were plan- intensive, and sustained BP reduction, in line ned to gain a deeper insight into the mecha- with the recommendations of current nisms of the antihypertensive effects of a guidelines. two-drug fixed combination between a RAAS antagonist and a thiazide diuretic [12–15]. In these non-inferiority trials, efficacy and safety Keywords: Ambulatory blood pressure; of the sulfhydryl ACE inhibitor zofenopril and Angiotensin converting enzyme inhibitors; of the ARB irbesartan both combined with Angiotensin II receptor blockers; Essential hydrochlorothiazide (HCTZ) 12.5 mg were tes- hypertension; Hydrochlorothiazide; Irbesartan; ted in hypertensive patients with one or more Office blood pressure; Thiazide diuretics; CV risk factors beyond hypertension (including Zofenopril diabetes, metabolic syndrome, and advanced age) and not responding to a previous monotherapy. In all studies, zofenopril and INTRODUCTION irbesartan were started at a dose of 30 and 150 mg, respectively, and were increased during Large intervention trials have shown that the the course of the follow-up to 60 and 300 mg, in majority of hypertensive patients may need a non-responders, in order to check the effec- combination of two or more antihypertensive tiveness and tolerability of a highest dose of the medications to achieve satisfactory blood pres- drugs. Efficacy was evaluated not only in the sure (BP) control and effective cardiovascular office but also over 24 h by ambulatory blood (CV) protection [1, 2]. This holds true particu- pressure monitoring (ABPM). In addition, larly for patients at high risk for CV events, such ancillary or pleiotropic features of the study as older individuals, patients with diabetes or drugs were evaluated by studying their effect on the metabolic syndrome, co-existing CV dis- inflammation, target organ damage, arterial ease, or other associated clinical conditions stiffness, and metabolic biochemical parameters [3, 4]. According to the evidence provided by (blood glucose and lipids). A summary of the major intervention trials, current guidelines for study designs and an overview of the number of Table 1 Overview of the study population, design, and main results of the studies based on zofenopril plus hydrochlorothiazide (HCTZ) or irbesartan plus HCTZ Adv Ther in hypertensive subjects (so-called Z studies) ZODIAC study [12] ZENITH study [13] ZAMES study [14] ZEUS study [15] Main inclusion criteria Office DBP C90 mmHg, Office SBP C140 and/or Office SBP C140 and/or Office SBP C140 and DBP uncontrolled by a previous C90 mmHg, uncontrolled C90 mmHg, uncontrolled \90 mmHg plus daytime monotherapy with C1CV by a previous monotherapy by a previous monotherapy, SBP C135 mmHg and risk factor with C1 CV risk factor with diabetes and C1CV daytime DBP \85 mmHg, risk factor for metabolic age C65 years, untreated or syndrome uncontrolled by B2 medications Study design 2 weeks of single-blind placebo 2 weeks of run-in under 2 weeks of run-in under 1-week single-blind run-in run-in, followed by 18 weeks current monotherapy, current monotherapy, under current treatment of double-blind treatment followed by 18 weeks of followed by 24 weeks of followed by 18 weeks of double-blind treatment double-blind treatment double-blind treatment Treatments Zofenopril 30 mg or irbesartan Zofenopril 30 mg or Forced up-titration of Zofenopril 30 mg or 150 mg (plus HCTZ irbesartan 150 mg (plus zofenopril (30 to 60 mg) irbesartan 150 mg (plus 12.5 mg) up-titrated to high HCTZ 12.5 mg) and irbesartan HCTZ 12.5 mg) dose (60 and 300 mg) after 6 up-titrated to high dose (60 (150–300 mg) plus HCTZ up-titrated to high dose (60 and 12 weeks in and 300 mg) after 6 and 12.5 mg after 8 weeks and and 300 mg) after 6 and non-normalized patients 12 weeks in withdrawal if not 12 weeks in (office DBP C90 mmHg) non-normalized patients normalized after 16 weeks non-normalized patients (office DBP C90 mmHg) (plus add-on therapy with nitrendipine 20 mg in non-responders at high dose) Extension phase 14 weeks of open-label 30 weeks of double-blind None None follow-up in patients taking follow-up in patients taking high dose treatment at study high dose treatment at end study end Primary efficacy Office DBP changes after Office BP response (\140/ Office DBP changes after Mean daytime SBP changes parameter 18 weeks 90 mmHg non-diabetics, 24 weeks after 6-weeks \130/80 mmHg diabetics, or SBP/DBP reduction C20/C10 mmHg) after 18 weeks Secondary efficacy ABPM, hs-CRP Target organ damage ABPM, metabolic Office BP, renal function, parameters progression (cardiac, parameters, renal function arterial stiffness (PWV and vascular, and renal), ABPM AIx) and central BP Table 1 continued ZODIAC study [12] ZENITH study [13] ZAMES study [14] ZEUS study [15] Centers (n)27344124 Countries (n) 5 (Europe) 1 (Italy) 2 (Europe) 3 (Europe) Type of treatment Zofenopril ? HCTZ Irbesartan ? Zofenopril ? Irbesartan ? Zofenopril ? Irbesartan ? Zofenopril ? Irbesartan ?
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