Reprinted from Chazova I.E., Martynyuk T.V., Rodnenkov O.V. et al. Implementation of the organoprotective properties of fixed combinations of valsartan, amlodipine and hydrochlorothiazide (Vamloset® and Co-Vamloset) in patients with grade 2 and 3 hypertension in the Russian clinical study VICTORY II. Systemic Hypertension. 2020; 17 (3): 59–70. DOI: 10.26442/2075082X.2020.3.200414. with permission from Consilium Medicum LLD, Moscow, Russian Federation. Под защитой авторских прав ООО «Консилиум Медикум», Moscow, Russian Federation. Первоначально статья опубликована Системные гипертензии (Systemic Hypertension) 17 (3): 59–70. Напечатано с разрешения «Консилиум Медикум», Moscow, Russian Federation.
In spite of optimization and simplification of arterial hypertension (AH) treatment, achieving blood pressure (BP) control is still challenging, with most patients requiring combination treatment to achieve target BP. Due to the multifactorial effect of AH, additional prevention of hypertension-mediated end-organ damage and the maintenance of vascular integrity achieved by antihypertensive medications in addition to the BP-lowering effect are beneficial for the optimal reduction of cardiovascular (CV) risk. The aim of VICTORY II, a multicenter, open, prospective clinical study with 100 patients included in the active phase was to assess the safety and the efficacy of single-pill combinations (SPC) of amlodipine/valsartan (Wamlox®) and amlodipine/valsartan/hydrochlorothiazide (Valtricom®) in naïve or previously treated but uncontrolled patients with grade 2 or 3 AH. All patients with grade 2 AH started the treatment with the SPC of amlodipine/valsartan 5 mg/80 mg, which if necessary could be up-titrated step by step to the final option – the SPC of amlodipine/valsartan/hydrochlorothiazide 10/160/12.5 mg to achieve the target levels of BP. Patients with grade 3 AH started the treatment with the SPC of amlodipine/valsartan 5 mg/160 mg, which could be up-titrated step-by-step to the SPC of amlodipine/valsartan/hydrochlorothiazide 10/160/25 mg if necessary to achieve the target levels of BP. In addition to achieving the target office BP in 90% of the patients after 16 weeks of therapy, the amlodipine/valsartan-based treatments also decreased the prevalence of albuminuria and the central aortic pressure, improved vessel elasticity, and exerted a positive effect on the vascular endothelial function through its effect on the markers involved in the endothelial function.
Unatoč optimizaciji i pojednostavnjenju liječenja arterijske hipertenzije (AH), postizanje kontrole arterijskoga tlaka (AT) i dalje je izazov, a većini je bolesnika potrebno kombinirano liječenje da bi postigli ciljnu kontrolu AT-a. Zbog višefaktorskog učinka AH-a, uz smanjenje vrijednosti AT-a, dodatna prevencija oštećenja ciljnih organa te održavanje vaskularnog integriteta postignuta antihipertenzivima korisni su za optimalno smanjenje kardiovaskularnog (KV) rizika. Cilj multicentričnog, otvorenog, prospektivnog kliničkog ispitivanja VICTORY II u 100 bolesnika uključenih u aktivnu fazu bio je procijeniti sigurnost i djelotvornost fiksnih kombinacija amlodipina/valsartana (Wamlox®) i amlodipina/valsartana/hidroklorotiazida (Valtricom®) u prethodno neliječenih ili prethodno liječenih bolesnika s AH-om 2. ili 3. stupnja u kojih nije postignuta kontrola vrijednosti AT-a. Svi bolesnici s AH-om 2. stupnja započeli su liječenje fiksnom kombinacijom amlodipina/valsartana 5 mg / 80 mg, koja se po potrebi mogla titrirati naviše korak po korak do konačne opcije – fiksne kombinacije amlodipina/valsartana/hidroklorotiazida 10/160/12,5 mg kako bi se postigle ciljne vrijednosti AT-a. Bolesnici s AH-om 3. stupnja započeli su liječenje fiksnom kombinacijom amlodipina/valsartana 5 mg / 160 mg, koja se po potrebi mogla titrirati naviše korak po korak do fiksne kombinacije amlodipina/valsartana/hidroklorotiazida 10/160/25 mg kako bi se postigle ciljne vrijednosti. Uz postizanje ciljne vrijednosti AT-a mjerena u ordinaciji, u 90% bolesnika nakon 16 tjedana liječenja, terapije na bazi kombinacije amlodipina/valsartana također su smanjile prevalenciju albuminurije i centralnoga aortalnog tlaka, poboljšale elastičnost krvnih žila i pokazale pozitivan učinak na funkciju vaskularnog endotela putem svojeg djelovanja na markere uključene u funkciju endotela.
The main goal of arterial hypertension (AH) treatment is to reduce the risk of fatal and non-fatal cardiovascular (CV) complications, cerebrovascular complications, and chronic kidney disease. (
The 2018 European Society of Cardiology / European Society of Hypertension Guidelines for the management of AH recommend that antihypertensive treatment be initiated with a two-medication combination, preferably in the form of a single-pill combination (SPC) to improve treatment compliance. Angiotensin receptor blockers (ARBs) are among the five major classes of medications that form the basis of antihypertensive therapy. ARBs (e.g. valsartan) are also among the recommended first-line medications, administered in combination with a calcium channel blocker (CCB) or a diuretic, preferably in the form of an SPC. (
The primary objective of VICTORY II, a multicenter, open, prospective clinical study was to assess the efficacy and safety of SPCs of amlodipine/valsartan and amlodipine/valsartan/ hydrochlorothiazide in achieving the target levels of different types of BP (office BP, home measured BP, and 24-h ambulatory BP) in adult patients with grade 2 or 3 AH. The secondary objectives were to assess the effects of the amlodipine/valsartan-based treatments (amlodipine/valsartan or amlodipine/valsartan/hydrochlorothiazide) on metabolic parameters, albuminuria levels, central aortic pressure levels, elasticity of the arteries, endothelial function, effect on erectile function, effect on patient quality of life, and the effect on the convenience of treatment. The results regarding the BP effect of the tested medication – SPCs of amlodipine/valsartan (Wamlox®) and amlodipine/valsartan/hydrochlorothiazide (Valtricom®) – were already published (
The VICTORY II clinical study, which was conducted when the 2013 ESH/ESC Guidelines for the management of AH were valid, involved patients with essential grade 2 or 3 AH, previously untreated patients (office systolic BP ≥160 mmHg and/or office diastolic BP ≥100 mmHg), or those with office BP uncontrolled by previous therapy. The duration of treatment was 16 weeks. Patients were required to visit the clinical center in a 4-week interval. Each patient had to participate in 5 visits, with an additional visit for a subgroup of patients. At Visit 1, all the patients with grade 2 AH started the treatment with the SPC of amlodipine/valsartan (Wamlox®) 5/80 mg, which could be up-titrated to the SPC of amlodipine/valsartan/ hydrochlorothiazide (Valtricom®) 10/160/12.5 mg to achieve target office BP. The patients with grade 3 AH started treatment with the SPC of amlodipine/valsartan (Wamlox®) 5/160 mg, which could be up-titrated to amlodipine/valsartan/hydrochlorothiazide (Valtricom®) 10/160/25 mg to achieve target office BP. At monitoring visits, the physician made the decision about the correction of the antihypertensive therapy based on the analysis of office BP measurement results, physical examination, general condition, and the patient’s complaints.
The effect of the studied medications on the level of albumin in urine was determined at the Screening visit and at Visit 5 in order to assess organ-protective properties in all patients. The effect on central (aortic) pressure and the elasticity of the arteries was evaluated by measuring pulse wave velocity (PWV) and determining the augmentation index at baseline and after 16 weeks of therapy (at Visit 5) using the SphygmoCor device on a subgroup of patients. Additionally, the levels of different parameters connected to the endothelial function (necrosis factor α (TNFα), interleukins 6 (IL-6) and 10 (IL-10), type 1 vascular cell adhesion molecules (sVCAM-1) and the vascular endothelial growth factor (VEGF-A)) were assessed at baseline and after 16 weeks of treatment in a subgroup of patients.
This study included 100 patients: 59 women and 41 men with grade 2 (n=60) and grade 3 (n=40) AH. The mean age of patients was 59.5±10.9 years, with a duration of AH of 83.4±8.4 months. The groups of patients with grade 2 and 3 AH were comparable in age, gender, duration of AH, and body mass index (BMI). The most frequently present comorbid CV diseases included dyslipidemia/hypercholesterolemia (41% of patients), obesity (32% of patients), endocrine disorders (12% of patients), cardiac conduction abnormalities and heart rhythm disorders (11% of patients), chronic heart failure (11% of patients), and type 2 diabetes mellitus (11% of patients).
Out of 60 patients with grade 2 AH at the screening visit starting the treatment with the dual SPC of amlodipine/valsartan 5/80 mg, 17 patients (28.3%) completed the study on the initial dose, while the rest required up-titration. 30 patients (50.0%) completed the study on the 5/160 mg dose of amlodipine/valsartan, 11 patients (18.3%) on the 10/160 mg amlodipine/valsartan dose, and only 2 patients (3.4%) required the triple SPC of amlodipine/valsartan/hydrochlorothiazide 10/160/12.5 mg.
Out of 30 patients with grade 3 AH at the screening visit starting the treatment with the dual SPC of amlodipine/valsartan 5/160 mg, only 7 patients (17.9%) completed the study on the initial dose. 21 patients (53.8%) up-titrated the therapy to amlodipine/valsartan 10/160 mg, 11 patients (28.2%) up-titrated the therapy to the triple SPC, 8 of them (20.5%) to 10/160/12.5 mg, and 3 of them (7.7%) to amlodipine/valsartan/hydrochlorothiazide 10/160/25 mg. The results of the study showed that SPCs of amlodipine/valsartan and amlodipine/valsartan/hydrochlorothiazide effectively reduced BP in patients with grade 2 or 3 AH and had a good tolerability profile.
At baseline, elevated levels of albumin (≥30 mg/day) were present in 17 patients. After 16 weeks of treatment, amlodipine/valsartan-based therapy significantly decreased albuminuria in 10 (58.8%) studied patients: a change from ≥30 mg/day to less than 30 mg/day was observed in 60.0% and 57.1% of patients in the grade 2 and 3 AH groups, respectively.
A minimum improvement of 5% in central (aortic) systolic BP was observed in 73% of all patients from the subgroup with additional examination (n=38). Central (aortic) systolic BP (SBP) was reduced by 16.1 mmHg, from 138.3 mmHg to 122.2 mmHg. In the groups with grade 2 and 3 AH, the 5% improvement of central (aortic) SBP was achieved in 66.7% and 90.0% of patients, respectively. The greatest reduction (from 147.4 mmHg to 122.7 mmHg) of central (aortic) SBP was observed in the group of patients with grade 3 AH (n=11). In the group of patients with grade 2 AH (n=27), amlodipine/valsartan-based therapy reduced central (aortic) SBP from 134.6 mmHg to 122.2 mmHg.
When evaluating the effect of amlodipine/valsartan-based SPC treatment on arterial elasticity in the subgroup of patients with additional examinations, improvement in PWV of at least 5% was observed in 57.1% of patients; 48.0% and 80.0% in groups with grades 2 and 3 AH, respectively. In the group of patients with grade 2 AH, a reduction of PWV from 10.37 m/s at baseline to 9.92 m/s after 16 weeks of treatment was observed (
Pulse wave velocity (PWV; m/s) during treatment with amlodipine/valsartan-based single-pill combinations in patients with grade 2 hypertension.
An improvement in the augmentation index of
The levels of parameters involved in endothelial damage (IL-6, IL-10, TNFα, sVCAM, VEGF-A) were assessed before the administration of the amlodipine/valsartan-based therapy and after 16 weeks of treatment (
IL-6, median | 1.26 | 1.39 | 1.17 | 1.46 | 1.25 | 1.42 |
IL-10, median | 0.42 | 0.09 | 0.49 | 0.19 | 0.44 | 0.10 |
sVCAM-1, median | 655.80 | 723.30 | 679.65 | 547.70 | 669.30 | 586.50 |
VEGF-A, median | 79.40 | 57.35 | 87.38 | 63.73 | 79.40 | 57.88 |
TNFα, median | 0.25 | 0.68 | 0.39 | 1.14 | 0.25 | 0.70 |
IL – interleukin, sVCAM-1 – soluble vascular cell adhesion molecules-1, VEGF-A – vascular endothelial growth factor molecules, TNFα – tumor necrosis factor α, n – number of patients. |
The first objective of AH treatment is to achieve target BP levels of <140/90 mmHg in all patients. (
Many patients included in the VICTORY II study had concomitant conditions that affect the progression of the CV disease, making and the choice of antihypertensive treatment, which has a beneficial effect on slowing the progression of CV disease, was therefore of great importance. Increased BP and neurohumoral dysregulation are likely to have an adverse effect on the kidneys. Reduction of albuminuria, as an early marker of kidney disease, translates into a decreased occurrence of CV and renal outcomes. (
Increased BP can increase arterial stiffness in patients with AH. In the 2018 ESC/ESH Guidelines for the management of AH, carotid-femoral PWV is the golden standard for measuring large artery stiffness. A PWV >10 m/s is considered a conservative estimate of significant alterations of the aortic function in middle-aged hypertensive patients. (
Atherosclerosis is primarily a disorder of lipid metabolism, but there is also a prominent chronic inflammatory component that drives atherosclerotic lesion progression in the arterial wall. (
The results of the VICTORY II clinical study showed that therapy with amlodipine/valsartan-based SPCs in patients with grade 2 or 3 AH not only effectively reduces BP but also provides a broad spectrum of clinical benefits in addition to BP control, such as decreased prevalence of albuminuria, decreased central aortic pressure, improved vessel elasticity, and a positive effect on the vascular endothelial function through their effect on the markers involved in endothelial function.