Introduction
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. (1) It is therefore important not only to reduce blood pressure (BP) to the target levels but also to diminish hypertension-mediated organ damage – hypertension-induced structural and/or functional changes in the heart, brain, retina, kidney, and vasculature. (2)
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. (2) Treatment with an SPC may lead to more adequate control of BP and may show additional synergistic vasoprotective or pleiotropic effects. (2,3)
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 (4). In this article, we focus on the evaluation of the additional effects in addition to BP control: the effect on albuminuria, central aortic pressure, elasticity of the arteries (pulse wave velocity and augmentation index), and on endothelial function (the levels of necrosis factor α (TNFα), interleukins 6 (IL-6) and 10 (IL-10), type 1 vascular cell adhesion molecules (sVCAM-1), and vascular endothelial growth factor (VEGF-A).
Patients and Methods
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.
Results
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 (Figure 1).
An improvement in the augmentation index of >5% was observed in 66.7% of patients; 61.5% and 80.0% in groups with grades 2 and 3 AH, respectively. The largest decrease was observed in the group with grade 2 AH. The combined improvement in PWV and the augmentation index of >5% was observed in 44.1% of subgroup patients and in 33.3% and 70.0% in groups with grades 2 and 3 AH, respectively.
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 (Table 1). Intra-group absolute changes of these parameters were statistically significant at the 5% level of change in values for IL-6, IL-10, VEGF-A, TNFα, with the exception of VCAM-1, in the subgroup of 38 patients after 16 weeks of treatment (Visit 5). Relative decrease in values of IL-10 levels by a minimum of 5-15% was observed in 76.3% of patients. A decrease in the level of vascular endothelial adhesion molecules (sVCAM-1) by a minimum of 5% was observed in 47.4% of patients. A decrease in TNFα levels by a minimum of 5-10% was observed in 10.5% of patients. A decrease in the level of vascular endothelial growth factor (VEGF-A) molecules by a minimum of 5%, 10%, and 15% was observed in 68.4%, 63.2%, and 60.5% of patients, respectively.
Discussion
The first objective of AH treatment is to achieve target BP levels of <140/90 mmHg in all patients. (2) The results of the VICTORY II clinical study showed that the amlodipine/valsartan-based SPC treatment strategy has a strong antihypertensive effect, reducing BP to the target levels in 90% of newly diagnosed or previously treated, but uncontrolled patients with grade 2 or 3 AH. Meta-analyses have shown that central BP is a better predictor of CV events in hypertensive patients compared with brachial BP. (5) There is also a different effect of antihypertensive medicines on central BP compared with brachial BP. (2) The reduction of central BP also decreases CV risk and HMOD. (5) Treatment with amlodipine/valsartan-based SPCs showed a significant reduction of central (aortic) BP in almost three quarters of patients. Interestingly, similar data were obtained in VICTORY, the international multicenter clinical study in which valsartan and a SPC of valsartan/hydrochlorothiazide significantly reduced the stiffness of the aorta and thus PWV and central BP in 74% of patients with grade 1 and grade 2 AH. (6)
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. (7) It is well-established that ARBs (e.g. valsartan), exert renoprotective effects in addition to their BP-lowering effects due to the benefits on renal injury during the development of AH. Furthermore, ARB-induced renal vasodilation results in an increase in renal blood flow, leading to an improvement of renal ischemia and hypoxia. ARB is effective in reducing the urinary albumin excretion rate independently of BP reduction. (8) It has been shown that a treatment strategy that includes an angiotensin-converting enzyme (ACE) inhibitor or ARB decreased albuminuria and the appearance or progression of diabetic nephropathy more effectively than other medication classes. (2) A decrease in albuminuria by amlodipine/valsartan SPC-based treatment was also observed in the VICTORY II clinical study, since there was an improvement in albuminuria, and thus improved kidney function, in more than half of included patients with initial albuminuria.
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. (2) Significant evidence suggests that the increase in arterial stiffness is an independent risk factor for CV diseases (9), and an ideal antihypertensive medication should both lower BP and improve arterial stiffness. (2) Thus, all antihypertensive medicines reduce arterial stiffness by reducing BP. (2) Meta-analyses of many randomized clinical trials suggest that ACE inhibitors and ARBs may reduce PWV on a long-term basis in addition to the BP-lowering effect. (2,9) The positive effect of amlodipine/valsartan SPC-based therapy was also observed in the VICTORY II clinical study. In the group of patients with additional examination, 2 out of 3 patients treated with a SPC based on amlodipine/valsartan showed at least a 5% drop in PWV, leading to a mean PWV of 10 m/s after 16 weeks of treatment. This indicated a positive marked effect of the treatment on arterial elasticity. The beneficial effect of amlodipine/valsartan-based SPC therapy on arterial stiffness can be explained by a potential impact of valsartan and amlodipine on the vascular wall that is included in the SPC. Valsartan, by blocking the renin-angiotensin-aldosterone system, suppresses proinflammatory angiotensin II signals and reduces the severity of oxidative stress. It promotes normalization of the endothelium and ensures proper vasodilatation, which slows down remodeling and connective tissue restructuring of the vascular wall. (10) CCBs can block N-calcium channels at the endings of sympathetic nerves, which has a local sympatholytic effect through a suppression of adrenergic effects on blood vessels. A decrease in the basal tone of smooth muscle cells and inhibition of the tonic component contribute to a decrease in the rigidity of the arterial wall. (11)
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. (12) The accumulation of inflammatory cells within the arterial wall leads to a local production of inflammatory markers, such as interleukins (e.g. IL-6, IL-10), cytokines, and proteases. They enhance the influx of monocytes and lymphocytes, thereby promoting the progression of atherosclerotic lesions. (13) The vascular endothelial growth factor (VEGF) is an important angiogenic factor. It induces migration and proliferation of endothelial cells, enhances vascular permeability, and modulates thrombogenicity. (14) Macrophage recruitment by abnormal endothelium in developing atherosclerotic plaques is aided by the endothelial expression of adhesion molecules (e.g. the vascular cell adhesion molecule; VCAM). (14) Antihypertensives as anti-inflammatory agents can play a key role in atherosclerotic lesions. Previous studies have revealed that valsartan may inhibit the development of atherosclerosis by lowering serum pro-inflammatory cytokines. (15) The effect of amlodipine/valsartan-based SPCs on inflammatory parameters was also evaluated in the VICTORY II clinical study. The levels of the vascular endothelial growth factor A (VEGF-A), a key regulator of angiogenesis, significantly decreased in all patients of the subgroup with additional examinations, including the group of patients with grade 3 AH. The obtained data on the effect of amlodipine/valsartan-based SPCs on inflammatory parameters require further study, since multidirectional changes were detected among the many parameters. This may be associated with the design features of this study that are close to real clinical practice: open design and lack of randomization of patients and control groups, which did not allow for a comparison of SPC effects with other treatments. The use of a SPC, including those with two and three antihypertensives, did not demonstrate an isolated effect of individual components of treatment, which is important in assessing all secondary parameters, especially endothelial damage parameters.
Conclusion
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.