Effective antihypertensive therapy: what should the doctor pay attention to?

Introduction

As is known, one of the most important tasks of modern antihypertensive therapy is to achieve the target level of blood pressure (BP). According to new guidelines for the diagnosis and treatment of arterial hypertension (AH), four classes of antihypertensive drugs are recommended for this purpose: diuretics, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin II receptor blockers (ARBs). Regardless of the choice of drug, it is necessary to achieve the main goal of antihypertensive therapy - achieving the target blood pressure level, which in all patients with hypertension should be <140/90 mm Hg. Art. If well tolerated, blood pressure can be reduced to lower values ​​- <130/80 mmHg. Art. As for beta blockers (BB), new guidelines recommend their use mainly in very high-risk patients - after myocardial infarction and in heart failure [1–3]. At the same time, taking into account the main goal of treatment of hypertension - the maximum possible reduction in the risk of cardiovascular complications (CVC), organ protection is of great importance, since organ damage (left ventricular hypertrophy, microalbuminuria) significantly increases the risk of CVC. Moreover, target organ damage is quite common in hypertension, even at a very early stage [4–6].

Antihypertensive therapy: focus on central aortic pressure

Research data suggests that hypertension affects approximately 65 million Americans aged 18–39 years and 1 billion people worldwide. Arterial hypertension (AH) is a risk factor for the development and progression of atherosclerosis, coronary heart disease, chronic heart failure and cerebral stroke.

Changes in elastic vessels (aorta, pulmonary artery and large arteries branching from them) are an important part of the pathogenesis of hypertension. Normally, the elastic properties of these vessels, especially the aorta, help smooth out the periodic waves of blood produced by the left ventricle during systole and convert them into continuous peripheral blood flow. The elastic properties of the aorta modulate left ventricular function by reducing left ventricular afterload and end-systolic and diastolic volume. This leads to a decrease in the tension of the walls of the left ventricle, as a result of which the trophism of the subendocardial layers of the myocardium, which are most sensitive to hypoxia, improves and coronary blood flow improves.

One of the significant characteristics of elastic-type vessels is rigidity, which determines the ability of the arterial wall to resist deformation. The stiffness of the vascular wall depends on age, the severity of atherosclerotic changes, the speed and degree of age-related involution of the most important structural proteins elastin and fibulin, an age-related increase in collagen stiffness, genetically determined characteristics of elastin fibers and the level of blood pressure (BP). A number of studies have emphasized the role of inflammation in the pathogenesis of large artery stiffness.

The classic marker of arterial stiffness/elasticity of large vessels is pulse wave velocity (PWV). The value of this indicator largely depends on the ratio of the thickness of the vessel wall to their radius and its elasticity. The more distensible the vessel, the slower the pulse wave propagates and the faster it weakens, and vice versa - the more rigid and thick the vessel and the smaller its radius, the higher the PWV. Normally, PWV in the aorta is 4–6 m/s; in less elastic arteries of the muscular type, in particular the radial artery, it is 8–12 m/s. The gold standard for assessing aortic stiffness is the PWV between the carotid and femoral arteries.

Central (aortic) and peripheral blood pressure

In a normal arterial system, after contraction of the ventricle in systole, the pulse wave is directed from the site of origin (aorta) to large medium and then small vessels at a certain speed. Along the way, the pulse wave encounters various obstacles (for example, bifurcations, resistive vessels, stenoses), leading to the appearance of reflected pulse waves directed to the aorta. With sufficient elasticity of large vessels, primarily the aorta, the reflected wave is absorbed.

The sum of direct and reflected pulse waves differs in different vessels; as a result, blood pressure, primarily systolic blood pressure (SBP), differs in different main vessels and does not coincide with that measured on the shoulder. The degree of increase in SBP in the peripheral arteries relative to SBP in the aorta varies greatly between subjects and is determined by the elastic modulus of the arteries studied and the distance from the measurement site. Because of this, the cuff pressure in the brachial artery does not always correspond to the pressure in the descending aorta. A certain contribution to the increase in blood pressure in the brachial artery relative to blood pressure in the aorta is made by an increase in the rigidity of its wall, which means the need to create greater compression in the cuff. Unlike peripheral blood pressure, the level of central blood pressure is modulated by the elastic characteristics of large arteries, as well as the structural and functional state of medium-sized arteries and the microvasculature and, thus, is an indicator that indirectly reflects the state of the entire cardiovascular system.

The greatest prognostic value is blood pressure in the ascending and central parts of the aorta, or central blood pressure. In the case of increased stiffness (decreased elasticity) of the aorta, the reflected wave is not absorbed sufficiently and, as a rule, due to a higher PWV, returns during systole, which leads to an increase in central SBP. The consequence of increased rigidity and increased central blood pressure is a change in afterload on the left ventricle and impaired coronary perfusion, which leads to left ventricular hypertrophy and increased myocardial oxygen demand.

In recent years, special techniques have appeared (for example, applanation tonometry of the radial or carotid arteries) that make it possible to record such determinants of pulse pressure as pulse (oscillations of the arterial wall from the heart to resistive vessels) and reflected (oscillations of the arterial wall from resistive vessels to the heart) waves, and, using computer processing when recording radial artery oscillations, calculate the values ​​of central pressure in the aorta (Fig. 1).

Rice. 1. Graph of central pressure in the aorta obtained by applanation tonometry of the radial artery. Within 10 seconds, the pressure curve in the radial artery of the upper limb is recorded using an applanation tonometer. The data is processed using software: the average shape of the curve is calculated, which is transformed using the accepted mathematical method into a graph of central pressure in the aorta (CPA). Computer processing of the obtained central pressure curves allows one to determine the parameters of the central pressure: the time to the first (T1) and second (T2) systolic peaks of the wave. The pressure at the first peak/kink (P1) is taken as the ejection pressure, a further increase to the second peak (ΔP) means the reflected pressure, their sum (maximum pressure during systole) is the systolic central pressure (CPAs)

In addition to the value of central blood pressure, there is an indicator of pressure increase, the augmentation index (amplification, AIx) expressed as a percentage, which is defined as the pressure difference between the first, early peak (caused by cardiac systole) and the second, late (appearing as a result of the reflection of the first pulse wave) systolic peak , divided by central pulse pressure.

Thus, central aortic pressure is a calculated hemodynamic parameter that depends not only on cardiac output and peripheral vascular resistance, but also on the structural and functional characteristics of the main arteries (their elastic properties). Differences between central and peripheral SBP levels are most pronounced in young people and decrease in older people. Central blood pressure, especially central pulse pressure, and the augmentation index have been shown to correlate with the degree of large artery remodeling and PWV as a classic indicator of vascular wall stiffness.

Arterial stiffness as a cardiovascular risk factor

Changes in the mechanical properties of large arteries have a clear pathophysiological relationship with clinical outcomes. Research suggests that PWV, a measure of arterial stiffness, may be a better predictor of subsequent cardiovascular events than known risk factors such as age, blood pressure, hypercholesterolemia and diabetes. Studies assessing PWV have established that increased arterial stiffness is a predictor of cardiovascular risk in apparently healthy individuals, patients with diabetes mellitus, end-stage renal disease, and the elderly. It has been demonstrated that arterial stiffness is a predictor of mortality in patients with hypertension. Thus, in a population-based study of the Copenhagen County population, it was demonstrated that an increase in PWV (>12 m/s) is associated with a 50% increase in the risk of cardiovascular events. In addition, the prognostic value of PWV was found in a Japanese study with an average follow-up of 8.2 years.

Indirect indices of aortic stiffness and reflected waveforms, such as central aortic pressure and augmentation index, have been found to be independent predictors of cardiovascular events and mortality. Thus, in a study that included 1272 normotensive and untreated patients with hypertension, it was demonstrated that central SBP was an independent predictor of cardiovascular mortality after adjustment for various cardiovascular risk factors, including left ventricular myocardial mass and determination of intima-media thickness. with ultrasound examination of the carotid arteries. Moreover, patients with high aortic pressure have a worse cardiovascular prognosis than patients with better control of central aortic pressure.

Increased aortic stiffness is also an independent predictor of diastolic dysfunction in patients with hypertension (Fig. 2) and may also limit exercise capacity in dilated cardiomyopathy. In patients with heart failure with preserved left ventricular ejection fraction, systolic dysfunction and arterial stiffness appear with age and/or progression of hypertension.

Rice. 2. Pathophysiological pathways by which aortic stiffness contributes to the development of diastolic dysfunction in hypertension. Notes: SBP – systolic blood pressure, DBP – diastolic blood pressure.

Increased arterial stiffness is associated with endothelial dysfunction and decreased nitric oxide (NO) bioavailability. Endothelial dysfunction in patients at high cardiovascular risk may explain why these conditions are associated with increased arterial stiffness in the early stages before the onset of atheroma. Therefore, drugs such as nebivolol that increase NO production may reduce large artery stiffness, which in turn may lead to a reduction in cardiovascular risk.

Thus, the importance of arterial stiffness, assessed by PWV, for the risk of cardiovascular outcomes has been demonstrated in a number of prospective studies both in patients with hypertension and in the general population. Since 2007, assessment of PWV on the carotid-femoral segment has been recommended as an additional research method for identifying target organ damage in hypertension.

Arterial stiffness and antihypertensive therapy

Antihypertensive drugs have been found to differ in their effects on large artery stiffness and reflected pulse wave. The CAFE (Conduit Artery Function Evaluation) study, a part of ASCOT, examined the effects of two combination antihypertensive therapy regimens in 2199 patients with hypertension: a calcium antagonist ± angiotensin-converting enzyme inhibitor (ACEI) and a β-adrenergic receptor blocker (β-blocker) ± a diuretic. in relation to the characteristics of arterial stiffness and central blood pressure. By the end of the study, similar changes in blood pressure in the brachial artery were noted in both groups of patients, but the dynamics of central blood pressure and central hemodynamics were different. Thus, in the treatment group that included a calcium antagonist ± ACEI, central SBP was lower by 4.3 mmHg. (p < 0.0001), and central aortic pulse pressure - by 3.0 mm Hg. (p < 0.0001). There were no differences in the effect on PWV in both groups of patients. This allowed us to conclude that higher central blood pressure during therapy that included a β-blocker ± diuretic may be due to different effects on the characteristics of the reflected wave. Thus, reflected wave values ​​were higher in the β-blocker ± diuretic group due to bradycardia and/or peripheral vasoconstriction. The augmentation index, reflecting the percentage of increase in SBP due to the reflection wave, was significantly greater by 6.5% during therapy that included a β-blocker ± diuretic compared with the combination of a calcium antagonist ± ACEI. This difference in the effects of antihypertensive therapy on central BP has been discussed as one explanation for the results of the ASCOT–BPLA trial, which demonstrated superiority of the calcium antagonist/ACEI combination over the β-blocker/thiazide diuretic combination in reducing all-cause mortality.

Of interest are the results of the REASON study, which compared the effect of a year of therapy with a beta-blocker (atenolol) with a combination of an ACEI/thiazide diuretic on central SBP and central pulse pressure. With a similar decrease in diastolic blood pressure in both groups of patients, a more pronounced decrease in peripheral (brachial artery), central (carotid artery) SBP and pulse pressure was noted under the influence of the ACEI/diuretic combination. A greater decrease in central pulse pressure during the ACEI/diuretic combination corresponded to a more pronounced decrease in left ventricular myocardial mass. Both treatment regimens resulted in similar reductions in aortic PWV due to comparable reductions in mean and diastolic blood pressure. The main difference between the groups was that the ACEI/diuretic combination, unlike atenolol, caused a decrease in the carotid augmentation index, a marker of the reflected wave from the carotid artery.

Thus, antihypertensive drugs have different effects on large artery stiffness and the reflected wave, which does not always change in the same direction.

β-adrenergic receptor blockers in the treatment of arterial hypertension

Data from randomized controlled trials and meta-analyses suggest that in patients with hypertension, monotherapy with β-blockers and diuretics is as effective in lowering blood pressure as the use of ACE inhibitors and calcium channel blockers. In patients with hypertension associated with heart failure or diabetes mellitus, treatment with β-blockers is preferable due to the presence of antiatherogenic, antiarrhythmic and anti-ischemic properties in this group of drugs. Clinical studies have demonstrated the beneficial effects of β-adrenergic blockers in patients with coronary heart disease, after myocardial infarction, and in patients with diabetes mellitus. Concerns about the use of β-blockers as first-line agents for hypertension have been stimulated by a meta-analysis that found that β-blockers have no significant effect in reducing cardiovascular events, especially stroke, compared with other classes of antihypertensive drugs. However, three quarters of the studies included in the meta-analysis analyzed the β-adrenergic blocker atenolol (others included propranolol, oxprenolol, metoprolol, pindolol). It has been demonstrated that in patients with hypertension, long-term therapy with atenolol does not reduce all-cause mortality compared with other drugs. Of course, this makes you think about choosing an antihypertensive drug.

The recommendations for the diagnosis and treatment of hypertension indicate that a significant problem in the treatment of so-called “classical” cardioselective beta-blockers is their unfavorable metabolic effect (dyslipidemia, decreased glucose tolerance), therefore they are not recommended for use in persons with metabolic syndrome and a high risk of developing diabetes mellitus, especially in combination with thiazide diuretics. The expert opinion in the ESC/EASD Guidelines on Diabetes, Pre-diabetes and Cardiovascular Disease is as follows: “...in patients with hypertension and established diabetes mellitus, β-blockers should remain part of the therapeutic intervention to achieve effective blood pressure control,” and when selecting a β-blocker for the treatment of such patients, all properties of a particular drug should be carefully taken into account: β-selectivity and additional properties not related to β-blockade (α-blockade, effect on the expression of NO synthase, effect on hemodynamic parameters, etc.). Thus, the third generation β-blockers, non-selective carvedilol and highly selective nebivolol, did not have a negative effect on the glycemic profile and had a neutral effect on lipid metabolism in patients with hypertension and diabetes mellitus. In this regard, the American Association of Clinical Endocrinologists (AACE) recognizes the vasodilatory benefits of carvedilol and nebivolol and confirms that these drugs may have a beneficial effect in patients with hypertension and diabetes mellitus. Thus, when choosing a β-blocker as an antihypertensive drug in patients at high risk of developing complications of cardiovascular diseases, knowledge of the characteristics of a particular drug is of great importance.

Third-generation β-adrenergic blockers (labetalol, carvedilol, nebivolol) reduce blood pressure by reducing total peripheral vascular resistance (vasodilation) instead of reducing cardiac output observed with earlier generation drugs. The vasodilating properties of nebivolol, in contrast to other third-generation β-blockers that have a vasodilatory effect due to α1-blocking activity, can be explained by the ability of nebivolol to increase the bioavailability of nitric oxide (NO), which has been confirmed in experimental and clinical studies in healthy volunteers and patients with AG. Nebivolol has been experimentally shown to improve endothelial function by increasing NO production by stimulating endothelial NO synthase (eNOS) and reducing oxidative inactivation of NO. Therefore, nebivolol has significant protective properties against the endothelium by improving the bioavailability of NO. The antioxidant properties of nebivolol and its neutral and, in some cases, beneficial effects on carbohydrate and lipid metabolism have been demonstrated. In addition, nebivolol has antiproliferative properties, potentially important in terms of regression of structural changes in blood vessels, often observed in patients with hypertension. Therefore, the NO-mediated effects of nebivolol could theoretically lead to a reversal of endothelial dysfunction, reducing large artery stiffness and systemic vascular resistance.

Effect of β-blockers on arterial stiffness

Clinical studies on the dynamics of aortic stiffness under the influence of β-blockers in healthy volunteers and patients with hypertension are few. However, available data suggest that all “classical” β-adrenergic blockers from atenolol to bisoprolol have a negative effect on central hemodynamic parameters. In a comparative study of bisoprolol 10 mg, propranolol 40 mg and placebo conducted in healthy volunteers, it was shown that both drugs significantly reduced SBP and heart rate (HR) compared to placebo. Under the influence of both β-blockers, a decrease in blood flow velocity in the brachial and femoral arteries was detected, which was apparently due to a decrease in cardiac output. At the same time, propranolol increased the vascular resistance of the brachial artery; bisoprolol did not affect this indicator. Moreover, both drugs induced an equal increase in vascular resistance of the femoral artery.

The different effects of beta-blockers on central and peripheral blood pressure may be due to changes in heart rate, as well as the presence or absence of vasodilating properties. In a randomized crossover study, which included 20 healthy volunteers, the dynamics of central and peripheral blood pressure, cardiac output and peripheral vascular resistance were analyzed in an acute pharmacodynamic test with the selective β-blocker bisoprolol (at a dose of 20 mg), and the non-selective β-blocker propranolol (at a dose of 80 mg). ) at rest and during physical activity. Under resting conditions, both β-blockers reduced brachial SBP but had no effect on central SBP (compared with placebo). During physical activity, a significant decrease in SBP in the brachial artery was noted (by 19.9 ± 4.3 mm Hg and 23.2 ± 2.7 mm Hg when using propranolol and bisoprolol, respectively, at a load of 100 W, all p < 0.0001) in the absence of significant changes in central SBP and peripheral vascular resistance. Thus, in healthy individuals at rest and during exercise, acute blockade of β-adrenergic receptors with propranolol and bisoprolol does not reduce central blood pressure.

An analysis of six studies examining the effect of β-blocker monotherapy on brachial and central BP concluded that β-blockers reduced central aortic pressure to a lesser extent than brachial BP. This adversely affects the amplification of pulse pressure (the ratio of brachial to central pulse pressure): for a given level of blood pressure at the brachial artery, the level of central aortic pressure is correspondingly higher. In most studies, atenolol was used, but there are reports of a similar effect on the level of central blood pressure of bisoprolol. Obviously, it was these data that contributed to the fact that since 2007, in the European guidelines for the treatment of hypertension, bisoprolol has been considered as a “traditional” or “classical” β-blocker with all the inherent restrictions on clinical use of this subclass of β-blockers. Thus, in a study by Deary et al., a comparison was made of the antihypertensive effectiveness and central aortic pulse wave when using various antihypertensive drugs (calcium antagonist amlodipine at a dose of 5 mg, α-blocker doxazosin at a dose of 4 mg, ACE inhibitor lisinopril at a dose of 10 mg, β-blocker bisoprolol at a dose of 5 mg, the thiazide diuretic bendrofuazide at a dose of 2.5 mg) and placebo. It was found that bisoprolol caused the greatest decrease in blood pressure, but, unlike other drugs, led to an increase in the augmentation index. This paradoxical response to bisoprolol was associated with a threefold increase in plasma levels of brain natriuretic peptide, confirming that the increase in the augmentation index was accompanied by an increase in left ventricular afterload.

Similar data were obtained in a crossover randomized study by D. Neal et al., which compared the effect of a dihydropyridine calcium antagonist (amlodipine), a β-blocker (bisoprolol) and an ACE inhibitor (lisinopril) on peripheral and central blood pressure and the augmentation index in patients with hypertension after liver transplantation. It was found that with the same decrease in peripheral SBP in all groups of patients, the augmentation index increased only when treated with a β-blocker. This change in the augmentation index under the influence of bisoprolol indicates an increase in the reflected wave, indicating that central aortic pressure decreases less than peripheral SBP. These data are important because it is central aortic pressure, and not brachial artery blood pressure, that determines left ventricular load and coronary perfusion.

In summary, a number of studies have demonstrated that all cardioselective nonvasodilating β-blockers are less effective in lowering central aortic pressure, which may be a result of the lower effect of this class of drugs on aortic stiffness or due to their negative effect on the reflected wave. Comparative studies, including the REASON project, have demonstrated that β-blockers can reduce aortic stiffness, but this reduction is most likely due to a reduction in mean BP. However, almost all studies have noted that β-adrenergic blockers (in particular, atenolol, bisoprolol) lead to an increase in the aortic augmentation index, while almost all other antihypertensive drugs, as a rule, reduce it. These data confirm that “traditional” non-vasodilating β-blockers increase the reflected wave. The increase in the augmentation index under the influence of β-blockers may be based on various physiological mechanisms. One of the most convincing is a decrease in heart rate in response to β-adrenergic receptor blockade. A decrease in heart rate increases the absolute duration of systole, thereby lengthening the period during which the reflected wave returns to the aorta and increases systolic pressure. In other words, bradycardia actually moves the reflected wave from diastole to systole. A decrease in heart rate for every 10 beats implies an increase in the augmentation index by approximately 4% and aortic systolic pressure by approximately 5 mmHg. This point is reflected in the new revision of the 2009 European guidelines for the treatment of hypertension: “In a meta-analysis of nine of 22 randomized controlled trials of beta-blockers, a significant inverse correlation was noted between heart rate achieved during beta-blocker therapy and cardiovascular outcomes (i.e., the lower the heart rate, the higher the outcome rate).” However, this document makes clear that “when discussing β-blockers, it should not be ignored that they are not a homogeneous class and that vasodilatory β-blockers such as celiprolol, carvedilol and nebivolol appear to lack some negative properties indicated for other compounds." In particular, the fact that nebivolol reduces heart rate less than other cardioselective beta-blockers is recognized as an advantage of this drug: “Nebivolol in doses that cause an equivalent reduction in blood pressure reduces heart rate significantly less than atenolol, and due to less bradycardia in combination with peripheral vasodilation has a better effect on central blood pressure than atenolol.”

The fact that third-generation beta-blockers may have a greater ability to lower central aortic pressure is supported by current scientific evidence.

In an in vivo experiment, C. McEniery et al compared the β-blockers nebivolol and atenolol on PWV. With intra-arterial administration of nebivolol, a significant decrease in PWV was observed, while atenolol did not affect this indicator (p = 0.11), despite a decrease in mean blood pressure. The results of this study suggest that nebivolol, in contrast to atenolol, increases arterial distensibility due to the effect of nebivolol on the formation of nitric oxide. The authors concluded that the use of nebivolol may be preferable in conditions of increased large artery stiffness, such as isolated systolic hypertension.

Kelly et al were the first to recognize the potential benefits of vasodilating β-blockers over atenolol in lowering central pressure. They compared the effect of 12 weeks of therapy with atenolol with dilevalol (an isomer of labetalol not currently used in clinical practice) in patients with hypertension. Both drugs resulted in equivalent reductions in brachial artery blood pressure and large artery stiffness, but the augmentation index decreased more significantly with dilevalol than with atenolol.

A study by Mahmud and Feely, which included 40 patients with untreated hypertension, compared the effects of atenolol and nebivolol on arterial stiffness (as measured by carotid-femoral PWV) and augmentation index. Both drugs caused an equivalent reduction in brachial artery blood pressure, but aortic pulse pressure decreased to a greater extent in the nebivolol group (from 51 ± 2 to 35 ± 2 mmHg, p < 0.01) than in patients taking atenolol (from 54±3 to 43±3 mm Hg, p < 0.05). In both groups, a significant decrease in PWV was observed, but a significant decrease in the augmentation index was observed only with treatment with nebivolol. Atenolol also had a negative effect on pulse blood pressure. Under the influence of atenolol, heart rate decreased more significantly (by 14±3 beats/min in the atenolol group versus 8±2 beats/min in treatment with nebivolol, p < 0.05). It is assumed that nebivolol, due to an increase in local levels of NO, in contrast to atenolol, causes a decrease in the resistance of small arteries and a decrease in the intensity of the reflected wave. The authors concluded that these properties have an important effect on hemodynamics, confirming that β-blockers cannot be considered a homogeneous group in this regard. Dhakam et al compared the effect of 5 weeks of therapy with nebivolol with atenolol in 16 patients with isolated systolic hypertension. Both drugs reduced peripheral blood pressure in a similar manner and reduced aortic stiffness. However, nebivolol reduced aortic pulse pressure more significantly than atenolol. Another study in patients with hypertension compared the effects of nebivolol and enalapril on insulin sensitivity, hemodynamic parameters and arterial stiffness. Since no differences were observed in both groups, the authors concluded that nebivolol, like enalapril, has a beneficial effect on arterial compliance and glucose metabolism in patients with hypertension.

So, a decrease in the reflected wave due to the use of vasodilating β-blockers, in particular nebivolol, compensates for the unfavorable increase in the heart rate-dependent augmentation index of β-blockers. In addition, the decrease in heart rate is usually less with cardioselective vasodilating drugs.

In general, we can conclude that the beneficial effects on arterial stiffness and endothelial function are an important advantage of nebivolol, which fundamentally distinguishes it from “traditional” cardioselective β-blockers.

Thus, studying the structural and functional characteristics of the main arteries makes it possible to more accurately determine the risk of cardiovascular complications in patients with hypertension and can be used as a marker of the effectiveness of drug therapy. Antihypertensive drugs differ in their effect on the structural and functional characteristics of the main arteries, including central aortic pressure. It has been established that when taking the most selective β1-blocker nebivolol with vasodilating properties due to an increase in the bioavailability of NO and a beneficial effect on endothelial function, a decrease in arterial stiffness and a decrease in central aortic pressure are observed. These effects of nebivolol, along with antiproliferative and endothelium-protective properties, as well as neutral or beneficial effects on carbohydrate and lipid metabolism, open up broad prospects for its clinical use in the treatment of hypertension and cardiovascular diseases.

A.N. Belovol, Doctor of Medical Sciences, Professor, Corresponding Member of the National Academy of Medical Sciences of Ukraine; I.I. Kknyazkova, Doctor of Medical Sciences, Associate Professor Kharkov National Medical University

source https://medstrana.com/articles/2040/

Organoprotection and antihypertensive drugs

Analysis of a number of large-scale studies indicates the significant importance of organ protection in reducing the risk of cardiovascular complications and improving the prognosis. Thus, organ protection, as well as achieving target blood pressure levels, plays an important role in antihypertensive therapy. This is especially true for combination therapy. According to modern recommendations, all patients with hypertension (except low-risk patients with blood pressure <150/90 mm Hg, patients over 80 years of age and patients with frailty syndrome) are recommended to use a combination of antihypertensive drugs as initial therapy, preferably a fixed one to improve adherence to therapy . Combinations that include an ARB, an ACE inhibitor, a dihydropyridine CCB, or a diuretic are advantageous. Numerous randomized clinical trials have shown that monotherapy effectively reduces blood pressure only in a limited number of patients with hypertension; most patients require a combination of at least two drugs to control blood pressure. A meta-analysis of more than 40 studies showed that a combination of two drugs from any two classes of antihypertensive drugs lowers blood pressure much better than an increased dose of a single drug [3]. Another advantage of combination therapy is the possible physiological and pharmacological synergism of drugs of different classes, which can provide a more pronounced reduction in blood pressure and better tolerability. Combination therapy also makes it possible to suppress counterregulatory mechanisms of increased blood pressure. However, the advantages of combination therapy are inherent only in rational combinations of antihypertensive drugs. These include: ACEI + diuretic, ARB + ​​diuretic, ACEI + CCB, ARB + ​​CCB, dihydropyridine CCB + BB, CCB + diuretic, BB + diuretic. One such effective combination is the fixed combination of ramipril and amlodipine. The components of this drug, on the one hand, provide adequate blood pressure control in most patients, and on the other, effective organ protection.

The multicenter randomized clinical trial (RCT) ACCOMPLISH (Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension) [7] compared the effectiveness of two fixed combination therapy regimens—ACEI + diuretic and ACEI + CCB—in preventing cardiovascular events. The study included patients with high and very high risk hypertension. Patients were randomized to receive a fixed combination of benazepril (ACEI) plus amlodipine (a dihydropyridine CCB) or hydrochlorothiazide (a diuretic). CVE or death from cardiovascular causes was considered as the composite primary endpoint. The rate of achieving this was 9.6% in the ACEI + CCB group and 11.8% in the ACEI + diuretic group (hazard ratio (HR) 0.80; p<0.001). Moreover, greater effectiveness was not associated with greater adherence of patients to therapy. Discontinuation rates were comparable: 28.8% in the ACEI + CCB group and 31.2% in the ACEI + diuretic group. The hypotensive effect of both combinations was also comparable. The rate of achieving target BP was 75.4% in the ACEI + CCB group and 72.4% in the ACEI + diuretic group. The results of the study, as emphasized by its authors, should not raise doubts about the ability of diuretics to reduce the risk of cardiovascular events in patients with hypertension, but should push for wider use of fixed combinations of ACE inhibitors + CCBs in medical practice.

Two key studies, HOPE [8] and ALLHAT [9], demonstrated the ability of these drugs to reduce the risk of death and major CV events in patients with hypertension. It was ramipril in the HOPE study [8] that significantly reduced the risk of death, myocardial infarction and stroke in high-risk patients, which at one time brought ACE inhibitors to the forefront in the treatment of patients with type 2 diabetes mellitus (T2DM), coronary heart disease (CHD) and kidney disease. Ramipril has the widest range of indications among ACE inhibitors. It is recommended for patients with hypertension, chronic heart failure, peripheral arterial disease, diabetic and non-diabetic nephropathy, myocardial infarction and stroke in history. The organoprotective effect of ramipril is associated with its pharmacological characteristics, namely lipophilicity, which ensures a high degree of binding to tissue ACE [10]. L. Pilote et al. [11] analyzed data from 7512 patients aged 65 years and older who were hospitalized with myocardial infarction and discharged with an ACE inhibitor. It was found that the greatest survival rate was observed in the group of people taking ramipril. Enalapril, fosinopril, captopril, quinapril and lisinopril were associated with higher mortality rates.

Amlodipine, as shown by the ALLHAT study [9], reduces the risk of overall mortality and the occurrence of coronary artery disease and its complications. According to SA Lee et al. [12] it was amlodipine that reduced the risk of myocardial infarction by 9%, stroke by 16%, and all cardiovascular events by 10% (compared to regimens not containing CCBs).

The ASCOT study compared the effectiveness of amlodipine followed by perindopril with the combination of atenolol + bendroflumethiazide. In the study, 19,257 patients with hypertension aged 40–79 years showed a comparable reduction in blood pressure, but in the group treated with amlodipine and ACE inhibitors, the relative risk of stroke was 23% lower than in the group treated with atenolol and a diuretic (p = 0.0003 ) [13]. These results suggest that CCBs and ACEIs have organoprotective properties that reduce the risk of developing cerebrovascular complications.

The angioprotective effect of amlodipine was demonstrated in the PREVENT study: in patients with coronary artery disease, the use of amlodipine led to a decrease in intima media thickness compared to the placebo group [14]. The CAMELOT study included 1991 patients with angiographically confirmed coronary artery stenosis [15]. Patients were divided into 3 groups depending on the drug that was added to the previously prescribed therapy: amlodipine (5–10 mg/day), or enalapril (10–20 mg/day), or placebo. During two years of observation, both amlodipine and enalapril caused a significant decrease in blood pressure. CVEs were recorded in 23.1% of cases in the placebo group, in 16.6% of cases in the amlodipine group and in 20.2% of cases in the enalapril group. Intravascular ultrasound did not reveal progression of atherosclerosis in the amlodipine group, while it was observed in the placebo group. Perhaps it is the slowdown in the progression of atherosclerosis of the carotid and coronary arteries that explains the reduced risk of developing circulatory disorders when using CCBs.

Arterial hypertension (AH) is one of the most pressing health problems both in Russia and throughout the world. This is due to the high prevalence and high risk of its complications - coronary heart disease (CHD), cerebral strokes, heart and kidney failure. The prevalence of hypertension in economically developed countries reaches 25% [1].

In Russia, 40% of men and women over 18 years of age have elevated blood pressure (BP) [2]. According to Russian recommendations for the diagnosis and treatment of hypertension, the strategic goal of therapy for this disease is to reduce the risk of cardiovascular complications (CVC) as much as possible. The most important condition for effective antihypertensive therapy is adequate blood pressure control, i.e. achieving its target level, which is taken as blood pressure

However, in Russia, only 5.7% of men and 17.5% of women with hypertension achieve target blood pressure levels. If you do not increase the effectiveness of therapy, i.e., do not increase the proportion of adequately treated patients with hypertension, you cannot count on a turning point in reducing cardiovascular risk.

Currently, it is possible to use two strategies for treating hypertension to achieve target blood pressure: monotherapy and combination treatment (see figure). Monotherapy is based on finding the optimal drug for a particular patient, and switching to combination therapy is advisable only if the latter has no effect. Combination therapy already at the start of treatment involves the selection of an effective combination of drugs with different mechanisms of action.

Each of these approaches has its own advantages and disadvantages. The advantage of monotherapy is that if the drug is successfully selected, the patient will not need to additionally take another drug. However, as a rule, with monotherapy it is possible to achieve target blood pressure on average only in 30–40% of patients with hypertension. This is quite natural, since one class of drugs is not able to control all pathogenetic mechanisms of increased blood pressure: the activity of the sympathetic nervous system and the renin-angiotensin-aldosterone system, volume-dependent mechanisms. In addition, monotherapy requires the doctor to painstakingly search for the most optimal antihypertensive drug for the patient with frequent changes in drugs and their dosages, which often deprives the doctor and the patient of confidence in success and ultimately reduces adherence to treatment. This is especially true for patients with mild and moderate hypertension, most of whom do not experience discomfort from increased blood pressure and are not motivated to treatment.

The disadvantage of combination therapy is the inconvenience associated with the fact that the patient has to additionally take one more, and sometimes several, drugs. However, in most cases, the prescription of antihypertensive drugs with different mechanisms of action allows, on the one hand, to achieve target blood pressure, and on the other hand, to minimize the number of side effects. Combination therapy also makes it possible to suppress counterregulatory mechanisms of increased blood pressure. Thus, the transition to combination therapy, which allows effective control of various mechanisms of increased blood pressure, gives hope for increasing the effectiveness of antihypertensive therapy.

There are various combinations of antihypertensive drugs. Among the combinations of two drugs, the following are considered effective and safe: diuretic + beta-blocker; diuretic + ACE inhibitor (ACE inhibitor); diuretic + angiotensin II receptor antagonist (ARA); dihydropyridine calcium antagonist + beta-blocker; calcium antagonist + ACE inhibitor; calcium antagonist + diuretic; alpha-blocker + beta-blocker; centrally acting drug + diuretic. In addition, combinations of an ACE inhibitor, a calcium antagonist, an ARA and a diuretic with an I1 imidazoline receptor agonist are possible. The most popular in Russia is the combination of an ACE inhibitor and a diuretic. As the results of the Pythagoras study show, almost a third of doctors in Russia prefer a combination of these drugs [4].

The most important step towards improving the strategy of combination therapy was the creation of fixed combinations of antihypertensive drugs (two components in one tablet), which significantly improve patient adherence to therapy. However, along with the advantages (the ability to take one tablet containing two drugs), this approach also has serious disadvantages. Thus, the doctor cannot vary the doses of each of the drugs included in the combination, which complicates treatment, especially when adverse reactions occur that are clearly related to one of the components included in the combination. To avoid such difficulties, it was necessary to create several different dosage forms, which may partially alleviate the problem (for example, the drugs Enap-H and Enap-HL, containing different doses of the diuretic), but does not solve it completely.

In this regard, it is of interest to create non-fixed combinations containing two drugs in one blister, which will allow, if necessary, to vary the doses of each of them. The first drug of this type in Russia was Enzix - a combination of enalapril with indapamide.

The creation of this form of the drug was largely facilitated by the results of the multicenter study EPIGRAF, in which doctors from 38 clinics from 17 cities of Russia took part [5]. In total, the study included 550 patients with grades II–III hypertension (initial systolic blood pressure > 160 mm Hg), and among them there were patients not only with essential, but also with symptomatic hypertension. A feature of this study was that already at the beginning of treatment, patients were prescribed a combination of enalapril and indapamide. Moreover, if the dose of indapamide was constant - 2.5 mg, then the dose of enalapril varied depending on the initial blood pressure level. However, doctors had the opportunity to adjust doses depending on the achievement of the target blood pressure level within 14 weeks. The average dose of enalapril in the study was 15.2 mg. As a result of treating patients with hypertension with differentiated doses of enalapril and indapamide, it was possible to achieve a significant reduction in both systolic and diastolic blood pressure. Moreover, in 70% of patients it was possible to achieve the target blood pressure level, despite its very high initial level. Adverse reactions were noted in only 8.1% of patients, and in 5.4% they were due to an excessive decrease in blood pressure, which can be eliminated with more careful selection of drug dosages.

The main conclusion of the study is that the effectiveness and safety of the combination of enalapril with indapamide in the treatment of hypertension does not depend on gender, age and the cause of the increase in blood pressure (primary hypertension or secondary hypertension of renal origin). Particular attention should be paid to the latter circumstance in connection with the entrenched opinion that the effectiveness of antihypertensive therapy is lower in patients with symptomatic hypertension. The combination of enalapril with indapamide was especially preferred in women in whom ACE inhibitor monotherapy may be less effective.

The results of the EPIGRAF study made it possible to work out the most effective doses of enalapril and indapamide for patients with hypertension of varying degrees, which became the basis for the creation of three types of the drug Enzix: ENZIX - 10 mg of enalapril and 2.5 mg of indapamide (single dose in the morning) for patients with stage I hypertension; ENZIX DUO – 10 mg enalapril and 2.5 mg indapamide (morning) + 10 mg enalapril (evening) for patients with stage II hypertension; ENZIX DUO FORTE – 20 mg enalapril and 2.5 mg indapamide (morning) + 20 mg enalapril (evening).

The effectiveness and safety of Enzix were assessed in the EPIGRAPH-2 study, which was a comparative randomized multicenter study that included nine centers in Russia and one in Serbia [6]. A total of 313 patients were included in the study and randomized into two groups. The Enzix group included 211 patients, and the control group included 102 patients. The control group was treated with other classes of antihypertensive drugs (except ACE inhibitors and diuretics). After 2, 4 and 6 weeks of treatment in cases where it was not possible to achieve target blood pressure (

All patients randomized to the Enzix group were divided into two subgroups depending on the initial blood pressure level.

In the first subgroup, 118 patients with stage I hypertension and initial systolic blood pressure of 140–160 mm Hg. Art. a combination of 10 mg enalapril and 2.5 mg indapamide (corresponding to the ENZIX form) was prescribed. During treatment, 88 (74.6%) of them continued to take the original dose, and in 26 (22.1%) patients the dose of enalapril was doubled (10 mg in the morning + 10 mg in the evening) while maintaining the dose of indapamide (2.5 mg in the morning ), which corresponded to the ENZIX DUO form. Only one patient with stage I hypertension required a combination of 40 mg of enalapril (20 mg in the morning + 20 mg in the evening) and 2.5 mg of indapamide, which corresponded to the ENZIX DUO FORTE form. Three patients did not complete the study.

In the second subgroup, 93 patients with stage II hypertension and systolic blood pressure 160–180 mm Hg. Art. Therapy began with 20 mg of enalapril (10 mg each morning and evening) and 2.5 mg of indapamide (corresponding to the ENZIX DUO form). During treatment in 46 patients, this dosage was maintained, and in 45 patients, the dose of enalapril was increased to 40 mg/day (20 mg in the morning + 20 mg in the evening) with a constant dose of indapamide 2.5 mg, which corresponded to the form of ENZIX DUO FORTE. For two more patients, the initial dose of enalapril was reduced to 10 mg while maintaining the original dose of 2.5 mg of indapamide, which corresponded to the ENZICS form.

When analyzing the number of patients whose blood pressure levels normalized as a result of treatment, the group of patients receiving Enzix (72.5%) had some advantages compared to the control group (66.7%). And this, despite the fact that systolic blood pressure in the “experimental” group was initially 2.7 mm Hg. Art. higher than in the control. If we sum up the total number of patients who responded positively to treatment (the number of patients with normalization of blood pressure or a decrease in systolic blood pressure by more than 20 mm Hg from the initial level), then by the end of treatment it reached 82.4% on average for the group, taking Enzix, and among patients with stage I hypertension this value was 89.8%, and in patients with stage II hypertension – 77.2%.

Thus, early treatment of patients with grades I–II hypertension with a non-fixed combination of enalapril and indapamide (Enzix) in comparison with routine antihypertensive therapy makes it possible to achieve normalization of blood pressure levels more often. In addition, the Enzix group was able to significantly reduce the number of patients with left ventricular hypertrophy and proteinuria, improve quality of life, and reduce the number of hospitalizations and additional visits to the doctor. Among other things, Enzix therapy is cost-effective.

Very important importance is currently attached to the metabolic effects of antihypertensive therapy. The essence of the metabolic theory is that a number of antihypertensive drugs, such as diuretics and beta-blockers (especially non-selective ones), tend to worsen the lipid profile and worsen insulin resistance, which can in the long term increase the risk of developing diabetes mellitus and reduce the effectiveness of therapy in preventing the development of cardiovascular disease [7].

Recently completed large-scale studies have confirmed the validity of the metabolic theory. In groups of patients taking diuretics and beta-blockers, the incidence of diabetes was significantly higher than when treated with calcium antagonists, ACE inhibitors and ARBs [8–10]. In this regard, the effectiveness of antihypertensive therapy must be assessed not only from the point of view of achieving target blood pressure, but also from the standpoint of the likelihood of metabolic effects. This fully applies to combination therapy. It is appropriate to emphasize that the components of Enzix do not cause concern in this regard. Enalapril, as studies show, is metabolically neutral, and indapamide occupies a special place among diuretics. At recommended doses (1.5–2.5 mg per day), it not only provides adequate antihypertensive effects, but is also metabolically neutral. It has been proven that indapamide does not cause hypokalemia or changes in carbohydrate [11] and lipid profiles [12]. Particularly compelling evidence for the metabolic indifference of indapamide comes from a meta-analysis of three studies involving a total of 1195 patients. Based on the results of treatment with the retard form of indapamide for 9–12 months, no effect on carbohydrate and lipid profiles, as well as uric acid levels, was detected [13].

In addition to the diuretic effect, indapamide has a vasodilating effect by reducing the sodium content in the arterial wall, regulating the entry of calcium into vascular smooth muscle cells, as well as increasing the synthesis of prostaglandin E2 in the kidneys and prostacyclin in the endothelium [14]. Thus, indapamide, having a more pronounced direct effect on blood vessels compared to other diuretics, affects endothelial function. It has an antioxidant effect, increasing the bioavailability of NO and reducing its destruction [15]. The LIVE study demonstrated the ability of indapamide therapy to cause regression of left ventricular myocardial hypertrophy [16].

Combination of ramipril with amlodipine

Currently on the Russian market, the fixed combination of ramipril + amlodipine is represented by the drug Egipres® (“Egis”). This drug has demonstrated its effectiveness and safety in a number of studies conducted in accordance with the principles of evidence-based medicine. It is presented in four dosage options, which eliminates the main disadvantage of fixed combinations - the difficulty of accurately selecting the dose.

The most significant of the studies of this combination is the open, prospective, observational clinical phase IV RAMONA trial involving more than 6 thousand patients with stage 1–2 hypertension with varying risks of cardiovascular events who failed to achieve target blood pressure values ​​on previously received therapy [16]. The observation lasted 4 months. (1st visit - initial, 2nd visit - after 1 month of treatment and 3rd, final visit - after 4 months). All patients were prescribed a fixed combination of ramipril + amlodipine at a dose of 5/5, 5/10, 10/5, or 10/10 mg, respectively, with possible titration at the discretion of the attending physician. Antihypertensive efficacy was assessed as a primary endpoint, and the effect on metabolic parameters (creatinine, uric acid, glucose, lipid profile) and adherence to treatment was assessed as a secondary endpoint.

After 4 months treatment, there was a decrease in systolic blood pressure (SBP) and diastolic blood pressure (DBP) (p<0.05 for both), as well as a decrease in total cholesterol, low-density lipoprotein cholesterol and fasting blood glucose (p<0.05 for all). The combination of ramipril + amlodipine was well tolerated by patients; no severe side effects were recorded when taking the drug. The RAMONA study conducted additional data analyzes in separate subgroups.

Patients with T2DM

[17]. In this subgroup, prescription of a fixed combination of ramipril + amlodipine allowed achieving target blood pressure values ​​in 69.8% of patients. SBP in patients with T2DM decreased from 157.5±9.6 mmHg. Art. up to 130.9±7.4 mm Hg. Art., DBP - from 91.3±7.6 mm Hg. Art. up to 79.6±5.8 mm Hg. Art. By the end of the study, a statistically significant decrease in both fasting glucose levels and glycated hemoglobin (HbA1c) levels was recorded, which indicates at least the metabolic neutrality of the drug. Thus, the study showed that the studied fixed combination can be prescribed to patients with a combination of hypertension and T2DM or metabolic syndrome.

Patients with chronic kidney disease
(CKD)
[16]. Therapy with a fixed combination of ramipril + amlodipine led to the achievement of target blood pressure values ​​in 52.1% of patients. After 4 months therapy, there was a significant increase in estimated glomerular filtration rate (p<0.05) and a decrease in uric acid levels (p<0.0001). These results allow us to conclude about the nephroprotective potential of this combination and recommend this drug for the treatment of hypertensive patients with CKD.

Observational studies, of course, do not have the evidentiary value of RCTs. But they have their advantage: they help to understand what happens in real life, and not in the refined conditions of an RCT.

Thus, in a retrospective study, the data of which were published by G. Simonyi et al. in 2016 [18], “naive” patients with hypertension who had not previously received regular antihypertensive therapy were included, who were prescribed fixed combinations of ramipril + amlodipine or ramipril + hydrochlorothiazide in the period from October 1, 2012 to September 30, 2013. as initial therapy. Patients were selected from the database of the Unified Hungarian Health Insurance Company, the National Health Insurance Fund of Hungary (NHIFH). NHIFH covers the entire population of Hungary, so these data can be considered representative of the entire population of this state. 39,095 patients in the NHIFH database met inclusion criteria (n=10,295 ramipril + amlodipine; n=28,800 ramipril + hydrochlorothiazide). All patients received prescriptions for 14 months. The percentage of patients remaining on therapy in any given month after treatment initiation was recorded. Treatment was considered discontinued if the patient did not receive a prescription for more than 60 days. After 2 months after the start of treatment, 42% of patients receiving ramipril + hydrochlorothiazide stopped treatment, which is very significant given the absence of such patients in the group of the fixed combination ramipril + amlodipine. At 1 year after the start of therapy, adherence to treatment in the ramipril + hydrochlorothiazide group was only 29% compared to 54% in the ramipril + amlodipine group. The average time spent on therapy is 9 months. for the combination of ramipril + amlodipine and 5.9 months. for the combination of ramipril + hydrochlorothiazide (p <0.05). The data obtained once again confirmed better adherence to the combination of an ACEI with a CCB than an ACEI with a diuretic, although they do not allow us to judge the effectiveness of therapy and the reasons for discontinuation of the combination of ramipril + hydrochlorothiazide.

A large-scale observational study was conducted in Poland, the purpose of which was to evaluate the effectiveness and tolerability of the fixed combination of ramipril + amlodipine depending on body weight [19]. The study included patients with hypertension who were divided into 3 groups: with normal body weight, overweight and obesity. All 24,240 patients recently switched from the free combination of ramipril and amlodipine to the fixed combination of ramipril + amlodipine without changing the drug dose. However, at the same doses of the same drugs, the effectiveness of antihypertensive therapy increased more than 2 times: from 32.9% to 76.5%. Overweight and, to an even greater extent, obesity were associated with a lower likelihood of achieving BP targets: an age-adjusted OR of 0.70 (0.61–0.81) for overweight and 0.49 (0.42–0.81) for overweight. 0.57) for obesity. Tolerability of the drug was assessed as “very good” or “good” by 98.8%, 97.6% and 96.4% of respondents, respectively. Adverse events were reported in 0.35% of patients regardless of nutritional status. A high level of satisfaction with therapy was reported by 57.0% of hypertensive patients with normal weight, 54.5% with overweight and 50.6% with obesity. Despite the slightly lower effectiveness in the latter group, the authors recommended the drug for the treatment of hypertension in obese patients.

In the Russian prospective observational study GRANAT-1 [20], the goal was to study adherence to antihypertensive therapy in patients with hypertension and metabolic syndrome using the example of prescribing a fixed combination of ramipril + amlodipine (Egipres®). The work was carried out as part of a large study GRANAT-1 (Observation program for patients with arterial hypertension and metabolic syndrome). A total of 101 patients were included in the study (41.6% men and 58.4% women, mean age 56.1±8.8 years) from Moscow, Nizhny Novgorod, Tomsk, Rostov-on-Don, and Tula. Of these, 23% had not previously received antihypertensive therapy. The treating physician recommended that patients take the study drug, determining an initial dose followed by titration based on effectiveness. The study lasted 5 months. Adherence to therapy was assessed using the Morisky-Green questionnaire. Initially, only 22 (21.8%) people were adherent to therapy (4 points out of 4 possible). By the end of the study, their share had increased to 69%. Statistically significant differences were identified in the proportion of patients who achieved target blood pressure in the groups that took the drug until the end of the study (91.3%) and switched to other drugs (66.7%, p = 0.02). However, the second group consisted of only 9 patients, so the authors admit that the results of the comparative analysis may be incorrect. A total of 3 cases of side effects in the form of swelling of the ankles were reported in patients taking the drug at a maximum dose of 10/10 mg.

A logical continuation of the GRANATE-1 study was the GRANATE-2 study [21], which posed similar tasks, but in patients with chronic obstructive pulmonary disease (COPD). The study included 52 patients (41 men and 11 women, mean age 65.1±9.2 years). The study design was consistent with the previous one. The diagnosis of COPD was made according to the conclusion of a pulmonologist or according to the results of a pulmonary function test confirming the presence of bronchial obstruction. Moreover, patients with stage IV COPD and bronchial asthma were excluded from the study. Among the patients there were 11 (22.8%) “naive” patients; the rest of the study participants took various drugs. After 1 month It turned out that 48 people started taking the recommended drug, the rest received other therapy. 60% of patients achieved target blood pressure. At the final visit, out of 50 patients who came, 45 took ramipril + amlodipine, the remaining 5 took other drugs. All study participants achieved target blood pressure. As for adherence, according to the Morisky-Green test, the proportion of patients adherent to therapy increased from 21% at the beginning of the study to 65% at the end. According to the authors, increased adherence was facilitated by frequent visits to the doctor (4 visits in 5 months) and the rapid achievement of a hypotensive effect. Side effects in the form of a dry cough were noted in 2 patients.

Another interesting study was conducted by Yu.V. Bochkareva et al. [22] in 2009 in Penza. It is interesting because it analyzed not only the physical, but also the mental state of the patients. The study included 25 patients with hypertension in combination with T2DM (mean age 53.1±4.1 years). The study of the psychological status of patients was carried out using a whole set of specialized questionnaires: the Zung depression questionnaire, the MMPI (Minnesota Multiphasic Personality Inventory), the Hamilton Anxiety and Depression Scale, the Spielberg-Khanin questionnaire for assessing personal and situational anxiety. As a result, the majority (81.2%) of patients showed symptoms of depression. In addition, the patients showed an increase in the level of personal and reactive anxiety. During therapy, a significant hypotensive effect was achieved, there was a significant improvement in HbA1c, a decrease in all scales of the neurotic triad (neurotic overcontrol, pessimism and emotional lability) and a decrease in the average depression score. Thus, the combination of amlodipine + ramipril, even in a low dose, demonstrated not only high antihypertensive efficacy in this therapeutically difficult category of patients, but also a beneficial effect on the metabolic profile and clinical and psychological status.

Why is this approach important? First, the role of depression and, possibly, anxiety [23] as an important independent risk factor for the development of CVS is beyond doubt. According to our data [24], even subclinical depression increased the ten-year risk of cardiovascular events in individuals at low and moderate risk by 2.9 times (odds ratio (OR) 2.9). The combination of subclinical depression and anxiety increased this risk by almost 5 times compared with individuals without such symptoms. Secondly, it appears that the reduction in symptoms of depression and anxiety during therapy is not only due to an improvement in general well-being. Recently, the role of the renin-angiotensin system (RAS) in the pathogenesis of not only cardiovascular diseases (CVDs), but also depression has been widely discussed. As it turned out, the RAS is activated in a similar way both in CVD and in the development of affective disorders and under stress. For example, circulating aldosterone and renin levels were found to be increased in patients with depression compared with age- and sex-matched controls [25, 26]. Hyperactivation of the angiotensin II type 1 receptor is considered one of the determinants of chronic inflammation [27] and pathological response to stress [28]. Chronic low-grade inflammation appears to be a common link in the pathogenesis of atherosclerosis, T2DM, neurodegenerative diseases, depression and a number of other disorders. Therefore, the antidepressant effectiveness of drugs that block the RAS is quite expected. This effect has been confirmed by a number of experimental studies [29–31]. As for clinical data, several observational studies and small RCTs have shown that ACEIs and ARBs, along with their antihypertensive effect, reduce stress, anxiety and depression and increase the effectiveness of antidepressants, partially restore reduced cognitive function, sexual activity and improve quality of life. Moreover, similar effects were noted not only in patients with hypertension, but also in normotensive individuals [32–34].

Modern rational combination therapy in the treatment of patients with arterial hypertension

According to epidemiological studies, the prevalence of arterial hypertension (AH) among adults in developed countries ranges from 20 to 40% and increases with age [1]. Elevated blood pressure is found in more than 50% of men and women over 60 years of age [2]. The relevance of the problem is supported by the increasing processes of urbanization of society, which create the preconditions for the emergence of risk factors (RFs), such as stress, physical inactivity, obesity, bad habits and disturbed ecology. Elevated blood pressure is one of the main risk factors for the development of cerebral stroke, coronary heart disease (CHD) and other cardiovascular diseases of atherosclerotic origin, which are associated with more than 50% of all deaths [3].

Clinical practice and the results of many multicenter studies have shown [4–6] that the use of monotherapy in the treatment of hypertension rarely leads to target blood pressure levels, increases the risk of adverse events and reduces patient adherence to treatment. The use of drugs in a rational combination regimen requires compliance with a number of mandatory conditions: safety and effectiveness of the components; the contribution of each component to the expected result; different but complementary mechanism of action of the components; the best result compared to each of the components; balance of components in terms of bioavailability and duration of action; strengthening organoprotective properties; impact on the universal (most common) mechanisms of blood pressure increase; reduction in adverse events and improved tolerability [7–9].

According to modern national recommendations [10], recommendations of the European Society of Arterial Hypertension (EOH) and the European Society of Cardiology (ESC) [11], the treatment tactics for essential hypertension depend on the level of blood pressure and the degree of risk of cardiovascular complications. The main goal of treatment is to minimize the risk of developing cardiovascular complications (CVD) and death from them. The main objectives are normalization of blood pressure levels in order to prevent complications, in the absence or minimal level of adverse drug reactions (ADRs), correction of all modifiable risk factors (smoking, dyslipidemia, hyperglycemia, obesity), prevention, slowing down the rate of progression and/or reducing organ damage - targets, as well as treatment of associated and concomitant diseases - coronary artery disease, diabetes mellitus (DM), etc. [10, 11].

When treating patients with hypertension, blood pressure should be less than 140/90 mm Hg. Art., which is its target level. If the prescribed therapy is well tolerated, it is advisable to reduce blood pressure to lower values. In patients with a high and very high risk of cardiovascular disease, it is necessary to reduce blood pressure to 140/90 mm Hg. Art. or less within 4 weeks. In the future, subject to good tolerance, it is recommended to reduce blood pressure to 130/80 mmHg. Art. and less. In patients with coronary artery disease, blood pressure should be reduced to the target value of 130/85 mm Hg. Art. In patients with diabetes and/or kidney disease, the target blood pressure level should be less than 130/85 mmHg. Art. [10].

Of course, treatment for hypertension should begin with lifestyle changes: reducing excess body weight, limiting the consumption of table salt and alcoholic beverages, increasing physical activity, etc. Limiting the consumption of table salt is a fairly effective way to reduce blood pressure. It was noted that limiting the consumption of table salt enhances the antihypertensive effect of many antihypertensive drugs, including AT1-angiotensin receptor blockers and β-blockers.

One of the most important conditions for ensuring adequate blood pressure control and increasing patient adherence to treatment is the optimal choice of antihypertensive drug as part of mono- or combination pharmacotherapy.

Currently, five main classes of antihypertensive drugs are recommended for the treatment of hypertension [10]:

1. angiotensin-converting enzyme inhibitors (ACE inhibitors) (captopril, enalapril, perindopril, lisinopril, fosinopril, quinapril, trandolapril, etc.);

2. AT1 receptor blockers (ARBs) (valsartan, losartan, telmisartan, candesartan, irbesartan, etc.);

3. slow calcium channel blockers (SCBC) (nifedipine, amlodipine, etc.);

4. beta-blockers (BAB) (carvedilol, bisoprolol, nebivolol, metoprolol tartrate, metoprolol succinate, atenolol, etc.);

5. thiazide and thiazide-like diuretics (hydrochlorothiazide (HCTZ), indapamide).

As additional classes of antihypertensive drugs for combination therapy, α-blockers (prazosin, doxazosin), imidazoline receptor agonists (moxonidine), and a direct renin inhibitor (aliskiren) can be used.

According to these national recommendations [10], the choice of an antihypertensive drug should be related to the characteristics of its action, belonging to a certain class, since at present, the results of clinical studies conducted according to the rules of evidence-based medicine have made it possible to establish situations of preferential class choice of drugs. When choosing an antihypertensive drug, it is necessary first of all to evaluate the effectiveness, the likelihood of side effects and the benefits of the drug in a specific clinical situation (Table 1).

The choice of drug is influenced by many factors, the most important of which are:

• the patient has a risk factor;
• target organ damage;
• concomitant clinical conditions, kidney damage, MS, diabetes;
• concomitant diseases for which it is necessary to prescribe or limit the use of antihypertensive drugs of various classes;
• the patient’s previous individual reactions to drugs of various classes;
• the likelihood of interaction with medications prescribed to the patient for other reasons;
• socioeconomic factors, including the cost of treatment.

It is necessary to begin treatment with the use of one drug in the minimum daily dose (this recommendation does not apply to patients with severe hypertension or those in whom previous therapy was ineffective). The use of new drugs should begin with the use of low doses, the goal of each successive stage of treatment should be to reduce blood pressure levels by 10–15% [10]. If blood pressure does not decrease to the desired level, further treatment is carried out by gradually - step by step - increasing doses or adding new drugs. Ineffective drugs (not causing a decrease in blood pressure by 10–15 mm Hg) and drugs that cause ADRs should be replaced [12].

There are no uniform recommendations regarding which drugs should be used to start treating a patient. The choice of drugs depends on age, gender and the presence of concomitant diseases.

Currently, the treatment of most patients with hypertension uses drugs that alter the activity of the RAAS. These are ACE inhibitors, beta blockers and angiotensin II receptor blockers (ARBs). ARBs are one of the modern and most dynamically developing classes of antihypertensive drugs. ARBs suppress the effect of angiotensin II through AT1 receptors. It has been established that hypersecretion of angiotensin II leads not only to the development of hypertension, but also to damage to target organs, being one of the main factors in the progression of hypertension and its complications, remodeling of the heart and blood vessels. It is no coincidence that AT1-angiotensin receptor blockers are classified as the main antihypertensive drugs. Numerous controlled studies, such as LIFE, VALUE, MARVAL, PRIME, IDNT, DETAIL [13], have shown that AT1 blockers are effective and safe antihypertensive drugs. AT1-angiotensin receptor blockers have proven to be particularly effective in preventing the development of cerebral stroke. To prevent stroke in patients with hypertension, AT1 blockers can be used both instead of diuretics or calcium antagonists, and together with them. ARBs, like ACEIs, can also prevent the development of type 2 diabetes, reducing the risk of its occurrence by 20–25% [14]. Therefore, it can be assumed that AT1-angiotensin receptor blockers should be used for the treatment of hypertension primarily in patients with a high risk of developing stroke or diabetes. Excellent tolerability is an undoubted advantage of AT1 blockers during long-term antihypertensive therapy. The use of AT1-angiotensin receptor blockers can improve patient adherence to long-term therapy, since ARBs are much less likely than other antihypertensive drugs to be discontinued due to the development of side effects. Unlike thiazide diuretics, beta blockers and ACE inhibitors, the antihypertensive effectiveness of AT1-angiotensin receptor blockers does not depend on the age, gender or race of patients [15].

The renin-angiotensin-aldosterone system (RAAS) plays a central role both in the occurrence of hypertension and in the implementation of pathophysiological processes that ultimately lead to serious cardiovascular complications such as cerebral stroke, myocardial infarction, vascular remodeling, nephropathy, congestive heart failure and the development of atherosclerotic processes. ACE inhibitors were the first group of drugs acting directly on the RAAS, which were widely introduced into clinical practice. The long period of their use, numerous clinical studies, and extensive experience of practical doctors in their use have led to the fact that these drugs are currently used in Russia more often than other antihypertensive drugs. ACE inhibitors in moderate doses reduce SBP to a slightly lesser extent than diuretics and calcium antagonists. The choice of a specific ACEI for long-term therapy in patients with hypertension has important clinical implications, since these drugs are prescribed essentially for life. Of the ACE inhibitors with proven effectiveness, perindopril and ramipril seem to be the most promising [16, 17].

Clinical practice and the results of many multicenter studies have shown that the use of monotherapy in the treatment of hypertension rarely leads to target blood pressure levels, increases the risk of adverse events and reduces patient adherence to treatment. The most important conditions for increasing patients’ adherence to treatment are their understanding of the goals, objectives, modern methods and principles of treatment, as well as the correct choice of antihypertensive treatment by the doctor. The tactics of using combination therapy with the selection of drugs with different mechanisms of action already at the beginning of treatment gives a much greater chance of successful blood pressure control. Low-dose combination rational antihypertensive therapy may be the first choice measure, especially in patients with a high risk of developing cardiovascular complications, the advantages of which include: a simple and convenient dosage regimen for the patient; facilitating titration; ease of prescribing the drug; increasing patient adherence; reduction of adverse events by reducing doses of components used; reducing the risk of using irrational combinations; confidence in the optimal and safe dosage regimen; reduction in price [17–21].

It should be noted that the latest both American and European recommendations emphasize the need to avoid, if possible, the tactics of frequent changes in medications and their dosages in patients. It is now becoming obvious that the effectiveness of monotherapy with drugs of all main groups is low and comparable: after a year of treatment, even with almost perfect adherence to treatment, the effect of monotherapy does not exceed 50% versus almost 30% with placebo. The tactics of “sequential monotherapy” in reality may require 4–5 changes in therapy, each of which may be complicated by the development of side effects. This tactic takes a lot of time, deprives the doctor and the patient of confidence in success, which ultimately has a negative psychological impact on the patient and leads to low adherence to treatment for hypertension. It is the underestimation of the role of combination therapy that is one of the common reasons for unsatisfactory blood pressure control [17–21].

Combination antihypertensive therapy has many advantages:

• enhancing the antihypertensive effect due to the multidirectional effects of drugs on the pathogenetic mechanisms of hypertension development, which increases the number of patients with a stable decrease in blood pressure;
• reducing the incidence of side effects both due to lower doses of combined antihypertensive drugs and due to the mutual neutralization of these effects;
• ensuring the most effective organ protection and reducing the risk of development and number of cardiovascular complications.

Numerous randomized clinical trials and real clinical practice experience have shown all the advantages of combination therapy, which can be summarized as follows [22, 23]:

• simultaneous use of drugs from two different pharmacological groups more actively reduces blood pressure due to the fact that there is an effect on various pathogenetic mechanisms of hypertension;
• the combined use of lower doses of two drugs acting on different regulatory systems will allow for better control of blood pressure, given the heterogeneity of the response of hypertensive patients to antihypertensive drugs;
• prescribing a second drug may weaken or balance the triggering of mechanisms to counteract the decrease in blood pressure that occurs when prescribing one drug;
• a sustained decrease in blood pressure can be achieved with smaller doses of two drugs (than with monotherapy);
• smaller doses allow you to avoid dose-dependent side effects, the likelihood of which is higher with a larger dose of a particular drug (during monotherapy);
• the use of two drugs can to a greater extent prevent damage to target organs (heart, kidneys) caused by hypertension;
• prescribing a second drug can to a certain extent reduce (and even completely eliminate) the undesirable effects caused by the first (even if quite effective) drug;
• Prescribing a second drug (in particular, a diuretic) allows you to obtain a rapid antihypertensive effect of a combination of drugs, since most antihypertensive drugs (ACE inhibitors, CCBs, ARBs, and partly beta blockers) exhibit their full effect only in the 2-3rd week . reception (and even later).

Combinations of two antihypertensive drugs are divided into rational (effective), possible and irrational. All the advantages of combination therapy are inherent only in rational combinations of antihypertensive drugs [24].

These include [10]:

• ACE inhibitor + diuretic;
• ARB + ​​diuretic;
• ACEi + dihydropyridine BMCC;
• ARB + ​​dihydropyridine BMCA;
• dihydropyridine BMCC + BAB;
• dihydropyridine BMCC + diuretic;
• beta blocker + diuretic;
• BAB + α-adrenergic blocker.

The issue of combining three or more drugs has not yet been sufficiently studied, since there are no results from randomized controlled clinical trials studying the triple combination of antihypertensive drugs. Thus, the antihypertensive drugs in these combinations are grouped together on a theoretical basis. However, in many patients, including patients with refractory hypertension, only with the help of three or more component antihypertensive therapy can the target blood pressure level be achieved [25]. Recommended combinations of three antihypertensive drugs include:

• ACE inhibitor + dihydropyridine BMCC + beta blocker;
• ARB + ​​dihydropyridine BMCA + BAB;
• ACE inhibitor + BMCC + diuretic;
• ARB + ​​BMCC + diuretic;
• ACE inhibitor + diuretic + beta blocker;
• ARB + ​​diuretic + beta blocker;
• dihydropyridine BMCC + diuretic + beta-blocker.

Since combination therapy has become one of the main directions in the treatment of patients with hypertension, fixed combinations of antihypertensive drugs containing two drugs in one tablet have become widespread, which improves the patient’s psychological attitude towards treatment and makes it possible to reduce the risk of complications and side effects. The optimal combination of components implies the absence of unwanted hypotension, which can lead, especially in elderly patients, to increased cardiovascular risk. Rational selection of components according to their pharmacokinetic profile creates the prerequisites for single use of drugs that require two or three times in monotherapy.

The advantages of fixed (official) combinations include:

• potentiation of the antihypertensive effect of drugs;
• ease of administration and dose titration process;
• reduction in the frequency of side effects (low dose, mutual neutralization of NDR);
• increasing patient adherence to treatment;
• reducing the cost of treatment.

Currently, there are quite a lot of official combination drugs: Capozide (captopril + HCTZ), Co-Renitek (enalapril + HCTZ), Noliprel (perindopril + indapamide), Accusid (quinapril + HCTZ), Co-diovan (valsartan + HCTZ), Gizaar (losartan + HCTZ), Exforge (valsartan + amlodipine), Equator (lisinopril + amlodipine), Logimax (metoprolol + felodipine), Tarka (verapamil + trandolapril), etc. The most frequently prescribed of all non-fixed and fixed drug combinations is the combination of an ACE inhibitor with a thiazide diuretic or an ARB with a thiazide diuretic. The high effectiveness and safety of this combination in the treatment of hypertension is noted in the recommendations of the WHO, VNOK, EOG - EOC and JNS 7. The action of type 1 AT receptor blockers is specific, since they, unlike ACE inhibitors, do not affect the activity of other neurohumoral systems, in particular bradykinin, which are associated with characteristic side effects (dry cough and angioedema). The effect of “escape” of pharmacological blockade of the RAAS from the action of ACE inhibitors is explained by the synthesis of angiotensin II in some organs and tissues with the help of other enzymes without the participation of ACE.

It is currently believed that chronic stimulation of the RAAS leads to the activation of growth factors and fibrosis at the tissue level, which determines the development of pathological processes in target organs, therefore the possibility of blocking the tissue link of the RAAS seems promising for achieving the organoprotective effect of antihypertensive therapy. A number of studies have not revealed a direct dependence of the reno- and cardioprotective effect of antihypertensive therapy on the degree of blood pressure reduction, which indicates the importance of non-hemodynamic effects of RAAS blockade. When used together, thiazide diuretics not only enhance but also prolong the antihypertensive effect of ARBs. The combined use of ARBs and diuretics has been shown to significantly reduce blood pressure in patients with both high and low renin activity, and the response to this combination therapy is about 80% or higher.

Another example of a favorable combination is the combination of BMCC with an ACE inhibitor, which leads to a decrease in the severity of edema associated with the use of dihydropyridines. In addition, the combination of a non-dihydropyridine BMCC with an ACE inhibitor may potentially enhance the positive effect of the latter on vascular elastic properties.

Irrational combinations, in which there is no potentiation of the antihypertensive effect of drugs and/or side effects are enhanced when used together, include combinations of beta blockers and centrally acting drugs, beta blockers and non-dihydropyridine BMCCs, and beta blockers with ACE inhibitors, ARBs, and imidazoline receptor agonists. The combination of ACEIs and ARBs is currently considered prohibited.

Conclusion

The most important conditions for increasing patients’ adherence to treatment are their understanding of the goals, objectives, modern methods and principles of treatment, as well as the correct choice of antihypertensive treatment by the doctor. The tactics of using combination therapy with the selection of drugs with different mechanisms of action already at the beginning of treatment provides a significantly greater chance of successfully controlling blood pressure and the risk of developing cardiovascular complications. The advantages of combination therapy consist in potentiating the antihypertensive effect and reducing the number of side effects and are inherent only in so-called rational combinations of antihypertensive drugs. For adequate treatment of hypertension, it is advisable to use combination therapy, starting with low doses of drugs.

Literature

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2. ABC Of Hypertension / edited by D. Gareth Beevers, Gregory H. Lip and Eoin O'Brien. 5th ed. Malden, Mass.: BMJ Books, 2007. p. 88.
3. Ezzati M., Lopez AD, Rodgers A. et al. Selected major risk factors and global and regional burden of disease // Lancet. 2002. Vol. 360(9343). P. 1347–1360.
4. Hansson L., Zanchetti A., Carruthers SG et al. Effects of intensive blood–pressure lowering and low–dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial // Lancet. 1998. Vol. 351. P. 1755–1762.
5. Dahlof B. Sweedish trial in old patients with hypertension (STOP-Hypertension). //Clm. Exp. Hypertens. 1993. Vol. 15. P. 925–939.
6. Chazova I.E., Belenkov Yu.N. ROSA – Russian study on optimal blood pressure lowering. https://www. cardiosite.ru/research/article.asp? id=2559.
7. Karpov Yu.A. Combination therapy of arterial hypertension - control effect and treatment success // Breast Cancer. 2006. No. 20. pp. 1458–1461.
8. 1999 World Health Organization – International Society of Hypertension Guidelines for the Management of Hypertension // J. Hypertens. 1999. Vol. 17. P. 151–183.
9. Kobalava Zh.D. Evolution of combination antihypertensive therapy: from multicomponent high-dose free combinations to low-dose fixed combinations as the first choice // Breast Cancer. 2001. No. 18. pp. 789–794.
10. Diagnosis and treatment of arterial hypertension. Recommendations of the Russian Medical Society on arterial hypertension and the All-Russian Scientific Society of Cardiologists. Fourth revision // Systemic hypertension. 2010. No. 3. P. 5–26.
11. ESH-ESC Guidelines Committee. 2013 guidelines for the management of arterial hypertension // J. Hypertension. 2013. Vol. 31. P. 1281–1357.
12. Karpov Yu.A. New recommendations for arterial hypertension RMOAG/VNOK 2010: issues of combination therapy // RMZh. 2010. No. 22. P. 1290.
13. Polosyants O.B. Sartans in cardiological practice // RMZh. 2008. No. 11. pp. 1593–1597.
14. Preobrazhensky D.V., Peresypko M.K., Nosenko N.S. and others. AT1-angiotensin receptor blockers: range of organoprotective effects // Handbook of a polyclinic physician. 2004. No. 1. P. 8–14.
15. Matcar DB, McCrory DC, Orlando LA et al. Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin II Receptor Antagonists (ARBs) for Treating Essential Hypertension. Comparative Effectiveness Review no. 10. (Prepared by Duke Evidence-based Practice Center under Contract No. 290-02-0025.) Rockville, MD: Agency for Healthcare Research and Quality. November 2007. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm
16. Moiseev S.V. Valsartan: from the realities of clinical practice to new opportunities // Clinical pharmacology and pharmacotherapy. 2009. No. 3. P. 32–43.
17. Kirichenko A.A., Ebzeeva E.Yu. Differentiated approach to the treatment of arterial hypertension // Consilium Medicum. 2006. T. 4. No. 3.
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20. Gosse P., Sheridan DJ, Zannad F. et al. Regression of LVH in hypertensive patients treated with indapamide SR 1.5 mg versus enalapril 20 mg: the LIVE study // J. Hypertens. 2000. Vol. 18. P. 1465–1475.
21. Chalmers J., Castaigne A., Morgan T. et al. Long-term efficacy of a new, fixed, very-low-dose angiotesin-converting enzyme-inhibitor/diuretic combination as first-line therapy in elderly hypertensive patients // J. Hypertens. 2000. Vol. 18. P.1–11.
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Clinical use of fixed combinations of antihypertensive drugs

Currently, the issues of rational pharmacotherapy and the optimal choice of drugs for various diseases are of particular relevance, including cardiovascular diseases (CVD), which remain the leading cause of mortality throughout the world. The number of people with diseases of the cardiovascular system (CVD), according to modern foreign sources, exceeds 100 million. Every year, 16.7 million people worldwide die from CVD, and in almost 50% of cases the cause of death is coronary heart disease (CHD) and almost in 30% of cases - cerebral stroke (MI) [1]. Among CVDs, the most common is arterial hypertension (AH). It is this problem that practitioners most often have to deal with, and it is this that is a serious prognostic risk factor (RF) for the development of myocardial infarction (MI), MI, chronic heart failure (CHF), general and cardiovascular mortality [2].

In this regard, the issues of rational pharmacotherapy and optimal choice of drugs for CVD are of particular relevance. Based on evidence-based medicine, treatment algorithms for various CVDs are being actively developed. They are reflected in international and national clinical guidelines. The use of clinical recommendations in the practical work of a doctor undoubtedly helps to improve treatment results and prognosis for CVD [3, 4].

However, often prescribing optimal therapy is a difficult task, especially in the context of the expansion of the pharmaceutical market and the emergence of a large number of more and more new drugs (drugs), as well as due to the increasing prevalence of comorbid conditions, which in many ways complicate the implementation of drug therapy and require special close attention to monitoring the effectiveness and safety of drugs. As practice shows, the degree of compliance of the pharmacotherapy with accepted recommendations in real clinical practice remains quite low both in our country and abroad [5, 6].

In 2013, new recommendations of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) for the treatment of hypertension were issued [7], as well as Russian recommendations “Diagnostics and treatment of arterial hypertension” [8 ], which are the basis for the selection of rational pharmacotherapy for hypertension by doctors of all specialties. The main goal of treatment of patients with hypertension is to minimize the risk of developing cardiovascular complications (CVD) and death from them. To achieve this goal you need:

• reducing blood pressure (BP) to the target level;
• correction of all modifiable risk factors (smoking, dyslipidemia, hyperglycemia, obesity);
• prevention, slowing the rate of progression and/or reducing target organ damage;
• treatment of associated and concomitant diseases (coronary artery disease, diabetes mellitus, etc.).

Choice of pharmacotherapy

Currently, five classes of antihypertensive drugs with a proven effect on the degree of cardiovascular risk and no significant differences in the severity of the antihypertensive effect are recommended for the treatment of patients with hypertension:

• angiotensin-converting enzyme inhibitors (ACEIs);
• angiotensin II receptor blockers (ARBs);
• beta-blockers (BAB);
• calcium antagonists (CA);
• thiazide diuretics.

Each class has its own application features, advantages and limitations associated with the possibility of developing undesirable reactions.

The large arsenal of available drugs makes it extremely important and at the same time difficult to select specific drugs, and the differentiated choice of drugs remains a pressing problem for practicing physicians at the present time. This is especially true for patients who have additional risk factors and concomitant diseases, which, on the one hand, worsen the prognosis for hypertension, and on the other hand, limit the use of a number of antihypertensive drugs. Pharmacotherapeutic approaches to the treatment of patients with hypertension with concomitant risk factors and associated diseases require an integrated approach that makes it possible to influence not each disease separately, but the patient as a whole.

Of course, each patient requires serious thought and analysis of the characteristics of his clinical situation, and taking this into account, one or another class of drugs should be chosen. Recommendations summarizing the evidence base for all classes of antihypertensive drugs can be of great help to the practitioner at this stage. It is reasonable to consider certain drugs to be preferred for specific situations because they have been used in those situations in clinical trials or have demonstrated superior efficacy for specific types of target organ damage.

Adherence to treatment

When discussing the problem of rational pharmacotherapy of hypertension, one cannot help but dwell on its very important aspect - the low effectiveness of treatment of hypertension and failure to achieve target blood pressure (BP) values. This is explained by various factors, not the least of which is the low adherence of patients with hypertension to treatment. This is evidenced by the results of clinical and epidemiological studies conducted both abroad and in our country. Thus, according to various researchers, up to 50% of patients with hypertension independently stop treatment prescribed by a doctor [9, 10]. Low adherence to treatment is also evidenced by the results of the Russian multicenter study RELIF (Regular Treatment and Prevention), conducted in the Central and Northwestern Federal Districts, which showed that 58.2% of patients with hypertension take medications only when their blood pressure increases. Of these, 63.6% do not take drugs every day, 39.7% stop treatment after normalization of blood pressure, 32.9% skip doses due to forgetfulness, and only 3.3% do not skip medications [11].

Basic concepts of adherence to treatment

Adherence to treatment refers to the compliance of the patient's behavior with the doctor's recommendations, including taking medications, diet and/or lifestyle changes. Adherence to treatment involves concepts such as retention in therapy (persistence) and compliance.

Retention on therapy is determined by the length of time a patient receives drug therapy and is measured by the number of days a patient receives therapy or the percentage of patients who remain on treatment over a given period.

Compliance is an indicator of adherence to drug therapy (compliance with the dose, frequency and regimen). Compliance is assessed by the drug use index, which is the quotient of the number of days of taking the full dose of the drug (or its amount given to the patient) by the duration (in days) of the entire study (observation) period. Achieving 100% adherence seems to be the ideal goal, but this is difficult to achieve with any chronic disease. If the drug utilization index reaches 80% or more, compliance is considered acceptable.

In order to increase the information content of patient surveys regarding adherence to treatment, specialized questionnaires and scales for assessing adherence are being created. They, as a rule, include not only questions directly related to compliance with recommendations for taking medications and non-drug treatment methods, but also questions of a general psychological nature regarding the patient’s readiness to interact, responsibility, follow advice, etc. Some of these scales have now been validated and recommended for widespread use.

The simplest test for assessing compliance is the Morisky-Green test, consisting of four questions:

1. Have you ever forgotten to take your medications?
2. Are you sometimes inattentive to the hours of taking medications?
3. Do you skip taking medications if you feel well?
4. If you feel unwell after taking medication, do you skip the next dose?

Patients who score 4 points are considered compliant, and those who score less than 3 are considered non-compliant [12]. Using this simple and accessible method will help the practitioner pay attention to those patients who need additional attention in order to increase their compliance.

What are the ways to increase patients' adherence to treatment?

Today there is no single effective strategy for increasing compliance, however, when talking about the impact on treatment adherence, two main aspects should be kept in mind.

The first, concerning the patient’s actual adherence to the doctor’s recommendations, primarily depends on the motivation for treatment. In this aspect, the main efforts should be aimed at creating this motivation, which, first of all, requires establishing contact with the patient and training him. A number of authors and groups of experts, based on large analytical reviews of the literature, emphasize a fundamental change in the very approach to patient participation in the treatment process and more active involvement in medical decision-making. In their opinion, without the active participation and desire of the patient to be treated, it is difficult to achieve solutions to short- and medium-term, and even more so long-term problems.

It has also been proven that patients do not tend to follow doctor’s recommendations if they are not informed about their disease and its complications. Therefore, in this aspect, the main efforts should be aimed at creating a stable and high-quality doctor-patient relationship, at providing the patient with complete information about the disease and its complications in order to create motivation for strict and regular implementation of preventive measures and taking medications.

One of the ways to form a “doctor-patient” partnership is to educate patients, in particular in health schools for patients with hypertension, which essentially represent a medical preventive technology based on a combination of individual and group influence on patients and aimed at increasing the level of their knowledge, awareness and practical skills for the rational treatment of hypertension, increasing patient adherence to treatment and preventing complications of the disease, improving the prognosis and improving the quality of life.

The second aspect of adherence to therapy is the actual daily intake of drugs without significant deviations from the dose and regimen. This aspect can be significantly improved by simplifying the treatment regimen itself and introducing special techniques to help the patient not miss the next dose.

The need to use combination therapy for hypertension

The key point of modern antihypertensive therapy is combination therapy using rational combinations of drugs, which allows not only to achieve the target blood pressure level without reducing the quality of life of patients with hypertension, but also to reduce the risk of developing cardiovascular complications.

The results of a meta-analysis of large-scale clinical trials in recent years strongly suggest that to achieve target blood pressure and reduce cardiovascular risk (CVR), most patients need to be prescribed multiple antihypertensive drugs [13]. Combination therapy, in fact, is currently a priority in the treatment of patients with hypertension, which is reflected in the new European and Russian guidelines on hypertension [7, 8]. Combinations of two or more antihypertensive drugs are recommended to be prescribed to patients already at the stage of initial therapy, primarily to patients with high cardiovascular risk, i.e. patients with three or more risk factors, with subclinical target organ damage, as well as those with there are already associated clinical conditions.

Carrying out combination therapy for patients with hypertension seems justified and justified also due to the fact that, according to the mechanisms of development and formation, hypertension is a multifactorial disease, and the combination of drugs with different mechanisms of action, complementary to each other, makes it possible to optimally influence the various pathogenetic mechanisms of hypertension. A rational combination of drugs involves the use of drugs from different classes with different mechanisms of action in order to obtain an additional hypotensive effect and reduce the risk of adverse events. The combination of drugs with different mechanisms of action can also reduce changes in tissues, differently affecting the mechanisms of damage to target organs: the heart, blood vessels and kidneys.

Fixed drug combinations - a path to improving patient adherence

Increasing adherence to antihypertensive therapy is one of the most realistic ways to increase its effectiveness. Obviously, compliance with recommendations can only be achieved through cooperation between the doctor and the patient, which is largely achieved through detailed and at the same time accessible informing the latter about the purpose of treatment for hypertension.

The use of fixed combinations of antihypertensive drugs, which have become increasingly widespread in recent years, can also help improve adherence [14]. Clinical studies have shown that fixed combinations of small doses of antihypertensive drugs belonging to different classes are more effective than the use of the same drugs alone. Fixed combination drugs, for the creation of which improved dosage forms are used, are of great importance for rational pharmacotherapy. The advantages of fixed drug combinations are ease of prescription and dose titration, increased treatment efficiency and more frequent achievement of target blood pressure, convenience for the patient, improved patient adherence to treatment, as well as pharmacoeconomic advantages - improved cost/effectiveness ratio. The widespread use of fixed combinations of drugs already at the initial stage of treatment is a priority trend in the rational pharmacotherapy of hypertension today.

The advantages of fixed combinations are that they allow you to simultaneously influence different parts of the pathogenesis of hypertension. As a result, this approach to treatment makes it possible to achieve a more pronounced hypotensive effect compared to the use of monotherapy with drugs included in the combination drug, especially in cases where one of them sufficiently completely blocks the activation of counter-regulatory mechanisms caused by the action of the other component. This often eliminates the need to use high doses of individual drugs.

An important advantage of the use of fixed-dose combination antihypertensive drugs is improved patient compliance with the prescribed treatment regimen.

Most patients do not take medications regularly and often stop treatment for several days. Even in cases where patients take prescribed antihypertensive drugs, they do not always do so at the prescribed time. In a special study using electronic devices, it was shown that in 25% of patients, the time of taking the drug was 6 hours different from the one prescribed by the doctor. The greatest deviations from the prescribed therapy regimen are observed in cases where the drug dosage regimen is too complex or significant adverse drug reactions occur. Reducing the number of tablets taken daily to lower blood pressure is considered an important advantage of fixed-dose combinations. Moreover, if a combination drug has to be taken 2 times a day, the degree of compliance with the prescribed therapy regimen decreases, so preference is given to drugs that are effective when taken once a day.

To date, a large evidence base has been accumulated in the world to study the effectiveness, tolerability, benefits in terms of the effect on the state of target organs and cardiovascular indicators of various two-component combinations of antihypertensive drugs.

One of the relatively new combination drugs is the drug Concor AM, which is a fixed combination of a beta blocker (bisoprolol) and a dihydropyridine AK (amlodipine). Each of these drugs has been used in clinical practice for a long time and has a large evidence base.

Over the past 50 years, beta blockers have taken a strong position in the pharmacotherapy of the most common CVDs, and it is no longer possible to imagine modern cardiology without them. A large evidence base has made it possible to include this class of drugs in almost all modern recommendations - for the treatment of hypertension, coronary artery disease, and heart failure. They reduce the risk and frequency of CVD, have a positive effect on the clinical manifestations of the disease and improve the quality of life of patients with various CVD, as well as with concomitant pathology [7, 8].

The basis for the widespread use of beta blockers was the identification of the role of chronic hyperactivation of the sympathoadrenal system (SAS) in the development of endothelial dysfunction, left ventricular hypertrophy, malignant heart rhythm disorders and the progression of chronic heart failure. BBs are a very heterogeneous group of drugs in their pharmacological effects, within which there are significant differences in pharmacokinetics and pharmacodynamics regarding two main indicators - cardioselectivity and lipophilicity. A common property of all beta blockers is competitive antagonism of β1-adrenergic receptors. Along with blocking β1-adrenergic receptors, beta-blockers can also block β2-adrenergic receptors.

Experience in the clinical use of beta blockers in the treatment of hypertension indicates that they, especially β1-selective drugs, have fairly high antihypertensive efficacy and good tolerability when used long-term in average therapeutic doses in a wide variety of categories of patients [15–21].

Bisoprolol, which has high cardioselectivity, is widely used in clinical practice. If we take the ability to block β1 receptors in carvedilol as one, then for metoprolol this figure will be 6, for bisoprolol - 21 [22]. Also, being amphophilic, that is, soluble in both fats and water, bisoprolol has two elimination routes - renal excretion and hepatic metabolism. This ensures greater safety of use in patients with concomitant liver and kidney damage, elderly patients, as well as a low likelihood of drug interactions.

In terms of antihypertensive effect, bisoprolol is not only not inferior to other beta blockers, but is superior to them in a number of indicators. Thus, in the BISOMET study, it was shown that bisoprolol is comparable to metoprolol in terms of the degree of reduction in blood pressure at rest, but significantly exceeds it in its effect on the level of systolic blood pressure and heart rate during physical activity [23]. The effectiveness of bisoprolol in reducing cardiovascular risk in combination with the absence of a negative effect on carbohydrate metabolism has been proven in large randomized clinical studies, including such well-known ones as CIBIS-II (Cardiac Insufficiency Bisoprolol Study II) [24], TIBBS (Total Ischemic Burden Bisoprolol Study) [25], etc.

Amlodipine, which is part of Concor AM, is a third-generation AK, with a half-life of more than 35 hours, and has greater selectivity for coronary and cerebral vessels. The drug is practically devoid of inotropic effect and influence on the function of the sinus node, atrioventricular conduction, which determines its advantage over other AKs (the verapamil and diltiazem groups).

From the point of view of clinical pharmacology, the combination of a highly selective beta blocker and dihydropyridine AK is reasonable and justified. The effects of bisoprolol and amlodipine are complementary in reducing blood pressure, since they affect different parts of the pathogenesis, allowing for increased antihypertensive effectiveness: the vasoselective effect of amlodipine (reduction of total peripheral vascular resistance (TPVR)) and the cardioprotective effect of bisoprolol (reduction of cardiac output, reduction of heart rate) ), which in turn helps reduce the risk of developing pathological conditions in hypertension, such as angina pectoris, myocardial infarction, myocardial remodeling, and myocardial infarction [27].

In accordance with Russian recommendations for the treatment of hypertension, the primary indications for prescribing Concor AM are a combination of hypertension with coronary artery disease, atherosclerotic lesions of the carotid and coronary arteries, tachyarrhythmias, as well as isolated systolic hypertension, hypertension in elderly patients, and hypertension in pregnant women.

Clinical experience with the use of Concor AM indicates good antihypertensive efficacy of the drug with a high frequency of achieving target blood pressure values ​​[26, 28, 29].

It is important to note that the studies conducted have demonstrated a good tolerability profile of the drug. Adverse events were mild and did not require discontinuation of the drug. Also, none of the ongoing clinical studies noted negative effects on carbohydrate and lipid metabolism [28, 29].

Important from a practical point of view is the fact that the drug is available in a wide range of doses of bisoprolol and amlodipine: 5 mg + 5 mg, 5 mg + 10 mg, 10 mg + 5 mg, 10 mg + 10 mg. This allows you to choose the optimal dosage regimen for each patient, taking into account individual hemodynamic characteristics.

Conclusion

Currently, the issues of rational pharmacotherapy and the optimal choice of drugs for various diseases are of particular relevance.

The quality of pharmacotherapy directly depends on the degree of patient adherence to treatment. Adherence is a key position linking the process and outcome of medical intervention. The use of fixed combinations of antihypertensive drugs in clinical practice simplifies the treatment regimen for patients with hypertension and helps improve adherence to treatment.

The drug Concor AM is a fixed combination of different doses of bisoprolol and amlodipine, has proven antihypertensive effectiveness in combination with a good safety profile. The components of the drug are complementary in relation to lowering blood pressure, since they affect different parts of the pathogenesis, allowing for increased antihypertensive effectiveness: the vasoselective effect of amlodipine (reduction of vascular resistance) and the cardioprotective effect of bisoprolol (reduction of cardiac output, decrease in heart rate), which in turn helps reduce the risk of developing pathological conditions in hypertension, such as angina pectoris, myocardial infarction, myocardial remodeling, cerebral stroke.

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I. Yu. Yudina T. E. Morozova1, Doctor of Medical Sciences, Professor

GBOU VPO First Moscow State Medical University named after. I. M. Sechenova Ministry of Health of the Russian Federation, Moscow

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