High risk patients

In recent years, the term “high risk patients” has become very popular. A number of publications are devoted to high-risk patients, and Russian and international CVD congresses often hold symposia on this topic. However, there is no common understanding of this term. The high-risk category includes patients of varying severity. For example, in the European guidelines for the prevention of CVD in clinical practice (2007), patients with high clinical risk include both patients with any clinical manifestations of atherosclerosis (coronary, cerebral, peripheral), and those without clinical signs of atherosclerosis. but there is a high risk of its development [91]. In the latest European and Russian recommendations on the diagnosis and treatment of hypertension, high-risk patients include those who have 3 risk factors,MS or sub-clinical lesions of target organs. If hypertensive patients have associated CVD, then they are classified as “very high risk”.

In order to objectively approach the definition of high-risk patients, it is necessary to recall the well-known concepts of the risk factors. There are three strategies for the prevention of CVDs that complement each other and are aimed at minimizing the risk of complications: a population strategy, a high risk strategy and secondary prevention.

The population strategy aims to influence those lifestyle and environmental factors that increase the risk of CVD development among the entire population. A high risk strategy involves identifying people at high risk of developing CVD among patients without clinical manifestations of atherosclerosis and implementing multifactorial prophylaxis. In essence, a high-risk strategy is the same as primary prevention. Thus, the key feature of high-risk patients is the absence of clinical manifestations of atherosclerosis. As for patients with clinical manifestations of atherosclerosis (coronary, cerebral, peripheral vessels), they are the object of secondary prevention, which is aimed at preventing the progression of CVD.

The relevance of a high-risk strategy is determined by the fact that high-risk patients in the total mass of cardiac patients are the overwhelming majority, therefore the main share of complications falls on this group. In this regard, timely identification of patients with high risk and the correct strategy for their management can significantly reduce the incidence of complications. If we talk about the strategy of managing high-risk patients, in recent years there have been major changes, and the importance of the drug component of managing such individuals has increased. Essentially, the principle of management of high-risk patients is the same as patients who already have CVD. For example, if you analyze the treatment strategy patients with stable angina pectoris, it can be noted that it consists of two aspects – the use of drugs to eliminate symptoms (nitrates) and the appointment of means to improve the prognosis (beta-blockers, statins, anti-aggregates).

For high-risk hypertensive patients, a modern management strategy will look similar: use of antihypertensive drugs (to lower blood pressure and improve patient well-being) and administer statins and antiplatelet agents to improve the prognosis. However, the problem of high-risk patients is that, unlike very high-risk patients, they are less motivated for treatment (risk factors do not “hurt”). Therefore, there is a gap between the need for intensive medical treatment and the weak motivation of these patients to treatment. However, this is another problem, and the physician should make every effort to guide these patients in terms of current requirements.

Let us dwell on the most important sections of the drug treatment of high-risk patients.

Antihypertensive therapy

The following chapter describes the main goals and objectives of antihypertensive therapy. Here we only note that high-risk patients, as well as very high-risk patients, need starting combination therapy, that is, quite intensive antihypertensive therapy at the initial stage of treatment.

Starting combination therapy is the key to the rapid achievement of target blood pressure in the majority of patients and significantly improves adherence to therapy. In actual clinical practice, patients with hypertension, most of whom are not motivated for treatment, need to quickly prove the effectiveness of the treatment chosen. Any delay in time associated with changing the dose, drug, or combination of drugs, undermines the patient’s confidence in the treatment and reduces adherence to it.

Lipid-lowering therapy

Recent studies have significantly expanded niches for the use of lipid-lowering therapy. If only recently the expediency of prescribing statins was justified by the presence of cardiovascular diseases, at present, lipid-lowering therapy is also indicated as a means of primary prophylaxis. A convincing evidence of this is the recently completed prematurely large randomized ASCOT – LL study [92]. The ASCOT – LL study on the efficacy of primary prevention of atorvastatin included 10305 patients, 40–79 years old, with moderate arterial hypertension, no history of IHD, but at least 3 risk factors for its development, in addition to arterial hypertension, with moderate hyperlipidemia (total plasma cholesterol <6.5 mmol / l, plasma triglycerides <4.5 mmol / l). In middle-aged patients with arterial hypertension, who, according to the existing recommendations, statin prescription is optional, atorvastatin for 3.5 years significantly reduced the combined risk of nonfatal heart attack and death from coronary heart disease (–36%), the total risk of cardiovascular complications and the need for revascularization ( –21%), risk of coronary complications (–29%), strokes (–27%) and the occurrence of stable coronary artery disease (–41%). In this way,According to the results of the ASCOT – LL study, there is an obvious need for the static use of statins in middle-aged patients with arterial hypertension and additional cardiovascular risk factors – even with normal or slightly elevated levels of atherogenic plasma lipid spectrum. However, in such patients, the positive effect of statins on the prognosis is not as impressive as in those with proven coronary artery disease and severe hyperlipidemia. A meta-analysis published in 2009, which compared statins with placebo, other active therapies or standard treatment of people without CVD, but with risk factors for their development, demonstrated the advisability of statin use in primary prevention. 10 recently completed randomized clinical trials, (70388 people, mean age 63 years,34% of women, 23% of patients with diabetes, the average duration of observation was 4.1 years, the initial LDL level was 3.63 mmol / l.) The primary end point of the meta-analysis was mortality from any cause. The secondary endpoints were: a) a combination of major coronary complications (death from coronary heart disease or nonfatal myocardial infarction), b) a combination of major cerebrovascular complications (fatal and nonfatal stroke). Lipid-lowering therapy significantly reduced overall mortality by 12%. The reduction in the risk of major coronary complications was 30%, of the main cerebrovascular complications – 19%. The risk of developing endpoints did not differ in the further analysis by subgroups depending on age (younger than 65 and over 65), gender, and the presence of diabetes. In this way,This meta-analysis demonstrated the effectiveness of statins in primary prevention of CVD, comparable to the use of statins in secondary prophylaxis in reducing the risk of death from all causes, as well as the main coronary and cerebrovascular complications.

Antiplatelet therapy

A joint analysis of studies, the Antiplatelet Trialist ‘Collaboration, devoted to evaluating the effectiveness of antiplatelet agents in various clinical manifestations of atherosclerosis, showed the possibility of reducing the risk from cardiovascular causes. Acetylsalicylic acid (ASA) was the most popular tool in studies subjected to meta-analysis. Despite convincing evidence of the feasibility of antiplatelet therapy obtained in evaluating many antiplatelet agents, only ASC is recommended as the gold standard. On the one hand, ASA drugs are recognized as the gold standard of antiplatelet therapy, but on the other hand, they cause side effects: gastropathy, gastrointestinal bleeding. Therefore, to ensure a balance between efficacy and safety, minimum doses of ASA (75–150 mg) are recommended.

In recent years, the niche for the use of Aspirin ® has significantly expanded . It has become possible to use this drug in high-risk patients, that is, as mentioned above, individuals without clinical manifestations of atherosclerosis [94]. This is evidenced by the results of a large-scale study, which included 4495 people with at least one of the traditional RF of coronary heart disease – age> 65 years, hypertension, hypercholesterolemia, diabetes, obesity, premature development of myocardial infarction in close relatives. Study participants were randomized to receive either Rowan 100 mg Aspirin ® Cardio or placebo. For 3.5 years of intervention among 2226 who took Aspirin ® 17 people died of cardio-vascular causes, and among 2269, in the control group, 31 patients died of these same causes – a 44% reduction in risk (p <0.05). Currently, in a number of recommendations, aspirin in small doses is recommended as an antiplatelet therapy not only for patients with clinical manifestations of atherosclerosis, but also for persons without clinical manifestations, but with a high risk (risk is more than 10% on the scale).

Nevertheless, according to the general opinion, the ratio of the effectiveness and safety of using aspirin in secondary prophylaxis exceeds a similar indicator when using this drug as a means of primary prophylaxis. In this regard, an individual approach and an assessment of the benefit / risk ratio is required when prescribing aspirin for primary prevention of SSO.

Objectives of antihypertensive therapy

According to current guidelines for the diagnosis and treatment of hypertension, five main classes of anti-hypertensive drugs are currently recommended for the treatment of hypertension: diuretics, beta-blockers, calcium antagonists, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists. These classes of drugs are conventionally considered basic, since they have a solid evidence base not only in order to reduce blood pressure, but also to reduce the risk of cardiovascular complications.

Based on the results of international multicenter, randomized studies, we can see that none of these classes of antihypertensive drugs have a significant advantage in terms of reducing blood pressure and preventing the development of MTR. At the same time, the choice of the drug in hypertension is determined by many factors associated with this disease: lesion of target organs , associated clinical conditions, renal pathology, diabetes mellitus, and other diseases. In the new version of the recommendations, when choosing a drug, great importance is attached to pleiotropic (multiple) effects, which will be discussed below. In general, each of the main classes of drugs has its own niche of use.

As for the I1 agonists of the imidazoline receptor and α-adrenoblockers, they are recommended mainly as part of a combination therapy.

Regardless of the choice of drug, it is necessary to achieve the main objective of antihypertensive therapy – to achieve the target level of blood pressure, which is the basis for ensuring the strategic goal of treatment of hypertension – the maximum possible reduction in the risk of SSO.

In the new recommendations for the diagnosis and treatment of arterial hypertension, target blood pressure levels in the treatment of patients with hypertension should be a blood pressure of less than 140/90 mm Hg. In patients with high and very high risk of SSO, it is necessary to reduce blood pressure to 140/90 mm Hg. and less for 4 weeks. In the future, under the condition of good tolerability, a decrease in blood pressure to 130–139 / 80–89 mm is recommended.

In this work, I would like to dwell on the new possibilities of various classes of drugs, as well as the problematic issues of their use, taking into account the pleiotropic effects outlined in modern guidelines.

Beta-blockers and diuretics

Without BB, which have been used in clinical practice since the 60s, it is impossible to provide treatment for a wide range of cardiac diseases, such as hypertension, coronary heart disease, heart failure, tachyarrhythmias. However, in recent years, the issue of negative side effects of BB has been widely discussed. This enabled some researchers to raise the question of restricting their use.

Back in the early 90s, based on an analysis of large-scale studies, it was suggested that the positive side effects of antihypertensive drugs may affect the effectiveness of therapy in the long term [4]. The basis of this assumption is a meta-analysis of placebo-controlled studies on the efficacy of long-term treatment of BB and diuretics from the point of view of preventing SSO [5].

As it is known, BB and diuretics were the first of antihypertensive drugs, which proved to be effective not only in terms of adequate blood pressure control, but also in reducing the risk of MTR. On the other hand, this meta-analysis showed that the existing decrease in the risk of SSO was significantly lower than expected (calculated on the basis of a decrease in blood pressure). This was especially true for CHD. AT the risk of developing coronary artery disease was only 14–16% lower than in the placebo group. Considering that coronary artery disease is the main complication of hypertension, the efficacy of treatment of BB and diuretics was considered insufficient. Among the main causes of this phenomenon were considered and the negative side effects of these classes of drugs that could level the positive effect of reducing blood pressure. The negative effects of BB and diuretics include the worsening of insulin resistance, deterioration of the lipid profile and a decrease in glucose tolerance. Thus, if the positive effect of a decrease in blood pressure competes with the proatherogenic and prodiabetogenic effect of anti-hypertensive therapy, then the risk of developing diabetes increases, and in the long run, the SSO. Further studies have shownthat other classes of drugs – calcium antagonists, ACE inhibitors, ARA are, at least, metabolically neutral. Recently completed large-scale international multicenter studies have convincingly confirmed the validity of the metabolic theory. The frequency of development of type 2 diabetes with the use of calcium antagonist – verapamil SR in an INVEST (International Verapamil SR / Trandolapril Study) study [6], and an ACE inhibitor – lisinopril in a study of ALLHAT [ 7] and ARA-losartan in the LIFE (Losartan Intervention for Endpoint reduction) study [8] was significantly lower than in the group of patients who received BB and diuretics. Moreover, a meta-analysis of 22 studies published in 2007 that included more than 160,000 patients showedthat the use of BB and diuretics is associated with a higher risk of developing diabetes than placebo. In the same meta-analysis, it was revealed that the lowest risk of developing diabetes is observed when using ACE inhibitors and ARA [9].

The subject of negative side effects of some BB (mainly atenolol) and diuretics is currently being used by some scientists to limit their use in clinical practice. For example, a number of authors propose to completely remove BB from the arsenal of drugs used to treat patients with uncomplicated hypertension, leaving this class of drugs only for the purposes of secondary prevention of diseases [10]. Experts of the British recommendations for the treatment of hypertension, issued in 2006, went further than that in this regard. In them, they recommend using BB as a fourth-line treatment for treating hypertension [11]. How to be a practical doctor in this situation?

The recent criticism of the BB by individual researchers should not be misleading as a practical doctor. He should always ask himself what kind of BB are we talking about. Indeed, a number of BB, especially non-selective, have negative metabolic effects and in a number of clinical situations (metabolic disorders, COPD, peripheral atherosclerosis) cannot be used. At the same time, modern superselective BBs do not have these negative effects and can be widely used in clinical practice, including those with uncomplicated AH.

Thus, regarding the use of BB in clinical practice, it is necessary to take a flexible position. This is the opinion of experts from the European and Russian recommendations for the treatment of diagnosis and treatment of hypertension. These documents noted that modern BB have a less pronounced negative effect on metabolism. This number of BB includes, as is known, metoprolol, nebivolol, bisoprolol, carvedilol.

For example, bisoprolol has a solid evidence base regarding its metabolic neutrality: lack of influence on the lipid and carbohydrate profile. Moreover, in a recent randomized study in 92 patients with hypertension and compensated type 2 diabetes, bioprolol, like captopril, did not adversely affect glycated hemoglobin, fasting sugar and 2 hours after the glucose tolerance test.

Of particular interest is nebivolol with additional vasodilating effect by increasing the synthesis of NO. First of all, it should be noted good antihypertensive efficacy and tolerance of nebivolol. It has a prolonged effect and at the same time provides uniform control of blood pressure throughout the day, which is the most important requirement of modern antihypertensive therapy. This is evidenced by the 90% value of the ratio of the residual hypotensive effect to the maximum (T / P). The data of foreign and domestic studies convincingly demonstrate the improvement of endothelial function in the treatment of people with hypertension with nebivolol [95-97].

Moreover, in our own open-label study, in 25 patients with mild and moderate hypertension, positive microcirculatory effects of Nebivolol (Nebilet, Berlin-Chemie, Germany) were revealed. The study of microcirculation was carried out using laser Doppler flowmetry on a LAKK-01 apparatus by Lazma, Russia. Laser Doppler flowmetry (LDF) is a simple and safe method for studying microcirculation and indirect assessment of endothelial function. The method allows to investigate changes in blood flow in the microvasculature using laser radiation, using the Doppler effect. The LDF method is objective, accurate and gives reproducible results.

The most important parameters for assessing the state of microcirculation are the microcirculation index (PM) and the capillary blood flow reserve (RCM). PM is formed as a result of the reflection of a laser signal from erythrocytes moving at different speeds in the arterio- lar, capillary and venu- lar parts of the microvasculature. The decrease in PM occurs with spasm bringing reduction of the number of functioning capillaries and desolation of the arteriolar microcirculation link (MC), or with a decrease in the speed of red blood cells, i.e., with symptoms of stasis. An increase in PM occurs when the arterioles tone decreases and the blood supply in the microcirculation system increases. PM is calculated in perfusion units (perf. Units). RSC, expressed as a percentage, is calculated by the ratio of the maximum PM to the initial PM. RCC reflects the microvascular reactivity. A decrease in RSC is observed both with an increase in the inflow into arterioles and an increase in the number of functioning capillaries, as well as with stasis and stagnation. An increase in RSC is noted in spastic phenomena, when initially the majority of microvessels are in a non-functioning state,but retains the ability to expand in response to stress (in this case, clamping the cuff). The parameters of PM and RSC are determined by the hemodynamic type of microcirculation, which is an integral indicator for assessing the functional state of microcirculation. Normocirculatory, spastic, hyperemic, and congestive-stasis hemodynamic types of microcirculation are distinguished.

After Nebilet therapy in the group of patients with spastic type of MC (14 people), there was a marked increase in the microcirculation index. PM before treatment was 3.4 ± 0.3; after treatment – 7.2 ± 0.8 perf.ed, p <0.05. This indicates an improvement in blood flow in the microcirculation system. This is also evidenced by the dynamics of the RSC. As a result of treatment, the initially elevated RCC decreased by 30.6% (p <0.001). These changes indicate a decrease in spastic phenomena, an increase in the number of functioning capillaries and an improvement in tissue perfusion.

In patients with hyperemic type of MC (8 people) while receiving Nebivolol there was a decrease in PM from 7.2 ± 1.1 perf. units up to 4.0 ± 0.6 perf. units (p <0.05). In this case, a decrease in PM can be regarded as a positive moment since this indicates a decrease in the phenomena of hyperemia. In addition, in this group of patients, there was an increase in the initially reduced RCC by 36.8% (p <0.001). This may be due to a decrease in excess blood filling in the arteriolar circuit of the ICR. Thus, the use of Nebivolol led in general to an improvement in the microcirculation system in patients with AH. Of course, the positive microcirculatory effects of Nebilet are a consequence of the vasodilating properties of this drug.

Thus, the emergence of super-selective beta-blockers significantly expanded the boundaries of their use, and the practitioner should be more boldly prescribed in various clinical situations, including in the case of the metabolic syndrome and diabetes.

The same ambiguous approach is necessary when prescribing diuretics in clinical practice. Appointment of diuretics, of course, requires consideration of their negative metabolic effects, especially characteristic of high doses [17]. However, in some situations it is necessary to be guided by clinical expediency. Diuretics have been and remain indispensable means of treating hypertension complicated by CHF. In hypertension and concomitant renal failure, the appointment of loop diuretics is indicated. In these situations, diuretics can be given in high doses, since the clinical relevance outweighs the risk of exacerbating metabolic disorders. However, with uncomplicated hypertension, especially in the presence of concomitant metabolic disorders, it is better to avoid prescribing high doses of thiazide diuretics because of the increased risk of diabetes, as was shown in large-scale studies. The same applies to patients with hypertension and diabetes,since the use of high doses of diuretics may increase the risk of developing vascular complications. In these situations, it is better to use a metabolically neutral indapamide. In addition, thiazide diuretics in low doses do not adversely affect metabolism, but they enhance the effects of almost all classes of antihypertensive drugs.

The use of calcium antagonists in clinical practice

Calcium antagonists, currently widely used in cardiological practice, are one of five classes of antihypertensive drugs, whose effectiveness has been proven in both placebo-controlled and comparative studies with end-point studies. The first study where calcium antagonists showed comparable efficacy with diuretics and BB in reducing the incidence and mortality from CVD was the Swedish study STOP Hypertension-2 (Swedish Trial in Old Patients with Hypertension). In 6614 patients who received either a dihydropyridine calcium antagonist (felodipine or isradipine), or a diuretic and / or BB, or an ACE inhibitor (enalapril or lisinopril), the effectiveness of these antihypertensive drugs was comparable.In general, no differences were established between them in terms of their impact on mortality from CVD [18]. Similarly, in a large-scale randomized study INSIGHT (Intervention as a Goal in Hypertension Treatment), in which 6321 patients with moderate and high AH for 4 years studied the effectiveness of prolonged nifedipine and diuretics (25 mg of hydrochlorothiazide in combination with 2.5 mg of amiloride), there were no significant differences between the groups by the primary end points (MI + stroke + death from CVD) and total mortality. In the same study, the most important data on the beneficial effects of nifedipine-GITS on metabolism were obtained. In the treatment group with this drug, the incidence of type 2 diabetes was significantly lower than in patients treated with diuretics.in a large-scale randomized study INSIGHT (Intervention as a Goal in Hypertension Treatment), in which 6321 patients with moderate and high AH for 4 years studied the effectiveness of prolonged nifedipine and diuretics (25 mg of hydrochlorothiazide in combination with 2.5 mg of amiloride ), there were no significant differences between groups on the primary endpoints (MI + stroke + death from CVD) and total mortality. In the same study, the most important data on the beneficial effects of nifedipine-GITS on metabolism were obtained. In the treatment group with this drug, the incidence of type 2 diabetes was significantly lower than in patients treated with diuretics.in a large-scale randomized study INSIGHT (Intervention as a Goal in Hypertension Treatment), in which 6321 patients with moderate and high AH for 4 years studied the effectiveness of prolonged nifedipine and diuretics (25 mg of hydrochlorothiazide in combination with 2.5 mg of amiloride ), there were no significant differences between groups on the primary endpoints (MI + stroke + death from CVD) and total mortality. In the same study, the most important data on the beneficial effects of nifedipine-GITS on metabolism were obtained. In the treatment group with this drug, the incidence of type 2 diabetes was significantly lower than in patients treated with diuretics.in which 6321 patients with moderate and high AH over 4 years studied the effectiveness of prolonged nifedipine and diuretics (25 mg of hydrochlorothiazide in combination with 2.5 mg of amiloride), no significant differences were found between the groups on the primary end points (MI + stroke + death from CVD) and total mortality. In the same study, the most important data on the beneficial effects of nifedipine-GITS on metabolism were obtained. In the treatment group with this drug, the incidence of type 2 diabetes was significantly lower than in patients treated with diuretics.in which 6321 patients with moderate and high AH over 4 years studied the effectiveness of prolonged nifedipine and diuretics (25 mg of hydrochlorothiazide in combination with 2.5 mg of amiloride), no significant differences were found between the groups on the primary end points (MI + stroke + death from CVD) and total mortality. In the same study, the most important data on the beneficial effects of nifedipine-GITS on metabolism were obtained. In the treatment group with this drug, the incidence of type 2 diabetes was significantly lower than in patients treated with diuretics.In the same study, the most important data on the beneficial effects of nifedipine-GITS on metabolism were obtained. In the treatment group with this drug, the incidence of type 2 diabetes was significantly lower than in patients treated with diuretics.In the same study, the most important data on the beneficial effects of nifedipine-GITS on metabolism were obtained. In the treatment group with this drug, the incidence of type 2 diabetes was significantly lower than in patients treated with diuretics.

Calcium antagonists are one of the most effective classes in terms of prevent the development of cerebral strokes. This is evidenced by a meta-analysis of large-scale studies. In this respect, the study of NORDIL stands out. This is the only study that demonstrated a statistically significant reduction in MI against the background of the use of a calcium antagonist compared with BB and diuretics. In the indicated randomized prospective study, which lasted 5 years and included 10881 previously untreated patients with hypertension aged 50- 74 years, compared the effectiveness of diltiazem (180-360 mg per day) and BB or diuretics. The frequency of the primary endpoints (total, including strokes, myocardial infarction, and death from other cardiovascular causes) was the same in both treatment groups. At the same time, the frequency of fatal and nonfatal MI was significantly lower in the diltiazem group (–20%, p = 0,04), despite the fact that the degree of blood pressure reduction in this group was slightly less than in the BB group or diuretics (–20.3 / 18.7 mm Hg vs. –23.3 / 18.7 mm Hg). Art.), which researchers explain is not sufficiently high dosage of diltiazem [21]. A possible explanation for the effectiveness of diltiazem in the prevention of stroke is the anti-atherogenic effect of the drug and the ability to reduce the activity of the SNA. Thus, in the VHAS study (Verapamil in Hypertension and Atherosclerosis Study), the same frequency of MTR was found in the treatment of Verapamil-SR and 1414 patients with hypertension with chlorthalidone. However, Verapamil-SR was superior to chlorthalidone in slowing the thickening of the carotid intima media (p <0.01) with a comparable decrease in blood pressure.3 / 18.7 mm Hg Art. against –23.3 / 18.7 mm Hg Art.), which researchers explain is not sufficiently high dosage of diltiazem [21]. A possible explanation for the effectiveness of diltiazem in the prevention of stroke is the anti-atherogenic effect of the drug and the ability to reduce the activity of the SNA. Thus, in the VHAS study (Verapamil in Hypertension and Atherosclerosis Study), the same frequency of MTR was found in the treatment of Verapamil-SR and 1414 patients with hypertension with chlorthalidone. However, Verapamil-SR was superior to chlorthalidone in slowing the thickening of the carotid intima media (p <0.01) with a comparable decrease in blood pressure.3 / 18.7 mm Hg Art. against –23.3 / 18.7 mm Hg Art.), which researchers explain is not sufficiently high dosage of diltiazem [21]. A possible explanation for the effectiveness of diltiazem in the prevention of stroke is the anti-atherogenic effect of the drug and the ability to reduce the activity of the SNA. Thus, in the VHAS study (Verapamil in Hypertension and Atherosclerosis Study), the same frequency of MTR was found in the treatment of Verapamil-SR and 1414 patients with hypertension with chlorthalidone. However, Verapamil-SR was superior to chlorthalidone in slowing the thickening of the carotid intima media (p <0.01) with a comparable decrease in blood pressure.A possible explanation for the effectiveness of diltiazem in the prevention of stroke is the anti-atherogenic effect of the drug and the ability to reduce the activity of the SNA. Thus, in the VHAS study (Verapamil in Hypertension and Atherosclerosis Study), the same frequency of MTR was found in the treatment of Verapamil-SR and 1414 patients with hypertension with chlorthalidone. However, Verapamil-SR was superior to chlorthalidone in slowing the thickening of the carotid intima media (p <0.01) with a comparable decrease in blood pressure.A possible explanation for the effectiveness of diltiazem in the prevention of stroke is the anti-atherogenic effect of the drug and the ability to reduce the activity of the SNA. Thus, in the VHAS study (Verapamil in Hypertension and Atherosclerosis Study), the same frequency of MTR was found in the treatment of Verapamil-SR and 1414 patients with hypertension with chlorthalidone. However, Verapamil-SR was superior to chlorthalidone in slowing the thickening of the carotid intima media (p <0.01) with a comparable decrease in blood pressure.01) with a comparable decrease in blood pressure.01) with a comparable decrease in blood pressure.

In the above-mentioned INSIGHT study among patients receiving nifedipine, there was a more pronounced slowing down of the intimal thickening of the carotid arteries than among patients treated with diuretics . In turn, the antiatherogenic effect attributable to calcium antagonists is associated with the ability of this class to correct endothelial dysfunction. This is evidenced by numerous clinical studies, including those performed at a high methodological level in the evaluation of the endothelial function .

The antiatherogenic effect of calcium antagonists is reflected in the new European guidelines for the diagnosis and treatment of hypertension: one of the most important niches for the use of calcium antagonists (both dihydropyridine and non-dihydropyridine) is associated with atherosclerosis of various localization vessels , including coronary . In addition, general indications for the use of all calcium antagonists are hypertension of various origins, arresting hypertensive crises, as well as prevention and relief of angina attacks of various nature (including vasopasmodic angina).

In conclusion, I would like to draw the attention of practitioners to one of the most important aspects of the use of calcium antagonists in clinical practice: the division of this class of drugs into two large subgroups based on their impact on the SNA, dysregulation of which plays an important role not only in raising and maintaining arterial levels – but also in the occurrence of a number of other negative effects , which significantly increase the risk of cardiovascular complications. . The first subgroup is the so-called pulse-reducing calcium antagonists (Verapamil and Diltiazem). These drugs reduce myocardial contractility, reduce the heart rate, and also have an anti-arrhythmic effect and slow down atrioventricular conductivity. Due to these properties, the drugs improve the function of the autonomic nervous system, restoring the balance between the sympathetic and parasympathetic nervous systems and reduce the myocardial oxygen demand . The second subgroup is pulse rate-increasing calcium antagonists, or dihydropyridines. In these drugs, the ability to cause dilatation of peripheral arteries prevails, as a result of which the SNS reflexively increases and the heart rate increases. . According to the results of numerous studies, on the basis of this, there are differences in the efficacy of dihydropyridine and non-dihydropyridine AK in different clinical situations. Pulse-reducing non-dihydropyridine calcium antagonists are effective and safe for treating various forms of coronary artery disease, whereas dihydropyridine calcium antagonists cause undesirable effects in acute conditions such as unstable angina and acute myocardial infarction, most likely due to SNA activation. . For example, in the HINT study (Holland Inter-University Nifedipine Trial), it was shown that intravenous administration of the short-range dihydropyridine calcium antagonist nifedipine resulted in a rate of adverse outcomes (recurrent ischemia and myocardial infarction) during the first 48 hours.(from the moment of hospitalization) was significantly higher than at using metoprolol . Another study demonstrated an increase in early mortality in these patients during therapy with nifedipine compared with nitrates and / or BB . In contrast, the diltiazem administered intravenously non-dihydropyridine calcium antagonist significantly reduced the incidence of some adverse outcomes (angina attacks, ischemic changes in the myocardium on the ECG) during the first two days and exceeded intravenous nitroglycerin in its efficacy . The use of dihydropyridine calcium antagonists (prolonged preparations) should be limited to cases of vasospastic angina pectoris and stable exertional angina pectoris.

It is no coincidence that the European recommendations for the control of hypertension emphasize the clinical significance of the division of calcium antagonists into two groups: dihydropyridine and non-dihydropyridine . In addition to the general indications for the use of these two subgroups of drugs, non-dihydropyridine calcium antagonists have an additional indication – treatment of tachyarrhythmias, as a fact indicating the sympatolytic effect of this subclass of calcium antagonists.

Inhibitors of ACE in clinical practice

In recent years, in the clinical practice, ACE inhibitors are increasingly prescribed. And this is quite natural, since the imbalance of the renin-angiotensin system plays an important role in the development of cardiovascular diseases. Throughout the last decade, numerous studies have been conducted in which the clinical efficacy of ACE inhibitors in various cardiovascular diseases has been studied. The results of these studies are reflected in domestic recommendations, according to which an ACE inhibitor should be prescribed to patients with arterial hypertension, heart failure, acute and myocardial infarction and diabetic nephropathy .

ACE inhibitors are one of the most studied classes of antihypertensive drugs, the effectiveness of which, following diuretics and BB, has been proven in large-scale randomized trials with endpoints. The first study of this kind was the CAPPP study, which compared the effectiveness of ACE inhibitors (captopril 50 mg per day) with atenolol and metoprolol (50–100 mg per day) or hydrochlorothiazide (25 mg per day) for 6 years in the treatment of 10985 patients with hypertension There were no differences in the frequency of the combined endpoint (fatal and non-fatal strokes and myocardial infarction, as well as mortality from other cardiovascular causes) between groups of patients who received ACE inhibitors and BB or diuretics.In this study, a more favorable metabolic profile of captopril was also demonstrated compared with BB and diuretic. The incidence of diabetes by the end of the study in the captopril group was 21%. lower than the other group .

A relatively new scope of ACE inhibitors is the prevention of complications and an increase in mortality in patients with high cardiovascular risk. This is explained by the fact that ACE inhibitors are one of the most effective classes of drugs in terms of improving endothelial function. At least two possible mechanisms of the effect of an ACE inhibitor on the endothelial function have been described. It is possible that ACE inhibitors increase the level of tissue bradykinin [37–38], a powerful stimulator of the release of endothelium-dependent relaxation factors: NO, endothelium-dependent hyperpolarization factor and prostacyclin (PGI2). Another mechanism of action of an ACE inhibitor is the blockade of the formation of angiotensin II, which is considered as an inducer of oxidative stress, leading to a decrease in the bioavailability of NO. AII has the opposite effect with respect to NO.Inhibition of ACE can restore the balance between two vasoactive systems . The dual mechanism of ACE inhibitors is to block the formation of angiotensin II and prevent the destruction of bradykinin, which stimulates the synthesis of endothelial NO, causes the antihypertensive, antiproliferative and angioprotective action of these drugs.

The ability of an ACE inhibitor to improve endothelial function and inhibit atherogenesis processes was first demonstrated in a study of TREND (Trial on Reversing Endothelial Dysfunction) [41]. In a randomized trial lasting half a year in the treatment of 129 IHD patients, the effectiveness of quinapril in relation to the restoration of impaired endothelial function of the coronary arteries was examined, which was assessed using a sample with intracoronary acetylcholine during coronaryography. A reduction of 10–20% in the severity of vasoconstrictor reactions after quinapril therapy was found.

In the BANFF Study, a comparative assessment of the correction of endothelial function was performed with 8 weeks of treatment with different classes of antihypertensive drugs (amlodipine, quinapril, enalapril, losartan) in 80 patients with CHD. The majority of the sample were men (80%), the average age was 58 ± 0.9 years. The risk factors were as follows: hypercholesterolemia was in 54% of patients, AH – in 26%, diabetes – in 10%. A history of myocardial infarction was recorded in 47% of patients, 95% of patients underwent coronary angioplasty. In the course of treatment, blood pressure and blood lipid spectrum did not differ significantly, and the endothelium-dependent vasodilation of the brachial artery in patients with risk factors improved only during treatment with quinapril, while amlodipine, enalapril and losartan did not affect endothelial function [42].

The powerful effect of ACE inhibitors on endothelial function is also confirmed by the results of our own research on the advantages of this class of drugs over others in the treatment of smoking patients with hypertension.

Analysis of large-scale studies indicates a decrease in the effectiveness of antihypertensive drugs in the treatment of smoking patients with hypertension. The use of b- blockers allowed to reduce the number of coronary episodes in non-smoking hypertensive patients, while smokers had no such effect . According to the results of the study using Smad in patients with arterial hypertension, it was found that in smoking patients the levels of systolic and diastolic blood pressure, as well as the heart rate, are statistically significantly higher than in non-smoking patients. The authors make the assumption that such results may indicate that patients with hypertension are not treated . . An analysis of the national sample of treated individuals with hypertension in Sweden, which included 4,424 patients, observed in 189 doctors, indicates a decrease in the effectiveness of antihypertensive therapy in smoking patients. The percentage of inadequately treated persons in relation to DBP (≥ 90 mm. Mercury) in the group of smokers is 32.7%, in the group of non-smokers – 25%, p <0.01. The corresponding figures of systolic blood pressure (≥ 140 mm Hg) are 72.8% and 68.9%, p <0.01 . In the Russian multicenter study Prologue in the group of the main treatment (starting therapy with an ACE inhibitor followed by the addition of hydrochlorothiazide and atenolol), the effectiveness of blood pressure reduction in the smoking group was significantly less than in the non-smoking group [46]. The most important reason for reducing the effectiveness of antihypertensive drugs for the treatment of smokers is endothelial dysfunction that develops in this category of patients [47, 48]. Endothelial dysfunction leads to pronounced peripheral vasospasm, which in turn reduces blood flow at the level of microcirculation followed by ischemia of organs and tissues, which leads to the maintenance of high blood pressure. Therefore, it can be assumed that antihypertensive drugs, corrective DE should have an advantage in smoking patients with hypertension. Such classes of drugs primarily include ACE inhibitors. Let us take an example of another study:23 smokers of patients with hypertension (mean age 38 ± 12 years, smoking experience – 21 years, the average number of cigarettes smoked – 19), who had no other risk factors for 8 weeks, received 20 mg of lisinopril and placebo alternately. The treatment with lisinopril showed a significant increase in the blood flow in the forearm in response to the intraarterial administration of acetylcholine. This fact indicates an improvement and endothelial function . There are few studies confirming the effectiveness of an ACE inhibitor in the treatment of smoking patients with hypertension. In the randomized crossover study, the antihypertensive efficacy of enalapril and atenolol was studied in the treatment of male smokers with AH. The ACE inhibitor enalapril in the smoking group was found to be more effective than the b- blocker atenolol .

In the randomized crossover study itself, 30 smoking patients, men aged 35–64 years with mild and moderate essential arterial hypertension, were included. Within 12 weeks, patients received the drug Iruzid, which is a fixed combination of 20 mg of lisinopril and 12.5 mg of hydrochlorothiazide, and a combination of 50 mg of atenolol with 12.5 mg of hydrochlorothiazide. The decrease in systolic blood pressure after Iruzid treatment amounted to an average of 16.6 mm Hg. Art., and diastolic blood pressure – 10.3 mm Hg. Art. The corresponding figures for a decrease in blood pressure during treatment with a combination of atenolol and hydrochlorothiazide are 11, 9, and 7.6 mm Hg. Art. Differences in decreases and systolic
 
 
 
 
 
 
 
 
 
 
 and diastolic blood pressure is significant (p <0.005). Thus, Iruzid provided a more pronounced decrease in blood pressure in smokers than the combination of 0.15 % atenolol and hydrochlorothiazide. These differences

Patients who reach the combined primary endpoint (myocardial infarction, stroke, cardiovascular death). Ashley reflected in the effect of two strategies of treatment on endothelial hydrochloric function which is evaluated using a cuff test,
 
 
 
 
 
 those. assessment of endothelium- dependent vasodilation (EDVD) of the brachial artery using high-resolution ultrasound. Iruzid therapy led to a marked improvement in endothelial function. Against the background of therapy with Iruzid, a significant pronounced increase in EDVD was observed – 7.9% ± 3.0 before treatment and 15.5% ± 2.2 after treatment (p <0.05). During treatment with a combination of atenolol and hydrochlorothiazide, the change in EDVD was statistically insignificant – 8.2% ± 3.4 and 9.6% ± 3.6 (p> 0.05).

The hypothesis of the possibility of preventing complications and death in patients with high cardiovascular risk of ACE inhibitors has been tested in a number of large multi-site studies: HOPE (Heart Outcomes Prevention Evaluation Study), EUROPEA (EURopean trial coronary Arte-ry disease), PEACE (Prevention of events with Anti- ingin-converting Enzyme inhibition). This list stands out as the HOPE study [51], which involved 9297 men and women with confirmed atherosclerosis of various localization (coronary heart disease, peripheral arterial disease, stroke) or diabetes mellitus at least another risk factor (arterial hypertension, cigarette smoking, microalbuminuria, or dyslipidemia). 80% of patients had coronary heart disease,55% – angina, 52% – history of myocardial infarction, 43% – atherosclerosis of the peripheral arteries, 25% – unstable angina in history, and 26% – coronary artery bypass surgery in history, 18% – percutaneous regstrium, and 18% – acute coronary artery bypass graft bypass, in 18% – percutaneous regstrosis, in 18% – acute coronary artery bypass surgery. 11% have a stroke or transient ischemic attack. Almost half of the patients suffered from hypertension and about 40% – type 2 diabetes. Patients were given a placebo or an ACE inhibitor ramipril (with titration of doses from 1.25 to 10 mg) and continued monitoring for an average of 5 years. The primary endpoint (cardiovascular death, MI, or stroke) was recorded in 17.8% of patients in the placebo group and 14.0% of patients in the ramipril group, reflecting a 22% reduction in risk, p <0.001 (Fig. 3). Ramipril therapy led to a decrease in the frequency of the most important components of this end point – MI, MI (Fig. 4.5). Besides,a reduction in total mortality (from 12.2 to 10.4% within 5 years), the need for revascularization, diabetic complications, diabetes, heart failure, progression of angina pectoris, or cardiac insufficiency. An interesting fact is that the decrease in blood pressure in the ramipril group was relatively small (BP is 3/3 mm Hg), so the results of treatment cannot be explained only by antihypertensive drugs. the effect of the drug .

Thus, in this study, the protective role of ramipril was confirmed in terms of preventing the development of complications in patients with high risk. Moreover, the protective effect of ramipril is in no way associated with a decrease in blood pressure.

Additional evidence of the effectiveness of long-term treatment of ACE inhibitors for the purpose of secondary prophylaxis is the results of the EUROPA study [52]. It included 13,655 patients in the low-risk group, without heart failure, who suffered from stable coronary heart disease. For an average of 4.2 years, they were treated with perindopril or placebo. In patients with perindopril, a decrease in the incidence of cardiovascular outcomes (cardiovascular death, myocardial infarction, sudden death) from 10 to 8% was detected, which meant that for the prevention of a single cardiovascular outcome, treatment was necessary for 4 , 2 years in 50 patients. The benefits of ACE inhibitors were comparable in all subgroups of patients.

HOPE study results

The results of the HOPE and EUROPA study suggest a new clinical direction in the use of ACE inhibitors to slow the progression of atherosclerosis-related diseases. However, if we strictly rely on the principles of evidence-based medicine, we can talk about the protective effect of perindopril in treating patients with stable ischemic heart disease (CHD) and the universal protective effect of ramipril in treating all patients with clinical manifestations of atherosclerosis (CHD, strokes, peripheral atherosclerosis). Can the protective effect of ramipril and perindopril, associated with slowing the progression of atherosclerosis, be transferred to the entire class of ACE inhibitors? The answer must be negative, because in relation to other drugs in this regard there is no evidence base. Moreover,in the placebo-controlled PEACE study involving 8290 patients with stable angina without signs of heart failure, the addition of 4 mg of trandolapril during basic therapy did not lead to an additional reduction of complications [53]. Similarly, in the placebo-controlled study CAMELOT, which involved 1991 patients with stable coronary artery disease without signs of heart failure, the addition of 20 mg of enalapril to the main therapy did not lead to a more pronounced decrease in complicationswhich involved 1991 patients with stable coronary artery disease with no signs of heart failure, the addition of 20 mg of enalapril to the main therapy did not lead to a more pronounced decrease in complications compared with the patientwhich involved 1991 patients with stable coronary artery disease with no signs of heart failure, the addition of 20 mg of enalapril to the main therapy did not lead to a more pronounced decrease in complications compared with the patient placebo therapy . It is not by chance that only ramipril and perindopril are recommended in the European guidelines for the diagnosis and treatment of stable angina for these patients in terms of slowing the progression of the disease and improving the prognosis of this category of patients from an ACE inhibitor [55]. Similarly, in the second revision of the Russian recommendations on chronic heart failure for the prevention of this disease in patients with coronary artery disease, the prescription of either ramipril or perindopril is recommended as having an evidence base [35]. Moreover, ramipril has an evidence base in relation to the anti-atherogenic effect. The SECURE study, which was carried out within the framework of HOPE, studied the effect of ramipril and vitamin E on the condition of the carotid arteries, examined using the ultrasound method. Was shown,that long-term ramipril therapy delayed the progression of carotid atherosclerosis in patients with atherosclerosis or diabetes mellitus who did not have heart failure [56]. Largely due to this research, in the latest European guidelines for the treatment of AH 2007, a new niche for the use of ACE inhibitors has appeared – a concomitant terosclerosis of the carotid arteries . In another program MICRO-HOPE in the framework of the study NORE in 3577 patients with type 2 diabetes mellitus ramipril reduced the risk of microvascular complications of diabetes mellitus, such as chronic renal failure by 24% (p = 0.027) and retinopathy by 22% (p = 0.024) [57]. In a double-blind, randomized trial of AASK, a pronounced nephroprotective effect of ramipril was demonstrated. In the case of 1094 patients with hypertensive nephropathy (glomerular filtration rate (GFR) within 20–65 ml / min), ramipril at a dose of 2.5–10 mg is more effective than amlodipine and metoprolol slowed the decrease in GFR, the development of chronic renal failure and prolonged the life of patients [58]. Thus, the above studies indicate a powerful vazoprotective effect of ramipril, which has important clinical significance. In clinical practice, in addition to the traditional use of ramipril in hypertension and heart failure,It is necessary to provide patients with practically any manifestations of atherosclerosis – coronary, cerebral and great vessels, as well as patients with nephropathy. At present, an effective generic generic of ramipril – charter has appeared on the Russian pharmaceutical market. A preliminary analysis of a recently completed proprietary study indicates a high antihypertensive efficacy and safety of the charter. Summing up, the overview of international and Russian data presented above makes it possible to take a fresh look at the possibilities of an ACE inhibitor. Traditional niches for the use of ACE inhibitors (hypertension, cardiac insufficiency, diabetic nephropathy) have expanded in recent years thanks to the powerful vasoprotective effect of ACE inhibitors, which opens up new clinical possibilities for their use – in terms of slowing the progression of diseasesassociated with atherosclerosis. At the same time, it is necessary to understand that this effect is not inherent in the whole class of drugs, but is characteristic only of ramipril (charter) and perindopril. At least, based on evidence from evidence-based medicine, a protective effect on the progress of cardiovascular diseases can only be talked about these two drugs.

Organ-protective effects

In recent years, ARA has made a huge leap forward in terms of conquering new niches for the treatment of hypertension in various clinical situations. If earlier this class of drugs was in the shadow of an ACE inhibitor (their prescription for hypertension was limited mainly by situations related to side effects due to the administration of ACE inhibitors), then at present the niche of their use, as follows from Table 1, extensive. To better understand the possibilities of ARA, it is necessary to recall their mechanism of action. It is known to inhibit the angiotensin II receptor AT1 – conductors of the main negative effects of this hormone – as a result of which, unlike the ACE inhibitor, the synthesis of AII is not disturbed. The negative effects of AII include vasoconstriction, increased secretion of endothelin, stimulation of the synthesis of peroxide radicals, hypertrophy of smooth muscle cells,increased activity of tissue activator inhibitor type 1 plasminogen. Many of these effects are atherogenic. On the other hand, angiotensin II stimulation of unblocked type 2 receptors (AT2) causes effects opposite to those listed above, namely, vasodilatation, increased production of nitric oxide, and stimulation of antiproliferative processes. Thus, ARA have a double positive mechanism of action, which has a powerful anti-thrombogenic potential.

An illustration of the possibilities of ARA is the LIFE study (a study of the effectiveness of losartan in reducing end points in people with arterial hypertension), the results of which were expected with great interest and are likely to be discussed for a long time [8, 59]. In this study, not only was antihypertensive efficacy of ARA proved for the first time in terms of its effect on end points, but other possibilities were also demonstrated.

In a double-blind, randomized, controlled international study, 9193 hypertensive patients aged 55–80 years participated, with left ventricular hypertrophy. The study participants were randomized into 2 groups for the purpose of treatment as initial with either losartan or atenolol. The initial dose of drugs was, respectively, 50 mg of lazan 1 time per day and 50 mg of atenolol 1 time per day. The drugs could be combined with hydrochlorothiazide – 12.5 mg per day and further increase their dose to 100 mg per day in order to achieve the target blood pressure reduction of less than 140/90 mm Hg. Art. Finally, if the maximum doses of the studied drugs in combination with a diuretic did not provide adequate control of blood pressure, then it was allowed to prescribe additional drugs (with the exception of ARA, ACE inhibitors and BB). The duration of the study averaged 4.8 years.

The objective of the study was to study the comparative efficacy of losartan and atenolol in order to reduce the main endpoint, which included a total of MI, MI and cardiovascular mortality. Other endpoints included the incidence of diabetes mellitus, all-cause mortality, regression of left ventricular hypertrophy, the frequency of hospitalizations for angina or heart failure.

In total, 508 cases of a combined endpoint were detected in the losartan group , and 588 in the atenolol group. Thus, compared to atenolol, losartan reduced the frequency of the main endpoint (cardiovascular mortality, MI and MI) by 13% (p <0.021). The frequency of fatal and nonfatal MI in the losartan group was 25% lower than in the atenolol group (p <0.001), despite the fact that the blood pressure in both groups decreased almost the same – by 30/17 mm Hg. in the group of losartan and at 29/17 mm Hg in the group atenolol. However, there were no differences in the incidence of myocardial infarction in both groups. Another important finding is the significantly lower incidence of diabetes in the Losar group – by 25% (p <0.001). In the subgroup of patients with initial diabetes, the frequency of the main endpoint was lower by 24% (p <0.031), and the rate of cardiovascular mortality was 37% (p <0.028) in the losartan group than in the atenolol group. This indicates a beneficial side effect of losartan. Thanks to this study, a new niche for ARA – AG and myocardial hypertrophy has appeared, since it was shown that a significantly more regressive hypertrophied left ventricle was observed in the subgroup of individuals with losartan compared with atenolol. It was also important thatthat the frequency of side effects when using losartan was significantly less than in the atenolol group. As a result, at the end of the study, significantly more patients continued to take losartan than atenolol.

New possibilities in the treatment of such a problematic group of patients as hypertension with concomitant CHF are associated with ARA. As is known, currently in the treatment of hypertension with CHF, an arsenal of drugs is successfully used that can effectively eliminate the symptoms of heart failure and prolong the life of such patients. These classes of drugs, as is known, include ACE inhibitors, BB, diuretics, and cardiac glycosides. For a long time, the ACE inhibitors, considered to be the gold standard for treating CHF, lacked an alternative to blocking the renin-angiotensin system, which is absolutely necessary in CHF. However, there are a number of situations where patients do not tolerate an ACE inhibitor. In addition, for unknown reasons, the effectiveness of ACE inhibitors in women is significantly lower than in men. In these situations, the doctor needs an alternative to an ACE inhibitor.And this alternative appeared due to the data obtained in the CHARM project, which combined three studies. In a placebo-controlled study CHARM-ALTERNATIVE with more than 2000 patients with CHF, the effectiveness of candesartan in the treatment of patients not taking ACE inhibitors due to their intolerance was studied [60]. The results showed that in case of an intolerance to an ACE inhibitor, the use of candesartan reduces the incidence of MTR and mortality from them, and also reduces the frequency of hospitalization due to the progression of CHF (Fig. 7).in the case of an intolerance to an ACE inhibitor, the use of candesartan reduces the incidence of mortality and mortality from them, and also reduces the frequency of hospitalization due to the progression of heart failure (Fig. 7).in the case of an intolerance to an ACE inhibitor, the use of candesartan reduces the incidence of mortality and mortality from them, and also reduces the frequency of hospitalization due to the progression of heart failure (Fig. 7).

In another study, CHARM-ADDED [61], it was found that the addition of candesartan to IAP F and BB in patients with CHF leads to a clinically significant decrease in the incidence of CCO and death from them, as well as hospitalization due to progression CHF .

In both of these studies , the use of candesartan was characterized by good tolerability. It is not unimportant to note that the effectiveness of desa-sartan was almost the same in both men and women. A comparative analysis of the results of the CHARM project and the SOLVD study showed that the effectiveness of candesartan in order to reduce the risk of death from SSO and the frequency of hospitalization due to the progression of CHF is comparable to the effectiveness of the standard ACE enalapril. It is very important for practical physicians to know the dose titration rules.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 candesartan, which was used in the CHARM project. The starting dose is 4 mg per day once, which
 
 
 
 
 with stable blood pressure and the absence of complications, it doubled every 3-5 days until reaching 16 mg per day. The maximum dosage per day is 32 mg. To date, the use of candesartan in the treatment of patients with CHF is the most reasonable, and it can be used on a par with an ACE inhibitor (evidence grade A). This fact is reflected in the latest European and Russian recommendations on the diagnosis and treatment of CHF. Moreover, in the latest European guidelines for the treatment of hypertension, a new niche for the use of ARA has appeared – a concomitant CHF. Of the other representatives of the ARA, it is also recommended to use losartan and valsartan. In the new recommendations for the diagnosis and treatment of hypertension, there is also a very interesting niche for the use of ARA – preventing the development of atrial fibrillation in patients with a history of arrhythmia paroxysms.All of these new APA niches indicate the most important pleiotropic effect of this class – organ protection, not associated with a decrease in blood pressure.

Therapy of arterial hypertension

As clinical practice shows, in most cases it is possible to achieve target blood pressure against the background of combination therapy with drugs with different mechanisms of action, especially in groups of patients with high risk, which are observed among practitioners. This is quite natural, since a single class of drugs is not able to control all the pathogenetic mechanisms for increasing blood pressure: the activity of the CNS and the renin-angiotensin – aldosterone system, volume-dependent mechanisms. There are various combinations of antihypertensive drugs. Combinations of two anti-hypertensive drugs are divided into rational (effective), possible and irrational. All the benefits of combination therapy are found only in rational combinations of antihypertensive drugs. These include: ACE inhibitor + diuretic; ARA + diuretic; IAPF + AK; ARA + AK;dihydropyridine AK + β-AB; AK + Diu retic; β-ab + diuretic .

There are certain nuances of combination therapy. It can be of two types: starting monotherapy with a transition to a combination therapy in the absence of an effect (i.e. achieving the target level of blood pressure) or a combination therapy at the start of treatment . If you start from the strategy of starting monotherapy, then the doctor inevitably faces a situation of painstaking search for the most optimal antihypertensive agent for the patient with frequent changes 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 an increase in blood pressure and are not motivated to treat. Combined therapy at the start of treatment, provided effective doses of the drugs allow for faster adequate blood pressure control in most cases of hypertension.

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 physicians in Russia prefer the combination of these particular drugs [62]. It is possible that these two classes of drugs provide control of almost all mechanisms for increasing blood pressure. Fixed combinations of antihypertensive drugs, which are significant but increase patients’ commitment to the treatment of hypertension. Among the fixed combinations, noliprel and noliprel-forte (2–4 mg of perindopril and 0.625–1.5 mg of indapamide), korenitek (20 mg of enalapril and 12.5 mg of hypothiazide), tarka (180 mg of isoptin CP) are successfully used. and 2 mg of trandolapril). At the same time, fixed combinations of drugs limit titration of doses, if necessary, both upwards and downwards. Therefore, the emergence of the first non-fixed combination Enzix containing two drugs in one blister – enalapril and indapamide is important. The drug owes its appearance to the EPIGRAF project, which was carried out under the auspices of the All-Russian Scientific Society of Cardiology (coordinator Academician of the Russian Academy of Sciences Yu.N. Belenkov). The project consisted of two multicenter studies, EPIGRAF-1 and EPIGRAF-2.

A doctor and 38 polyclinics from 17 cities took part in the open study of EPIGRAPH-1 . A total of 550 patients with grade II – III hypertension (baseline systolic blood pressure> 160 mmHg) were included in the study, and among them were patients not only with essential, but also with symptomatic hypertension. A special feature of the 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 level of blood pressure. At the same time, doctors had the possibility of adjusting the doses of enalapril depending on the achievement of the target blood pressure within 4 weeks. As a result of the treatment of hypertensive patients with differentiated doses of enalapril and indapamide, a significant reduction in both systolic and diastolic blood pressure was achieved. At the same time, target BP was achieved in 70% of patients (<140/90 mmHg).The percentage of patients who responded to treatment in general (decrease in systolic and diastolic blood pressure –∆20 / 10 mm Hg) was 77.1. Adverse reactions were observed in only 8.2% of patients. Only 2.7% of patientsntov was a cough . The main conclusion of the study was that efficacy and safety The combination of enalapril with indapamide in the treatment of hypertension did not depend on gender, age, and the cause of the increase in blood pressure (primary hypertension or secondary hypertension of renal origin). It is especially necessary to pay attention to the latter circumstance, in connection with the ingrained opinion that the effectiveness of antihypertensive therapy in patients with symptomatic hypertension decreases. The combination of enalapril with indapamide was especially preferred in women, in whom the ACE inhibitor monotherapy may be less effective. The results of the EPIGRAPH-1 study allowed us to work out the most effective doses of enalapril and indapamide for hypertensive patients of varying degrees, which became the basis for the creation of 3 types of Enzix preparation: Enzixil – 10 mg of enalapril and 2.5 mg of indapamide (single dose in the morning) for hypertensive patients I degree; Enzix Duo – 10 mg enalapril and 2,5 mg of indapamide (in the morning) + 10 mg of enalapril (in the evening) for patients with hypertension of II degree; Enzaprim Enzapi Duo Forte – 20 mg of enalapril and 2.5 mg of indapamide (in the morning) + 20 mg of enalapril (in the evening).

The effectiveness and safety of the Enzix was evaluated in the study EPIGRAF-2, which by design was a comparative, randomized multicenter, which included 9 centers in Russia and 1 center in Serbia [64]. A total of 313 patients were included in the study, which were randomized into two groups. The Enzix group included 211 patients, the control group included 102 patients.

In the control group, treatment was carried out with antihypertensive drugs of any class, except for ACE inhibitors and diuretics.

This study also confirmed the high efficacy of the combination of enalapril and indapamide. In the group receiving Enzix – 72.5% of patients reached the target level of blood pressure. Thus, the early initiation of treatment of patients with hypertension of grades I – II with the unstable combination of enalapril and indapamide (Enzix), in comparison with routine antihypertensive therapy, makes it possible to achieve normalization of blood pressure more often. In addition, Ensix therapy is cost effective.

The presence of a diuretic of indapamide in the Enzix composition without undesirable side effects is of significant clinical importance. As already noted, diuretics and BB (especially non-selective) have a negative metabolic effect and increase the risk of diabetes.

This fully applies to combination therapy. In this regard, the components of the drug Enzix do not cause concern. Enalapril, as an ACE inhibitor, is by definition metabolically neutral, and indapamide occupies a special place among diuretics. At the recommended doses (1.5–2.5 mg per day), it not only provides an adequate antihypertensive effect, but is also metabolically neutral. It has been proven that indapamide does not cause hypokalemia, changes in the carbohydrate [65] and lipid profile [66]. Especially convincing evidenceThe metabolic neutrality of indapamide was obtained as a result of a meta-analysis of three studies involving a total of 1195 patients. According to the results of treatment with the retard form of indapamide for 9–12 months, no effect on the carbohydrate and lipid profile, as well as the level of uric acid was found .

Indapamide, in addition to the diuretic effect, has a vasodilating effect by reducing the sodium content in the artery wall, regulating calcium intake in vascular smooth muscle cells, as well as increasing the synthesis of prostaglandin E2 in the kidneys and prostacyclin in the endothelium . Thus, indapamide, having a more pronounced effect on the vessels than the other diuretics, affects endothelial function. It has an antioxidant effect, increasing the bioavailability of NO . Moreover, the LIVE study proved that indapamide therapy can cause regression of hypertrophy and left ventricular myocardium .

The presence of 2 antihypertensive drugs in a single double blister will certainly help to increase adherence to treatment. Three different dosages of Enzix will contribute to the adequate selection of non-fixed combination in various clinical situations related to the degree of increase in blood pressure.