All international guidelines emphasize that at a certain stage in the treatment of hypertension, one drug becomes insufficient for adequate control of blood pressure. However, a significant question arises: in what clinical situations is it advisable to start with monotherapy, and in which it is necessary, without exchanging for trifles, to immediately prescribe combined antihypertensive therapy? In general, the concept in the guidelines is that the higher the blood pressure numbers at diagnosis and the more concomitant risk factors, the more justified is the combination therapy from the very beginning of treatment. At the same time, the least aggressive strategies should be followed, gradually increasing the dosage and adding additional drugs only if clearly necessary (see chart).

The second most important issue is, of course, the choice of specific drugs. Not all antihypertensive drugs are compatible with each other. The thoughtless addition of drugs from alternative classes is unacceptable and can lead to dangerous consequences for the patient's health. For example, a combination of non-dihydropyridine calcium blockers and beta-blockers are more likely to cause bradycardia or atrioventricular blockade. Another example: the combination of alpha-blockers with myotropic antihypertensive agents (for example, hydralazine) can lead to severe reflex tachyarrhythmia.

Thiazide diuretics increase the excretion of electrolytes and fluids, which leads to the activation of the renin-angiotensin-aldosterone system. That is why the combination of thiazides with ACE inhibitors and angiotensin receptor blockers is justified clinically and pathophysiologically. A large number of such combined preparations are presented on the Russian market: Lorista H (), Valz N (), Coaprovel (+), Lysinoton N (), Kapozid (+) and many others.

IN last years much attention is paid to the combination "ACE inhibitor + calcium channel blocker". In two large clinical research - ASCOT and ACCOMPLISH have been shown to be superior to beta-blocker + thiazide diuretic and ACE inhibitor + thiazide diuretic, respectively. Thus, in patients with newly diagnosed high-grade hypertension (2 and 3), treatment should begin with these combinations. Preparations on the Russian market: Equator (

Peter A. van Zwieten,
Department of Pharmacotherapy,
cardiology and cardio-thoracic
Surgery, Academic Medical
Center, Netherlands

Csaba Farsang, 1st Division
Internal Medicine, St. Imre Hospital,
Budapest, Hungary

Introduction

It has been established that in approximately half of patients with arterial hypertension, the disease can be effectively controlled by prescribing one antihypertensive drug, in combination with compliance with recommendations for correcting adverse lifestyle factors. This means that the remaining 50% of patients may need to use 2 or more antihypertensive drugs to adequately control blood pressure levels.

It is hypothesized that a combination of two or more drugs can lead to a more effective reduction in high blood pressure, and these ideas have received demonstrative evidence in numerous, usually small, clinical studies.

In large randomized intervention trials, only a few combinations of antihypertensive drugs have been specifically studied (in particular, the combination of a diuretic and a β-blocker). In addition, at present, the use of fixed combinations as part of one tablet is gaining more and more recognition, since this approach significantly reduces the number of tablets that need to be taken during the day, which, accordingly, improves the patient's adherence to treatment - the most significant factor in insufficient therapeutic effect in patients with arterial hypertension. The group of drugs with a fixed combination of doses has recently been supplemented with drugs with a fixed combination of low doses.

Effective combinations of two antihypertensive drugs of different classes

To date, studies have been conducted of individual combinations of antihypertensive drugs, in which their effectiveness in reducing high blood pressure has been proven. In this chapter, we will discuss a number of drug combinations that have been shown to be effective in lowering blood pressure, in addition to having effective action in separate subgroups of patients. Although not all of the presented combinations have been studied in large intervention studies conducted in accordance with the principles of evidence-based medicine, we selected these combinations based on the characteristics of the drugs to influence hemodynamic and other parameters. The effectiveness of such combinations in most cases is confirmed by the results of studies.

Thiazide diuretics + β-blockers: the widespread use of this combination for a long time was facilitated by recommendations for its primary use in patients with uncomplicated hypertension who do not have target organ damage. This combination has been studied in several large intervention studies (such as STOP ; MRS, ALLHAT ) and its effectiveness can now be considered conclusive evidence.

Thiazide diuretics + ACE inhibitors: have an effect in patients with hypertension and congestive chronic heart failure (CHF), isolated systolic hypertension (ISH), as well as in elderly patients with arterial hypertension (usually with ISH). This combination in some cases can have a sufficiently strong antihypertensive effect, and therefore the addition of an ACE inhibitor to a diuretic (or vice versa) should be carried out with caution in order to prevent too rapid a decrease in blood pressure. In addition, both classes of drugs - ACE inhibitors and diuretics - are standard drugs for the treatment of CHF.

: it has been proven that in the treatment of arterial hypertension in combination with left ventricular hypertrophy, this combination is more effective than the combination of β-blocker + diuretic. This combination can be successfully used in patients with ISH, and also has a beneficial effect in patients with arterial hypertension in combination with CHF.

: This combination has not been studied in large intervention studies, but should be considered if adding a β-blocker to diuretic therapy is not possible due to contraindications.

Diuretics + calcium antagonists (dihydropyridines): dihydropyridine calcium antagonists are strong vasodilators and can be used in combination with diuretics in patients with ICH, most of whom are elderly. There is strong evidence that both diuretics and dihydropyridine calcium antagonists are effective in lowering blood pressure in patients with ICH, and also have a protective effect against the development of complications of hypertension.

α-blockers + β-blockers: this combination can be used in malignant hypertension, but the effectiveness of its use is not well understood. Malignant hypertension is thought to be due to sympathetic hyperactivity and its consequences. In this regard, the sympatholytic effect characteristic of both drugs in this combination is the rationale for the use of this combination in patients with ISH. In addition, in the case of sympathetic hyperactivity, the use of centrally acting antihypertensive drugs (imidazoline I1 receptor agonists), as well as non-dihydropyridine calcium antagonists, can be discussed.

β-blockers + ACE inhibitors: despite the fact that the antihypertensive effect of this combination is less pronounced than the combination of diuretic + β-blocker, it can be used in patients with arterial hypertension who have had myocardial infarction (MI), in the presence of coronary heart disease (CHD) and / or CHF.

Calcium antagonists (dihydropyridine series) + β-blockers: this combination can be prescribed in patients with arterial hypertension in the presence of coronary artery disease. These two classes of drugs, in addition to being effective antihypertensive agents, show a pronounced beneficial effect in patients with coronary artery disease. The appointment of a fixed combination of these drugs can improve the adherence of patients to treatment.

: this combination may be recommended for the treatment of patients with arterial hypertension in the presence of nephropathy, coronary artery disease or documented atherosclerosis. This combination has a pronounced antihypertensive effect. Calcium antagonists are known to have an anti-ischemic effect in IHD. ACE inhibitors have proven renoprotective properties, which may be particularly useful in patients with diabetic nephropathy.

Calcium antagonists also have anti-atherogenic properties, as demonstrated for lacidipine in the ELSA study, amlodipine in the PREVENT study, and nifedipine-GITS (long-acting) in the INSIGHT study. Similar effects were found in ACE inhibitors (SECURE study).

Calcium antagonists (dihydropyridines) + AT1 receptor blockers: the expected beneficial effects of this combination are generally the same as for the combination of calcium antagonists + ACE inhibitors. The renoprotective effect of drugs in diabetic nephropathy has been convincingly established ( diabetes 2 types). It has been shown that calcium antagonists of the dihydropyridine series and the AT1 receptor blocker losartan have a uricosuric effect, which may be especially useful in patients with gout.

: the use of this combination can be discussed if a patient with arterial hypertension has diabetic nephropathy or glomerulonephritis, since the combination of drugs of these two classes has been shown to reduce proteinuria to a greater extent than with monotherapy. Thus, this combination is capable of exerting a renoprotective effect.

ACE inhibitors + imidazoline receptor agonists: theoretically, this combination is indicated if it is necessary to simultaneously suppress the activity of both the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system(SNS). Another therapeutic target for drugs that suppress the activity of the SNS (such as moxonidine) is the metabolic syndrome, the development of which is supposed to be associated to some extent with SNS hyperactivity.

Three drug combinations

A few preliminary remarks should be made regarding triple combinations of different antihypertensive drugs.

The drugs in these combinations are combined together only for theoretical basis, in fact, in the absence of the necessary clinical evidence. The arguments in favor of using the first pair of drugs in a drug combination are the same as for the combinations of 2 drugs of different classes discussed above. Consider potentially significant triple drug combinations:

: a very powerful combination that can be used in the treatment of malignant hypertension.

: a potentially beneficial combination in the treatment of hypertensive diabetic patients who have ISH or malignant hypertension.

AT1 receptor antagonists + calcium antagonists + diuretics: This triple combination can help you reach your BP targets (<130 и 85 мм рт. ст.) у больных с артериальной гипертонией, имеющих сахарный диабет 2 типа или у больных с ИСГ.

ACE inhibitors + α1-adrenergic receptor antagonists + imidazoline receptor agonists: a potentially favorable combination in the treatment of patients with arterial hypertension and diabetes mellitus, as well as patients with metabolic syndrome, especially in the presence of contraindications or poor tolerance of β-blockers.

: a potentially favorable combination in the treatment of patients with arterial hypertension and coronary heart disease.

Preparations	Potential application
β-blockers + diuretics	Uncomplicated arterial hypertension without target organ damage
Diuretics + ACE inhibitors	Arterial hypertension + congestive chronic heart failure (CHF)
Diuretics + AT1 receptor blockers	Isolated systolic hypertension (ISH) + CHF. Possibly with ISG.
Diuretics + imidazoline I1 receptor agonists	If it is not possible to add a β-blocker to the diuretic (due to contraindications)
Diuretics + calcium antagonists (dihydropyridine series)	ISH (usually in older patients)
α-blockers + β-blockers	Malignant hypertension
β-blockers + ACE inhibitors	Patients with arterial hypertension who have undergone myocardial infarction (secondary prevention), have CHF and / or coronary artery disease
Calcium antagonists + β-blockers
Calcium antagonists + ACE inhibitors	Arterial hypertension + nephropathy, ischemic heart disease or atherosclerosis
Calcium antagonists + AT1 receptor blockers	Arterial hypertension + nephropathy, ischemic heart disease or atherosclerosis (?)
ACE inhibitors + AT1 receptor blockers	Arterial hypertension + nephropathy
ACE inhibitors + imidazoline I1 receptor agonists	Patients with RAAS and SNS hyperactivity
Diuretics + β-blockers + calcium antagonists	Malignant arterial hypertension
Diuretics + calcium antagonists + ACE inhibitors	Malignant ISH, arterial hypertension + diabetes mellitus
Diuretics + calcium antagonists + AT1 receptor blockers	Same
ACE inhibitors + α1-blockers + imidazoline I1 receptor agonists	Arterial hypertension + diabetes mellitus. metabolic syndrome
ACE inhibitors + calcium antagonists + β-blockers	Arterial hypertension + ischemic heart disease

Conclusion

Combination therapy is increasingly recognized as the main approach in the treatment of patients with arterial hypertension, since in a significant proportion of patients the disease is more effectively controlled by prescribing two or, in some cases, three antihypertensive drugs.

Fixed-combination 2 drugs can simplify the drug regimen and thus improve patient adherence to treatment. The choice of drug combination is mainly based on the hemodynamic and metabolic properties of the individual drugs and their combination, and formal evidence of efficacy has not yet been obtained for most possible combinations.

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Efficiency of a fixed triple combination of antihypertensive drugs for the treatment of arterial hypertension in real clinical practice

Attention! The article is addressed to medical specialists

Sujayeva V.A.

Republican Scientific and Practical Center “Cardiology”, Minsk, Belarus

Effectiveness of fixed triple combinations

of anti-hypertensive drugs

in the treatment of hypertension in real clinical practice

Summary. An assessment of the effectiveness of the fixed combination of perindopril / amlodipine / indapamide is presented ( Koh Amlessa, Krka, Slovenia) in real clinical practice. The study involved 231 patients with arterial hypertension of I-III degree aged 26 to 88 years (mean 60.7±10.6 years) who were under outpatient supervision and treated under the supervision of Minsk general practitioners in 2016. Of the 231 patients included in the study, 131 (57%) patients had comorbidities, 224 had previously received antihypertensive treatment, but only 10% of them reached the target level of blood pressure (BP). Use of a triple fixed combination of perindopril/amlodipine/indapamide ( Ko-Amlessa, Krka, Slovenia) contributed to the achievement of the target level of blood pressure after 4 weeks - in 79%, after 8 weeks - in 92% of patients with arterial hypertension, previously ineffectively treated. After 4 weeks of taking the drug Koh Amlessa (Krka, Slovenia) a decrease in SBP was achieved from 160.2±13.5/93.3±8.7 to 135.1±11.7/81.6±7.1 mm Hg. Art. (R<0,05), через 8 недель - до 129,2±10,5/78,6±5,9 мм рт. ст. (р<0,05). У лиц, не достигших целевого уровня АД, исходный уровень САД - 175,4±9,9 мм рт. ст. - был выше, чем в среднем по группе - 160,2±13,5 мм рт. ст. (р<0,05). Через 4 недели в этой группе лиц выявлено значительное снижение САД до 159,2±9,8 мм рт. ст. (р<0,05), через 8 недель - до 153,1±9,6 мм рт. ст. (р<0,05). Фиксированная комбинация периндоприл/амлодипин/индапамид (Ko-Amlessa, Krka, Slovenia) has demonstrated high efficacy for the treatment of arterial hypertension (including 92% of persons who received previous antihypertensive therapy, but did not reach the target level of blood pressure) in real clinical practice.

Keywords: arterial hypertension, treatment, fixed combinations, amlodipine, perindopril, indapamide.

Medical News. - 2017. - No. 11. - WITH . 19-23.

summary. Estimate efficiency of the fixed combination of perindopril/amlodipine/indapamide in real clinical practice. We exanimate 231 outpatients with the arterial hypertension (AH) of the I-III degree aged from 26 up to 88 years (on average 60.7±10.6 years) treated by therapists of Minsk who in 2016. 131 (57%) from 231 included patients had associated diseases, 224 patients already received anti-hypertensive treatment, but the target level of the blood pressure (BP) was reached by only 10%. Use of the triad fixed combination perindopril/amlodipine/indapamide (WITH o-Amlessa , KRKA, Slovenia) promoted achievement of the BP target level in 4 weeks - at 79%, in 8 weeks - at 92% of patients which were earlier not reached the BP target level despite the carried-out treatment. In 4 weeks ofWITH o-Amlessa therapy we revealed decreasing of BP from 160.2±13.5/93.3±8.7 to 135.1±11.7/81.6±7.1 mm Hg ( R <0.05), and in 8 weeks - to 129.2±10.5/78.6±5.9 mm Hg ( R <0.05). At the persons which didn’t reach the BP target after 8 weeks we found higher initial BP - 175.4±9.9 mm Hg than on average on group - 160.2±13.5 mm Hg, R <0,05. In 4 weeks in group hadn’t reached target level of BP we found significantly lower than initially level of BP - 159.2±9.8 mm Hg ( R <0,05), in 8 weeks mentioned level became lower - 153.1±9.6 mm Hg taped ( R <0.05). The fixed combination perindoprile/amlodipine/indapamide (Co-Amlessa, KRKA, Slovenia) demonstrated high efficiency for treatment of AH (including 92% of the persons who have received previous anti-hypertensive therapy, but didn’t reach target level of BP) in real clinical practice.

keywords: arterial hypertension, treatment, the fixed combinations, perindopril, amlodipine, indapamide.

Meditsinskie news. - 2017. - N11. - P. 19-23.

An increase in blood pressure (BP) is one of the most common of these modifiable risk factors for the development of cardiovascular disease (CVD). However, despite the availability of a large number of highly effective antihypertensive drugs, the fight against arterial hypertension (AH) still did not lead to the expected success: about 1/3 of treated patients reach the target level of blood pressure. At the same time, it was found that, regardless of the type of drug, monotherapy in achieving target levels of blood pressure is effective only in 30-50% of people with hypertension; in most cases, a combination of at least two drugs is required. In a meta-analysis of more than 40 randomized clinical trials (RCTs), the combination of two drugs from any two classes of antihypertensive drugs enhances the degree of BP reduction much more than dose escalation of a single drug.

However, the effectiveness of antihyperthene effective drugs in achieving target levels of blood pressure, achieved in multicenter studies, does not always take place in practice. This may be due to a number of factors. Thus, RCTs often do not include elderly patients, persons with concomitant cardiac and extracardiac pathology, impaired liver and kidney function, etc. In addition, adherence to treatment in patients included in RCTs, as a rule, is significantly higher than in real clinical practice.

One of the directions of modern hypertension is the study of the effectiveness of fixed combinations of antihypertensive drugs. Such combinations, as a rule, consist of agents with drug synergism of action. Important in the use of fixed combinations is the possibility of a single dose of drugs, which helps to increase patient adherence to treatment. The downside of using combined drugs is the risk of side effects, and sometimes it is difficult to determine which of the components of the combined drug.

This paper presents an estimate Efficacy of fixed combination perindopril/indapamide/amlodipine ( Ko-Amlessa, Krka, Slovenia) in real clinical practice. The study included 231 patients with hypertension I-III degrees at the age of 26 to 88 years (average 60.7±10.6 years) of those who were under observation and treated on an outpatient basis by general practitioners in Minsk in 2016. All patients were prescribed a fixed combination of perindopril/amlodipine/indapamide ( Ko-Amlessa, Krka, Slovenia).

According to the requirements for observational studies, the prescription of drug therapy was carried out strictly in accordance with the instructions for the medical use of the drug ( Ko-Amlessa, Krka, Slovenia), only for registered indications for use and in accordance with accepted clinical practice. The appointment of drug therapy was based only on medical indications and the decision of the doctor, and did not depend on the desire of the patient.

Such a risk factor as smoking occurred in 54 (23%) patients. The duration of AH ranged from 1 to 50 years (average 13.4±8.0 years).

It is noteworthy that the majority of patients belonged to the high and very high risk group: more than half of the examined - 131 (57%) - had concomitant diseases. Ischemic heart disease (IHD) in the form of stable exertional angina I - II functional class (FC) according to the Canadian classification was diagnosed in 27 (1 2%) of patients, coronary artery disease with a history of arrhythmias - in 14 (6%) patients (in 11 - atrial fibrillation (AF), in 3 - extrasystole (ES), requiring constant intake of antiarrhythmic drugs). Myocardial infarction (MI) before inclusion in the study (from 1993 to 2015) was suffered by 16 (7%) patients, and three of them had 2 MI or more. In 2 people, myocardial revascularization was previously performed by coronary artery bypass grafting (CABG), in another one - by percutaneous coronary intervention (PCI). 10 (4%) patients had cerebrovascular accidents/cerebral infarction. Type 2 diabetes mellitus (DM) was detected in 51 (22%) of those included in the study; another 2 were previously diagnosed with type 1 DM. 2 patients had metabolic syndrome (MS), 7 patients had grade 3 obesity (Table 1).

Table 1. Concomitant diseases in patients with arterial hypertension

Disease	Number of patients, abs. (%)
IHD: stable exertional angina FC I-II
IHD: post-infarction cardiosclerosis
Coronary artery/percutaneous bypass
IHD: atherosclerotic cardiosclerosis with rhythm disturbances
Cerebral circulation disorders / cerebral infarction
Diabetes: 2nd type 1st type
metabolic syndrome
Obesity 3 degrees
Respiratory diseases: bronchial asthma (BA) chronic obstructive pulmonary disease (COPD)
Chronic kidney disease (CKD)
Pathology of the thyroid gland (TG)
Cancer (skin, breast)
Pathology of the gastrointestinal tract (GIT): chronic gastropathy/duodenopathy Chronic gastric / duodenal ulcer
Liver pathology: chronic hepatitis C Gilbert's syndrome · cholelithiasis · chronic cholecystitis
Diseases of the veins
Joint diseases: osteoarthritis psoriatic arthritis · rheumatoid arthritis
Chronic heart failure (CHF)
Eye diseases: cataract glaucoma

Criteria for exclusion from the study: contraindications to the use of perindopril, amlodipine and indapamide, indicated in the instructions for them.

At the first visit, the specialist doctor measured blood pressure on the right and left arms using a manual aneroid sphygmomanometer in the sitting position of the subject, after a five-minute rest. The analysis included the mean BP value from three measurements on each arm. At follow-up examinations, blood pressure was measured on the arm on which higher values ​​were recorded at the first visit: the right hand was chosen for measuring blood pressure in 164 patients, the left hand - in 67 examined.

Visit 2 was carried out after 4 weeks and after inclusion in the study, visit 3 - after another 4 weeks. At each visit, in addition to systolic and diastolic blood pressure (SBP and DBP, respectively), the patient's clinical condition, heart rate (HR), concomitant therapy, adherence to treatment, side effects and adverse events were also assessed.

According to the guidelines of the European Society of Cardiology ( European Society of Cardiology - ESC ) and the European Society of Hypertension ( European Society of Hypertension - ESH ) in 2013, the SBP value was taken as the target level of blood pressure<140 мм рт. ст. и значение ДАД<90 мм рт. ст. (у лиц без СД) и <85 мм рт. ст. - у лиц с СД .

The patient information database was compiled using the standard Excel 2007 program. Statistical data analysis was performed using the STATISTICA 7.0 program (StatSoft Inc.). When analyzing the significance of the difference between the obtained results, Student's t-test was used. Data are presented as M±SD. Differences in indicators were considered significant at p value<0,05.

At entry into the study, the majority (224 of 231) of patients were already receiving antihypertensive treatment. The number of drugs taken initially ranged from 1 to 6 (group average 2.6±1.1). Most of the surveyed - 92 (40%) of 231 - initially took three drugs, 62 (27%) - two drugs, 25 (11%) - one drug, 45 (19%) - more than four drugs, another 7 (3% ) patients initially did not receive antihypertensive treatment, although newly diagnosed hypertension occurred only in one of them.

The majority - 167 (72%) of 231 - of those included in the study initially received a drug from the group of angiotensin-converting enzyme inhibitors (ACE inhibitors), 154 (67%) patients received calcium ion antagonists (CA), 157 (68%) - diuretics, 92 (40%) - other antihypertensive drugs.

From the ACE inhibitor group, perindopril was most often prescribed - 54 (32%) of 167 patients (at a dose of 8 mg - 15 examined, 4 mg - ten, 2 mg - two, 5 mg - 11 and 10 mg - 16 patients). The average dose of perindopril was 6.6±2.2 mg.

Enalapril at a dose of 5-40 mg (mean 23.9±12.1 mg) was initially prescribed to 26 (16%) participants in the study, lisinopril at a dose of 5-40 mg (mean 21.2±11.7 mg) - 48 (29%), ramipril at a dose of 2.5-10 mg (average 8.4±2.4 mg) - 37 (22%), other ACE inhibitors (fosinopril and zofenopril) - one patient each.

Thus, initially all patients received ACE inhibitors in average therapeutic dosages.

Of the drugs of the AK group, amlodipine was most often prescribed: this drug at a dose of 5-10 mg (average 6.2 ± 2.1 mg) was received when 136 (88%) of 154 patients were included in the study, lecarnidipine at a dose of 5-10 mg (mean 8.9±2.1 mg) was administered to 9 (6%) patients, nifedipine XL at a dose of 30-60 mg (average 41.3±14, 5 mg) - 8 (5%) patients, another examined received a retard form of diltiazem at a daily dose of 360 mg.

Thus, drugs from the AK group were also prescribed in average therapeutic doses.

Of the diuretics, indapamide was most often prescribed: 116 (74%) of 157 examined patients received it, and retard form at a dose of 1.5 mg was prescribed to 11 (9%) of 116 patients, the remaining 105 received indapamide at a dose of 2.5 mg. Hypothiazide at a dose of 12.5-25 mg (average 19.0 ± 6.4 mg) was prescribed to 37 (24%) participants in the study, other diuretics (diuver, spironolactone, furosemide) at medium therapeutic doses were received by 4 (2% ) of the patient.

Among other antihypertensive drugs, β-adrenergic blockers (BAB) were most frequently used - in 91 out of 92 examined patients. Preference was given to bisoprolol - 40 (44%) of 91 received it, metoprolol, atenolol, betaxolol, carvedilol, nebivolol were prescribed less frequently.

Medicines from the antagonis group angiotensin receptors II (ARA) losartan, valsartan, irbersartan were received by 17 patients, moxonidine - 25, a drug from the group of ?-adrenergic blockers was prescribed to one patient.

Given the high incidence of comorbidities, 77 of 231 patients were prescribed antiplatelet agents (acetylsalicylic acid at a dose of 75 mg and/or clopidogrel at a dose of 75 mg), warfarin, These are anti-inflammatory, peripheral vasodilators (long-acting nitrates or molsidomine), ivabradine, trimetazidine, hypoglycemic agents, statins, bronchodilators, antiarrhythmic drugs.

It is noteworthy that initially at the first visit, 54 (23%) of 231 patients already received fixed combinations of antihypertensive drugs: 11 were prescribed a combination of perindopril/amlodipine, 9 - a fixed combination of perindopril/indapamide, 34 - a triple combination of perindopril/amlodipine /indapamide. However, only 22 (10%) patients had the target BP at baseline. The mean BP at baseline was: SBP (right arm) 160.2±13.5 mm Hg. Art., DBP (right hand) 93.3±8.7 mm Hg. Art., GARDEN (left arm) 159.6±14.9 mm Hg. Art., DBP (left hand) 93.0±8.4 mm Hg. Art., heart rate 73.0±8.6 beats/min (figure).

At the first visit, the initial therapy was canceled, starting from the third day, all 231 patients were prescribed the drug Koh Amlessa (Krka, Slovenia), which is a fixed combination of perindopril / amlodipine / indapamide in various doses (Table 2).

Table 2. Use of a fixed combination of perindopril/amlodipine/indapamide (Ko-Amlessa, KRKA, Slovenia)

Dose of perindopril/amlodipine/ indapamide	The number of patients taking the drug at the indicated dose, abs. (%)
	Visit 1	Visit 2 (after 4 weeks)	Visit 3 (after 8 weeks)
4 mg/ 5 mg/ 1.25 mg
4 mg/ 10 mg/ 1.25 mg
8 mg/ 5 mg/ 2.5 mg
8 mg/ 10 mg/ 2.5 mg

During the first 4 weeks of therapy, adverse events developed in 6 patients: in 1 - pain in the epigastric region, in 1 - excessive (up to 100/60 mm Hg) decrease in blood pressure, in 3 more examined patients with a decrease in blood pressure to 90/60 mmHg Art. dizziness was noted. For this reason, the dose of the drug Koh Amlessa (Krka, Slovenia) at visit 2 was reduced by 2 times. Drug withdrawal due to poor tolerance was not required in any of the patients included in the study.

At visit 2 in 6 patients, the dose of the drug Koh Amlessa (Krka, Slovenia) was reduced due to the achievement of the target level of blood pressure. The average value of SBP in the group was 135.1±11.7 mm Hg. Art., which is significantly lower than the original - 160.2±13.5 mm Hg. Art. (R<0,05). При этом выявлена также тенденция к уменьшению уровня ДАД при отсутствии роста ЧСС (см. рисунок, р>0.05). Absence of reflex tachycardia during drug therapy , which includes AA, is very important, since 46 (20%) included in the study had concomitant coronary heart disease (angina pectoris, myocardial infarction or arrhythmias).

At the second visit, 183 (79%) patients reached the target BP level, which is significantly more than at visit 1 - 10% (p<0,05). Среди остальных 48 пациентов у 8 (3%) для достижения целевого уровня АД была увеличена в 2 раза доза препарата Koh Amlessa (Krka, Slovenia), in 4 more people BAB was added to the treatment with Co-Amlessa (in 2 - bisoprolol, in 2 - carvedilol).

In a differentiated analysis, it was found that individuals who did not reach the target level of blood pressure had the most pronounced AH - SBP initially amounted to 175.4±9.9 mm Hg. Art. and was higher than the group average - 160.2±13.5 mm Hg. Art. (R<0,05). Среднее ДАД - 92,2±9,2 мм рт. ст. - было сопоставимым со средним показателем в группе - 93,3±8,7 мм рт. ст. (р>0.05). Despite the lack of achievement of the target BP level, at visit 2 in this group of more severe patients, a decrease in the level of both SBP and DBP was registered - to 159.2±9.8 and 88.8±7.3 mm Hg. Art. respectively, and the level of SBP became significantly lower than at visit 1 (p<0,05).

When conducting an analysis using the method of pairwise related variants, y it was found that in persons who did not reach the target level of blood pressure at visit 2, the decrease in SBP averaged -16.2±13.9 mm Hg. Art. (R<0,05), уменьшение ДАД было менее выраженным и составило -2,8±9,4 мм рт. ст. (р>0,05).

At visit 3, no adverse events were recorded in any of the examined, that is, they were stopped after a dose reduction at visit 2. The mean SBP value for the group was 129.2±10.5 mm Hg. Art., that is, not only lower than the original, but also, taking into account the value of the standard quadratic, did not exceed the norm. The level of DBP at visit 3 was 78.6±5.9 mm Hg. Art., which is significantly lower than the original (see figure, p<0,05). Прироста ЧСС при этом не наблюдалось (р<0,05).

212 (92%) patients already had the target level of blood pressure - significantly more than at baseline (p<0,05). Лишь 19 (8%) из всех включенных в исследование лиц не смогли достичь целевого уровня АД на визите 3.

However, the average level of SBP in the group of people who did not reach the target level of blood pressure was 153.2±9.6 mm Hg at the third visit. Art., that is, significantly lower than the original (p<0,05). При анализе методом попарно связанных вариант снижение САД в сравнении с визитом 1 составило -22,2±14,4 мм рт. ст. (р<0,05), в сравнении с показателем на визите 2 - -6,6±7,5 мм рт. ст. (р<0,05). Снижение ДАД в сравнении с показателем во время визита 1 составило -5,3±12,2 мм рт. ст. (р>0.05), compared with that at visit 2 - -1.4±7.0 mm Hg. Art. (p>0.05).

Similar results on the effect on levels b BP has been demonstrated with the combination of perindopril/indapamide/amlodipine in studies PIANIST, PAINT, ADVANCE.

So, in the study PIANIST the initial level of blood pressure was 160.5±13.3/93.8±8.7 mm Hg. Art. (comparable to that identified in this work - 160.2±13.5/93.3±8.7 mm Hg). After 4 months of taking the combination of perindopril / amlodipine / indapamide, a decrease in blood pressure was achieved to 132.2 ± 8.6 / 80.0 ± 6.6 mm Hg. Art. (in the present study - up to 129.2 ± 10.5 / 78.6 ± 5.9 mm Hg after 8 weeks of taking the drug). BP reduction in study PIANIST averaged 28.3±13.5/13.8±9.4 mm Hg. Art. (when taking Co-Amlessa - 22.2±14.4/1.4±7.0 mm Hg). Target blood pressure level in the study PIANIST reached 72% of patients, in the present study - 92% of the examined.

The PAINT study included 6088 patients aged 62.8±11.3 years with baseline office BP 158.1±13.0/92.6±8.8 mm Hg. Art., comparable to that in the present study. After 4 months, office BP decreased by 26.7±13.3/12.9±9.4 mm Hg. Art., that is, the results are consonant with those obtained when taking a fixed antihypertensive combination Koh Amlessa(Krka, Slovenia).

The ADVANCE (Action in Diabetes and Vascular Disease) study randomized 11,140 patients (5569 to receive the fixed combination of perindopril/indapamide, 5571 to the placebo group). At baseline, mean BP was slightly lower than in the drug study. Koh Amlessa (Krka, Slovenia) and was 145/81 mm Hg. Art. Under the influence of a fixed combination of perindopril / indapamide, a decrease in blood pressure was achieved to 134.7 / 74.8 mm Hg. Art., that is, an average of 5.6 / 2.2 mm Hg. Art. (R<0,01). Но еще более важным явилось снижение риска смерти от ССЗ на 18% и общей смертнawn by 14%. The authors concluded that routine administration of the fixed combination of perindopril/indapamide in individuals with type 2 DM is well tolerated and improves prognosis. Taking a fixed combination of perindopril/indapamide for 5 years saved the life of 1 out of 79 treated patients.

J. Chalmers et al. (2014) found that out of 11,140 patients who entered the ADVANCE study, 3427 people (1669 from the active treatment group and 1758 from the placebo group) received AA, the remaining 7713 patients (3900 from the active treatment group and 3813 and placebo group) did not receive AA. The inclusion of AK in the combination therapy of an ACE inhibitor perindopril and the metabolically neutral diuretic indapamide contributed to an even more pronounced effect on the prognosis, in particular, on cardiovascular death and death from all causes, than when using a combination of the two indicated drugs.

So the generic drug Koh Amlessa (Krka, Slovenia), which is a fixed combination of perindopril/amlodipine/indapamide, has demonstrated high efficacy for the treatment of arterial hypertension (including 92% of people who received antihypertensive therapy, but did not reach the target level of blood pressure) in real clinical practice. The data obtained on the effect of the drug Koh Amlessa (Krka, Slovenia) on the level of blood pressure are comparable with the results of the PIANIST, PAINT, ADVANCE studies conducted using original drugs.

Conclusions:

1. The use of a triple fixed combination of perindopril / amlodipine / indapamide ( Ko-Amlessa, Krka, Slovenia) contributed to the achievement of the target level of blood pressure after 4 weeks - in 79%, after 8 weeks - in 92% of patients with arterial hypertension who had previously received antihypertensive therapy, but did not achieve their goals.

2. Persons who received antihypertensive treatment, including the use of fixed combinations of drugs, had a SBP level of 160.2 ± 13.5 mm Hg when included in the study. Art., DBP - 93.3±8.7 mm Hg. Art., which significantly exceeded the generally accepted target level<140/90 мм рт. ст. и свидетельствовало о низкой эффективности проводимого лечения.

3. After 4 weeks of taking the drug Koh Amlessa (Krka, Slovenia) achieved a decrease in SBP to 135.1±11.7 mm Hg. Art. (R<0,05), ДАД - до 81,6±7,1 мм рт. ст., а через 8 недель - до 129,2±10,5 и 78,6±5,9 мм рт. ст. соответственно (р<0,05), что свидетельствует о нормализации артериального давления у лиц, ранее достигавших его контроля, несмотря на проводимое лечение.

4. While taking the drug Koh Amlessa (Krka, Slovenia) failed to achieve the target level of blood pressure after 4 weeks in 21% of patients, after 8 weeks - only in 8% of the examined. In this most difficult group of patients to manage, the baseline SBP was 175.4±9.9 mm Hg. Art., that is, it was higher than the average for the group (p<0,05). Через 4 недели у лиц с резистентной и более выраженной артериальной гипертензией выявлено снижение САД до 159,2±9,8 мм рт. ст. (р<0,05), через 8 недель - до 153,1±9,6 мм рт. ст. (р<0,05), при анализе методом попарно связанных вариант снижение САД составило -16,2±2,3 и -22,2±3,4 мм рт. ст. соответственно (р<0,05).

5. In persons with severe treatment-resistant hypertension, taking the drug Koh Amlessa (Krka, Slovenia) led to an additional decrease in SBP by 16 mm Hg. Art. - after 4 weeks and 22 mm Hg. Art. - after 8 weeks of admission.

6. Fixed combination perindopril/amlodipine/indapamide ( Ko-Amlessa, Krka, Slovenia) has demonstrated high efficacy for the treatment of arterial hypertension (including 92% of persons who received previous antihypertensive therapy, but did not reach the target level of blood pressure) in real clinical practice.

L I T E R A T U R A

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2. Mancia G., De Backer G., Dominiczak A., et al. // J. Hypertens. - 2007. - Vol.25. - P.1105-1187.

3. Wald D.S., Law M., Morris J.K., Bestwick J.P., Wald N.J.// Am. J. Med. - 2009. - Vol.122. - P.290-300.

4. T ó th K . // Am. J. Cardiovasc Drugs. - 2014. - Vol.14, N2. - P.137-145. doi:10.1007/s40256-014-0067-2.

5. Páll D., Szántó I., Szabó Z.// clinic. Drug Investig. - 2014. - Vol.34, N10. - P.701-708.

6. hellerS.R. // Diabetes Care . - 2009 . - Vol. 32 (Suppl. 2). - S357-S361.

7. Chalmers J., Arima H., Woodward M., et al. // Hypertension. - 2014. - Vol.63. - P.259-264.

Medical news. - 2017. - No. 11. - S. 19-23.

Attention! The article is addressed to medical specialists. Reprinting this article or its fragments on the Internet without a hyperlink to the original source is considered a copyright infringement.

Cardiologist

Higher education:

Cardiologist

Saratov State Medical University. IN AND. Razumovsky (SSMU, media)

Level of education - Specialist

Additional education:

"Emergency Cardiology"

1990 - Ryazan Medical Institute named after Academician I.P. Pavlova

Hypertension, representing a constantly elevated blood pressure above the norm, requires immediate correction of the patient's condition. After all, its complications can carry a serious threat and danger to human health and even life. And combined antihypertensive drugs, which have gained considerable popularity today due to their high efficiency and the elimination of the need for patients to take a large number of medications at a time, have firmly taken one of the leading positions in the list of effective drugs designed to stabilize the blood pressure indicator.

Rational combinations of antihypertensive drugs provide an opportunity both to increase the effectiveness of the ongoing therapeutic effect, and to eliminate the likely negative manifestations for the patient's body. Modern formulas of such drugs make it possible to stabilize blood pressure indicators in a short time, reduce the negative impact of hypertension manifestations. The psychological factor that determines the patient's lack of dependence on a large number of medications is also important, because the combined therapy of arterial hypertension is today recognized as one of the most effective methods of really effective exposure to high blood pressure.

The most effective combinations of two drugs with antihypertensive action

The following list of drugs, represented by a combination of two antihypertensive drugs, is considered the most popular among cardiologists due to the positive results of numerous studies aimed at studying the dependence of blood pressure indicators on the drugs used.

And although some of them have not become widely known due to the relatively small scale of ongoing laboratory studies, the results of using these drugs speak for themselves: a steady decrease in blood pressure, stabilization of the patient's condition are the best indicators of health for this disease.

The combination of "thiazide diuretics and β-blockers"

This combination has become the most widely known due to its excellent performance in the treatment of conditions such as uncomplicated hypertension. It is these components that have proven to be an effective combination even in the presence of concomitant organic lesions in an unstarted stage of development.

However, a contraindication to the use of this combination should be considered gout, physical activity of the patient (for example, athletes), as well as the state of atrioventricular blockade of 2 and 3 degrees. Relative contraindications to the use of a combination of thiazide diuretics and β-blockers include the state of pregnancy.

The combination of "thiazide diuretics and ACE inhibitors"

When using a combination such as thiazide diuretics and ACE inhibitors in the treatment of hypertension, the presence of the following diseases must be considered:

• congestive heart failure;
• hypertension;
• isolated systolic hypertension;
• elderly people with advanced hypertension.

These conditions and diseases are best treated with a combination of thiazide diuretics and ACE inhibitors.

Both components of the presented combination have a high degree of effectiveness, which should be taken into account when prescribing a combined drug to a patient: an excessively rapid decrease in blood pressure may adversely affect the patient's general well-being. Elderly people are most susceptible to such influence, therefore, in this age group, the drug in question should be used as a potent substance and the therapeutic effect should be carried out with increased caution.

The combination of "diuretics and AT1 receptor blockers"

This combination has proven itself in the best way in the treatment of high blood pressure in the presence of parallel current lesions of the left ventricle of the heart. However, due to the increased effectiveness of exposure (a sharp decrease in blood pressure), increased caution should be exercised.

The combination of diuretics with AT1 receptor blockers has proven to be excellent in the treatment of severe hypertension in the presence of concurrent progressive chronic heart failure.

The combination of "diuretics and agonists of imidazoline I1 receptors"

This combination is not widely known due to the paucity of ongoing laboratory studies of the effect on blood pressure indicators in hypertension. However, the effectiveness was noted in many cases of practical use of this combination, and it is excellently used when it is necessary to use complex antihypertensive drugs in the presence of allergic reactions or the body's immunity to the treatment with β-blockers.

The combination of "diuretics and calcium antagonists"

The considered combination makes it possible to obtain a positive dynamics of treatment in the presence of a pronounced increase in blood pressure in the elderly, since calcium antagonists belonging to the dihydropyridine series, in such therapy, manifest themselves as potent vasodilators. At the same time, according to numerous laboratory studies, this combination allows you to eliminate the consequences of high blood pressure, chronic heart failure and significantly reduce the negative manifestations of ISH.

The combination of "β-blockers and ACE inhibitors"

Possessing a pronounced effectiveness in hypertension, chronic heart failure and ISH, the combination of ACE inhibitors and β-blockers makes it possible to eliminate the manifestations of high pressure in the shortest possible time. Also, this complex of substances allows you to eliminate or minimize the residual effects of coronary heart disease, myocardial infarction in combination with chronic heart failure.

And although this combination is less effective than the combination of diuretics and β-blockers, studies have provided information about the possibility of treatment using the presented components.

The combination of "calcium antagonists of the dihydropyridine series and β-blockers"

This combination makes it possible to almost completely cure hypertension in patients with parallel current coronary heart disease. With the help of studies, evidence was obtained of the effectiveness of the ongoing drug exposure using these components.

With the help of these combined drugs, it becomes possible to increase the adherence of patients to the treatment, which guarantees the most stable effect, ensures the long-term results.

The combination of "calcium antagonists and ACE inhibitors"

The combination of these components provides an excellent opportunity for the most effective treatment of high blood pressure when combined with severe signs and manifestations of nephropathy, severe manifestations and documented atherosclerosis.

With the help of calcium antagonists, a positive effect can be obtained in the treatment of hypertension against the background of coronary heart disease, since these substances have a pronounced anti-ischemic effect. ACE inhibitors have shown themselves well as renoprotective components, therefore they will be correctly prescribed if patients have signs of diabetic nephropathy.

The combination of "dihydropyridine calcium antagonists and AT1 receptor blockers"

This combination proved to be the most effective in eliminating high blood pressure against the background of existing gout, in violation of heart rhythms and after coronary disease. These properties of the considered combination were revealed in the course of ongoing laboratory studies, which confirmed the high effectiveness of the treatment of people with the listed organic disorders.

Also, this combination showed positive results in eliminating the signs of diabetic nephropathy, in diabetes mellitus.

Combination "ACE inhibitors and imidozaline receptor agonists"

This combination is currently not widely used due to insufficiently studied action. However, its use made it possible to obtain excellent results in eliminating the manifestations of such diseases and pathological conditions as increased excitability of the sympathetic nervous system, coronary heart disease.

A decrease in blood pressure, stabilization of the general condition of the patient with a gradual elimination of the consequences of increased SNS activity - these positive effects make it possible to call the combination of ACE inhibitors with imidozaline receptor agonists one of the most promising and effective combinations.

The listed two-component combinations allow to increase the degree of influence of the treatment process in arterial hypertension. High blood pressure, accompanying pathological conditions in the form of a significant deterioration in the patient's health, the presence of concurrent diseases (ischemic heart disease, chronic heart failure) - these conditions can be corrected and largely improved through the use of the above two-component combinations.

An additional alternative to complex antihypertensive drugs

Today, in the practice of treating high blood pressure, three-component drugs can also be used, which have shown themselves excellently in eliminating the cause of this condition and the consequences of its occurrence. However, they can be considered more theoretical studies, since not enough practical experiments have been carried out to study their degree of effectiveness.

These include the following list of funds:

• diuretics, β-blockers and calcium antagonists, which should be called one of the most potent combinations;
• diuretics, calcium antagonists and ACE inhibitors - this combination can be used to eliminate the effects of high blood pressure, which provides a reliable improvement in the patient's condition;
• A1 receptor antagonists, calcium antagonists and diuretics.

The listed combinations of drugs have a high degree of effectiveness when used in the treatment of severe hypertension, in the presence of many organic disorders accompanying this pathological condition. Fixed combinations of antihypertensive combinations have already been sufficiently studied, which allows them to be used both for the treatment of the main lesion with an increase in blood pressure, and to prevent possible negative manifestations.

The main direction of application of the listed combinations of drugs increases the patient's desire for their use, which greatly contributes to the effectiveness of the ongoing therapeutic effect.

Opportunities for the use of the most common combinations in high blood pressure

If we present all the most commonly used complex drugs with antihypertensive action and their combinations in the fight against hypertension, we can get the following table, which presents the possibilities for the use of such drugs:

Combinations of drugs and substances	Potential applications
β-blockers + diuretics	High blood pressure (hypertension), uncomplicated hypertension that does not have target organ damage
Diuretics + ACE inhibitors	Persistent arterial hypertension with high blood pressure + chronic congestive heart failure (CHF)
Diuretics + AT1 receptor blockers	The presence of hypertension, isolated systolic hypertension (or ISH) + chronic heart failure. Possibly during ISH.
Diuretics + imidazoline I1 receptor agonists	If it is impossible to include a β-blocker in combination with a diuretic (due to existing contraindications)
Diuretics + calcium antagonists (dihydropyridine series)	Chronic heart failure against the background of sharply increased blood pressure, ISH (most often in elderly patients)
α-blockers + β-blockers	Hypertension, its malignant variety
β-blockers + ACE inhibitors	Patients with arterial hypertension who have undergone myocardial infarction (secondary prevention), have CHF and / or coronary artery disease
Calcium antagonists + β-blockers	Arterial hypertension + ischemic heart disease
Calcium antagonists + ACE inhibitors	Arterial hypertension + signs of nephropathy, coronary artery disease or developing atherosclerosis
Calcium antagonists + AT1 receptor blockers	Arterial hypertension + manifestations of nephropathy, ischemic heart disease or the initial stage of atherosclerosis
ACE inhibitors + AT1 receptor blockers	Arterial hypertension + atherosclerosis + nephropathy
ACE inhibitors + imidazoline I1 receptor agonists	Patients with SNS hyperactivity
Diuretics + β-blockers + calcium antagonists	Malignant arterial hypertension
Diuretics + calcium antagonists + ACE inhibitors	Malignant ISH, long-term arterial hypertension + nephropathy and diabetes mellitus
Diuretics + calcium antagonists + AT1 receptor blockers	Malignant ISH, hypertension + diabetes mellitus with signs of nephropathy
ACE inhibitors + α1-blockers + imidazoline I1 receptor agonists	Arterial hypertension + diabetes mellitus. May develop metabolic syndrome
ACE inhibitors + calcium antagonists + β-blockers	Long-term arterial hypertension + coronary artery disease

This table clearly presents the possibilities for the use of certain combinations of the listed components. The effectiveness of the use of any of the listed drugs depends on the presence of certain indications, and their action is based on certain metabolic and hemodynamic properties of each component.

Recommendations for treatment with antihypertensive complex drugs

An important point for obtaining a pronounced positive dynamics with the help of the considered drugs should be considered the need for both preliminary diagnosis for an accurate diagnosis, and contacting a specialist in his field, who will help draw up the most effective treatment regimen, taking into account the individual characteristics of the organism, the presence of concomitant organic changes. For the treatment of arterial hypertension, you should fully follow the advice of your doctor and do not self-medicate.

Self-medication in this case can only harm the healing process with the help of the listed medicines, therefore, in order to obtain the expected result, it is recommended to consult a doctor and follow all his recommendations. Making certain adjustments to the ongoing treatment will prevent a decrease in the degree of effectiveness of the impact.

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

In this regard, the issues of rational pharmacotherapy and the optimal choice of drugs for CVD are of particular relevance. Based on evidence-based medicine, algorithms for the treatment of 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 contributes to improving the results of treatment and prognosis in CVD.

At the same time, the appointment of optimal therapy is often 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 in connection with the growing prevalence of comorbid conditions, which greatly complicate the implementation of drug therapy and require special close attention to monitoring the effectiveness and safety of medicines. As practice shows, the degree of compliance of ongoing pharmacotherapy with accepted recommendations in real clinical practice remains quite low both in our country and abroad.

In 2013, new recommendations of the European Society of Hypertension (ESH) and the European Society of Cardiology (European Society of Cardiology, ESC) for the treatment of hypertension, as well as Russian recommendations "Diagnosis and treatment of arterial hypertension", which are the basis for choice of rational pharmacotherapy of hypertension by doctors of all specialties. The main goal of treating hypertensive patients is to minimize the risk of developing cardiovascular complications (CVD) and death from them. To achieve this goal, it is required:

• lowering blood pressure (BP) to the target level;
• correction of all modifiable risk factors (smoking, dyslipidemia, hyperglycemia, obesity);
• preventing, slowing down the rate of progression and/or reducing damage to target organs;
• treatment of associated and concomitant diseases (IHD, 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 (ACE inhibitors);
• angiotensin II receptor blockers (ARBs);
• beta-blockers (BAB);
• calcium antagonists (AK);
• thiazide diuretics.

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

A large arsenal of available drugs makes it extremely important and at the same time difficult to select specific drugs, and a differentiated choice of drugs remains an urgent problem for practicing physicians at the present time. This is especially true for patients with additional risk factors and concomitant diseases, which, on the one hand, worsen the prognosis in hypertension, 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 suggest an integrated approach that allows you to influence not each disease separately, but the patient as a whole.

Of course, each patient requires serious reflection, analysis of the characteristics of his clinical situation, and with this in mind, one or another class of drugs should be chosen. Great help to the practitioner at this stage can be provided by recommendations summarizing the evidence base for all classes of antihypertensive drugs. Some drugs may be considered preferable in specific situations because they have been used in these situations in clinical trials or have been shown to be more effective in specific types of target organ damage.

Adherence to treatment

Discussing the problem of rational pharmacotherapy of AH, one cannot help but dwell on its very important aspect — the low effectiveness of AH treatment and the failure to achieve target blood pressure (BP) values. This is due to various factors, not least among 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. So, according to various researchers, up to 50% of patients with hypertension stop the treatment prescribed by the doctor on their own. 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 drugs only when blood pressure rises. Of these, 63.6% do not take drugs every day, 39.7% stop treatment after normalization of blood pressure, 32.9% miss a dose due to forgetfulness, and only 3.3% do not allow missed medications.

Basic concepts of adherence to treatment

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

Retention on therapy is determined by the length of the period of drug therapy and is measured by the number of days during which the patient received therapy, or the percentage of patients continuing treatment over a certain period.

Compliance is an indicator of adherence to drug therapy (compliance with the dose, frequency and mode of administration). Compliance is assessed by the index of use of the drug, which is a quotient of the number of days of taking the full dose of the drug (or the 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 achieving such a result is difficult in any chronic disease. If the drug utilization index reaches 80% or more, compliance is considered acceptable.

In order to increase the information content of the survey of patients 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 drugs and non-drug methods of treatment, but also questions of a general psychological nature regarding the patient's readiness for interaction, responsibility, following advice, etc. Some of these scales have already been validated and recommended for widespread use.

The simplest compliance test is the Morisky-Green test, which consists of four questions:

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

Compliant patients are considered to have scored 4 points, non-compliant - less than 3. The use of this simple and accessible method will help the practitioner to focus on those patients who need extra attention in order to improve their compliance.

What are the ways to improve patient adherence to treatment?

To date, there is no single effective strategy for improving compliance, however, speaking about the impact on adherence to treatment, two main aspects should be borne in mind.

The first one, which concerns the actual adherence to the doctor's recommendations by the patient, 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 his education. A number of authors and expert groups, based on large analytical reviews of the literature, focus on a fundamental change in the very approach to the patient's participation in the treatment process and more active involvement in making a medical decision. In their opinion, without the active participation and desire of the patient to be treated, it is difficult to achieve a solution to short- and medium-term, and even more so long-term problems.

It has also been proven that patients do not seek to follow the 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, 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 patient education, in particular, in health schools for patients with hypertension, which are essentially a medical preventive technology based on a combination of individual and group impact on patients and aimed at increasing their level of knowledge, awareness and practical skills in the rational treatment of hypertension, increasing patient adherence to treatment and preventing complications of the disease, improving 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 that help the patient not to miss the next dose.

The need for 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 level of blood pressure 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 in order to achieve the target level of blood pressure and reduce cardiovascular risk (CVR), most patients need to prescribe several antihypertensive drugs. Combination therapy, in fact, today is a priority in the treatment of patients with hypertension, which is reflected in the new European and Russian recommendations for hypertension. 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 damage to target organs, as well as those who have already associated clinical conditions.

Carrying out combination therapy for patients with AH seems justified and justified also due to the fact that, according to the mechanisms of development and formation of AH, it is a multifactorial disease, and the combination of drugs with different mechanisms of action, complementary to each other, makes it possible to optimally influence various pathogenetic mechanisms of AH. 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 Combinations of Drugs – A Way to Improve Patient Adherence

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

The use of fixed combinations of antihypertensive drugs, which have become increasingly widespread in recent years, can also help improve adherence. 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 in monotherapy. Of great importance for rational pharmacotherapy are fixed combined preparations, for the creation of which improved dosage forms are used. The advantages of fixed drug combinations are ease of prescribing and dose titration, increased treatment efficacy and more frequent achievement of target BP, convenience for the patient, improved patient adherence to treatment, as well as pharmacoeconomic benefits - 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 act simultaneously on different links in 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 of drugs that are part of the combined drug, especially in cases where one of them sufficiently completely blocks the activation of counterregulatory mechanisms due to the action of another 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 the improvement in patient compliance with the prescribed therapy regimen.

Most patients do not take drugs regularly and often interrupt treatment for several days. Even in cases where patients take prescribed antihypertensive drugs, they do not always do it at the right time. In a special study using electronic devices, it was shown that in 25% of patients the time of taking the drug is 6 hours different from that prescribed by the doctor. The greatest deviations from the prescribed regimen of therapy are noted in cases where the dosage regimen of the drug is too complicated or significant adverse drug reactions occur. Reducing the number of daily pills needed to lower blood pressure is considered an important benefit of fixed-dose combinations. Moreover, if the combined drug has to be taken 2 times a day, the degree of compliance with the prescribed therapy regimen decreases, therefore, 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 relation to the effect on the state of target organs and cardiovascular risk indicators of various two-component combinations of antihypertensive drugs.

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

BAB over the past 50 years have taken a strong position in the pharmacotherapy of the most common CVD, and without them it is already impossible to imagine modern cardiology. A large evidence base has made it possible to include this class of drugs in almost all modern recommendations - both for the treatment of hypertension, and coronary artery disease, and CHF. They reduce the risk and frequency of CV events, positively affect the clinical manifestations of the disease and improve the quality of life of patients with various CVDs, as well as those with comorbidity.

The basis for the widespread use of BAB was the identification of the role of chronic hyperactivation of the sympathoadrenal system (SAS) in the development of endothelial dysfunction, left ventricular hypertrophy, malignant cardiac arrhythmias, and progression of chronic heart failure. BABs are a group of drugs that is very heterogeneous in terms of 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 BAB is competitive antagonism against β 1 -adrenergic receptors. Along with the blockade of β 1 -adrenergic receptors, BAB can also block β 2 -adrenergic receptors.

The experience of the clinical use of β-blockers in the treatment of hypertension suggests that they, especially β 1 -selective drugs, have a sufficiently high antihypertensive efficacy and good tolerance with long-term use in medium therapeutic doses in various categories of patients.

Bisoprolol, which has a high cardioselectivity, is widely used in clinical practice. If we take the ability to block β 1 receptors in carvedilol as a unit, then for metoprolol this figure will be 6, for bisoprolol - 21. 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.

According to the antihypertensive effect, bisoprolol is not only not inferior to other BBs, but surpasses 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 its effect on systolic blood pressure and heart rate during exercise. The effectiveness of bisoprolol in reducing cardiovascular risk, combined with the absence of a negative effect on carbohydrate metabolism, has been proven in large randomized clinical trials, including such well-known ones as CIBIS-II (Cardiac Insufficiency Bisoprolol Study II), TIBBS (Total Ischemic Burden Bisoprolol Study) and others

Amlodipine, which is part of Concor AM, is an AK III generation, with a half-life of more than 35 hours, has a high 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 (verapamil and diltiazem groups).

From the point of view of clinical pharmacology, the combination of a highly selective BAB and dihydropyridine AA is reasonable and justified. The effects of bisoprolol and amlodipine are complementary in terms of lowering blood pressure, since they affect different parts of the pathogenesis, which make it possible to enhance antihypertensive efficacy: the vasoselective effect of amlodipine (decrease in total peripheral vascular resistance (TPVR)) and the cardioprotective effect of bisoprolol (decrease in cardiac output, slowing of heart rate). ), which in turn helps to reduce the risk of developing pathological conditions in hypertension, such as angina, myocardial infarction, myocardial remodeling, MI.

In accordance with Russian recommendations for the treatment of hypertension, the predominant indications for prescribing Concor AM are the 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, hypertension in pregnant women.

Clinical experience with the use of Concor AM indicates a good antihypertensive efficacy of the drug with a high frequency of achieving target blood pressure values.

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.

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 dosing regimen for each patient, taking into account the individual characteristics of hemodynamics.

Conclusion

Currently, the issues of rational pharmacotherapy, 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. Commitment is a key position that links the process and the result of medical intervention. The use of fixed combinations of antihypertensive drugs in clinical practice simplifies the treatment regimen for patients with hypertension and improves adherence to treatment.

Concor AM is a fixed dose combination of bisoprolol and amlodipine with proven antihypertensive efficacy combined with a good safety profile. The components of the drug are complementary in terms of lowering blood pressure, since they affect different parts of the pathogenesis, which make it possible to enhance antihypertensive efficacy: the vasoselective effect of amlodipine (decrease in peripheral vascular resistance) and the cardioprotective effect of bisoprolol (decrease in cardiac output, decrease in heart rate), which in turn helps to reduce the risk of developing pathological conditions in hypertension, such as angina pectoris, myocardial infarction, myocardial remodeling, cerebral stroke.