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 . 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 . 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  and lipid profile . 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.