Characteristics of the Course and Patterns of Pharmacological Therapy in Elderly Patients with Grade 1–2 Arterial Hypertension

The dissertation is devoted to the study of the characteristics of the course of grade 1–2 arterial hypertension in persons older than 60 years and to a comparative evaluation of antihypertensive treatment in this age group. It examines the isolated systolic and systolo-diastolic forms of the disease and analyses the state of target organs — the heart, the vessels and the kidneys — including left ventricular diastolic function and vascular endothelial function. A separate assessment is made of the effects of 24-week monotherapy with prolonged-action nifedipine (Cordaflex RD) and with enalapril, as well as of their combination, using ambulatory blood pressure monitoring, echocardiography and microalbuminuria data. The work aims to substantiate a rational scheme of investigation of elderly patients with different variants of the course of arterial hypertension and to determine the possibilities of correcting endothelial dysfunction as a surrogate endpoint for the prognosis of the disease.

Relevance of the research. At present, arterial hypertension (AH) is one of the most widespread chronic diseases. In the developed countries of the world, arterial hypertension occurs in 20–40% of the adult population. In elderly and senile age, the prevalence of arterial hypertension exceeds 40–50% [29,69,70,114,115].

In Russia, the number of elderly people is growing quite rapidly. At present, one fifth of the Russian population are persons of pensionable age, and about 11% (3.2 million) are over 80 years of age, which naturally affects the prevalence of AH. According to data from a number of authors, the expected life span of untreated patients is 14–16 years shorter than that of persons with normal arterial pressure [43,82].

Hypertensive disease is one of the main risk factors for cerebral stroke, ischaemic heart disease and other cardiovascular diseases of atherosclerotic origin, which account for about half of all deaths. Up to the age of 80 years, the rate of complications of AH depends on the duration of the disease, whereas in older age this pattern is no longer observed [5,48,50,57].

Among the factors of stabilisation and progression of AH, researchers are attracted to lesions of the vascular bed, first and foremost of the endothelium, which acts, on the one hand, as the earliest target organ to be damaged and, on the other, as the effector of many links in the pathogenesis of AH, being directly involved in the rise of arterial pressure. By the beginning of the present century, the significance of endothelial dysfunction as one of the most important pathophysiological mechanisms of AH had been studied in detail. It has been established that the endothelium is not a passive barrier between blood and tissues, but an active organ whose dysfunction is an obligatory component of such cardiovascular diseases as atherosclerosis, AH, ischaemic heart disease, and chronic heart failure [24,36,37,38,52,105].

The identification of these circumstances led to the emergence of the concept of pharmacotherapy of AH, according to which the correction of endothelial dysfunction is regarded as an important factor determining the adequacy of antihypertensive therapy [1,16,18,36,37,38,91,123].

Special requirements are placed on the pharmacological treatment of AH in elderly patients, taking into account the features of pathogenesis and the age-related changes in homeostasis. For use in geriatric practice, the prescription of diuretics and β-adrenoblockers (SHEP, X-CELLENT) is recommended. At the same time, the drugs that possess undoubted advantages for the treatment of AH in elderly and senile persons are ACE inhibitors and calcium antagonists, as evidenced by the results of multicentre studies (Syst-Eur, INTACT, Syst-China, Hall, ELSA, INSIGHT, TOMHS, CAPPP). However, important aspects of the pharmacodynamics of drugs of these groups during long-term use in the elderly deserve in-depth investigation.

Aim of the research. A comprehensive assessment of the influence of different variants of the course of arterial hypertension in persons older than 60 years on clinical and instrumental parameters, with a study of the corrective action of 24-week therapy with a controlled-release calcium antagonist, nifedipine, and with enalapril on target organs.

Objectives of the research. In carrying out the present work, in accordance with the stated aim, the following objectives were pursued:

1. To conduct a comparative analysis of the state of target organs (heart, vessels, kidneys) in patients older than 60 years with different variants of the course of grade 1–2 arterial hypertension and in normotensive subjects;

2. To assess the effect of long-term treatment with a controlled-release calcium antagonist, nifedipine, and with enalapril in elderly patients with isolated systolic arterial hypertension on prognostically significant parameters of ambulatory blood pressure monitoring and on the cardioprotective and nephroprotective action;

3. To assess the effect of long-term treatment with a controlled-release calcium antagonist, nifedipine, and with enalapril in elderly patients with systolo-diastolic arterial hypertension on prognostically significant parameters of ambulatory blood pressure monitoring and on the cardioprotective and nephroprotective action;

4. To study the corrective influence of 24-week therapy with prolonged-action nifedipine and with enalapril on parameters of endothelial function in different variants of the course of arterial hypertension in the elderly;

5. To investigate the expediency of the combined use of prolonged-action nifedipine and enalapril in different variants of the clinical course of arterial hypertension in persons older than 60 years.

Scientific novelty. For the first time, a comprehensive comparative evaluation of the state of target organs has been carried out in different variants of the course of arterial hypertension in persons older than 60 years. For the first time, endothelial function has been studied by the method of investigation of the vasomotor response of the brachial artery to reactive hyperaemia in elderly patients, and a comparative assessment of endothelial function parameters in different variants of the course of arterial hypertension has been performed. For the first time, a comparative analysis of the antihypertensive effect (by office arterial pressure and ambulatory monitoring) has been performed with 24-week therapy using a controlled-release calcium antagonist, nifedipine, and enalapril in patients older than 60 years with different variants of the course of grade 1–2 arterial hypertension. For the first time, a comprehensive comparative evaluation of the influence of long-term antihypertensive therapy on target organs has been carried out in elderly persons with different variants of the course of grade 1–2 arterial hypertension.

Data have been obtained indicating a regression of endothelial dysfunction in patients older than 60 years with arterial hypertension during 24-week therapy with prolonged-action nifedipine and enalapril.

Practical significance. As a result of the research, a rational scheme of investigation has been developed for elderly patients with different variants of the course of arterial hypertension.

A marked and equally pronounced impairment of endothelial function has been established in persons older than 60 years with different variants of the course of arterial hypertension.

The aggregate of data on the severity of endothelial dysfunction in elderly patients with isolated systolic and systolo-diastolic arterial hypertension makes it possible to regard the vascular endothelium as a surrogate endpoint in determining the prognosis of this disease.

It has been revealed that a controlled-release calcium antagonist, nifedipine, and enalapril exert a comparable antihypertensive effect in patients older than 60 years with different variants of the course of arterial hypertension.

Statements submitted for defence:

1. In elderly persons suffering from arterial hypertension, diastolic dysfunction of the left ventricle and endothelial dysfunction are observed significantly more often than in normotensive subjects.

2. A controlled-release calcium antagonist, nifedipine, and enalapril, during 24-week treatment, exert a positive influence on systemic haemodynamics and on the regression of pathological remodelling on the part of target organs.

3. The combined use of prolonged-action nifedipine and enalapril is accompanied not only by potentiation of the antihypertensive effect but also by a more pronounced angioprotective action.

Approval of the work. The materials and main statements of the dissertation were reported at the Interregional Scientific Conference "Current Problems of Medical Science and Education" (Penza, 2007), the Russian National Congress of Cardiologists "Cardiology without Borders" (Moscow, 2007), the IV All-Russian Scientific and Practical Conference "Hypertensive Disease and Secondary Arterial Hypertension" (Moscow, 2007), the X Anniversary Scientific and Educational Forum "Cardiology" (Moscow, 2008), the III All-Russian Scientific and Practical Conference (Kazan, 2007), the Second Congress of Cardiologists of the Volga Federal District "The Present and the Future in Cardiology" (Saratov, 2008), the XVI Interregional Scientific Conference in memory of Academician N.N. Burdenko "Current Issues of Modern Practical Public Health" (Penza, 2008), and the Russian National Congress of Cardiologists "Improvement of the Quality and Accessibility of Cardiologic Care" (Moscow, 2008).

Publications. On the subject of the dissertation, 15 works have been published, including 3 works in journals recommended by the Higher Attestation Commission of the Ministry of Education.

Scope and structure of the work. The dissertation consists of an introduction, a review of the literature (Chapter 1), a description of the material and methods of investigation (Chapter 2), the author's own investigations (Chapters 3–5), a conclusion, conclusions and practical recommendations. The work is set out on 116 pages of typewritten text, illustrated with 5 figures and 52 tables. The bibliographic list contains 251 sources, of which 128 are by foreign authors.