Comparative Assessment of the Influence of Plant-Based Preparations (Using Oxycardin as an Example) and Classical Nitrates on the Clinical Course, Haemostasis, and Rheological Properties of Blood in Patients with Stable Effort Angina

The dissertation is devoted to a comparative evaluation of the clinical effectiveness of the plant-based preparation oxycardin and the classical nitrate isosorbide dinitrate in patients with stable effort angina of functional class II–III. The work addresses current directions of antianginal therapy, the limitations of nitrate use associated with the development of tolerance and adverse effects, and provides a rationale for the interest in plant-based preparations as an alternative or adjunct to conventional pharmacological therapy of coronary heart disease.

The study includes an assessment of the dynamics of the clinical state of patients, treadmill test parameters, indices of the haemostasis system, and blood rheological properties during a course of treatment. The data obtained are compared between groups of patients receiving oxycardin and isosorbide dinitrate, which allows judging the comparable clinical effectiveness of the plant-based preparation and its more favourable tolerability profile.

Relevance of the Topic

At present, coronary heart disease (CHD) prevails among the causes of mortality, morbidity, and disability in the population [76, 135]. According to WHO data, in 2005, 17 million people in the world died from cardiovascular diseases. In Russia, 1 million 200 thousand people die from cardiovascular diseases every year. Stable angina is the first manifestation of CHD in 45–56% of cases [19]. The onset of effort angina impairs patients' quality of life and is accompanied, within one year, by the development of acute coronary syndrome in 2–4% of patients, while mortality reaches 2–3% [12, 29].

At present, three main directions in the treatment of stable angina have been defined: antithrombotic, antiatherosclerotic, and anti-ischaemic (or antianginal). Medicinal preparations that affect lipoproteins or reduce the risk of thrombosis substantially improve the prognosis both with respect to the frequency of myocardial infarction and sudden death, which has determined their obligatory use in the basic treatment of patients with various forms of coronary heart disease [29, 30, 145, 180]. Antianginal treatment of coronary heart disease presupposes the relief of pain syndrome and the prevention of the development of angina attacks, an increase in exercise tolerance, and includes the use of medicinal agents, non-pharmacological methods of treatment, and myocardial revascularization [2, 26, 107, 127].

Nitrates, calcium antagonists, and beta-adrenoceptors are especially effective in the therapy of stable angina owing to their capacity to prevent the development or eliminate the clinical and electrocardiographic manifestations of painful and painless myocardial ischaemia [4, 52, 145]. Organic nitrates (tri-, di-, and mononitrates) are the most well-known preparations from the group of vasodilators used in practical cardiology. Nitrates still hold firm positions in the treatment of patients with various clinical forms of coronary heart disease, while rapid-acting nitrates remain the principal agents for the relief of angina attacks and acute heart failure [4, 15, 41, 145].

The antianginal effect of nitrates is realized through a reduction in myocardial oxygen demand and an improvement in myocardial perfusion by decreasing myocardial preload, dilating coronary arteries, and improving endothelial function of arterial vessels by increasing NO content in the bloodstream [63, 89]. In addition, nitrates also possess an antithrombotic and antiplatelet effect [151]. The administration of nitro-preparations to patients with stable effort angina results in a reduction in the number and duration of ischaemic episodes, an improvement in the main parameters of stress tests, and social adaptation of patients, but does not affect the long-term life prognosis in this contingent of patients [107, 136].

The main problem arising with the regular intake of nitrates is the development of tolerance, which reduces the effectiveness of the preparations in preventing angina attacks by 25–30% [6, 53, 67, 150, 167]. Tolerance extends not only to the antianginal and haemodynamic effects but also to their anti-aggregatory action [145, 165]. Unfortunately, with the use of nitrates, such a side effect as headache frequently occurs, arising from dilation of cerebral vessels and preventing the intake of the preparations. Less frequent side effects include hypotension, presyncopal or syncopal states, and bradycardia. Nitrates are contraindicated in patients with low arterial pressure, closed-angle glaucoma, and increased intracranial pressure [67].

The high effectiveness of medicinal agents with vasodilatory action in patients with effort angina stimulated the search for new preparations with a similar mechanism of action, a representative of which is nicorandil — a potassium channel modulator. The results of clinical studies testify to the high antianginal and antihypertensive effectiveness of potassium channel modulators [9, 112]. It was also revealed that, unlike existing antianginal agents of nitrate structure, no development of tolerance has been registered for the action of nicorandil with long-term use [18]. At the same time, it should be noted that the main side effect associated with the administration of nicorandil is headache caused by dilation of cerebral veins.

At the end of the twentieth century, reports appeared in the medical literature of the positive action of plant-based preparations on the course and prognosis of coronary heart disease, mainly due to their vasodilatory effect and/or lipid-lowering, antioxidant, and antithrombotic action [11, 39, 72, 95, 146, 149]. The plant-based preparations with marked vasodilatory action include oxycardin, which contains Salvia miltiorrhiza, ginseng, borneol, and macrogol [17, 50, 70]. A number of works by Chinese and domestic researchers have demonstrated the positive influence of the preparation on the clinical picture of stable angina, which was manifested in patients as a reduced need for the intake of nitrates, a decrease in the number of anginal attacks and their severity, and a significant increase in exercise tolerance in 60–93% of patients [25, 34, 36, 57, 77]. Data have been obtained indicating the hypolipidaemic properties of oxycardin, manifested in a reduction in the blood content of total cholesterol, low-density lipoprotein cholesterol, and triglycerides, without a significant effect on the content of high-density lipoprotein cholesterol [20, 51, 70]. Information is available on the capacity of oxycardin to suppress the adhesive ability of platelets, spontaneous and stimulated by various agents platelet aggregation, and to reduce the viscosity of whole blood and plasma by lowering the blood fibrinogen concentration [25, 58, 117]. At the same time, in other studies, no reliable changes in the aggregatory ability of platelets in the process of treatment with oxycardin have been obtained [33, 68, 106]. The influence of the preparation on coagulation haemostasis in CHD patients remains insufficiently studied, although in animal experiments oxycardin prevented the formation of thrombi in the arterial vascular bed [50]. All the foregoing makes the chosen topic relevant.

Aim of the Study

To evaluate the effectiveness of oxycardin application in patients with stable effort angina and to investigate the effect of the preparation on haemostasis and blood rheology.

Objectives of the Study

1. To evaluate the clinical effectiveness of oxycardin application in patients with effort angina of FC II–III.

2. To investigate the influence of oxycardin therapy on haemostasis parameters in patients with effort angina of FC II–III.

3. To investigate the influence of oxycardin therapy on blood rheological properties in patients with effort angina of FC II–III.

Scientific Novelty

For the first time, it has been shown that the plant-based preparation oxycardin is not inferior in clinical effectiveness to isosorbide dinitrate in patients with effort angina of functional class II–III. The use of oxycardin is accompanied by a smaller number of side effects than with the intake of isosorbide dinitrate. For the first time, it has been shown that a course of treatment with oxycardin reduces the aggregatory ability of erythrocytes and platelets and improves the rheological properties of blood without a substantial effect on the haemostasis system in patients with effort angina of functional class II–III.

Practical Significance of the Work

Oxycardin is an effective preparation for the treatment of patients with effort angina of functional class II–III, which makes it possible to recommend its independent application, especially in patients with poor tolerance of nitrates or the development of tolerance to them. The positive influence of oxycardin on the functional activity of platelets, erythrocytes, and the viscosity characteristics of blood makes the preparation most indicated for the treatment of patients with effort angina of functional class II–III with poor tolerance or ineffectiveness of antiplatelet agents.

Implementation of the Results of the Work into Practice

The main propositions of the dissertation work have been implemented and are used in the work of the 2nd Department of Emergency Cardiology and the 6th Cardiology Department of City Clinical Hospital No. 15 named after O. M. Filatov in Moscow, and the Cardiology Department of the Central City Hospital of Reutov. The results of the study are used in the educational process at the Department of Hospital Therapy No. 1 of the Medical Faculty of RGMU.