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CARDIOLOGY AND CARDIO SURGERY
INVENTION
Patent of the Russian Federation RU2232543

METHOD OF INDIVIDUAL SELECTION OF HYPOTHENNIAL PREPARATION FOR TREATMENT OF ARTERIAL HYPERTENSION

METHOD OF INDIVIDUAL SELECTION OF HYPOTENZIVE PREPARATION
FOR TREATMENT OF ARTERIAL HYPERTENSION

The name of the inventor: Burkovskaya E.N. (RU); Burkovsky A.V. (RU); Minakov E.V.
The name of the patent holder: Burkovskaya Elena Nikolaevna (RU); Burkovsky Alexander Viktorovich (RU); Minakov Eduard Vasilyevich
Address for correspondence: 394000, Voronezh, ul. Student, 10, Voronezh State Medical Academy. N.N. Burdenko, Patent Department
The date of the commencement of the patent: 1999.12.15

The invention relates to medicine, cardiology. Patients undergo laboratory and instrumental examinations. Conduct a test poll. Analyze the presence of increased values: OPSS, heart rate, UO, cholesterol, creatinine, glucose, uric acid, blood potassium, the presence of LVH, orthostatic reactions, senile age, pregnancy, bradycardia, heart block, gout, diabetes, COPD, heart failure, renal Insufficiency, angina of tension, arrhythmia, encephalopathy, diseases of peripheral arteries. For each drug, the a posteriori probability of his choice according to the Bayesian formula is calculated. The choice of the drug that is most preferable in a specific case is made on the basis of the maximum correspondence of effects of the drug on the parameters of the patient's condition. The method allows treatment to be carried out individually and economically.

DESCRIPTION OF THE INVENTION

The invention relates to the field of medicine, namely cardiology.

Modern approaches to the treatment of arterial hypertension are aimed at preventing its complications and provide, above all, maintaining a stable normal level of blood pressure. Traditionally, antihypertensives of 7 groups are used to treat arterial hypertension, namely: β- adrenoblockers, diuretics, calcium antagonists, angiotensin-converting enzyme inhibitors, α- adrenoblockers, a-agonists central mechanism of action), angiotensin receptor antagonists. Each group (and even a separate drug within the group) has an individual spectrum of pharmacological effects. In numerous manuals on the treatment of hypertension, among which the guidance of experts from the WHO and the Joint National Committee for the Prevention, Recognition, Evaluation and Treatment of High Blood Pressure (USA) is of particular authority (Combating arterial hypertension, WHO report., Ed. - RAMS RG Oganova, Prof. VVKukharchuk, Prof. AN Britova - Moscow: The National Center for Preventive Medicine of the Ministry of Health of the Russian Federation, 1997, 64 pp. Joint National Committee on Prevention , Detection, Evaluation, and Treatment of High Blood Pressure, The Sixth Report of the National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI) // Arch.Intern. Med .- 1997. - Vol.157 - P.2413-2446), the active participation of the attending physician in the choice of the drug is assumed in each case, but the advantage is still given to diuretics and b- adrenoblockers, as the most tested and tested in numerous randomized trials of drugs. To improve the quality of medical decisions to manage a patient with arterial hypertension, and consequently the effectiveness of subsequent treatment, the use of formalization methods and modern information technologies is justified, as was also noted in the report of the WHO Expert Committee (Fighting arterial hypertension.) WHO report. Corresponding Member of RAMS RGOganova, Prof. VVKukharchuk, Prof. ANBritova - Moscow: The State Center for Preventive Medicine of the Ministry of Health of the Russian Federation, 1997, p.56).

In modern clinical practice, it is proposed to use several alternative formalized descriptions of the individualized choice of antihypertensive therapy, taking into account the degree of increase in arterial pressure, such as central hemodynamics, risk factors for cardiovascular complications and target organ damage (Combating arterial hypertension. Corresponding Member of RAMS RG Oganova, Prof. VVKukharchuk, Prof. AN Britova.- Moscow: The State Center for Preventive Medicine of the Ministry of Health of the Russian Federation, 1997, p.44, Sixth report Joint United National Committee for the Prevention, Recognition, Evaluation and Treatment of High Blood Pressure (USA) - JNC-6, Statement of Fundamental Principles // Cardiology, 1998. - No. 3. - P.81, 82; Olbinskaya LI, Styazhkin V.Yu., Yamshchikov SN New approaches in the selection of therapy for patients with hypertensive disease // Therapeutic archive - 1989. - T.61 .- No. 9. - P.27).

At the same time, the choice of the drug is performed empirically by the doctor, since it is almost impossible to isolate the leading links in the pathogenesis of this disease in broad clinical practice and to influence them purposefully. Therefore, the clinician struggles with hypertensive syndrome as such, and not with arterial hypertension as a complex disease. Hence the often inadequate treatment effectiveness, the growth of iatrogenic complications, and the low adherence of patients to treatment, which in turn leads to poor prognosis of the disease. Given the pharmacological features, a spectrum of side effects and contraindications to the appointment of antihypertensive drugs, a qualitatively new, more rational and devoid of subjectivity approach to the choice of drugs for the therapy of arterial hypertension is needed. Difficulties arising in the evaluation of diagnostic data, especially in conditions of incompleteness of information, and the subsequent appointment of treatment, taking into account the individual characteristics of the course of the patient's illness, make the problem of formalizing the process of selecting tactics for management of patients with arterial hypertension urgent.

None of the existing formalized descriptions of the process of therapy of arterial hypertension does not take into account the whole complex of parameters of the patient's condition that need correction or control. Another significant drawback of most of the approaches considered, which makes it difficult to use them in real clinical practice, is the impossibility of working in the conditions of incompleteness of diagnostic information.

A method for formalizing the process of making informed decisions based on the mathematical apparatus of fuzzy logic is known (Bayesian approach). This approach has found its application in the development of many industrial expert systems applied in various fields (Naylor K. How to build your own expert system.) Translated from English - M .: Energoatomizdat, 1991, p.220-232; Expert systems, principles of work And examples: Translated from English / A. Brooking, P.Jones, F. Cox, etc. / Edited by R. Forsait .- Moscow: Radio and Communication, 1987, p.51-74; E. Uryev. V., Murmanskiy BE, Brodov Yu.M., The concept of the system of vibration diagnostics of a steam turbine .- Thermal power .- M., 1995. - ISSN 0040-3636 .- N 4, pp.36-40). This method involves considering a set of competing hypotheses (possible solutions) that have predetermined a priori probabilities. When evidence appears that confirms certain hypotheses from the initial population, the a posteriori probabilities of each hypothesis are calculated. This process is repeated for each certificate that appears.

Calculation of a posteriori probabilities is performed in accordance with the Bayes conditional probability formula

Where P (E: H) is an estimate of the probability of having a certificate in the presence of a hypothesis;

P (H) is the a priori probability of the hypothesis;

P (E) - the probability of having a certificate is defined as

P i (E) = S P (E: H j ) (P (H i )).

The aim of our invention is to increase the effectiveness of antihypertensive therapy.

This goal is achieved by using the results of previously conducted laboratory-instrumental examinations, a test poll, to select a hypotensive drug. Based on the generated data on the patient's state of arterial hypertension, the most preferable in the particular case of the disease drug is selected from the 26 antihypertensive drugs we propose 8 known pharmacological groups based on the maximum correspondence of effects of the drug to the patient's needing correction parameters by calculating for each drug a posteriori Probability of its choice according to the Bayes formula. In this case, the drug that received the highest estimate of a posteriori probability is considered to be the best for carrying out antihypertensive therapy to a specific patient.

As a set of hypotheses according to the Bayes formula, many available antihypertensive drugs are considered; As evidence are signs (logical expressions), characterizing the patient's condition; A priori, hypotheses are considered equally probable, which corresponds to the situation when the doctor does not have information about the patient's condition. As probabilistic probabilities of evidence, probabilistic estimates of the effectiveness of antihypertensive drugs against each of the monitored parameters were used in large-scale randomized clinical trials and described in the literature. This circumstance allows us not to use expert estimates of conditional probabilities, which increases the objectivity of decision-making.

To obtain the initial data involved in the formation of a variety of evidence, laboratory and instrumental examinations are carried out (blood tests - general and biochemical, general urine analysis, renal function tests: Reberg's test, ECG, ECHO-CG, chest R-picture, Electrolyte blood composition), the patient's personal data, data on concomitant diseases and conditions are formed. The total number of analyzed input data is 26, the total number of certificates (signs) based on them is 23 (OPSS, heart rate, UO, LVH, cholesterol, creatinine, glucose, uric acid, potassium blood, orthostatic reactions, age, pregnancy, bradycardia, Heart block, arrhythmia, angina pectoris, diabetes mellitus, COPD, heart and kidney failure, peripheral arterial disease and encephalopathy). A variety of evidence includes those modified by the use of an antihypertensive drug. The list of signs (logical expressions) describing the patient's condition, the corresponding effects of the drugs, and the input data for the formation of signs are given in Table 1.

When choosing the most optimal in a particular case of the disease, 26 antihypertensive drugs from 8 pharmacological groups are involved ( b- adrenoblockers, diuretics, calcium antagonists, angiotensin converting enzyme inhibitors, α- adrenoblockers, a-agonists central mechanism of action), antagonists of angiotensin receptors, Drugs with a mixed mechanism of action: a - b adrenoblockers), within each group, individual preparations are individually described in accordance with their pharmacological properties.

The choice for the treatment of each of the hypotensive drugs is considered as one of many competing hypotheses. The a priori probabilities of competing hypotheses are defined as 1 / N, where N is the number of drugs included by the physician in the examination.

To calculate the a posteriori probabilities of each of the hypotheses, a multiple calculation is carried out (based on the number of evidence-signs available at the time of the individual patient's examination) using formula (1) using the conditional probabilities of the tests given in Tables 2-6.

After calculating a posteriori probabilities of hypotheses (the choice of each of the drugs), they are compared. The drug that received the highest probability estimate is considered to be the most preferred for carrying out antihypertensive therapy in this particular case. Data processing can be performed using an IBM PC-compatible personal computer.

The use of the proposed method makes it possible to carry out an individual choice of an antihypertensive drug that maximally satisfies the goals of complex correction of the modifiable parameters of a particular patient's condition. The structure of the model allows you to choose the best in each case, the drug from the set of available (physically or economically), which corresponds to the tasks solved in real medical practice.

Clinical example

Patient H.M.N., 42 years old. History of the disease № 8296/1 (1998). At the time of curation, he suffers from arterial hypertension for 6 years. Has arrived with complaints on the expressed headache, dizziness, потатывание at walking, compressing stitching paines to the left of a breast bone appearing in the mornings, sometimes at night hours, because of it a bad dream, irritability. The pain lasts for hours, the intake of nitroglycerin does not stop. Periodically accepts adelphan. The reception of kapotena notes the deterioration of health (a strong cough), in connection with which from its further admission refused. Obviously: the condition is closer to the average, in the mind. Skin of usual color, dry to the touch. Correct physique, satisfactory nutrition - height 158 ​​cm, weight 58 kg. Peripheral lymph nodes without features. BP 160/80 mmHg, pulse 75 beats per minute, rhythmic, increased tension and filling. The decrease in systolic blood pressure during the transition to the vertical position was 5 mm Hg. The thorax is of regular shape, both halves of the chest are evenly involved in the act of breathing. Percutary - pulmonary sound, auscultatory - vesicular breathing. Boundary of the heart: left - 1.5 cm to the left of the mid-clavicular line; Upper - III intercostal space on the left along the parasternal line; Right - on the right side of the sternum. Auscultatory: heart sounds are muffled, rhythmic. Tongue moist, clean. The abdomen is soft, painless with superficial and deep palpation. Liver on the right mid-clavicular line at the lower edge of the costal arch, elastic, painless.

The kidneys are not palpable, the symptom of effleurage in the lumbar region is negative on both sides.

Data from the additional study: ECG-75 beats per minute, QT-0.38 ms, EOS horizontal, rhythm sinus, violation of intraventricular conduction.

The general blood test from 24.02.1998: erythrocytes - 4 h 10 12 / l, hemoglobin - 120 g / l, color index - 0.9, leukocytes - 6.3 × 10 9 / l (eosinophils - 2%, neutrophils : Stab - 3%, segment - nuclear - 62%, lymphocytes - 30%, monocytes - 3%), ESR - 14 mm / hour.

The general analysis of urine: specific gravity 1025, reaction acidic, protein - is not present, leucocytes - unitary in the field of vision, erythrocytes - single changed in the field of vision.

Salts: oxalate - a little.

Biochemical blood test: glucose 3.7 mMol / L, amylase 2.5 mg / ml, urea 5.9 mMol / L, creatinine 0.06 mMol / L, ACAT 40.0 nMol / L, ALAT -102 nMol / L, total cholesterol - 5.0 mMol / L, triglycerides - 0.66 mMol / L, prothrombin index - 91%.

Reberg's test: blood creatinine - 0,08 mMol / l, urine creatinine - 11,2 mMol / l, glomerular filtration - 119 ml / min, reabsorption - 98%, minute diuresis - 1,2 ml / min.

ECHO-CG: the dimensions of the left ventricle cavity are not enlarged: the CWD is 47 mm, the KSR is 33 mm, the FV is 56%, the thickness of the MZV and the LLW is 10 mm, the kinetics is sufficient in all segments, the mitral valve - the flaps are thin, unchanged, In the antiphase, regurgitation is not present, LP is 29 mm, the aorta is 30 mm, the walls are thin, the valves of the aortic valve are not changed, the valve is closed, normal ventricle, right ventricle is 17 mm, right atrium is not widened, tricuspid valve - A pulmonary artery - without features. Conclusion: an organic valvular pathology has not been identified, sufficient global function of the left ventricle.

CHPES: initial ECG - rhythm sinusoidal, correct, EOS. Is located horizontally, the Wenkebach point is 170 cpm, no pre-excitation of the ventricles is detected, tachycardia is not induced, the stress test is negative.

REG: In the system of internal carotid arteries there is a decrease in pulse blood filling from both sides by 13%, an increase in the tone of the arteries and arterioles, and the tone of the veins is normal.

Holter monitoring: 51 fragments are taken, maximum heart rate is recorded at day 142, minimum 63, at night 84/54 beats per minute, rhythm sinus, rarely single supraventricular extrasystoles; in one fragment with moderate physical exertion, there was a moderate transient change in the lateral wall of the myocardium in the form of a flattening of the T wave In lead V 5 .

The conclusion of the oculist: angiopathy of the retina.

The conclusion of a neurologist: discirculatory encephalopathy I-II st. Cervical osteochondrosis. Syndrome of vertebral arteries. Osteochondrosis of the thoracic spine with radicular syndrome.

The daily profile of blood pressure was estimated from 24-hour 24-hour blood pressure monitoring.

Diagnosis: Hypertension 2 items, dyscirculatory encephalopathy of the II stage, atherosclerosis of the aorta, coronary arteries, retinal angiopathy, vertebral osteochondrosis with radicular syndrome (cervical and thoracic divisions), vertebral artery syndrome.

Parameters of daily variability of blood pressure before and after hospital treatment are given in Table 7.

In this case, when choosing an antihypertensive drug, the following signs participated in the examination: OPSS, heart rate, absence of LVH, lack of cholesterol, creatinine, glucose, uric acid, absence of orthostatic reactions, young patient age, absence of pregnancy, normocardia, Arrhythmias, stenocardia, absence of gout, diabetes mellitus, COPD, cardiac and renal insufficiency, the presence of peripheral arterial diseases and encephalopathy. In the process of processing the initial diagnostic data, 6 hypotensive drugs (verapamil, diltiazem, amlodipine, nifedipine, nitrendipine, ramipril), having equiprobability estimates, were the most preferred as a result of the calculation by formula (1), 5 of them being from the group of calcium antagonists. When carrying out antihypertensive therapy of this patient, a calcium antagonist from the benzothiazepine-diltiazem group (dilrem) is used, since it is a prolonged-release drug, and reduces the increased OPSS with a probability of 0.99 that is present in this patient and does not increase the manifestations of encephalopathy with probability 0.95.

In the hospital prescribed: diet number 10, dilren 300 mg once a day (in the morning), trental parenteral in saline, during 15 days of hospital stay.

After the course of treatment, there was a marked improvement in overall well-being: there were no headaches and pains in the left side of the chest, there were no dizziness, sleep and mood improved significantly.

On the parameters of daily blood pressure variability, positive dynamics was noted (mean daily systolic and diastolic arterial pressure decreased, while normal values ​​were attained, daytime SAD of SBP was significantly decreased, and IV DBP for the night, daytime and nighttime variability of SBP decreased, and And the variability of DBP at night), which indicates the restoration of the normal daily rhythm of blood pressure.

Thus, the use of our method allows us to carry out an individualized appointment of an antihypertensive drug, which increases the effectiveness of antihypertensive therapy.

CLAIM

The method of treatment of arterial hypertension, including medication with preliminary laboratory and instrumental examinations, test interrogation, characterized by the following diagnostic features: elevated OPSS, heart rate, UO, cholesterol, creatinine, glucose, uric acid, blood potassium, the presence of LVH, Orthostatic reactions, senile age, pregnancy, bradycardia, cardiac blockade, gout, diabetes mellitus, COPD, heart failure, renal failure, angina pectoris, arrhythmia, encephalopathy, peripheral arterial diseases, and the choice of the most preferred drug in a particular case is made on the basis of maximum compliance Effects of the drug on the parameters of the patient's condition, by calculating for each drug the a posteriori probability of its choice according to the Bayes formula

Where P (H: E) is the estimate of the a posteriori probability of drug selection;

P (E: H) is an estimate of the probability of drug exposure to the modifiable state parameter described by sign E;

P (H) is the a priori probability of drug selection;

P (E) is the probability of the presence of a characteristic, which is defined as

P i (E) = S P (T: H i ) P P (H i ),

Where i = I ... N, N - the number of alternative drugs,

The drug that received the highest esti- mate of a posteriori probability is considered to be the best for carrying out antihypertensive therapy to a particular patient.

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Date of publication 05.04.2007gg