RU2702753C1 - Method for predicting the effectiveness of an antiplatelet therapy with the preparation "clopidogrelum" - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to clinical pharmacology, and concerns predicting the effectiveness of antiplatelet therapy with Clopidogrelum. That is ensured by determining laboratory blood counts – hematocrit, hemoglobin, lipid plasma fractions and total cholesterol, high-density lipoprotein content, prothrombin index, international normalized ratio. Also, the level of neurological deficiency is assessed by the National Institute of Health Stroke Assessment Scale and the degree of main arterial involvement by the ultrasound Doppler sonography findings. Method includes determining gradations and numerical values of laboratory and clinical values, afterwards calculating prognostic coefficients F₁ and F₂ by formulas. If F₁ is more than F₂, a probability of high efficacy of the antiaggregant therapy with Clopidogrelum in ischemic stroke is predicted, and if F₁ is less than F₂, the probability of low efficacy is predicted.

EFFECT: invention provides the possibility of determining the laboratory effectiveness of the preparation Clopidogrelum until it is prescribed for treatment, as well as for secondary prevention of the patient with ischemic stroke.

1 cl, 4 tbl, 2 ex

Description

The present invention relates to medicine, namely to clinical pharmacology, and can be used to select the tactics of antiplatelet therapy in patients with ischemic stroke.

It is known that stroke, due to its widespread prevalence, high mortality and disability of the population, remains one of the main medical and social problems. Antiplatelet agents, including clopidogrel, are a key element in the treatment and secondary prevention of ischemic stroke. One of the main problems of antiplatelet therapy is resistance and, as a consequence, the ineffectiveness of the drugs used. The number of patients with ischemic stroke with a reduced response to clopidogrel varies from 8 to 25%.

Clopidogrel ( INN Clopidogrel ¹ ) is a prodrug, one of the active metabolites of which is an inhibitor of platelet aggregation. The active clopidogrel metabolite selectively inhibits the binding of adenosine diphosphate (ADP) to P2Y ₁₂ platelet receptors and the subsequent ADP-mediated activation of the IIb / IIIa glycoprotein complex, which leads to the suppression of platelet aggregation (http://grls.rosminzdrav.ru/ = & MnnR =% d0% ba% d0% bb% d0% be% d0% bf% d0% b8% d0% b4% d0% be% d0% b3% d1% 80% d0% b5% d0% bb & lf = & TradeNmR = & OwnerName = & MnfOrg = & MnfOrgCountry = & isfs = 0 & isND = -1 & regtype = 1% 2c & pageSize = 10 & order = RegDate & orderType = desc & pageNum = 1. Date of access: 15.06.2019).

A known method for determining the antiplatelet effectiveness of clopidogrel by conducting light-optical aggregometry. In this case, the change in light transmission of platelet-rich plasma is measured both before and after the addition of various aggregation inducers, for example, ADP (Chan NC, Eikelboom JW, Ginsberg JS, Lauw MN, Vanassche T., Weitz JI, Hirsh J. Role of phenotypic and genetic testing in managing clopidogrel therapy. Blood. 2014; 124 (5): 689-699. DOI 10.1182 / blood-2014-01-512723).

For this, 8 ml of venous blood from the patient's ulnar vein is collected in 2 tubes. Blood is centrifuged: one tube at 1000 rpm for 5 minutes, the other at 3000 rpm for 15 minutes. This gives platelet-rich plasma (BTP) and platelet-poor plasma (OTP). The obtained OTP is used to calibrate the aggregometer. Prepared patient samples (separately with each inductor) after mixing in a centrifuge at 600 rpm are placed in the aggregometer module. The device automatically registers platelet aggregation with the construction of a detailed aggregation schedule

The disadvantages of this method include the impossibility of predicting the effectiveness of clopidogrel until its appointment due to the individual sensitivity of the patient to the drug, as well as the complexity and multi-stage performance of the study, the need for daily calibration of the equipment. In addition, centrifugation of blood samples should be carried out no later than one hour after the collection of material, and plasma sampling for examination immediately after centrifugation; blood samples with hemolysis with clots are not allowed to be examined by this method. The method has low reproducibility.

Closest to the technical nature of the proposed is a method for predicting the effectiveness of antiplatelet therapy with the drug "Clopidogrel", which includes determining laboratory blood parameters - hematocrit, hemoglobin, lipid blood plasma fractions, followed by determining the effectiveness of the drug according to the calculation formula (Miura G., Ariyoshi N., Sato Y., Yamaguchi H., Iwata Y., Fujimoto Y., Kobayashi Y., Ishii I. Genetic and non-genetic factors responsible for antiplatelet effects of clopidogrel in Japanese patients undergoing coronary stent implantation: an algorithm to predict on-clopidogrel plate let reactivity. Thromb Res. 2014 Oct; 134 (4): 877-883).

The known method is as follows. A patient who has undergone coronary stenting and is taking the drug “Clopidogrel” takes a blood sample from the ulnar vein, which determines such clinical and laboratory parameters as hematocrit, hemoglobin, lipids and genetic markers, namely, the CYP2C19 and ABCB1 genotypes. The data obtained are used for calculation according to the formula:

PRU = 565.273-7.891 * (Hct) + 27.569 × (CYP2C19 genotype) + 17.924 × (DL) + 14.9 × (PPI) -4.72 × (WBC) + 25.277 × (ABCB1 2677 genotype), where:

PRU - P2Y12 Reaction Units - reactivity units P2Y12 - residual platelet reactivity;

Hct - hematocrit, in%;

CYP2C19 genotype: * 1 / * 1 - 0; * 1 / * and * 1 / * 3 - 1; * 2 / * 2 or * 2 / * 3 and * 3 / * 3 - 2;

DL - dyslipidemia - 1 - is; 0 - no;

PPI - proton pump inhibitors: the patient took - 1; 0 - no - 0;

WBC - white blood cells, quantity;

ABCB1 2677 genotype: T / T - 1; G / G, G / A, G / T, A / A or A / T - 0;

The calculated value of the residual platelet reactivity predicts the effectiveness of antiplatelet therapy with the drug "Clopidogrel". So, if the PRU is less than or equal to 85, the risk of hemorrhagic complications is predicted; with a PRU greater than 208 - high residual platelet reactivity, drug inefficiency and the risk of developing an ischemic event, including death, myocardial infarction and stent thrombosis. The optimal range of residual platelet activity is not more than 208 and not less than 85 PRU (“therapeutic window”) when optimal antiplatelet efficacy is predicted.

The disadvantages of this method include the lack of accuracy of individual forecasting due to the features of the blood sampling technique, the influence of low hematocrit and platelet counts on the result of aggregometry.

In addition, this method is designed for patients with acute coronary syndrome, therefore, this method may be less effective for patients with cerebral stroke.

The use of pharmacogenetic testing indicators (CYP2C19 and АВСВ1) in the calculation formula does not allow us to attribute this method to express methods for predicting clopidogrel effectiveness, since performing genotyping significantly increases the time to obtain final results. It should also be noted that the forecasting method using genetic testing was developed with the participation of only the Japanese population and, without additional research, this method is incorrectly used to predict the effectiveness of this drug in patients of other nationalities.

The task of the invention is to develop a method for predicting the laboratory effectiveness of the drug "Clopidogrel" in a patient with ischemic stroke using a personalized approach.

The technical result of the proposed method consists in the possibility of determining the laboratory effectiveness of the drug "Clopidogrel" before taking it, both for treatment and for the secondary prevention of ischemic stroke (II) in a patient.

The technical result of the proposed solution is achieved by the fact that the method for predicting the effectiveness of antiplatelet therapy with the drug "Clopidogrel" is carried out by determining such laboratory blood parameters as hematocrit, hemoglobin, plasma lipid fractions. Determining the effectiveness of the drug is carried out by the calculation formula.

Distinctive techniques of the proposed method are that in the blood of a patient with ischemic stroke, total cholesterol, the content of high density lipoproteins, prothrombin index, and the value of the international normalized ratio are determined.

The differences of the proposed method is also the assessment of the level of neurological deficit according to the National Institute of Health's Stroke Scale, and the degree of damage to the main arteries of the head according to ultrasound dopplerography.

The difference between the method and that determine the gradation and numerical values of the established laboratory and clinical indicators, after which the prognostic factors F ₁ and F ₂ are calculated by the formulas:

F1 = -182.57 + 19.67 × X1 + 21.09 × X2 + 0.46 × X3 + 2.17 × X4 + 4.0 × X5 + 95.01 × X6 + 0.92 × X7;

F2 = -188.27 + 23.5 × X1 + 17.59 × X2 + 0.34 × X3 + 3.04 × X4 + 0.44 × X5 + 102.92 × X6 + 1.13 × X7,

where F1 and F2 are prognostic factors;

X1,2 ... 7 - clinical and laboratory indicators, moreover:

X1 - indicator of the National Institute of Health Stroke Scale: less than or equal to 12 points - 1; more than 12 points - 2;

X2 - the degree of damage to the main arteries of the head according to Doppler ultrasound: none - 1; hemodynamically insignificant, i.e. less than 70% - 2; hemodynamically significant, i.e. more than 70% - 3;

X3 - hemoglobin level, g / l;

X4 - total blood cholesterol, mmol / l;

X5 - the content of high density lipoproteins, mmol / l

X6 - international normalized ratio, units;

X7 - prothrombin index,%.

The authors of the proposed method found that with an absolute value of F1 greater than the absolute value of F2, the probability of high efficiency of antiplatelet therapy with the drug “Clopidogrel” in a patient with ischemic stroke is predicted, and with F1 less than F2, the probability of low efficiency.

A comparative analysis with the prototype showed that the proposed method differs from the known above methods and, therefore, meets the criteria of the invention of "novelty."

From the analysis of patent and specialized literature, the authors found that the proposed method has features that distinguish it not only from the prototype, but also from other technical solutions in this and related fields of medicine. When analyzing the literature, the authors of the method did not identify a method for predicting the effectiveness of the drug “Clopidogrel” in patients with ischemic stroke according to the above clinical and laboratory indicators.

Clinical observations of the authors of the proposed method indicate that the use of the proposed technical solution allows to predict the effectiveness of antiplatelet therapy with the drug "Clopidogrel", both in the acute and acute periods of ischemic stroke, and in the early and late recovery periods. The forecast accuracy is 94.62%. The above allows us to conclude that the proposed technical solution meets the criterion of "inventive step".

A method for predicting the effectiveness of antiplatelet therapy with the drug "Clopidogrel" in patients with ischemic stroke, constituting the claimed invention, is intended for use in healthcare. The implementation of its capabilities is confirmed by the methods and means described in the application. From the above it follows that the claimed invention meets the condition of patentability "industrial applicability".

The proposed method is as follows.

Upon admission to the hospital for a patient with ischemic stroke in the acute and acute period of the disease, antiplatelet agents, including Klopidogrel, are given a comprehensive clinical and laboratory examination in accordance with the standard for the provision of specialized medical care for cerebral infarction (order of the Ministry of Health of the Russian Federation No. 1740 of December 29, 2012 g.).

The following indicators are determined in the blood of a patient with ischemic stroke: hematocrit, hemoglobin, total cholesterol, high density lipoprotein (HDL), prothrombin index (PI), international normalized ratio (MHO). Additionally, the level of neurological deficit is assessed in points on the National Institute of Health's Stroke Scale and the degree of damage to the main arteries of the head according to ultrasound dopplerography. Then determine the gradation and numerical values of the obtained clinical and laboratory parameters (see Table 1).

Then the prognostic factors F ₁ and F ₂ are calculated by the formulas:

F1 = -182.57 + 19.67 × X1 + 21.09 × X2 + 0.46 × X3 + 2.17 × X4 + 4.0 × X5 + 95.01 × X6 + 0.92 × X7;

F2 = -188.27 + 23.5 × X1 + 17.59 × X2 + 0.34 × X3 + 3.04 × X4 + 0.44 × X5 + 102.92 × X6 + 1.13 × X7.

The obtained numerical values of F1 and F2 are compared with each other. If F1 is greater than F2, the probability of high efficiency is predicted, and if F1 is less than F2, the probability of low effectiveness of antiplatelet therapy with Clopidogrel in patients with ischemic stroke is predicted, and the appointment of another antiplatelet drug should be considered.

The proposed method for predicting the effectiveness of antiplatelet therapy with the drug "Clopidogrel" in patients with ischemic stroke is illustrated by examples of specific performance.

Example 1. Patient M.A.V., 63 years old. The diagnosis of ischemic atherothrombotic stroke in the pool of the right midbrain artery. Atherosclerosis of cerebral vessels. Left-sided hemiparesis: moderate in the leg and before plegia in the arm. The initial clinical and laboratory data of this patient are presented in table 2 below.

The calculation of the prognostic factors F1 and F2 is carried out according to the formulas:

F1 = -182.57 + 19.67 × 2 + 21.09 × 2 + 0.46 × 150.0 + 2.17 × 5.70 + 4.0 × 0.90 + 95.01 × 0.96 + 0.92 × 10.40 = 84.73

F2 = -188.27 + 23.5 × 2 + 17.59 × 2 + 0.34 × 150.0 + 3.04 × 5.70 + 0.44 × 0.90 + 102.92 × 0.96 + 1.13 × 10.40 = 73.19

When comparing the two evaluation functions F1 and F2 for the patient M.A. revealed that F1 is greater than F2. The data obtained allow us to predict the effectiveness of the use of the drug “Clopidogrel” (in a standard dose - 0.075 g / day) for the treatment and secondary prevention of ischemic stroke in this patient. Patient M.A. “Positively” responded to antiplatelet therapy, for example, ADP-induced platelet aggregation upon admission to the hospital during the onset of ischemic stroke was 66.8%, 66.8% on the 7th day, and 33.2% on the 13th day of treatment.

Example 2. Patient C.L.B., 68 years old. The diagnosis is an atherothrombotic stroke in the vertebrobasilar basin. Atherosclerosis of cerebral vessels. Right-sided pyramidal insufficiency (residual). Initial clinical and laboratory data of the patient Ch. are given in table 3.

The values of prognostic factors F1 and F2 for the patient Ch.L.B. calculated by the formulas:

F1 = -182.57 + 19.67 × 1 + 21.09 × 2 + 0.46 × 79.0 + 2.17 × 4.0 + 4.0 × 1.10 + 95.01 × 0.99 + 0.92 × 89.19 = 104.76

F2 = -188.27 + 23.5 × 1 + 17.59 × 2 + 0.34 × 79.0 + 3.04 × 4.0 + 0.44 × 1.10 + 102.92 × 0.99 + 1.13 × 89.19 = 112.58

As a result of comparing the two evaluation functions F1 and F2 for the patient, Ch. found that F2 is greater than F1. Therefore, laboratory resistance to Clopidogrel was predicted in this patient (in a standard dose of 0.075 g / day). In this patient, the ADP-induced platelet aggregation upon admission to the hospital during the onset of ischemic stroke was 91.5%, 89.2% on the 7th day, and 91.1% on the 13th day of clopidogrel therapy. Patient C.L.B. shows the transfer from the drug "Clopidogrel" to another antiplatelet agent.

The proposed method for predicting clopidogrel efficacy was developed on the basis of a prospective clinical and laboratory study conducted on the basis of the regional vascular center GBUZ Irkutsk Order of the Badge of Honor Regional Clinical Hospital. The study included 121 patients with a diagnosis of non-cardioembolic ischemic stroke. All patients took the drug "Clopidogrel" at a dose of 0.075 g for 14 days. Based on a discriminant analysis of the obtained clinical and laboratory data, formulas were determined to predict the effectiveness of the drug “Clopidogrel”. The forecast accuracy was 94.62%.

The results of the analysis of discriminant functions in patients with ischemic stroke are presented in table 4.

Thus, the proposed method allows to predict the laboratory effectiveness of the drug "Clopidogrel" in patients with ischemic stroke before taking the drug with minimal time, and a uniform calculation makes this method affordable and simple. The absence of molecular genetic indicators in the prediction formula makes this method acceptable for patients regardless of their ethnicity. This forecasting method is the only one developed for use in patients with cerebrovascular pathology. The application of the proposed method for predicting the effectiveness of the drug “Clopidogrel” in patients with ischemic stroke will increase the effectiveness and safety of antiplatelet therapy with clopidogrel in the treatment and secondary prevention of ischemic stroke, taking into account a personalized approach.

Claims (13)

A method for predicting the effectiveness of antiplatelet therapy with the drug "Clopidogrel", which includes determining laboratory blood parameters - hematocrit, hemoglobin, plasma lipid fractions and determining the effectiveness of the drug according to the calculation formula, characterized in that the total cholesterol, high density lipoproteins, prothrombin are determined in the blood of a patient with ischemic stroke index, the magnitude of the international normalized ratio, additionally assess the level of neurological deficit on the scale of assessment and National Institutes of Health Stroke and degree of damage to cerebral arteries according to the Doppler ultrasound, and then determine their gradation and numerical values, whereupon prognostic factors F ₁ and F ₂ are calculated by the formulas: F1 = -182.57 + 19.67 × X1 + 21.09 × X2 + 0.46 × X3 + 2.17 × X4 + 4.0 × X5 + 95.01 × X6 + 0.92 × X7; F2 = -188.27 + 23.5 × X1 + 17.59 × X2 + 0.34 × X3 + 3.04 × X4 + 0.44 × X5 + 102.92 × X6 + 1.13 × X7, where F1 and F2 are prognostic factors; X1, 2 ... 7 - clinical and laboratory indicators, moreover: X1 - indicator of the National Institute of Health Stroke Scale: less than or equal to 12 points - 1; more than 12 points - 2; X2 - the degree of damage to the main arteries of the head according to ultrasound dopplerography: none - 1; hemodynamically insignificant, i.e. less than 70% - 2; hemodynamically significant, i.e. more than 70% - 3; X3 - hemoglobin level, g / l; X4 - total blood cholesterol, mmol / l; X5 - the content of high density lipoproteins, mmol / l X6 - international normalized ratio, units .; X7 - prothrombin index,%, and with a value of F1 greater than F2, the probability of high efficiency is predicted, and with F1 less than F2, the probability of low effectiveness of antiplatelet therapy with Clopidogrel in a patient with ischemic stroke is predicted.