Method for assessing risk of adverse coronary events in patients with acute coronary syndrome receiving dual antiplatelet therapy

Abstract

FIELD: clinical pharmacology; cardiology.SUBSTANCE: method includes registration of the following anamnesis data upon admission to inpatient treatment: gender (designation 1 – men, 2 – women); age (full years), weight (kg), height (cm). Laboratory tests include assessment of venous blood creatinine (cr) in μmol / l; creatinine clearance (CC) calculated using the Cockcroft-Gault formula in ml / min; platelet volume (MPV) in femtoliter / platelet; relative platelet count (PLCR) in %, and assessment of spontaneous platelet aggregation (Spr), according to the tr-aggregation curve, on the 5th day of hospitalization: in 1 μmol ADP (Ind1t), in 5 μmol ADP (Ind5t), and in 15 μl arachidonic acid (Apxt). Based on the obtained data, an original linear regression equation is constructed. If the Kpred value calculated for the patient is less than 1.56 conventional units, then the absence of adverse coronary events is expected within the next year, the patient is transferred to dynamic observation, and no additional treatment measures are carried out. If the Kpred value lies in the range from 1.56 conventional units to 2.09 conventional units, an exacerbation of the disease with hospitalization or seeking outpatient care is expected within a year. In this case, the patient undergoes platelet aggregation monitoring every three months and adherence to therapy is determined. When the calculated value of the Kpred indicator is equal to or exceeds 2.1 conventional units, a fatal outcome is likely within a year of observation; platelet aggregation and adherence to therapy are monitored monthly, and vigilance is exercised in the event of progression of disease symptoms. The method allows for an accurate assessment of the risk of developing acute coronary events within the next year.EFFECT: method is simple to use, does not require additional material or human resources, and serves as the basis for developing a personalized treatment plan, prevention, and reduction of patient mortality.1 cl, 4 tbl, 3 ex

Description

[0001] The invention relates to medicine, namely to clinical pharmacology and cardiology, and can be used to develop an individual regimen of dual antiplatelet therapy for a patient after acute coronary syndrome (ACS).

[0002] Currently, circulatory diseases, including acute coronary syndrome, are the leading cause of decreased life expectancy. Dual antiplatelet therapy (DAPT) administered for one year after acute coronary syndrome is aimed at reducing the risk of recurrent vascular events.

[0003] In clinical practice, DAPT contains acetylsalicylic acid in combination with Clopidogrel or in combination with Ticagrelor.

[0004] Variability in response to antiplatelet therapy determines the dynamics of probable outcomes: resistance to DAPT components is associated with an up to 8-fold increase in the frequency of vascular events [Snoep JD, Hovens MM, Eikenboom JC, van derBom JG, Jukema JW, Huisman MV Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. AmHeart J. 2007; 154(2): 221-31. doi: 10.1016 / j.ahj.2007.04.014]. The effectiveness of antiplatelet therapy when prescribing DAPT depends on the individual response, which is influenced by the patient's phenotype and genotype.

[0005] In real clinical practice, after a clinically significant event, such as myocardial infarction, there is a need to obtain an accurate prognosis of the effectiveness of dual antiplatelet therapy depending on the individual variability of the patient's response to DAPT.

[0006] A method for determining the sensitivity of platelets to acetylsalicylic acid (ASA) is known [patent. RU No. 2699569], which includes blood sampling, while ADP-induced lucigenin-dependent chemiluminescence of platelets is studied; the resistance of platelets to ASA is determined by the value of the area (S) under the chemiluminescence curve: S < 360,000 c.u. indicates platelet resistance to ASA, if S ≥ 360,000, then we speak of platelet sensitivity to ASA.

[0007] This method is aimed at determining resistance to only one drug, namely acetylsalicylic acid, and does not provide for an assessment of the individual response to DAPT.

[0008] The authors of the method for rapid diagnosis of resistance and sensitivity to acetylsalicylic acid [RU patent no. 2578428] propose collecting blood from the patient before starting antiplatelet therapy, using 3.2% sodium citrate as an anticoagulant. Next, 0.5 ml of blood is placed in a cuvette with the anticoagulant, and a short, approximately 10-minute cycle is passed through the blood sample. -5 s, a current pulse, followed by recording the sample's polarization decay function. This function is then Fourier transformed, and the impedance hodograph parameters are calculated in the frequency range of 0.1–125 kHz using a dielectric Fourier spectrometer.

[0009] At the reference interval values ​​r0=4.518-4.551, x0=1.925-1.939, y0=-1.395-1.385, sensitivity to acetylsalicylic acid is diagnosed, and at the values ​​r0=4.504-4.517, x0=1.914-1.926, y0=-1.384-1.375, resistance to acetylsalicylic acid is diagnosed. The invention enables rapid and reliable diagnosis of resistance to ASA in a patient before treatment, which will prevent the development of adverse coronary events in patients with coronary heart disease.

[0010] The method is labor-intensive and requires special equipment and highly qualified personnel to carry out the research.

[0011] A known method for determining platelet resistance to dual antiplatelet therapy in patients with coronary heart disease [RU Patent No. 2710272], in which the authors propose determining, individually for the patient, the light transmittance values ​​​​with graphic registration for 5 minutes with constant stirring and a temperature of 37 ° C, adding a platelet aggregation inducer to the platelet suspension in a 10:1 ratio once at a concentration of 2 μmol / L for 10 seconds of recording platelet aggregation on a laser aggregometer. Then, in addition to platelet-rich plasma, the inducer is added in a 2:1 ratio of 2 μmol / L at the 1st, 2nd, 3rd and 4th minutes of the study. Adenosine diphosphate is used as an aggregation inducer, and when platelet aggregation values ​​are obtained in the range from 50 to 100%, platelet resistance to dual antiplatelet therapy is determined.

[0012] The disadvantage of this method is that it determines the effectiveness of only one drug, Clopidogrel, which is insufficient to predict the effectiveness of dual antiplatelet therapy, which includes two drugs.

[0013] A method for predicting the effectiveness of antiplatelet therapy with Clopidogrel is known [RU Patent No. 2702753], which includes determining clinical and laboratory parameters in a patient who has undergone coronary stenting, such as hematocrit, hemoglobin, lipids, and genetic markers, namely, the CYP2C19 and ABCB1 genotype. The authors' formula is used to calculate the residual platelet reactivity, which is the basis for predicting the antiplatelet effect during Clopidogrel therapy.

[0014] This method is designed for patients with acute coronary syndrome, however, the result is aimed at predicting the effectiveness of only one drug, Clopidogrel.

[0015] The source [Chan NC et al. Role of phenotypic and genetic testing in managing clopidogrel therapy / / Blood. 2014 Jul 31; 124(5):689-99. doi: 10.1182 / blood-2014-01-512723. Epub 2014 Jim 20] states that P2Y12 inhibitors, clopidogrel, prasugrel, and ticagrelor, are prescribed in fixed doses without laboratory monitoring. However, patients receiving a standard dose of clopidogrel have significant variability in platelet inhibition, which is partly explained by genetic polymorphisms encoding CYP2C19, a liver enzyme involved in the biotransformation of clopidogrel into its active metabolite.

[0016] Technical result - an accurate quantitative assessment of the risk of developing acute coronary events over the next year, which does not require the involvement of additional material and human resources, early detection of the danger of its occurrence for the preparation of a personalized treatment plan, prevention and reduction of patient mortality.

[0017] eliminating the stage of empirical selection of a dual antiplatelet therapy regimen, increasing the clinical effectiveness of treatment.

[0018] The development of the method was based on the results of observation of 130 patients with ischemic heart disease who underwent treatment at the clinical base of the Federal State Budgetary Educational Institution of Higher Education Voronezh State Medical University named after N.N. Burdenko of the Ministry of Health of the Russian Federation at the Voronezh City Clinical Hospital No. 3 in the period from 2019 to 2024 with a diagnosis of acute coronary syndrome (120.0 according to ICD-10).

[0019] For each patient on admission to hospital, standard medical history data were recorded, namely: gender, digital designation 1 - male, 2 - female; age, indicating the number of completed years at the time of hospitalization; weight in kilograms; height in centimeters. Laboratory tests included assessment of venous blood creatinine (cr) in μmol / L; creatinine clearance (CC), calculated according to the Cockcroft-Gault formula in ml / min; platelet value (MPV) in femtoliter / platelet; the relative number of large platelets (PLCR) in %;

[0020] On the 5th day of hospitalization, spontaneous aggregation (Sp) was determined using the Biola aggregometer (Russia) r ). According to the tr-curve of platelet aggregation, in conventional units, the value of three indicators of induced aggregation in percent was estimated, namely in one μMol ADP (Ind 1t ), in five µmol ADP (Ind 5t ), and in fifteen µl of arachidonic acid (Apx t ).

[0021] Patients were followed dynamically for one year, after which the occurrence or absence of adverse coronary events (ACEs) was recorded. The absence of medical care visits for ACEs was coded as 1; hospitalizations to the cardiology department or outpatient visits to a cardiologist for exacerbation of the disease were coded as 2; death as a result of acute coronary events was coded as 3.

[0022] Next, a regression equation was constructed, where the predicted indicator was the occurrence of an adverse coronary event one year after hospitalization, and the influencing indicators were the patient’s examination indicators upon initial admission to the hospital.

[0023] The equation is:

[0024] K прогн =-2.478+0.477*gender+0.05*age - 0.044*weight - 0.014*height

[0025] +0.05*Kr+0.063*KK - 0.448*MPV+0.029*PLCR

[0026] +0.054*Sp r+ 0.012*Ind 1t - 0.006*Ind 5t + 0.027*Apx t

[0027] The designations of the indicators are indicated above in the text.

[0028] Next, we calculated the value of K прогн for each patient in the study group, the median, first and third quartiles were determined in subgroups formed based on the type of adverse coronary event: no events, hospitalization or referral to a cardiologist, or the patient had a fatal outcome of the disease (Table).

[0029]

[0030] As follows from the results of our calculations, in patients who did not have NCS within a year after hospitalization, the level of the third quartile of the prognosis coefficient K прогн was below 1.57 conventional units, the median was 1.406 conventional units. Fluctuations in the value of K прогнin the subgroup of patients who had an exacerbation of the disease and sought help from a cardiologist about it, they were in the range of 1.95 (1.58:2.087) conventional units. In case of a fatal outcome within a year due to the development of adverse coronary events, the value of the first quartile of the prognosis coefficient K прогн was higher than 2.2 conventional units.

[0031] Testing the effectiveness of the formula on newly admitted patients showed that it is most optimal to base decisions on treatment tactics based on the calculated value of the prediction coefficient on the values ​​of the third quartile.

[0032] Thus the following rule was formulated. If the value of K прогн If the K value is less than 1.56 conventional units, then no adverse coronary events are expected within the next year, the patient is transferred to dynamic observation, and no additional treatment measures are carried out. If the K value прогнlies in the range from 1.56 conventional units to 2.09 conventional units, then an exacerbation of the disease is expected within a year. The patient undergoes platelet aggregation monitoring every three months and adherence to therapy is determined. If the calculated value of the K indicator is exceeded прогн values ​​of 2.1 conventional units indicate a likely fatal outcome within a year of observation; platelet aggregation and adherence to therapy are monitored monthly, and vigilance is exercised in the event of progression of disease symptoms.

[0033] The implementation of the method is confirmed by clinical examples.

[0034] Clinical example 1. Patient D., 49 years old. Received treatment in the cardiology department with a diagnosis of ischemic heart disease. Acute myocardial infarction without ST-segment elevation, without Q waves, lateral left ventricular region and interventricular septum, class I according to the Killip scale. Persistent atrial fibrillation. Left ventricular myocardial hypertrophy. Atherosclerotic cardiosclerosis. Hypertension 3, stage 3, CV risk 4. Chronic heart failure 2a, functional class 3 (according to NYHA).

[0035] At the pre-hospital stage (emergency medical care): acetylsalicylic acid 250 mg, clopidogrel 300 mg, heparin 5000 IU intravenously. During hospitalization, the following therapy was prescribed: nitroglycerin 5 ml intravenously by drip, cardiket 20 mg × 2 times a day, enoxaparin 0.8 ml × 2 times, clopidogrel 75 mg, acecardol 100 mg, atorvastatin 80 mg, lisinopril 5 mg, furosemide 6 ml.

[0036] During treatment, the condition improved; on the 5th day of hospitalization, aggregometry was performed.

[0037]

[0038] The value of K was calculated using the formula прогн = -2.478+0.477*gender + 0.05*age - 0.044*weight - 0.014*height + 0.05*Kr + 0.063*KK - 0.448*MPV+0.029*PLCR + 0.054*Sp r +0.012*Ind 1t - 0.006*Ind 5t +0.027*Apx t

[0039] K прогн = -2.478+0.477*2+0.05*49-0.044*76-0.014*159+0.05*87+0.063*74.86-0.448*8.5+0.029*16.9+0.054*1.6+0.012*3.3-0.006*28.9+0.027*0.2

[0040] K прогн =1.06

[0041] The obtained value is less than 1.06 conventional units, which corresponds to the prognosis of no adverse coronary events over the next year. Dynamic monitoring confirmed the accuracy of the prognosis; no repeat hospitalizations due to vascular events were recorded over the 12 months. The patient continues to be monitored by a cardiologist and a general practitioner.

[0042] Clinical example 2. Patient T., 73 years old. Received treatment in the cardiology department with a diagnosis of ischemic heart disease. Acute myocardial infarction without ST-segment elevation, without Q waves, lateral left ventricular region, class I according to the Killip scale. Persistent atrial fibrillation. Left ventricular myocardial hypertrophy. Moderate pulmonary hypertension. Atherosclerotic cardiosclerosis. Hypertension 3, stage 3, CV risk 4. Chronic heart failure 26, functional class 3 (according to NYHA).

[0043] At the pre-hospital stage (emergency medical care): acetylsalicylic acid 250 mg, clopidogrel 300 mg, heparin 5000 IU intravenously. During hospitalization, the following therapy was prescribed: nitroglycerin 5 ml intravenously by drip, cardiket 20 mg × 2 times a day, heparin 30,000 units intravenously through an infusion pump, clopidogrel 75 mg, acecardol 100 mg, atorvastatin 80 mg, enalapril 5 mg, spironolactone 50 mg.

[0044] During treatment, the condition showed positive dynamics; on the 5th day of hospitalization, aggregometry was performed.

[0045]

[0046] The value of K was calculated using the formula прогн = -2.478+0.477*gender + 0.05*age - 0.044*weight - 0.014*height + 0.05*Kr + 0.063*KK - 0.448*MPV+0.029*PLCR+0.054*Sp r +0.012*Ind 1t - 0.006*Ind 5t +0.027*Apx t

[0047] K прогн =1,859

[0048] The obtained value ranges from 1.56 conventional units to 2.09 conventional units, with a possible exacerbation of the disease within a year. Dynamic monitoring confirmed the accuracy of the prognosis; within 12 months, a repeat hospitalization due to vascular events was recorded.

[0049] The patient continues to be monitored by a cardiologist and a therapist.

[0050] Clinical example 3. Patient S, 56 years old. Received treatment in the cardiology department with a diagnosis of ischemic heart disease. Acute myocardial infarction without ST-segment elevation. Moderate pulmonary hypertension. Atherosclerotic cardiosclerosis. Hypertension stage 2, CV risk 3. Chronic heart failure 26, functional class 3 (according to NYHA).

[0051] Pre-hospital (emergency medical care): acetylsalicylic acid 250 mg, clopidogrel 300 mg, heparin 5000 IU intravenously. During hospitalization, the following therapy was prescribed: nitroglycerin 5 ml intravenously by drip, cardiket 20 mg × 2 times a day, heparin 20,000 units intravenously through an infusion pump, clopidogrel 70 mg, acecardol 100 mg, atorvastatin 80 mg, enalapril 5 mg.

[0052] During treatment, the condition showed positive dynamics; on the 5th day of hospitalization, aggregometry was performed.

[0053]

[0054] The value of K was calculated using the formula прогн = -2.478+0.477*gender + 0.05*age - 0.044*weight - 0.014*height + 0.05*Kr + 0.063*KK - 0.448*MPV + 0.029*PLCR + 0.054*Sp r + 0.012*Ind 1t - 0.006*Ind* + 0.027*Apx t

[0055] K прогн = 3.22

[0056] The obtained value of K value прогн exceeds 2.1 conventional units. A fatal outcome is likely within the next year of observation.

[0057] Ten months after hospitalization and prognosis, the patient developed acute transmural anterior myocardial infarction and was urgently hospitalized in the intensive care unit.

[0058] Thus, we have developed a method that allows for an accurate assessment of the risk of acute coronary events over the next year. This method is easy to use, does not require additional material or human resources, and serves as the basis for developing a personalized treatment plan, preventing and reducing mortality in patients.

Claims

A method for assessing the risk of adverse coronary events in patients with acute coronary syndrome receiving dual antiplatelet therapy, including recording anamnesis data, laboratory test results, and an assessment of spontaneous and induced platelet aggregation based on the tr-aggregation curve on the 5th day of hospitalization upon admission to hospitalization, characterized in that a linear regression equation is constructed: TO прогн = – 2.478 + 0.477×gender + 0.05×age – 0.044×weight – 0.014×height + 0.05×Kr + 0.063×KK – 0.448×MPV + 0.029×PLCR + 0.054×Sp r + 0.012×Ind 1t – 0.006×Ind 5t + 0.027×Arch t , Where TO прогн – the coefficient of prediction of the occurrence of adverse coronary events within the next year, gender is indicated by the number 1 for men, by the number 2 for women, age is taken into account in the number of full years, weight in kg, height in cm, Kr is the level of creatinine in venous blood in μmol / l, CC - creatinine clearance in ml / min; MPV - mean platelet volume in femtoliters; PLCR - percentage of large platelets, Sp r – spontaneous platelet aggregation in conventional units, Ind. 1t - induced platelet aggregation in one μmol of ADP, Ind 5t - induced platelet aggregation in five μmol ADP, Arch t - in fifteen µl of arachidonic acid; if the value of K прогн less than 1.56 conventional units, it is judged that there will be no adverse coronary events within the next year; if the value of K прогн lies in the range from 1.56 conventional units to 2.09 conventional units, they judge the exacerbation of the disease with hospitalization or seeking outpatient care during the year; if the value of the indicator K прогн equal to or exceeds the value of 2.1 conventional units, the probable fatal outcome is judged during the year of observation.

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