CN112967750B - Model for predicting antiplatelet efficacy of clopidogrel and application thereof - Google Patents
Model for predicting antiplatelet efficacy of clopidogrel and application thereof Download PDFInfo
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Abstract
The invention discloses a model for predicting antiplatelet effect of clopidogrel and application thereof, and belongs to the technical field of biological detection. The model comprises a data input unit, an assignment unit, a curative effect prediction unit and a report output unit for three independent risk factors of the age, the basic platelet activity and the CYP2C19 genotype of a tested objectConstructing an ABC scoring system according to the units, and taking the total score as 7 points, wherein if the ABC score is less than or equal to 3 points, clopidogrel can be used as platelet P2Y 12 Receptor inhibitors against platelets; if the ABC score is more than or equal to 4 points, the combination of ticagrelor, clopidogrel and cilostazol or the combination of clopidogrel and small-dose rivaroxaban can be selected. The model can be used to guide the clinician in precisely selecting platelets P2Y 12 Receptor inhibitors, which predict accurate results for clopidogrel Lei Liaoxiao, are able to balance the benefits of anti-thrombosis with the risk of hemorrhage.
Description
Technical Field
The invention belongs to the technical field of biological detection, and particularly relates to a model for predicting the efficacy of clopidogrel on platelets and application thereof, which can be used for guiding clinicians to accurately select platelets P2Y 12 Receptor inhibitors assess the risk of ischemia and hemorrhage.
Background
Platelet activation is a key element in the occurrence and development of coronary heart disease, and plays an important role in thrombotic events, and anti-platelet therapy is a cornerstone of coronary heart disease therapy. Coronary heart disease patients in China are increased year by year, and patients undergoing coronary intervention therapy (percutaneous coronary intervention, PCI) are nearly 100 ten thousand cases each year, wherein most patients need to use platelet P2Y in combination on the basis of aspirin 12 Receptor inhibitors, because dual anti-platelet therapy is effective in reducing the occurrence of acute ischemic events. Compared with ticagrelor, clopidogrel has the advantages of low price, high use compliance, lower bleeding risk and the like, and is the platelet P2Y which is most commonly used at present 12 Receptor inhibitors.
Notably, there are significant individual differences in clopidogrel efficacy, and the antiplatelet effect of the same dose of drug is not the same for different patients. After 20% or more of patients take conventional doses of clopidogrel, their platelet aggregation ability is not effectively inhibited, and the residual high platelet activity (high residual platelet reactivity, HRPR) makes this part of patients still in a high risk state of intrastent thrombosis, myocardial infarction, etc. Obviously, the unpredictability of the antiplatelet effect of clopidogrel presents a hindrance and challenge to clinical work, and if the efficacy of clopidogrel can be estimated in advance, there is an opportunity to identify high-risk patients early and also an opportunity to apply an individualized antiplatelet strategy to the patients.
Clopidogrel pharmacogenetics offers the possibility for personalized antiplatelet therapy, but there is still a need for improvement. Clopidogrel is a prodrug that requires biotransformation in the liver via the liver cytochrome P450 (CYP 450) to an active metabolite to exert antiplatelet effects, with CYP2C19 involved in two steps of clopidogrel oxidative metabolism. Thus, if the patient carries a CYP2C19 loss of function (LOF) site, the activity of the enzyme may be decreased, so that the active metabolite of clopidogrel is decreased, and thus the antiplatelet effect is reduced. It was found that nearly 60% of coronary heart disease patients carried CYP2C19LOF sites and that CYP2C19 x 2 and x 3LOF sites affect the efficacy of clopidogrel from four levels of intracellular molecular level, platelet function, perioperative events, and long-term prognosis. In addition, although the eastern asia population carries CYP2C19LOF sites at a much higher frequency than the european and american population, the rate of events was not increased, and even was lower, in the same manner as clopidogrel treatment than in the european and american population, perhaps due to the differences in platelet activity inherent in the population. CYP2C19 gene polymorphism affects the metabolism of clopidogrel, but does not directly affect platelets; the therapeutic effect of antiplatelet drugs is related to the activity of the platelets themselves, in addition to the drug. For patients with coronary heart disease in China, if the therapy is guided only according to CYP2C19 genotype, which means that more than half of patients need to replace clopidogrel, the method is excessive and inaccurate. TAILOR-PCI studies published by ACC conference 2020 also demonstrate that reliance on CYP2C19 genotype alone is insufficient to guide individualized platelet therapy, and that the maximum assessment of protocols to date uses CYP2C19 gene detection to guide selection of anti-platelet strategies, with study populations including east Asia patients, and results in failure to reach a positive endpoint.
Disclosure of Invention
The invention aims to provide a model for predicting the efficacy of clopidogrel on thrombocytes, which is good in prediction effect by constructing an ABC scoring model for accurately predicting the efficacy of clopidogrel on thrombocytes by combining the age of a patient and the activity of basic thrombocytes based on the prior study of CYP2C19 genotype factors.
A second object of the present invention is to provide the above model for predicting clopidogrel antiplatelet efficacy in guiding a clinician to precisely select platelets P2Y 12 Use of a receptor inhibitor to balance the risk of ischemia and hemorrhage in a patient.
In order to achieve the above purpose, the invention adopts the following technical scheme:
a model for predicting the antiplatelet efficacy of clopidogrel comprises a data input unit, an assignment unit, an efficacy prediction unit and a report output unit for three independent risk factors of age (age, A), basic platelet activity (baseline platelet reactivity, B) and CYP2C19 genotype (C) of a tested object, and an ABC scoring system is constructed according to the units; wherein,
the data input module acquires and records three independent risk factor data of age, basic platelet activity and CYP2C19 genotype of a detected object and stores the three independent risk factor data; wherein the basal platelet activity is expressed by thrombin-induced MA values determined by thromboelastography, and the CYP2C19 genotype is selected from one of a CYP2C19 LOF-free site, a CYP2C19LOF site, and two CYP2C19LOF sites;
the assignment module comprises an age assignment subunit, a basic platelet activity subunit and a CYP2C19 genotype subunit which are arranged in parallel, and performs assignment in the following way:
in the age assignment subunit, if the age is less than or equal to 60 years old, the score is 0; if the age is 61-75 years, the score is 1; if age >75 years, then score 2;
in the basic platelet activity subunit, if the MA value induced by thrombin is greater than 65.7mm, the score is 3, otherwise, the score is 0;
in the CYP2C19 genotype subunit, if the CYP2C19 genotype is a CYP2C19LOF locus free, the CYP2C19 genotype subunit is scored as 0; if the CYP2C19 genotype is a CYP2C19LOF locus, the score is 1; if the CYP2C19 genotype is two CYP2C19LOF loci, the score is 2;
the curative effect prediction unit receives the assignment of the assignment module, predicts the antiplatelet curative effect of clopidogrel according to the total score of the assignment, and is divided into 7 points according to the total score:
if the ABC score is less than or equal to 3 points, clopidogrel can be selected as platelet P2Y alone 12 The receptor inhibitor is anti-platelet, low in price and low in bleeding risk;
if the ABC score is more than or equal to 4 points, the combination of ticagrelor, clopidogrel and cilostazol or the combination of clopidogrel and small-dose rivaroxaban can be selected.
According to some embodiments of the invention, the subject is a patient who is chronically antiplatelet with clopidogrel.
The invention also provides a model for predicting the antiplatelet effect of clopidogrel, which guides a clinician to accurately select the platelet P2Y 12 Use of a receptor inhibitor to balance the risk of ischemia and hemorrhage in a patient.
According to one embodiment of the invention, if the ABC score is less than or equal to 3 points, the patient is estimated to respond acceptably to clopidogrel, which can be used as platelet P2Y 12 Receptor inhibitors against platelets; if the ABC score is more than or equal to 4 minutes, the clopidogrel reaction difference is estimated, and the ticagrelor, the clopidogrel and the cilostazol can be used together or the clopidogrel and the small-dose rivaroxaban can be used together.
Compared with the prior art, the invention has the beneficial effects that:
(1) According to the invention, on the basis of early research, the age and basic platelet activity (expressed by thrombin-induced MA values measured by thromboelastography) of patients are also independent risk factors for predicting the clopidogrel curative effect, and the three independent risk factors have a superposition effect on the clopidogrel curative effect, so that compared with the existing method for predicting the clopidogrel curative effect by simply relying on the CYP2C19 genotype, the prediction result is more accurate and reliable. In addition, all three factors can be detected rapidly, simply, conveniently and rapidly in clinic.
(2) The model of the invention pertains to upstream prediction rather than post-evaluation for guiding clinicians to precisely select platelets P2Y 12 The receptor inhibitor balances the ischemia and hemorrhage risks of patients, and can effectively avoid insufficient curative effect of the anti-thrombus medicament in the perioperative period.
The above as well as additional features, aspects, and advantages of the present application will become more readily apparent with reference to the following detailed description.
Drawings
Other features, objects and advantages of the present invention will become more apparent upon reading of the detailed description of non-limiting embodiments, given with reference to the accompanying drawings in which:
FIG. 1 is a schematic diagram of a model structure for predicting the antiplatelet effect of clopidogrel in the present invention;
FIG. 2 is an evaluation system of a model for predicting the efficacy of clopidogrel in resisting platelets in the present invention;
FIG. 3 is a graph showing the relationship between basal maximum platelet activity and residual platelet activity in the inhibition of the metabolic process of the platelet activity by the drug;
FIG. 4 shows the dose-effect relationship of CYP2C19LOF of the population in China on the effect of clopidogrel on anti-platelet efficacy;
fig. 5 is a correlation of residual high platelet activity (HRPR) and one year ischemic events (MACE) following clopidogrel treatment.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which can be made by a person skilled in the art without creative efforts, based on the described embodiments of the present invention fall within the protection scope of the present invention.
Unless defined otherwise, technical or scientific terms used herein should be given the ordinary meaning as understood by one of ordinary skill in the art to which this invention belongs. The terms "first," "second," and the like in the description and in the claims, are not used for any order, quantity, or importance, but are used for distinguishing between different elements. Likewise, the terms "a" or "an" and the like do not denote a limitation of quantity, but rather denote the presence of at least one.
In the prior art, CYP2C19 genotype only affects the metabolism of clopidogrel, so that the concentration of active drugs is different, and the effect of clopidogrel is not predicted sufficiently. The invention discovers that the antiplatelet effect of the medicine is related to the medicine and the patient and the platelet on the basis of the prior study, integrates clinical factors of the patient such as age, platelet activity (thrombin induced MA value (MAthrombin) detected by thromboelastography can be used as an index of the intrinsic baseline platelet activity of coronary heart disease patient) and CYP2C19 genotype, better predicts the curative effect of the patient on using clopidogrel to resist the platelet, and accurately guides the platelet P2Y 12 Selection of receptor inhibitors, as shown in figures 1 and 2, wherein:
if ABC score is less than or equal to 3 score, platelet P2Y 12 The receptor inhibitor can be clopidogrel, and has low price and low bleeding risk;
if ABC score is greater than or equal to 4 score, platelet P2Y 12 The receptor inhibitor can be selected from ticagrelor, clopidogrel and cilostazol, or clopidogrel and small-dose rivaroxaban.
The application object is as follows: patients who use clopidogrel for a long period of time are required.
And (3) detecting:
(1) detecting CYP2C19 genotype, wherein the detection of the site of the 2 and the site of the 3 is required;
if the genotype is CYP2C19 x 1/x 1, the genotype is wild type, and CYP2C19LOF is not carried;
if the genotype is CYP2C19 x 1/x 2 or x 1/x 3, then 1 CYP2C19LOF is carried;
if the genotype is CYP2C 19/2 or 2/3 or 3/3, then 2 CYP2C19 LOFs are carried.
(2) Thrombin-induced MA values were detected by Thromboelastography (TEG), which analyzer consisted of two parts: an oscillatable rotary heating cup and a needle freely suspended from the tension wire. The fresh blood drawn is placed in a small cup, the suspended needle is immersed in the blood, and the movement of the small cup does not affect the needle when the blood sample is in a liquid state. And when the clot begins to form, the cellulose and platelets in the clot form a clot mass, coupling the movement of the cuvette to the needle, the magnitude of the movement of the needle being related to the strength of the formed clot, and when the clot is retracted or dissolved, the coupling of the needle to the clot is released. The above changes and the elasticity of the blood clot are transmitted by the effect information generated by connection with the needle, amplified and transmitted to the TEG scanner, and recorded on the thermosensitive paper at a rate of 2mm/min to form a thromboelastane pattern. The MA value can be obtained by simulating slow venous blood flow in vitro during detection, inducing blood clot formation by adding reagent containing kaolin, measuring time and quantity of thrombus formation by using a receptor, and drawing a blood coagulation speed and intensity curve by a computer.
The process of constructing the model for predicting the antiplatelet effect of clopidogrel is as follows:
(1) studies have shown that the final factor in determining the efficacy of antiplatelet drugs is residual platelet activity, not just the ratio of drug to platelet activity inhibition, and that individualized antiplatelet therapy cannot place eye light only on pharmacokinetics (figure 3).
(2) CYP2C19 Gene polymorphism affects the metabolism of clopidogrel and the use of CYP2C19 genotypes alone directs individualization of P2Y 12 The choice of receptor inhibitors is not accurate enough.
(3) The efficacy of the CYP2C19LOF effect on clopidogrel Lei Liaoxiao varies from population to population, and the efficacy of the CYP2C19LOF effect is lower and has a dose-effect relationship among the east asian populations. Studies show that CYP2C19 x 2 and CYP2C19 x 3 are obviously related to ADP-induced platelet aggregation rate and clopidogrel platelet inhibition rate, the frequency of carrying CYP2C19 x 2 allele reaches 53.7%, the frequency of carrying CYP2C19 x 3 allele also reaches 10.5%, and the two are independent risk factors for predicting clopidogrel antiplatelet effect and have no obvious difference in effect; the study also found that the platelet aggregation rate was higher for 2 LOF carriers (CYP 2C19 x 2/. 2, CYP2C19 x 2/. 3 and CYP2C19 x 3/. 3) than for 1 LOF carrier (CYP 2C 19/. 1 and CYP2C19 x 1/. 3) (57.6% ± 22.9% to 48.2% ± 25.2%, p=0.008), whereas the platelet aggregation rate was lowest for no LOF carrier (CYP 2C19 x 1/. 1) (38.6±22.7% to 48.2% ± 25.2%, p < 0.001) (fig. 4).
(4) Multiple regression analysis (table 1) of clinical factors, biochemical factors, and CYP2C19 genotypes, which may affect clopidogrel antiplatelet effects, showed that age, thrombin-induced MA values, and CYP2C19 genotypes were independent risk factors for predicting residual high platelet activity (HRPR) after clopidogrel antiplatelet treatment, so that an ABC scoring model was established for predicting clopidogrel efficacy, giving corresponding assignments according to OR values.
TABLE 1
(5) Comparing the ABC scoring model with the predicted clopidogrel efficacy purely dependent on the CYP2C19 genotype, analysis by ROC curve with HRPR and one year ischemic event as endpoints showed that AUC of the ABC scoring model was significantly better than CYP2C19 genotype (table 2 and fig. 5).
TABLE 2
| Predicting HRPR | AUC(95％CI) | P value | Sensitivity | Specificity |
| CYP2C19 genotype | 0.597(0.550-0.643) | <0.001 | 72.82 | 43.02 |
| ABC scoring model | 0.738(0.695-0.778) | <0.001 | 59.22 | 74.41 |
| Predicting 1 year ischemic events | AUC(95％CI) | P value | Sensitivity | Specificity |
| CYP2C19 genotype | 0.604(0.550-0.643) | 0.0312 | 31.58 | 86.80 |
| ABC scoring model | 0.676(0.630-0.719) | <0.001 | 57.89 | 69.19 |
While the fundamental and principal features of the invention and advantages of the invention have been shown and described, it will be apparent to those skilled in the art that the invention is not limited to the details of the foregoing exemplary embodiments, but may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and the description is provided for clarity only, and those skilled in the art will recognize that the embodiments of the disclosure may be combined appropriately to form other embodiments that will be understood by those skilled in the art.
Claims (4)
1. A method of constructing a model for predicting the efficacy of clopidogrel in resisting platelets, comprising:
the method comprises the steps of constructing an ABC scoring system according to a data input unit, an assignment unit, a curative effect prediction unit and a report output unit of three independent risk factors of age, basic platelet activity and CYP2C19 genotype of a detected object; wherein,
the data input unit acquires and records three independent risk factor data of age, basic platelet activity and CYP2C19 genotype of a detected object, wherein the basic platelet activity is represented by a thrombin-induced MA value measured by a thromboelastography, and the CYP2C19 genotype is selected from one of a CYP2C19 LOF-free site, a CYP2C19LOF site and two CYP2C19LOF sites;
the assignment unit comprises an age assignment subunit, a basic platelet activity subunit and a CYP2C19 genotype subunit which are arranged in parallel, and assignment is carried out in the following mode:
in the age assignment subunit, if the age is less than or equal to 60 years old, the score is 0; if the age is 61-75 years, the score is 1; if age >75 years, then score 2;
in the basic platelet activity subunit, if the MA value induced by thrombin is greater than 65.7mm, the score is 2, otherwise, the score is 0;
in the CYP2C19 genotype subunit, if the CYP2C19 genotype is a CYP2C19LOF locus free, the CYP2C19 genotype subunit is scored as 0; if the CYP2C19 genotype is a CYP2C19LOF locus, the score is 1; if the CYP2C19 genotype is two CYP2C19LOF loci, the score is 2;
the curative effect prediction unit receives the assignment of the assignment unit, predicts the antiplatelet curative effect of clopidogrel according to the total score of the assignment, and calculates 7 points according to the total score:
if the ABC score is less than or equal to 3, the patient is estimated to be acceptable in response to clopidogrel, and the clopidogrel can be used as platelet P2Y 12 Receptor inhibitors against platelets;
if the ABC score is more than or equal to 4 points, the clopidogrel reaction difference is estimated, and the ticagrelor, the clopidogrel and the cilostazol are combined or the clopidogrel and the small-dose rivaroxaban are combined to resist the platelet.
2. The method of constructing a model for predicting antiplatelet efficacy of clopidogrel as recited in claim 1, wherein the subject is a patient who uses clopidogrel antiplatelet for a prolonged period of time.
3. The method for constructing a model for predicting the anti-platelet efficacy of clopidogrel according to claim 1 or 2, wherein the clinician is guided to precisely select platelets P2Y 12 Use of a receptor inhibitor to balance the risk of ischemia and hemorrhage in a patient.
4. The use according to claim 3, wherein clopidogrel is used as platelet P2Y if ABC score is less than or equal to 3 points 12 Receptor inhibitors against platelets; if the ABC score is more than or equal to 4 points, selecting ticagrelor, clopidogrel and cilostazol to be combined or clopidogrel and small-dose rivaroxaban to be combined for anti-platelet.
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