A model for predicting the risk of rivaroxaban anticoagulation bleeding and its application

Abstract

The application discloses a model for predicting the risk of rivaroxaban anticoagulation bleeding and application thereof, and belongs to the technical field of biological detection. The model comprises a data input unit of two independent risk factors of a CYP3A4 genotype and clinical bleeding history of a subject, an assignment unit, an efficacy prediction unit and a report output unit, a C&B scoring system is formed according to the units, the total score is 3 points, if the C&B score is less than or equal to 1 point, rivaroxaban can be used as a coagulation factor X inhibitor for anticoagulant therapy, and if the C&B score is greater than or equal to 2 points, warfarin can be selected for anticoagulant therapy. The model can be used for guiding a clinician to accurately select a coagulation factor X inhibitor, the result of predicting the risk of rivaroxaban bleeding is accurate and reliable, and balance between anticoagulation benefits and bleeding risks can be achieved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of biological detection, and particularly relates to a model for predicting the anticoagulation bleeding risk of rivaroxaban and application thereof. BACKGROUND

[0002] Rivaroxaban is a coagulation factor X inhibitor, which is widely used in non-valvular atrial fibrillation (NVAF) patients to reduce the risk of stroke and systemic embolism. As a new type of oral anticoagulant, rivaroxaban has a fixed dose and does not need frequent monitoring, and is more easily accepted by patients. However, serious bleeding events such as intracranial hemorrhage and fatal bleeding still occur during rivaroxaban treatment, although studies have shown that the incidence is lower than that of warfarin.

[0003] The reason is that there are considerable inter-individual differences in pharmacokinetics (PK) and pharmacodynamics (PD) during the treatment of different patients with rivaroxaban, and there are differences in the blood drug concentration of rivaroxaban among different individuals, and research results show that the blood drug concentration (trough concentration) of rivaroxaban is highly related to the bleeding result. This difference in PK and PD may be related to the genes of rivaroxaban absorption, distribution and metabolism, such as CES1, ABCB1, CYP3A4 and CYP3A5, among which CYP3A4 mediates the main metabolic pathway of rivaroxaban. In addition, a large number of studies have shown that the simultaneous use of CYP3A4 inhibitors will increase the exposure of rivaroxaban, so it is expected to guide the reasonable application of rivaroxaban according to the CYP3A4 gene polymorphism, and reduce thrombosis and bleeding events.

[0004] At present, the main application of HAS-BLED bleeding risk score is used in clinical prediction of bleeding, and HAS-BLED≥3 indicates a high risk of bleeding. The score has achieved certain effect in clinical application, and HAS-BLED has been verified in atrial fibrillation patients receiving warfarin treatment. However, there is insufficient evidence for the role of rivaroxaban in new anticoagulants. Studies have also tried to improve the HAS-BLED score to assess the bleeding risk of rivaroxaban, but the effect is not good. Therefore, there is no good scoring tool to predict the bleeding risk of new anticoagulants rivaroxaban. SUMMARY

[0005] To solve the above problems, the application provides a model for predicting the anticoagulation bleeding risk of rivaroxaban. On the basis of previous research, the C&B scoring model for accurately predicting the anticoagulation bleeding risk of rivaroxaban is constructed by combining the existing CYP3A4 genotype factors and the bleeding history of patients, and a practical tool is provided for evaluating the individual bleeding risk.

[0006] Specifically, the first aspect of the present application provides a model for predicting the bleeding risk of rivaroxaban anticoagulation, comprising a data input unit, an assignment unit, an efficacy prediction unit and a report output unit.

[0007] Further, the data input unit collects and saves the data of two independent risk factors of CYP3A4 genotype and bleeding history of the subject, and the CYP3A4 genotype is selected from one of no CYP3A4 mutation site, carrying one CYP3A4 mutation site and two CYP3A4 mutation sites.

[0008] Further, the assignment module comprises a CYP3A4 genotype subunit and a bleeding history subunit in parallel, and the assignment is performed in the following manner: in the CYP3A4 genotype subunit, if the CYP3A4 genotype is no CYP3A4 mutation site, the score is 0; if the CYP3A4 genotype is one CYP3A4 mutation site, the score is 1; if the CYP3A4 genotype is two CYP3A4 mutation sites, the score is 2; in the bleeding history assignment subunit, if there is no bleeding event within five years, the score is 0; otherwise, the score is 1.

[0009] Further, the no CYP3A4 mutation site means that rs3735451 is TT and rs2246709 is AA, the one CYP3A4 mutation site means that rs3735451 is TC or rs2246709 is GA, and the two CYP3A4 mutation sites mean that rs3735451 is CC, rs2246709 is GG, or rs3735451 is TC and rs2246709 is GA.

[0010] Further, the efficacy prediction unit receives the assignment of the assignment module, and predicts the bleeding risk of rivaroxaban anticoagulation according to the total score of the assignment, and according to the total score of 3 points: if the C&B score is ≤1 point, it is estimated that the patient's bleeding risk of rivaroxaban is acceptable, and rivaroxaban can be selected as an anticoagulant drug for anticoagulant factor X inhibitors; if the C&B score is ≥2 points, it is estimated that the bleeding risk of rivaroxaban is large, and warfarin can be selected for anticoagulant therapy.

[0011] Further, the subject is a patient who uses rivaroxaban anticoagulation for a long time.

[0012] The second aspect of the present application provides the use of the model for predicting the bleeding risk of rivaroxaban anticoagulation in the first aspect of the present application in guiding the selection of anticoagulant factor X inhibitors to balance the efficacy and bleeding risk of anticoagulant therapy in patients.

[0013] Further, it is particularly suitable for guiding clinicians.

[0014] Further, if the C&B score is ≤1, rivaroxaban is used as an anticoagulant for inhibiting factor X; if the C&B score is ≥2, warfarin is selected for anticoagulant therapy.

[0015] Compared with the prior art, the present application has the following beneficial effects:

[0016] Based on the previous research, it is found that the CYP3A4 genotype is highly related to the blood drug concentration, prothrombin time and the incidence of hemorrhagic events of rivaroxaban, and is an independent risk factor for the hemorrhagic risk of rivaroxaban anticoagulant therapy; in addition, the hemorrhagic history of the patient can also be an independent risk factor. Moreover, the two independent risk factors have a superimposed effect on the prediction of the hemorrhagic risk of rivaroxaban anticoagulant therapy, and the result is accurate and reliable. In addition, the two factors can be quickly detected in the clinic, which is simple and fast.

[0017] The model of the present application belongs to upstream prediction rather than post-evaluation, and is used for guiding the clinical doctors to accurately select anticoagulant drugs, balancing the anticoagulant efficacy and the hemorrhagic risk of the patients, and can effectively avoid the occurrence of the inappropriately strong anticoagulation and the resulting serious hemorrhage in the perioperative period.

[0018] The above and other features, aspects and advantages of the present application will be more fully understood from the following detailed description taken in conjunction with the accompanying drawings.

[0019] The present application provides a practical tool for evaluating the hemorrhagic risk of an individual, guiding the clinical doctors to accurately select anticoagulant drugs, and balancing the anticoagulant efficacy and the hemorrhagic risk of the patients BRIEF DESCRIPTION OF DRAWINGS

[0020] Other features, objects and advantages of the present application will become more apparent from the following detailed description of non-limiting embodiments thereof, taken in conjunction with the accompanying drawings:

[0021] Figure 1 A main operation flowchart of the model for predicting the anticoagulant risk of rivaroxaban in the present application is shown.

[0022] Figure 2 An evaluation system of the model for predicting the anticoagulant risk of rivaroxaban in the present application is shown.

[0023] Figure 3 A dose-effect relationship between the CYP3A4 mutation of the Chinese population and the blood drug concentration and the anticoagulant efficacy of rivaroxaban is shown.

[0024] Figure 4 A relationship between the CYP3A4 mutation and the prothrombin time is shown.

[0025] Figure 5 A high correlation between the model for predicting the anticoagulant risk of rivaroxaban in the present application and the one-year hemorrhagic event is shown.

[0026] Figure 6Nomogram graph is shown to analyze the relationship between CYP3A4 gene polymorphism, bleeding history and bleeding risk of rivaroxaban.

[0027] Figure 7 Clinical decision curve is shown to compare the bleeding risk of rivaroxaban anticoagulation predicted by C&B score model and HAS-BLED score (Note: Y coordinate represents clinical net benefit, and X coordinate represents risk threshold. C&B score model, HAS-BLED score model, and C&B score combined with other clinical indicators model are represented by red, green and blue curves respectively. The two gray curves represent the clinical 0 net benefit and 0 risk threshold. The larger the area under the curve, the higher the clinical net benefit. DETAILED DESCRIPTION

[0028] In order to make the objects, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions of the embodiments of the present application will be described clearly and completely below with reference to the drawings of the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the described embodiments of the present application, all other embodiments obtained by those of ordinary skill in the art without any creative effort fall within the scope of protection of the present application.

[0029] Unless otherwise defined, technical terms or scientific terms used herein should be understood as having the common meaning in the field of the present application to those of ordinary skill. The terms "first", "second" and similar terms used in the specification and claims of the present patent application do not represent any order, number or importance, but are only used to distinguish different components. Similarly, the terms "one" or "a" and similar terms do not represent a quantity limitation, but represent the existence of at least one.

[0030] In the prior art, CYP3A4 genotype affects the metabolism of rivaroxaban, resulting in differences in the active drug concentration of rivaroxaban, so as to predict the anticoagulation efficacy and bleeding risk of rivaroxaban. In addition to CYP3A4 genotype, the present application also integrates clinical factors of patients such as bleeding history, better predicts the bleeding risk of patients using rivaroxaban, and accurately guides the selection of anticoagulant factor X inhibitors. The main operation process is as shown in Figure 1 The evaluation system is as shown in Figure 2

[0031] If the C&B score is ≤1, rivaroxaban is used as an anticoagulant therapy of anticoagulant factor X inhibitors.

[0032] If the C&B score is ≥2, warfarin is selected for anticoagulant therapy.

[0033] Applicable object: patients who need to use rivaroxaban for a long time.

[0034] The main tests required are:​

[0035] Detecting CYP3A4 genotype, the main SNP is rs3735451 and rs2246709;

[0036] If rs3735451 is TT and rs2246709 is AA, it is no carrying CYP3A4 mutation;

[0037] If rs3735451 is TC or rs2246709 is GA, it is carrying 1 CYP3A4 mutation;

[0038] If rs3735451 is CC; rs2246709 is GG; rs3735451 is TC and rs2246709 is GA, it is carrying 2 CYP3A4 mutations.

[0039] The process of constructing the above model for predicting the risk of rivaroxaban anticoagulation bleeding is as follows:

[0040] ①CYP3A4 gene polymorphism affects the blood concentration of rivaroxaban and shows a dose-effect relationship; CYP3A4 mutations in different populations have different effects on the metabolism of rivaroxaban. This study shows that carrying 1 / 2 CYP3A4 mutations is significantly associated with the blood trough concentration of rivaroxaban, and carrying 2 CYP3A4 mutations has a higher trough blood concentration than no carrying CYP3A4 mutations. Among them, the trough concentration of rs3735451 is TT, TC, CC, which is 42.11±3.516 ng / ml, 56.6±6.704 ng / ml, 74.73±20.31 ng / ml (P=0.0214); The trough concentration of rs2246709 is AA, GA, GG, which is 42.78±4.728 ng / ml, 49.38±5.813 ng / ml, 70.89±9.83 ng / ml, 42.78±4.728 ng / ml (P=0.0189) Figure 3 )。

[0041] ②CYP3A4 gene polymorphism affects the efficacy of rivaroxaban and shows a dose-effect relationship: carrying 1 / 2 CYP3A4 mutations is significantly associated with the prothrombin time (PT) of rivaroxaban, and the PT value of carrying 2 CYP3A4 mutation sites is significantly higher than that of no carrying CYP3A4 mutation. Among them, the PT value of rs3735451 is TT, TC, CC, which is 12.4±2.012 s, 13.31±2.627 s, 14.36±3.625 s (P=0.0119), suggesting the risk of bleeding Figure 4 )。

[0042] ③CYP3A4 gene polymorphism is highly related to the incidence of bleeding events of rivaroxaban in one year. A total of 165 patients with NVAF were included in the study, and a total of 16 cases (9.7%) of bleeding events occurred during 12 months of follow-up. Among them, the number of bleeding cases of rs3735451 TT, TC and CC was 4 (25.0%), 10 (62.5%) and 2 (12.5%), respectively. The chi-square test result showed that the incidence of bleeding events was different (p=0.038); the number of bleeding cases of rs2246709 AA, GA and GG was 2 (12.5%), 8 (50%) and 6 (37.5%), respectively. The chi-square test result showed that the incidence of bleeding events was different (p=0.028) (Table 1).

[0043] Table 1 Relationship between CYP3A4 gene polymorphism and clinical factors and the incidence of bleeding events of rivaroxaban in one year

[0044]

[0045]

[0046] ④The clinical factors, biochemical factors and CYP3A4 genotypes that may affect the bleeding risk of rivaroxaban anticoagulation were analyzed by multiple regression analysis (Table 2). The results showed that CYP3A4 genotype and bleeding history were independent risk factors for predicting the bleeding risk of rivaroxaban anticoagulation. And the Nomogram risk chart showed that CYP3A4 genotype (bleeding risk > 30%) and bleeding history (bleeding risk > 60%) were highly related to the bleeding risk of rivaroxaban ( Figure 6 ). Therefore, the C&B score model was established to predict the bleeding risk of rivaroxaban, and the corresponding assignment was given according to the OR value.

[0047] Table 2 Multivariate analysis of bleeding

[0048]

[0049] ⑤Compare the C&B score model with the HAS-BLED score alone to predict the bleeding risk of rivaroxaban anticoagulation, with the incidence of bleeding events in one year as the endpoint. Through ROC curve analysis, it is shown that the AUC of C&B score model is significantly better than that of HAS-BLED genotype (Table 3).

[0050] Table 3 Comparison of AUC of C&B score model and HAS-BLED score

[0051]

[0052] ⑥ Comparing the C&B scoring model with HAS-BLED alone in predicting the bleeding risk of rivaroxaban anticoagulation, and using one year of bleeding events as the endpoint, clinical decision curves were plotted. The results showed that the C&B scoring model had significantly better clinical benefits than the HAS-BLED score, and its benefits were comparable to those of the C&B model combined with other clinical indicators. Figure 7 ).

[0053] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered illustrative and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the scope of the invention. No reference numerals in the claims should be construed as limiting the scope of the claims.

[0054] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This description is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A system for predicting the risk of bleeding during rivaroxaban anticoagulation, characterized in that, The system includes a data input unit, a value assignment unit, a treatment efficacy prediction unit, and a report output unit. The data input unit collects and stores data on two independent risk factors: the subject's CYP3A4 genotype and bleeding history. The CYP3A4 genotype is selected from three options: no CYP3A4 mutation site, carrying one CYP3A4 mutation site, and carrying two CYP3A4 mutation sites. The value assignment unit includes parallel CYP3A4 genotype subunits and bleeding history subunits, assigned values ​​as follows: In the CYP3A4 genotype subunit, if the CYP3A4 genotype has no CYP3A4 mutation site, the score is 0; if the CYP3A4 genotype has one CYP3A4 mutation site, the score is 1; if the CYP3A4 genotype has two CYP3A4 mutation sites, the score is 2. In the bleeding history subunit, if no bleeding events have occurred within the past five years, the score is 0. If the score is 1, then the score is 1. Here, "no CYP3A4 mutation site" means rs3735451 is TT and rs2246709 is AA; "one CYP3A4 mutation site" means rs3735451 is TC or rs2246709 is GA; "two CYP3A4 mutation sites" means rs3735451 is CC, rs2246709 is GG, or rs3735451 is TC and rs2246709 is GA. The efficacy prediction unit accepts the assignment from the assignment unit and predicts the bleeding risk of rivaroxaban anticoagulation based on the total score. The total score is 3 points: if the C&B score is ≤1 point, the patient's bleeding risk with rivaroxaban is considered acceptable, and rivaroxaban can be chosen as an anticoagulant factor X inhibitor; if the C&B score is ≥2 points, the bleeding risk with rivaroxaban is considered high, and warfarin can be chosen for anticoagulation therapy.

2. The system according to claim 1, characterized in that, The subjects of the study were patients who had been using rivaroxaban for anticoagulation for a long time.

3. The application of the system for predicting bleeding risk from rivaroxaban anticoagulation according to claim 1 or 2 in guiding the selection of anticoagulation factor X inhibitors to balance anticoagulation efficacy and bleeding risk in patients.

4. According to the application described in claim 3, if the C&B score is ≤1, rivaroxaban is used as an anticoagulation factor X inhibitor for anticoagulation therapy; if the C&B score is ≥2, warfarin is selected for anticoagulation therapy.

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