Clinical trial NCT03797534: Individualized Administration of Warfarin by Polymorphisms of VKORC1 and CYP2C9 Genes
Official title: Individualized Administration of Warfarin by Polymorphisms of VKORC1 and CYP2C9 Genes:A Randomized Controlled Trial, Multi-center Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Heart Valve Prosthesis
Keywords: warfarin
gene
Lead sponsor: Fujian Medical University
Sponsor class: OTHER
First posted: 2019-01-09
Enrollment: 600
Sex: ALL
Minimum age (years): 14
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: The purpose of this study is to explore the individualized administration model of warfarin suitable for Chinese people, and provide a scientific reference for the use of warfarin to Chinese people.

Detailed description: About 600 patients with VKORC1 and CYP2C9 gene mutations were included in the treatment of warfarin anticoagulant therapy. The main indications include valve replacement, atrial fibrillation, pulmonary embolism, etc., randomly divided into 2 groups, respectively, the control group (that is, the use of fixed-dose group), Bayesian-model group, the use of single-blind treatment method, to evaluate the number of major adverse events, TTR and INR adjustments in patients between different groups after three months of taking warfarin, and then to explore the individualized drug use model of warfarin suitable for Chinese population.

In the Bayesian group, according to the genotype of VKORC1 and CYP2C9, the stable dose was calculated by the dose prediction model of Bayesian, and the first three drugs were taken at this dose, and then adjusted to the actual stable dose according to the change of INR. Meanwhile, the control group was administered according to the traditional way, that is, the initial dose is 2.5 or 3mg/d and is gradually adjusted to a stable dose according to changes of INR. The monitoring frequency of INR is: once a day from the beginning of the drug to the time of discharge, once a week after discharge, and once a month after the stable dose is obtained. Detailed records of the number of days to reach a stable dose, the INR value and the occurrence of side effects and time are documented. The concrete steps are as follows:

1. clinicians to judge the standard of the selection criteria;
2. to obtain the consent of the patient and sign an informed consent certificate;
3. to collect 2ml anticoagulant blood before the drug, fill in the application form for individualized drug use in warfarin, and indicate the experimental group and control group;
4. the specimen assigned to the laboratory for Genotyping;
5. lab to calculate the predicted stable warfarin dose and the results fed back to the clinician within one working day after receiving the specimen;
6. in the control group, the drug retained at the regular dose, and the first 3 days of the experimental group administered at the predicted dose;
7. the dosage of warfarin in the two groups of cases adjusted to the stable dose according to the value, and the adjustment amplitude of the experimental group also referred to the predicted stable dose.
8. to monitor INR once a day during hospitalization, and to those who do not receive a stable dose of discharge, follow up and monitor INR once a week until a stable dose or medication is obtained for 90 days;
9. to document clinical trial records, including the daily use of warfarin, each detection of the appearance of the situation like INR value, bleeding, venous embolism and other side effects.

Finally，according to the outcome parameters,statistical analysis were performed with SPSS 11.5 software. A value of P \< 0.05 was considered statistically significant.

Eligibility criteria: Inclusion Criteria:

1. Age \> 14 years old；
2. Warfarin anticoagulant therapy is required for at least 3 months；
3. The genotype of patient VKORC1 is non-AA, CYP2C9 genotype is non\*1/\*1； the patients who are followed up, regularly monitored for INR and willing to provide peripheral blood for DNA extraction and genetic testing；
4. The patient or family members can understand the research plan and will participate in this study and provide a written informed consent；

Exclusion Criteria:

1. Severe liver dysfunction (ChildPugh ≥ 10);
2. Severe infection, respiratory failure;
3. Severe heart failure ( NYHA ≥ IV);
4. Severe renal insufficiency (Ccr ≤ 20ml / min);
5. Cancer;
6. Diseases of the blood system;
7. Severe pulmonary hypertension (PAPm ≥ 45mmHg);
8. Abnormal thyroid function;
9. Patients with a history of venous thromboembolism, or serious events such as severe bleeding or embolism;
10. Women who are pregnant or breastfeeding;
11. Taking or planning to take other oral anticoagulants;
12. The base INR value is \>1.4;
13. VKORC1, CYP2C9 genotypes are AA, \*1/\*1;
14. Secondary valve replacement surgery;
15. Emergency hospital admission for valve surgery;
16. Diagnosis of coronary atherosclerotic heart disease;
17. Severe mental illness, mental disorder ; -

Primary outcomes:
measure: excessive anticoagulant time ratio
timeFrame: 3 months postoperatively
measure: The occurrence of primary bleeding events
timeFrame: 3 months postoperatively
measure: The occurance of secondary bleeding events
timeFrame: 3 months postoperatively
measure: The occurrence of thrombosis events
timeFrame: 3 months postoperatively
Secondary outcomes:
measure: Percentage of time in therapeutic range
timeFrame: 3 months, 6 months, 12 months postoperatively
measure: The time required to reach the treatment target INR for the first time;
timeFrame: 3 months postoperatively
measure: The time required from the beginning of treatment to the stable dose;
timeFrame: 3 months postoperatively
measure: The percentage of time below the target INR range;
timeFrame: 3 months postoperatively
measure: The percentage of time above the target INR range;
timeFrame: 3 months postoperatively
measure: The number of dose adjustments and the number of INR measured during the first month of treatment;
timeFrame: 3 months postoperatively
measure: The proportion of patients in each group receiving a stable dose after follow-up;
timeFrame: 3 months postoperatively
measure: The proportion of patients in each group having side effects after follow-up
timeFrame: 3 months postoperatively
Other outcomes:
Locations:
city: FuZhou
country: China
facility: the Department of Cardiovascular Surgery
state: Fujian
Study officials:
References:
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