Genotype-guided Warfarin Individualized Treatment

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the international pharmacogenetic algorithm is better than the standard initiation dosing and whether the two algorithms are suitable for Chinese elderly patients.

Detailed Description
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The study protocol is a multicenter, randomized, patient-blinded and controlled trial, comparing two approaches among 864 enrolled AF(atrial fibrillation) or DVT(deep venous thrombosis) patients for guiding warfarin initial anticoagulation in Chinese elderly patients: the intervention group using the algorithm of International Warfarin Pharmacogenetic Consortium and its dose revision, and the control group using a standard initiation dose (2.25 mg).The study hypothesis is that the intervention group relative to the control group will increase the percentage of time in therapeutic INR (international normalized ratio) range during the first 3 months.This trial is the first prospective large-scale randomized controlled trial for elders in China. It is of great significance for promoting special crowd individualization of anticoagulants at home and abroad.

Official Title
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Pharmacogenetic Algorithm of Response to Warfarin During Initial Anticoagulation in Chinese Elderly Patients

Conditions
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Atrial Fibrillation, Deep Venous Thrombosis

Intervention / Treatment
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* Behavioral: Genotype-guided dosing algorithm for warfarin
* Behavioral: Standard initiation dose for warfarin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria：1) Chinese male or female aged ≥18 years; 2) Requiring at least 12-week warfarin therapy as judged by clinicians; 3) Subjects with DVT/AF and a post-therapy target INR of 1.5-2.5; 4) Capable of providing written informed consent; 5) Capable of maintaining excellent communications with investigators and completing trial in accordance with trial stipulations. Exclusion criteria：1) Subjects previously taking warfarin; 2) Known genotypes of CYP2C9 or/and VKORC1; 3) Subjects receiving or expecting to receive other therapies or other anticoagulants; 4) Subjects with contraindications for warfarin; 5) Subjects with severe cognitive dysfunctions; 6) Baseline INR ≥1.5; 7) Subjects with drug or alcohol dependence within the last 12 months; 8) Subjects receiving blood transfusion or bone marrow transplantation within the last 2 weeks; 9) Planning to receive invasive examinations (except for standard endoscopy) with a hemorrhagic tendency or undergoing surgery during trial.10) Prior to randomization, subjects receiving any trial drug or device within the last 3 months or planning to receive such an investigational therapy during trial; 11) Subjects with the following diagnoses or conditions: active malignant carcinomas (diagnosed within the last 5 years), but excluding adequately-treated non-melanoma skin cancer or other non-invasive or in situ cancer (e.g. cervical cancer in situ); anti-neoplastic therapy within the last 5 years (medication, radiotherapy or/and surgery); overt active disease or infection; life expectancy <6 months; 12）Other clinical reasons for unsuitable recruitment as judged by clinicians.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: genotype-guided group<br>Interventions：on day1 day3, patients received dose according to IWPC formula (PGx-1) included clinical variables and genotype data for VKORC1, CYP2C9*1, CYP2C9*2, and CYP2C9*3; on day4 day7, patients received dose according to Lenzini formula consisted of clinical variables, VKORC1, CYP2C9*2, CYP2C9*3 and previous INR and dosing information (PGx-2); and on day8, the clinicians adjusted the dose according to observed INR.The overall follow-up period is 12 weeks. | Behavioral: Genotype-guided dosing algorithm for warfarin<br>* Intervention：initial dosing of warfarin for the first 3 days of treatment will be determined by IWPC( International Warfarin Pharmacogenetics Consortium) algorithm (PG-1),a second dose adjustment will be made after 3 doses of warfarin using a dose revision algorithm (PG-2) that combined INR values,the dose will be adjusted depending on the measurements of INR values after 7 days.The overall follow-up period is 12 weeks.<br>|
| Active Comparator: control group<br>Interventions：on day1 day3, patients were given initial dose (2.25mg); and starting from day4, the clinicians began to adjust the dose for patients according to observed INR.The overall follow-up period is 12 weeks. | Behavioral: Standard initiation dose for warfarin<br>* Intervention：initial dosing of warfarin for the first 3 days of treatment will be determined by standard initiation dose. Following this initiation dose of warfarin,the dose will be adjusted depending on the measurements of INR values after 3 days.The overall follow-up period is 12 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| %TTR | percentage of time in the therapeutic INR (%TTR) of INR 2-3 (<60 years old) or 1.5-2.5 (≥ 60 years old) within 12 weeks | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the time to reach therapeutic INR | the time to reach therapeutic INR | 12 weeks | 
| the time to reach stable warfarin dose which defined as the dose to achieve INR within ±0.1 of therapeutic range at Day 8 post-dose | the time to reach stable warfarin dose which defined as the dose to achieve INR within ±0.1 of therapeutic range at Day 8 post-dose | 12 weeks | 
| The number of adjustment units in the dose of warfarin (with 0.375 mg (1/8 tablet) as a unit); Incidence of INR ≥ 4 | The number of adjustment units in the dose of warfarin (with 0.375 mg (1/8 tablet) as a unit); Incidence of INR ≥ 4 | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AF or DVT, Age Over 18 Years, Acquired