Applying Pharmacogenetics to Warfarin Dosing in Chinese Patients

NCT ID: NCT01610141

Last Updated: 2013-10-09

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 500 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-06-30
• Study Completion Date: 2015-06-30

Brief Summary

The purpose of this study is to determine whether pharmacogenetic guided dosing of warfarin is promising for the improvement of efficiency, therapeutic efficacy, and, especially, safety of warfarin therapy than a dosing regimen without the pharmacogenetic information in Chinese patients initiated on warfarin anticoagulation.

Detailed Description

Warfarin is the most widely used oral anticoagulation drug for preventing and treating thromboembolic events, but there is greater than 10-fold interindividual variability in the dose required to attain a therapeutic response. In 2007, the US Food and Drug Administration updated the label of warfarin, recommending consideration of pharmacogenetic information which has been confirmed to contribute significantly to the variability in warfarin dose requirements. Thereafter, multiple pharmacogenetic dosing algorithms were constructed to predict warfarin dose by integrating clinical and genetic factors. Taken together, approximately between one-third and one- half of the variability in warfarin dose could be explained by the proposed algorithms. However, the potential benefit of these dosing algorithms in terms of their safety and clinical utility has not been adequately investigated in randomised settings in Chinese patients.

Study objectives:

1. To apply routine pharmacogenetic (PG)-guided dosing of warfarin in clinical practice in Chinese patients.

2. To compare the percentage out-of-range (%OOR) International Normalized Ratios (INRs) during the first 3 month of warfarin therapy using PG-guided dosing with historical standard (STD), empiric dosed controls.

3. To compare the cost effectiveness, number of thromboembolic and bleeding events, time within therapeutic INR range, time to reach stable dose and number of supratherapeutic INR peaks during the first 3 month of warfarin therapy using PG-guided dosing with historical standard (STD), empiric dosed controls.

Study design:

This is a prospective, randomized study of Chinese patients who are to initiate chronic warfarin anticoagulation for specific, qualifying clinical reasons (i.e., atrial fibrillation, Deep vein thrombosis/pulmonary embolism, or Prosthetic valve replacement). Qualifying patients will be consented and randomized to an individualized, pharmacogenetic guided warfarin-dosing regimen (PG group) or to standard care (without knowledge of genotype)(STD group). All patients will receive a baseline INR. For patients in PG group, a maintenance dose for each patient will be predicted by the pharmacogenetic algorithm derived previously in Chinese. A maintenance dose of 3 mg/day will designed to each patients in STD group. The starting dose of warfarin that is twice the assigned daily maintenance dose will be prescribed on the first and second days, and then the dose will revert to the assigned maintenance dose.

Study duration:

Each patient will participate for at least 3 months.

Conditions

Atrial Fibrillation; Deep Vein Thrombosis; Pulmonary Embolism; Heart Valve Disease

Keywords

warfarin metabolism; pharmacogenetics; CYP2C9; genotyping; VKORC1; CYP4F2; anticoagulation; atrial fibrillation; deep vein thrombosis; pulmonary embolism; Artificial Heart Valve

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Genotype-guided warfarin dosing

A pharmacogenetic dosing algorithm including clinical factors and genotype information (VKORC1, CYP2C9 and CYP4F2) will be used to determine warfarin doses.

Group Type: EXPERIMENTAL

Genotype-guided warfarin dosing

Intervention Type: OTHER

Applying a Pharmacogenetic-guided warfarin dosing algorithm derived from Chinese to determine the daily maintenance dose of warfarin, based on clinical factors (age, sex, body surface area, etc.), and VKORC1, CYP2C9 and CYP4F2 genotypes, to individualize the dosing of warfarin.

Non-genotype guided warfarin dosing

A fixed warfarin dose of 3 mg/day was given to the patients for at least 3 days. Following doses were adjusted according to the INR measurement.

Group Type: ACTIVE_COMPARATOR

Non-genotype guided warfarin dosing

Intervention Type: OTHER

A Empiric fixed warfarin dose of 3 mg/day was given to the patients for at least 3 days. Following doses were adjusted according to the INR measurement.

Interventions

Genotype-guided warfarin dosing

Applying a Pharmacogenetic-guided warfarin dosing algorithm derived from Chinese to determine the daily maintenance dose of warfarin, based on clinical factors (age, sex, body surface area, etc.), and VKORC1, CYP2C9 and CYP4F2 genotypes, to individualize the dosing of warfarin.

Intervention Type: OTHER

Non-genotype guided warfarin dosing

A Empiric fixed warfarin dose of 3 mg/day was given to the patients for at least 3 days. Following doses were adjusted according to the INR measurement.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Patients ≥18 years old
• Patients initiated on warfarin for venous thromboembolism, pulmonary embolism, atrial fibrillation or heart valve replacement that require long- term oral anticoagulation with target INR ranged 1.5-3.0 for at least 3 months
• Ability to attend scheduled visits
• Signed informed consent

Exclusion Criteria

• Non-eligible subject
• Pregnant,lactating or of child-bearing potential women
• Patients with severe co-morbidities (e.g., renal insufficiency/creatinine > 2.5 mg/dL,hepatic insufficiency, active malignancy, terminal disease)
• Known genotype CYP2C9 or VKORC1 at start of the study

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Chinese PLA General Hospital

OTHER

Sponsor Role: lead

Responsible Party

Tong Yin

Institute of Geriatric Cardiology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Tong Yin, Dr.

Role: PRINCIPAL_INVESTIGATOR

Institute of Geriatric Cardiology, General Hospital of People's Liberation Army, Beijing China

Locations

Institute of geriatric Cardiology, General Hospital of People's Liberation Army

Beijing, , China

Site Status: RECRUITING

Countries

China

Central Contacts

Tong Yin, Dr.

Role: CONTACT

Phone: 86-13693693085

Email: yintong2000@yahoo.com

Xiaoqi Li, Dr.

Role: CONTACT

Phone: 86-15901075996

Email: xiaoqili_2012@126.com

Facility Contacts

Tong Yin, Dr.

Role: primary

Xiaoqi Li, Dr.

Role: backup

References

Liu Y, Yang J, Xu Q, Xu B, Gao L, Zhang Y, Zhang Y, Wang H, Lu C, Zhao Y, Yin T. Comparative performance of warfarin pharmacogenetic algorithms in Chinese patients. Thromb Res. 2012 Sep;130(3):435-40. doi: 10.1016/j.thromres.2012.02.003. Epub 2012 Feb 27.

Reference Type: BACKGROUND

PMID: 22374335 (View on PubMed)

Other Identifiers

NSFC-30971259

Identifier Type: -

Identifier Source: org_study_id