Applying Pharmacogenetics to Warfarin Dosing in Chinese Patients

Atrial Fibrillation Clinical Trial

Official title:

Applying Pharmacogenetics to Warfarin Dosing in Chinese Patients

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01610141
• Other study ID #: NSFC-30971259
• Status: Recruiting
• Phase: Phase 4
• First received: May 30, 2012
• Last updated: October 7, 2013
• Start date: June 2012
• Est. completion date: June 2015

Study information

• Verified date: October 2013
• Source: Chinese PLA General Hospital
• Contact: Tong Yin, Dr.
• Phone: 86-13693693085
• Email: yintong2000[@]yahoo.com
• Is FDA regulated: No
• Health authority: China: National Natural Science Foundation
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 500
• Est. completion date: June 2015
• Est. primary completion date: June 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Atrial Fibrillation
• Deep Vein Thrombosis
• Embolism
• Heart Valve Disease
• Heart Valve Diseases
• Pulmonary Embolism
• Thrombosis
• Venous Thrombosis

Intervention

Other:
• 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.
• 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.

Locations

Country	Name	City	State
China	Institute of geriatric Cardiology, General Hospital of People's Liberation Army	Beijing

Sponsors (1)

Lead Sponsor	Collaborator
Chinese PLA General Hospital

Country where clinical trial is conducted

China, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	A comparison between the pharmacogenetic and standard arms of the per-patient percentage of out-of-range INRs (<1.5, >3).		3 months	Yes
Secondary	Time to the first supratherapeutic INR		3 months	Yes
Secondary	The proportion of time within the therapeutic INR range		3 months	No
Secondary	The proportion of patients reaching therapeutic INR on days 5 and 8		3 months	No
Secondary	The total number of INR measurements and number of dose adjustments made		3 months	No
Secondary	Proportion of INRs > 4		3 months	Yes
Secondary	Major bleeding events		3 months	Yes
Secondary	Minor bleeding events		3 months	Yes
Secondary	Thromboembolic complications		3 months	Yes