Clinical trial NCT01610141: Applying Pharmacogenetics to Warfarin Dosing in Chinese Patients
Official title: Applying Pharmacogenetics to Warfarin Dosing in Chinese Patients
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
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
Lead sponsor: Chinese PLA General Hospital
Sponsor class: OTHER
First posted: 2012-06-01
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: A comparison between the pharmacogenetic and standard arms of the per-patient percentage of out-of-range INRs (<1.5, >3).
timeFrame: 3 months
Secondary outcomes:
measure: Time to the first supratherapeutic INR
timeFrame: 3 months
measure: The proportion of time within the therapeutic INR range
timeFrame: 3 months
measure: The proportion of patients reaching therapeutic INR on days 5 and 8
timeFrame: 3 months
measure: The total number of INR measurements and number of dose adjustments made
timeFrame: 3 months
measure: Proportion of INRs > 4
timeFrame: 3 months
measure: Major bleeding events
timeFrame: 3 months
measure: Minor bleeding events
timeFrame: 3 months
measure: Thromboembolic complications
timeFrame: 3 months
Other outcomes:
Locations:
city: Beijing
country: China
facility: Institute of geriatric Cardiology, General Hospital of People's Liberation Army
Study officials:
affiliation: Institute of Geriatric Cardiology, General Hospital of People's Liberation Army, Beijing China
name: Tong Yin, Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.