VKORC1 and CYP2C9 Gene Polymorphisms and Warfarin Management

September 2, 2009 updated by: Ankara University

Evaluation of VKORC1 and Cytochrome P450 CYP2C9 Gene Polymorphisms and Management of Warfarin Dose Using Pharmacogenetic Data

The investigators aimed to use pharmacogenetic information in clinical practise which may lead to rapid, efficient, and safe warfarin dosing in this observational prospective study. In this context, the investigators plan to develop an algorithm for estimating the appropriate warfarin dose that is based on both clinical and genetic data from the Turkish study population. This study is unique not only investigating clinical factors, demographic variables, CYP2C9, and VKORC1 gene variations which contribute to the variability among patients in dose requirements for warfarin but also including thrombogenic single nucleotide polymorphisms (SNP) in the same patient population. Thus, warfarin would be a good example by being the first cardiovascular drug for pharmacogenetic guided "personalized medicine" applications.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Long-term anticoagulation therapy with warfarin is recommended for patients with atrial fibrillation/flutter (AF), left atrial thrombus, deep vein thrombosis (DVT), pulmonary thromboembolism (PE), mechanical heart valve replacement, cardiomyopathy, and ischemic stroke. Warfarin, a coumarin derivative, produces an anticoagulant effect by interfering with the vitamin K 2,3 epoxide reductase (VKOR) enzyme and γ-carboxylation of vitamin K-dependent clotting factors such as II, VII, IX, and X. However, management of warfarin therapy is complicated with interindividual differences in drug response, delayed onset of action, difficulty with reversal and a narrow therapeutic window leading to increased risk of life-threatening hemorrhagic adverse events or thromboembolism. Furthermore, in order to determine safe and effective loading dose during the early phase of therapy and maintenance doses require frequent laboratory monitoring and adjustments to compensate for changes in patients' age, body size, vitamin K intake through diet, disease state, comorbidities, concomitant use of other medications, and patient-specific genetic factors.

Poor anticoagulant control may cause fatal complications such as thromboembolism with undertreatment or bleeding with excessive anticoagulation. Indeed, the risk of major bleeding in patients on warfarin is between 1% and 5% per year. Identifying the optimal therapeutic range and managing the dose of therapy to achieve the maximal time in therapeutic range are two of the most important determinants of therapeutic effectiveness and of reducing hemorrhagic risk. Currently, there have been substantial efforts to improve the safety of warfarin anticoagulation therapy. Recent warfarin pharmacogenetic studies have largely focused on two candidate genes: CYP2C9, responsible for warfarin metabolism, and VKORC1, which encodes vitamin K epoxide reductase, the site of warfarin action. Current evidence is clear that polymorphisms in either CYP2C9 or VKORC1 affect warfarin sensitivity.

We aimed to use pharmacogenetic information in clinical practise which may lead to rapid, efficient, and safe warfarin dosing in this observational prospective study. In this context, we plan to develop an algorithm for estimating the appropriate warfarin dose that is based on both clinical and genetic data from the Turkish study population. This study is unique not only investigating clinical factors, demographic variables, CYP2C9, and VKORC1 gene variations which contribute to the variability among patients in dose requirements for warfarin but also including thrombogenic single nucleotide polymorphisms (SNP) in the same patient population. Thus, warfarin would be a good example by being the first cardiovascular drug for pharmacogenetic guided "personalized medicine" applications.

Study Type

Observational

Enrollment (Anticipated)

500

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Turkey
      • Ankara, Turkey, 06340
        • Recruiting
        • Ankara University Medical Faculty, Department of Cardiovascular Surgery and Pulmonary Disease
        • Contact:
        • Contact:
        • Sub-Investigator:
          • HILAL OZDAG, Assoc. Prof.
        • Sub-Investigator:
          • RUCHAN A AKAR, Assoc. Prof.
        • Sub-Investigator:
          • ALTAY GUVENIR, Prof.
        • Sub-Investigator:
          • ISMAIL SAVAS, Prof.
        • Sub-Investigator:
          • GUNSELI CUBUKCUOGLU DENIZ, MSc
        • Sub-Investigator:
          • UMIT OZYURDA, Prof.
        • Sub-Investigator:
          • HAKAN GURDAL, Prof.
        • Sub-Investigator:
          • GOKHAN H ILK, Assoc. Prof.
        • Sub-Investigator:
          • FILIZ CETINKAYA, BSc

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Patients who require warfarin for at least 6 months under care of cardiovascular surgery, cardiology and pulmonary disease.

Description

Inclusion Criteria:

Patients who require warfarin for at least 6 months with the indications listed below:

  • Permanent Atrial Fibrillation/Flutter
  • Left atrial or ventricular thrombus
  • Deep Vein Thrombosis
  • Pulmonary Embolism
  • Heart Valve Replacement (Mechanical or Biological With AF)
  • Cardiomyopathy (Ischemic or Dilated)
  • Peripheral Vascular Disease

Exclusion Criteria:

  • History of GI bleeding or peptic ulcer disease
  • Significant liver disease, active hepatitis or chronic HBV/HCV infection
  • Uncontrolled hypertension
  • Chronic diarrhea or malabsorption syndrome
  • Viral or bacterial infection prior to enrollment
  • Active or previous infective endocarditis
  • Hospital stay > 30 days as a result of septicemia, mediastinitis or pneumonia
  • Cardiac cachexia
  • Morbid obesity
  • Expected pregnancy, pregnancy or lactation
  • Psychiatric disease
  • Malignancy with Life expectancy less than 1 year

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Warfarin related complications including bleeding and thromboembolism
Time Frame: 6 months
6 months

Secondary Outcome Measures

Outcome Measure
Time Frame
Maximal time in international normalized ratio (INR) therapeutic range and deviation from target INR levels
Time Frame: 6 months
6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Ankara University

Investigators

  • Principal Investigator: Nejat Akar, Prof, Ankara University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2009

Primary Completion (Anticipated)

July 1, 2012

Study Completion (Anticipated)

December 1, 2012

Study Registration Dates

First Submitted

September 2, 2009

First Submitted That Met QC Criteria

September 2, 2009

First Posted (Estimate)

September 3, 2009

Study Record Updates

Last Update Posted (Estimate)

September 3, 2009

Last Update Submitted That Met QC Criteria

September 2, 2009

Last Verified

September 1, 2009

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • B.30.2.ANK.0.20.05.04

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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