VKORC1 and CYP2C9 Gene Polymorphisms and Warfarin Management

The recruitment status of this study is unknown because the information has not been verified recently.
Verified September 2009 by Ankara University.
Recruitment status was  Recruiting
Sponsor:
Information provided by:
Ankara University
ClinicalTrials.gov Identifier:
NCT00970892
First received: September 2, 2009
Last updated: NA
Last verified: September 2009
History: No changes posted
  Purpose

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.


Condition Intervention
Atrial Fibrillation
Cardiac Thrombus
Deep Vein Thrombosis
Pulmonary Embolism
Heart Valve Replacement (Mechanical or Biological With AF)
Cardiomyopathy (Ischemic or Dilated)
Peripheral Vascular Disease
Drug: Warfarin dose titration

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Evaluation of VKORC1 and Cytochrome P450 CYP2C9 Gene Polymorphisms and Management of Warfarin Dose Using Pharmacogenetic Data

Resource links provided by NLM:


Further study details as provided by Ankara University:

Primary Outcome Measures:
  • Warfarin related complications including bleeding and thromboembolism [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Maximal time in international normalized ratio (INR) therapeutic range and deviation from target INR levels [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples With DNA

Blood


Estimated Enrollment: 500
Study Start Date: July 2009
Estimated Study Completion Date: December 2012
Estimated Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Warfarin dose titration
    Dosage
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.

  Eligibility

Ages Eligible for Study:   18 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.

Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00970892

Contacts
Contact: RUCHAN A AKAR, Assoc. Prof. +905336460684 akarruchan@gmail.com
Contact: SERKAN DURDU +905336373535 serkandurdu@gmail.com

Locations
Turkey
Ankara University Medical Faculty, Department of Cardiovascular Surgery and Pulmonary Disease Recruiting
Ankara, Turkey, 06340
Contact: RUCHAN AKAR, Assoc. Prof.    +905336424994    akarruchan@gmail.com   
Contact: SERKAN DURDU    +905336373535    serkandurdu@gmail.com   
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: SERKAN DURDU, MD         
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         
Sponsors and Collaborators
Ankara University
Investigators
Principal Investigator: Nejat Akar, Prof Ankara University
  More Information

No publications provided

Responsible Party: NEJAT AKAR, Prof., Ankara University
ClinicalTrials.gov Identifier: NCT00970892     History of Changes
Other Study ID Numbers: B.30.2.ANK.0.20.05.04
Study First Received: September 2, 2009
Last Updated: September 2, 2009
Health Authority: Turkey: Ethics Committee

Keywords provided by Ankara University:
Anticoagulation
warfarin
VKORC1
CYP2C9
thromboembolism
pharmacogenetics

Additional relevant MeSH terms:
Atrial Fibrillation
Embolism
Pulmonary Embolism
Thrombosis
Vascular Diseases
Venous Thrombosis
Peripheral Vascular Diseases
Peripheral Arterial Disease
Cardiomyopathies
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Embolism and Thrombosis
Lung Diseases
Respiratory Tract Diseases
Atherosclerosis
Arteriosclerosis
Arterial Occlusive Diseases
Warfarin
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 24, 2014