Study to Develop a Reliable Nomogram That Incorporates Clinical and Genetic Information - Full Text View

Sponsor:	Brigham and Women's Hospital
Collaborators:	Massachusetts General Hospital Newton-Wellesley Hospital Spaulding Rehabilitation Hospital
Information provided by:	Brigham and Women's Hospital
ClinicalTrials.gov Identifier:	NCT00401414

Purpose

In this research study, the investigators are trying to find a better way to set the dose of a common blood-thinning medication.

Patients with blood clots or a risk of blood clots (or stroke) sometimes have to take an approved medication called warfarin. Warfarin is a commonly prescribed, approved blood thinning medicine taken by mouth. There is a certain level of warfarin that is best for each patient at a particular time. It is hard for a doctor to choose and maintain the right dose of warfarin for each patient. Too much or too little warfarin in the blood can cause serious health problems.

A "nomogram" is a tool that helps doctors decide on the right dose of warfarin. The usual way for finding the right dose of warfarin is for doctors to take an educated guess and use a "trial and error" approach. Patients have frequent blood tests to help doctors keep track of how well the dose level is working.

Up until now, if a patient had good blood test results over half of the time, that was as well as doctors could do. The purpose of this study is to see whether the investigators can create a reliable new warfarin nomogram that will allow them to dose a patient correctly more often, perhaps about 3 times out of 4. The nomogram the investigators are studying uses information about a patient's health and genes to decide on the best dose of warfarin.

The investigators don't yet have a reliable, safe way to choose the correct dose. In this study, the investigators will use a genetic blood test to try to find a better way. Genes are the parts of each living cell that allow characteristics to be passed on from parents to children. The investigators know that people with certain genes seem to respond to warfarin in a certain way. From a blood sample, the investigators can look at patients' genes and try to predict the response to the blood-thinning medication.

There will be about 500 subjects taking part in this study. They will come from participating Partners' Hospitals, including Brigham and Women's Hospital, Massachusetts General Hospital, Faulkner Hospital, Newton-Wellesley Hospital, Spaulding Rehabilitation Hospital, and North Shore Medical Center. The U.S. Food and Drug Administration (FDA) has approved warfarin for use as a blood thinner.

Condition	Intervention
Pulmonary Embolism Deep Vein Thrombosis Atrial Fibrillation	Drug: Warfarin

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	CReating an Optimal Warfarin Nomogram (CROWN) Trial

Resource links provided by NLM:

Genetics Home Reference related topics: Brugada syndrome familial atrial fibrillation short QT syndrome Help Me Understand Genetics

MedlinePlus related topics: Atrial Fibrillation Blood Thinners Deep Vein Thrombosis Pulmonary Embolism

Drug Information available for: Warfarin Warfarin sodium Warfarin potassium

U.S. FDA Resources

Further study details as provided by Brigham and Women's Hospital:

Primary Outcome Measures:

Primary end point: mean percentage of time that INR within therapeutic range using linear interpolation (Rosendaal et al). [ Time Frame: 90 Days ] [ Designated as safety issue: No ]
Primary end point: mean percentage of time INR is within therapeutic range. Though target INR was 2.0-3.0, therapeutic INR is considered 1.8-3.2 (allows for INR measurement error and avoids problems inherent in overcorrection). Secondary end points: 1) time to first therapeutic INR, 2) per-patient percentage of INRs out of therapeutic range, 3) time to stable anticoagulation, and 4) proportion of patients with serious adverse clinical events, defined as INR > 4.0, use of vitamin K, major bleeding events thromboembolic events, stroke (all cause), myocardial infarction, and death (all cause).

Estimated Enrollment:	500
Study Start Date:	January 2007
Study Completion Date:	June 2011
Primary Completion Date:	June 2011 (Final data collection date for primary outcome measure)

Intervention Details:

2 mg tablets take as directed by study staff (based on INR)

Show Detailed Description

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Age ≥ 18 years old
Any newly diagnosed condition that will require treatment with therapeutic doses of warfarin for at least 4-6 weeks, e.g. deep venous thrombosis (DVT), pulmonary embolism (PE), atrial fibrillation (AF), orthopedic surgery, etc.
Written informed consent

Exclusion Criteria:

Current treatment with warfarin
Contraindication to therapeutic anticoagulation:
- Active major bleeding
- History of intracranial bleeding
- Surgery, delivery, organ biopsy within 3 days
- Gastrointestinal bleeding within 10 days
- Major trauma within 3 days
- Head injury requiring hospitalization within 3 months
- Intracranial tumor
- Neurosurgery or ophthalmologic surgery within the past month
Life expectancy < 3 months
Pregnancy

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00401414

Locations

United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114

Sponsors and Collaborators

Brigham and Women's Hospital

Massachusetts General Hospital

Newton-Wellesley Hospital

Spaulding Rehabilitation Hospital

Investigators

Principal Investigator:

Mark A Creager, MD

Brigham and Women's Hospital

More Information

Additional Information:

North American Thrombosis Forum This link exits the ClinicalTrials.gov site

Publications:

Fennerty A, Dolben J, Thomas P, Backhouse G, Bentley DP, Campbell IA, Routledge PA. Flexible induction dose regimen for warfarin and prediction of maintenance dose. Br Med J (Clin Res Ed). 1984 Apr 28;288(6426):1268-70.

Cooper MW, Hendra TJ. Prospective evaluation of a modified Fennerty regimen for anticoagulating elderly people. Age Ageing. 1998 Sep;27(5):655-6. No abstract available.

Nebert DW, Russell DW. Clinical importance of the cytochromes P450. Lancet. 2002 Oct 12;360(9340):1155-62. Review.

Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet. 1999 Feb 27;353(9154):717-9.

Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh SL, Farin FM, Rettie AE. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA. 2002 Apr 3;287(13):1690-8.

Joffe HV, Goldhaber SZ. Effectiveness and safety of long-term anticoagulation of patients >/=90 years of age with atrial fibrillation. Am J Cardiol. 2002 Dec 15;90(12):1397-8. No abstract available.

Fanikos J, Grasso-Correnti N, Shah R, Kucher N, Goldhaber SZ. Major bleeding complications in a specialized anticoagulation service. Am J Cardiol. 2005 Aug 15;96(4):595-8.

Joffe HV, Xu R, Johnson FB, Longtine J, Kucher N, Goldhaber SZ. Warfarin dosing and cytochrome P450 2C9 polymorphisms. Thromb Haemost. 2004 Jun;91(6):1123-8.

Voora D, Eby C, Linder MW, Milligan PE, Bukaveckas BL, McLeod HL, Maloney W, Clohisy J, Burnett RS, Grosso L, Gatchel SK, Gage BF. Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype. Thromb Haemost. 2005 Apr;93(4):700-5.

Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, Blough DK, Thummel KE, Veenstra DL, Rettie AE. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med. 2005 Jun 2;352(22):2285-93.

Responsible Party:	Mark A. Creager, MD, Brigham and Women's Hospital
ClinicalTrials.gov Identifier:	NCT00401414 History of Changes
Other Study ID Numbers:	2006-P-001896
Study First Received:	November 16, 2006
Last Updated:	June 24, 2011
Health Authority:	United States: Institutional Review Board

Keywords provided by Brigham and Women's Hospital:

Warfarin
Thrombosis
Genetics
Nomogram
Pulmonary Embolism
Deep Vein Thrombosis

Dosing
INR
Anticoagulation
Therapy
Orthopedic Surgery

Additional relevant MeSH terms:

Atrial Fibrillation
Embolism
Pulmonary Embolism
Thrombosis
Venous Thrombosis
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes

Embolism and Thrombosis
Vascular Diseases
Lung Diseases
Respiratory Tract Diseases
Warfarin
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on February 09, 2012