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Study to Develop a Reliable Nomogram That Incorporates Clinical and Genetic Information

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00401414
First Posted: November 20, 2006
Last Update Posted: August 30, 2013
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
Massachusetts General Hospital
Newton-Wellesley Hospital
Spaulding Rehabilitation Hospital
Information provided by (Responsible Party):
Mark Alan Creager, MD, Brigham and Women's Hospital
  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
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: CReating an Optimal Warfarin Nomogram (CROWN) Trial

Resource links provided by NLM:


Further study details as provided by Mark Alan Creager, MD, Brigham and Women's Hospital:

Primary Outcome Measures:
  • Mean Percentage of Time That INR Within Therapeutic Range Using Linear Interpolation (Rosendaal et al). [ Time Frame: 90 Days ]

    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).

    The international normalized ratio (INR) is one way of presenting prothrombin time test results for people taking the blood-thinning medication warfarin. The INR formula adjusts for variation in laboratory testing methods so that test results can be comparable.



Secondary Outcome Measures:
  • Time to the First Therapeutic INR. [ Time Frame: 90 Days ]
    The INR (international normalized ratio) is a derived measure of the prothrombin time. In this trial, a therapeutic INR was considered 1.8 to 3.2

  • Per-patient Percentage of INRs Out of the Therapeutic Range [ Time Frame: 90 Days ]
    The INR (international normalized ratio) is a derived measure of the prothrombin time. In this trial, a therapeutic INR was considered 1.8 to 3.2

  • Time to Stable Anticoagulation (in Days). [ Time Frame: 90 Days ]
    Defined as two consecutive INRs within the therapeutic range >7 days apart and with no dose change during this time.

  • Proportion of Patients With Serious Adverse Clinical Events. [ Time Frame: 90 Days ]
    Defined as an INR>4.0, use of vitamin K, major bleeding events (as defined by the Thrombolysis in Myocardial Infarction [TIMI] criteria), thromboembolic events, stroke (all cause), myocardial infarction, and death (all cause).


Enrollment: 344
Study Start Date: January 2007
Study Completion Date: June 2011
Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Warfarin
We will develop a nomogram for warfarin dosing that uses rapid turnaround genetic testing and monthly nomogram modification (if necessary) to achieve effective and safe warfarin induction and maintenance. More than 70% of the time, we will maintain warfarin naïve patients within the target therapeutic range. The percent of time in the therapeutic range will be analyzed beginning 2 weeks after initiation of warfarin. Analyses will be stratified by the indication for anticoagulation.
Drug: Warfarin
2 mg tablets take as directed by study staff (based on INR)

  Show Detailed Description

  Eligibility

Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥ 18 years old
  2. 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.
  3. Written informed consent

Exclusion Criteria:

  1. Current treatment with warfarin
  2. 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
  3. Life expectancy < 3 months
  4. Pregnancy
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00401414


Locations
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
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:
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.
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.
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 Alan Creager, MD, Director, Vascular Center, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT00401414     History of Changes
Other Study ID Numbers: 2006-P-001896
First Submitted: November 16, 2006
First Posted: November 20, 2006
Results First Submitted: March 20, 2013
Results First Posted: August 30, 2013
Last Update Posted: August 30, 2013
Last Verified: July 2013

Keywords provided by Mark Alan Creager, MD, 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
Thrombosis
Embolism
Pulmonary Embolism
Venous Thrombosis
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Embolism and Thrombosis
Vascular Diseases
Lung Diseases
Respiratory Tract Diseases
Warfarin
Anticoagulants


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