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

NCT00401414 | Completed Results DMC

• 1 other identifier: 2006-P-001896
• Study Type: interventional
• Target: 344
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Pulmonary Embolism; Deep Vein Thrombosis; Atrial Fibrillation

Keywords

Warfarin; Thrombosis; Genetics; Nomogram; Pulmonary Embolism; Deep Vein Thrombosis; Dosing; INR; Anticoagulation; Therapy; Orthopedic Surgery

Outcome Measures

Primary Outcomes (1)

• Mean Percentage of Time That INR Within Therapeutic Range Using Linear Interpolation (Rosendaal et al).

  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.

  90 Days

Secondary Outcomes (4)

• Time to the First Therapeutic INR.

  90 Days

• Per-patient Percentage of INRs Out of the Therapeutic Range

  90 Days

• Time to Stable Anticoagulation (in Days).

  90 Days

• Proportion of Patients With Serious Adverse Clinical Events.

  90 Days

Study Arms (1)

Warfarin

EXPERIMENTAL

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

Interventions

Warfarin DRUG

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

Warfarin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Brigham and Women's Hospital: lead
• Massachusetts General Hospital: collaborator
• Newton-Wellesley Hospital: collaborator
• Spaulding Rehabilitation Hospital: collaborator

Study Sites (2)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Related Publications (10)

• 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. doi: 10.1136/bmj.288.6426.1268.

  PMID: 6424820 BACKGROUND

• Cooper MW, Hendra TJ. Prospective evaluation of a modified Fennerty regimen for anticoagulating elderly people. Age Ageing. 1998 Sep;27(5):655-6. doi: 10.1093/ageing/27.5.655. No abstract available.

  PMID: 12675109 BACKGROUND

• Nebert DW, Russell DW. Clinical importance of the cytochromes P450. Lancet. 2002 Oct 12;360(9340):1155-62. doi: 10.1016/S0140-6736(02)11203-7.

  PMID: 12387968 BACKGROUND

• 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. doi: 10.1016/S0140-6736(98)04474-2.

  PMID: 10073515 BACKGROUND

• 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. doi: 10.1001/jama.287.13.1690.

  PMID: 11926893 BACKGROUND

• 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. doi: 10.1016/s0002-9149(02)02883-7. No abstract available.

  PMID: 12480055 BACKGROUND

• 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. doi: 10.1016/j.amjcard.2005.03.104.

  PMID: 16098319 BACKGROUND

• 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. doi: 10.1160/TH04-02-0083.

  PMID: 15175798 BACKGROUND

• 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. doi: 10.1160/TH04-08-0542.

  PMID: 15841315 BACKGROUND

• 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. doi: 10.1056/NEJMoa044503.

  PMID: 15930419 BACKGROUND

Related Links

• North American Thrombosis Forum

MeSH Terms

Conditions

Pulmonary Embolism; Venous Thrombosis; Atrial Fibrillation; Thrombosis

Interventions

Warfarin

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Embolism; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Heart Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Mark A. Creager
• Organization: Brigham and Women's Hospital

mcreager@partners.org

617-732-5267

Study Officials

• Mark A Creager, MD

  Brigham and Women's Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Vascular Center

Study Record Dates

• First Submitted: November 16, 2006
• First Posted: November 20, 2006
• Study Start: January 1, 2007
• Primary Completion: June 1, 2011
• Study Completion: June 1, 2011
• Last Updated: August 30, 2013
• Results First Posted: August 30, 2013

Record last verified: 2013-07

Locations

US (2)