The Effect of Medication Timing on Anticoagulation Stability in Users of Warfarin: The "INRange" RCT

NCT02376803 | Completed Phase 4

• 1 other identifier: INRange
• Study Type: interventional
• Target: 217
• Locations: 1 country
• Sites: 2

Brief Summary

Warfarin is an anticoagulant medication that is highly effective at preventing clotting disorders but which has a narrow therapeutic window. If warfarin is under effective patients are at risk of stroke, if it is over effective patients are at risk of bleeding complications. Physicians routinely and regularly measure a blood test (called the "INR") that determines the effectiveness of warfarin and have a range of test values (the "therapeutic range") in which they try to keep the patient. By convention warfarin is taken at dinnertime, however this is the same time of day that highly variable consumption of dietary vitamin K occurs (found largely in green leafy vegetables) and vitamin K alters the effectiveness of warfarin. Given vitamin K has a very short half-life (i.e. it is only active for a short period of time after it is ingested) it may make more sense to take warfarin in the morning (when very little vitamin K is ingested) to produce a more consistent drug effect. The purpose of this study is to determine whether switching current warfarin users from evening to morning dosing decreases time spent outside the therapeutic INR range.

Conditions

Atrial Fibrillation; Thrombus Due to Heart Valve Prosthesis; Deep Venous Thrombosis; Thromboembolism; DVT

Keywords

Randomized controlled trial; Warfarin; Time in therapeutic range; Bleeding; Thromboembolic; Hemorrhage; Anticoagulant; TTR; Chronobiology; Chronotherapeutic; Coumadin; INR; International normalized ratio; RCT

Outcome Measures

Primary Outcomes (1)

• Percentage change in time spent OUTSIDE of therapeutic range

  Our primary outcome, percentage change in time spent OUTSIDE of therapeutic range is chosen because we believe this is a measure more likely to be shared by patients across a wide range of TTR (i.e. a patient with high baseline TTR and a patient with low baseline TTR may still share a similar % change in time outside of therapeutic range as a response to our intervention). This would not be true for change in TTR itself. It is also the time spent outside of range which contributes more directly to risk of thrombosis and hemorrhage and hence the change in this measure is more clinically meaningful than the change in TTR itself.

  7 months

Secondary Outcomes (6)

• Percentage change in time in therapeutic range (TTR)

  7 months

• Percentage of patients with TTR > 75%

  7 months

• Percentage of patients with TTR < 60%

  7 months

• Major warfarin related cardiovascular events

  7 months

• Maximum observed INR

  7 months

Other Outcomes (3)

• Major thromboembolic events

  7 months

• Major bleeding events

  7 months

• Allocation adherence

  7 months

Study Arms (2)

Morning warfarin ingestion

EXPERIMENTAL

Patients switch from taking warfarin in the evening to taking warfarin in the morning.

Drug: Warfarin

Evening warfarin ingestion

ACTIVE COMPARATOR

Patients continue taking warfarin in the evening as per their usual routine.

Drug: Warfarin

Interventions

Warfarin DRUG

Morning vs Evening administration

Also known as: Coumadin

Evening warfarin ingestion; Morning warfarin ingestion

Eligibility Criteria

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

You may qualify if:

• Dinner or evening use of warfarin
• ≥ 3 months of continuous warfarin use
• Expectation of long-term warfarin use
• Baseline INR data made available by family physician
• Community dwelling

You may not qualify if:

• Patient is palliative
• Patient is unable to provide informed consent

Sponsors & Collaborators

• University of Alberta: lead
• Vancouver Coastal Health Research Institute: collaborator

Study Sites (2)

University of Alberta

Edmonton, Alberta, T6G 2C8, Canada

Location

Vancouver Coastal Health Research Institute

Vancouver, British Columbia, V5Z 1M9, Canada

Location

Related Publications (8)

• Hirsh J, Fuster V, Ansell J, Halperin JL; American Heart Association; American College of Cardiology Foundation. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation. 2003 Apr 1;107(12):1692-711. doi: 10.1161/01.CIR.0000063575.17904.4E. No abstract available.

  PMID: 12668507 BACKGROUND

• van Walraven C, Jennings A, Oake N, Fergusson D, Forster AJ. Effect of study setting on anticoagulation control: a systematic review and metaregression. Chest. 2006 May;129(5):1155-66. doi: 10.1378/chest.129.5.1155.

  PMID: 16685005 BACKGROUND

• Hylek EM. Vitamin K antagonists and time in the therapeutic range: implications, challenges, and strategies for improvement. J Thromb Thrombolysis. 2013 Apr;35(3):333-5. doi: 10.1007/s11239-013-0900-5.

  PMID: 23456572 BACKGROUND

• UpToDate. Antithrombotic therapy to prevent embolization in atrial fibrillation. 2014; http://www.uptodate.com. Accessed June 6, 2014.

  BACKGROUND

• Franco V, Polanczyk CA, Clausell N, Rohde LE. Role of dietary vitamin K intake in chronic oral anticoagulation: prospective evidence from observational and randomized protocols. Am J Med. 2004 May 15;116(10):651-6. doi: 10.1016/j.amjmed.2003.12.036.

  PMID: 15121490 BACKGROUND

• Olson RE. The function and metabolism of vitamin K. Annu Rev Nutr. 1984;4:281-337. doi: 10.1146/annurev.nu.04.070184.001433.

  PMID: 6380538 BACKGROUND

• Hansson L, Hedner T, Dahlof B. Prospective randomized open blinded end-point (PROBE) study. A novel design for intervention trials. Prospective Randomized Open Blinded End-Point. Blood Press. 1992 Aug;1(2):113-9. doi: 10.3109/08037059209077502.

  PMID: 1366259 BACKGROUND

• Heran BS, Allan GM, Green L, Korownyk C, Kolber M, Olivier N, Flesher M, Garrison S. Effect of medication timing on anticoagulation stability in users of warfarin (the INRange RCT): study protocol for a randomized controlled trial. Trials. 2016 Aug 4;17(1):391. doi: 10.1186/s13063-016-1516-9.

  PMID: 27488365 DERIVED

MeSH Terms

Conditions

Atrial Fibrillation; Venous Thrombosis; Thromboembolism; Hemorrhage

Interventions

Warfarin

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

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

Study Officials

• Scott R Garrison, MD PhD

  University of Alberta

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: February 25, 2015
• First Posted: March 3, 2015
• Study Start: February 1, 2015
• Primary Completion: September 30, 2016
• Study Completion: April 27, 2018
• Last Updated: May 4, 2018

Record last verified: 2018-05

Data Sharing

• IPD Sharing: Will share

Locations

CA (2)