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Low INR to Minimize Bleeding With Mechanical Valves Trial (LIMIT)

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ClinicalTrials.gov Identifier: NCT03636295
Recruitment Status : Recruiting
First Posted : August 17, 2018
Last Update Posted : January 19, 2023
Sponsor:
Collaborator:
Hamilton Health Sciences Corporation
Information provided by (Responsible Party):
Emilie Belley-Cote, Population Health Research Institute

Brief Summary:
This study evaluates the use of a lower INR target (1.5 to 2.5) in patients with a mechanical bileaflet heart valve in the aortic position. This study will inform physicians about whether a lower INR target will decrease the risk of bleeding or increase the risk of blood clot formation and stroke. These results have the potential to reduce the burden of bleeding in patients with a mechanical heart valve who require lifelong warfarin (Coumadin) treatment.

Condition or disease Intervention/treatment Phase
Bleeding Post-mechanical Valve Replacement Thromboembolism Post-mechanical Valve Replacement Drug: Warfarin Phase 3

Detailed Description:

Warfarin (Coumadin) is a blood thinner used to prevent blood clot formation in patients with mechanical heart valves. Blood clots can block blood flow to the brain, heart, or other parts of the body. Mechanical heart valves increases the risk of clot so patients with a mechanical heart valve must take warfarin to reduce their risk of stroke and other blood clot-related problems.

The degree to which warfarin 'works' varies from person to person, and so dosage is determined by measuring each person's response to the drug as an 'international normalized ratio' or INR. A patient with an INR over 1.0 has blood that takes longer to clot than average, and increasing INR values represent increasing time required for blood to clot. While an INR over 1.0 decreases clotting risk, it also increases bleeding risk. It is important to carefully balance these risks.

Specific INR targets have been recommended for patients with a mechanical heart valve, but these recommendations differ between scientific groups and are based on low quality evidence. Recent studies suggest that a lower INR target range than is currently recommended can be used safely. A laboratory study showed that warfarin effectively prevents blood clot formation on mechanical heart valves as long as the INR is 1.5 or above. Two moderately-sized clinical studies showed that an INR target range of 1.5-2.5 resulted in less bleeding than the usual higher target range without increasing blood clot formation or stroke in patients with a newer valve model. Whether we could use a lower INR target range for patients with a mechanical aortic valve remains controversial.

This study evaluates the use of a lower INR target (1.5 to 2.5) in patients with a mechanical bileaflet heart valve in the aortic position. This study will inform physicians about whether a lower INR target will decrease the risk of bleeding or increase the risk of blood clot formation and stroke. These results have the potential to reduce the burden of bleeding in patients with a mechanical heart valve who require lifelong warfarin (Coumadin) treatment.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 2625 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: A prospective, randomized, open-label, blinded end-point (PROBE) clinical trial.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Low INR to Minimize Bleeding With Mechanical Valves Trial
Actual Study Start Date : September 5, 2019
Estimated Primary Completion Date : March 31, 2025
Estimated Study Completion Date : April 30, 2026

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Reduced INR Target
Warfarin therapy will be titrated to a target INR in the range of 1.5 to 2.5.
Drug: Warfarin
Participants in both arms will be on warfarin therapy post-mechanical valve replacement as is standard, but will have different INR target ranges.
Other Name: Coumadin

Active Comparator: Standard INR Target
Warfarin therapy will be titrated to a "standard of care" target INR range.
Drug: Warfarin
Participants in both arms will be on warfarin therapy post-mechanical valve replacement as is standard, but will have different INR target ranges.
Other Name: Coumadin




Primary Outcome Measures :
  1. Thrombosis/thromboembolism [ Time Frame: Through study completion, an expected mean of 2-3 years ]
    Number of patients who have at least one of the following: ischemic stroke, systemic thromboembolism, and valve thrombosis

  2. Major bleeding [ Time Frame: Through study completion, an expected mean of 2-3 years ]

    Number of patients that have bleeding that results in the following:

    1. Death and/or,
    2. Symptomatic bleeding in critical area or organ (e.g. intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, pericardial, or intramuscular with compartment syndrome) and/or,
    3. Bleeding that causes drop of hemoglobin level by 20 g/L or more, or that requires the transfusion of 2 or more units of packed red blood cells or whole blood


Secondary Outcome Measures :
  1. All cause mortality [ Time Frame: Through study completion, an expected mean of 2-3 years ]
    Selected rather than cardiovascular mortality, as cause-specific mortality is often difficult to ascertain or define in complex cardiovascular patients in whom multi-end-organ dysfunction may accompany cardiovascular decline.

  2. All clinically important bleeding [ Time Frame: Through study completion, an expected mean of 2-3 years ]
    Number of patients that experience all clinically important bleeding (major and minor)

  3. Minor bleeding [ Time Frame: Through study completion, an expected mean of 2-3 years ]

    Number of patients that experience a bleed that does not meet major bleeding criteria and leads to at least one of:

    1. Hospital admission
    2. Requires medical or surgical management
    3. Requires interruption or discontinuation of study drug

  4. All stroke [ Time Frame: Through study completion, an expected mean of 2-3 years ]
    Number of patients that experience a strokes, including ischemic stroke, ischemic with secondary transformation, stroke of uncertain classification and hemorrhagic stroke

  5. Ischemic stroke [ Time Frame: Through study completion, an expected mean of 2-3 years ]
    Number of patients that experience an ischemic stroke, defined as focal brain infarction caused by an arterial (or rarely venous) obstruction and as documented by CT/MRI that is normal or shows an infarct in the clinicall expected area

  6. Hemorrhagic stroke [ Time Frame: Through study completion, an expected mean of 2-3 years ]
    Number of patients that experience a hemorrhagic stroke, defined as requiring neuroimaging or autopsy confirmation, and includes two subcategories: primary intracerebral hemorrhage and primary subarachnoid hemorrhage

  7. Type 1, 2 or 3 myocardial infarction [ Time Frame: Through study completion, an expected mean of 2-3 years ]
    Number of patients who experience a type 1, 2 or 3 myocardial infarction

  8. Systemic thromboembolism [ Time Frame: Through study completion, an expected mean of 2-3 years ]
    Number of patients who experience a systemic thromboembolism

  9. Valve thrombosis [ Time Frame: Through study completion, an expected mean of 2-3 years ]
    Number of patients who experience a valve thrombosis

  10. Pulmonary embolism [ Time Frame: Through study completion, an expected mean of 2-3 years ]
    Number of patients who experience a pulmonary embolism

  11. Deep vein thrombosis [ Time Frame: Through study completion, an expected mean of 2-3 years ]
    Number of patients who experience a deep vein thrombosis

  12. New renal replacement therapy [ Time Frame: Through study completion, an expected mean of 2-3 years ]
    Number of patients requiring new renal replacement therapy

  13. Time in therapeutic range [ Time Frame: Through study completion, an expected mean of 2-3 years ]
    The percentage of time the patient's INR was within the target range

  14. Proportion of patients with extreme INR values (>4) [ Time Frame: Through study completion, an expected mean of 2-3 years ]
    The proportion of patients with at least one reported INR value above 4



Information from the National Library of Medicine

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

Inclusion criteria:

  • Age is 18 or older at the time of enrolment
  • Have had a bileaflet mechanical heart valve implant in the aortic position 3 or more months ago
  • Written informed consent from either the patient or substitute decision maker

Exclusion criteria:

  • Has a second implanted mechanical valve (any position)
  • Lower boundary of planned INR range is less than 2.0
  • Pregnant or expecting to become pregnant during the study follow-up
  • On-X Valve

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): NCT03636295


Contacts
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Contact: Emilie Belley-Côté, MD, MSc 905-527-4322 ext 40306 emilie.belley-cote@phri.ca
Contact: Richard Whitlock, MD, PhD 905-527-4322 ext 40306 richard.whitlock@phri.ca

Locations
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Belgium
Universitair Ziekenhuis Leuven Recruiting
Leuven, Belgium, 3000
Principal Investigator: Filip Rega, MD         
Canada, Ontario
Hamilton General Hospital Recruiting
Hamilton, Ontario, Canada, L8L 2X2
Contact: Emilie Belley-Cote, MD    905-527-4322 ext 40306    emilie.belley-cote@phri.ca   
Canada, Quebec
Jewish General Hospital Recruiting
Montréal, Quebec, Canada, H3T 1E2
Contact: Mark Blostein, MD         
Netherlands
Erasmus University Medical Centre Recruiting
Rotterdam, Netherlands, 3015
Principal Investigator: Jolien Roos-Hesselink, MD         
Russian Federation
Meshalkin National Medical Research Center Recruiting
Novosibirsk, Russian Federation
Contact: Alexander Bogachev-Prokophiev, MD         
Spain
Hospital de la Santa Creu i Sant Pau Recruiting
Barcelona, Spain, 08025
Contact: Ekaterine Popova, MD         
Principal Investigator: Juan Carles Souto Andres, MD         
Sponsors and Collaborators
Population Health Research Institute
Hamilton Health Sciences Corporation
Investigators
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Principal Investigator: Emilie Belley-Côté, MD, MSc McMaster University
Publications:
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Responsible Party: Emilie Belley-Cote, Principal Investigator, Population Health Research Institute
ClinicalTrials.gov Identifier: NCT03636295    
Other Study ID Numbers: 5139
First Posted: August 17, 2018    Key Record Dates
Last Update Posted: January 19, 2023
Last Verified: January 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: We will establish a plan for the full-scale study but there is no plan to make IPD available to other researchers.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Emilie Belley-Cote, Population Health Research Institute:
Mechanical valve replacement
Vitamin K antagonist
INR targets
Bleeding
Thromboembolism
Additional relevant MeSH terms:
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Thromboembolism
Hemorrhage
Pathologic Processes
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Warfarin
Anticoagulants