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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

Tracking Information
First Submitted Date  ICMJE July 25, 2018
First Posted Date  ICMJE August 17, 2018
Last Update Posted Date January 19, 2023
Actual Study Start Date  ICMJE September 5, 2019
Estimated Primary Completion Date March 31, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 22, 2022)
  • 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
  • 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
Original Primary Outcome Measures  ICMJE
 (submitted: August 15, 2018)
Recruitment rate [ Time Frame: One year ]
Recruitment 200 subjects at one centre over 1 year
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 22, 2022)
  • 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.
  • 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)
  • 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
  • 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
  • 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
  • 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
  • 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
  • Systemic thromboembolism [ Time Frame: Through study completion, an expected mean of 2-3 years ]
    Number of patients who experience a systemic thromboembolism
  • Valve thrombosis [ Time Frame: Through study completion, an expected mean of 2-3 years ]
    Number of patients who experience a valve thrombosis
  • Pulmonary embolism [ Time Frame: Through study completion, an expected mean of 2-3 years ]
    Number of patients who experience a pulmonary embolism
  • Deep vein thrombosis [ Time Frame: Through study completion, an expected mean of 2-3 years ]
    Number of patients who experience a deep vein thrombosis
  • New renal replacement therapy [ Time Frame: Through study completion, an expected mean of 2-3 years ]
    Number of patients requiring new renal replacement therapy
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: August 15, 2018)
  • Bleeding [ Time Frame: One year ]
    Occurrence of major and minor bleeding events over the course of follow-up
  • Thrombosis/thromboembolism [ Time Frame: One year ]
    Occurrence of systemic thromboembolism, venous thrombosis, pulmonary embolism, and valve thrombosis over the course of follow-up
  • Stroke [ Time Frame: One year ]
    Occurrence of ischemic and hemorrhagic stroke over the course of follow-up
  • Time in INR range [ Time Frame: One year ]
    Percentage of time spent in designated INR range over the course of follow-up
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Low INR to Minimize Bleeding With Mechanical Valves Trial
Official Title  ICMJE Low INR to Minimize Bleeding With Mechanical Valves Trial
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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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
Condition  ICMJE
  • Bleeding Post-mechanical Valve Replacement
  • Thromboembolism Post-mechanical Valve Replacement
Intervention  ICMJE 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
Study Arms  ICMJE
  • Experimental: Reduced INR Target
    Warfarin therapy will be titrated to a target INR in the range of 1.5 to 2.5.
    Intervention: Drug: Warfarin
  • Active Comparator: Standard INR Target
    Warfarin therapy will be titrated to a "standard of care" target INR range.
    Intervention: Drug: Warfarin
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 18, 2023)
2625
Original Estimated Enrollment  ICMJE
 (submitted: August 15, 2018)
200
Estimated Study Completion Date  ICMJE April 30, 2026
Estimated Primary Completion Date March 31, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
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
Listed Location Countries  ICMJE Belgium,   Canada,   Netherlands,   Russian Federation,   Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03636295
Other Study ID Numbers  ICMJE 5139
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
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.
Current Responsible Party Emilie Belley-Cote, Population Health Research Institute
Original Responsible Party Emilie Belley-Cote, McMaster University, Principal Investigator
Current Study Sponsor  ICMJE Population Health Research Institute
Original Study Sponsor  ICMJE McMaster University
Collaborators  ICMJE Hamilton Health Sciences Corporation
Investigators  ICMJE
Principal Investigator: Emilie Belley-Côté, MD, MSc McMaster University
PRS Account Population Health Research Institute
Verification Date January 2023

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP