Low INR to Minimize Bleeding With Mechanical Valves Trial

Overview

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

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: March 31, 2025

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.

Interventions

  • 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.

Arms, Groups and Cohorts

  • Experimental: Reduced INR Target
    • Warfarin therapy will be titrated to a target INR in the range of 1.5 to 2.5.
  • Active Comparator: Standard INR Target
    • Warfarin therapy will be titrated to a “standard of care” target INR range.

Clinical Trial Outcome Measures

Primary Measures

  • 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: Death and/or, Symptomatic bleeding in critical area or organ (e.g. intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, pericardial, in a non-operated joint, or intramuscular with compartment syndrome) and/or, 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 Measures

  • 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
  • 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

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Population Health Research Institute
  • Collaborator
    • Hamilton Health Sciences Corporation
  • Provider of Information About this Clinical Study
    • Principal Investigator: Emilie Belley-Cote, Principal Investigator – Population Health Research Institute
  • Overall Official(s)
    • Emilie Belley-Côté, MD, MSc, Principal Investigator, McMaster University
  • Overall Contact(s)
    • Emilie Belley-Côté, MD, MSc, 905-527-4322, emilie.belley-cote@phri.ca

References

Puskas J, Gerdisch M, Nichols D, Quinn R, Anderson C, Rhenman B, Fermin L, McGrath M, Kong B, Hughes C, Sethi G, Wait M, Martin T, Graeve A; PROACT Investigators. Reduced anticoagulation after mechanical aortic valve replacement: interim results from the prospective randomized on-X valve anticoagulation clinical trial randomized Food and Drug Administration investigational device exemption trial. J Thorac Cardiovasc Surg. 2014 Apr;147(4):1202-1210; discussion 1210-1. doi: 10.1016/j.jtcvs.2014.01.004. Epub 2014 Jan 12.

Torella M, Torella D, Chiodini P, Franciulli M, Romano G, De Santo L, De Feo M, Amarelli C, Sasso FC, Salvatore T, Ellison GM, Indolfi C, Cotrufo M, Nappi G. LOWERing the INtensity of oral anticoaGulant Therapy in patients with bileaflet mechanical aortic valve replacement: results from the "LOWERING-IT" Trial. Am Heart J. 2010 Jul;160(1):171-8. doi: 10.1016/j.ahj.2010.05.005.

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