Low INR to Minimize Bleeding With Mechanical Valves Trial

Study Overview
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Brief Summary
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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
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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.

Official Title
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Low INR to Minimize Bleeding With Mechanical Valves Trial

Conditions
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Bleeding Post-mechanical Valve Replacement, Thromboembolism Post-mechanical Valve Replacement

Intervention / Treatment
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* Drug: Warfarin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A prospective, randomized, open-label, blinded end-point (PROBE) clinical trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Reduced INR Target<br>Warfarin therapy will be titrated to a target INR in the range of 1.5 to 2.5. | Drug: Warfarin<br>* Participants in both arms will be on warfarin therapy post-mechanical valve replacement as is standard, but will have different INR target ranges.<br>* Other names: Coumadin;|
| Active Comparator: Standard INR Target<br>Warfarin therapy will be titrated to a standard of care target INR range. | Drug: Warfarin<br>* Participants in both arms will be on warfarin therapy post-mechanical valve replacement as is standard, but will have different INR target ranges.<br>* Other names: Coumadin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Thrombosis/thromboembolism | Number of patients who have at least one of the following: ischemic stroke, systemic thromboembolism, and valve thrombosis | Through study completion, an expected mean of 2-3 years | 
| Major bleeding | 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 | Through study completion, an expected mean of 2-3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All cause mortality | 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. | Through study completion, an expected mean of 2-3 years | 
| All clinically important bleeding | Number of patients that experience all clinically important bleeding (major and minor) | Through study completion, an expected mean of 2-3 years | 
| Minor bleeding | Number of patients that experience a bleed that does not meet major bleeding criteria | Through study completion, an expected mean of 2-3 years | 
| All stroke | Number of patients that experience a strokes, including ischemic stroke, ischemic with secondary transformation, stroke of uncertain classification and hemorrhagic stroke | Through study completion, an expected mean of 2-3 years | 
| Ischemic stroke | 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 | Through study completion, an expected mean of 2-3 years | 
| Hemorrhagic stroke | 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 | Through study completion, an expected mean of 2-3 years | 
| Type 1, 2 or 3 myocardial infarction | Number of patients who experience a type 1, 2 or 3 myocardial infarction | Through study completion, an expected mean of 2-3 years | 
| Systemic thromboembolism | Number of patients who experience a systemic thromboembolism | Through study completion, an expected mean of 2-3 years | 
| Valve thrombosis | Number of patients who experience a valve thrombosis | Through study completion, an expected mean of 2-3 years | 
| Pulmonary embolism | Number of patients who experience a pulmonary embolism | Through study completion, an expected mean of 2-3 years | 
| Deep vein thrombosis | Number of patients who experience a deep vein thrombosis | Through study completion, an expected mean of 2-3 years | 
| New renal replacement therapy | Number of patients requiring new renal replacement therapy | Through study completion, an expected mean of 2-3 years | 
| Time in therapeutic range | The percentage of time the patient's INR was within the target range | Through study completion, an expected mean of 2-3 years | 
| Proportion of patients with extreme INR values (>4) | The proportion of patients with at least one reported INR value above 4 | Through study completion, an expected mean of 2-3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mechanical valve replacement, Vitamin K antagonist, INR targets, Bleeding, Thromboembolism