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

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 Overview

• Status: Recruiting
• Conditions: Bleeding Post-mechanical Valve Replacement; Thromboembolism Post-mechanical Valve Replacement
• Intervention / Treatment: Drug: Warfarin

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: Interventional
• Enrollment (Estimated): 2625
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Emilie Belley-Côté, MD, MSc; Phone Number: 40306 905-527-4322; Email: emilie.belley-cote@phri.ca
• Study Contact Backup: Name: Richard Whitlock, MD, PhD; Phone Number: 40306 905-527-4322; Email: richard.whitlock@phri.ca

Study Locations

• Belgium
  • Keerbergen, Belgium, 2820
    • Recruiting
    • Imelda Hospital
    • Principal Investigator: Herbert De Praetere, MD
  • Leuven, Belgium, 3000
    • Recruiting
    • Universitair Ziekenhuis Leuven
    • Principal Investigator: Filip Rega, MD
  • Limburg
    • Genk, Limburg, Belgium, 3600
      • Recruiting
      • Ziekenhuis Oost-Limburg
      • Contact: Philippe Bertrand, MD
      • Principal Investigator: Philippe Bertrand, MD
  • West-Vlaanderen
    • Ostend, West-Vlaanderen, Belgium, 8400
      • Recruiting
      • AZ Oostende
      • Principal Investigator: Johannes Heymeriks, MD
• Botswana
  • Gaborone, Botswana
    • Recruiting
    • University of Botswana, at Princess Marina Hospital
    • Principal Investigator: Julius Mwita, MD, MSc
• Brazil
  • Brasília, Brazil
    • Recruiting
    • Fundação Universitária de Cardiologia mantededora do Instituto de Cardiologia e Transplantes do Distrito Federal
    • Principal Investigator: Adegil Silva, MD
    • Contact: Kaytussia Sena
  • São Paulo, Brazil
    • Recruiting
    • Dante Pazzanese Institute of Cardiology
    • Contact: Mayara Silva
    • Principal Investigator: Auristela Ramos, MD
  • Paraná
    • Campina Grande do Sul, Paraná, Brazil, 83430-000
      • Recruiting
      • Sociedade Hospitalar Angelina Caron
      • Principal Investigator: Dalton Precoma, MD
      • Contact: Dalton Precoma, MD
  • Santa Catarina
    • Joinville, Santa Catarina, Brazil, 89204-250
      • Recruiting
      • HEW Cardiologia LTDA
      • Contact: Conrado R. Hoffmann Filho, MD
      • Principal Investigator: Conrado R. Hoffmann Filho, MD
  • São Paulo
    • Cerqueira César, São Paulo, Brazil, 05403-000
      • Recruiting
      • InCor-HCFMUSP
      • Contact: Roney Sampaio, MD
      • Principal Investigator: Roney Sampaio, MD
• Cameroon
  • Kumbo, Cameroon
    • Recruiting
    • St. Elizabeth Catholic General Hospital
    • Principal Investigator: Tantchou Tchoumi Jacques Cabral, MD, PhD
• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3S 0H6
      • Not yet recruiting
      • Nova Scotia Health Authority
      • Principal Investigator: Robbie Stewart, MD
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Recruiting
      • Hamilton General Hospital
      • Contact: Emilie Belley-Cote, MD; Phone Number: 40306 905-527-4322; Email: emilie.belley-cote@phri.ca
    • London, Ontario, Canada, N6C 2R5
      • Recruiting
      • London Health Sciences Centre Research Inc.
      • Contact: Linrui Guo, MD
      • Principal Investigator: Linrui Guo, MD
    • Ottawa, Ontario, Canada, K1H 8L6
      • Recruiting
      • The Ottawa Hospital Research Institute
      • Contact: Joseph Shaw, MD
      • Principal Investigator: Joseph Shaw, MD
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Recruiting
      • Jewish General Hospital
      • Contact: Mark Blostein, MD
• China
  • Beijing, China
    • Recruiting
    • Fuwai Hospital, CAMS & PUMC
    • Contact: Xiaolu Sun, MD
    • Principal Investigator: Yan Liang, MD, PhD
• Denmark
  • Aabenraa, Denmark, 6200
    • Recruiting
    • Southern Jutland Hospital
    • Principal Investigator: Michael S Hansen, MD
  • Aarhus, Denmark, 8200
    • Recruiting
    • Aarhus University Hospital
    • Principal Investigator: Erik Grove, MD, PhD
  • Region Syddanmark
    • Esbjerg, Region Syddanmark, Denmark, 6700
      • Recruiting
      • Esbjerg & Grindsted Hospital - University Hospital of Southern Denmark
      • Principal Investigator: Axel Brandes, MD
• Germany
  • Jena, Germany, 07747
    • Recruiting
    • Universitätsklinikum Jena
    • Principal Investigator: Torsten Doenst, MD, PhD
• Italy
  • Foggia, Italy, 71122
    • Recruiting
    • Azienda Ospedaliero Universitaria Policlinico Riuniti Foggia
    • Principal Investigator: Domenico Paparella, MD
    • Principal Investigator: Gaetano Serviddio, MD
  • Apulia
    • Lecce, Apulia, Italy, 73100
      • Recruiting
      • Città di Lecce Hospital
      • Principal Investigator: Giuseppe Santarpino, MD
• Nepal
  • Bagmati
    • Kathmandu, Bagmati, Nepal, 44600
      • Recruiting
      • Shahid Gangalal National Heart Centre
      • Principal Investigator: Raamesh Koirala, MD
  • Koshi
    • Biratnagar, Koshi, Nepal, 56613
      • Recruiting
      • Nobel Medical College and Teaching Hospital
      • Principal Investigator: Rajesh Nepal, MD
    • Dharān, Koshi, Nepal, 56700
      • Recruiting
      • BP Koirala Institute of Health Sciences
      • Principal Investigator: Sanjib Kumar Sharma, MD
• Netherlands
  • Rotterdam, Netherlands, 3015
    • Recruiting
    • Erasmus University Medical Centre
    • Principal Investigator: Jolien Roos-Hesselink, MD
• Pakistan
  • Capital Territory
    • Islamabad, Capital Territory, Pakistan, 44000
      • Recruiting
      • Shifa Clinical Research Center
      • Principal Investigator: Muhammad Asghar Nawaz, MBBS
• Russia
  • Novosibirsk, Russia
    • Recruiting
    • Meshalkin National Medical Research Center
    • Contact: Alexander Bogachev-Prokophiev, MD
• Saudi Arabia
  • Riyadh, Saudi Arabia
    • Recruiting
    • King Faisal Specialist Hospital & Research Centre
    • Principal Investigator: Eman Alrajhi, MD
• South Korea
  • Gumi, South Korea
    • Recruiting
    • Soonchunhyang University Gumi Hospital
    • Contact: Hun-Gyu Hwang, MD
    • Principal Investigator: Hun-Gyu Hwang, MD
• Spain
  • Barcelona, Spain, 08025
    • Recruiting
    • Hospital De La Santa Creu I Sant Pau
    • Contact: Ekaterine Popova, MD
    • Principal Investigator: Juan Carles Souto Andres, MD
• United Kingdom
  • Liverpool, United Kingdom, L143PE
    • Recruiting
    • Liverpool Heart & Chest Hospital
    • Principal Investigator: Bilal Kirmani, MD
  • Middlesbrough, United Kingdom
    • Recruiting
    • South Tees Hospitals NHS Foundation Trust of The James Cook University Hospital
    • Principal Investigator: David Austin, MD
    • Contact: Carmen Neave
    • Principal Investigator: Enoch Akowuah, MD FRCSC
  • Glasgow
    • Clydebank, Glasgow, United Kingdom, G81 4HX
      • Recruiting
      • Golden Jubilee National Hospital
      • Principal Investigator: Nawwar Al-Attar, FRCS, FETCS, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: Coumadin

What is the study measuring?

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
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
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

Collaborators and Investigators

• Sponsor: Population Health Research Institute
• Collaborators: Hamilton Health Sciences Corporation
• Investigators: Principal Investigator: Emilie Belley-Côté, MD, MSc, McMaster University

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 5, 2019
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: July 25, 2018
• First Submitted That Met QC Criteria: August 15, 2018
• First Posted (Actual): August 17, 2018

Study Record Updates

• Last Update Posted (Estimated): January 6, 2026
• Last Update Submitted That Met QC Criteria: December 31, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Bleeding; Thromboembolism; Vitamin K antagonist; Mechanical valve replacement; INR targets
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Embolism and Thrombosis; Pathological Conditions, Signs and Symptoms; Thromboembolism; Hemorrhage; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pyrans; Coumarins; Benzopyrans; 4-Hydroxycoumarins; Warfarin
• Other Study ID Numbers: 5139

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: We will establish a plan for the full-scale study but there is no plan to make IPD available to other researchers.

Drug and device information, study documents

• 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