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Bleeding Post-mechanical Valve ReplacementPhase 3LIMITNCT03636295

Low INR to Minimize Bleeding With Mechanical Valves Trial

A Phase 3 study testing Warfarin in people with Bleeding Post-mechanical Valve Replacement and Thromboembolism Post-mechanical Valve Replacement, run by Population Health Research Institute at 45 sites in 18 countries.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Warfarin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
2,625 participants
Where
45 sitesin 18 countries
Study dates
5 Sep 2019to 31 Dec 2028
Phase
Phase 3
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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

Trial locations and contacts

45 sites in 18 countries. Contact the study team or a site near you to ask about taking part.

Emilie Belley-Côté, MD, MSc contact

905-527-4322 ext. 40306

emilie.belley-cote@phri.ca

Richard Whitlock, MD, PhD contact

905-527-4322 ext. 40306

richard.whitlock@phri.ca

45 sites in 18 countries

Brazil7 sites, 7 recruiting

  • Fundação Universitária de Cardiologia mantededora do Instituto de Cardiologia e Transplantes do Distrito Federal

    Brasília

    Kaytussia Sena

    Adegil Silva, MD

    Recruiting

  • Sociedade Hospitalar Angelina Caron

    Campina Grande do Sul, Paraná, 83430-000

    Dalton Precoma, MD

    Dalton Precoma, MD

    Recruiting

  • InCor-HCFMUSP

    Cerqueira César, São Paulo, 05403-000

    Roney Sampaio, MD

    Roney Sampaio, MD

    Recruiting

  • Hospital de Messejana

    Fortaleza

    Sandra Nivea Reis Saraiva Falcao, MD, (85) 31017845, unidadepesquisaclinica@gmail.com

    Recruiting

  • HEW Cardiologia LTDA

    Joinville, Santa Catarina, 89204-250

    Conrado R. Hoffmann Filho, MD

    Conrado R. Hoffmann Filho, MD

    Recruiting

  • Dante Pazzanese Institute of Cardiology

    São Paulo

    Mayara Silva

    Auristela Ramos, MD

    Recruiting

  • Centro de Pesquisa Cardiolima

    Teresina

    Carlos Eduardo B De Lima, MD, 86 3085-3048, admin@cardiolima.com.br

    Recruiting

Other trials in Brazil

Canada5 sites, 5 recruiting

  • Nova Scotia Health Authority

    Halifax, Nova Scotia, B3S 0H6

    Robbie Stewart, MD

    Recruiting

  • Hamilton General Hospital

    Hamilton, Ontario, L8L 2X2

    Emilie Belley-Cote, MD, 905-527-4322 ext. 40306, emilie.belley-cote@phri.ca

    Recruiting

  • London Health Sciences Centre Research Inc.

    London, Ontario, N6C 2R5

    Linrui Guo, MD

    Linrui Guo, MD

    Recruiting

  • Jewish General Hospital

    Montreal, Quebec, H3T 1E2

    Mark Blostein, MD

    Recruiting

  • The Ottawa Hospital Research Institute

    Ottawa, Ontario, K1H 8L6

    Joseph Shaw, MD

    Joseph Shaw, MD

    Recruiting

Other trials in Canada

United Kingdom5 sites, 5 recruiting

  • Golden Jubilee National Hospital

    Clydebank, Glasgow, G81 4HX

    Nawwar Al-Attar, FRCS, FETCS, PhD

    Recruiting

  • Liverpool Heart & Chest Hospital

    Liverpool, L143PE

    Bilal Kirmani, MD

    Recruiting

  • Barts Health NHS Trust

    London

    John Yap, MD, 02037658635, John.yap2@nhs.net

    Recruiting

  • South Tees Hospitals NHS Foundation Trust of The James Cook University Hospital

    Middlesbrough

    Carmen Neave

    Enoch Akowuah, MD FRCSC

    Recruiting

  • Sheffield Teaching Hospitals

    Sheffield

    Norman Briffa, MD, 01142714951, n.briffa@nhs.net

    Recruiting

Other trials in United Kingdom

Belgium4 sites, 4 recruiting

  • Ziekenhuis Oost-Limburg

    Genk, Limburg, 3600

    Philippe Bertrand, MD

    Philippe Bertrand, MD

    Recruiting

  • Imelda Hospital

    Keerbergen, 2820

    Herbert De Praetere, MD

    Recruiting

  • Universitair Ziekenhuis Leuven

    Leuven, 3000

    Filip Rega, MD

    Recruiting

  • AZ Oostende

    Ostend, West-Vlaanderen, 8400

    Johannes Heymeriks, MD

    Recruiting

Other trials in Belgium

Italy4 sites, 4 recruiting

  • AOU SS Antonio e Biagio e Cesare Arrigo

    Alessandria

    Andrea Audo, MD, 390131206589, aaudo@ospedale.al.it

    Recruiting

  • AOU delle Marche

    Ancona

    Pietro Giorgio Malvindi, MD, 00393209172475, p.g.malvindi@univpm.it

    Recruiting

  • Azienda Ospedaliero Universitaria Policlinico Riuniti Foggia

    Foggia, 71122

    Domenico Paparella, MD

    Gaetano Serviddio, MD

    Recruiting

  • Città di Lecce Hospital

    Lecce, Apulia, 73100

    Giuseppe Santarpino, MD

    Recruiting

Other trials in Italy

Nepal4 sites, 4 recruiting

  • Nobel Medical College and Teaching Hospital

    Biratnagar, Koshi, 56613

    Rajesh Nepal, MD

    Recruiting

  • BP Koirala Institute of Health Sciences

    Dharān, Koshi, 56700

    Sanjib Kumar Sharma, MD

    Recruiting

  • Shahid Gangalal National Heart Centre

    Kathmandu, Bagmati, 44600

    Raamesh Koirala, MD

    Recruiting

  • National Academy of Medical Sciences, Bir Hospital

    Kathmandu

    Kunjana Sherpa, MD, 9779812360157, prajwala412@gmail.com

    Recruiting

Other trials in Nepal

Denmark3 sites, 3 recruiting

  • Southern Jutland Hospital

    Aabenraa, 6200

    Michael S Hansen, MD

    Recruiting

  • Aarhus University Hospital

    Aarhus, 8200

    Erik Grove, MD, PhD

    Recruiting

  • Esbjerg & Grindsted Hospital - University Hospital of Southern Denmark

    Esbjerg, Region Syddanmark, 6700

    Axel Brandes, MD

    Recruiting

Other trials in Denmark

Cameroon2 sites, 2 recruiting

  • Coeur et Vie Clinic

    Douala

    Djomou Ngongang Florent Armel, MD, 237 651 11 71 87, fouedjioverlain@coeur-vie.org

    Recruiting

  • St. Elizabeth Catholic General Hospital

    Kumbo

    Tantchou Tchoumi Jacques Cabral, MD, PhD

    Recruiting

Other trials in Cameroon

Germany2 sites, 2 recruiting

  • Justus-Liebig-Universitat

    Giessen

    Prof. Andreas Boening, MD PhD, 49-641985 43178, irina.oswald@chiru.med.uni-giessen.de

    Recruiting

  • Universitätsklinikum Jena

    Jena, 07747

    Torsten Doenst, MD, PhD

    Recruiting

Other trials in Germany

Botswana1 site, 1 recruiting

  • University of Botswana, at Princess Marina Hospital

    Gaborone

    Julius Mwita, MD, MSc

    Recruiting

Other trials in Botswana

China1 site, 1 recruiting

  • Fuwai Hospital, CAMS & PUMC

    Beijing

    Xiaolu Sun, MD

    Yan Liang, MD, PhD

    Recruiting

Other trials in China

Kenya1 site, 1 recruiting

  • The Karen Hospital

    Nairobi

    Anthony Gikonyo, 254700535280, anthony.gikonyo@karenhospital.org

    Recruiting

Other trials in Kenya

Netherlands1 site, 1 recruiting

  • Erasmus University Medical Centre

    Rotterdam, 3015

    Jolien Roos-Hesselink, MD

    Recruiting

Other trials in Netherlands

Pakistan1 site, 1 recruiting

  • Shifa Clinical Research Center

    Islamabad, Capital Territory, 44000

    Muhammad Asghar Nawaz, MBBS

    Recruiting

Other trials in Pakistan

Russia1 site, 1 recruiting

  • Meshalkin National Medical Research Center

    Novosibirsk

    Alexander Bogachev-Prokophiev, MD

    Recruiting

Other trials in Russia

Saudi Arabia1 site, 1 recruiting

  • King Faisal Specialist Hospital & Research Centre

    Riyadh

    Eman Alrajhi, MD

    Recruiting

Other trials in Saudi Arabia

South Korea1 site, 1 recruiting

  • Soonchunhyang University Gumi Hospital

    Gumi

    Hun-Gyu Hwang, MD

    Hun-Gyu Hwang, MD

    Recruiting

Other trials in South Korea

Spain1 site, 1 recruiting

  • Hospital de la Santa Creu i Sant Pau

    Barcelona, 08025

    Ekaterine Popova, MD

    Juan Carles Souto Andres, MD

    Recruiting

Other trials in Spain

About this study

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.

Read the 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.

Being tested
Warfarin
Keywords
Mechanical valve replacement, Vitamin K antagonist, INR targets, Bleeding, Thromboembolism
Medical subject headings
Hemorrhage, Thromboembolism

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • WarfarinDrug

    Also called Coumadin

    Participants in both arms will be on warfarin therapy post-mechanical valve replacement as is standard, but will have different INR target ranges.

Study groups in NCT03636295
Study groupRoleWhat they receive
Reduced INR TargetExperimentalWarfarin therapy will be titrated to a target INR in the range of 1.5 to 2.5.
Receives: Drug: Warfarin
Standard INR TargetActive comparatorWarfarin therapy will be titrated to a "standard of care" target INR range.
Receives: Drug: Warfarin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Thrombosis/thromboembolism

    Number of patients who have at least one of the following: ischemic stroke, systemic thromboembolism, and valve thrombosis

    Measured: Through study completion, an expected mean of 2-3 years

  2. Major bleeding

    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, in a non-operated joint, 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

    Measured: Through study completion, an expected mean of 2-3 years

Secondary outcomes (14)

  1. 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.

    Measured: Through study completion, an expected mean of 2-3 years

  2. All clinically important bleeding

    Number of patients that experience all clinically important bleeding (major and minor)

    Measured: Through study completion, an expected mean of 2-3 years

  3. Minor bleeding

    Number of patients that experience a bleed that does not meet major bleeding criteria

    Measured: Through study completion, an expected mean of 2-3 years

  4. All stroke

    Number of patients that experience a strokes, including ischemic stroke, ischemic with secondary transformation, stroke of uncertain classification and hemorrhagic stroke

    Measured: Through study completion, an expected mean of 2-3 years

  5. 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

    Measured: Through study completion, an expected mean of 2-3 years

  6. 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

    Measured: Through study completion, an expected mean of 2-3 years

  7. Type 1, 2 or 3 myocardial infarction

    Number of patients who experience a type 1, 2 or 3 myocardial infarction

    Measured: Through study completion, an expected mean of 2-3 years

  8. Systemic thromboembolism

    Number of patients who experience a systemic thromboembolism

    Measured: Through study completion, an expected mean of 2-3 years

  9. Valve thrombosis

    Number of patients who experience a valve thrombosis

    Measured: Through study completion, an expected mean of 2-3 years

  10. Pulmonary embolism

    Number of patients who experience a pulmonary embolism

    Measured: Through study completion, an expected mean of 2-3 years

  11. Deep vein thrombosis

    Number of patients who experience a deep vein thrombosis

    Measured: Through study completion, an expected mean of 2-3 years

  12. New renal replacement therapy

    Number of patients requiring new renal replacement therapy

    Measured: Through study completion, an expected mean of 2-3 years

  13. Time in therapeutic range

    The percentage of time the patient's INR was within the target range

    Measured: Through study completion, an expected mean of 2-3 years

  14. Proportion of patients with extreme INR values (>4)

    The proportion of patients with at least one reported INR value above 4

    Measured: Through study completion, an expected mean of 2-3 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Aug 2018
  2. Study start5 Sep 2019
  3. Primary completion31 Dec 2028 (estimated)
  4. Study completion31 Dec 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
A prospective, randomized, open-label, blinded end-point (PROBE) clinical trial.
Masking
None (open label)
Enrolment
2,625 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03636295
Sponsor's protocol ID
5139
Acronym
LIMIT
Status last verified
Sep 2026
First submitted
25 Jul 2018
Last updated
17 Sep 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No: We will establish a plan for the full-scale study but there is no plan to make IPD available to other researchers.

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.

    PubMed 24512654

  • 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.

    PubMed 20598989

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Warfarin in people with Bleeding Post-mechanical Valve Replacement and Thromboembolism Post-mechanical Valve Replacement, run by Population Health Research Institute at 45 sites in 18 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 17 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 45 sites in Brazil, Canada, United Kingdom, Belgium, Italy and 13 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Emilie Belley-Côté, MD, MSc (905-527-4322 ext. 40306, emilie.belley-cote@phri.ca), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Thrombosis/thromboembolism (time frame: Through study completion, an expected mean of 2-3 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03636295, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Sep 2026.

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