Clinical trial NCT03636295: Low INR to Minimize Bleeding With Mechanical Valves Trial
Official title: Low INR to Minimize Bleeding With Mechanical Valves Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Bleeding Post-mechanical Valve Replacement
Thromboembolism Post-mechanical Valve Replacement
Keywords: Mechanical valve replacement
Vitamin K antagonist
INR targets
Bleeding
Thromboembolism
Lead sponsor: Population Health Research Institute
Sponsor class: OTHER
Collaborators: name: Hamilton Health Sciences Corporation
First posted: 2018-08-17
Enrollment: 2625
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A prospective, randomized, open-label, blinded end-point (PROBE) clinical trial.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Thrombosis/thromboembolism
timeFrame: Through study completion, an expected mean of 2-3 years
measure: Major bleeding
timeFrame: Through study completion, an expected mean of 2-3 years
Secondary outcomes:
measure: All cause mortality
timeFrame: Through study completion, an expected mean of 2-3 years
measure: All clinically important bleeding
timeFrame: Through study completion, an expected mean of 2-3 years
measure: Minor bleeding
timeFrame: Through study completion, an expected mean of 2-3 years
measure: All stroke
timeFrame: Through study completion, an expected mean of 2-3 years
measure: Ischemic stroke
timeFrame: Through study completion, an expected mean of 2-3 years
measure: Hemorrhagic stroke
timeFrame: Through study completion, an expected mean of 2-3 years
measure: Type 1, 2 or 3 myocardial infarction
timeFrame: Through study completion, an expected mean of 2-3 years
measure: Systemic thromboembolism
timeFrame: Through study completion, an expected mean of 2-3 years
measure: Valve thrombosis
timeFrame: Through study completion, an expected mean of 2-3 years
measure: Pulmonary embolism
timeFrame: Through study completion, an expected mean of 2-3 years
measure: Deep vein thrombosis
timeFrame: Through study completion, an expected mean of 2-3 years
measure: New renal replacement therapy
timeFrame: Through study completion, an expected mean of 2-3 years
measure: Time in therapeutic range
timeFrame: Through study completion, an expected mean of 2-3 years
measure: Proportion of patients with extreme INR values (>4)
timeFrame: Through study completion, an expected mean of 2-3 years
Other outcomes:
Locations:
city: Genk
country: Belgium
facility: Ziekenhuis Oost-Limburg
state: Limburg
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis Leuven
city: Campina Grande Do Sul
country: Brazil
facility: Sociedade Hospitalar Angelina Caron
state: Parana
city: Joinville
country: Brazil
facility: HEW Cardiologia LTDA
state: Santa Catarina
city: Cerqueira César
country: Brazil
facility: InCor-HCFMUSP
state: São Paulo
city: Brasilia
country: Brazil
facility: Fundação Universitária de Cardiologia mantededora do Instituto de Cardiologia e Transplantes do Distrito Federal
city: Sao Paulo
country: Brazil
facility: Dante Pazzanese Institute of Cardiology
city: Halifax
country: Canada
facility: Nova Scotia Health Authority
state: Nova Scotia
city: Hamilton
country: Canada
facility: Hamilton General Hospital
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre Research Inc.
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital Research Institute
state: Ontario
city: Montréal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Beijing
country: China
facility: Fuwai Hospital, CAMS & PUMC
city: Gumi
country: Korea, Republic of
facility: Soonchunhyang University Gumi Hospital
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Centre
city: Novosibirsk
country: Russian Federation
facility: Meshalkin National Medical Research Center
city: Riyadh
country: Saudi Arabia
facility: King Faisal Specialist Hospital & Research Centre
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Middlesbrough
country: United Kingdom
facility: South Tees Hospitals NHS Foundation Trust of The James Cook University Hospital
Study officials:
affiliation: McMaster University
name: Emilie Belley-Côté, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.