Lower INR Warfarin for Mechanical Valve Patients

(LIMIT Trial)

Recruiting at 36 trial locations

Overseen By Emilie Belley-Côté, MD, MSc

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Population Health Research Institute

Must be taking: Warfarin

Disqualifiers: Second mechanical valve, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 2-3 years

2625 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a lower blood thickness level, called INR (a measure of how long it takes blood to clot), can be safely used in people with a mechanical heart valve in the aortic position. Researchers aim to determine if maintaining an INR between 1.5 and 2.5 can reduce bleeding risk without increasing the chances of blood clots or stroke. Participants will either follow this new INR range or adhere to the usual care for comparison. This trial may suit individuals who had a bileaflet mechanical heart valve implanted in the aortic position at least three months ago. Participants will take Warfarin (also known as Coumadin or Jantoven), a medication that helps prevent blood clots. As a Phase 3 trial, this research represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does require that you continue taking warfarin (Coumadin) for your mechanical heart valve.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that setting a lower INR target for individuals on warfarin with mechanical heart valves can be safe. INR is a blood test that measures how long it takes for blood to clot. Studies found that a lower INR target reduced major bleeding by 87% and total bleeding by 71% compared to standard targets, without increasing the risk of blood clots. Additionally, other research found that a specific type of mechanical heart valve remained safe with a lower INR target over five years. These findings suggest that lowering the INR target might reduce bleeding risks without increasing the chances of clots or strokes. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the warfarin treatment protocol being tested because it targets a lower INR range of 1.5 to 2.5, which could potentially reduce the risk of bleeding complications for patients with mechanical heart valves. Unlike the standard treatment, which maintains a higher INR range, this new approach aims to balance effective anticoagulation with improved safety. By adjusting the INR target, researchers hope to provide a safer and more tailored anticoagulation strategy for patients, enhancing their overall quality of life.

What evidence suggests that this trial's treatments could be effective for patients with mechanical heart valves?

This trial will compare two different INR (international normalized ratio) targets for warfarin therapy in patients with mechanical aortic valves. Research has shown that setting a lower INR target might reduce the risk of bleeding. For instance, one study found that patients with a lower INR target experienced fewer major bleeding incidents, with rates of 1.6% compared to 3.9% per patient-year. This finding suggests that maintaining the INR within a narrower range could help balance the risks of bleeding and clotting. However, regular INR checks are important to ensure safety. While these findings are encouraging, more research is needed to determine the best INR targets for everyone. ^{4 6 7 8 9}

Who Is on the Research Team?

Emilie Belley-Côté, MD, MSc

Principal Investigator

McMaster University

Are You a Good Fit for This Trial?

This trial is for adults over 18 who have had a bileaflet mechanical heart valve placed in the aortic position at least 3 months ago and can provide informed consent. It's not for those with multiple mechanical valves, pregnant individuals, or anyone using an On-X Valve.

Inclusion Criteria

I had a mechanical heart valve replacement in the aortic position over 3 months ago.

Written informed consent from either the patient or substitute decision maker

Exclusion Criteria

I'm sorry, but the provided criterion "On-X Valve" doesn't provide enough context for me to rewrite it in simpler language. Can you please provide more details or clarify the criterion?

You have a second mechanical heart valve implanted.

Pregnant or expecting to become pregnant during the study follow-up

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive warfarin therapy titrated to either a standard or reduced INR target range

2-3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Warfarin

Trial Overview The study is testing if patients with mechanical heart valves can maintain a lower INR target (1.5 to 2.5) to reduce bleeding without increasing the risk of blood clots and stroke while on warfarin treatment.

How Is the Trial Designed?

Group I: Reduced INR Target Experimental Treatment 1 Intervention

Warfarin therapy will be titrated to a target INR in the range of 1.5 to 2.5.

Group II: Standard INR Target Active Control 1 Intervention

Warfarin therapy will be titrated to a "standard of care" target INR range.

Warfarin is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Warfarin for:

• Prophylaxis and treatment of thromboembolic complications from atrial fibrillation or cardiac valve replacement
• Reduction in the risk of death, recurrent myocardial infarction, and thromboembolic events after myocardial infarction

Approved in European Union as Warfarin for:

• Prevention of thromboembolic events in patients with atrial fibrillation
• Treatment of deep vein thrombosis and pulmonary embolism
• Prevention of recurrent myocardial infarction

Approved in Canada as Warfarin for:

• Prophylaxis and treatment of thromboembolic complications from atrial fibrillation or cardiac valve replacement
• Reduction in the risk of death, recurrent myocardial infarction, and thromboembolic events after myocardial infarction

Who Is Running the Clinical Trial?

Population Health Research Institute

Lead Sponsor

Trials

165

Recruited

717,000+

Hamilton Health Sciences Corporation

Collaborator

Trials

380

Recruited

345,000+

Published Research Related to This Trial

A 65-year-old male patient with a mechanical prosthetic aortic valve experienced warfarin resistance, where increasing doses of warfarin did not raise his INR levels adequately for effective thromboembolism prevention.

Switching from warfarin to acenocoumarol successfully stabilized the patient's INR over a year, suggesting that acenocoumarol may be a viable alternative for patients with warfarin resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Warfarin resistance: possibilities to solve this problem. A case report. Mostbauer, H., Nishkumay, O., Rokyta, O., et al.[2022]

Direct oral anticoagulants, like rivaroxaban, are not approved for patients with mechanical heart valves due to safety concerns.

A case study highlighted a serious complication where a patient developed thrombosis of a mechanical mitral valve after switching from warfarin to rivaroxaban, emphasizing the risks of using these medications inappropriately.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanical Prosthetic Heart Valve Thrombosis in a Patient Receiving Rivaroxaban. Carvalho Silva, DM., Braga, A., de Jesus, I., et al.[2020]

For patients with new generation prosthetic mechanical mitral valves, the optimal target INR for warfarin therapy is between 2.5 and 3.5, while older valve types require a higher target INR of 3.5 to 4.5, based on a review of 12 key studies.

Maintaining stable INR values with minimal variation is crucial for effective anticoagulation, and in certain patients with a history of thromboembolic events or coronary artery disease, low-dose aspirin may be added to warfarin therapy for enhanced safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

What is the optimal level of anticoagulation in adult patients receiving warfarin following implantation of a mechanical prosthetic mitral valve? Bayliss, A., Faber, P., Dunning, J., et al.[2013]

Switching patients with prosthetic mechanical mitral valves from traditional anticoagulants (warfarin and acenocoumarol) to the new oral anticoagulant dabigatran resulted in severe complications, including stroke and cardiogenic shock, leading to death in both cases.

These cases highlight the potential safety risks of using dabigatran in patients with mechanical heart valves, emphasizing the need for caution and further research before approving its use in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fatal association of mechanical valve thrombosis with dabigatran: a report of two cases. Atar, S., Wishniak, A., Shturman, A., et al.[2017]

In a Phase II clinical trial involving 252 patients with mechanical heart valves, dabigatran was associated with a higher risk of thromboembolic events (8%) compared to warfarin (2%), suggesting it may not be a safer alternative.

The study also found that dabigatran led to significantly higher bleeding rates (27%) compared to warfarin (12%), indicating that it may pose greater safety risks without providing additional benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabigatran use in mechanical heart valve patients. Zough, F., Tafreshi, J., Pai, RG.[2018]

In a pilot study involving 72 patients with mechanical heart valves, rivaroxaban (15 mg twice daily) showed a similar incidence of thromboembolic events compared to warfarin, with only 4.3% of patients in the rivaroxaban group experiencing such events versus 14.3% in the warfarin group.

Minor bleeding rates were also comparable between the two groups, with 26.1% in the rivaroxaban group and 28.6% in the warfarin group, indicating that rivaroxaban may be a safe alternative to warfarin for anticoagulation in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rivaroxaban Versus Warfarin in Patients with Mechanical Heart Valves: Open-Label, Proof-of-Concept trial-The RIWA study. Duraes, AR., de Souza Lima Bitar, Y., Schonhofen, IS., et al.[2021]

In a study of 384 patients who underwent mechanical valve surgery, achieving a therapeutic international normalized ratio (INR) within 4 to 13 days post-surgery was linked to a shorter hospital stay, highlighting the importance of timely anticoagulation management.

Patients who reached a therapeutic INR had a significantly higher rate of hospital discharge, with an adjusted hazard ratio of 2.17, indicating that faster attainment of therapeutic INR can improve recovery times and reduce hospital length of stay.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between time to therapeutic INR and length of stay following mechanical heart valve surgery. Godoy, LC., Tomlinson, G., Abumuamar, AM., et al.[2022]

In a study of 2111 patients with mechanical prosthetic heart valves, those treated with acenocoumarol had a significantly lower time in therapeutic range (TiTR) compared to those on warfarin, indicating poorer anticoagulation quality (56.1% vs. 61.6%).

Acenocoumarol use was consistently associated with a higher prevalence of low TiTR across various patient subgroups, suggesting that patients on acenocoumarol may face increased risks related to anticoagulation management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Anticoagulation Quality between Acenocoumarol and Warfarin in Patients with Mechanical Prosthetic Heart Valves: Insights from the Nationwide PLECTRUM Study. Menichelli, D., Poli, D., Antonucci, E., et al.[2021]

In a study of 2111 patients with mechanical prosthetic heart valves, nearly half (48.5%) had a low time in the therapeutic range (TiTR <60%), indicating suboptimal warfarin therapy management.

Factors such as arterial hypertension, diabetes, heart failure, and higher INR ranges were significantly associated with lower TiTR, suggesting that these conditions may complicate effective anticoagulation therapy in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determinants of low-quality warfarin anticoagulation in patients with mechanical prosthetic heart valves. The nationwide PLECTRUM study. Pastori, D., Lip, GYH., Poli, D., et al.[2021]

In a study of 394 patients with mechanical heart valve prostheses, INR variability was found to be as effective as time in therapeutic range (TTR) in predicting the risk of thromboembolism, major bleeding, and death.

High INR variability significantly increased the risk of adverse outcomes, even within patients who had low or high TTR, indicating that monitoring INR variability could provide crucial additional information for patient management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

INR variability and outcomes in patients with mechanical heart valve prosthesis. Labaf, A., Själander, A., Stagmo, M., et al.[2016]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36610532/

Low-Dose vs Standard Warfarin After Mechanical Mitral ... Background: Current guidelines recommend a target international normalized ratio (INR) range of 2.5 to 3.5 in patients with a mechanical mitral prosthesis.

2. jtcvs.org jtcvs.org/article/S0022-5223(24)00359-3/fulltext

Low-dose warfarin with a novel mechanical aortic valve This prospective, observational clinical registry assessed adverse event rates in adult patients receiving low-dose warfarin (target international normalized ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2666572724000063

Anticoagulation for mechanical aortic valves At five-year follow-up, patients in the lower INR target arm experienced significantly lower rates of major bleeding events (1.6% versus 3.9% per patient-year; ...

4. evidence.nejm.org evidence.nejm.org/doi/full/10.1056/EVIDoa2300067

Apixaban or Warfarin in Patients with an On-X Mechanical ... Apixaban did not demonstrate noninferiority to warfarin and is less effective than warfarin for the prevention of valve thrombosis or thromboembolism.

5. healthcare-bulletin.co.uk healthcare-bulletin.co.uk/article/the-efficacy-of-anticoagulation-strategies-in-patients-with-mechanical-heart-valve-3144/

The Efficacy of Anticoagulation Strategies in Patients with ... This study compared the efficacy and safety of three anticoagulation strategies in patients with mechanical heart valves: warfarin alone, ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11199045/

Outcomes of Patients with a Mechanical Heart Valve and ... Conclusion In contemporary patients with a MHV, poor anticoagulation control on warfarin was associated with increased risks of thrombotic events, bleeding, and ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0022522324003593

Low-dose warfarin with a novel mechanical aortic valve Major bleeding and total bleeding were reduced by 87% and 71%, respectively, versus the comparator group, without an increase in thromboembolic events.

8. aats.org aats.org/resources/registry-results-of-low-dose-w-7574

164. Registry Results of Low-Dose Warfarin with a Novel ... Conclusions: This novel mechanical aortic valve prosthesis remains safe with an INR target of 1.8 (range 1.5-2.0) at 5 years post implant with reduced ...

9. onxlti.com onxlti.com/on-x-heart-valve-shows-safety-with-reduced-blood-thinners/

On-X Heart Valve Shows Safety with Reduced Blood ... Preliminary data show promising results for a regimen that may reduce the risk of bleeding by reducing the amount of warfarin therapy below now-standard levels ...