Lower INR Warfarin for Mechanical Valve Patients

(LIMIT Trial)

Recruiting at 19 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

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the drug Warfarin for patients with mechanical heart valves?

Warfarin is the only oral anticoagulant approved for use after mechanical valve surgery, and it is essential for preventing blood clots in patients with mechanical heart valves. The quality of treatment with warfarin is mainly assessed by the time in therapeutic range (TTR), which is crucial for reducing the risk of complications like thromboembolism (blood clots) and major bleeding. ^{1 2 3 4 5}

Is warfarin generally safe for patients with mechanical heart valves?

Warfarin is generally considered safe for patients with mechanical heart valves, as it is the standard treatment to prevent blood clots. However, some patients may experience warfarin resistance, requiring alternative treatments like acenocoumarol. Other anticoagulants like dabigatran and rivaroxaban have shown higher risks and are not recommended for these patients. ^{1 6 7 8 9}

How does the drug Warfarin differ from other treatments for patients with mechanical heart valves?

Warfarin is unique because it is the only oral anticoagulant approved for use in patients with mechanical heart valves, and it requires careful monitoring to maintain a specific INR (a measure of blood clotting) to prevent complications. Unlike newer anticoagulants, Warfarin's effectiveness and safety in this specific condition are well-established, although it can be challenging to manage due to potential resistance and the need for regular blood tests. ^{1 2 6 9 10}

Research Team

Emilie Belley-Côté, MD, MSc

Principal Investigator

McMaster University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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 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]

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]

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 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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Warfarin resistance: possibilities to solve this problem. A case report. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Association between time to therapeutic INR and length of stay following mechanical heart valve surgery. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

INR variability and outcomes in patients with mechanical heart valve prosthesis. [2016]

4. Switzerland 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. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Determinants of low-quality warfarin anticoagulation in patients with mechanical prosthetic heart valves. The nationwide PLECTRUM study. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Dabigatran use in mechanical heart valve patients. [2018]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Mechanical Prosthetic Heart Valve Thrombosis in a Patient Receiving Rivaroxaban. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Fatal association of mechanical valve thrombosis with dabigatran: a report of two cases. [2017]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Rivaroxaban Versus Warfarin in Patients with Mechanical Heart Valves: Open-Label, Proof-of-Concept trial-The RIWA study. [2021]

10. England 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? [2013]