Evaluation of Safety and Efficacy of Lower INR Range in Patients with Bileaflet Aortic Mechanical Valves on Warfarin, Acenocoumarol, and Phenprocoumon Therapy

The primary objective of the Low INR to Minimize bleeding with mechanical valves Trial (LIMIT) is to evaluate the **safety** and **efficacy** of a common, lower International Normalized Ratio (INR) range in patients with bileaflet aortic mechanical valves. This is clinically relevant as it aims to reduce the risk of bleeding complications associated with the use of Vitamin K Antagonists, such as **warfarin**, in patients who have undergone mechanical bileaflet aortic valve replacement. The study focuses on optimizing anticoagulation therapy to enhance patient safety while maintaining therapeutic effectiveness.

The clinical trial involves a total of **1650 participants** who are undergoing treatment with a **Vitamin K Antagonist** due to having a mechanical bileaflet aortic valve replacement. The study population includes both male and female subjects, aged 18 years and older, who have had a bileaflet mechanical heart valve implant in the aortic position for at least three months. Participants were selected based on their ability to provide written informed consent, either personally or through a substitute decision-maker. The trial does not include a vulnerable population. The general health status of participants is characterized by their need for anticoagulation therapy following valve replacement. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data. The study aims to evaluate the safety and efficacy of a common, lower INR range in this specific patient group.

The clinical trial is designed to evaluate the safety and efficacy of a common, lower International Normalized Ratio (INR) range in patients with bileaflet aortic mechanical valves. This is a **Phase III** randomized, double-blind, controlled trial. The trial is expected to run from October 2021 to December 2026, with participant involvement lasting up to 36 months. The study involves the administration of **warfarin**, **acenocoumarol**, and **phenprocoumon**, all in tablet form, with a maximum daily dose of 20 mg for warfarin, 4 mg for acenocoumarol, and 12 mg for phenprocoumon, administered orally.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as having had a bileaflet mechanical heart valve implant in the aortic position at least three months prior and being at least 18 years of age. Following the screening, participants will be randomized into treatment groups. Regular follow-up visits will be scheduled to monitor INR levels, assess for any adverse events, and ensure compliance with the study protocol. The primary endpoint is the occurrence of thrombosis/thromboembolism and major bleeding, while secondary endpoints include all-cause mortality, all clinically important bleeding, and other cardiovascular events.

The end-of-study visit will occur at the conclusion of the 36-month treatment period or upon early termination. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial aims to provide valuable data on the optimal INR range for patients with mechanical heart valves, potentially influencing future treatment guidelines.

The clinical trial involves the administration of **Warfarin**, a well-known anticoagulant, in the form of a **tablet**. The active substance, **warfarin**, is of chemical origin. The maximum daily dose is set at 20 mg, with the same amount as the maximum total dose. The treatment period is capped at 36 months. The route of administration is **oral**, and the medication is not formulated for pediatric use. Participants are required to adhere to the dosing schedule, and compliance will be monitored throughout the trial.

Another treatment used in the trial is **Acenocoumarol**, also administered as a **tablet**. The active substance, **acenocoumarol**, is chemically derived. The maximum daily and total dose is 4 mg, with a treatment duration of up to 36 months. This medication is also administered orally and is not intended for pediatric patients. Participant adherence to the dosing regimen will be closely monitored to ensure compliance.

**Phenprocoumon** is included as a comparator treatment in the trial, provided in **tablet** form. The active substance, **phenprocoumon**, is administered orally with a maximum daily and total dose of 12 mg. The treatment period is limited to 36 months. This medication is not designed for pediatric use, and participant compliance with the dosing schedule will be assessed regularly.

Throughout the trial, the administration of these medications will be carefully monitored to ensure participant safety and adherence to the prescribed dosing schedules. Compliance monitoring will be conducted to maintain the integrity of the trial data and to evaluate the efficacy and safety of the treatments in patients with bileaflet aortic mechanical valves.

The clinical trial aims to evaluate the safety and efficacy of a common, lower International Normalized Ratio (INR) range in patients with bileaflet aortic mechanical valves. The primary efficacy endpoint is the composite of **thrombosis/thromboembolism**, including ischemic stroke, systemic thromboembolism, and valve thrombosis, as well as major bleeding events. Secondary endpoints include all-cause mortality, all clinically important bleeding, minor bleeding, all types of stroke (ischemic and hemorrhagic), myocardial infarction (types 1, 2, or 3), systemic thromboembolism, valve thrombosis, pulmonary embolism, deep vein thrombosis, new renal replacement therapy, time in therapeutic range, and the proportion of patients with extreme INR values (>4).

Efficacy parameters will be measured and collected at specified intervals throughout the trial duration, which is estimated to conclude by December 31, 2026. The trial will utilize validated clinical assessments and laboratory tests to monitor these endpoints. The data collected will be analyzed to determine the effectiveness of maintaining a lower INR range in reducing thromboembolic events and bleeding complications in the target patient population. The trial is categorized as a Phase III clinical trial, focusing on the therapeutic benefits and safety profile of the treatment regimen.