Advanced Heart Failure, Anticoagulation Treatment, Bleeding Complications, Left Ventricular Assist Devices, Thrombotic Complications
Conditions
Keywords
HeartMate 3 LVAD, Left Ventricular Assist Device, Advanced Heart Failure, Anticoagulation, Warfarin, International Normalized Ratio (INR), Low-intensity Anticoagulation, Major Bleeding, Gastrointestinal Bleeding, Pump Thrombosis, Stroke, Thromboembolism, Hemocompatibility, Randomized Controlled Trial, Safety and Efficacy
Brief summary
The TARGET trial is a prospective, single-center, randomized, open-label, active-controlled inequality clinical trial designed to evaluate the safety and efficacy of low-intensity anticoagulation therapy (target INR 1.5-2.0) compared to standard anticoagulation therapy (target INR 2.0-3.0) in patients receiving a HeartMate 3 Left Ventricular Assist Device (LVAD). Despite the demonstrated effectiveness of HeartMate 3 LVAD in reducing thromboembolic complications, standard anticoagulation treatment guidelines recommend maintaining an INR between 2.0 and 3.0, which can lead to a substantial risk of bleeding, especially gastrointestinal (GI) bleeding. Preliminary studies, such as MAGENTUM 1, have indicated potential safety and reduced bleeding events at lower INR targets (1.5-1.9). However, robust evidence through randomized controlled trials is still required. The primary objective of the TARGET trial is to determine if low-intensity anticoagulation therapy significantly reduces the incidence of major bleeding and thrombotic events compared to standard therapy within 6 months post-randomization. Secondary objectives include evaluating the safety and hematological complications associated with low-intensity anticoagulation. The study will enroll adult patients aged ≥19 years who have been stably maintained on standard INR therapy (2.0-3.0) for at least 30 days post-HeartMate 3 LVAD implantation. Participants will be randomized in a 1:1 ratio into two groups: the low-intensity INR group (target INR 1.5-2.0) and the standard INR group (target INR 2.0-3.0). Randomization will be stratified based on the presence of atrial fibrillation. The primary endpoint is a composite of hemocompatibility-related events, including major bleeding, stroke, and pump thrombosis, occurring within 6 months after randomization, as defined by INTERMACS criteria. Secondary endpoints encompass clinical outcomes such as all-cause mortality, cardiac death, LVAD-related thromboembolic events, stroke, systemic embolism, myocardial infarction, major bleeding incidents, and the rate and number of LVAD-related hospital readmissions and reoperations. Additionally, INR management outcomes, including time in therapeutic range (TTR) and frequency of warfarin dose adjustments, will be assessed. The trial duration is approximately 36 months, including a 24-month enrollment period, a 6-month follow-up period for each participant, and time allocated for data analysis and reporting. Safety will be rigorously monitored by a Data Safety Monitoring Board (DSMB) and Clinical Events Committee (CEC), ensuring participant safety and data integrity throughout the study. This trial aims to provide critical insights that could optimize anticoagulation strategies in LVAD patients, potentially improving patient safety by reducing bleeding risks without compromising thrombotic event protection.
Interventions
DRUGWarfarin (standard anticoagulation)
Standard INR group (Active Comparator): Participants will receive anticoagulation therapy with warfarin, maintaining an INR within the standard therapeutic range of 2.0-3.0. Warfarin dosing adjustments will be made regularly according to standard clinical practice and INR monitoring throughout the 6-month study period.
DRUGWarfarin (low-intensity anticoagulation)
Low-intensity INR group (Experimental): Participants will receive anticoagulation therapy with warfarin, aiming for a reduced INR range of 1.5-2.0, which is lower than the current standard recommendation. Warfarin dosing will be regularly adjusted based on INR monitoring throughout the 6-month study period.
Sponsors
Asan Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients who meet all of the following criteria will be eligible for randomization: Adults aged ≥19 years who have successfully undergone implantation of a HeartMate 3 LVAD. Patients who are at least 30 days post-implantation of HeartMate 3 LVAD. Patients who have maintained stable anticoagulation therapy with standard INR (2.0-3.0) for at least 30 days post-LVAD implantation. Patients or their legal representatives who provide documented informed consent and agree to the study protocol and follow-up schedule.
Exclusion criteria
* Patients who meet any of the following criteria will be excluded: Patients implanted with any mechanical assist device other than HeartMate 3 LVAD (e.g., other LVAD models, RVAD, BiVAD). Patients with a clinically significant stroke or transient ischemic attack (TIA) within the past 6 months. Patients with a history of hemorrhagic stroke. Patients who experienced major bleeding events within the past 6 months (based on INTERMACS major bleeding criteria). Patients with uncontrolled severe hypertension (systolic ≥180 mmHg or diastolic ≥110 mmHg). Patients requiring active treatment or surgical intervention for acute LVAD-related thrombosis or hemodynamic instability, or patients who underwent LVAD-related reoperation within the past 30 days. Patients with severe renal dysfunction (estimated Glomerular Filtration Rate \<15 mL/min) or patients undergoing dialysis. Patients with severe liver dysfunction causing coagulation abnormalities or those classified as Child-Pugh class B or C. Patients with active bleeding or ongoing hemorrhagic conditions. Patients with a high bleeding risk due to: Gastrointestinal bleeding or ulcers within the past 6 months. Surgery involving the brain, spine, or eyes within the past 6 months. Major central nervous system, ophthalmologic, or major open surgical procedures within the past 6 months. Presence or suspicion of esophageal varices. Arteriovenous malformation or vascular aneurysm. Patients who have received thrombolytic therapy for bleeding or thromboembolism within the past 30 days. Patients receiving long-term concurrent treatment with other anticoagulants (low molecular weight heparin, NOAC, Fondaparinux, etc.). However, temporary administration for warfarin bridging or heparin use for central venous or arterial catheter maintenance is permitted. Patients with persistent anemia (hemoglobin \<8 g/dL) or thrombocytopenia (platelet count \<50,000/µL) within the past 6 months. Patients currently experiencing infective endocarditis. Patients with a history of severe allergy or hypersensitivity to warfarin or other anticoagulants used in this study. Pregnant or lactating women, or women planning pregnancy during the study period. Patients with severe terminal illness with a life expectancy of less than 12 months. Patients with alcohol dependence or severe psychiatric conditions hindering study participation. Patients unwilling or unable to adhere to the procedures or evaluations required by the study protocol. Patients currently participating in another randomized drug or medical device clinical trial who have not yet completed the primary endpoint assessment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of composite hemocompatibility-related events | Within 6 months after randomization | The primary outcome is defined as a composite of hemocompatibility-related events including major bleeding (INTERMACS major bleeding criteria), stroke (ischemic or hemorrhagic), and pump thrombosis occurring within 6 months post-randomization. Events will be centrally adjudicated based on standardized INTERMACS definitions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All-cause mortality | Within 6 months after randomization | Incidence of death due to any cause. |
| Cardiac death | Within 6 months after randomization | Incidence of death directly attributed to cardiac causes, including heart failure, myocardial infarction, or sudden cardiac death. |
| LVAD pump thrombosis | Within 6 months after randomization | Incidence of pump thrombosis as defined by INTERMACS criteria, requiring intervention, replacement, or explantation of the LVAD. |
| LVAD-related thromboembolism | Within 6 months after randomization | Incidence of thromboembolic events directly related to LVAD, including embolic strokes or systemic embolisms. |
| Transient ischemic attack (TIA) | Within 6 months after randomization | Incidence of transient neurologic deficits lasting less than 24 hours without evidence of acute infarction. |
| Stroke | Within 6 months after randomization | Incidence of ischemic or hemorrhagic stroke with clinical neurologic deficits lasting ≥24 hours, as defined by NeuroARC criteria. |
| Systemic embolism | Within 6 months after randomization | Incidence of acute systemic embolism affecting major organs or limbs, confirmed by imaging or surgical findings. |
| Myocardial infarction | Within 6 months after randomization | Incidence of myocardial infarction diagnosed by typical symptoms, ECG changes, and elevation of cardiac biomarkers. |
| Time in therapeutic range (TTR) | Within 6 months after randomization | Proportion of time patients' INR values remain within the predefined therapeutic target range. |
| Composite (cardiac death, pump thrombosis, thromboembolism) | Within 6 months after randomization | Combined incidence of cardiac death, LVAD pump thrombosis, and LVAD-related thromboembolic events. |
| Composite (cardiac death, thrombosis, stroke, embolism, MI) | Within 6 months after randomization | Combined incidence of cardiac death, LVAD pump thrombosis, stroke, systemic embolism, and myocardial infarction. |
| Composite (stroke, embolism, TIA, MI) | Within 6 months after randomization | Combined incidence of stroke, systemic embolism, transient ischemic attack, and myocardial infarction. |
| Composite (death, stroke, embolism, TIA, MI) | Within 6 months after randomization | Combined incidence of all-cause mortality, stroke, systemic embolism, transient ischemic attack, and myocardial infarction. |
| LVAD-related readmission | Within 6 months after randomization | Incidence and frequency of hospital readmissions directly related to LVAD management or complications. |
| LVAD-related reoperation | Within 6 months after randomization | Incidence and frequency of surgical reoperations directly related to LVAD complications or device malfunction. |
| Out-of-range INR proportion | Within 6 months after randomization | Proportion of INR measurements falling outside the predefined therapeutic target range. |
| Warfarin dose adjustments | Within 6 months after randomization | Number of warfarin dose adjustments required to maintain target INR range. |
| Major bleeding event | Within 6 months after randomization | Incidence of major bleeding as defined by INTERMACS major bleeding criteria, including events requiring transfusion or intervention. |
Countries
South Korea
Contacts
Primary ContactMin-Seok Kim, MD, PhD
Backup ContactKitae Kim, MD
Outcome results
None listed