Highlights
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Antithrombotic therapy following transcatheter edge-to-edge repair is essential to mitigate ischemic complications, whereas no randomized controlled trial has established the optimal anticoagulation strategies.
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STAR-TEER trial is an investigator-initiated, multicenter, randomized, parallel controlled, open-label trial, aiming to compare the safety and efficacy of different antithrombotic strategies.
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A total of 1,912 post-TEER patients is scheduled to recruit.
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The dual-cohort design allows for individualized evaluation based on the presence or absence of an indication for long-term oral anticoagulation.
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The incorporation of superiority and noninferiority hypotheses in a hierarchical testing framework enables the trial to rigorously evaluate both safety and efficacy outcomes.
ABSTRACT
Background
Transcatheter edge-to-edge repair (TEER) has emerged as an important therapy for severe mitral regurgitation. Current guidelines lack evidence-based recommendations for optimal postprocedural antithrombotic strategies, leading to heterogeneous clinical practices. And there are no randomized controlled trials (RCTs) available to compare different antithrombotic strategies following TEER.
Methods
STAR-TEER trial is an investigator-initiated, multicenter, randomized, parallel controlled, open-label trial, aiming to assess the safety and efficacy of de-escalated antithrombotic strategies with monotherapy in post-TEER patients with or without indications for oral anticoagulation (OAC) respectively. This trial plans to enroll 1,912 patients stratified into 2 cohorts: patients in Cohort A (requiring long-term OAC, n = 880) will be randomized 1:1 to rivaroxaban monotherapy or rivaroxaban plus clopidogrel, and patients in Cohort B (no OAC indication, n = 1,032) will be randomized 1:1 to aspirin monotherapy or aspirin plus clopidogrel. The primary outcome is all bleeding complications within 12 months post-TEER. The 2 key secondary outcomes are nonprocedure-related bleeding within 12 months post-TEER (key secondary outcome 1) and a composite of ischemic events including all-cause mortality, stroke, systemic embolism, and myocardial infarction within 12 months post-TEER (key secondary outcome 2). A hierarchical hypothesis testing will be performed, with the primary outcome and key secondary outcome 1 tested for superiority, followed by the key secondary outcome 2 tested for noninferiority.
Conclusion
The STAR-TEER trial is the first large randomized controlled trial (RCT) to stratify patients based on OAC indication and compare different antithrombotic strategies following TEER in these 2 distinct cohorts.
Trial Registration
URL: https://www.clinicaltrials.gov . Unique identifier: NCT06901466 (Cohort A), NCT07007143 (Cohort B).
Background
Mitral regurgitation is a common valvular disorder that can lead to left ventricular enlargement and dysfunction, and if untreated, can cause congestive heart failure and death. Over the past 2 decades, transcatheter edge-to-edge repair (TEER) has emerged as a key therapeutic option for patients with symptomatic severe MR who are ineligible or high risk for surgery. ,,,
During TEER, transseptal puncture and the implantation of foreign materials create thrombogenic surfaces, increasing the risk of peri-procedural thrombosis and ischemic events. Additionally, TEER may induce relative mitral stenosis or restrict leaflet mobility, leading to abnormal blood flow patterns and elevated thrombus risk. , Moreover, atrial fibrillation (AF), present in over 60% of TEER patients, further necessitates long‐term oral anticoagulation (OAC). Consequently, antithrombotic therapy following TEER is essential to mitigate ischemic complications.
However, no randomized controlled trial (RCT) has established the optimal anticoagulation strategies post-TEER, and neither the American College of Cardiology/American Heart Association (ACC/AHA) nor the European Society of Cardiology (ESC) has issued definitive recommendations. , Current practice is largely guided by physicians’ discretion and strategies used in earlier TEER trials, , leading to a heterogeneous spectrum of prescriptions. Among patients with an OAC indication, the most common regimen is OAC combined with single antiplatelet therapy (SAPT). For patients without an indication for OAC, aligning with earlier TEER trials, dual antiplatelet therapy (DAPT) is the most prevalent postoperative strategy, despite a lack of direct comparisons of different regimens in this population.
On the other hand, TEER patients are prone to elevated bleeding risks due to comorbidities such as hypertension, advanced age, renal or hepatic dysfunction, and diabetes mellitus. In these individuals, antithrombotic therapy may increase bleeding risk, which is associated with a higher rate of death and rehospitalization. Therefore, the balance of thrombosis prevention and bleeding risk is critical.
De-escalated antithrombotic strategies, validated as safe and effective following percutaneous coronary intervention (PCI) and transcatheter aortic valve implantation (TAVI), represent a promising approach to address this issue. ,, Previous observational studies have shown that OAC monotherapy showed reduced bleeding risk compared to dual or triple therapy (OAC plus aspirin or clopidogrel) in post-TEER patients, without compromised thrombotic protection. , Data directly comparing different antiplatelet strategies in post-TEER patients are limited. However, SAPT has been proven to reduce the incidence of bleeding and the composite of bleeding or ischemic events among patients who underwent TAVI. Thus, monotherapy with a single antiplatelet or anticoagulation agent may be beneficial for post-TEER patients.
We therefore designed this trial to test the hypothesis that de-escalated antithrombotic strategies with aspirin or rivaroxaban alone after TEER are safer, without compromise in preventing ischemic events, compared with the most commonly adopted combined regimens in the current clinical practice.
Methods
Trial design
This investigator-initiated, prospective, randomized, parallel-controlled, open-label multicenter trial evaluates the efficacy and safety of antithrombotic monotherapy with aspirin or rivaroxaban (treatment group) compared to the combined therapy (with an added clopidogrel; control group) over 12 months in patients who have undergone TEER. The trial consists of 2 cohorts:
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Cohort A includes patients with an indication for long-term OAC (eg, presence of AF) at the time of randomization. Participants are randomized 1:1 to receive either rivaroxaban alone or rivaroxaban plus clopidogrel.
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Cohort B includes patients without an indication for OAC, who are randomized 1:1 to aspirin alone or aspirin plus clopidogrel.
A total of 1,912 patients will be enrolled, with 880 in Cohort A and 1,032 in Cohort B. The study design is illustrated in Figure 1 .
STAR-TEER study design. This figure illustrates the study design and patient allocation. Patients will be stratified based on the presence or absence of OAC indications firstly, then randomly assigned to receive different antithrombotic strategies separately. OAC, oral anticoagulation; QD, quaque die.
Patient selection
Eligible patients must have undergone successful TEER, defined according to the technical success criteria established by the Mitral Valve Academic Research Consortium (MVARC). Patients with an indication for OAC are included in Cohort A, while those without such an indication are in Cohort B. All antithrombotic regimens must be approved by the investigator. Women of childbearing potential must use effective contraception from the time of informed consent until the final dose of antithrombotic agents.
Shared exclusion criteria for both cohorts include:
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Severe renal impairment.
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Ongoing postoperative bleeding or vascular complications following the index TEER procedure.
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Platelet count <50 × 10 9/L.
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Need for reoperation due to complications of the index TEER procedure.
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Recent (<12 month) intracranial or intracerebral hemorrhage.
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Recent (<12 month) gastrointestinal ulcers or hemorrhage.
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Hepatic disease with coagulopathy.
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Allergy, intolerance, or contraindication to research drugs.
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Participation in another investigational drug or device study within 30 days.
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Life expectancy <12 months.
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Pregnancy or breastfeeding.
Cohort-specific exclusions include:
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For Cohort A: Absolute indication for anticoagulation in combination with antiplatelet therapy (eg, recent PCI); occurrence of stroke/transient ischemic attack within the past 6 weeks.
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For Cohort B: Absolute indication for DAPT (eg, recent PCI); indication for long-term OAC.
A comprehensive list of inclusion and exclusion criteria is provided in Table 1 .
Table 1
Inclusion and exclusion criteria.
| Inclusion criteria | |
|---|---|
| Cohort A | Cohort B |
| 1. Successful TEER procedure, defined as technical success per MVARC criteria. | 1. Successful TEER procedure, defined as technical success per MVARC criteria. |
| 2. Indication for long-term OAC. | 2. Ability and willingness to comply with the trial protocol. |
| 3. Ability and willingness to comply with the trial protocol. | 3. Provision of written informed consent. |
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4. Provision of written informed consent.
5. Women of childbearing potential must use effective contraception from the time of consent until the final dose of antithrombotic therapy. |
4. Women of childbearing potential must use effective contraception from the time of consent until the final dose of antithrombotic therapy.
5. Antithrombotic strategy approved by the investigator. |
| 6. Antithrombotic strategy approved by the investigator. | |
| Exclusion criteria | |
| Cohort A | Cohort B |
| 1. Severe renal impairment (creatinine clearance <15 mL/min or requiring dialysis). | 1. Severe renal impairment (creatinine clearance <15 mL/min or requiring dialysis). |
| 2. Ongoing postoperative bleeding (defined as overt bleeding with a ≥3.0 g/dL drop in hemoglobin or requiring ≥3 units of blood transfusion), or vascular complications following the index TEER procedure. | 2. Ongoing postoperative bleeding (defined as overt bleeding with a ≥3.0 g/dL drop in hemoglobin or requiring ≥3 units of blood transfusion), or vascular complications following the index TEER procedure. |
| 3. Platelet count <50 × 10⁹/L. | 3. Platelet count <50 × 10⁹/L. |
| 4. Need for reoperation due to complications of the index TEER procedure. | 4. Need for reoperation due to complications of the index TEER procedure. |
| 5. Recent (<12 mo) intracranial or intracerebral hemorrhage. | 5. Recent (<12 mo) intracranial or intracerebral hemorrhage. |
| 6. Recent (<12 mo) gastrointestinal ulcers or hemorrhage. | 6. Recent (<12 mo) gastrointestinal ulcers or hemorrhage. |
| 7. Hepatic disease with coagulopathy (eg, Child-Pugh class B or C cirrhosis). | 7. Hepatic disease with coagulopathy (eg, Child-Pugh class B or C cirrhosis). |
| 8. Allergy, intolerance, or contraindication to research drugs. | 8. Allergy, intolerance, or contraindication to research drugs. |
| 9. Participation in another investigational drug or device study within 30 d. | 9. Participation in another investigational drug or device study within 30 d. |
| 10. History of stroke or TIA within the past 6 wk. | 10. Indication for long-term OAC. |
| 11. Absolute indication for anticoagulation in combination with antiplatelet therapy (eg, recent PCI). | 11. Absolute indication for DAPT (eg, recent PCI). |
| 12. Life expectancy <12 mo. | 12. Life expectancy <12 mo. |
| 13. Pregnancy or breastfeeding. | 13. Pregnancy or breastfeeding. |
Abbreviations: DAPT, dual antiplatelet therapy; MVARC, mitral valve academic research consortium; OAC, oral anticoagulation; PCI: percutaneous coronary intervention; TEER, transcatheter edge-to-edge repair; TIA, transient ischemic attack.
Study treatments and follow-ups
In Cohort A, patients are randomized 1:1 to receive either:
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Rivaroxaban monotherapy (20 mg once daily, minimum 12 months).
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Rivaroxaban (20 mg once daily, minimum 12 months) plus clopidogrel (75 mg once daily for 3 months).
According to current guidelines, bridging is not recommended for patients receiving rivaroxaban. Nevertheless, the final decision regarding perioperative management of rivaroxaban is left to the attending physician’s discretion in accordance with local practice. The dosage of rivaroxaban can be adjusted by the research physicians according to the patients’ clinical conditions, following the package insert.
In Cohort B, patients are randomized 1:1 to receive either:
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Aspirin monotherapy (100 mg once daily, minimum 12 months).
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Aspirin (100 mg once daily, minimum 12 months) plus clopidogrel (75 mg once daily for 3 months).
The selection of study medications and treatment strategies was based on current international guidelines, and antithrombotic treatment regimens used in prior large RCTs, as well as contemporary real-world clinical practice (Supplementary Materials for details).
During the procedure, unfractionated heparin is recommended to maintain an activated clotting time (ACT) > 250 seconds for both cohorts. Heparin reversal with protamine will not be routinely performed after the procedure. Block randomization with stratified by site will be performed via an interactive web-response system (IWRS) between 12 hours and 7 days following TEER, after subjects are transferred from the intensive care unit to the general ward and before hospital discharge, at which time their clinical condition is stable.
All patients will be followed up for 12 months from the date of randomization, with follow-up visits at 1, 3, 6, 9, and 12 months.
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