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Abstract
Introduction The purpose of this study is to evaluate the safety and efficacy of two different antithrombotic strategies, dual antiplatelet therapy (DAPT, aspirin and ticagrelor) and direct oral anticoagulant (DOAC, rivaroxaban), after left atrial appendage closure (LAAC) using the LACbes occluder.
Methods and analysis This study is a prospective, randomised, controlled and multicentre clinical trial that will compare the clinical efficacy of antiplatelet and anticoagulation therapy after LAAC with the LACbes occluder. It is planned to enrol 296 subjects with non-valvular atrial fibrillation (NVAF) who complete transcatheter closure of the left atrial appendage successfully. All subjects who pass the screening process and sign informed consent forms will be randomised in a 1:1 ratio to the DAPT group (aspirin 100 mg/day and ticagrelor 90 mg two times a day) or the DOAC group (rivaroxaban 15 mg/day). Baseline data within 24 hours after the operation and follow-up information at 3, 6 and 12 months will be recorded to investigate the difference in the incidence of device-related thrombosis, clinical thrombotic events, bleeding and other adverse events.
Ethics and dissemination Ethics approval has been obtained from the Ethics Committee of Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (Approval number SH9H-2022-T426-1). The protocol (Version: V1, 20230105) has also been submitted and approved by the institutional ethics committee at each participating centre. Results are expected in 2025 and will be disseminated through peer-reviewed journals and presentations at national and international conferences.
Trial registration number ChiCTR2100046712.
Trial registration name Different antithrombotic strategies after left atrial appendage closure with the LACbes occluder.
- Adolescent
- CARDIOLOGY
- Clinical Trial
- Protocols & guidelines
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This study is the first multicentre, randomised, non-inferiority comparative study of dual antiplatelet therapy (DAPT) and direct oral anticoagulant (DOAC) after left atrial appendage closure with the LACbes occluder.
This study evaluates the antithrombotic efficacy of the DAPT regimen after disk occluder implantation.
Computed tomography angiography (CTA) and transoesophageal echocardiography (TEE) will be performed at 3 months after surgery to better define the blocking effect (device-related thrombus, peridevice leak, endothelialisation) and to guide the development of antithrombotic strategies.
Only the Chinese population will be enrolled in the study, and no ethnic differences will be involved.
The use of rivaroxaban 15 mg instead of the standard 20 mg/day in the DOAC group may have an impact on the results of this study.
Introduction
Non-valvular atrial fibrillation (NVAF) is the most common arrhythmia in clinical practice.1–3 The latest data show that the prevalence of atrial fibrillation in China is as high as 1.6%.4 With the ageing of the population, it is speculated that the number of NVAF patients will still increase significantly in the next few years.5 Compared with the non-AF population, patients with NVAF have a fivefold increased risk of ischaemic stroke and systemic embolism, accounting for 20% of all ischaemic stroke events, and have a worse prognosis than patients with stroke from other causes.1 Currently, the CHA2DS2-VASc score is recommended to assess the risk of stroke caused by NVAF in patients. Men with a score ≥2 or women with a score ≥3 should take oral anticoagulants (OACs) for life to reduce the risk of stroke. OACs include vitamin K antagonists and direct oral anticoagulants (DOACs), such as thrombin inhibitors (dabigatran) and Xa inhibitors (rivaroxaban, edoxaban, etc). DOACs show more stable anticoagulant properties than the vitamin K antagonist warfarin.1 6 However, due to the increased risk of bleeding, their widespread clinical use is limited.7–11 The annual incidence of major bleeding and minor bleeding caused by DOACs is 1.5–3.6% and 15–20%, respectively, so the use of DOACs in patients with a high bleeding risk should be more cautious.7
More than 90% of thrombi in NVAF patients originate from the left atrial appendage (LAA).12 Therefore, in recent years, left atrial appendage closure (LAAC) has been used to prevent thrombus detachment. This technique can achieve the same preventive effect as OACs and significantly reduce the risk of disability or death caused by thromboembolism in NVAF patients.13–15 In addition, LAAC has significant advantages in reducing the risk of bleeding.13 15 However, to prevent device-related thrombosis (DRT) and promote endothelialisation, patients still need antithrombotic therapy in the short term after LAAC. Although European and American guidelines and LAAC expert consensus in China have proposed corresponding antithrombotic strategy recommendations according to different occluder types,16–18 with anticoagulation preferentially recommended, recently published real-world data suggest that the strategy has not been widely used.19 In China, LAAC operators often choose medication regimens considering patients’ wishes and the risks of bleeding and stroke. Current statistics show that antithrombotic therapy is still dominated by DOACs, accounting for approximately 80%,20 which will undoubtedly pose problems in patients who cannot tolerate anticoagulation or need combined antiplatelet drugs, such as patients managed after coronary heart disease intervention.
With the continuous practice of LAAC worldwide and new breakthroughs in device development, the antithrombotic management strategy of NVAF patients receiving LAAC also needs to be optimised accordingly. The LACbes occluder is one of the LAA occluders developed independently in China, which has gone through the stages of appearance design, barb development, finalisation, animal experiments and pre-market clinical research.21 22 It was approved and available only in China, and went public in 2019. The LACbes occluder was approved for patients who cannot tolerate anticoagulation in the long term, and also used for patients as an alternative for anticoagulation. It has a stable structure, good positioning and sealing effect on the LAA cavity wall, and is easy to be repeatedly operated. It can be introduced into the delivery catheter several times and fully recovered without damaging the barb and the catheter. The location area can be selected according to the actual shape and size of the LAA, so as to shorten the operation time and reduce the risk of operation. However, in terms of postoperative medication, there is no evidence-based guideline on the best strategy of antithrombotic therapy after LAAC implantation of LACbes occluders, and different medical centres can only refer to other occluders for empirical anticoagulation or antiplatelet therapy in clinical practice. A total of 98 LAAC patients who used LACbes blockers and completed 3 months of postoperative transoesophageal echocardiography (TEE) follow-up in our centre from 2020 to 2021 were retrospectively analysed. 61 patients in the DOAC group were treated with DOAC, while 27 patients in the DAPT group were treated with DAPT. TEE examination at 3 months after surgery showed that the incidence of DRT in the two groups was 6.6% and 3.7%, respectively, and the difference was not statistically significant (p=0.76, see table 1).
DRT results at the 3-month follow-up after LAAC with the LACbes Occluder
In the above retrospective analysis of our small sample, there was no significant difference in DRT formation between the two antithrombotic regimens, DAPT and DOAC, after the use of the LACbes occluder for LAAC, but the level of evidence was low due to the small sample and non-randomised controlled study. Therefore, we propose to conduct a prospective clinical study to compare the efficacy and safety of two antithrombotic strategies, DAPT including aspirin and ticagrelor and DOAC with rivaroxaban, after LAAC with a LACbes occluder using a randomised, controlled, open-label methodology, with the aim of providing strong evidence-based results for the optimal postoperative antithrombotic strategy for LACbes occluders.
Methods and analysis
Patient selection
This study intends to enrol 296 consecutive patients with atrial fibrillation after LACbes LAAC. Patient selection criteria are presented in table 2.
Patient selection
Study design
This study is a prospective, randomised, controlled, multicentre clinical trial that will compare the efficacy and safety of two different antithrombotic strategies, DAPT versus DOAC, after left atrial appendage closure with the LACbes occluder. The trial plans to enrol 296 subjects with NVAF who have successfully completed LAAC and randomly assign patients to the enrolment using a multicentre competitive enrolment and central randomisation system. The central randomisation system was designed by the trial statistician.
After determining the indication for LAAC, preoperative TEE or cardiac computed tomography angiography (CTA) will be performed to exclude thrombus and to measure and assess LAA anatomy. If the patient is a appropriate candidate for LAAC with LACbes occluder, the study will be explained and informed consent (online supplemental form 1) will be signed. Patients will be randomised into two groups on a 1:1 basis after the successful LACbes occlusion procedure. The randomisation process will be achieved via the internet with a centralised randomisation system designed by the statistical side of the trial. Patients will not be included if the procedure fails (device not implanted or complications in the immediate postoperative period of the procedure).
Supplemental material
According to the results of randomisation, patients in the DAPT group will be given aspirin 100 mg+clopidogrel 75 mg/day for 12 weeks, and patients in the DOAC group will be given rivaroxaban (15 mg/day) for 12 weeks. Conditions requiring aspirin use, such as acute coronary syndrome (ACS), within 3 months after LAAC will be reported as adverse events. After completion of the 12-week follow-up visit to rule out DRT, both groups will be switched to DAPT until 6 months postoperatively, and then switched to single antiplatelet therapy. After 12 months, the surgeon will decide whether the patient should be maintained on aspirin therapy.
The investigators will record baseline data within 24 hours after the procedure and relevant follow-up information at 3, 6 and 12 months after the procedure to investigate differences in the incidence of comparative occluder-associated thrombosis, clinical thrombotic events, other thrombotic events and bleeding events. The patient enrolment schemes are shown in figure 1.
Patient enrolment scheme. *If DRT is detected by TEE at postoperative week 12, the treatment will be changed to anticoagulation for 3 months, after which TEE will be repeated and the antithrombotic regimen will be adjusted according to the assessment. CTA, computed tomography angiography; DAPT, dual antiplatelet therapy; DOAC, direct oral anticoagulants; DRT, device-related thrombus; LAAC, left atrial appendage closure; TEE, transoesophageal echocardiography; SAPT, single antiplatelet therapy.
Endpoints
Primary endpoints
The primary efficacy endpoint is the 12-month freedom from major adverse clinical events in both groups, including stroke/transient ischaemic attack, other thromboembolic events, device-related thrombotic events and all-cause mortality.
The primary safety endpoint comprises bleeding events (referred to Bleeding Academic Research Consortium (BARC) criteria ≥3 a) at 3 months after surgery.
Secondary endpoints
Device-related thrombotic events at 3 months after surgery.
Incidence of minor bleeding at 6 and 12 months.
Degree of endothelialisation at 6 and 12 months. The incidence of complete endothelialisation will be evaluated by CTA, which was defined as a radiation density CT value of less than 100 HU in the atrial appendage or less than 25% of the left atrial CT value.
Postoperative follow-up and evaluation/endpoints
Clinical follow-up, including clinical visits and physical examinations, will be performed at 3, 6 and 12 months. Clinical visits will include specific assessments of thrombotic and bleeding events as well as general adverse events and serious adverse events. During these clinical visits, special questions will be asked about concomitant therapy, subject discontinuation following any use of the study drug, consent withdrawal, risk of overdose or pregnancy. At 3, 6 and 12 months, we will perform general laboratory tests, including haemoglobin levels, platelet counts, coagulation status and renal function. Imaging follow-up will include TEE (at 3 months after surgery) and CTA (at 3, 6 and 12 months). Antithrombotic therapy will be continued, stopped or changed according to the treating physician’s criteria in the event of any clinical thromboembolic event, device-related thrombotic event or major bleeding. The outcome and event definitions are shown in table 3.
Outcome and event definitions
Sample size justification
A total of 296 patients are expected to be enrolled in this trial and randomised into the study or control group at a 1:1 ratio, with 148 cases in each group. The sample size calculation is based on the primary evaluation measure, that is, no occurrence of major clinical events. Considering the available clinical evidence and the experience of clinical experts, it is assumed that the control group would have a 95% non-incidence rate of major clinical events, and it is expected that the test group would be able to achieve the same level of safety with the application of the test product. As determined by clinical discussions, the non-inferiority cut-off value has been set at 8%, referring to the study23 initiated by the Structural Heart Disease Center of Fuwai Hospital which also used antithrombotic drugs after disk occluder implantation and taking into account our prior clinical experience and practical implications. The significance level of the statistical test has been adopted at 0.025 unilaterally; the certainty level has been accepted at 90%. According to the maximum possible fall-out rate of 10% in the study, 148 patients need to be enrolled in each group based on the principle of statistics, and the total number of cases in the two groups will be 296.
The corresponding sample size calculation formula is as follows:
in the formula corresponds to the non-incidence of major clinical events in the test group, 
represents the non-incidence level of major clinical events in the control group, 
represents the non-incidence rate of average major clinical events in the two groups, Δ corresponds to the non-inferiority margin, μ represents the quantile of the standard normal distribution, α corresponds to the type I error level of the statistical test and 0.025 (one-sided) is taken here, while β corresponds to the type II error level of the test, and 0.1 (corresponding to the 90% power level) is taken for calculation. No additional cases will be added after certain subjects have withdrawn for various reasons.
Data management
Data will be collected by the investigators from each participating institution and then uploaded and stored on the electronic data capture system by the clinical research coordinator (CRC) to protect confidentiality before, during and after the trial. The database will not be unblinded until protocol violations have been identified, data collection has been declared as complete and the medical and scientific review has been completed. The final dataset will be encrypted and stored in an online database accessible only to the main researchers and administrators.
All study-related information will be stored securely at the study site. All participant information will be stored in locked file cabinets in areas with limited access. All laboratory specimens, reports, data collection, process and administrative forms will be identified by a coded ID number only to maintain participant confidentiality. All records that contain names or other personal identifiers, such as locator forms and informed consent forms, will be stored separately from study records identified by code number. All local databases will be secured with password-protected access systems. Forms, lists, logbooks, appointment books and any other listings that link participant ID numbers to other identifying information will be stored in a separate, locked file in an area with limited access.
Data analysis
Efficacy analysis will be performed by intent-to-treat set, which consisted of all randomised patients. All results of the efficacy analysis will be analysed in the full analysis set (FAS) and per-protocol set (PPS), which included all randomised patients without major protocol deviations. Descriptions of quantitative indicators will include the mean, SD, median, minimum, maximum, lower quartile (Q1) and upper quartile (Q3). Descriptions of categorical indicators will include the number and percentage of each type. Statistical tests will first apply parametric statistical methods; if the data distribution is markedly different from the distribution assumed by the statistical tests, non-parametric statistical methods will be used. The primary evaluation indicators will adopt a one-sided 0.025 significance level, whereas other statistical tests, if not otherwise specified, will adopt a two-sided test with a significance level of 0.05. Two-sided 95% CIs will be calculated. Pearson’s χ2 or Fisher’s exact probability tests will be performed on the freedom from major adverse events between the test and control groups, and point estimates and CIs for the difference in rates between groups will be calculated using the Newcombe-Wilson method. If the lower CI of the rate difference is >−8%, the null hypothesis will be rejected, and the test group will be considered non-inferior to the control group; if the lower CI of the rate difference is >0, the test group will be considered superior to the control group. HR point estimates and 95% CIs will also be calculated for the relative risk of incidence in both groups. The primary efficacy evaluation will be based on the FAS and PPS, and other efficacy evaluations will be based on the FAS. Safety evaluations will be performed on the safety analysis set. Analysis of the safety parameters will be conducted as follows: The vital signs, laboratory tests and other adverse events that were normal before treatment and abnormal after treatment will be described, and the number of cases and the proportions will be listed. Groupings according to the number and incidence of all adverse events and serious adverse events, as well as according to the number and incidence of device-related adverse events and serious adverse events, will be conducted. Moreover, the specific manifestations and degree of all adverse events that occur in each group and their relationship with the investigational device shall be described in detail. The incidences of device-related adverse events and device malfunctions will be compared between the test group and the control group.
The statistical analysis involves relevant links that are consistent with ICH E9 (The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use - Statistical principles for clinial trials E9) Statistical principles for clinial trials and relevant requirements in the Biostatistics Guidelines for Clinical Trials issued by the National Medical Products Administration (NMPA). After the study protocol is determined, the statistical analysis plan will be prepared by the statistician in consultation with the principal investigator. Each evaluation indicator and corresponding statistical analysis method in this trial will be described in detail in the statistical analysis plan. For missing data that may occur in the trial, a relatively conservative approach will be used to impute the primary analysis. Other missing indicators will not be imputed. For the processing of incorrect data and unreasonable data, logical verification and quality management will be performed for data in the database during data management. Queries will be used to raise questions to the investigator in case of any wrong data or unreasonable data, and the unreasonable data will be adjusted according to the investigator’s written reply until all unreasonable data or wrong data are resolved before locking the database.
Study organisation
The study steering committee is responsible for managing the scientific aspects of the study and formed by principal investigators of each participating institution and representatives from the sponsor and from the clinical research organisation (CRO). The study steering committee interacts with the sponsor and the CRO on study progress and related issues. Of note, as an investigator-sponsored research programme, the manufacturer (Shanghai Pushi Medical Instrument) of the LACbes occluder is not a participant in the design, conduct, data collection and statistical analysis of the study. The manufacturer only provides technical and coordination support to this study. An independent clinical events committee (CEC) is responsible for adjudicating events that are reported during this clinical trial. The CEC consists of three independent members, including two cardiologists and one neurologist. The CEC is blinded to the patient’s treatment arm for the adverse events they are adjudicating. In addition, an independent data monitoring committee (DMC) has been established, including two cardiologists and one biostatistician. The DMC holds meetings periodically to review study data. The DMC may recommend stopping the study early if the observed event rate is deemed to be unacceptable, and may also recommend the protocol be revised if deemed necessary to maintain the safety and welfare of the subjects involved. DMC also has the right to unblind the patient and the investigator when the patient has serious adverse events suspected to be related to the DAPT or DOAC.
Patient and public involvement
Neither patients nor the public will directly be involved in the design or conduct of this study, nor are they invited to participate in the writing or editing of this document. The recruitment of patients to participate in the study is based on their eligibility and participation protocol (signed informed consent). When signing the informed consent form, all participants will be asked if they wish to be informed about the results of the trial. They will receive a summary of the results, if desired.
Ethics and dissemination
Ethics approval was obtained from the Ethics Committee of Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (Approval number SH9H-2022-T426-1) and other participating centres table 4. This clinical study is being conducted in compliance with the Declaration of Helsinki (2013), Good Clinical Practice for Medical Devices and relevant national regulations. Any modifications to the protocol which may impact the conduct of the study, potential benefit of the patient or may affect patient safety, including changes of study objectives, study design, patient population, sample sizes, study procedures or significant administrative aspects, will require a formal amendment to the protocol. Such amendment will be approved by the Ethics Committee prior to implementation and notified to the health authorities in accordance with local regulations. Clinical trial insurance is purchased to provide compensation in the event of physical damage to the participants through the trial as well as in the events of health impairment and death. The results are expected in 2025 and will be disseminated through peer-reviewed journals and presentations at national and international conferences.
DAAL trial investigators
Ethics statements
Patient consent for publication
References
Footnotes
TZ, JZ and KZ contributed equally.
Collaborators Junfeng Zhang, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Guang'an Liu, Suzhou Kowloon Hospital, Shanghai Jiao Tong University School of Medicine, Suzhou, China; Yuan Bai, The First Affiliated Hospital of Naval Medical University（Changhai Hospital）, Shanghai, China; Zhuo Shang, Bengbu Municipal Second People Hospital, Bengbu, China; Shuxin Zhang, The First People's Hospital of Tongxiang City, Tongxiang, China; Jiahong Xu, Shanghai Pudong Gongli Hospital, Shanghai, China; Zhongping Ning, Shanghai Pudong New District Zhoupu Hospital, Shanghai, China; Lei Hou, Songjiang Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Wei Hu, Minhang District Central Hospital of Shanghai, Shanghai, China; Xiangdong Xu, Jiading District Central Hospital of Shanghai, Shanghai, China; Suxia Han, Shanghai Pudong New Area People's Hospital, Shanghai, China; Yansong Li, Shanghai Baoshan District Luodian Hospital, Shanghai, China; Xintao Deng, Jiangsu Xinghua People's Hospital, Xinghua, China; Xiaoli Chen, Nantong First People's Hospital, Nantong, China; Chengxing Shen, Shanghai Sixth People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Contributors JZ and QH initiated the study design and are the principal investigators. TZ, JZ and KZ wrote the first manuscript draft and subsequent revisions. CZ, KC, ZH, ZT, ZZ and QZ provided input on the study design, statistical analysis and daily research management. DAAL trial investigators performed this trial. All authors read and approved the final manuscript. JZ is the guarantor.
Funding This work was supported by the Shanghai Hospital Development Center Three-Year Action Plan for Promoting Clinical Skills and Innovation Ability of Municipal Hospitals (No. SHDC2022CRD045 to Junfeng Zhang), Clinical Research Program of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine (No. JYLJ202014 to Junfeng Zhang and Biobank for Coronary Heart Disease of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine (No. YBKA202206 to Junfeng Zhang).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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