Patient selection

Patients with paroxysmal, persistent, long-standing persistent or permanent NVAF, between 18 and 90 years of age, are eligible for this study. Inclusion criteria are as follows (box 1): (1) Diagnosis of NVAF; (2) Patients who have implanted with a Watchman LAA-Occluder 6 months prior to enrolment. The implantation of Watchman device was done with full informed consent. Patients should have paroxysmal or persistent NVAF with ECG evidence, with contraindications or unwillingness to receive long-term OAC or HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalised ratio, elderly, drugs/alcohol concomitantly) score ≥3 and with CHA₂DS₂-VASc (congestive heart failure, hypertension, 65 years of age and older, diabetes mellitus, previous stroke or transient ischemic attack, vascular disease, 65 to 74 years of age, female) score ≥2. The clinical exclusion criteria for the current trial (box 1) include patients taking aspirin for secondary prevention for established vascular diseases (such as coronary artery or carotid diseases), prior strokes and systemic embolisms, or having conditions contraindicated for aspirin therapy (such as active peptic ulcer, thrombocytopenia or anaemia). Patients with uncontrolled malignancy, abnormal liver, renal or coagulation function, or terminal illness with life expectancy less than 1 year are also excluded. The transesophageal echocardiography (TEE) exclusion criteria include peridevice residual leak >5 mm, or any DRT or other intracardiac thrombi. TEE will be performed to further evaluate the echocardiographic exclusion criteria. Of note, TEE performed between 6 weeks and 6 months postimplant are acceptable as baseline TEE evaluation. If the patients have had multiple TEEs within this period, the evaluation is determined by the last examination.

Study design

The ASPIRIN LAAO trial is a prospective, multicentre, randomised, double-blinded, placebo-controlled non-inferiority study. A total of 12 academic hospitals from mainland China will participate in the trial. NVAF patients who implanted Watchman device will be identified during the routinely 6-month postimplant follow-up visit. If informed consent is obtained, screening will be performed and patients who meets the inclusion criteria and does not meet any of the exclusion criteria will be enrolled. Randomisation will be subsequently performed which is prepared by the biostatistician. The eligible participants will be randomised in a 1:1 ratio to either the Aspirin group or the control (placebo) group. The randomisation code will be computer generated with a block size of 4, and the randomisation will be stratified by sites. Both patients and treating physicians will be blinded to the allocated therapy. Study patients assigned to Aspirin group will receive enteric coated aspirin (100 mg/day, by Yung Shin Pharm, Jiangsu, China). The control group receives placebo (by Yung Shin Pharm, Jiangsu, China). The recruited patients will start to receive randomised drugs from the day after the allocation day. Subjects of both groups will have follow-up visits by the investigators at AF Centre of each participating institution at 6 and 12 months and then every 12 months until 24 months after the last patient recruitment. Additionally, investigators will enhance telephone follow-up every 2 months to guarantee medication regimen according to the protocol. The enrolment begins in June 2020 and the anticipated completion will be in December 2024. The patient enrolment schemes are shown in figure 2.

• Download figure
• Open in new tab
• Download powerpoint

Figure 2

Patient enrolment scheme. *Concomitant catheter ablation of atrial fibrillation might be performed in the same procedure of LAAO. LAAO, left atrial appendage occlusion; NVAF, non-valvular atrial fibrillation.

The protocol and informed consent (see online supplemental file) are approved by each investigator’s institutional review board before patient recruitments. Prior to enrolment, informed consent will be obtained from patients. Patients who have fulfilled all the inclusion criteria will also undergo baseline characteristics evaluation, including intraprocedural parameters and antithrombotic regimen in the initial 6 months post-implant.

Endpoints

The primary endpoint is a composite consisting of stroke, systemic embolism, cardiovascular or unexplainable death, acute coronary syndrome, coronary artery disease or periphery vascular disease requiring revascularisation and major bleeding. The secondary endpoints are all-cause death, DRT, minor bleeding and rehospitalisation due to heart failure. The outcome definitions, as shown in table 1, are adhered to the Munich consensus which document on definitions, endpoints and data collection requirements for clinical studies of LAAO.29

Sample size justification

The statistical objective is to determine if the control group is non-inferior to the aspirin group with respect to the event rate for the composite endpoints. The reasons for the non-inferiority design are as follows. First, aspirin, as one of the most widely used drugs, serves as a standard treatment. Second, if placebo is non-inferior to aspirin, discontinuation of aspirin post LAAO will be of high cost effectiveness and may improve quality of life if not on medication. Also, testing the non-inferiority hypothesis requires smaller sample size.

Event rate is defined as the expected number of events per 100 patient years of follow-up. The study event rate is the combination of event rates from both the aspirin and placebo arms. The estimated event rates for this trial were established based on the rates seen in the LAAO arm of previous Watchman studies and the aspirin arm of previous aspirin trials.13 14 16–18 20 30–33 In the EWOLUTION study, the rates of stroke, major bleeding and cardiovascular death were 1.3%, 2.7% and 2.25%, respectively.17 In the ASCEND (A Study of Cardiovascular Events iN Diabetes) trial, the rates of myocardial infarction and vascular diseases requiring revascularisation were approximately 0.9%.32 Therefore, we conservatively estimate a combined rate for the primary endpoint of 7 events per 100 patient-years. A risk ratio criterion (control group over aspirin group) of 1.5 will be used to establish non-inferiority with a power of 0.8. Therefore, 191 events are required to be observed based on one-sided alpha of 0.025. The subject recruitment is assumed to be over a 2-year period and all subjects will be followed up until 2 years after the last recruitment. Given these assumptions, the sample size of the ASPIRIN LAAO trial is calculated as 1120 subjects, considering a 10% attrition rate. The attrition rate is estimated according to our follow-up data of a previous registry regarding Watchman device implantation (ClinicalTrials.gov: NCT03788941). Achieving adequate participant enrollment to reach target sample size should be feasible within the 2-year recruitment period due to the large operation volume of the participating centres. To further facilitate the recruitment of patients, advertisement of this study will be exhibited by posters in the wards and outpatient clinics.

Data management

Data will be collected by the investigators from each participating institution and be uploaded and stored on the secure Research Electronic Data Capture 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 is encrypted and stored in an online database accessible only to main researchers and administrators.

Data analysis

All comparisons of the primary endpoints between treatments will be on an intention-to-treat (ITT) basis, with each patient analysed as being part of their group regardless of the actual treatment received. The ITT population will also be used for the primary analysis of all secondary endpoints. The primary composite endpoint and each component of the primary endpoint (stroke, systemic embolism, cardiovascular or unexplained death, acute coronary syndrome, coronary artery disease or periphery vascular disease requiring revascularisation and major bleeding) will be summarised as a rate per 100 patient-years of follow-up. The event rates will be analysed using the same method as the composite endpoint. The analysis will include 95% CIs with these analyses. Secondary endpoints will be presented as proportions with 95% CIs.

The per-protocol (PP) analysis will also be conducted for both primary and secondary endpoints, as PP analysis may be of lower efficacy but provide more reliable data. The PP population includes patients receive at least 80% of planned trial medication. For patients who do not complete the study or do not have an outcome event, their time-to-event measure will be censored at the last contact date. In addition, Net Clinical Benefit (NCB) analysis will also be performed post hoc. We define the NCB of aspirin as the sum of the differences between the annualised rates of death event, stroke, systemic embolism, acute coronary syndrome, coronary artery disease or periphery vascular disease requiring revascularisation and major bleeding occurring after the randomisation and the respective rates on placebo, weighting each component by a factor reflecting the severity of functional impact relative to death event (unity).

Descriptive data will be collected at baseline (6 months post-implant) and at follow-up. The information of device-related and intraprocedural properties, as well as postimplant antithrombotic regimen at the initial 6 months will also be reviewed. For continuous variables, the mean, SD and 95% CIs will be reported. Differences between groups, including means, proportions and ratios, will be reported by 95% credible intervals. The Poisson, logistic and Cox regression models will be used for rates in patient years, binary response variables and time-to-event analysis, respectively.

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 (Boston Scientific) of the LAAO device does not participate in the design, conduct, data collection and statistical analysis of the study. The manufacturer only provides funding, 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. 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 unblinding the patient and the investigator when the patient has serious adverse events suspected to be related to aspirin or placebo.

Patient and public involvement

Patients or the public are not directly involved in the design or conduct of this study, and are not invited to contribute to the writing or editing of this document. Patients are recruited in the study based on their eligibility and agreement to participate (signed informed consent form). All participants are asked if they want to be informed about the results of the trial when signing the informed consent. If required, they will receive a summary of the results.