Left atrial appendage occlusion for patients with valvular diseases without atrial fibrillation (the OPINION Study): study protocol for a multicentre, randomised controlled trial

Abstract

Introduction

Atrial fibrillation (AF) is a significant cause of perioperative stroke in aortic and mitral valve surgeries. Although several large studies have evaluated surgical left atrial appendage occlusion (SLAAO) during cardiac surgeries, their retrospective nature and an uncontrolled broad spectrum of conditions leave them subject to potential residual confounding. This trial aims to test the hypothesis that opportunistic SLAAO can prevent long-term stroke after cardiac surgery in patients receiving mitral or aortic valve surgeries without a history of AF and with a CHA2DS2-VASc score of 2 or higher.

Methods and design

This study is a single-blinded, multicentre, randomised controlled trial. A total of 2118 patients planning to undergo aortic or mitral surgery without AF will be recruited and equally randomised into intervention or control arms at a 1:1 ratio. In the intervention arm, suture excision of the left atrial appendage (LAA) will be performed during the operation in addition to the original surgery plan. In the control arm, the operation will be performed according to the surgery plan without any intervention on the LAA. The primary outcome is a composite of newly occurred ischaemic stroke or transient ischaemic attack and cardiovascular mortality during a 1-year follow-up. Secondary outcomes include postoperative AF, cardiovascular mortality, newly occurred ischaemic stroke, newly occurred transient ischaemic attack, newly occurred haemorrhagic stroke, bleeding events, and AF-associated health utilisation.

Ethics and dissemination

The Ethics Committee in Fuwai Hospital approved this study. Patients will give informed consent to the study. An information leaflet will be provided to participating patients to introduce the SLAAO procedure. Patients and the public will not get involved in developing the research hypothesis, study design or any other part of this protocol. We plan to publish several papers in peer-reviewed journals about the current research and these will include a description of the study’s development and the main findings of the study.

Trial registration number

ChiCTR2100042238.

Correspondence to Dr Hansong Sun; [email protected]

Strengths and limitations of this study

• This will be the first randomised trial to investigate the efficacy of surgical left atrial appendage occlusion in patients with valvular disease, high CHA2DS2-VASc scores, and no atrial fibrillation.

• Postoperative anticoagulation schemes vary considerably among individuals, necessitating subgroup analyses.

• Regular postoperative ECG monitoring will not be conducted due to cost constraints, but this issue will be addressed in the following studies.

With the global population ageing trend, valvular heart diseases have been increasing, affecting more than 10% of individuals over 75 years.^1–3 The risk of perioperative stroke in these patients remains high and confers a six times greater risk of all-cause death and a 12.7 times greater risk of stroke-specific death.^4–7 Previous studies have shown that perioperative strokes are mainly composed of ischaemic strokes, which are often the embolism results.⁸

Atrial fibrillation (AF) manifests in 40.3% of patients presenting for mitral valve surgery and 11.3% for aortic valve surgery and is recognised as a significant cause of perioperative stroke.^{9 10} The left atrial appendage (LAA) is the major source of emboli in patients with AF, accounting for 57% of rheumatic and 91% of non-rheumatic AF-related strokes.^{11 12}

Although the first surgical LAA occlusion (SLAAO) as an attempt to prevent stroke could be traced back to as early as 1948, the role of SLAAO during routine cardiac surgery is not well identified. There is increasing evidence showing the efficacy of percutaneous LAA occlusion in reducing stroke risks in patients with non-valvular AF.^13–17 However, these data could not be readily generalised to SLAAO for patients with valvular diseases. Numerous studies, most of which are small sample sized and flawed in study design, have yielded conflicting evidence ever since the debut of this manoeuvre.

In 2021, a multicentre randomised trial concluded that concomitant LAA occlusion performed during cardiac surgery reduced the risk of ischaemic stroke or systemic embolism among participants with AF.¹⁸ Recently, three large cohort studies also published focused on the evaluation of SLAAO during cardiac surgeries. These studies convey essential information for further studies:

First, the association between SLAAO and stroke reduction seems to be confined to patients with AF history. Nevertheless, the results are conflicting with evidence in favour of SLAAO in two studies and against SLAAO in one. Second, for patients in the absence of baseline AF, SLAAO may not provide any benefit and may be associated with increased AF in the early postoperative period and 2 years after surgery. Third, although SLAAO in all-comers has been proven to be ineffective, the risk profile of patients without AF was not well defined in the above studies. In light of the ability of CHADS2 and CHA₂DS₂-VASc scores to identify patients at high risk of postoperative AF (POAF), it will be interesting to explore the potential benefit of SLAAO for those at high risk but without baseline AF.

To address the evidence gap, we planned to launch the OPINION study with a prospective study design. The current research aims to test the hypothesis that, in patients receiving mitral or aortic valve surgeries and without a history of AF and with a CHA₂DS₂-VASc score ≥2, opportunistic SLAAO can prevent long-term stroke after cardiac surgery in a prospective, open-label, multicentre, randomised controlled trial.

Methods and design

In this article, the Standard Protocol Items: Recommendations for Interventional Trials reporting guidelines are followed.¹⁹

Overview

The OPINION study is a single-blinded, multicentre, randomised controlled trial with the purpose to evaluate the efficacy of SLAAO (only LAA suture excision is allowed) to reduce 1-year embolism events in patients with valvular diseases, without AF, and receiving cardiovascular surgeries (see figure 1 for flow charts).

Figure 1. The flowchart of the study. LAA, left atrial appendage.

Three cardiovascular surgery centres in Beijing, China will participate in the study, including Fuwai Hospital, Beijing Anzhen Hospital and Beijing Chaoyang Hospital. Among the three, two are from big local tertiary hospitals with an annual volume of around 1000 cardiovascular surgeries, and one is from a specialty hospital with an annual volume of over 10 000 cardiovascular surgeries. All the participant surgeons are senior surgeons. Patient enrolment started at the first hospital in February 2021 and at the last hospital in November 2023. Patient recruitment is expected to be completed in February 2024.

Inclusion/exclusion criteria

The study recruits participants among patients who are hospitalised and require surgery.

The inclusion criteria include (1) over 18 years of age; (2) at least undergoing mitral valve or aortic valve surgeries; (3) without baseline AF and atrial flutter; (4) with CHA2DS2-VASc score ≥2; (5) agreed to participate in the clinical study and consented to annual postoperative ultrasound examinations and telephone follow-ups.

The exclusion criteria include (1) undergoing heart transplantation, complex congenital heart surgery or ventricular assist device implantation; (2) redo cardiovascular surgeries; (3) left atrium diameter over 6 cm; (4) presence of thrombus in the left atrium or LAA; (5) with a history of stroke/cerebrovascular accident within 1 month before surgeries.

SLAAO procedure and evaluation

In this study, suture excision of the LAA is considered the standard procedure. The LAA will be amputated and its opening is sutured in two layers of polypropylene suture from the outside of the heart.

Intraoperative transoesophageal echocardiography (TEE) will be routinely performed to document the successful occlusion of the LAA (see definition in the Inclusion/exclusion criteria section). Residue LAA stump over 1 cm by intraoperative TEE is defined as SLAAO failure. TEE will be used throughout the operation to ensure that additional manoeuvres will be performed immediately to rectify the failure when the initial occlusion fails.

Blinding and randomisation

The steering committee is responsible for recruiting patients for the trial and supervising the research process but had no access to the randomisation procedure. Extraction of the outcome measures will be performed primarily by research staff not directly involved in the study. The data analysts will be blinded to randomisation.

Neither the research staff will directly involve in the intervention, the participant surgeons, nor the patients are blinded to the randomisation due to the intervention nature.

Patients will be randomised 1:1 to the intervention or control arm using a central randomisation system. A unique web-based central randomisation system has been developed specifically tailored for the three hospitals participating in the trial. This system ensures that randomisation is conducted independently for each hospital, thereby eliminating any potential selection bias. The randomisation plan will be established by research staff not directly involved in the study. The surgeon team will not be informed of the grouping by the central telephone until anaesthesia is administered.

In the intervention arm, suture excision of the LAA will be performed during the operation in addition to the original surgery plan. In the control arm, the operation will be performed according to the surgery plan without any intervention on the LAA. Relevant concomitant care and interventions are permitted for the safety of patients during the trial.

Outcomes measures

The primary outcome is a composition of newly occurred ischaemic stroke/transient ischaemic attack and cardiovascular mortality during a 1-year follow-up.

Secondary outcomes include POAF (defined as newly diagnosed AF within 30 postoperative days (ICD-9 427.31; ICD-10 I48.0, I48.1, I48.2, I48.91)), cardiovascular mortality, newly occurred ischaemic stroke, newly occurred transient ischaemic attack, newly occurred haemorrhagic stroke (ICD-9 codes 430–432), bleeding events of BARC (Bleeding Academic Research Consortium) type III, IV and V, and AF-associated health utilisation.

Sample size calculation

The estimation of the primary outcome in the control group is based on reasonable assumptions about the patient risk and the possible types of antithrombotic therapy during follow-up (table 1 and figure 2). If the event rates are lower than expected, follow-up can be extended with this study design.

Table 1

Estimate proportions and event rates

	Proportions (%) or event rates (per 100 person-year)	Additional remarks
Proportion estimates
Surgery types (for stroke/TIA estimation)
Mechanical valve replacement	63.2	Based on a large registry from the US comparing mechanical and biological prostheses (n=45 639); the proportion of valve repair is estimated based on our data (unpublished).
Bioprosthesis or valve repair	36.8
Anticoagulant conditions among patients with a history of AF (for stroke/TIA estimation)
No anticoagulant therapies	43.9	Based on the medical insurance database in Yunnan Province, China; 1237 out of 471 446 participants were diagnosed with AF, thus creating 4859 person-years of experience.
Warfarin	8.0
Aspirin	46.1
New anticoagulant agents	2.0
Distribution of CHA2DS2-VASc scores among patients without baseline AF (for stroke/TIA estimation)
2	33.4	By using the Outcomes Assessment in Coronary Heart Disease (APPROACH) prospective registry involving 20 970 patients with a primary diagnosis of ACS and without baseline AF.
3	27.9
≥4	38.7
Event rate estimates
Stroke/TIA rates among the four types of anticoagulant conditions (for stroke/TIA estimation)
No anticoagulant therapies	5.1	Based on large randomised controlled trials: Warfarin: RELY, n=6022; Aspirin: ACTIVE A, n=3782; New anticoagulants: AVERROES, n=2808; RELY, n=6015; No therapies: ACTIVE A and AVERROES.
Warfarin	1.7
Aspirin	3.7
New anticoagulant agents	1.5
Stroke/TIA rates among the three CHA2DS2-VASc score categories (for stroke/TIA estimation)
2	0.4	By using the Outcomes Assessment in Coronary Heart Disease (APPROACH) prospective registry involving 20 970 patients with a primary diagnosis of ACS and without baseline AF.
3	0.9
≥4	1.5
Development of POAF at each CHA2DS2-VASc score category (for stroke/TIA estimation)
CHA2DS2-VASc score=2		Based on two institutional data involving 277 patients and 518 patients in the absence of previous AF receiving cardiac surgeries
Yes	19.0
No	81.0
CHA2DS2-VASc score=3
Yes	70.0
No	30.0
CHA2DS2-VASc score≥4
Yes	48.5
No	51.5
Cardiovascular mortality	5.0	According to three large registries with a sample size of 75, 782, 10,524 and 9,792, respectively.

ACS, acute coronary syndrome; AF, atrial fibrillation; POAF, postoperative atrial fibrillation; TIA, transient ischaemic attack.

Figure 2. Estimates proportions, event rates and sample size. AF, atrial fibrillation; POAF, postoperative AF; TIA, transient ischaemic attack.

The scheme for estimation of the primary outcome of the study is as follows (table 1 and figure 2):

Based on previous large registries, the proportion of patients receiving mechanical valve replacement is estimated to be 63.2%. We assume that all these patients take warfarin and adhere to standard warfarin medication during 1-year follow-up.

As for those receiving bioprosthesis or valve repair, four medication conditions are assumed: taking warfarin, aspirin, new anticoagulant or no anticoagulant therapy. Assuming 1059 patients in each group, we would detect a relative reduction rate of at least 40%, with a power of 80% and two-sided type I error of 0.05, in the primary outcomes with an estimated control event rate of 6.8 per 100 person-year.

As aforementioned, we could easily estimate the annual stroke/TIA event rate in patients receiving mechanical valve replacement who will take warfarin for life long time.

As for those receiving bioprosthesis or valve repair, we first categorise the patients into three proportions: CHA2DS2-VASc score=2, CHA2DS2-VASc score=3 and CHA2DS2-VASc score ≥4. We have estimated the three proportions from a recent large registry study. We also have estimates about the occurrence rate of POAF in the three categories.

For patients receiving bioprosthesis/valve repair and not developing POAF, we have good estimates of the stroke/TIA in each category.

For patients receiving bioprosthesis/valve repair and developing POAF, we assume four medication conditions and have a reliable estimate of the four proportions: taking warfarin, aspirin, new anticoagulant, or no anticoagulant therapy.

Based on the recent large trials, we estimate the newly occurred ischaemic stroke/TIA in the control group taking warfarin will be 1.7 per 100 people per year²⁰; taking aspirin will be 3.7 per 100 person-years²¹; taking new anticoagulants (dabigatran and the Factor 10a) will be 1.5 per 100 person-year^{20 22}; without any anticoagulant therapy will be 5.1 per 100 person-year.^{21 22}

Thus, the ischaemic stroke/TIA event rate in the control arm is estimated at 1.8 per 100 person-year. We assume that cardiovascular mortality will be 5.0 per 100 person-year. Then we get the final estimates of the overall event rate of 6.8 per 100 person-year in the control arm without SLAAO.

Hence, a total of 2118 patients (1059 per group) is required. Power calculations were performed using the Power Analysis & Sample Size (PASS) V.14.0 software.

TEE is employed throughout the surgical procedure to reduce the incidence of postoperative SLAAO failure as low as possible. Any postoperative SLAAO failure would prompt a discussion with the statistics team to reassess and potentially recalculate the sample size.

Case report form abstraction, follow-up, and data process

Research staff from each site will scan all the patient’s medical charts in either the prospective longitudinal study of the randomised controlled trial, then transmit the scanned copy to the coordinating centre through the mail on encrypted, password-protected flash drives. The CRF will be quality-controlled, and the medical records will be deidentified by hiding all personal information in the records.

The case report form (CRF)s includes the patients’ baseline information (age, gender and cardiac/non-cardiac history, etc), invasive/non-invasive testing (ECG, echocardiography, chest X-ray, CT scans, angiography, etc), laboratory results, in-hospital medications and surgical interventions, in-hospital complications and discharge medications (table 2). Trained abstractors will abstract this information under the supervision of trained quality control personnel. 10% of these records will be randomly selected for review by project managers to ensure adherence to the research protocol.

Table 2

OPINION data elements

Variables	Baseline	Follow-up
		3rd month	12th month
Clinical characteristics
Medical history/risk factors
Clinical characteristics
Preoperation care
Diagnostic tests
Surgical information
Discharge medication
In-hospital outcomes
Echocardiography
Size of the left atrium
Size of left atrial appendage
Left atrial thrombus
Size of the right atrium
EF
LVEDD
LVESD
Information about the valves
Lab tests
Blood routine test
Blood biochemical test
Urine routine test
Chest X-ray
CT scan
ECG
Angiography (if applicable)
Patient interviews
Education
Work status
Marital/living status
Household income
Postoperative medication
Outcomes
Ischaemic stroke/TIA
Cardiovascular mortality
Haemorrhagic stroke
Bleeding events
Newly occurred AF
AF-associated health utilisation

AF, atrial fibrillation; EF, left ejection fraction; LVEDD, left ventricular end diastolic diameter; LVESD, left ventricular end systolic diameter; TIA, transient ischaemic attack.

The detailed protocol for the follow-up will be described elsewhere. Briefly, patients discharged alive are interviewed at the time point of the 7th day, the 6th month and the 12th month. A face-to-face interview is the most preferred approach, but a telephone interview is also acceptable. If the patients report adverse events, the patient’s medical records in the outpatient clinic of the three participating hospitals are double checked. If the patients visit other hospitals, patients are required to send paper copies of medical records by mail or photocopies through the Internet.

The data will be stored at the coordinating centre and protected in an encrypted and password-protected database. The paper records will be securely stored in a locked room. Data will be imported into SAS V.9.4 (SAS Institute, Cary, North Carolina) for analysis. Only investigators directly involved in the trial will have access to the data. All the data will be stored on secure servers with backup systems for 5 years after the trial.

Statistical analysis

The prespecified primary endpoint and secondary endpoints will be presented using Kaplan-Meier survival curves, and the treatment effect as measured by the HR and 95% CI will be derived by the Cox proportional hazards model. If a patient experienced the same type of clinical event more than once, only the first one will be used in the analysis.

In the study, cases of SLAAO failure or instances where SLAAO procedures are converted to non-SLAAO procedures will remain in the SLAAO group based on the ‘intention-to-treat’ principle.

A p value of <0.05 for the proportional hazards model will be considered significant.

Data monitoring

A steering committee has been set up to supervise the study’s conduct and the management of the data. The committee members will include research staff and three surgeons who are not directly involved in managing the data. Members of the committee will meet regularly throughout the study period.

During the interim analyses at 18 months, in-hospital complications and adverse events will be reported to the steering committee, which will advise the sponsor to pause or terminate the trial if adverse events occur more frequently than expected.

Auditing committee

An auditing committee will be formed, consisting of members with prior adjudication experience, to assess and classify all data occurring in the trial. The members will independently assess all adverse events followed by classification into subcategories. Any disagreements will be resolved by consensus or by requesting additional information from the hospitals if disagreements persist.

Duration of the study

The study period, lasting 36 months, comprises two parts: an internal pilot period (3 months) and a research period (33 months).

Before the research launch, an internal pilot period will be conducted to demonstrate the feasibility of the research. The pilot period will also allow a period for the participant surgeons to get familiar with the research protocols and SLAAO procedures. We are confident that the pilot period will aid in standardising SLAAO procedures, thereby minimising the influence of varying surgical preferences on the study outcomes.

In the pilot phase, intermediate outcome measures will include (1) the success rate of SLAAO (see definition in ‘inclusion/exclusion criteria’ section); (2) successful transmission and abstraction of CRF; (3) the time span of the follow-up interview and the completion rate of the interview items.

Ethics and dissemination

The Ethics Committee in Fuwai Hospital approved this study. The three centres participating in this study are all members of the Beijing Ethical Review Mutual Recognition Alliance. After the primary centre obtained the ethical review permit, the two subsidiary centres were granted permission to conduct research through expedited ethical approval access. The relevant documentation can be accessed on the official website of the Beijing Municipal Health Commission. (http://wjw.beijing.gov.cn/zwgk_20040/zxgk/202011/t20201127_2152258.html; http://wjw.beijing.gov.cn/zwgk_20040/qt/202103/t20210318_2310146.html; http://wjw.beijing.gov.cn/zwgk_20040/qt/202203/t20220329_2642370.html.)

Participants will give informed consent to the study. An information leaflet will be provided to participating patients to introduce the SLAAO procedure. Any modifications to the protocol must be approved by the Ethics Committee at Fuwai Hospital before being communicated to relevant parties, including the steering committee, REC/IRBs, trial participants, trial registries, journals, and regulators.

Before participating in a clinical study, each participant must provide voluntary written informed consent. If the participant is unable to sign, an acceptable legal representative may do so on their behalf. Participants who cannot fully comply with study procedures or have follow-up questions will not be admitted to the study.

If serious adverse events occur, the participants will receive compensation following the Chinese regulations on medical malpractice punishment.

We plan to publish several papers in peer-reviewed journals about the current research and these will include a description of the study’s development and the main findings of the study. Also, the findings are planned to be presented at national and international conferences. Only members of the research team are eligible for authorship, and professional writers are not authorised to be included as authors.

Patient and public involvement

Patients and the public will not get involved in developing the research hypothesis, study design, or any other part of this protocol.

Discussion

Enlightened by previous studies, the OPINION study is designed to evaluate the efficacy of SLAAO to reduce embolism events 1 year after mitral or aortic surgeries.

Recently, three cohort studies with many patients of a broad spectrum of conditions were published to explore the association between SLAAO and the long-term risk of stroke. Those studies may have better generalisability than previous studies but are subjected to confounding and not quite granular due to their retrospective nature.

In 2021, a multicentre, randomised trial (Left Atrial Appendage Occlusion Study III, LAAOS III trial, NCT01561651) that enrolled 2379 patients was published in the New England Journal of medicine.¹⁸ Nevertheless, this trial is focused on patients with a history of AF or atrial flutter undergoing coronary artery bypass graft (CABG) and will not include those without AF and those undergoing valve surgeries.

Another large, multicentre, randomised, controlled trial (Left Atrial Appendage Exclusion Concomitant to Structural Heart Procedures, ATLAS trial, NCT02701062) plans to enrol more than 2000 patients without preoperative AF and with a CHA2DS2-VASc score >2 and a HAS-BLED score >3 undergoing CABG or valve surgeries. However, this study is not adequately powered to detect the treatment effects of SLAAO to reduce embolism events.

A key outcome of this research will be to determine whether LAAO reduces long-term embolism events in valve surgery patients without AF. To our knowledge, the OPINION study is the first to assess the effectiveness of SLAAO in patients with valvular disease, high CHA2DS2-VASc scores and no AF. This could provide strong evidence for updating clinical guidelines.

However, there are still some limitations in the study. This study encompasses a broad range of diseases and surgical procedures, with considerable variation in postoperative anticoagulation schemes among individuals. Subgroup analyses will be conducted later in the study, with sensitivity adjustments to control for confounding factors to the greatest extent possible. In addition, due to cost constraints, it is not feasible to conduct regular postoperative ECG monitoring for all patients during the follow-up period. As a result, the determination of POAF recurrence relies on patients’ self-reported symptoms. This issue will be addressed in the following studies.

Ethics statements

Patient consent for publication

Not applicable.

Footnote

FJ and XY contributed equally.

Contributors HS conceived the study idea and designed the study together with XY. XY and FJ carried out the analyses. FJ and XY organised the writing and wrote the initial draft. All authors participated in the discussion and formulation of the protocol. All authors critically revised the manuscript for intellectual content and approved the final version before submission. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. HS is the guarantor.

Funding This study is funded by the Beijing Municipal Science & Technology Commission as part of the Capital Research and Application Project: Clinical Diagnosis and Treatment Techniques (Grant Number Z201100005520033).

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.

References

¹ Rostagno C. Heart valve disease in elderly. World J Cardiol 2019; 11: 71–83. doi:10.4330/wjc.v11.i2.71

² Petty GW, Khandheria BK, Whisnant JP, et al. Predictors of cerebrovascular events and death among patients with valvular heart disease: a population-based study. Stroke 2000; 31: 2628–35. doi:10.1161/01.str.31.11.2628

³ Nkomo VT, Gardin JM, Skelton TN, et al. Burden of valvular heart diseases: a population-based study. Lancet 2006; 368: 1005–11. doi:10.1016/S0140-6736(06)69208-8

⁴ Selim M. Perioperative stroke. N Engl J Med 2007; 356: 706–13. doi:10.1056/NEJMra062668

⁵ Maisel WH, Rawn JD, Stevenson WG. Atrial fibrillation after cardiac surgery. Ann Intern Med 2001; 135: 1061–73. doi:10.7326/0003-4819-135-12-200112180-00010

⁶ Bucerius J, Gummert JF, Borger MA, et al. Stroke after cardiac surgery: a risk factor analysis of 16,184 consecutive adult patients. Ann Thorac Surg 2003; 75: 472–8. doi:10.1016/s0003-4975(02)04370-9

⁷ Mérie C, Køber L, Olsen PS, et al. Risk of stroke after coronary artery bypass grafting: effect of age and comorbidities. Stroke 2012; 43: 38–43. doi:10.1161/STROKEAHA.111.620880

⁸ Likosky DS, Marrin CAS, Caplan LR, et al. Determination of etiologic mechanisms of strokes secondary to coronary artery bypass graft surgery. Stroke 2003; 34: 2830–4. doi:10.1161/01.STR.0000098650.12386.B3

⁹ Badhwar V, Rankin JS, Ad N, et al. Surgical ablation of atrial fibrillation in the United States: trends and propensity matched outcomes. Ann Thorac Surg 2017; 104: 493–500. doi:10.1016/j.athoracsur.2017.05.016

¹⁰ Patel BM, Reinert NJ, Al-Robaidi K, et al. Independent predictors of perioperative stroke-related mortality after cardiac surgery. J Stroke Cerebrovasc Dis 2020; 29: 104711. doi:10.1016/j.jstrokecerebrovasdis.2020.104711

¹¹ Al-Saady NM, Obel OA, Camm AJ. Left atrial appendage: structure, function, and role in thromboembolism. Heart 1999; 82: 547–54. doi:10.1136/hrt.82.5.547

¹² Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996; 61: 755–9. doi:10.1016/0003-4975(95)00887-X

¹³ Bayard Y-L, Omran H, Neuzil P, et al. PLAATO (percutaneous left atrial appendage transcatheter occlusion) for prevention of cardioembolic stroke in non-anticoagulation eligible atrial fibrillation patients: results from the European PLAATO study. EuroIntervention 2010; 6: 220–6.

¹⁴ Block PC, Burstein S, Casale PN, et al. Percutaneous left atrial appendage occlusion for patients in atrial fibrillation suboptimal for warfarin therapy: 5-year results of the PLAATO (percutaneous left atrial appendage transcatheter occlusion) study. JACC Cardiovasc Interv 2009; 2: 594–600. doi:10.1016/j.jcin.2009.05.005

¹⁵ Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 2009; 374: 534–42. doi:10.1016/S0140-6736(09)61343-X

¹⁶ Reddy VY, Sievert H, Halperin J, et al. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial. JAMA 2014; 312: 1988–98. doi:10.1001/jama.2014.15192

¹⁷ Holmes DR, Lakkireddy DR, Whitlock RP, et al. Left atrial appendage occlusion: opportunities and challenges. J Am Coll Cardiol 2014; 63: 291–8. doi:10.1016/j.jacc.2013.08.1631

¹⁸ Whitlock RP, Belley-Cote EP, Paparella D, et al. Left atrial appendage occlusion during cardiac surgery to prevent stroke. N Engl J Med 2021; 384: 2081–91. doi:10.1056/NEJMoa2101897

¹⁹ Chan A-W, Tetzlaff JM, Gøtzsche PC, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ 2013; 346: e7586. doi:10.1136/bmj.e7586

²⁰ Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139–51. doi:10.1056/NEJMoa0905561

²¹ Investigators A. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009; 360: 2066–78. doi:10.1056/NEJMoa0901301

²² Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364: 806–17. doi:10.1056/NEJMoa1007432