CLOSURE-AF (Left atrial appendage CLOSURE in patients with Atrial Fibrillation at high risk of stroke and bleeding compared to medical therapy: a prospective randomized clinical trial) was designed to determine the clinical outcome after percutaneous catheter‐based LAA closure in patients with AF at high risk of stroke (CHA2DS2‐VASc Score ≥ 2) as well as high risk of bleeding as compared to best medical care (including a nonvitamin K antagonist oral anticoagulant [NOAC] when eligible).

CLOSURE-AF is an investigator-initiated clinical study that is funded by the German Center for Cardiovascular Research (DZHK) and performed in collaboration with Atrial Fibrillation Network Association (AFNET, Muenster, Germany). Sponsor is Charité Universitätsmedizin, Berlin, Germany. The trial is registered at www.clinicaltrials.gov (Identifier NCT03463317). Project management is performed by AFNET (Muenster, Germany). Study site management and monitoring is performed largely by the Clinical Trial Unit of the Charité University Medicine Berlin.

Data cleaning and preparation is performed by the German Center for Cardiovascular Research data management group in collaboration with the Clinical Trial Unit of the Charité. An independent data and safety monitoring board (DSMB) monitors patient safety on an ongoing basis and has access to unblinded data.

The study adheres to the ethical principles of the Declaration of Helsinki and to specifications of the International Conference of Harmonization. The study underwent approval by a central ethics committee (LAGESO, Berlin) and institutional review board at each site.

CLOSURE-AF was designed as a prospective, multicenter, event-driven, randomized open clinical trial with a 2-arm parallel group design and blind outcome assessment (PROBE design). Catheter-based LAA closure will be compared in a 1:1 randomization to best medical care (including NOAC therapy) in AF patients at high risk of stroke and bleeding ( Figure 1 ). Randomization is performed electronically stratified by study center.

CLOSURE-AF study design diagram (of original study plan). *At least 18 months and 6 months follow up after 1th and 2nd interim analysis, respectively. BARC = bleeding academic research consortium definition for bleeding; HASBLED = hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly score; eGFR = estimated glomerular filtration rate; TEE = transesophageal echocardiography, LAAC group only

The CHA ₂ DS ₂ Vasc score, HASBLED score and BARC classification, can be found in Online Table 1 – 3.

Patients allocated to the intervention group receive percutaneous catheter-based closure of the LAA one of the currently available CE-mark LAA closure devices with reported efficacy and safety data of at least 500 patients (initially WATCHMAN™ LAA System or the successor device WATCHMAN FLX™ [Boston Scientific, Natick, MA, USA], AMPLATZER® Cardiac Plug [St. Jude Medical, Golden Valley, MN, USA] or the successor device Amplatzer Amulet). ^, All participating centers need to have experience with LAA closure implantations prior to participation and operators need to be certified for the LAA occlusion with the device used (at least 20 implants per device).

Postimplantation antithrombotic treatment was individualised based on the bleeding risk of the patient and decided by the treating physician ( Figure 2 ). After deployment of the LAA closure device, at least 3 months dual antiplatelet therapy (DAPT) should be considered by the treating physician. If there is a complete LAA occlusion or only a small residual shunt (< 5mm jet width) in the absence of device surface thrombi according to trans-esophageal echocardiography (TEE) discontinuation of DAPT should be considered. Single antiplatelet therapy with aspirin can be discontinued after 6 months unless there is a clear indication for aspirin therapy (eg, coronary artery disease). In patients with excessive bleeding risk DAPT duration can be shortened to 6 weeks and aspirin stopped at 3 months. ^,, Alternatively, monotherapy with aspirin for up to 6 weeks can be provided. As CLOSURE-AF only includes patients with high bleeding risk, the limited DAPT exposure of 3 months following LAA occlusion may contribute to a reduced cumulative risk of bleeding in the LAA device group.

Therapy recommendations of CLOSURE-AF.

Patients eligible for long-term OAC allocated to the best medical care group should receive NOAC therapy whenever considered eligible by the treating physician. ^, In case of contraindications to OAC (ie, excessive bleeding risk) patients in the BMC group might receive no antithrombotic/antiplatelet therapy according to the discretion of the treating physician.

CLOSURE-AF is an investigator-initiated trial. The trial conducted in cooperation with the AFNET and German Stroke Society with its associated networks of more than 200 German stroke units which constitute potential screening sites for the trial and strengthens the feasibility. To maximise external validity and to enable broad enrolment, the trial has an open design with blind adjudication of outcome events. Both LAA implanting and other sites can participate in the study. The DZHK study platform further facilitates enrolment and follow-up.

Inclusion and major exclusion criteria are shown in Table 1 . In brief, patients need to be eligible for both management strategies and be able to consent. Key exclusion criteria are limited to study medication safety/intolerance and end stage kidney disease (estimated glomerular filtration rate [eGFR] <15 ml/min/1.73m ² or dialysis treatment), in line with a pragmatic trial. The trial enrolled patients in 46 clinical cardiology departments in Germany.

The open design facilitates broad enrolment, potentially reducing selection bias inherent to double-blind studies.

In order to generate clinically important data, a patient‐relevant composite primary endpoint of „net clinical benefit” was constructed and used as the primary outcome ( Table 2 ). The outcome includes events that have a demonstrable impact on patients´ lives, namely stroke (both ischemic and hemorrhagic), cardiovascular or unexplained death and major bleeding events ( ≥ 3 according to the BARC classification). Comparable endpoints have been used in previous LAA closure studies. ^, All components of the combined clinical endpoint will be adjudicated by an independent clinical endpoint committee (CEC), blinded to the patient’s assigned treatment group, as required by the PROBE design. The composite primary endpoint has direct implications on patients’ morbidity and mortality and also a significant economic impact. Efficacy and safety will be studied as secondary endpoints.

Table 2

Primary, secondary and safety outcomes of the CLOSURE-AF trial.

Primary endpoint (“net clinical benefit”)	Secondary endpoints	Safety endpoints
Survival time free of – Stroke including ischemic or hemorrhagic stroke – Systemic embolism – Major bleeding (BARC type 3‐5) – Cardiovascular or unexplained death	-Primary endpoint events per year (assessed by the number of primary endpoint events during the follow-up period) – Combined endpoint: MACCE (major adverse cardiac and cerebrovascular events, ie stroke/systemic embolism/cardiovascular death/myocardial infarction) – Mortality (including all-cause death, cardiovascular death, non‐cardiovascular death, peri‐procedural death) – Major bleeding (BARC type 3‐5) – Systemic embolism (assessed by the rate of systemic embolism during the follow-up period) – Ischemic stroke – Hemorrhagic stroke – Stroke of any origin – Ischemic stroke and systemic embolism – Hemorrhagic stroke and systemic embolism – Stroke of any origin and systemic embolism – Cardiovascular or unexplained death – Transient ischemic attack (TIA; defined as neurological deficit of vascular origin lasting ≤ 24 hours without corresponding brain lesion) – Myocardial infarction – Hospitalization for bleeding or cardiovascular event – Changes from baseline in cognitive function assessed by MoCA (Montreal Cognitive Assessment) at 24 months – Changes from baseline in health-related quality of life (EQ-5D-5L) at 24 months (Index and Visual analog scale) – Change from baseline in modified Rankin Score (mRS) at 3 and 24 months	– Device-related complications until day 7 or discharge ∘ Device-related thrombus ∘ Pericardial effusion ∘ Leaks – Pericardial tamponade procedure-related death – Technical and procedural success of device implantation ∘ Device success (device deployed and implanted in correct position) ∘ Technical success (device implanted in correct position with a peri-device leak ≤5mm and no device-related complications until day 30) ∘ Leak <3mm ∘ Procedural success (technical success with no procedure-related complications) ∘ Peri-procedural outcomes at 7 or discharge and 30 calendar days after implantation: ∘ Pericardial tamponade • Treated with pericardiocentesis • Treated surgically • Resulted in death ∘ Pericardial effusion, no intervention ∘ Major bleeding requiring transfusion (BARC 3-5) (additionally split up into: procedural bleedings within first 7 days and nonprocedural bleedings afterwards until 30 days) ∘ Pulmonary embolism ∘ Air embolism ∘ Device embolization • Removed percutaneously • Removed surgically ∘ Procedure-related stroke/TIA ∘ Peripheral embolism ∘ Systemic infection ∘ Additional mortality within 7 and 30 days Additionally the total number of serious adverse events (SAEs) will be analysed.

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