Early Closure of Left Atrial Appendage for Patients With Atrial Fibrillation and Ischemic Stroke Despite Anticoagulation Therapy

NCT05976685 | Recruiting DMC

• 1 other identifier: 2023-02340
• Study Type: interventional
• Target: 482
• Locations: 6 countries
• Sites: 30

Brief Summary

Atrial fibrillation (AF) is one of the most common cardiac arrhythmias and cardioembolic stroke due to AF is its major complication. Direct oral anticoagulants (DOAC) reduce the risk of cardioembolism in patients with AF. Despite DOAC therapy, there is a significant residual stroke risk of 1-2%/year. Recent data from the Swiss Stroke Registry found 38% of patients with AF and ischemic stroke were on prior anticoagulant therapy (approximately 400 patients per year in Switzerland). The investigators found in a prior observational study, that patients with AF who have ischemic stroke despite anticoagulation are at increased risk of having another ischemic stroke (HR 1.6; 95% confidence interval, CI 1.1-2.1). Combining observational data from 11 international stroke centres, the investigators found that the majority of ischemic strokes despite anticoagulation in patients with AF is "breakthrough" cardioembolism (76% of patients) and only a minority of 24% is related to other causes unrelated to AF. Optimal secondary prevention strategy is unknown. The investigators have conducted two independent observational studies including together \>4000 patients but did not identify any strategy (e.g. switch to different DOAC, additional antiplatelet therapy) that seems superior. A recent randomized controlled trial on surgical occlusion of the left atrial appendage (LAAO) found that LAAO may provide additional protection from ischaemic stroke in addition to oral anticoagulation. Triggered by this finding, the investigators performed a matched retrospective observational study and found that patients with AF and stroke despite anticoagulation who received a combined mechanical-pharmacological therapy (DOAC therapy + LAAO) had lower rates of adverse outcomes compared to those with DOAC therapy alone. Therefore, the investigators hypothesize that in patients with AF and ischemic stroke despite anticoagulant therapy, LAAO in addition to anticoagulation with a DOAC is superior to DOAC therapy alone. The investigators propose an international, multi-center randomized controlled two-arm trial to assess the effect of LAAO in patients with AF suffering from strokes despite anticoagulation therapy and without competing stroke etiology. The investigators will use the PROBE design with blinded endpoint assessment. The investigators will enrol patients with non-valvular AF and a recent ischemic stroke despite anticoagulation therapy at stroke onset. Patients will be randomized 1:1 to receive LAAO + DOAC therapy (experimental arm) or DOAC therapy alone (standard treatment arm). The primary endpoint is the first occurrence of a composite outcome of recurrent ischemic stroke, systemic embolism and cardiovascular death during follow-up. Secondary outcomes include individual components of the primary composite outcome, safety outcomes (i.e. symptomatic intracranial haemorrhage, major extracranial bleeding, serious device- or procedure-related complication), functional outcome (modified Rankin Scale) and patient-oriented outcomes. The minimum follow-up is 6 months and all patients will receive follow-ups every 6 months until end of study, the maximal follow-up will be 48 months. Based on prior observational data from the investigators' group and others (5 observational studies, \>5000 patients), the investigators estimate the proportion of patients with the primary outcome in the standard treatment arm to be 18% in the first year and 9% in the second year (=cumulative 27% after 2 years). A relative risk reduction of 40% at 2 years would be clinically relevant. Based on these assumptions and a log-rank test, the investigators would need 98 events for a power of 80% at an alpha-level of 5%. Assuming a recruitment rate of 52, 118, 156 and 156 patients in years 1 to 4, an additional 6 months of follow-up (mean follow-up time of 2.1 years) and a uniform drop-out rate of 7.5% per year, 482 patients would need to be enrolled. How to treat patients with an ischemic stroke despite anticoagulation is a major yet unresolved clinical dilemma. This trial has the potential to answer the question whether LAAO plus DOAC therapy is superior to current standard of care for patients with AF who have ischemic stroke despite anticoagulation.

Conditions

Ischemic Stroke; Atrial Fibrillation

Keywords

Stroke; Direct oral anticoagulation; Left atrial appendage occlusion

Outcome Measures

Primary Outcomes (1)

• Composite of recurrent ischemic stroke, systemic embolism, or cardiovascular death (whatever comes first).

  The primary endpoint is the first occurrence of a composite outcome of recurrent ischemic stroke, systemic embolism and cardiovascular death during follow-up. Stoke is defined as - New sudden focal neurological deficit of presumed cerebrovascular aetiology, occurring \> 24 hours after the index ischaemic stroke, that persisted beyond 24 hours and was not due to another identifiable cause 18 (transient ischaemic attack (TIA), defined as a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischaemia without cerebral infarction on imaging, is not judged as stroke) and/or by brain imaging (CT or MRI). Systemic embolism is defined as abrupt vascular insufficiency associated with clinical or radiological evidence of arterial occlusion of an extremity or organ in absence of another likely mechanism (e.g. atherosclerosis, instrumentation or trauma). Cardiovascular death is defined as any death that is due to a vascular cause.

  6 months

Secondary Outcomes (12)

• Recurrent ischemic stroke

  6 months

• Systemic embolism

  6 months

• Cardiovascular death

  6 months

• Symptomatic intracranial hemorrhage

  6 months

• Major extracranial bleeding (ISTH)

  6 months

Study Arms (2)

LAAO and DOAC therapy

EXPERIMENTAL

Left atrial appendage occlusion and therapy with direct oral anticoagulants

Procedure: Left atrial appendage Occlusion; Drug: DOAC

DOAC therapy only

OTHER

Therapy with direct oral anticoagulants alone

Drug: DOAC

Interventions

Left atrial appendage Occlusion PROCEDURE

Left atrial appendage Occlusion and therapy with direct oral anticoagulants. Choice of DOAC is at the discretion of the treating physician.

LAAO and DOAC therapy

DOAC DRUG

Therapy with direct oral anticoagulants. Choice of DOAC is at the discretion of the treating physician.

DOAC therapy only; LAAO and DOAC therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years
• Written informed consent
• Permanent, persistent, or paroxysmal spontaneous AF previously known or diagnosed during the index hospitalization.
• Recent (≤3 months) symptomatic ischemic stroke.
• Active or planned long-term therapy with DOAC

You may not qualify if:

• Contraindications to DOAC therapy
• Life expectancy \<1 year according to the opinion of the investigator
• Stroke due to: Ipsilateral intra/extracranial high-grade stenosis, Isolated lacunar stroke, Other well-defined stroke aetiologies (i.e., endocarditis, vasculitis, Reversible Cerebral Vasoconstriction Syndrome \[RCVS\], Posterior Reversible Encephalopathy Syndrome \[PRES\], cerebral sinus venous thrombosis)
• Previous persistent foramen ovale or atrial septum defect closure.
• Rheumatic heart disease
• Severe heart valve disease that requires treatment (severe aortic stenosis or regurgitation, severe mitral stenosis or regurgitation).
• Contraindications for TEE (relevant esophageal varices, esophageal stricture, history of esophageal cancer).
• Cardiac or non-cardiac surgical procedure within 30 days of randomization
• Enrolled in another investigation of a cardiovascular device or investigating secondary prevention therapy.
• Severely reduced Left Ventricular Ejection Fraction (LVEF) \<30%.
• Severe renal impairment as described in the summary of medicinal product characteristics for the chosen DOAC (e.g. rivaroxaban, apixaban and edoxaban creatinine clearance \<15 ml/min; dabigatran creatinine clearance \<30 ml/min).
• Hypertrophic cardiomyopathy
• Intracardiac tumor
• Ventricular thrombus
• Acute cardiac decompensation

Sponsors & Collaborators

• Insel Gruppe AG, University Hospital Bern: lead

Study Sites (30)

UCLouvain - Cliniques universitaires Saint-Luc

Brussels, Brussels Capital, 1200, Belgium

RECRUITING

AZ Sint Jan Brugge

Bruges, 8000, Belgium

RECRUITING

Brussels University Hospital

Brussels, 1090, Belgium

RECRUITING

HUmani CHU Charleroi-Chimay

Charleroi, 6000, Belgium

RECRUITING

Universitair Ziekenhuis (UZ) Leuven

Leuven, 3000, Belgium

RECRUITING

CHU Liège Sart-Tilman

Liège, 4000, Belgium

RECRUITING

Asklepios Klinik Altona

Hamburg, Free and Hanseatic City of Hamburg, 22763, Germany

RECRUITING

Universitätsklinikum Leipzig

Leipzig, Leipzig, 04103, Germany

RECRUITING

Universitätsmedizin Mannheim

Mannheim, Mannheim, 68167, Germany

RECRUITING

UKSH, Campus Lübeck

Lübeck, Schleswig-Holstein, 26538, Germany

RECRUITING

Charité-Universitätsmedizin Berlin

Berlin, State of Berlin, 12203, Germany

RECRUITING

Universitätsklinikum Bonn

Bonn, 53127, Germany

RECRUITING

Universitätsmedizin Göttingen

Göttingen, 37075, Germany

RECRUITING

University Hospital Heidelberg

Heidelberg, 69120, Germany

RECRUITING

Universitätsklinikum Tübingen

Tübingen, 72076, Germany

RECRUITING

Christchurch Hospital

Christchurch, Christchurch, 8011, New Zealand

RECRUITING

Hosp. Barcelona Santa Creu y Sant Pau

Barcelona, 08025, Spain

RECRUITING

Vall d'Hebron University Hospital

Barcelona, 08035, Spain

RECRUITING

Hosp. Clínic of Barcelona

Barcelona, 08036, Spain

RECRUITING

Hospital Clínico San Carlos (HCSC)

Madrid, 28040, Spain

RECRUITING

University Hospital Basel

Basel, Basel, 4031, Switzerland

RECRUITING

Inselspital, University Hospital Bern

Bern, Canton of Bern, 3010, Switzerland

RECRUITING

Hôpitaux universitaires de Genève

Geneva, Canton of Geneva, 1211, Switzerland

NOT YET RECRUITING

Luzerner Kantonsspital

Lucerne, Canton of Lucerne, 6000, Switzerland

NOT YET RECRUITING

Kantonsspital St. Gallen

Sankt Gallen, Canton of St. Gallen, 9007, Switzerland

RECRUITING

Ente Ospedaliero Cantonale

Lugano, Canton Ticino, 6900, Switzerland

RECRUITING

Centre Hospitalier Universitaire Vaudois

Lausanne, Vaude, 1011, Switzerland

RECRUITING

St Bartholomew's Hospital

London, EC1A 7BE, United Kingdom

RECRUITING

St Thomas' Hospital

London, United Kingdom

RECRUITING

University Hospitals Sessex NHS Trust

Worthing, United Kingdom

RECRUITING

MeSH Terms

Conditions

Ischemic Stroke; Atrial Fibrillation; Stroke

Interventions

Left Atrial Appendage Closure

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Heart Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cardiac Catheterization; Catheterization; Therapeutics; Investigative Techniques

Study Officials

• Lorenz Räber, Prof., MD

  Cardiovascular Center, Inselspital Bern

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Lorenz Räber, Prof., MD, PhD

CONTACT

+41316320929; Lorenz.Raeber@insel.ch

David Seiffge, Prof., MD

CONTACT

+41316640509; david.seiffge@insel.ch

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 27, 2023
• First Posted: August 4, 2023
• Study Start: May 1, 2024
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): June 1, 2028
• Last Updated: July 24, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

DE (9); GB (3); CH (7); ES (4); NZ (1); BE (6)