Background and rationale

Atrial fibrillation (AF) poses a significant risk of cardioembolic stroke, despite the availability of oral anticoagulation therapies like Vitamin K Antagonists (VKA) and Direct Oral Anticoagulants (DOACs). Data from the Swiss Stroke Registry indicate that approximately 38% of stroke cases in AF patients occur despite anticoagulant therapy, highlighting the ongoing challenge in stroke prevention.

Patients who experience strokes despite anticoagulation therapy are at a heightened risk of recurrent stroke, necessitating effective secondary prevention strategies. While switching or adjusting anticoagulation therapy is common, recent studies have not shown significant reductions in stroke risk with these approaches. Additionally, supplementary antiplatelet therapy has not proven effective in improving outcomes.

Research has identified the Left Atrial Appendage (LAA) as a key site for thrombus formation in AF patients. This has led to exploration of Left Atrial Appendage Occlusion (LAAO) as an alternative intervention, particularly for patients unsuitable for oral anticoagulation therapy due to contraindications. A recent trial (LAOOS-III) showed promising results for surgical LAAO in reducing the risk of ischemic stroke when combined with anticoagulation therapy.

A pilot study comparing AF patients who suffered strokes despite anticoagulation therapy found that those who underwent endovascular LAAO alongside DOAC therapy had a significantly lower rate of ischemic stroke. These findings emphasize the need to explore novel interventions like LAAO to address the persistent risk of stroke in AF patients despite anticoagulation therapy. Further research, including well-designed randomized controlled trials, is necessary to validate these findings and establish the efficacy of LAAO as part of comprehensive secondary prevention strategies for ischemic stroke in AF patients.

Trial design

The multi-center randomized-controlled trial is designed as a two-arm parallel group study, employing a 1:1 randomization ratio. It is conducted in a blinded manner with endpoint adjudication, aiming to establish the superiority of one treatment strategy over another. This adaptive clinical trial follows the PROBE (Prospective Randomized Open Blinded Endpoint) design, allowing for flexibility in treatment allocation and outcome assessment.

The trial focuses on comparing two well-established treatment strategies, both of which are commonly used in clinical practice but have not been directly compared in a randomized setting for ischemic stroke patients with atrial fibrillation. This study aims to provide valuable insights into which strategy offers superior outcomes for this patient population.

Participants in the trial will receive either medication therapy or an intervention (device), with the specific treatment determined by the treating physician according to local routine and the clinical study protocol. This approach ensures that patients receive appropriate and individualized care while contributing to the overall objectives of the trial.

Randomization

Participants are randomized at a 1:1 ration to the LAAO+DOAC or DOAC-only group. 

Hypothesis and Endpoints

Research hypothesis

Early (within 3 months of index stroke) LAAO plus DOAC in patients with AF and acute stroke despite optimal anticoagulation reduces the risk for subsequent cardioembolic events compared to DOAC alone.

Primary objective

The primary aim of this trial is to evaluate whether in patients with AF and acute stroke despite optimal anticoagulation, a combination of LAAO plus DOAC reduces the risk of the composite endpoint recurrent ischaemic stroke, systemic embolism and cardiovascular death compared to DOAC alone.

Primary endpoint

Primary Endpoint (composite)

The primary endpoint is a composite of recurrent ischemic stroke, systemic embolism, and cardiovascular death (whatever comes first). All patients will be followed-up until study end, resulting in minimum and maximum follow-up times of 6 months and 54 months (i.e. 48 months inclusion period plus minimal follow-up time 6 months), respectively.

Key secondary safety endpoints

• Symptomatic intracranial haemorrhage
• All-cause death

Additional secondary endpoints

• Recurrent ischemic stroke
• Systemic embolism
• Cardiovascular death
• Major extracranial bleeding (ISTH)
• Major extracranial bleeding (International Society on Thrombosis and Hemostasis [ISTH]) and BARC 3-5 bleedings
• All-cause hospitalization – any hospital stay of at least 24 hours not including planned procedures
• Serious device- or procedure-related complications
• Type and burden of atrial fibrillation at 6 months

Scores

• Quality of life (EQ5D)  at 6 months
• Functional neurological outcome (mRS; ordinal) at 6 months (phone visit)
• For patients with recurrent stroke: mRS 3 months after recurrent stroke event

Inclusion and exclusion criteria

Key inclusion criteria

• Age ≥ 18 years
• Written informed consent
•  Permanent, persistent, or paroxysmal spontaneous AF previously known or diagnosed during the index hospitalization.
• Recent (≤3 months) ischemic stroke.
• Active and ongoing anticoagulation therapy at stroke onset assessed based on medical history (i.e. any therapeutic oral anticoagulation therapy [Vitamin K antagonist/DOAC according to prescription recommendations for AF; inadequate low-dose DOAC therapy allowed for inclusion] not stopped/paused for >48 hours due to any reason, i.e. medical intervention or non-adherence).
• Active or planned long-term therapy with DOAC

Key exclusion criteria

• Contraindication 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
• LAA is obliterated or surgically ligated
• Persistent proximal LAA thrombus despite 4 weeks of anticoagulation (if a proximal thrombus in the LAA is found, anticoagulation with vitamin K antagonist (INR 2.5-3.5) may be started, and if the thrombus disappears, the patient may be eligible for LAAO)
• Pregnancy or breastfeeding (pregnancy test in urine or blood to be performed at screening for women of childbearing potential)

Trial structure

Steering Committee

Literature

• Secondary stroke prevention in people with atrial fibrillation: treatments and trials – The Lancet Neurology
• Left Atrial Appendage Occlusion vs Standard of Care After Ischemic Stroke Despite Anticoagulation | Cardiology | JAMA Neurology | JAMA Network