Elsevier

American Heart Journal

Volume 243, January 2022, Pages 28-38
American Heart Journal

Trial Design
Left atrial appendage occlusion vs novel oral anticoagulation for stroke prevention in atrial fibrillation: rationale and design of the multicenter randomized occlusion-AF trial

https://doi.org/10.1016/j.ahj.2021.08.020Get rights and content

Background

The prevalence of atrial fibrillation (AF) is increasing globally, which is a major clinical and public health concern due to the 5-fold increased risk of stroke. Oral anticoagulation with novel oral anticoagulants (NOACs) is the current primary option for stroke prevention in patients with AF, although it increases the risk of major bleeding. Patients with prior ischemic cerebrovascular events are at particularly high risk of both recurrent ischemic events and major bleeding. Left atrial appendage occlusion (LAAO) provides an alternative option for stroke prevention in high-risk patients, however, with currently limited evidence. Thus, randomized trials comparing LAAO to NOACs are needed.

Objective

The Occlusion-AF trial is designed to assess whether LAAO is non-inferior to NOAC therapy for reduction of the combined endpoint of stroke, systemic embolism, major bleeding (Bleeding Academic Research Consortium 3) and all-cause mortality in patients with AF and a recent ischemic stroke or transient ischemic attack (TIA).

Methods and analysis

Investigator-initiated multicenter, multinational, randomized open-label non-inferiority trial with blinded outcome evaluation (PROBE design). Patients with documented AF, and an ischemic stroke or TIA within 6 months will be eligible for enrollment. Major exclusion criteria are modified Rankin Scale > 3 at enrollment, glomerular filtration rate < 15 ml/min, and life-expectancy less than 2 years. A total of 750 patients will be randomized 1:1 to receive either a NOAC or LAAO using the Amplatzer Amulet (Abbott, MN, USA) or Watchman FLX (Boston Scientific, MN, USA) with subsequent life-long aspirin 75 mg daily. Follow-up will be based on in-office and telephone follow-up in combination with long-term follow-up (10 years) through national hospital discharge registries in the individual Nordic countries. The primary outcome will be a composite endpoint of stroke, systemic embolism, major bleeding (BARC 3) and all-cause mortality at 2-year follow-up.

Conclusions

The Occlusion-AF trial is designed to compare LAAO to NOAC therapy for secondary stroke prevention in AF patients with a high risk of recurrent thromboembolic events, i.e. with previous ischemic stroke or TIA, and otherwise eligible for anticoagulation. The results are expected to contribute significantly to the understanding of the effects of LAAO compared to the standard contemporary pharmacological treatment in these patients.

Section snippets

Study objective

The Occlusion-AF trial is designed to examine the hypothesis that transcatheter LAAO is non-inferior to NOAC therapy for prevention of the combined endpoint of stroke, systemic embolism, major bleeding (Bleeding Academic Research Consortium 3) or all-cause mortality in patients with AF and a recent ischemic stroke or TIA.

Study design

Occlusion-AF is an investigator-initiated multicenter, multinational, prospective randomized, open-label non-inferiority trial with blinded endpoint assessment (PROBE design) comparing the efficacy and safety of LAAO to NOAC therapy for prevention of thromboembolism and bleeding in AF.

The study will recruit patients from neurological and LAAO centers in the Nordic countries, including Denmark, Norway, Sweden and Finland. Patients aged ≥ 18 years, with non-valvular paroxysmal, persistent or

Discussion

Stroke prevention is key to reduce morbidity and mortality related to AF. Both primary and secondary prevention is crucial, particularly as ischemic stroke is the strongest predictor of recurrent ischemic events. The recent LAAOS III trial demonstrated superiority of surgical LAA ligation combined with anticoagulation over anticoagulation alone for prevention of ischemic stroke or systemic embolism in a general AF population undergoing heart surgery. These data are intriguing, and clearly

Conclusion/summary

There are limited randomized data available on the effects of LAAO compared to NOAC therapy in AF patients eligible for oral anticoagulation. The Occlusion-AF trial is an investigator-initiated randomized open-label trial designed to generate knowledge on the treatment effects of LAAO in patients with AF and a recent ischemic stroke or transient ischemic attack.

Funding

This work was funded by Novo Nordisk Foundation (NNF17OC0029510), Boston Scientific and Abbott.

Conflict of interest

Dr. Korsholm has received speaker's honorarium and institutional grants from Abbott/Boston Scientific, Dr. Odenstedt has received speaker's honorarium from Abbott/Boston Scientific and is proctor for Abbott. Dr. Karlsson has received speaker's honorarium from Bayer, DMS, Pfizer and Boehringer-Ingelheim. Professor Nielsen-Kudsk is proctor for Abbott/Boston Scientific and has received institutional grants from Abbott/Boston Scientific and Novo Nordisk.

References (41)

  • G Lippi et al.

    Global epidemiology of atrial fibrillation: an increasing epidemic and public health challenge

    Int J Stroke

    (2020)
  • L Friberg et al.

    High prevalence of atrial fibrillation among patients with ischemic stroke

    Stroke

    (2014)
  • C Marini et al.

    Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a population-based study

    Stroke

    (2005)
  • G Hindricks et al.

    2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS)

    Eur Heart J

    (2020)
  • P Kirchhof et al.

    2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS: the task force for the management of atrial fibrillation of the European Society of Cardiology (ESC)Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESCEndorsed by the European Stroke Organisation (ESO)

    Eur Heart J

    (2016)
  • SJ Connolly et al.

    Dabigatran vs warfarin in patients with atrial fibrillation

    N Engl J Med

    (2009)
  • CB Granger et al.

    Apixaban vs warfarin in patients with atrial fibrillation

    N Engl J Med

    (2011)
  • Cunningham M, Giugliano R. Edoxaban noninferior to warfarin in the ENGAGE AF-TIMI 48 Trial. MD Conference Express...
  • MR Patel et al.

    Rivaroxaban versus warfarin in nonvalvular atrial fibrillation

    N Engl J Med

    (2011)
  • K Gadsbøll et al.

    Increased use of oral anticoagulants in patients with atrial fibrillation: temporal trends from 2005 to 2015 in Denmark

    Eur Heart J

    (2017)
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    • Clinical outcomes of left atrial appendage occlusion versus direct oral anticoagulation in patients with atrial fibrillation and prior ischemic stroke: A propensity-score matched study

      2022, International Journal of Cardiology
      Citation Excerpt :

      We attempted to account for this through sensitivity analyses, however, risk of residual confounding should be acknowledged when interpreting results. We acknowledge that the present study should be regarded as hypothesis-generating, and the results must be confirmed in a randomized clinical trial like the ongoing Occlusion-AF trial initiated by the authors (Clinicaltrials.gov NCT03642509) [28]. This propensity-score matched study based on the Amulet Observational Study and the Danish Patient Registries, indicated a significantly lower risk of the composite outcome of ischemic stroke, major bleeding, and all-cause mortality with LAAO therapy as compared to DOAC in AF-patients with prior ischemic stroke.

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