Left Atrial Appendage Occlusion Versus Novel Oral Anticoagulation for Stroke Prevention in Atrial Fibrillation

Official title

Left Atrial Appendage Occlusion Versus Novel Oral Anticoagulation for Stroke Prevention in Atrial Fibrillation. A Multicenter Randomized Clinical Trial. (Occlusion-AF)

Overview

Atrial fibrillation (AF) is progressively common, and increases the risk of stroke five-fold. Oral anticoagulation is the mainstay therapy; however, it increases the risk of bleeding. Moreover, 30% with AF and at risk of stroke are not in relevant anticoagulation. The randomized PROTECT-AF trial has demonstrated the superiority of left atrial appendage occlusion (LAAO) as compared to warfarin for prevention of the combined endpoint of stroke, major bleeding and cardiovascular mortality. However, studies comparing LAAO to therapy with novel oral anticoagulants (NOAC) have not been carried out. This study aims to assess the effect of left atrial appendage occlusion (LAAO) to reduce the incidence of stroke, systemic embolism, major bleeding and all-cause mortality in patients with atrial fibrillation (AF) and a prior ischemic stroke or transient ischemic attack (TIA).

Detailed description

An investigator-initiated multicenter, randomized open-label non-inferiority trial with blinded outcome evaluation (PROBE design). The active comparison LAAO is tested against NOAC therapy in a 1:1 stratified randomization. Patients should have AF, and an ischemic stroke or TIA within 6 months prior to enrollment. In total 750 patients will be included. Follow-up will be based on in-office and telephone follow-up during the first 3 years after randomization, along with up to 10 years long-term follow-up through the National Patient Registries.

The main study outcomes: The primary outcome is a composite of stroke (hemorrhagic or ischemic), systemic embolism, major bleeding or all-cause mortality assessed after at least two years follow-up for the last enrolled patient. Secondary outcomes will examine early and late safety outcome measures. The long-term outcome will be assessed up to 10-years after randomization through the National Patient Registries.

Interventions

• Device Left atrial appendage occlusion
  Interventional left atrial appendage occlusion with the Amulet or Watchman device
• Drug NOAC
  Medical treatment arm. Patients will be treated with one of the available NOAC drugs; Apixaban, Dabigatran, Edoxaban or Rivaroxaban. The specific drug and dose is at the discretion of the treating physician.

Primary outcome measures

• Composite endpoint of stroke (ischemic and hemorrhagic), systemic embolism, major bleeding and all-cause mortality. [Time frame: Up to 5-years from randomization]

Secondary outcome measures (12)

• Incidence of ischemic stroke [Time frame: 2-, 3-, 5- and 10-years]
• Incidence of hemorrhagic stroke [Time frame: 2-, 3-, 5- and 10-years]
• Incidence of systemic embolism [Time frame: 2-, 3-, 5- and 10-years]
• Incidence of major or life-threatening bleeding [Time frame: 2-, 3-, 5- and 10-years]
• Incidence of all-cause mortality [Time frame: 2-, 3-, 5- and 10-years]
• Incidence of Transient ischemic attack (TIA) [Time frame: 2-, 3-, 5- and 10-years]
• Number of patients with a device-related complication [Time frame: 2 months]
• Number of patients with a procedure-related complication [Time frame: 2 months]
• Number of patients with a device success [Time frame: 2 months]
• Number of patients with technical success [Time frame: 2 Months]
• Number of patients with procedural success [Time frame: 2 months]
• Number of patients with peri-device leaks at follow-up imaging [Time frame: 2 months]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years
• documented non-valvular atrial fibrillation (paroxysmal, persistent or permanent)
• Eligible for long-term Novel Oral Anticoagulation (NOAC) therapy
• Ischemic stroke within the recent 6 months verified by neuroimaging, or
• Transient ischemic attack within 6 months with proven cerebral ischemia based on cerebral magnetic resonance imaging (MRI)

Exclusion criteria

• Modified rankin scale > 3 at time of enrollment
• Glomerular filtration rate (GFR) below 15 ml/min/1.73 m2
• Contraindication towards long-term aspirin therapy
• Planned combined cardiovascular interventional procedures at the time of enrollment
• Terminal illness or cancer with life expectancy less than 2 years.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Prevention

Study locations

Denmark · 5 centers

• Aarhus University Hospital — Aarhus
• Odense University Hospital — Odense
• Aalborg University Hospital — Aalborg
• Rigshospitalet — Copenhagen
• Regional Hospital West Jutland — Holstebro

Finland · 3 centers

• Helsinki University Central Hospital — Helsinki
• Oulu University Hospital — Oulu
• Turku University Hospital — Turku

Norway · 3 centers

• Haukeland University Hospital — Bergen
• Oslo University Hospital — Oslo
• Trondheim University Hospital — Trondheim

Sweden · 3 centers

• Sahlgrenska University Hospital — Gothenburg
• Skånes University Hospital — Lund
• Karolinska University Hospital — Stockholm

Germany · 1 center

• Jena University Hospital — Jena

Publications

• Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: European perspective. Clin Epidemiol. 2014 Jun 16;6:213-20. doi: 10.2147/CLEP.S47385. eCollection 2014. PMID 24966695
• Marini C, De Santis F, Sacco S, Russo T, Olivieri L, Totaro R, Carolei A. Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a population-based study. Stroke. 2005 Jun;36(6):1115-9. doi: 10.1161/01.STR.0000166053.83476.4a. Epub 2005 May 5. PMID 15879330
• Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg. 1996 Feb;61(2):755-9. doi: 10.1016/0003-4975(95)00887-X. PMID 8572814
• Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC, Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, Popescu BA, Schotten U, Van Putte B, Vardas P; ESC Scientific Document Group. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016 Oct 7;37(38):2893-2962. doi: 10.1093/eurheartj/ehw210. PMID 27567408
• Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Sep 17;361(12):1139-51. doi: 10.1056/NEJMoa0905561. Epub 2009 PMID 19717844
• Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators. A PMID 21870978
• Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Spinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013 Nov 28;369(22):2093-104. doi: 10.1056/NEJMoa1310907. Epub PMID 24251359
• Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883-91. doi: 10.1056/NEJMoa1009638. Epub 2011 Aug 10. PMID 21830957

Identifiers

NCT: NCT03642509 · Occlusion-AF-AUH250418-32

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗