Clinical trial NCT03642509: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Atrial Fibrillation
Stroke
Keywords: Left atrial appendage occlusion
Novel oral anticoagulation
Lead sponsor: University of Aarhus
Sponsor class: OTHER
Collaborators: name: Aarhus University Hospital
name: Aalborg University Hospital
name: Odense University Hospital
name: Sahlgrenska University Hospital
name: Karolinska University Hospital
name: Haukeland University Hospital
name: Helsinki University Central Hospital
name: Gødstrup Hospital
name: Lund University Hospital
name: Oslo University Hospital
name: Trondheim University Hospital
name: Rigshospitalet, Denmark
name: Jena University Hospital
First posted: 2018-08-22
Enrollment: 750
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

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.

Primary outcomes:
measure: Composite endpoint of stroke (ischemic and hemorrhagic), systemic embolism, major bleeding and all-cause mortality.
timeFrame: Up to 5-years from randomization
Secondary outcomes:
measure: Incidence of ischemic stroke
timeFrame: 2-, 3-, 5- and 10-years
measure: Incidence of hemorrhagic stroke
timeFrame: 2-, 3-, 5- and 10-years
measure: Incidence of systemic embolism
timeFrame: 2-, 3-, 5- and 10-years
measure: Incidence of major or life-threatening bleeding
timeFrame: 2-, 3-, 5- and 10-years
measure: Incidence of all-cause mortality
timeFrame: 2-, 3-, 5- and 10-years
measure: Incidence of Transient ischemic attack (TIA)
timeFrame: 2-, 3-, 5- and 10-years
measure: Number of patients with a device-related complication
timeFrame: 2 months
measure: Number of patients with a procedure-related complication
timeFrame: 2 months
measure: Number of patients with a device success
timeFrame: 2 months
measure: Number of patients with technical success
timeFrame: 2 Months
measure: Number of patients with procedural success
timeFrame: 2 months
measure: Number of patients with peri-device leaks at follow-up imaging
timeFrame: 2 months
measure: Changes in functional status based on Modified Rankin Scale
timeFrame: 24 months
measure: Changes in Quality of life
timeFrame: 12 months
measure: Compliance to NOAC
timeFrame: 2-, 3-, 5-, and 10-years
measure: Changes in neurological status based on National Institute of Health (NIH) Stroke scale score
timeFrame: 12 months
Other outcomes:
measure: Minor bleeding
timeFrame: 24 months
measure: Comparison of the cost-effectiveness of LAAO and NOAC therapy
timeFrame: 24 months
Locations:
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
state: Central Denmark Region
city: Odense
country: Denmark
facility: Odense University Hospital
state: Region Of Southern Denmark
city: Aalborg
country: Denmark
facility: Aalborg University Hospital
state: The North Denmark Region
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Holstebro
country: Denmark
facility: Regional Hospital West Jutland
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital
city: Oulu
country: Finland
facility: Oulu University Hospital
city: Turku
country: Finland
facility: Turku University Hospital
city: Jena
country: Germany
facility: Jena University Hospital
city: Bergen
country: Norway
facility: Haukeland University Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Trondheim
country: Norway
facility: Trondheim University Hospital
city: Göteborg
country: Sweden
facility: Sahlgrenska University Hospital
city: Lund
country: Sweden
facility: Skånes University Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
Study officials:
affiliation: Aarhus University Hospital
name: Kasper Korsholm, MD
role: STUDY_CHAIR
affiliation: Aarhus University Hospital
name: Jens Erik Nielsen-Kudsk, MD DMSc Prof
role: STUDY_CHAIR
affiliation: Aarhus University Hospital
name: Dorte Damgaard, MD PhD
role: STUDY_CHAIR
affiliation: Aalborg University Hospital
name: Søren Paaske Johnsen, MD PhD Prof
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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. Epub 2016 Aug 27. No abstract available.
citation: 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 Aug 30.
citation: 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. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011 Sep 15;365(11):981-92. doi: 10.1056/NEJMoa1107039. Epub 2011 Aug 27.
citation: 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 2013 Nov 19.
citation: 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.
citation: Diener HC, Connolly SJ, Ezekowitz MD, Wallentin L, Reilly PA, Yang S, Xavier D, Di Pasquale G, Yusuf S; RE-LY study group. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial. Lancet Neurol. 2010 Dec;9(12):1157-1163. doi: 10.1016/S1474-4422(10)70274-X. Epub 2010 Nov 6.
citation: Hankey GJ, Patel MR, Stevens SR, Becker RC, Breithardt G, Carolei A, Diener HC, Donnan GA, Halperin JL, Mahaffey KW, Mas JL, Massaro A, Norrving B, Nessel CC, Paolini JF, Roine RO, Singer DE, Wong L, Califf RM, Fox KA, Hacke W; ROCKET AF Steering Committee Investigators. Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol. 2012 Apr;11(4):315-22. doi: 10.1016/S1474-4422(12)70042-X. Epub 2012 Mar 7.
citation: Easton JD, Lopes RD, Bahit MC, Wojdyla DM, Granger CB, Wallentin L, Alings M, Goto S, Lewis BS, Rosenqvist M, Hanna M, Mohan P, Alexander JH, Diener HC; ARISTOTLE Committees and Investigators. Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial. Lancet Neurol. 2012 Jun;11(6):503-11. doi: 10.1016/S1474-4422(12)70092-3. Epub 2012 May 8.
citation: Rost NS, Giugliano RP, Ruff CT, Murphy SA, Crompton AE, Norden AD, Silverman S, Singhal AB, Nicolau JC, SomaRaju B, Mercuri MF, Antman EM, Braunwald E; ENGAGE AF-TIMI 48 Investigators. Outcomes With Edoxaban Versus Warfarin in Patients With Previous Cerebrovascular Events: Findings From ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48). Stroke. 2016 Aug;47(8):2075-82. doi: 10.1161/STROKEAHA.116.013540. Epub 2016 Jul 7.
citation: Gadsboll K, Staerk L, Fosbol EL, Sindet-Pedersen C, Gundlund A, Lip GYH, Gislason GH, Olesen JB. Increased use of oral anticoagulants in patients with atrial fibrillation: temporal trends from 2005 to 2015 in Denmark. Eur Heart J. 2017 Mar 21;38(12):899-906. doi: 10.1093/eurheartj/ehw658.
citation: Hellfritzsch M, Husted SE, Grove EL, Rasmussen L, Poulsen BK, Johnsen SP, Hallas J, Pottegard A. Treatment Changes among Users of Non-Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation. Basic Clin Pharmacol Toxicol. 2017 Feb;120(2):187-194. doi: 10.1111/bcpt.12664. Epub 2016 Oct 28.
citation: Reddy VY, Sievert H, Halperin J, Doshi SK, Buchbinder M, Neuzil P, Huber K, Whisenant B, Kar S, Swarup V, Gordon N, Holmes D; PROTECT AF Steering Committee and Investigators. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial. JAMA. 2014 Nov 19;312(19):1988-98. doi: 10.1001/jama.2014.15192.
citation: Holmes DR Jr, Kar S, Price MJ, Whisenant B, Sievert H, Doshi SK, Huber K, Reddy VY. Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial. J Am Coll Cardiol. 2014 Jul 8;64(1):1-12. doi: 10.1016/j.jacc.2014.04.029.
citation: Reddy VY, Doshi SK, Kar S, Gibson DN, Price MJ, Huber K, Horton RP, Buchbinder M, Neuzil P, Gordon NT, Holmes DR Jr; PREVAIL and PROTECT AF Investigators. 5-Year Outcomes After Left Atrial Appendage Closure: From the PREVAIL and PROTECT AF Trials. J Am Coll Cardiol. 2017 Dec 19;70(24):2964-2975. doi: 10.1016/j.jacc.2017.10.021. Epub 2017 Nov 4.
citation: Boersma LV, Schmidt B, Betts TR, Sievert H, Tamburino C, Teiger E, Pokushalov E, Kische S, Schmitz T, Stein KM, Bergmann MW; EWOLUTION investigators. Implant success and safety of left atrial appendage closure with the WATCHMAN device: peri-procedural outcomes from the EWOLUTION registry. Eur Heart J. 2016 Aug;37(31):2465-74. doi: 10.1093/eurheartj/ehv730. Epub 2016 Jan 27.
citation: Tzikas A, Shakir S, Gafoor S, Omran H, Berti S, Santoro G, Kefer J, Landmesser U, Nielsen-Kudsk JE, Cruz-Gonzalez I, Sievert H, Tichelbacker T, Kanagaratnam P, Nietlispach F, Aminian A, Kasch F, Freixa X, Danna P, Rezzaghi M, Vermeersch P, Stock F, Stolcova M, Costa M, Ibrahim R, Schillinger W, Meier B, Park JW. Left atrial appendage occlusion for stroke prevention in atrial fibrillation: multicentre experience with the AMPLATZER Cardiac Plug. EuroIntervention. 2016 Feb;11(10):1170-9. doi: 10.4244/EIJY15M01_06.
citation: Landmesser U, Schmidt B, Nielsen-Kudsk JE, Lam SCC, Park JW, Tarantini G, Cruz-Gonzalez I, Geist V, Della Bella P, Colombo A, Zeus T, Omran H, Piorkowski C, Lund J, Tondo C, Hildick-Smith D. Left atrial appendage occlusion with the AMPLATZER Amulet device: periprocedural and early clinical/echocardiographic data from a global prospective observational study. EuroIntervention. 2017 Sep 20;13(7):867-876. doi: 10.4244/EIJ-D-17-00493.
citation: Sahay S, Nombela-Franco L, Rodes-Cabau J, Jimenez-Quevedo P, Salinas P, Biagioni C, Nunez-Gil I, Gonzalo N, de Agustin JA, Del Trigo M, Perez de Isla L, Fernandez-Ortiz A, Escaned J, Macaya C. Efficacy and safety of left atrial appendage closure versus medical treatment in atrial fibrillation: a network meta-analysis from randomised trials. Heart. 2017 Jan 15;103(2):139-147. doi: 10.1136/heartjnl-2016-309782. Epub 2016 Sep 1.
citation: Tzikas A, Holmes DR Jr, Gafoor S, Ruiz CE, Blomstrom-Lundqvist C, Diener HC, Cappato R, Kar S, Lee RJ, Byrne RA, Ibrahim R, Lakkireddy D, Soliman OI, Nabauer M, Schneider S, Brachman J, Saver JL, Tiemann K, Sievert H, Camm AJ, Lewalter T. Percutaneous left atrial appendage occlusion: the Munich consensus document on definitions, endpoints and data collection requirements for clinical studies. EuroIntervention. 2016 May 17;12(1):103-11. doi: 10.4244/EIJV12I1A18.