Apixaban vs Dual Antiplatet Therapy Study After Left Atrial Appendage Occlosure (ADALA)

Summary

Objective: To demonstrate superiority of a strategy of anticoagulation with apixaban 5mg/2.5mg bid as compared with the current standard of care (dual antiplatelet therapy) after occlusion of the left atrial appendage (LAAC) in patients with atrial fibrillation (AF). Rationale: Data on antithrombotic therapy after LAAC are scarce and no randomized evaluation has been performed to demonstrate what is the best antithrombotic strategy. LAAO in patients without contraindication to chronic anticoagulants (PROTECT-AF regimen) is a 6-week period of anticoagulation with warfarin associated with aspirin, followed by once daily clopidogrel (75 mg) and aspirin (81-325 mg) until the 6 months visit, then aspirin alone is continued indefinitely, as tested in the pivotal trials. LAAO is also being used as an alternative to warfarin anticoagulation when patients have a contraindication or are unsuitable to warfarin. These patients usually receive a regimen of daily clopidogrel and aspirin (DAPT) for 3 months. Some may receive a shorter duration of DAPT or even only single antiplatelet therapy (SAPT) in case of excess bleeding risk. This antiplatelet regimen has never been compared with any anticoagulation regimen after LAAC. The Investigators propose to evaluate a unique antithrombotic strategy after LAAC for atrial fibrillation, whatever the indication of LAAC, including patients not suitable for long term warfarin anticoagulation. This strategy uses apixaban 5mg (with dose adjustment when necessary) which will be compared to the standard of care based on antiplatelet therapy and which may vary according to the risk profile of the patient. Apixaban, has demonstrated a mortality benefit associated with significant reductions in stroke, systemic embolism and major bleeding versus VKA. In addition, apixaban is the only NOAC which has demonstrated superiority over aspirin alone, in AF patients not suitable for chronic warfarin anticoagulation, to prevent cardio-embolic events with a safety profile similar to aspirin.The Investigators therefore formulate the hypothesis that apixaban is superior to standard of care (APT) to prevent cardiovascular events and bleeding complications after LAAO. Population: Inclusion criteria: AF patients who have undergone a successful LAAO procedure. Exclusion criteria include any indication for triple antithrombotic treatment, mechanical heart valve, use of prasugrel or ticagrelor, serious renal failure defined as a creatinine clearance \<15mL/min, contraindication to any form of anticoagulation or antiplatelet therapy. Randomization will occur always before hospital discharge as soon as the patient is stable or stabilized after the procedure. Randomization: Apixaban vs. APT, both for 3 months. Groups: 1/Apixaban 5mg or 2.5mg bid (if dose adjustment needed). 2/ DAPT using low-dose ASA (75-100mg) and clopidogrel (75mg); or in patients with a history of intracranial hemorrhage (ICH) SAPT (aspirin or clopidogrel) will be used instead of DAPT from the time of randomization. Follow-up: 12 months from randomization Primary endpoint: combined enpoint of death, MI, stroke, thromboembolic complications, major or significant bleeding at 3 months follow-up. Sample size: In order to find a 16% difference in the event rates among the two treatment strategies, using a logrank test with a 5% two-sided significance level, we will need 76 patients in each group (152 in total). However, to compensate patient drop out, a total of 160 patients will be included in the study. Recruitment : 24 months Centers: 3 centers in Spain.

Timeline

Start

2019-05-01

Primary completion

2019-06-12

Completion

2022-10-30

Publications

• Background Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991 Aug;22(8):983-8. doi: 10.1161/01.str.22.8.983.
• Background Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Van Mieghem W, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O'Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011 Mar 3;364(9):806-17. doi: 10.1056/NEJMoa1007432. Epub 2011 Feb 10.
• Background 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.
• Background Kirley K, Qato DM, Kornfield R, Stafford RS, Alexander GC. National trends in oral anticoagulant use in the United States, 2007 to 2011. Circ Cardiovasc Qual Outcomes. 2012 Sep 1;5(5):615-21. doi: 10.1161/CIRCOUTCOMES.112.967299. Epub 2012 Sep 4.
• Background Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, Hindricks G, Kirchhof P; ESC Committee for Practice Guidelines-CPG; Document Reviewers. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation--developed with the special contribution of the European Heart Rhythm Association. Europace. 2012 Oct;14(10):1385-413. doi: 10.1093/europace/eus305. Epub 2012 Aug 24. No abstract available.
• Background Meier B, Blaauw Y, Khattab AA, Lewalter T, Sievert H, Tondo C, Glikson M; Document Reviewers. EHRA/EAPCI expert consensus statement on catheter-based left atrial appendage occlusion. Europace. 2014 Oct;16(10):1397-416. doi: 10.1093/europace/euu174. Epub 2014 Aug 29. No abstract available.
• Background Holmes DR, Reddy VY, Turi ZG, Doshi SK, Sievert H, Buchbinder M, Mullin CM, Sick P; PROTECT AF Investigators. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet. 2009 Aug 15;374(9689):534-42. doi: 10.1016/S0140-6736(09)61343-X.
• Background 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.
• Background Lam YY, Yip GW, Yu CM, Chan WW, Cheng BC, Yan BP, Clugston R, Yong G, Gattorna T, Paul V. Left atrial appendage closure with AMPLATZER cardiac plug for stroke prevention in atrial fibrillation: initial Asia-Pacific experience. Catheter Cardiovasc Interv. 2012 Apr 1;79(5):794-800. doi: 10.1002/ccd.23136. Epub 2011 Nov 30.
• Background Reddy VY, Mobius-Winkler S, Miller MA, Neuzil P, Schuler G, Wiebe J, Sick P, Sievert H. Left atrial appendage closure with the Watchman device in patients with a contraindication for oral anticoagulation: the ASAP study (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology). J Am Coll Cardiol. 2013 Jun 25;61(25):2551-6. doi: 10.1016/j.jacc.2013.03.035. Epub 2013 Apr 10.
• Background Park JW, Bethencourt A, Sievert H, Santoro G, Meier B, Walsh K, Lopez-Minguez JR, Meerkin D, Valdes M, Ormerod O, Leithauser B. Left atrial appendage closure with Amplatzer cardiac plug in atrial fibrillation: initial European experience. Catheter Cardiovasc Interv. 2011 Apr 1;77(5):700-6. doi: 10.1002/ccd.22764. Epub 2011 Mar 8.
• Background Lopez-Minguez JR, Eldoayen-Gragera J, Gonzalez-Fernandez R, Fernandez-Vegas C, Fuentes-Canamero ME, Millan-Nunez V, Nogales-Asensio JM, Martinez-Naharro A, Sanchez-Giralt S, Doblado-Calatrava M, Merchan-Herrera A. Immediate and one-year results in 35 consecutive patients after closure of left atrial appendage with the Amplatzer cardiac plug. Rev Esp Cardiol (Engl Ed). 2013 Feb;66(2):90-7. doi: 10.1016/j.rec.2012.04.017. Epub 2012 Aug 29.
• Background 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.
• Background Freixa X, Tzikas A, Sobrino A, Chan J, Basmadjian AJ, Ibrahim R. Left atrial appendage closure with the Amplatzer Cardiac Plug: impact of shape and device sizing on follow-up leaks. Int J Cardiol. 2013 Sep 30;168(2):1023-7. doi: 10.1016/j.ijcard.2012.10.031. Epub 2012 Dec 27.
• Background Urena M, Rodes-Cabau J, Freixa X, Saw J, Webb JG, Freeman M, Horlick E, Osten M, Chan A, Marquis JF, Champagne J, Ibrahim R. Percutaneous left atrial appendage closure with the AMPLATZER cardiac plug device in patients with nonvalvular atrial fibrillation and contraindications to anticoagulation therapy. J Am Coll Cardiol. 2013 Jul 9;62(2):96-102. doi: 10.1016/j.jacc.2013.02.089. Epub 2013 May 9.
• Background Vidal-Jordana A, Barroeta-Espar I, Sainz Pelayo MP, Mateo J, Delgado-Mederos R, Marti-Fabregas J. [Intracerebral hemorrhage in anticoagulated patients: what do we do afterwards?]. Neurologia. 2012 Apr;27(3):136-42. doi: 10.1016/j.nrl.2011.04.020. Epub 2011 Jun 16. Spanish.
• Background Healey JS, Hart RG, Pogue J, Pfeffer MA, Hohnloser SH, De Caterina R, Flaker G, Yusuf S, Connolly SJ. Risks and benefits of oral anticoagulation compared with clopidogrel plus aspirin in patients with atrial fibrillation according to stroke risk: the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events (ACTIVE-W). Stroke. 2008 May;39(5):1482-6. doi: 10.1161/STROKEAHA.107.500199. Epub 2008 Mar 6.
• Background Kawakami T, Kobayakawa H, Ohno H, Tanaka N, Ishihara H. Resolution of left atrial appendage thrombus with apixaban. Thromb J. 2013 Dec 20;11(1):26. doi: 10.1186/1477-9560-11-26.
• Background Kappetein AP, Head SJ, Genereux P, Piazza N, van Mieghem NM, Blackstone EH, Brott TG, Cohen DJ, Cutlip DE, van Es GA, Hahn RT, Kirtane AJ, Krucoff MW, Kodali S, Mack MJ, Mehran R, Rodes-Cabau J, Vranckx P, Webb JG, Windecker S, Serruys PW, Leon MB. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. J Am Coll Cardiol. 2012 Oct 9;60(15):1438-54. doi: 10.1016/j.jacc.2012.09.001.
• Background Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011 Jun 14;123(23):2736-47. doi: 10.1161/CIRCULATIONAHA.110.009449. No abstract available.
• Background Lip GY, Frison L, Halperin JL, Lane DA. Identifying patients at high risk for stroke despite anticoagulation: a comparison of contemporary stroke risk stratification schemes in an anticoagulated atrial fibrillation cohort. Stroke. 2010 Dec;41(12):2731-8. doi: 10.1161/STROKEAHA.110.590257. Epub 2010 Oct 21.
• Background Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010 Nov;138(5):1093-100. doi: 10.1378/chest.10-0134. Epub 2010 Mar 18.
• Results 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.
• Freixa X, Cruz-Gonzalez I, Cepas-Guillen P, Millan X, Antunez-Muinos P, Flores-Umanzor E, Asmarats L, Regueiro A, Lopez-Tejero S, Li CP, Sanchis L, Rodes-Cabau J, Arzamendi D. Low-Dose Direct Oral Anticoagulation vs Dual Antiplatelet Therapy After Left Atrial Appendage Occlusion: The ADALA Randomized Clinical Trial. JAMA Cardiol. 2024 Oct 1;9(10):922-926. doi: 10.1001/jamacardio.2024.2335.

Drugs

Indications

No indication recorded.