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Apixaban in patients at risk of stroke undergoing atrial fibrillation ablation

Apixaban in patients at risk of stroke undergoing atrial fibrillation ablation CLINICAL RESEARCH European Heart Journal (2018) 39, 2942–2955 doi:10.1093/eurheartj/ehy176 Arrhythmia/electrophysiology Apixaban in patients at risk of stroke undergoing atrial fibrillation ablation 1,2,3,4 4,5 4 1,3 Paulus Kirchhof *, Karl Georg Haeusler , Benjamin Blank , Joseph De Bono , 6 7 8 9 David Callans , Arif Elvan , Thomas Fetsch , Isabelle C. Van Gelder , 10 11 12 13 Philip Gentlesk , Massimo Grimaldi , Jim Hansen , Gerhard Hindricks , 14 15 16 17 Hussein R. Al-Khalidi , Tyler Massaro , Lluis Mont , Jens Cosedis Nielsen , 18 15,19 20 21 Georg No ¨lker , Jonathan P. Piccini , Tom De Potter , Daniel Scherr , 4,22 23 24 25 Ulrich Schotten , Sakis Themistoclakis , Derick Todd , Johan Vijgen , and 26,27 Luigi Di Biase 1 2 Institute of Cardiovascular Sciences, University of Birmingham, and SWBH and UHB NHS Trusts, IBR 136, Wolfson Drive, Birmingham B15 2TT, UK; SWBH NHS Trust, 3 4 5 Birmingham, UK; University Hospitals Birmingham, Birmingham, UK; Atrial Fibrillation NETwork Association (AFNET), Germany, Mu ¨ nster; Center for Stroke Research Berlin 6 7 & Department of Neurology, Charite ´ – Universita ¨tsmedizin Berlin, Germany; Hospital of the University of Pennsylvania, PA, USA; Isala Heart Center Zwolle, Zwolle, The 8 9 10 Netherlands; The Clinical Research Institute, Munich, Germany; University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Sentara 11 12 13 Cardiovascular Research Institute, Norfolk, VA, USA; Ospedale Generale Regionale F. Miulli, Acquaviva delle Fonti, Italy; Gentofte Hospital, Hellerup, Denmark; Abteilung 14 15 fu ¨ r Rhythmologie, Leipzig Heart Center, Leipzig, Germany; Department of Biostatistics & Bioinformatics, Duke University School of Medicine, USA; Duke Clinical Research 16 17 Institute (DCRI), Durham, NC, USA; Hospital Clinic Barcelona, University of Barcelona, Barcelona, Spain; Department of Cardiology, Aarhus University Hospital, Denmark; 18 19 Herz- und Diabeteszentrum NRW, Ruhr-Universita ¨t Bochum, Bad Oeynhausen, Germany; Division of Cardiology Duke University Medical Center, Duke University, Durham, 20 21 22 NC, USA; Cardiovascular Center, OLV Aalst, Belgium; Department of Cardiology, Medical University Graz, Austria; Department of Physiology, University Maastricht, 23 24 25 Maastricht, Netherlands; Ospedale Dell’Angelo, Mestre, Italy; Liverpool Heart and Chest Hospital, Liverpool, UK; Jessa Ziekenhuis, Campus Virga Jesse, Hasselt, Belgium; 26 27 Albert Einstein College of Medicine, at Montefiore Hospital, New York, USA; and Texas Cardiac Arrhythmia Institute at St. David’s Medical Center, Austin, TX, USA Received 8 February 2018; revised 9 March 2018; editorial decision 12 March 2018; accepted 14 March 2018; online publish-ahead-of-print 20 March 2018 See page 2956 for the editorial comment on this article (doi: 10.1093/eurheartj/ehy274) Aims It is recommended to perform atrial fibrillation ablation with continuous anticoagulation. Continuous apixaban has not been tested. ................................................................................................................................................................................................... Methods We compared continuous apixaban (5 mg b.i.d.) to vitamin K antagonists (VKA, international normalized ratio 2–3) in and results atrial fibrillation patients at risk of stroke a prospective, open, multi-centre study with blinded outcome assessment. Primary outcome was a composite of death, stroke, or bleeding (Bleeding Academic Research Consortium 2–5). A high-resolution brain magnetic resonance imaging (MRI) sub-study quantified acute brain lesions. Cognitive function was assessed by Montreal Cognitive Assessment (MoCA) at baseline and at end of follow-up. Overall, 674 patients (median age 64 years, 33% female, 42% non-paroxysmal atrial fibrillation, 49 sites) were randomized; 633 received study drug and underwent ablation; 335 undertook MRI (25 sites, 323 analysable scans). The primary outcome was observed in 22/318 patients randomized to apixaban, and in 23/315 randomized to VKA {difference -0.38% [90% con- fidence interval (CI) -4.0%, 3.3%], non-inferiority P = 0.0002 at the pre-specified absolute margin of 0.075}, including 2 (0.3%) deaths, 2 (0.3%) strokes, and 24 (3.8%) ISTH major bleeds. Acute small brain lesions were found in a similar number of patients in each arm [apixaban 44/162 (27.2%); VKA 40/161 (24.8%); P = 0.64]. Cognitive function increased at the end of follow-up (median 1 MoCA unit; P = 0.005) without differences between study groups. ................................................................................................................................................................................................... Conclusions Continuous apixaban is safe and effective in patients undergoing atrial fibrillation ablation at risk of stroke with respect to bleeding, stroke, and cognitive function. Further research is needed to reduce ablation-related acute brain lesions. Keywords Atrial fibrillation Ablation Anticoagulation Bleeding Stroke Brain MRI � � � � � * Corresponding author. Tel: þ44 121 414 7042, Email: [email protected] V The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Apixaban in patients at risk of stroke 2943 procedure, raising concerns about peri-procedural protection of the Introduction 10,11 brain. Furthermore, acute brain lesions without corresponding 1–3 Catheter ablation is an effective and increasingly used component neurological symptoms are detected in ca. 25% of patients undergo- of rhythm control therapy to improve symptoms in patients with ing atrial fibrillation ablation by high-resolution diffusion-weighted 4–6 atrial fibrillation. Atrial fibrillation ablation is associated with a risk brain magnetic resonance imaging (MRI), a sequence that detects 4–6 12–15 of stroke and major bleeding. Continuous oral anticoagulation acute cytotoxic brain oedema. Cognitive function and acute using vitamin K antagonists (VKA) such as warfarin can reduce the . brain lesions have not been evaluated in controlled clinical trials of risk of embolic events to <1% when combined with peri-procedural . patients undergoing atrial fibrillation ablation. heparin. Therefore, continuous oral anticoagulation is recom- 4,6,7 mended in patients undergoing atrial fibrillation ablation. One Objectives randomized trial comparing rivaroxaban to warfarin in 218 patients Therefore, we conducted a randomized trial comparing continuous found similar bleeding rates with rivaroxaban compared to warfarin: apixaban to continuous VKA therapy in patients at risk of stroke 21/114 (18.4%) patients with bleeding on rivaroxaban, 18/104 . undergoing atrial fibrillation ablation, including assessment of cognitive 8 . (17.3%) patients with bleeding on VKA, one patient with stroke. . functioninall patients andMRI-detected brain lesions in a sub-study. Another trial randomizing 635 atrial fibrillation ablation patients to . dabigatran or VKA found 59/318 (18.6%) patients with bleeding on . Trial design dabigatran, 54/317 (17%) patients with bleeding on VKA, and one pa- . 9 . tient with transient ischaemic attack. Continuous apixaban has not . Anticoagulation using the direct factor Xa inhibitor apixaban during been compared to VKA in atrial fibrillation ablation patients. Atrial Fibrillation catheter Ablation: comparison to VKA therapy Atrial fibrillation ablation, unlike other ablation procedures, has (AXAFA – AFNET 5) was an investigator-initiated, prospective, been associated with declining cognitive function 90 days after the parallel-group, randomized, open, blinded outcome assessment study Table 1 Inclusion and exclusion criteria of the AXAFA – AFNET 5 trial Inclusion Exclusion .................................................................................................................................................................................................................... Non-valvular atrial fibrillation (ECG-docu- Any disease that limits life expectancy to <1 year mented) with a clinical indication for catheter ablation Clinical indication to undergo catheter abla- Participation in another clinical trial, either within the past 2 months or still ongoing tion on continuous anticoagulant therapy Presence of at least one of the CHADS Previous participation in AXAFA stroke risk factors Age > _ 18 years Pregnant women or women of childbearing potential not on adequate birth control: only women with a highly effective method of contraception (oral contraception or intra-uterine device) or sterile women can be randomized Provision of signed informed consent Breastfeeding women Drug abuse or clinically manifest alcohol abuse Any stroke within 14 days before randomization Concomitant treatment with drugs that are strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) or strong dual inducers of CYP3A4 and P-gp Valvular AF (as defined by the focused update of the ESC guidelines on AF, i.e. severe mitral valve sten- osis, mechanical heart valve). Furthermore, patients who underwent mitral valve repair are not eligible for AXAFA Any previous ablation or surgical therapy for AF Cardiac ablation therapy for any indication (catheter-based or surgical) within 3 months prior to randomization Clinical need for ‘triple therapy’ (combination therapy of clopidogrel, acetylsalicylic acid, and oral anticoagulation) Other contraindications for use of VKA or apixaban Documented atrial thrombi <3 months prior to randomization Severe chronic kidney disease with an estimated glomerular filtration rate (GFR) < 15 mL/min Reproduced from the AXAFA – AFNET 5 design paper. Stroke or TIA, age > _ 75 years, hypertension, defined as chronic treatment for hypertension, estimated need for continuous antihypertensive therapy or resting blood pressure > 145/90 mmHg, diabetes mellitus, symptomatic heart failure (NYHA > _ II). 2944 P. Kirchhof et al. comparing continuous apixaban therapy to VKA therapy. Details (age > _ 75 years, heart failure, hypertension, diabetes, or prior stroke). of the study design have been published. AXAFA – AFNET 5 was The full inclusion and exclusion criteria have been published (see conducted in Europe and North America. The trial sponsor was Table 1). AFNET, Mu ¨nster, Germany (www.kompetenznetz-vorhofflimmern.de). . AXAFA – AFNET 5 was designed by the steering committee in cooper- . Treatment ation with AFNET and conducted in accordance with the declaration of . At baseline, clinical parameters, stroke risk, heart rhythm, symptoms, Helsinki and the International Conference on Harmonization Good . 1 18 quality-of-life (EQ5D, SF-12, and Karnofsky performance status ), Clinical Practice Guidelines (ICH-GCP). The protocol was approved by . and cognitive function [Montreal Cognitive Assessment Test ethics review boards at all institutions. The Clinical Research Institute (MoCA)] were assessed. Patients were randomized in a ratio of 1:1 (CRI, Munich, Germany) executed the study in cooperation with to apixaban or VKA therapy. Randomization was stratified by study the steering committee and the sponsor. Data collection and entry site and AF type (paroxysmal vs. persistent or long-standing persist- R . V 16–18 were performed using the MARVIN eCRF system. An independ- ent). The randomization scheme was generated via a computer pro- ent steering committee and an independent data and safety monitoring gramme using permuted block of a random size. board guided the trial. All serious adverse events were adjudicated by an independent endpoint review committee blind to study group and international normalized ratio (INR) values. The Duke Clinical Research . Apixaban Institute served as the statistical core and performed the statistical ana- . Patients randomized to apixaban received 5 mg b.i.d. throughout the lyses for the trial. The authors vouch for the accuracy and completeness . study period. The apixaban dose was reduced to 2.5 mg b.i.d. if two of the data and for the fidelity of the trial to the protocol. This manu- . or more of the following characteristics were present: age > _80 years, script was written by the authors. body weight < _60 kg, or serum creatinine level > _1.5 mg/dL 16,20 (133lmol/L). Apixaban was continued during the ablation pro- Study population . cedure without interruption, including on the morning of ablation. AXAFA – AFNET 5 enrolled patients scheduled for a first atrial fibril- Continuous anticoagulation in this group was defined as having taken lation ablation. Patients had at least one established stroke risk factor all but one apixaban dose per week based on pill count. Screened: 676 2 patients not eligible (exclusion criteria) Randomized: 674 Allocated to Apixaban: 338 (ITT set) Allocated to VKA: 336 (ITT set) 10 did not receive study medication 9 did not receive study medication 7 declined continuation of study 6 declined continuation of study 1 left atrial thrombus 2 left atrial thrombus 2 other reasons 1 other reasons 328 received study drug (safety set) 327 received study drug (safety set) 10 discontinued treatment before ablation 12 discontinued treatment before ablation 7 declined continuation of study 7 declined continuation of study 1 left atrial thrombus 2 left atrial thrombus 2 other reason 3 other reasons 315 underwent ablation (ablation set, mITT) 318 underwent ablation (ablation set, mITT) 167 entered MRI substudy 168 entered MRI substudy 161 had analyzable MRI within 3-48 hours 162 analyzable MRI within 3-48 hours 6 had technically non-analyzable MRI 6 had technically non-analyzable MRI 311 had final visit (324 had final call) 308 had final visit (320 had final call) 2 declined continuation of study 6 declined continuation of study 2 lost to follow-up 0 lost to follow-up 3 death or stroke 1 death Figure 1 CONSORT diagram of the AXAFA – AFNET 5 study. Apixaban in patients at risk of stroke 2945 Figure 2 (A) Cumulative primary outcome events since randomization until 90 days after randomization at full scale (upper panel) and magnified (lower panel) in the ablation set. (B) Cumulative primary outcome events starting from ablation until 90 days after ablation at full scale (upper panel) and magnified (lower panel). VKA, vitamin K antagonist therapy. Vitamin K antagonist . All patients underwent follow-up visits at the time of the ablation procedure and 3 months after ablation. At the ablation visit, continu- Patients randomized to VKA were treated using the locally used . 21 . ous anticoagulation for at least 30 days prior to ablation was assessed VKA, e.g. warfarin, phenprocoumon, or acenocoumarol, prescribed . and dispensed following local routine. Vitamin K antagonist therapy . and an ECG performed. Transoesophageal echocardiography could be used following local practice. Interrupted anticoagulation required was monitored by INR measurements; a minimum of three INR . . rescheduling of the ablation for 30 days unless (i) atrial thrombi were measurements was mandatory prior to ablation. The last INR prior to ablation needed to be 1.8 or higher. The time in the therapeutic excluded by transoesophageal echocardiogram and (ii) effective anti- . coagulation was demonstrated prior to starting the ablation proced- range was calculated by the Rosendaal method. Continuous antico- . ure by either taking at least two doses of apixaban (patients agulation in this group was defined by therapeutic INR (INR > _2) in all INR measurements 30 days prior to catheter ablation. randomized to apixaban), or by an INR value > _ 1.8 (patients 2946 P. Kirchhof et al. Figure 2 Continued. randomized to VKA). A heparin bolus (100 IU/kg body weight) was was returned. A final phone call to assess serious adverse events was required prior to or directly after transseptal puncture. The ablation performed 30 days after discontinuation of study drug. 4–6 procedure followed local practice and current guidelines. The protocol encouraged pulmonary vein isolation, the use of irrigated Magnetic resonance imaging sub-study tip catheters, and flushing of all left atrial sheaths. Activated clotting . Centres participating in the MRI sub-study (n = 25) offered brain MRI time (ACT) was kept >300 s throughout the procedure. Activated . to all eligible study patients. A brain MRI was performed within 48 h clotting time measurements, details of the ablation technology used, . after the ablation procedure. The MRI sequences were designed to de- delivered energy, procedure time, rhythm at beginning and end of . tect all acute brain lesions, and to differentiate acute from chronic le- procedure, and the need for cardioversion during the procedure . sions. An imaging charta defined the MRI and adjudication workflow were collected. An echocardiogram (transthoracic or intracardiac) . and brain MRI requirements (Supplementary material online, Table S2). was mandated directly after ablation to detect pericardial effusion. . The following MRI sequences were used: T2*-weighted imaging to At the 3 month visit, cognitive function and quality-of-life were re- . screen for intracranial haemorrhage, diffusion-weighted imaging (DWI) assessed, a 24 h Holter ECG was performed, and study medication . and apparent diffusion coefficient (ADC) maps (post-processed) to Apixaban in patients at risk of stroke 2947 Figure 3 Forest plot of the differences (90% confidence intervals) in event rates in the main clinical subgroups. VKA, vitamin K antagonist therapy. assess acute brain infarction, and fluid-attenuated inversion recovery Adverse events 14,15 (FLAIR) to investigate the age of brain lesions. Diffusion-weighted All serious adverse events were collected, defined as adverse events imaging was conducted using a slice thickness of 2.5–3 mm (high-reso- . that caused or prolonged hospitalization, caused disability or incap- 14,15 . lution DWI) to enhance the sensitivity of MRI for small lesions. . acity, were life-threatening, resulted in death or were important med- Images failing the immediate quality check were repeated whenever . ical events. In addition, pregnancy, overdose, and cancer diagnosed feasible. All images were independently analysed by two experienced . after randomization were defined as serious adverse events. As neuro-radiologists blinded to treatment allocation. . AXAFA – AFNET 5 compared approved anticoagulants within their indications, non-serious adverse events were generally not reported, . but those of special interest were defined and assessed. These com- Study outcomes . prised ablation-related complications including non-serious bleeding. The primary outcome measured from randomization was the compos- . The protocol encouraged brain imaging in patients who developed ite of all-cause death, stroke, or major bleeding among modified . neurological abnormalities after the ablation procedure. All events intention-to-treat (mITT) population, defined as all randomized pa- . from randomization to 3 months after index ablation procedure or tients who received study drug and underwent catheter ablation. to premature study termination were analysed. Safety was assessed in all randomized patients receiving study drug (safety population). Sensitivity analyses were performed in all Statistical analysis randomized patients (ITT). Another sensitivity analysis compared events during the peri-ablation period defined from ablation to 7 days We estimated that a total of 650 patients (325 per group) were after the procedure. Major bleeding was defined according to the needed to detect a pre-specified margin of 7.5% (absolute difference) Bleeding Academic Research Consortium (BARC > _2). All bleeding . with 80% power using upper one-sided 95% confidence interval (i.e. events were centrally adjudicated according to the BARC, ISTH, and . two-sided 90% CI) with 3% attrition rate. The Farrington and 23,24 . TIMI classifications. . Manning score test was used to compute sample size and power. Secondary outcomes included time from randomization to ablation . The primary non-inferiority hypothesis was tested in the ablation (ITT population), nights spent in hospital after ablation, ACT during . population (mITT) using the method of Farrington and Manning ablation (summarized as median, 25th, 75th percentiles, and number . score test with the pre-specified absolute margin of 0.075. In addition, of ACT measurements within the target range), all bleeding events, a time-to-event analysis using Cox proportional hazards model with tamponade, need for transfusion, and changes in quality-of-life and a relative margin of 1.44 was conducted. A multivariable Cox propor- cognitive function compared to baseline. In the MRI sub-study, the tional hazards model controlling for the baseline risk factors of age, prevalence and number of MRI-detected acute brain lesions were sex, weight, type of atrial fibrillation, and the CHADS factors was con- compared between groups. ducted. Changes in quality-of-life and cognitive function were assessed 2948 P. Kirchhof et al. Table 2 Clinical characteristics of the AXAFA – AFNET 5 ablation population All patients Apixaban VKA n5 633 n5 318 (n5 317 n5 315 (n5 127 warfarin, 5 mg b.i.d., n5 102 phenprocoumon, n5 1 2.5 mg b.i.d.) n5 86 acenocoumarol) .................................................................................................................................................................................................................... Age (years) Median age (q1, q3) 64 (58, 70) 64 (57, 70) 64 (58, 70) Female sex 209 (33%) 100 (31%) 109 (35%) Weight (kg) Median weight (q1, q3) 87.0 (77.0, 99.3) 88.0 (77.0, 100.0) 86.6 (76.0, 98.0) Median body mass index (q1, q3) 28.3 (25.3, 31.6) 28.4 (25.5, 31.3) 28.2 (25.2, 31.9) Concomitant conditions, stroke risk factors, and CHA DS -VASc score 2 2 CHA DS -VASc score, mean (SD) 2.4 (1.2) 2.4 (1.2) 2.4 (1.2) 2 2 CHA DS -VASc score, median (q1, q3) 2 (2, 3) 2 (1, 3) 2 (2, 3) 2 2 Hypertension (n) 571 (90.2%) 283 (89.0%) 288 (91.4%) Median systolic blood pressure (q1, q3) 138.0 (125.0, 150.0) 137.0 (125.0, 149.5) 140.0 (125.0, 152.0) Median diastolic blood pressure (q1, q3) 82.0 (76.0, 90.0) 82.0 (75.0, 91.0) 82.0 (77.0, 90.0) Symptomatic heart failure (NYHA II–IV) 150 (23.7%) 78 (24.5%) 72 (22.9%) NYHA I 62 (9.8%) 30 (9.4%) 32 (10.2%) NYHA II 126 (19.9%) 67 (21.1%) 59 (18.7%) NYHA III 24 (3.8%) 11 (3.5%) 13 (4.1%) NYHA IV 0 0 0 Diabetes mellitus 76 (12.0%) 41 (12.9%) 35 (11.1%) Prior stroke or transient ischaemic attack 47 (7.4%) 24 (7.5%) 23 (7.3%) Age > _ 75 years 56 (8.8%) 28 (8.8%) 28 (8.9%) Age 65–74 years 240 (37.9%) 122 (38.4%) 118 (37.5%) Vascular disease, defined as coronary artery 83 (13.1%) 41 (12.9%) 42 (13.3%) disease, peripheral artery disease, or carotid disease Valvular heart disease 73 (11.5%) 39 (12.3%) 34 (10.8%) Mitral valve disease (moderate or more) 20 15 5 Aortic valve disease (moderate or more) 6 3 3 Confirmed coronary artery disease 77 (12.2%) 39 (12.3%) 38 (12.1%) Chronic obstructive lung disease 39 (6.2%) 21 (6.6%) 18 (5.7%) Clinical history of major bleeding 13 (2.1%) 10 (3.1%) 3 (1.0%) Concomitant medical therapy n (%) 633 318 315 Amiodarone 102 (16.1%) 49 (15.4%) 53 (16.8%) Dronedarone 13 (2.1%) 3 (0.9%) 10 (3.2%) Flecainide 125 (19.7%) 59 (18.6%) 66 (21.0%) Propafenone 16 (2.5%) 8 (2.5%) 8 (2.5%) Sotalol > 160 mg/day 16 (2.5%) 7 (2.2%) 9 (2.9%) ACE inhibitor or angiotensin receptor blocker 388 (61.3%) 192 (60.4%) 196 (62.2%) Calcium channel antagonists 147 (23.2%) 72 (22.6%) 75 (23.8%) Diuretics 221 (34.9%) 120 (37.7%) 101 (32.1%) Antianginal medication 2 (0.3%) 0 2 (0.6%) Antidiabetic medication 63 (10.0%) 32 (10.1%) 31 (9.8%) Statins 231 (36.5%) 111 (34.9%) 120 (38.1%) Platelet inhibitors or non-steroidal anti-inflammatory agents 30 (4.7%) 11 (3.5%) 19 (6.0%) Beta blockers 451 (71.2%) 230 (72.3%) 221 (70.2%) Digoxin or digitoxin 26 (4.1%) 17 (5.3%) 9 (2.9%) Last INR before ablation (n) 531 (83.9) 217 (68.2%) 314 (99.7%) Mean (SD) 1.9 (0.7) 1.2 (0.3), P < 0.001 vs. VKA 2.3 (0.5) Median (q1, q3) 2.0 (1.1, 2.4) 1.1 (1.0, 1.2) 2.3 (2.0, 2.6) Continued Apixaban in patients at risk of stroke 2949 Table 2 Continued All patients Apixaban VKA n5 633 n5 318 (n5 317 n5 315 (n5 127 warfarin, 5 mg b.i.d., n5 102 phenprocoumon, n5 1 2.5 mg b.i.d.) n5 86 acenocoumarol) .................................................................................................................................................................................................................... Quality-of-life at baseline SF-12 physical component, n (%) 44.6 (37.7, 51.4), n = 597 43.5 (38.1, 51.3), n = 301 45.2 (37.6, 51.5), n = 296 SF-12 mental component n (%) 598 (94.5%) 301 (94.7%) 297 (94.3%) SF-12 mental component n (%) 50.3 (42.8, 57.5), n = 598 51.2 (43.0, 57.9), n = 301 49.7 (42.6, 57.4), n = 297 Karnofsky scale 90 (80, 90) 80 (80, 90) 90 (80, 90) Cognitive function [Montreal Cognitive Assessment (MoCA)] at baseline Median MoCA(q1, q3) 27.0 (25.0, 29.0), n = 618 27.0 (25.0, 29.0), n = 313 27.0 (25.0, 29.0), n = 305 At least mild cognitive impairment (MoCA < 26) 188 (30.4%) 93 (29.7%) 95 (31.1%) Modified EHRA scale at baseline mEHRA I 40 (6.3%) 18 (5.7%) 22 (7.0%) mEHRA IIa 164 (25.9%) 76 (23.9%) 88 (27.9%) mEHRA IIb 205 (32.4%) 107 (33.6%) 98 (31.1%) mEHRA III 208 (32.9%) 110 (34.6%) 98 (31.1%) mEHRA IV 16 (2.5%) 7 (2.2%) 9 (2.9%) Ablation information Atrial fibrillation pattern Paroxysmal atrial fibrillation 367 (58.0%) 189 (59.4%) 178 (56.5%) Persistent or long-standing persistent atrial fibrillation 266 (42.0%) 129 (40.6%) 137 (43.5%) Time from randomization to ablation (days) Mean (SD) 38.0 (27.3) 36.9 (27.6) 39.1 (27.0) Median (q1, q3) 35.0 (20.0, 50.0) 34.0 (18.0, 48.0) 36.0 (21.0, 52.0) Rhythm at start of ablation Number of patients 633 318 315 Sinus rhythm 434 (68.6%) 212 (66.6%) 222 (70.6%) Atrial fibrillation 180 (28.4%) 98 (30.8%) 82 (26.0%) Atrial flutter 12 (1.9%) 3 (0.9%) 9 (2.8%) Pacing 7 (1.1%) 5 (1.6%) 2 (0.6%) Other 0 (0%) 0 (0%) 0 (0%) Type of ablation Pulmonary vein isolation, n (%) 571 (90.2%) 288 (90.6%) 283 (89.8%) Pulmonary vein isolation plus other ablation, n (%) 59 (9.3%) 29 (9.1%) 30 (9.5%) Other ablation without pulmonary vein isolation 3 (0.5%) 1 (0.3%) 2 (0.6%) Transoesophageal echocardiography prior to ablation 549 (86.7%) 269 (84.6%) 280 (88.9%) Total duration of ablation procedure (min), Median (q1, q3) 135 (110, 175) 136 (110, 175) 135 (105, 172) Ablation energy source Radiofrequency 402 (63.5%) 207 (65.1%) 195 (61.9%) Cryoablation 186 (29.3%) 92 (28.9%) 94 (29.8%) Other 45 (7.1%) 19 (6.0%) 26 (8.3%) Abnormal blood parameters Red blood cell count Abnormal 65/618 (10.5%) 32/311 (10.3%) 33/307 (10.7%) Platelet count abnormal 35/625 (5.6%) 20/315 (6.3%) 15/310 (4.8%) ALT abnormal 75/612 (12.3%) 39/307 (12.7%) 36/305 (11.8%) Bilirubin abnormal 38/596 (6.4%) 14/297 (4.7%) 24/299 (8.0%) Number of patients with valid information (n (%)) is only given when values were missing. BD, twice daily dosing; SD, standard deviation; q1, q3 are 25th and 75th percentiles, respectively; VKA, vitamin K antagonist. 2950 P. Kirchhof et al. Table 3 Primary outcomes in the AXAFA – AFNET 5 trial (ablation set), including details of the type of bleeding All patients Apixaban VKA .................................................................................................................................................................................................................... Patients with primary endpoint: composite of all-cause death, stroke or major 45/633 (7.1%) 22/318 (6.9%), 23/315 (7.3%) bleeding non-inferiority P=0.0002 Death 2 (0.3%) 1 (0.3%) 1 (0.3%) Stroke or TIA 2 (0.3%) 2 (0.6%) 0 Major bleeding (BARC 2–5) 45 (7.1%) 20 (6.2%) 25 (7.9%) Bleeding requiring medical attention (BARC 2) 24 (3.8%) 12 (3.7%) 12 (3.8%) Bleeding with haemoglobin drop of 30 to <50 g/L or requiring transfusion 9 (1.4%) 5 (1.6%) 4 (1.3%) (BARC 3a) Bleeding with haemoglobin drop > _50 g/L, or requiring surgery or iv vasoactive 11 (1.7%) 3 (0.9%) 8 (2.5%) agents, or cardiac tamponade (BARC 3b) Intracranial haemorrhage (BARC 3c) 1 (0.2%) 0 1 (0.3%, fatal) TIMI major bleeding (Intracranial bleed, or bleeding resulting in a haemoglobin 4 (0.6%) 1 (0.3%) 3 (1%) drop of > _50 g/L, or bleeding resulting in death within 7 days) ISTH major bleeding 24 (3.8%) 10 (3.1%) 14 (4.4%) Bleeding event by clinical type Tamponade 7 (1.1%) 2 (0.6%) 5 (1.6%) Access site bleed 27 (4.3%) 12 (3.8%) 15 (4.8%) Bleeding requiring transfusion of red blood cells 3 (0.5%) 2 (0.6%) 1 (0.3%) Other major bleed 7 (1.1%) 5 (1.6%) 2 (0.6%) Shown are number of patients per group. Some patients had more than one event. BARC4 events were not observed in the study. b.i.d., twice daily dosing. at 3 months compared to baseline using the EQ-5D and SF-12 ques- . balanced between groups (Table 1). Transoesophageal echocardiog- tionnaires, MoCA, and Karnofsky scale. Changes in quality-of-life were . raphy was used in 549/633 (86.7%) patients. All or all but one apixa- compared by analysis of covariance (ANCOVA) models including the ban doses per week were taken by 307/318 (97%) patients treatment arms as an indicator variable and the baseline quality-of-life randomized to apixaban in the ablation set. The median time in thera- variables as covariates. To accrue sufficient events for a formal non- peutic range in the 315 patients randomized to VKA in the ablation inferiority analysis, AXAFA – AFNET 5 was exclusively conducted in set was 84% (71, 97%). Time from randomization to ablation was not patients at risk of stroke (Table 1) and counted bleeding events follow- different between study groups (Table 1). ing the relatively broad BARC classification. An independent data and safety monitoring board monitored the study for safety. The Primary outcome Haybittle–Peto boundary was used as stopping rule guidance. Descriptive statistics for continuous and categorical variables were Primary outcome events (BARC 2–5 bleeding, stroke, or death) summarized as means (SDs) and medians (25th, 75th percentiles), were observed in 22/318 (6.9%) patients randomized to apixaban, and numbers (percentages), respectively. Comparisons between and in 23/315 (7.3%) patients randomized to VKA therapy in the abla- continuous variables were performed using the Wilcoxon rank-sum tion set. Four events were classified as TIMI major bleeding, and 24 test or two-sample t-test depending on normality; comparisons be- events are ISTH major bleeding (Table 3). Two patients died: one pa- tween nominal variables were performed using the Pearson’s v test tient randomized to VKA, female, age 70, hypertensive, last blood or Fisher’s exact test, depending on expected cell sizes. All analyses pressure 156/76, last INR 2.6, underwent pacemaker implantation were two-sided and tested at the nominal 0.05 significance level. No 8 days after ablation and experienced a massive intracerebral haem- adjustment was made for multiple testing. Statistical analyses were . orrhage. Another patient randomized to apixaban, male, age 69, with performed with SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). . paroxysmal atrial fibrillation, hypertension, heart failure, diabetes, and . chronic obstructive lung disease, was found dead in his bed 19 days . after ablation without identifiable cause of death upon autopsy. Two Results . patients randomized to apixaban had a stroke. Both had persistent . AF and underwent transoesophageal echocardiogram. One patient, Trial participants . male, age 63, hypertensive, ACT 236–398 s, developed slurred AXAFA – AFNET 5 randomized 674 patients across 49 sites in 9 speech with matching MRI lesion on the day of radiofrequency pul- countries from February 2015 to April 2017. Overall, 633 patients monary vein isolation that fully resolved. Another patient, male, age took study drug and underwent atrial fibrillation ablation (mITT, abla- 52, ACT 301–400 s, hypertensive, developed weakness of the right tion set, Figure 1). Demographic and clinical characteristics were well arm with paraesthesia of the right leg after cryoballoon pulmonary Apixaban in patients at risk of stroke 2951 Table 4 Secondary outcomes in the AXAFA – AFNET 5 trial (ablation set) All patients Apixaban VKA n5 633 n5 318 (n5 317 n5 315 (n5 127 5mg BD, warfarin, n5 102 n5 1 2.5 mg BD) phenprocoumon, n5 86 acenocoumarol) .................................................................................................................................................................................................................... Time from randomization to ablation in days, median 35.0 (20.0, 50.0) 34.0 (18.0, 48.0) 36.0 (21.0, 52.0) (q1, q3) Nights spent in hospital after index ablation, median 3 (2, 5) 2 (1, 5) 3 (2, 7) (q1, q3) ACT during ablation in seconds, median (q1, q3) 325.0 (285.0, 370.0) 310.0 (273.0, 350.0) 348.5 (304.0, 396.0) Number of subjects with all ACT values in range 234/631 (37.1%) 73/316 (23.1%) 161/315 (51.1%) (n (%)) Number of subjects with at least one ACT value < 250 214/631 (33.9%) 130/316 (41.1%) 84/315 (26.7%) (n (%)) Number of subjects with at least one ACT value < 300 397/631 (62.9%) 243/316 (76.9%) 154/315 (48.9%) (n (%)) Number of bleeding events (n) 118 54 64 Patients without recurrence of atrial fibrillation (n (%)) 434/619 (70.1%) 217/311 (69.8%) 217/308 (70.5%) Quality-of-life SF-12 physical component score at end of study, 48.6 (42.0, 54.2), n = 564 48.4 (41.9, 54.2), n = 289 48.8 (42.2, 54.4), n = 275 median (q1, q3), n Change in SF-12 physical component score at end of 2.5 (-2.1, 8.1), n = 547, P < 0.001* 2.4 (-2.2, 7.9), n = 280 2.8 (-2.0, 8.3), n = 267 study compared to baseline, median (q1, q3), n SF-12 mental component score at end of study, 54.4 (46.0, 58.6), n = 565 54.2 (45.8, 58.3), n = 290 54.5 (46.6, 59.7), n = 267 median (q1, q3), n Change in SF-12 mental component score at end of 1.2 (-3.2, 8.0), n = 548, P < 0.001* 0.4 (-3.6, 8.0), n = 281 1.6 (-2.8, 8.3), n = 267 study compared to baseline, median (q1, q3), n Karnofsky score at end of study, median (q1, q3), n 100 (90, 100), n = 619 100 (90, 100), n = 311 100 (90, 100), n = 308 Change in Karnofsky score at end of study compared 10 (0, 10), n = 619 10 (0, 10), n = 311 10 (0, 10), n = 308 to baseline (D Karnofsky), median (q1, q3), Cognitive function [Montreal Cognitive Assessment (MoCA)] Cognitive function at end of study (MoCA), median 28.0 (26.0, 29.0), n = 607 28.0 (26.0, 29.0), n = 305 28.0 (26.0, 29.0), n = 302 (q1, q3), n Abnormal MoCA at baseline (<26), n (%) 141 (23.2%) 75 (24.6%) 66 (21.9%) Change in MoCA at end of study compared to base- 1.0 (-1.0, 2.0), n = 597, P < 0.001* 0.0 (-1.0, 2.0), n = 301 1.0 (-1.0, 2.0), n = 296 line, median (q1, q3), n Change in patients with abnormal MoCA at end of 141/607 (23.2%), -7.2%, P = 0.005* 75/305 (24.6%) -5.1% 66/302 (21.9%) -9.2% study compared to baseline, n (%) Number of patients with valid information (n (%)) is only given when values were missing. P-values marked by asterisks (*) indicate differences between baseline and end of follow-up measurements. Twice daily (b.i.d.) dosing; q1 and q3 indicate 25th and 75th percentiles, respectively. vein isolation that persisted beyond hospital discharge. Tamponade all randomized patients as assessed by Cox proportional hazards occurred in 2 (apixaban) and 5 (VKA) patients and was managed by . model comparison between treatment groups using a relative non- pericardial drainage and administration of protamine and vitamin K. . inferiority margin of 1.44 (equivalent to 7.5% absolute; hazard One patient with tamponade in each study group received blood . ratio = 0.88, 90% CI 0.55, 1.41; P = 0.042, Figure 2). There was no stat- transfusions. Anticoagulants were continued in five patients with tam- . istical interaction between clinical stroke and bleeding risk factors ponade, and paused for 4 days in one patient randomized to apixa- . and treatment groups (Figure 3). ban, and for 8 days in one patient randomized to VKA. All patients . were discharged from hospital and attended the 3 months follow-up . Secondary outcome parameters (n = 6) or an end of study visit (n =1). Apixaban was non-inferior to VKA based on the non-inferiority There was no difference in time to ablation or nights spent in hospital margin of 7.5% (a difference of -0.38%, 90% CI -4.0%, -3.3%, non- after the ablation between groups (Table 4). As expected, the last inferiority P = 0.0002). Apixaban was also non-inferior to VKA among INR prior to ablation and ACTs achieved during ablation were lower 2952 P. Kirchhof et al. AB C D EF G H Figure 4 Examples of acute brain lesions detected in the brain magnetic resonance imaging sub-study. Acute brain lesions (arrows in A, C, E, G)are found by high-resolution diffusion-weighted brain magnetic resonance imaging without corresponding lesions in the fluid-attenuated inversion recov- ery images (arrows in B, D, F, H). Shown are representative lesions in two patients randomized to apixaban (A/B; C/D) and in two patients randomized to vitamin K antagonist (E/F; G/H). The fluid-attenuated inversion recovery images also detected chronic white matter lesions [asterisks (*) in F]. in the patients randomized to apixaban (Table 4). Quality-of-life as as- . Discussion sessed by the physical component of SF-12 [þ2.5(-2.1,8.1)units] AXAFA – AFNET 5 demonstrated that continuous anticoagulation and Karnofsky scale [þ10 (0, 10)] improved during the study without with apixaban is a safe and effective alternative to VKA in patients at differences between study groups (Table 4). At least mild cognitive risk of stroke undergoing atrial fibrillation ablation. AXAFA – AFNET dysfunction was found in 188/619 (30.4%) of the patients at baseline 5 observed four TIMI major bleeding events in 633 patients (0.6%, (pre-defined as MoCA < 26, Table 2). At the end of follow-up, MoCA Table 3) compared to one event in 248 patients in VENTURE-AF increased by a median of þ1.0 (-1.0, 2.0) unit without differences be- (0.4%). AXAFA – AFNET 5 observed 24 patients with ISTH major tween study groups, and only 141/607 patients (7.2% fewer than at bleeding events (3.8%, Table 3) compared to 27 events in 635 patients baseline) had mild cognitive impairment (Table 4). in RE-CIRCUIT (4.3%). The numerical differences in ISTH major bleeding rates between AXAFA – AFNET 5 [apixaban 10 patients Magnetic resonance imaging sub-study (3.1%); VKA 14 patients (4.4%); Table 3] and RE-CIRCUIT [dabigatran Acute brain MRI was performed in 335 patients across 25 centres. 5 patients (1.6%); VKA 22 patients (6.9%)] could be due to chance Clinical characteristics of the sub-study population were not different variations in outcomes, differences in risk profile between the from the main study population, with the exception of a lower me- AXAFA – AFNET 5 and RE-CIRCUIT study populations, and due to dian weight in patients undergoing MRI [85.0 kg (74.5, 96.0)] com- . the high time in therapeutic range in the VKA group in AXAFA – pared to non-MRI patients [90.0 kg (80.0, 103.0)]. Clinical . AFNET 5 (median TTR 84%). AXAFA – AFNET 5 included only pa- characteristics were well balanced between MRI sub-study treatment . tients with stroke risk factors, resulting in a mean CHA DS VASc 2 2 groups. There were 323 analysable MRIs. Acute brain MRI lesions . score of 2.4 and a population that was 4–5 years older than in the . 1–3,8,9 (Figure 4) were found in 44/162 (27.2%) patients randomized to apix- . published controlled trials in atrial fibrillation ablation. Despite aban, and in 40/161 (24.8%) patients randomized to VKA (P =0.635), . the higher stroke risk, we observed few strokes: AXAFA – AFNET 5 with very similar distribution of lesions between random groups found 2 strokes in 633 patients (0.3%), compared to 1 stroke in 248 (Table 5). Cognitive function at the end of follow-up was not different patients in VENTURE-AF (0.4%), and 1 TIA in 635 patients in RE- in patients with or without acute brain lesions (MoCA 27.1 ± 2.7 in CIRCUIT (0.2%). Equally, mortality was low (0.3%) and similar to 8 9 239 patients without MRI lesions, 27.1 ± 2.8 in 84 patients with MRI VENTURE-AF (0.4%), RE-CIRCUIT (0%), and the EORP AF abla- lesions, P =0.91). tion registry (0.2%). Apixaban in patients at risk of stroke 2953 Table 5 Acute brain lesions detected by high-resolution diffusion-weighted magnetic resonance imaging (MRI sub- study) All patients (n5 323) Apixaban (n5 162) VKA (n5 161) P-value .................................................................................................................................................................................................................... No lesion 239 (74.0%) 118 (72.8%) 121 (75.2%) 0.635 Exactly one lesion 46 (14.2%) 27 (16.7%) 19 (11.8%) 0.211 Exactly two lesions 21 (6.5%) 7 (4.3%) 14 (8.7%) 0.111 More than two lesions 17 (5.3%) 10 (6.2%) 7 (4.3%) 0.463 P-values were determined by Pearson’ s v test. differences between study groups. Continuous anticoagulation does not fully prevent acute brain lesions, which can be caused by debris 27,28 dislodging from ablation wounds, air emboli, or small thrombi. Procedural improvements are desirable to reduce acute brain lesions during atrial fibrillation ablation. Further analyses of the AXAFA – AFNET 5 data set may shed more light on risk factors for acute brain . lesions in patients undergoing AF ablation on continuous anticoagula- tion. One prior study found reduced cognitive function 90 days after atrial fibrillation ablation on interrupted warfarin therapy compared . to baseline. Reassuringly, cognitive function improved at the end of AXAFA – AFNET 5 without differences between study groups. 10% Death Stroke or TIA . Limitations Major Bleed (TIMI) 5% Major Bleed (ISTH) . AXAFA – AFNET 5 was an open study, but with blinded outcome as- . sessment. The non-inferoirity margin was wide. The findings are con- 0% . sistent with prior studies with continuous dabigatran and . rivaroxaban. While AXAFA – AFNET 5 was the first study comparing cognitive function after atrial fibrillation ablation in a controlled trial, the assessment was limited to global cognitive function. Differentiation between acute and chronic lesions was done by using 14,15 AXAFA-AFNET 5 RE-CIRCUIT VENTURE-AF Combined an accepted combination of MRI sequences. Take home figure Cumulative outcome events in AXAFA – AFNET 5 in patients undergoing atrial fibrillation ablation at risk of Conclusions stroke (top) and comparison to event rates in the two other con- trolled trials comparing continuous NOAC therapy with continu- Continuous apixaban therapy is a safe and effective alternative to ous vitamin K antagonist therapy (bottom). TIMI major bleeds were . VKA in patients at risk of stroke undergoing atrial fibrillation ablation not separately reported in the main paper of RE-CIRCUIT. ISTH with respect to stroke, major bleeding, cognitive function, and MRI- major bleeds were not separately reported in the main paper of . detected acute brain lesions. VENTURE-AF. . Acknowledgements The authors would like to thank Bianca-Maria Klein, Elisabeth Freund, and the study teams at CRI and AFNET for excellent project coord- AXAFA – AFNET 5 included 86 patients on acenocoumarol and ination, help with preparing the manuscript and ensuring complete 102 patients on phenprocoumon, 186 patients (29%) undergoing accordance of the paper with the trial protocol and eCRF, and the cryoablation, and 84 patients undergoing atrial fibrillation ablation members of the clinical trials statistics group at DCRI who provided without transoesophageal echocardiography without safety signals, the statistical analysis. providing some reassurance that these common patterns of clinical 4–6,26 practice can be used on continuous apixaban or VKA therapy. . Funding The secondary outcomes observed in AXAFA – AFNET5 under- AXAFA – AFNET 5 is an investigator-initiated trial. Sponsor of the trial is pin the safety of continuous apixaban in atrial fibrillation ablation: . AFNET. AXAFA – AFNET 5 was partially funded by BMS/Pfizer, the time to ablation was not different between groups and quality-of-life . . DZHK (German Centre for Cardiovascular Research) and by the BMBF and cognitive function improved equally in both study groups after . (German Ministry of Education and Research) to AFNET. Further sup- ablation. High-resolution diffusion-weighted brain MRI detected . port came from European Union [Grant Agreement No. 633196 12,14,15 . acute brain lesions at the expected rate (25%) without . (CATCH ME) to B.B., P.K., L.M., U.S., AFNET], British Heart Foundation Apixaban (318) VKA (315) Dabigatran (317) VKA (318) Rivaroxaban (113) VKA (107) NOAC (748) VKA (740) 2954 P. Kirchhof et al. C, Davies DW, Fields LE, Natale A; VENTURE-AF Investigators. Uninterrupted (FS/13/43/30324 to P.K.), Leducq Foundation to P.K., and the rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non- Netherlands Heart Foundation (RACE V) to U.S. and I.v.G. AFNET, valvular atrial fibrillation. Eur Heart J 2015;36:1805–1811. DZHK, BMS/Pfizer; AXAFA – AFNET 5; NCT02227550. . 9. Calkins H, Willems S, Gerstenfeld EP, Verma A, Schilling R, Hohnloser SH, Okumura K, Serota H, Nordaby M, Guiver K, Biss B, Brouwer MA, Grimaldi M; Conflict of interest: Authors disclose financial links with Abbott/St RE-CIRCUIT Investigators. Uninterrupted dabigatran versus warfarin for ablation Jude Medical (G.H., L.M., J.P., L.D.B.), AFNET (T.F., J.P.), Allergan (J.P.), in atrial fibrillation. N Engl J Med 2017;376:1627–1636. ARCA Biopharma (J.P.), Bayer (K.G.H., J.P., U.S.), Biosense Webster . 10. Medi C, Evered L, Silbert B, Teh A, Halloran K, Morton J, Kistler P, Kalman J. 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U, Reinecke H, Rostock T, Rustige J, Savelieva I, Schnabel R, Schotten U, 2013;6:23–30. Schwichtenberg L, Sinner MF, Steinbeck G, Stoll M, Tavazzi L, Themistoclakis S, 28. Takami M, Lehmann HI, Parker KD, Welker KM, Johnson SB, Packer DL. Effect Tse HF, Van Gelder IC, Vardas PE, Varpula T, Vincent A, Werring D, Willems S, of left atrial ablation process and strategy on microemboli formation during irri- . Ziegler A, Lip GY, Camm AJ. A roadmap to improve the quality of atrial fibrillation gated radiofrequency catheter ablation in an in vivo model. Circ Arrhythm management: proceedings from the fifth Atrial Fibrillation Network/European Electrophysiol 2016;9:e003226. Heart Rhythm Association consensus conference. Europace 2016;18:37–50. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal Oxford University Press

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology.
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0195-668X
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1522-9645
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10.1093/eurheartj/ehy176
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Abstract

CLINICAL RESEARCH European Heart Journal (2018) 39, 2942–2955 doi:10.1093/eurheartj/ehy176 Arrhythmia/electrophysiology Apixaban in patients at risk of stroke undergoing atrial fibrillation ablation 1,2,3,4 4,5 4 1,3 Paulus Kirchhof *, Karl Georg Haeusler , Benjamin Blank , Joseph De Bono , 6 7 8 9 David Callans , Arif Elvan , Thomas Fetsch , Isabelle C. Van Gelder , 10 11 12 13 Philip Gentlesk , Massimo Grimaldi , Jim Hansen , Gerhard Hindricks , 14 15 16 17 Hussein R. Al-Khalidi , Tyler Massaro , Lluis Mont , Jens Cosedis Nielsen , 18 15,19 20 21 Georg No ¨lker , Jonathan P. Piccini , Tom De Potter , Daniel Scherr , 4,22 23 24 25 Ulrich Schotten , Sakis Themistoclakis , Derick Todd , Johan Vijgen , and 26,27 Luigi Di Biase 1 2 Institute of Cardiovascular Sciences, University of Birmingham, and SWBH and UHB NHS Trusts, IBR 136, Wolfson Drive, Birmingham B15 2TT, UK; SWBH NHS Trust, 3 4 5 Birmingham, UK; University Hospitals Birmingham, Birmingham, UK; Atrial Fibrillation NETwork Association (AFNET), Germany, Mu ¨ nster; Center for Stroke Research Berlin 6 7 & Department of Neurology, Charite ´ – Universita ¨tsmedizin Berlin, Germany; Hospital of the University of Pennsylvania, PA, USA; Isala Heart Center Zwolle, Zwolle, The 8 9 10 Netherlands; The Clinical Research Institute, Munich, Germany; University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Sentara 11 12 13 Cardiovascular Research Institute, Norfolk, VA, USA; Ospedale Generale Regionale F. Miulli, Acquaviva delle Fonti, Italy; Gentofte Hospital, Hellerup, Denmark; Abteilung 14 15 fu ¨ r Rhythmologie, Leipzig Heart Center, Leipzig, Germany; Department of Biostatistics & Bioinformatics, Duke University School of Medicine, USA; Duke Clinical Research 16 17 Institute (DCRI), Durham, NC, USA; Hospital Clinic Barcelona, University of Barcelona, Barcelona, Spain; Department of Cardiology, Aarhus University Hospital, Denmark; 18 19 Herz- und Diabeteszentrum NRW, Ruhr-Universita ¨t Bochum, Bad Oeynhausen, Germany; Division of Cardiology Duke University Medical Center, Duke University, Durham, 20 21 22 NC, USA; Cardiovascular Center, OLV Aalst, Belgium; Department of Cardiology, Medical University Graz, Austria; Department of Physiology, University Maastricht, 23 24 25 Maastricht, Netherlands; Ospedale Dell’Angelo, Mestre, Italy; Liverpool Heart and Chest Hospital, Liverpool, UK; Jessa Ziekenhuis, Campus Virga Jesse, Hasselt, Belgium; 26 27 Albert Einstein College of Medicine, at Montefiore Hospital, New York, USA; and Texas Cardiac Arrhythmia Institute at St. David’s Medical Center, Austin, TX, USA Received 8 February 2018; revised 9 March 2018; editorial decision 12 March 2018; accepted 14 March 2018; online publish-ahead-of-print 20 March 2018 See page 2956 for the editorial comment on this article (doi: 10.1093/eurheartj/ehy274) Aims It is recommended to perform atrial fibrillation ablation with continuous anticoagulation. Continuous apixaban has not been tested. ................................................................................................................................................................................................... Methods We compared continuous apixaban (5 mg b.i.d.) to vitamin K antagonists (VKA, international normalized ratio 2–3) in and results atrial fibrillation patients at risk of stroke a prospective, open, multi-centre study with blinded outcome assessment. Primary outcome was a composite of death, stroke, or bleeding (Bleeding Academic Research Consortium 2–5). A high-resolution brain magnetic resonance imaging (MRI) sub-study quantified acute brain lesions. Cognitive function was assessed by Montreal Cognitive Assessment (MoCA) at baseline and at end of follow-up. Overall, 674 patients (median age 64 years, 33% female, 42% non-paroxysmal atrial fibrillation, 49 sites) were randomized; 633 received study drug and underwent ablation; 335 undertook MRI (25 sites, 323 analysable scans). The primary outcome was observed in 22/318 patients randomized to apixaban, and in 23/315 randomized to VKA {difference -0.38% [90% con- fidence interval (CI) -4.0%, 3.3%], non-inferiority P = 0.0002 at the pre-specified absolute margin of 0.075}, including 2 (0.3%) deaths, 2 (0.3%) strokes, and 24 (3.8%) ISTH major bleeds. Acute small brain lesions were found in a similar number of patients in each arm [apixaban 44/162 (27.2%); VKA 40/161 (24.8%); P = 0.64]. Cognitive function increased at the end of follow-up (median 1 MoCA unit; P = 0.005) without differences between study groups. ................................................................................................................................................................................................... Conclusions Continuous apixaban is safe and effective in patients undergoing atrial fibrillation ablation at risk of stroke with respect to bleeding, stroke, and cognitive function. Further research is needed to reduce ablation-related acute brain lesions. Keywords Atrial fibrillation Ablation Anticoagulation Bleeding Stroke Brain MRI � � � � � * Corresponding author. Tel: þ44 121 414 7042, Email: [email protected] V The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Apixaban in patients at risk of stroke 2943 procedure, raising concerns about peri-procedural protection of the Introduction 10,11 brain. Furthermore, acute brain lesions without corresponding 1–3 Catheter ablation is an effective and increasingly used component neurological symptoms are detected in ca. 25% of patients undergo- of rhythm control therapy to improve symptoms in patients with ing atrial fibrillation ablation by high-resolution diffusion-weighted 4–6 atrial fibrillation. Atrial fibrillation ablation is associated with a risk brain magnetic resonance imaging (MRI), a sequence that detects 4–6 12–15 of stroke and major bleeding. Continuous oral anticoagulation acute cytotoxic brain oedema. Cognitive function and acute using vitamin K antagonists (VKA) such as warfarin can reduce the . brain lesions have not been evaluated in controlled clinical trials of risk of embolic events to <1% when combined with peri-procedural . patients undergoing atrial fibrillation ablation. heparin. Therefore, continuous oral anticoagulation is recom- 4,6,7 mended in patients undergoing atrial fibrillation ablation. One Objectives randomized trial comparing rivaroxaban to warfarin in 218 patients Therefore, we conducted a randomized trial comparing continuous found similar bleeding rates with rivaroxaban compared to warfarin: apixaban to continuous VKA therapy in patients at risk of stroke 21/114 (18.4%) patients with bleeding on rivaroxaban, 18/104 . undergoing atrial fibrillation ablation, including assessment of cognitive 8 . (17.3%) patients with bleeding on VKA, one patient with stroke. . functioninall patients andMRI-detected brain lesions in a sub-study. Another trial randomizing 635 atrial fibrillation ablation patients to . dabigatran or VKA found 59/318 (18.6%) patients with bleeding on . Trial design dabigatran, 54/317 (17%) patients with bleeding on VKA, and one pa- . 9 . tient with transient ischaemic attack. Continuous apixaban has not . Anticoagulation using the direct factor Xa inhibitor apixaban during been compared to VKA in atrial fibrillation ablation patients. Atrial Fibrillation catheter Ablation: comparison to VKA therapy Atrial fibrillation ablation, unlike other ablation procedures, has (AXAFA – AFNET 5) was an investigator-initiated, prospective, been associated with declining cognitive function 90 days after the parallel-group, randomized, open, blinded outcome assessment study Table 1 Inclusion and exclusion criteria of the AXAFA – AFNET 5 trial Inclusion Exclusion .................................................................................................................................................................................................................... Non-valvular atrial fibrillation (ECG-docu- Any disease that limits life expectancy to <1 year mented) with a clinical indication for catheter ablation Clinical indication to undergo catheter abla- Participation in another clinical trial, either within the past 2 months or still ongoing tion on continuous anticoagulant therapy Presence of at least one of the CHADS Previous participation in AXAFA stroke risk factors Age > _ 18 years Pregnant women or women of childbearing potential not on adequate birth control: only women with a highly effective method of contraception (oral contraception or intra-uterine device) or sterile women can be randomized Provision of signed informed consent Breastfeeding women Drug abuse or clinically manifest alcohol abuse Any stroke within 14 days before randomization Concomitant treatment with drugs that are strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) or strong dual inducers of CYP3A4 and P-gp Valvular AF (as defined by the focused update of the ESC guidelines on AF, i.e. severe mitral valve sten- osis, mechanical heart valve). Furthermore, patients who underwent mitral valve repair are not eligible for AXAFA Any previous ablation or surgical therapy for AF Cardiac ablation therapy for any indication (catheter-based or surgical) within 3 months prior to randomization Clinical need for ‘triple therapy’ (combination therapy of clopidogrel, acetylsalicylic acid, and oral anticoagulation) Other contraindications for use of VKA or apixaban Documented atrial thrombi <3 months prior to randomization Severe chronic kidney disease with an estimated glomerular filtration rate (GFR) < 15 mL/min Reproduced from the AXAFA – AFNET 5 design paper. Stroke or TIA, age > _ 75 years, hypertension, defined as chronic treatment for hypertension, estimated need for continuous antihypertensive therapy or resting blood pressure > 145/90 mmHg, diabetes mellitus, symptomatic heart failure (NYHA > _ II). 2944 P. Kirchhof et al. comparing continuous apixaban therapy to VKA therapy. Details (age > _ 75 years, heart failure, hypertension, diabetes, or prior stroke). of the study design have been published. AXAFA – AFNET 5 was The full inclusion and exclusion criteria have been published (see conducted in Europe and North America. The trial sponsor was Table 1). AFNET, Mu ¨nster, Germany (www.kompetenznetz-vorhofflimmern.de). . AXAFA – AFNET 5 was designed by the steering committee in cooper- . Treatment ation with AFNET and conducted in accordance with the declaration of . At baseline, clinical parameters, stroke risk, heart rhythm, symptoms, Helsinki and the International Conference on Harmonization Good . 1 18 quality-of-life (EQ5D, SF-12, and Karnofsky performance status ), Clinical Practice Guidelines (ICH-GCP). The protocol was approved by . and cognitive function [Montreal Cognitive Assessment Test ethics review boards at all institutions. The Clinical Research Institute (MoCA)] were assessed. Patients were randomized in a ratio of 1:1 (CRI, Munich, Germany) executed the study in cooperation with to apixaban or VKA therapy. Randomization was stratified by study the steering committee and the sponsor. Data collection and entry site and AF type (paroxysmal vs. persistent or long-standing persist- R . V 16–18 were performed using the MARVIN eCRF system. An independ- ent). The randomization scheme was generated via a computer pro- ent steering committee and an independent data and safety monitoring gramme using permuted block of a random size. board guided the trial. All serious adverse events were adjudicated by an independent endpoint review committee blind to study group and international normalized ratio (INR) values. The Duke Clinical Research . Apixaban Institute served as the statistical core and performed the statistical ana- . Patients randomized to apixaban received 5 mg b.i.d. throughout the lyses for the trial. The authors vouch for the accuracy and completeness . study period. The apixaban dose was reduced to 2.5 mg b.i.d. if two of the data and for the fidelity of the trial to the protocol. This manu- . or more of the following characteristics were present: age > _80 years, script was written by the authors. body weight < _60 kg, or serum creatinine level > _1.5 mg/dL 16,20 (133lmol/L). Apixaban was continued during the ablation pro- Study population . cedure without interruption, including on the morning of ablation. AXAFA – AFNET 5 enrolled patients scheduled for a first atrial fibril- Continuous anticoagulation in this group was defined as having taken lation ablation. Patients had at least one established stroke risk factor all but one apixaban dose per week based on pill count. Screened: 676 2 patients not eligible (exclusion criteria) Randomized: 674 Allocated to Apixaban: 338 (ITT set) Allocated to VKA: 336 (ITT set) 10 did not receive study medication 9 did not receive study medication 7 declined continuation of study 6 declined continuation of study 1 left atrial thrombus 2 left atrial thrombus 2 other reasons 1 other reasons 328 received study drug (safety set) 327 received study drug (safety set) 10 discontinued treatment before ablation 12 discontinued treatment before ablation 7 declined continuation of study 7 declined continuation of study 1 left atrial thrombus 2 left atrial thrombus 2 other reason 3 other reasons 315 underwent ablation (ablation set, mITT) 318 underwent ablation (ablation set, mITT) 167 entered MRI substudy 168 entered MRI substudy 161 had analyzable MRI within 3-48 hours 162 analyzable MRI within 3-48 hours 6 had technically non-analyzable MRI 6 had technically non-analyzable MRI 311 had final visit (324 had final call) 308 had final visit (320 had final call) 2 declined continuation of study 6 declined continuation of study 2 lost to follow-up 0 lost to follow-up 3 death or stroke 1 death Figure 1 CONSORT diagram of the AXAFA – AFNET 5 study. Apixaban in patients at risk of stroke 2945 Figure 2 (A) Cumulative primary outcome events since randomization until 90 days after randomization at full scale (upper panel) and magnified (lower panel) in the ablation set. (B) Cumulative primary outcome events starting from ablation until 90 days after ablation at full scale (upper panel) and magnified (lower panel). VKA, vitamin K antagonist therapy. Vitamin K antagonist . All patients underwent follow-up visits at the time of the ablation procedure and 3 months after ablation. At the ablation visit, continu- Patients randomized to VKA were treated using the locally used . 21 . ous anticoagulation for at least 30 days prior to ablation was assessed VKA, e.g. warfarin, phenprocoumon, or acenocoumarol, prescribed . and dispensed following local routine. Vitamin K antagonist therapy . and an ECG performed. Transoesophageal echocardiography could be used following local practice. Interrupted anticoagulation required was monitored by INR measurements; a minimum of three INR . . rescheduling of the ablation for 30 days unless (i) atrial thrombi were measurements was mandatory prior to ablation. The last INR prior to ablation needed to be 1.8 or higher. The time in the therapeutic excluded by transoesophageal echocardiogram and (ii) effective anti- . coagulation was demonstrated prior to starting the ablation proced- range was calculated by the Rosendaal method. Continuous antico- . ure by either taking at least two doses of apixaban (patients agulation in this group was defined by therapeutic INR (INR > _2) in all INR measurements 30 days prior to catheter ablation. randomized to apixaban), or by an INR value > _ 1.8 (patients 2946 P. Kirchhof et al. Figure 2 Continued. randomized to VKA). A heparin bolus (100 IU/kg body weight) was was returned. A final phone call to assess serious adverse events was required prior to or directly after transseptal puncture. The ablation performed 30 days after discontinuation of study drug. 4–6 procedure followed local practice and current guidelines. The protocol encouraged pulmonary vein isolation, the use of irrigated Magnetic resonance imaging sub-study tip catheters, and flushing of all left atrial sheaths. Activated clotting . Centres participating in the MRI sub-study (n = 25) offered brain MRI time (ACT) was kept >300 s throughout the procedure. Activated . to all eligible study patients. A brain MRI was performed within 48 h clotting time measurements, details of the ablation technology used, . after the ablation procedure. The MRI sequences were designed to de- delivered energy, procedure time, rhythm at beginning and end of . tect all acute brain lesions, and to differentiate acute from chronic le- procedure, and the need for cardioversion during the procedure . sions. An imaging charta defined the MRI and adjudication workflow were collected. An echocardiogram (transthoracic or intracardiac) . and brain MRI requirements (Supplementary material online, Table S2). was mandated directly after ablation to detect pericardial effusion. . The following MRI sequences were used: T2*-weighted imaging to At the 3 month visit, cognitive function and quality-of-life were re- . screen for intracranial haemorrhage, diffusion-weighted imaging (DWI) assessed, a 24 h Holter ECG was performed, and study medication . and apparent diffusion coefficient (ADC) maps (post-processed) to Apixaban in patients at risk of stroke 2947 Figure 3 Forest plot of the differences (90% confidence intervals) in event rates in the main clinical subgroups. VKA, vitamin K antagonist therapy. assess acute brain infarction, and fluid-attenuated inversion recovery Adverse events 14,15 (FLAIR) to investigate the age of brain lesions. Diffusion-weighted All serious adverse events were collected, defined as adverse events imaging was conducted using a slice thickness of 2.5–3 mm (high-reso- . that caused or prolonged hospitalization, caused disability or incap- 14,15 . lution DWI) to enhance the sensitivity of MRI for small lesions. . acity, were life-threatening, resulted in death or were important med- Images failing the immediate quality check were repeated whenever . ical events. In addition, pregnancy, overdose, and cancer diagnosed feasible. All images were independently analysed by two experienced . after randomization were defined as serious adverse events. As neuro-radiologists blinded to treatment allocation. . AXAFA – AFNET 5 compared approved anticoagulants within their indications, non-serious adverse events were generally not reported, . but those of special interest were defined and assessed. These com- Study outcomes . prised ablation-related complications including non-serious bleeding. The primary outcome measured from randomization was the compos- . The protocol encouraged brain imaging in patients who developed ite of all-cause death, stroke, or major bleeding among modified . neurological abnormalities after the ablation procedure. All events intention-to-treat (mITT) population, defined as all randomized pa- . from randomization to 3 months after index ablation procedure or tients who received study drug and underwent catheter ablation. to premature study termination were analysed. Safety was assessed in all randomized patients receiving study drug (safety population). Sensitivity analyses were performed in all Statistical analysis randomized patients (ITT). Another sensitivity analysis compared events during the peri-ablation period defined from ablation to 7 days We estimated that a total of 650 patients (325 per group) were after the procedure. Major bleeding was defined according to the needed to detect a pre-specified margin of 7.5% (absolute difference) Bleeding Academic Research Consortium (BARC > _2). All bleeding . with 80% power using upper one-sided 95% confidence interval (i.e. events were centrally adjudicated according to the BARC, ISTH, and . two-sided 90% CI) with 3% attrition rate. The Farrington and 23,24 . TIMI classifications. . Manning score test was used to compute sample size and power. Secondary outcomes included time from randomization to ablation . The primary non-inferiority hypothesis was tested in the ablation (ITT population), nights spent in hospital after ablation, ACT during . population (mITT) using the method of Farrington and Manning ablation (summarized as median, 25th, 75th percentiles, and number . score test with the pre-specified absolute margin of 0.075. In addition, of ACT measurements within the target range), all bleeding events, a time-to-event analysis using Cox proportional hazards model with tamponade, need for transfusion, and changes in quality-of-life and a relative margin of 1.44 was conducted. A multivariable Cox propor- cognitive function compared to baseline. In the MRI sub-study, the tional hazards model controlling for the baseline risk factors of age, prevalence and number of MRI-detected acute brain lesions were sex, weight, type of atrial fibrillation, and the CHADS factors was con- compared between groups. ducted. Changes in quality-of-life and cognitive function were assessed 2948 P. Kirchhof et al. Table 2 Clinical characteristics of the AXAFA – AFNET 5 ablation population All patients Apixaban VKA n5 633 n5 318 (n5 317 n5 315 (n5 127 warfarin, 5 mg b.i.d., n5 102 phenprocoumon, n5 1 2.5 mg b.i.d.) n5 86 acenocoumarol) .................................................................................................................................................................................................................... Age (years) Median age (q1, q3) 64 (58, 70) 64 (57, 70) 64 (58, 70) Female sex 209 (33%) 100 (31%) 109 (35%) Weight (kg) Median weight (q1, q3) 87.0 (77.0, 99.3) 88.0 (77.0, 100.0) 86.6 (76.0, 98.0) Median body mass index (q1, q3) 28.3 (25.3, 31.6) 28.4 (25.5, 31.3) 28.2 (25.2, 31.9) Concomitant conditions, stroke risk factors, and CHA DS -VASc score 2 2 CHA DS -VASc score, mean (SD) 2.4 (1.2) 2.4 (1.2) 2.4 (1.2) 2 2 CHA DS -VASc score, median (q1, q3) 2 (2, 3) 2 (1, 3) 2 (2, 3) 2 2 Hypertension (n) 571 (90.2%) 283 (89.0%) 288 (91.4%) Median systolic blood pressure (q1, q3) 138.0 (125.0, 150.0) 137.0 (125.0, 149.5) 140.0 (125.0, 152.0) Median diastolic blood pressure (q1, q3) 82.0 (76.0, 90.0) 82.0 (75.0, 91.0) 82.0 (77.0, 90.0) Symptomatic heart failure (NYHA II–IV) 150 (23.7%) 78 (24.5%) 72 (22.9%) NYHA I 62 (9.8%) 30 (9.4%) 32 (10.2%) NYHA II 126 (19.9%) 67 (21.1%) 59 (18.7%) NYHA III 24 (3.8%) 11 (3.5%) 13 (4.1%) NYHA IV 0 0 0 Diabetes mellitus 76 (12.0%) 41 (12.9%) 35 (11.1%) Prior stroke or transient ischaemic attack 47 (7.4%) 24 (7.5%) 23 (7.3%) Age > _ 75 years 56 (8.8%) 28 (8.8%) 28 (8.9%) Age 65–74 years 240 (37.9%) 122 (38.4%) 118 (37.5%) Vascular disease, defined as coronary artery 83 (13.1%) 41 (12.9%) 42 (13.3%) disease, peripheral artery disease, or carotid disease Valvular heart disease 73 (11.5%) 39 (12.3%) 34 (10.8%) Mitral valve disease (moderate or more) 20 15 5 Aortic valve disease (moderate or more) 6 3 3 Confirmed coronary artery disease 77 (12.2%) 39 (12.3%) 38 (12.1%) Chronic obstructive lung disease 39 (6.2%) 21 (6.6%) 18 (5.7%) Clinical history of major bleeding 13 (2.1%) 10 (3.1%) 3 (1.0%) Concomitant medical therapy n (%) 633 318 315 Amiodarone 102 (16.1%) 49 (15.4%) 53 (16.8%) Dronedarone 13 (2.1%) 3 (0.9%) 10 (3.2%) Flecainide 125 (19.7%) 59 (18.6%) 66 (21.0%) Propafenone 16 (2.5%) 8 (2.5%) 8 (2.5%) Sotalol > 160 mg/day 16 (2.5%) 7 (2.2%) 9 (2.9%) ACE inhibitor or angiotensin receptor blocker 388 (61.3%) 192 (60.4%) 196 (62.2%) Calcium channel antagonists 147 (23.2%) 72 (22.6%) 75 (23.8%) Diuretics 221 (34.9%) 120 (37.7%) 101 (32.1%) Antianginal medication 2 (0.3%) 0 2 (0.6%) Antidiabetic medication 63 (10.0%) 32 (10.1%) 31 (9.8%) Statins 231 (36.5%) 111 (34.9%) 120 (38.1%) Platelet inhibitors or non-steroidal anti-inflammatory agents 30 (4.7%) 11 (3.5%) 19 (6.0%) Beta blockers 451 (71.2%) 230 (72.3%) 221 (70.2%) Digoxin or digitoxin 26 (4.1%) 17 (5.3%) 9 (2.9%) Last INR before ablation (n) 531 (83.9) 217 (68.2%) 314 (99.7%) Mean (SD) 1.9 (0.7) 1.2 (0.3), P < 0.001 vs. VKA 2.3 (0.5) Median (q1, q3) 2.0 (1.1, 2.4) 1.1 (1.0, 1.2) 2.3 (2.0, 2.6) Continued Apixaban in patients at risk of stroke 2949 Table 2 Continued All patients Apixaban VKA n5 633 n5 318 (n5 317 n5 315 (n5 127 warfarin, 5 mg b.i.d., n5 102 phenprocoumon, n5 1 2.5 mg b.i.d.) n5 86 acenocoumarol) .................................................................................................................................................................................................................... Quality-of-life at baseline SF-12 physical component, n (%) 44.6 (37.7, 51.4), n = 597 43.5 (38.1, 51.3), n = 301 45.2 (37.6, 51.5), n = 296 SF-12 mental component n (%) 598 (94.5%) 301 (94.7%) 297 (94.3%) SF-12 mental component n (%) 50.3 (42.8, 57.5), n = 598 51.2 (43.0, 57.9), n = 301 49.7 (42.6, 57.4), n = 297 Karnofsky scale 90 (80, 90) 80 (80, 90) 90 (80, 90) Cognitive function [Montreal Cognitive Assessment (MoCA)] at baseline Median MoCA(q1, q3) 27.0 (25.0, 29.0), n = 618 27.0 (25.0, 29.0), n = 313 27.0 (25.0, 29.0), n = 305 At least mild cognitive impairment (MoCA < 26) 188 (30.4%) 93 (29.7%) 95 (31.1%) Modified EHRA scale at baseline mEHRA I 40 (6.3%) 18 (5.7%) 22 (7.0%) mEHRA IIa 164 (25.9%) 76 (23.9%) 88 (27.9%) mEHRA IIb 205 (32.4%) 107 (33.6%) 98 (31.1%) mEHRA III 208 (32.9%) 110 (34.6%) 98 (31.1%) mEHRA IV 16 (2.5%) 7 (2.2%) 9 (2.9%) Ablation information Atrial fibrillation pattern Paroxysmal atrial fibrillation 367 (58.0%) 189 (59.4%) 178 (56.5%) Persistent or long-standing persistent atrial fibrillation 266 (42.0%) 129 (40.6%) 137 (43.5%) Time from randomization to ablation (days) Mean (SD) 38.0 (27.3) 36.9 (27.6) 39.1 (27.0) Median (q1, q3) 35.0 (20.0, 50.0) 34.0 (18.0, 48.0) 36.0 (21.0, 52.0) Rhythm at start of ablation Number of patients 633 318 315 Sinus rhythm 434 (68.6%) 212 (66.6%) 222 (70.6%) Atrial fibrillation 180 (28.4%) 98 (30.8%) 82 (26.0%) Atrial flutter 12 (1.9%) 3 (0.9%) 9 (2.8%) Pacing 7 (1.1%) 5 (1.6%) 2 (0.6%) Other 0 (0%) 0 (0%) 0 (0%) Type of ablation Pulmonary vein isolation, n (%) 571 (90.2%) 288 (90.6%) 283 (89.8%) Pulmonary vein isolation plus other ablation, n (%) 59 (9.3%) 29 (9.1%) 30 (9.5%) Other ablation without pulmonary vein isolation 3 (0.5%) 1 (0.3%) 2 (0.6%) Transoesophageal echocardiography prior to ablation 549 (86.7%) 269 (84.6%) 280 (88.9%) Total duration of ablation procedure (min), Median (q1, q3) 135 (110, 175) 136 (110, 175) 135 (105, 172) Ablation energy source Radiofrequency 402 (63.5%) 207 (65.1%) 195 (61.9%) Cryoablation 186 (29.3%) 92 (28.9%) 94 (29.8%) Other 45 (7.1%) 19 (6.0%) 26 (8.3%) Abnormal blood parameters Red blood cell count Abnormal 65/618 (10.5%) 32/311 (10.3%) 33/307 (10.7%) Platelet count abnormal 35/625 (5.6%) 20/315 (6.3%) 15/310 (4.8%) ALT abnormal 75/612 (12.3%) 39/307 (12.7%) 36/305 (11.8%) Bilirubin abnormal 38/596 (6.4%) 14/297 (4.7%) 24/299 (8.0%) Number of patients with valid information (n (%)) is only given when values were missing. BD, twice daily dosing; SD, standard deviation; q1, q3 are 25th and 75th percentiles, respectively; VKA, vitamin K antagonist. 2950 P. Kirchhof et al. Table 3 Primary outcomes in the AXAFA – AFNET 5 trial (ablation set), including details of the type of bleeding All patients Apixaban VKA .................................................................................................................................................................................................................... Patients with primary endpoint: composite of all-cause death, stroke or major 45/633 (7.1%) 22/318 (6.9%), 23/315 (7.3%) bleeding non-inferiority P=0.0002 Death 2 (0.3%) 1 (0.3%) 1 (0.3%) Stroke or TIA 2 (0.3%) 2 (0.6%) 0 Major bleeding (BARC 2–5) 45 (7.1%) 20 (6.2%) 25 (7.9%) Bleeding requiring medical attention (BARC 2) 24 (3.8%) 12 (3.7%) 12 (3.8%) Bleeding with haemoglobin drop of 30 to <50 g/L or requiring transfusion 9 (1.4%) 5 (1.6%) 4 (1.3%) (BARC 3a) Bleeding with haemoglobin drop > _50 g/L, or requiring surgery or iv vasoactive 11 (1.7%) 3 (0.9%) 8 (2.5%) agents, or cardiac tamponade (BARC 3b) Intracranial haemorrhage (BARC 3c) 1 (0.2%) 0 1 (0.3%, fatal) TIMI major bleeding (Intracranial bleed, or bleeding resulting in a haemoglobin 4 (0.6%) 1 (0.3%) 3 (1%) drop of > _50 g/L, or bleeding resulting in death within 7 days) ISTH major bleeding 24 (3.8%) 10 (3.1%) 14 (4.4%) Bleeding event by clinical type Tamponade 7 (1.1%) 2 (0.6%) 5 (1.6%) Access site bleed 27 (4.3%) 12 (3.8%) 15 (4.8%) Bleeding requiring transfusion of red blood cells 3 (0.5%) 2 (0.6%) 1 (0.3%) Other major bleed 7 (1.1%) 5 (1.6%) 2 (0.6%) Shown are number of patients per group. Some patients had more than one event. BARC4 events were not observed in the study. b.i.d., twice daily dosing. at 3 months compared to baseline using the EQ-5D and SF-12 ques- . balanced between groups (Table 1). Transoesophageal echocardiog- tionnaires, MoCA, and Karnofsky scale. Changes in quality-of-life were . raphy was used in 549/633 (86.7%) patients. All or all but one apixa- compared by analysis of covariance (ANCOVA) models including the ban doses per week were taken by 307/318 (97%) patients treatment arms as an indicator variable and the baseline quality-of-life randomized to apixaban in the ablation set. The median time in thera- variables as covariates. To accrue sufficient events for a formal non- peutic range in the 315 patients randomized to VKA in the ablation inferiority analysis, AXAFA – AFNET 5 was exclusively conducted in set was 84% (71, 97%). Time from randomization to ablation was not patients at risk of stroke (Table 1) and counted bleeding events follow- different between study groups (Table 1). ing the relatively broad BARC classification. An independent data and safety monitoring board monitored the study for safety. The Primary outcome Haybittle–Peto boundary was used as stopping rule guidance. Descriptive statistics for continuous and categorical variables were Primary outcome events (BARC 2–5 bleeding, stroke, or death) summarized as means (SDs) and medians (25th, 75th percentiles), were observed in 22/318 (6.9%) patients randomized to apixaban, and numbers (percentages), respectively. Comparisons between and in 23/315 (7.3%) patients randomized to VKA therapy in the abla- continuous variables were performed using the Wilcoxon rank-sum tion set. Four events were classified as TIMI major bleeding, and 24 test or two-sample t-test depending on normality; comparisons be- events are ISTH major bleeding (Table 3). Two patients died: one pa- tween nominal variables were performed using the Pearson’s v test tient randomized to VKA, female, age 70, hypertensive, last blood or Fisher’s exact test, depending on expected cell sizes. All analyses pressure 156/76, last INR 2.6, underwent pacemaker implantation were two-sided and tested at the nominal 0.05 significance level. No 8 days after ablation and experienced a massive intracerebral haem- adjustment was made for multiple testing. Statistical analyses were . orrhage. Another patient randomized to apixaban, male, age 69, with performed with SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). . paroxysmal atrial fibrillation, hypertension, heart failure, diabetes, and . chronic obstructive lung disease, was found dead in his bed 19 days . after ablation without identifiable cause of death upon autopsy. Two Results . patients randomized to apixaban had a stroke. Both had persistent . AF and underwent transoesophageal echocardiogram. One patient, Trial participants . male, age 63, hypertensive, ACT 236–398 s, developed slurred AXAFA – AFNET 5 randomized 674 patients across 49 sites in 9 speech with matching MRI lesion on the day of radiofrequency pul- countries from February 2015 to April 2017. Overall, 633 patients monary vein isolation that fully resolved. Another patient, male, age took study drug and underwent atrial fibrillation ablation (mITT, abla- 52, ACT 301–400 s, hypertensive, developed weakness of the right tion set, Figure 1). Demographic and clinical characteristics were well arm with paraesthesia of the right leg after cryoballoon pulmonary Apixaban in patients at risk of stroke 2951 Table 4 Secondary outcomes in the AXAFA – AFNET 5 trial (ablation set) All patients Apixaban VKA n5 633 n5 318 (n5 317 n5 315 (n5 127 5mg BD, warfarin, n5 102 n5 1 2.5 mg BD) phenprocoumon, n5 86 acenocoumarol) .................................................................................................................................................................................................................... Time from randomization to ablation in days, median 35.0 (20.0, 50.0) 34.0 (18.0, 48.0) 36.0 (21.0, 52.0) (q1, q3) Nights spent in hospital after index ablation, median 3 (2, 5) 2 (1, 5) 3 (2, 7) (q1, q3) ACT during ablation in seconds, median (q1, q3) 325.0 (285.0, 370.0) 310.0 (273.0, 350.0) 348.5 (304.0, 396.0) Number of subjects with all ACT values in range 234/631 (37.1%) 73/316 (23.1%) 161/315 (51.1%) (n (%)) Number of subjects with at least one ACT value < 250 214/631 (33.9%) 130/316 (41.1%) 84/315 (26.7%) (n (%)) Number of subjects with at least one ACT value < 300 397/631 (62.9%) 243/316 (76.9%) 154/315 (48.9%) (n (%)) Number of bleeding events (n) 118 54 64 Patients without recurrence of atrial fibrillation (n (%)) 434/619 (70.1%) 217/311 (69.8%) 217/308 (70.5%) Quality-of-life SF-12 physical component score at end of study, 48.6 (42.0, 54.2), n = 564 48.4 (41.9, 54.2), n = 289 48.8 (42.2, 54.4), n = 275 median (q1, q3), n Change in SF-12 physical component score at end of 2.5 (-2.1, 8.1), n = 547, P < 0.001* 2.4 (-2.2, 7.9), n = 280 2.8 (-2.0, 8.3), n = 267 study compared to baseline, median (q1, q3), n SF-12 mental component score at end of study, 54.4 (46.0, 58.6), n = 565 54.2 (45.8, 58.3), n = 290 54.5 (46.6, 59.7), n = 267 median (q1, q3), n Change in SF-12 mental component score at end of 1.2 (-3.2, 8.0), n = 548, P < 0.001* 0.4 (-3.6, 8.0), n = 281 1.6 (-2.8, 8.3), n = 267 study compared to baseline, median (q1, q3), n Karnofsky score at end of study, median (q1, q3), n 100 (90, 100), n = 619 100 (90, 100), n = 311 100 (90, 100), n = 308 Change in Karnofsky score at end of study compared 10 (0, 10), n = 619 10 (0, 10), n = 311 10 (0, 10), n = 308 to baseline (D Karnofsky), median (q1, q3), Cognitive function [Montreal Cognitive Assessment (MoCA)] Cognitive function at end of study (MoCA), median 28.0 (26.0, 29.0), n = 607 28.0 (26.0, 29.0), n = 305 28.0 (26.0, 29.0), n = 302 (q1, q3), n Abnormal MoCA at baseline (<26), n (%) 141 (23.2%) 75 (24.6%) 66 (21.9%) Change in MoCA at end of study compared to base- 1.0 (-1.0, 2.0), n = 597, P < 0.001* 0.0 (-1.0, 2.0), n = 301 1.0 (-1.0, 2.0), n = 296 line, median (q1, q3), n Change in patients with abnormal MoCA at end of 141/607 (23.2%), -7.2%, P = 0.005* 75/305 (24.6%) -5.1% 66/302 (21.9%) -9.2% study compared to baseline, n (%) Number of patients with valid information (n (%)) is only given when values were missing. P-values marked by asterisks (*) indicate differences between baseline and end of follow-up measurements. Twice daily (b.i.d.) dosing; q1 and q3 indicate 25th and 75th percentiles, respectively. vein isolation that persisted beyond hospital discharge. Tamponade all randomized patients as assessed by Cox proportional hazards occurred in 2 (apixaban) and 5 (VKA) patients and was managed by . model comparison between treatment groups using a relative non- pericardial drainage and administration of protamine and vitamin K. . inferiority margin of 1.44 (equivalent to 7.5% absolute; hazard One patient with tamponade in each study group received blood . ratio = 0.88, 90% CI 0.55, 1.41; P = 0.042, Figure 2). There was no stat- transfusions. Anticoagulants were continued in five patients with tam- . istical interaction between clinical stroke and bleeding risk factors ponade, and paused for 4 days in one patient randomized to apixa- . and treatment groups (Figure 3). ban, and for 8 days in one patient randomized to VKA. All patients . were discharged from hospital and attended the 3 months follow-up . Secondary outcome parameters (n = 6) or an end of study visit (n =1). Apixaban was non-inferior to VKA based on the non-inferiority There was no difference in time to ablation or nights spent in hospital margin of 7.5% (a difference of -0.38%, 90% CI -4.0%, -3.3%, non- after the ablation between groups (Table 4). As expected, the last inferiority P = 0.0002). Apixaban was also non-inferior to VKA among INR prior to ablation and ACTs achieved during ablation were lower 2952 P. Kirchhof et al. AB C D EF G H Figure 4 Examples of acute brain lesions detected in the brain magnetic resonance imaging sub-study. Acute brain lesions (arrows in A, C, E, G)are found by high-resolution diffusion-weighted brain magnetic resonance imaging without corresponding lesions in the fluid-attenuated inversion recov- ery images (arrows in B, D, F, H). Shown are representative lesions in two patients randomized to apixaban (A/B; C/D) and in two patients randomized to vitamin K antagonist (E/F; G/H). The fluid-attenuated inversion recovery images also detected chronic white matter lesions [asterisks (*) in F]. in the patients randomized to apixaban (Table 4). Quality-of-life as as- . Discussion sessed by the physical component of SF-12 [þ2.5(-2.1,8.1)units] AXAFA – AFNET 5 demonstrated that continuous anticoagulation and Karnofsky scale [þ10 (0, 10)] improved during the study without with apixaban is a safe and effective alternative to VKA in patients at differences between study groups (Table 4). At least mild cognitive risk of stroke undergoing atrial fibrillation ablation. AXAFA – AFNET dysfunction was found in 188/619 (30.4%) of the patients at baseline 5 observed four TIMI major bleeding events in 633 patients (0.6%, (pre-defined as MoCA < 26, Table 2). At the end of follow-up, MoCA Table 3) compared to one event in 248 patients in VENTURE-AF increased by a median of þ1.0 (-1.0, 2.0) unit without differences be- (0.4%). AXAFA – AFNET 5 observed 24 patients with ISTH major tween study groups, and only 141/607 patients (7.2% fewer than at bleeding events (3.8%, Table 3) compared to 27 events in 635 patients baseline) had mild cognitive impairment (Table 4). in RE-CIRCUIT (4.3%). The numerical differences in ISTH major bleeding rates between AXAFA – AFNET 5 [apixaban 10 patients Magnetic resonance imaging sub-study (3.1%); VKA 14 patients (4.4%); Table 3] and RE-CIRCUIT [dabigatran Acute brain MRI was performed in 335 patients across 25 centres. 5 patients (1.6%); VKA 22 patients (6.9%)] could be due to chance Clinical characteristics of the sub-study population were not different variations in outcomes, differences in risk profile between the from the main study population, with the exception of a lower me- AXAFA – AFNET 5 and RE-CIRCUIT study populations, and due to dian weight in patients undergoing MRI [85.0 kg (74.5, 96.0)] com- . the high time in therapeutic range in the VKA group in AXAFA – pared to non-MRI patients [90.0 kg (80.0, 103.0)]. Clinical . AFNET 5 (median TTR 84%). AXAFA – AFNET 5 included only pa- characteristics were well balanced between MRI sub-study treatment . tients with stroke risk factors, resulting in a mean CHA DS VASc 2 2 groups. There were 323 analysable MRIs. Acute brain MRI lesions . score of 2.4 and a population that was 4–5 years older than in the . 1–3,8,9 (Figure 4) were found in 44/162 (27.2%) patients randomized to apix- . published controlled trials in atrial fibrillation ablation. Despite aban, and in 40/161 (24.8%) patients randomized to VKA (P =0.635), . the higher stroke risk, we observed few strokes: AXAFA – AFNET 5 with very similar distribution of lesions between random groups found 2 strokes in 633 patients (0.3%), compared to 1 stroke in 248 (Table 5). Cognitive function at the end of follow-up was not different patients in VENTURE-AF (0.4%), and 1 TIA in 635 patients in RE- in patients with or without acute brain lesions (MoCA 27.1 ± 2.7 in CIRCUIT (0.2%). Equally, mortality was low (0.3%) and similar to 8 9 239 patients without MRI lesions, 27.1 ± 2.8 in 84 patients with MRI VENTURE-AF (0.4%), RE-CIRCUIT (0%), and the EORP AF abla- lesions, P =0.91). tion registry (0.2%). Apixaban in patients at risk of stroke 2953 Table 5 Acute brain lesions detected by high-resolution diffusion-weighted magnetic resonance imaging (MRI sub- study) All patients (n5 323) Apixaban (n5 162) VKA (n5 161) P-value .................................................................................................................................................................................................................... No lesion 239 (74.0%) 118 (72.8%) 121 (75.2%) 0.635 Exactly one lesion 46 (14.2%) 27 (16.7%) 19 (11.8%) 0.211 Exactly two lesions 21 (6.5%) 7 (4.3%) 14 (8.7%) 0.111 More than two lesions 17 (5.3%) 10 (6.2%) 7 (4.3%) 0.463 P-values were determined by Pearson’ s v test. differences between study groups. Continuous anticoagulation does not fully prevent acute brain lesions, which can be caused by debris 27,28 dislodging from ablation wounds, air emboli, or small thrombi. Procedural improvements are desirable to reduce acute brain lesions during atrial fibrillation ablation. Further analyses of the AXAFA – AFNET 5 data set may shed more light on risk factors for acute brain . lesions in patients undergoing AF ablation on continuous anticoagula- tion. One prior study found reduced cognitive function 90 days after atrial fibrillation ablation on interrupted warfarin therapy compared . to baseline. Reassuringly, cognitive function improved at the end of AXAFA – AFNET 5 without differences between study groups. 10% Death Stroke or TIA . Limitations Major Bleed (TIMI) 5% Major Bleed (ISTH) . AXAFA – AFNET 5 was an open study, but with blinded outcome as- . sessment. The non-inferoirity margin was wide. The findings are con- 0% . sistent with prior studies with continuous dabigatran and . rivaroxaban. While AXAFA – AFNET 5 was the first study comparing cognitive function after atrial fibrillation ablation in a controlled trial, the assessment was limited to global cognitive function. Differentiation between acute and chronic lesions was done by using 14,15 AXAFA-AFNET 5 RE-CIRCUIT VENTURE-AF Combined an accepted combination of MRI sequences. Take home figure Cumulative outcome events in AXAFA – AFNET 5 in patients undergoing atrial fibrillation ablation at risk of Conclusions stroke (top) and comparison to event rates in the two other con- trolled trials comparing continuous NOAC therapy with continu- Continuous apixaban therapy is a safe and effective alternative to ous vitamin K antagonist therapy (bottom). TIMI major bleeds were . VKA in patients at risk of stroke undergoing atrial fibrillation ablation not separately reported in the main paper of RE-CIRCUIT. ISTH with respect to stroke, major bleeding, cognitive function, and MRI- major bleeds were not separately reported in the main paper of . detected acute brain lesions. VENTURE-AF. . Acknowledgements The authors would like to thank Bianca-Maria Klein, Elisabeth Freund, and the study teams at CRI and AFNET for excellent project coord- AXAFA – AFNET 5 included 86 patients on acenocoumarol and ination, help with preparing the manuscript and ensuring complete 102 patients on phenprocoumon, 186 patients (29%) undergoing accordance of the paper with the trial protocol and eCRF, and the cryoablation, and 84 patients undergoing atrial fibrillation ablation members of the clinical trials statistics group at DCRI who provided without transoesophageal echocardiography without safety signals, the statistical analysis. providing some reassurance that these common patterns of clinical 4–6,26 practice can be used on continuous apixaban or VKA therapy. . Funding The secondary outcomes observed in AXAFA – AFNET5 under- AXAFA – AFNET 5 is an investigator-initiated trial. Sponsor of the trial is pin the safety of continuous apixaban in atrial fibrillation ablation: . AFNET. AXAFA – AFNET 5 was partially funded by BMS/Pfizer, the time to ablation was not different between groups and quality-of-life . . DZHK (German Centre for Cardiovascular Research) and by the BMBF and cognitive function improved equally in both study groups after . (German Ministry of Education and Research) to AFNET. Further sup- ablation. High-resolution diffusion-weighted brain MRI detected . port came from European Union [Grant Agreement No. 633196 12,14,15 . acute brain lesions at the expected rate (25%) without . (CATCH ME) to B.B., P.K., L.M., U.S., AFNET], British Heart Foundation Apixaban (318) VKA (315) Dabigatran (317) VKA (318) Rivaroxaban (113) VKA (107) NOAC (748) VKA (740) 2954 P. Kirchhof et al. C, Davies DW, Fields LE, Natale A; VENTURE-AF Investigators. Uninterrupted (FS/13/43/30324 to P.K.), Leducq Foundation to P.K., and the rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non- Netherlands Heart Foundation (RACE V) to U.S. and I.v.G. AFNET, valvular atrial fibrillation. Eur Heart J 2015;36:1805–1811. DZHK, BMS/Pfizer; AXAFA – AFNET 5; NCT02227550. . 9. Calkins H, Willems S, Gerstenfeld EP, Verma A, Schilling R, Hohnloser SH, Okumura K, Serota H, Nordaby M, Guiver K, Biss B, Brouwer MA, Grimaldi M; Conflict of interest: Authors disclose financial links with Abbott/St RE-CIRCUIT Investigators. Uninterrupted dabigatran versus warfarin for ablation Jude Medical (G.H., L.M., J.P., L.D.B.), AFNET (T.F., J.P.), Allergan (J.P.), in atrial fibrillation. N Engl J Med 2017;376:1627–1636. ARCA Biopharma (J.P.), Bayer (K.G.H., J.P., U.S.), Biosense Webster . 10. Medi C, Evered L, Silbert B, Teh A, Halloran K, Morton J, Kistler P, Kalman J. 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Journal

European Heart JournalOxford University Press

Published: Mar 20, 2018

Keywords: Atrial fibrillation; Ablation; Anticoagulation; Bleeding; Stroke; Brain MRI

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