Clinical Kidney Journal , 2023, vol. 16, no. 12, 2683–2692 https:/doi.org/10.1093/ckj/sfad221 Advance Access Publication Date: 4 September 2023 Original Article ORIGINAL ARTICLE Long-term safety and efficacy of left atrial appendage occlusion in dialysis patients with atrial fibrillation: a multi-center, prospective, open label, observational study Simonetta Genovesi 1 ,2 , Luca Porcu 3 , Paola Rebora 1 , Giorgio Slaviero 4 , Gavino Casu 5 , Silvio Bertoli 6 , Flavio Airoldi 7 , Monique Buskermolen 8 , Maurizio Gallieni 8 ,9 , Federico Pieruzzi 1 ,2 , Giovanni Rovaris 10 , Alberto Montoli 11 , Emanuela Piccaluga 12 , Giulio Molon 13 , Federico Alberici 14 , Marianna Adamo 15 , Achille Gaspardone 16 , Giuseppe D’Ang elo 17 , Pierluig i Merella 5 , Giuseppe Vezzoli 4 , Barbara Trezzi 1 and Patrizio Mazzone 18 1 School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy, 2 Istituto Auxologico Italiano, IRCCS, Milan, Italy, 3 Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK, 4 Nephrology Unit, IRCCS Ospedale San Raffaele, Milano, Italy, 5 Cardiology Unit, Azienda Ospedaliera Universitaria di Sassari, Sassari, Italy, 6 Dialysis and Nephrology Unit-IRCCS-Multimedica, Sesto S.Giovanni, Italy, 7 Electrophysiology Unit-IRCCS-Multimedica, Sesto S.Giovanni, Italy, 8 Nephrology and Dialysis Unit, ASST Fatebenefratelli Sacco, Milano, Italy, 9 Department of Biomedical and Clinical Sciences, University of Milano, Milano, Italy, 10 Interventional Electrophysiology Unit, San Gerardo Hospital, Monza, Italy, 11 Nephrology Unit, Niguarda Hospital, Milano, Italy, 12 Interventional Cardiology Unit, Niguarda Hospital, Milano, Italy, 13 Cardiology Department, IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Italy, 14 Nephrology Unit, ASST degli Spedali Civili di Brescia, Brescia, Italy, 15 Cardiology Unit, ASST degli Spedali Civili di Brescia, Brescia, Italy, 16 Cardiology Unit, S.Eugenio Hospital, Roma, Italy, 17 Cardiac Pacing Unit, IRCCS Ospedale San Raffaele, Milano, Italy and 18 Cardiology 3, “A. De Gasperis” Cardio Center, ASST GOM Niguarda Ca’ Granda, Milan, Italy Correspondence to: Simonetta Genovesi; E-mail: simonetta.genovesi@unimib.it ABSTRACT Background. The prevalence of atrial fibrillation ( AF ) in end stage kidney disease ( ESKD ) patients undergoing dialysis is high, however, the high risk of bleeding often hampers with a correct anticoagulation in ESKD patients with AF, despite high thromboembolic risk. Left atrial appendage ( LAA ) occlusion is a anticoagulation ( OAT ) for thromboembolism prevention in AF populations with high hemorrhagic risk. R © C a eceived: 17.6.2023; Editorial decision: 16.8.2023 The Author ( s ) 2023. Published by Oxford University Press on behalf of the ERA. This is an Open Access article distributed under the terms of the Creative ommons Attribution-NonCommercial License ( https://creativecommons.org/licenses/by-nc/4.0/ ) , which permits non-commercial re-use, distribution, nd reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 2683 https://academic.oup.com/ https:/doi.org/10.1093/ckj/sfad221 https://orcid.org/0000-0002-4699-4149 https://orcid.org/0000-0003-0606-5852 https://orcid.org/0000-0002-2011-2160 https://orcid.org/0000-0001-8287-0461 https://orcid.org/0000-0002-1686-5709 https://orcid.org/0000-0002-3855-1815 mailto:simonetta.genovesi@unimib.it https://creativecommons.org/licenses/by-nc/4.0/ mailto:journals.permissions@oup.com 2684 S. Genovesi et al . Methods and Results. The purpose of the study was to evaluate the efficacy and safety of LAA occlusion in a cohort of dialysis patients undergoing the procedure ( LAA occlusion cohort, n = 106 ) , in comparison with two other ESKD cohorts, one taking warfarin ( Warfarin cohort, n = 114 ) and the other without anticoagulation therapy ( No-OAT cohort, n = 148 ) . After a median follow-up of 4 years, a Cox regression model, adjusted for possible confounding factors, showed that the hazard ratios ( HRs ) of thromboembolic events in the LAA occlusion cohort were 0.19 ( 95%CI 0.04–0.96; p = 0.045 ) and 0.16 ( 95%CI 0.04–0.66; p = 0.011 ) as compared with Warfarin and No-OAT cohorts, respectively. The HR of bleeding in the LAA occlusion cohort was 0.37 ( 95%CI 0.16–0.83; p = 0.017 ) compared to Warfarin cohort, while there were no significant differences between the LAA occlusion and the No-OAT cohort ( HR 0.51; 95%CI 0.23–1.12; p = 0.094 ) . Adjusted Cox regression models showed lower mortality in patients undergoing LAA occlusion as compared with both the Warfarin cohort ( HR 0.60; 95%CI 0.38–0.94; p = 0.027 ) and no-OAT cohort ( HR 0.52; 95%CI 0.34–0.78; p = 0.002 ) . Thromboembolic events in the LAA occlusion cohort were lower than expected according to the CHA 2 DS 2 VASc score ( 1.7 [95%CI 0.3–3.0] vs 6.7 events per 100 person/years, p < 0.001 ) . Conclusion. In ESKD patients with AF, LAA occlusion is safe and effective and is associated with reduced mortality compared with OAT or no therapy. Keywords: atrial fibrillation, bleeding, end stage kidney disease, left atrial appendage occlusion, thromboembolism I T d h e b T R o a a g s c r t a n m g t t e O H p o t t o f a t s r s l o M T w p o s i l a M t t p b w e p f O P t f t t L L i i t t e a a p b t t t NTRODUCTION he prevalence of atrial fibrillation ( AF ) in patients undergoing ialysis is high [ 1 ], and probably underestimated because of the igh rate of asymptomatic, undiagnosed episodes [ 2 ]. Both thromboembolic and hemorrhagic risk is elevated in nd-stage kidney disease ( ESKD ) because pro-thrombotic and leeding promoting factors are simultaneously present [ 3 ]. herefore, there is uncertainty in how to treat these patients. andomized controlled trials ( RCTs ) demonstrating the efficacy f vitamin K antagonists ( VKAs ) for thromboembolic prevention re lacking and dialysis patients were excluded from RCTs that llowed direct oral anticoagulants ( DOACs ) to be included in the uidelines for thromboembolism prevention in AF [ 4 –7 ]. Real-life tudies on VKAs in hemodialysis ( HD ) patients showed incon- lusive results on efficacy and negative results on safety [ 8 ] and eal-life studies of DOACs failed to demonstrate an advantage on hromboembolic risk, either compared with warfarin or no oral nticoagulant therapy ( OAT ) [ 9 , 10 ]. Therefore, cardiology and ephrology guidelines have been unable to provide clear recom- endations for ESKD patients with AF [ 11 , 12 ], and nephrolo- ists often don’t prescribe OAT in these patients or discontinue he drug after a hemorrhagic event [ 13 ]. Left atrial appendage ( LAA ) occlusion is an available alterna- ive to OAT in patients with AF and high hemorrhagic risk. How- ver, two RCTs aiming to evaluate the safety of LAA occlusion vs. AT in patients with severe renal failure ( Watch-AFIB and STOP- ARM ) were stopped early because of under-recruitment [ 14 ]. A revious prospective cohort study demonstrated the feasibility f the procedure in a population of ESKD patients [ 15 ]. However, he follow-up was too short and the number of events too low o reach any conclusion regarding the efficacy and safety of LAA cclusion when compared with HD patients with AF taking war- arin or not taking OAT [ 16 ]. The main purposes of this study are ( i ) to assay the efficacy nd safety of LAA occlusion in a large population of dialysis pa- ients with a long follow-up ( ii ) to evaluate whether LAA occlu- ion leads to an advantage on thromboembolic and hemorrhagic isk compared to warfarin or no OAT. A secondary aim of the tudy is to compare the incidence of mortality and cardiovascu- ar events of the LAA occlusion cohort compared with warfarin r no-OAT cohorts of ESKD patients. ATERIALS AND METHODS his multi-center, prospective, open label, observational study as performed according to STROBE guidelines. All ESKD atients requiring renal replacement therapy ( hemodialysis r peritoneal dialysis ) , with documented AF ( paroxysmal, per- istent or permanent ) , CHA2DS2VASc score ≥1 if men and ≥2 f women and HASBLED score ≥3 or a contraindication for ong-term OAT ( e. g. previous life-threatening bleeding without reversible cause ) and who underwent LAA occlusion from ay 2014 to January 2021 at one of the study participant centers hat were included in the study. All patients recruited had o be age > 18 years and have signed an informed consent to articipate in the study. Primary outcomes were cumulative incidence of throm- oembolic and bleeding events ( first event ) , secondary outcomes ere mortality and cumulative incidence of cardiovascular vents ( first event ) at the end of follow-up. For comparative pur- oses, a historical cohort of dialysis patients with AF, deriving rom a prospective study previously performed running from ctober 2010 to December 2014 [ 17 ], was included in the study. atients were selected from the historical cohort according to he same inclusion criteria as the LAA occlusion cohort, except or the procedure, and were divided according to anticoagulant herapy in two groups: one taking VKAs ( Warfarin cohort ) and he other not taking any anticoagulant therapy ( No-OAT cohort ) . eft atrial appendage occlusion eft atrial appendage is the major source of thromboembolism n patients with AF. Percutaneous LAA occlusion is a minimally nvasive transcatheter procedure involving a device implanta- ion into the LAA to prevent thrombus formation and to reduce he risk of stroke. The procedure can be performed through an ndocardial approach, with trans-esophageal ultrasound guid- nce and under general anesthesia to ensure patient immobility nd minimize complications. The preferred access site for the rocedure is the right femoral vein, but the left femoral vein can e used if the right access is unavailable. The trans-septal punc- ure, a critical step of the procedure, is preferably performed in he postero-inferior area of the interatrial septum, considering he typical orientation of the LAA. Left atrial appendage occlusion in hemodalysis patients 2685 t f t m a i f p p D T w d f h s E b w b p r h o o c r t m t a w s p s f m a a S e B s l g b b t h a p F h f s b e o o s s s 2 U g e w o p S © S A c C s t a t e a w T w c fi V h m 9 R O w J s s ( t f b c d d t T p a v a p Pre-procedural imaging obtained by trans-esophageal ul- rasound or cardiac computerized axial tomography is crucial or LAA occlusion planning, allowing for the exclusion of LAA hrombi, detailed assessment of LAA anatomy, and measure- ent of LAA dimensions to select the appropriate device size nd location for the trans-septal puncture. Heparin is admin- stered before or during trans-septal puncture to prevent clot ormation. Trans-esophageal ultrasound is used during the rocedure to guide the trans-septal puncture, verify device osition, and check for peri-device leaks. ata collection he following comorbidities and echocardiography parameters ere collected: arterial hypertension, diabetes mellitus, dyslipi- emia, peripheral arterial disease, ischemic heart disease, heart ailure, chronic pulmonary disease, presence of left ventricular ypertrophy, left ventricular dysfunction and atrial dilation ( see upplementary material for definitions ) . Different types of AF were defined in agreement with the uropean Society of Cardiology [ 18 ]. In all patients, the throm- oembolic ( CHA 2 DS 2 VASc ) and hemorrhagic ( HASBLED ) scores ere determined to quantify patient-specific risk of throm- oembolic and bleeding events [ 18 ]. Systemic thromboembolism was collected only if imaging- roven ( computed tomographic scan or nuclear magnetic esonance ) and major bleeding was defined as a fall in emoglobin level of 2 g/dl or more or documented transfusion f at least two units of packed red blood cells, or an involvement f a critical anatomical site ( intracranial, spinal, ocular, peri- ardial, articular, intramuscular with compartment syndrome, etroperitoneal ) [ 19 ]. In patients taking warfarin, the International Normalized Ra- io ( INR ) values were assessed at least once a month. To deter- ine the achieved intensity of anticoagulation, the percentage ime in the target INR range ( target therapeutic range, TTR ) was lso calculated [ 20 ]. The rate of thromboembolic events observed was compared ith the expected rate according to the mean CHA 2 DS 2 VASc core [ 21 ] and the rate of major bleedings observed was com- ared with the expected rate according to the mean HASBLED core [ 21 ]. The study protocol adhered to the 1975 Helsinki Declaration or Ethical Treatment of Human Subjects, with local ethics com- ittee approval ( Comitato Etico della Provincia di Monza e Bri- nza, study LAAO-DIA, 17 032 016 ) . All involved subjects provided n informed consent to participate and for data publication. tatistical methods ( see supplementary material for xtended statistical methods ) aseline characteristics were summarized using descriptive tatistics ( median and range for continuous variables, and abso- ute and percentage frequencies for categorical variables ) . A lo- istic regression model was used to detect imbalances between aseline characteristics. Overall survival function was estimated y the Kaplan–Meier method. The cumulative incidence func- ion was used to estimate the probability of thromboembolic, emorrhagic and cardiovascular events in the presence of death s a competing event. The observed number of incidence events er 100 person/years was estimated as a weighted average. or each patient the expected number of thromboembolic and emorragic incidence events per 100 person/years was retrieved rom the reference [ 21 ] and it was weighted by the patient’s urvival time to obtain the expected number of thromboem- olic and hemorragic incidence events per 100 person/years in ach cohort. In order to evaluate the association between LAA cclusion and the four endpoints ( thromboembolic events, hem- rrhagic events, mortality and cardiovascular events ) with re- pect to the historical cohort, we ran a multivariable Cox regres- ion model adjusting for potential confounders. Survival analy- is was performed using Stata software version 18.0 ( StataCorp. 023. Stata Statistical Software: Release 18. College Station, TX, SA: StataCorp LLC ) . The Stata command stcompet was used to enerate cumulative incidence in the presence of competing vents. R statistical software, version 4.2.1 ( R Core Team 2022 ) as used to generate bar plots of expected and observed number f incidence events. Bar plots were generated using the ggplot2 ackage in R. Any other statistical analysis was performed using AS software, version 9.4 of the SAS System for Linux. Copyright 2012–2020, SAS Institute Inc., Cary, NC, USA. ensitivity analysis s a sensitivity analysis, we evaluated the effect of the LAA oc- lusion by an inverse probability of treatment weight ( IPTW ) ox model. We created a pseudo-population which mitigates the election bias in treatment assignment at recruitment [ 22 ] on he propensity to undergo LAA occlusion that included all vari- bles shown in Table 1 and several two and three-way interac- ions ( see online supplementary material for details ) . In order to valuate the balance induced by these weights, the confounders mong patients under the three arms in this pseudo-population ere compared by standardized differences and Chi-square test. he weighted Cox regression model with robust standard error as applied to the IPTW cohort to assess the effect of LAA oc- lusion on the different endpoints ( first thromboembolic event, rst bleeding event, overall mortality, first cardiovascular event ) . ariables with a maximum standardized difference among arms igher than 0.25 were included in the model. Results of the Cox odels are expressed in terms of estimated hazard ratios ( HR ) , 5% confidence intervals ( 95% CI ) and P -values. ESULTS ne hundred and six consecutive dialysis patients who under- ent LAA occlusion in 12 Italian centers between May 2014 and anuary 2021 were enrolled in the study. The characteristics of the study population at baseline are hown in Table 1 . The median values of the thromboembolic core ( CHA 2 DS 2 VASc ) and hemorrhagic score ( HASBLED ) were 4 range 3–5 ) and 5 ( range 4–5 ) , respectively, and 64.2% of the pa- ients had non-paroxysmal AF. A total of 12.3% of patients suf- ered a previous thromboembolic event and 62.3% had a major leeding. About 90% of the patients were hypertensive. The other ommon comorbidities were diabetes mellitus ( 37.7% ) , dyslipi- emia ( 54.7% ) , peripheral artery disease ( 53.8% ) , ischaemic heart isease ( 43.4% ) and heart failure ( 34.0% ) . The differences between the LAA occlusion cohort and he comparison cohorts ( Warfarin and No-OAT ) are shown in able S1 ( see online supplementary material ) . Left atrial ap- endage occlusion patients were more frequently male, with higher prevalence of paroxysmal AF, dyslipidemia and pre- ious major bleeding than other two cohorts. Dialysis age nd prevalence of peripheral arterial disease were lower com- ared with Warfarin and No-OAT patients. Table S2 ( see online https://academic.oup.com/ckj/article-lookup/doi/10.1093/ckj/sfad221#supplementary-data https://academic.oup.com/ckj/article-lookup/doi/10.1093/ckj/sfad221#supplementary-data https://academic.oup.com/ckj/article-lookup/doi/10.1093/ckj/sfad221#supplementary-data https://academic.oup.com/ckj/article-lookup/doi/10.1093/ckj/sfad221#supplementary-data https://academic.oup.com/ckj/article-lookup/doi/10.1093/ckj/sfad221#supplementary-data https://academic.oup.com/ckj/article-lookup/doi/10.1093/ckj/sfad221#supplementary-data 2686 S. Genovesi et al . Table 1: Clinical characteristics, and baseline comorbidities and anti-thrombotic therapy of the LAA occlusion population. N = 106 Gender Male N ( % ) 77 ( 72.6 ) Age ( yrs ) Median ( min-max ) 74 ( 46–87 ) ≥75 yrs N ( % ) 49 ( 46.2 ) Dialytic age ( yrs ) Median ( min-max ) 2.21 ( 0.47–7.33 ) ≥3 yrs N ( % ) 42 ( 39.6 ) BMI ( kg/m 2 ) Median ( Q1–Q3 ) 25 ( 22–28 ) Missing data ( % ) 20 ( 18.9 ) Current smoking Yes N ( % ) 10 ( 9.6 ) Missing data ( % ) 2 ( 1.9 ) CHA 2 DS 2 VASc Median ( Q1–Q3 ) 4 ( 3–5 ) HASBLED Median ( Q1–Q3 ) 4 ( 4–5 ) Atrial fibrillation Paroxysmal N ( % ) 38 ( 35.8 ) Persistent N ( % ) 18 ( 17.0 ) Permanent N ( % ) 50 ( 47.2 ) Comorbidities Hypertension N ( % ) 95 ( 89.6 ) Diabetes mellitus N ( % ) 40 ( 37.7 ) Dyslipidemia N ( % ) 58 ( 54.7 ) Peripheral artery disease N ( % ) 57 ( 53.8 ) Ischaemic heart disease N ( % ) 46 ( 43.4 ) Heart failure N ( % ) 36 ( 34.0 ) Chronic pulmonary disease N ( % ) 22 ( 20.8 ) Previous ischaemic stroke N ( % ) 11 ( 10.4 ) Previous pulmonary thromboembolism N ( % ) 2 ( 1.9 ) Previous major bleeding N ( % ) 66 ( 62.3 ) Echocardiography Atrium dilatation N ( % ) 88 ( 85.4 ) N of missing data 3 Left ventricular ejection fraction < 50% N ( % ) 20 ( 19.0 ) N of missing data 1 Left ventricular hypertrophy N ( % ) 52 ( 57.8 ) N of missing data ( % ) 16 Baseline antithrombotic therapy Antiplatelet N ( % ) 68 ( 64.2 ) Heparin N ( % ) 33 ( 31.1 ) Warfarin N ( % ) 31 ( 29.2 ) Baseline antiarrhythmic therapy Beta-blockers N ( % ) 59 ( 56.0 ) Amiodarone N ( % ) 9 ( 8.5 ) Sotalol N ( % ) 2 ( 1.9 ) Other antiarrhythmic drugs N ( % ) 5 ( 4.7 ) BMI, body mass index; LAA, left atrial appendage. s i T I ( ( d ( m o c p r a m s r h 0 r f T n upplementary material ) shows the weighted clinical character- stics of the three cohorts. hromboembolic and hemorrhagic events n the LAA occlusion cohort the median follow-up was 5 years minimum 0.1, maximum 9.2 years ) . During follow-up, 6 ( 5.7% ) thromboembolic events and 14 13.2% ) major bleeding events occurred. The cumulative inci- ence of thromboembolisms and bleedings is depicted in Fig. 1 A and B ) . No thromboembolic event occurred in the first three onths after the procedure, while at five years the percentage f thromboembolic events was 6.1% ( 95%CI 2.2–12.8% ) . The per- entage of bleedings occurred in the first three months after the rocedure was 6.8% ( 95%CI 3.0–12.7% ) , while at five years the esult was 13.7% ( 95%CI 7.6–21.7% ) . The incidence of thromboembolic events in the Warfarin nd No-OAT groups ( median follow-up 4 years, minimum 0.2, aximum 4.5 years ) were 8/114 ( 5.4% ) and 16/148 ( 10.8% ) , re- pectively. By the adjusted Cox regression model, the hazard atio ( HR ) of thromboembolic events in the LAA occlusion co- ort was 0.19 ( 95%CI 0.04–0.96; P = 0.045 ) and 0.16 ( 95%CI 0.04– .66; P = 0.011 ) as compared with Warfarin and No-OAT cohorts, espectively ( Table 2 ) . Major bleedings were 27/114 ( 23.7% ) in patients taking war- arin with an adjusted HR of 0.37 ( 95%CI 0.16–0.83; P = 0.017, able 2 ) compared to LAA occlusion patients. There were no sig- ificant differences between the incidence of bleeding in the https://academic.oup.com/ckj/article-lookup/doi/10.1093/ckj/sfad221#supplementary-data Left atrial appendage occlusion in hemodalysis patients 2687 Figure 1: Cumulative incidence of thromboembolisms ( A ) , bleeding ( B ) and cardiovascular events ( D ) and survival curve ( C ) in the Left Atrial Appendage Occlusion cohort. Table 2: Cox regression model results on thromboembolic ( Model 1 ) and hemorrhagic events ( Model 2 ) . Model 1: Model 2: N of patients = 368 N of patients = 368 N of thromboembolic events = 30 N of hemorrhagic events = 65 HR ( 95%CI ) P -value HR ( 95%CI ) P -value LAA occlusion vs warfarin 0 .19 ( 0.04–0.96 ) 0.045 0 .37 ( 0.16–0.83 ) 0.017 LAA occlusion vs No-OAT 0 .16 ( 0.04–0.66 ) 0.011 0 .51 ( 0.23–1.12 ) 0.094 Gender ( males ) 0 .98 ( 0.43–2.24 ) 0.954 1 .2 ( 0.68–2.15 ) 0.529 Age ( yrs ) 1 .01 ( 0.96–1.07 ) 0.634 1 .02 ( 0.98–1.05 ) 0.283 Dialytic age ( yrs ) 0 .95 ( 0.88–1.04 ) 0.261 1 .03 ( 0.99–1.06 ) 0.111 CHA 2 DS 2 VASc ( for each point ) 1 .22 ( 0.88–1.7 ) 0.236 0 .97 ( 0.74–1.27 ) 0.822 HASBLED ( for each point ) 1 .26 ( 0.71–2.25 ) 0.436 1 .17 ( 0.76–1.8 ) 0.466 Persistent vs paroxysmal AF 0 .62 ( 0.25–1.55 ) 0.309 1 .24 ( 0.6–2.56 ) 0.567 Permanent vs paroxysmal AF 0 .56 ( 0.2–1.58 ) 0.270 1 .33 ( 0.64–2.77 ) 0.442 Dyslipidemia 1 .15 ( 0.52–2.54 ) 0.723 0 .72 ( 0.4–1.28 ) 0.260 Peripheral artery disease 0 .61 ( 0.24–1.55 ) 0.299 0 .95 ( 0.52–1.72 ) 0.863 Previous major bleedings 0 .94 ( 0.33–2.65 ) 0.901 1 .77 ( 0.93–3.37 ) 0.085 Antiplatelet therapy 1 .11 ( 0.46–2.65 ) 0.813 0 .74 ( 0.4–1.36 ) 0.334 AF, atrial fibrillation; LAA, left atrial appendage; OAT, oral anticoagulant therapy. L 0 t a i o M D o w w c e AA occlusion cohort and the No-OAT cohort ( 24/148, 16.2%; HR .51; 95%CI 0.23–1.12; P = 0.094 ) . Sensitivity analyses performed after weighting confirmed hese results ( Table S3 , see online supplementary material ) . The INR range in patients taking warfarin was between 1.01 nd 7.69, with a median of 2.2 ( first-third quartile 1.68–2.59 ) . Dur- ng the study, the TRR in patients taking warfarin had a median f 53% ( first-third quartile 42–64% ) . ortality and cardiovascular events uring follow-up, 59/106 ( 55.7% ) patients in the LAA cclusion cohort died and 47 ( 44.3% ) patients under- ent a cardiovascular event. Nineteen out of 59 ( 32.2% ) ere cardiovascular deaths. Figure 1 shows the survival urve ( C ) and the cumulative incidence of cardiovascular vents ( D ) . https://academic.oup.com/ckj/article-lookup/doi/10.1093/ckj/sfad221#supplementary-data https://academic.oup.com/ckj/article-lookup/doi/10.1093/ckj/sfad221#supplementary-data 2688 S. Genovesi et al . Table 3: Cox regression on results on mortality ( Model 1 ) and cardiovascular events ( Model 2 ) . Model 1: Model 2: N of patients = 368 N of patients = 368 N of deaths = 220 N of cardiovascular events = 192 HR ( 95%CI ) P -value HR ( 95%CI ) P -value LAA occlusion vs warfarin 0 .60 ( 0.38–0.94 ) 0 .027 0 .38 ( 0.23–0.62 ) < 0 .001 LAA occlusion vs No-OAT 0 .52 ( 0.34–0.78 ) 0 .002 0 .45 ( 0.29–0.7 ) < 0 .001 Gender ( males ) 1 .06 ( 0.78–1.45 ) 0 .687 0 .74 ( 0.53–1.03 ) 0 .071 Age ( yrs ) 1 .02 ( 1.00–1.04 ) 0 .013 0 .97 ( 0.95–0.99 ) 0 .004 Dialytic age ( yrs ) 1 .01 ( 0.99–1.03 ) 0 .267 1 .03 ( 1–1.05 ) 0 .022 CHA 2 DS 2 VASc ( for each point ) 1 .23 ( 1.08–1.4 ) 0 .002 1 .1 ( 0.95–1.29 ) 0 .197 HASBLED ( for each point ) 0 .87 ( 0.69–1.1 ) 0 .245 1 .4 ( 1.09–1.78 ) 0 .008 Persistent vs paroxysmal AF 1 .02 ( 0.69–1.5 ) 0 .917 0 .86 ( 0.58–1.27 ) 0 .451 Permanent vs paroxysmal AF 1 .60 ( 1.09–2.33 ) 0 .016 0 .88 ( 0.58–1.32 ) 0 .526 Dyslipidemia 0 .94 ( 0.69–1.26 ) 0 .663 1 .11 ( 0.81–1.54 ) 0 .510 Peripheral artery disease 0 .96 ( 0.69–1.34 ) 0 .807 1 .67 ( 1.15–2.43 ) 0 .007 Previous major bleedings 1 .37 ( 0.93–2.02 ) 0 .108 1 .43 ( 0.97–2.11 ) 0 .069 Antiplatelet therapy 1 .43 ( 1.02–2.00 ) 0 .038 0 .69 ( 0.48–0.98 ) 0 .038 AF, atrial fibrillation; LAA, left atrial appendage; OAT, oral anticoagulant therapy. ( i p i s f i u c h v l M t w i B i a a r P A s w a ( t t i w i b f T a F s c l ( t t v r v o c t 0 h p N y a e D T t d p d t p Deaths in the warfarin and no-OAT and cohorts were 67/114 58.8% ) and 94/148 ( 63.5% ) , respectively. Cardiovascular events n patients taking warfarin were 68/114 ( 59.6% ) and those in atients not taking OAT 77/148 ( 52.1% ) . A table comparing causes of death in the three cohorts s shown as supplementary material ( Table S4 , see online upplementary material ) . Death from cachexia was more requent in patients who did not undergo the procedure than n the LAA occlusion cohort ( P = 0.021 ) . Cox regression models showed lower mortality in patients ndergoing LAA occlusion as compared with both the Warfarin ohort ( HR 0.60; 95%CI 0.38–0.94; P = 0.027 ) and no-OAT co- ort ( HR 0.52; 95%CI 0.34–0.78; P = 0.002 ) . Age, CHA 2 DS 2 VASc alue, presence of permanent AF, and taking antiplatelet at base- ine were all factors associated with reduced survival ( Table 3 , odel 1 ) . Cardiovascular events occurred less frequently in patients in he LAA occlusion cohort as compared with both patients taking arfarin ( HR 0.38; 95%CI 0.23–0.62; P < 0.001 ) and those not tak- ng OAT ( HR 0.45; 95%CI 0.29–0.70; P < 0.001 ) . Dialysis age, HAS- LED value, and presence of peripheral artery at baseline were ndependently associated with cardiovascular events. There was n inverse correlation between cardiovascular events and age nd antiplatelet assumption at baseline ( Table 3 , Model 2 ) . Sensitivity analysis performed after weighting confirmed the esults ( Table S5 , see online supplementary material ) . ost–procedural antithrombotic therapy and bleeding fter the procedure, the percentage of patients who were pre- cribed two-drug therapy ( two antiplatelet in the 93.5% of cases ) as 77/106 patients ( 72.6% ) . The prescription of two-drug ther- py ranged from 1 month ( 21% ) , to 3 months ( 40% ) , to 6 months 27% ) . Twenty-seven patients ( 25.5% ) were prescribed one-drug herapy ( one antiplatelet in 88.9% of cases ) and 2 ( 1.9% ) did not ake antithrombotic therapy. Of the 14 episodes of major bleed- ng observed in the follow-up, five ( 36% ) occurred in patients ho were taking a two-drug therapy, nine ( 64% ) in patients tak- ng only one drug, and 0 ( 0% ) in those not taking antithrom- otic therapy. No patients developed device thrombosis during ollow-up. hromboembolic and hemorrhagic events expected nd observed igure 2 shows the thromboembolisms and major bleedings ob- erved in the cohorts compared with the expected events ac- ording to the CHA 2 DS 2 VASC ( A ) and HASBLED ( B ) score value. Thromboembolic events in the LAA occlusion cohort were ower than expected according to the CHA 2 DS 2 VASC score ( 1.7 95%CI 0.3–3.0 ) vs 6.7 events per 100 person/years ) . The observed hromboembolic events were lower than those expected in both he Warfarin cohort and in the No-OAT cohort ( 2.9 ( 95% CI 0–24.7 ) s 8.1, and 4.9 ( 95% CI 0–17.7 ) vs 8.4 events per 100 person/years, espectively ) ( Fig. 2 A ) . However, the wide confidence inter- als did not allow to observe a significant difference between bserved and expected events except for the LAA occlusion ohort ( P < 0.001 ) . Hemorrhagic events in the LAA occlusion cohort were lower han expected according to the HASBLED score [4.1 ( 95% CI –18.2 ) vs 7.7 events per 100 person/years], while they were igher in the Warfarin cohort [11.1 ( 95% CI 0–27.3 ) vs 7.3 events er 100 person/years] and similar to the expected ones in the o-OAT cohort [7.4 ( 95% CI 0–17.7 ) vs 7.8 events per 100 person/ ears] ( Fig. 2 B ) . The high confidence intervals did not llow to observe a significant difference between observed and xpected events. ISCUSSION he study shows that LAA occlusion is associated with a long- erm reduction in thromboembolic events in a population of ialysis patients with AF. This evidence comes both from com- aring patients undergoing the procedure with two cohorts of ialysis patients with AF, one taking warfarin and the other not aking OAT, and from the analysis of actually observed and ex- ected events according to the CHA 2 DS 2 VASc score. https://academic.oup.com/ckj/article-lookup/doi/10.1093/ckj/sfad221#supplementary-data https://academic.oup.com/ckj/article-lookup/doi/10.1093/ckj/sfad221#supplementary-data https://academic.oup.com/ckj/article-lookup/doi/10.1093/ckj/sfad221#supplementary-data https://academic.oup.com/ckj/article-lookup/doi/10.1093/ckj/sfad221#supplementary-data https://academic.oup.com/ckj/article-lookup/doi/10.1093/ckj/sfad221#supplementary-data https://academic.oup.com/ckj/article-lookup/doi/10.1093/ckj/sfad221#supplementary-data Left atrial appendage occlusion in hemodalysis patients 2689 Figure 2: Thromboembolisms and major bleedings observed in the three cohorts compared with the expected events according to the CHA 2 DS 2 VAS C ( A ) and HASBLED ( B ) score value. o p 1 a t t g c h a l f f L i i t d a h r p t e b s t s s i t m e o m s o b j r i c o f c r p m t s S L u i t E r s t a s b l c c q d t o b h y 8 c O t c t p a w a O w t e The study results are relevant because to date there is a lack f clear evidence that OAT, either VKAs or DOACs, has an im- act on the thromboembolic risk of ESKD patients with AF [ 8 – 0 ]. This is a nontrivial problem for clinicians dealing with a di- lyzed patient presenting with AF, as this is a population at high hromboembolic risk with a lack of clear indications on herapeutic prescribing from cardiology and/or nephrology uidelines. Our study suggests that, after correction for possible onfounding factors, over a long follow-up, LAA occlusion may ave greater efficacy than medical therapy in reducing strokes nd systemic thromboembolism. However, due to the relatively ow TTR ( 53% ) , it is possible that some of the patients taking war- arin, not being in therapeutic range, were not fully protected rom thromboembolic risk. The incidence of major bleeding in patients included in the AA occlusion cohort is significantly lower than that observed n patients taking warfarin. As expected, there were no signif- cant differences between bleeding in patients who underwent he procedure and those who were not taking antithrombotic rugs. Both total mortality and incidence of cardiovascular events re lower in the LAA occlusion cohort than in the other two co- orts. The finding is not easily explained, although it has al- eady been reported in other LAA occlusion populations with reserved renal function [ 23 ]. The incidence of mortality is ex- remely high in our population, as is that of cardiovascular vents. For each CHA 2 DS 2 VASc point, the risk of death increases y 23%, and the presence of permanent AF is significantly as- ociated with reduced survival. Some previous studies showed hat HD patients with AF treated with warfarin have longer urvival than those not taking VKAs [ 17 , 24 , 25 ]. Our results uggest that LAA occlusion may provide an additional benefit n reducing the risk of death in this population. It is possible hat nephrology patients who underwent LAA occlusion were ore closely followed, particularly for their cardiovascular dis- ases. It is likely that they performed more frequent cardiol- gy controls and that this interdisciplinary follow-up allowed ore effective treatment of their comorbidities. This under- cores the importance of close collaboration between nephrol- gists and cardiologists in the management of patients with oth kidney and heart disease. Although all analyses were ad- usted for observed potential confounding factors, we cannot ule out the possibility that the patients proposed by the treat- ng physicians for LAA occlusion were less frail than those in- luded in the other cohorts. This hypothesis is supported by the bservation that patients in the LAA occlusion cohort die less requently from cachexia than patients in Warfarin and No-OAT ohorts. It is difficult to compare the results of our study with al- eady published data. Prospective studies performed in dialysis atients who underwent LAA occlusion are very limited and al- ost all include too few patients ( three studies recruited fewer han 10 patients and one recruited 25 patients ) and events ( no troke or bleeding reported ) to provide a comparison [ 26 –28 ]. A panish group published a letter describing the experience of AA occlusion in 51 HD patients followed for a median follow- p of 246 days. During follow-up, one stroke, five cases of bleed- ng, and 10 deaths were observed. The letter does not report fur- her analysis of the population [ 29 ]. Other information regarding SKD patients who underwent the procedure is derived from ret- ospective registry studies that included patients with various tages of renal failure, including very few dialysis patients. From hese studies it would appear that the ESKD patients do not have higher incidence of strokes and bleeding than patients without evere CKD [ 30 , 31 ]. The number of major peri-procedural complications reported y us [ 15 ] and the other prospective studies [ 26 –28 ] is extremely ow. However, a large retrospective registry study described ex- ess in-hospital mortality in ESKD patients undergoing LAA oc- lusion compared with those without CKD or with CKD not re- uiring dialysis [ 32 ]. Because of the high risk of complications ue to invasive cardiology procedures, our strong suggestion is o entrust LAA occlusion in ESKD patients only to skilled cardi- logy teams. In the LAA occlusion cohort, the actually observed throm- oembolic events according to the CHA 2 DS 2 VASc score are igher than those expected ( 1.7 vs 6.7 events per 100 person/ ears ) . This is also the case in the cohort taking warfarin ( 2.9 vs .1 events per 100 person/years ) and, to a lesser extent, in the ohort not taking OAT ( 4.9 vs 8.4 events per 100 person/years ) . ne possible explanation could be that almost all of our pa- ients ( only two were peritoneal dialysis patients ) were periodi- ally treated with heparin, fractionated or low molecular weight, o prevent clot formation in the dialysis circuit. Therefore, these atients are at least partially uncoagulated three times a week, nd this could reduce their risk of developing thrombi, even hen they are not taking OAT. Frequent administration of hep- rin does not appear to expose patients in the cohort not taking AT to excess bleeding ( 7.4 vs 7.8, observed vs expected events ) , hile the risk of bleeding is higher than expected in HD pa- ients who are taking warfarin ( 11.1 vs 7.3, observed vs expected vents ) . Based on these observations, LAA occlusion could be a 2690 S. Genovesi et al . Figure 3: Proposed algorithm for thromboembolism prevention in hemodialysis patients with atrial fibrillation. Good OAT: patients taking VKA with TTR ≥65% or patients taking DOAC ( off-label situation in Europe ) ; Poor OAT: patients taking VKA with TTR < 65% or patients not taking OAT; DOAC: direct oral anticoagulant; OAT: oral anticoagulant therapy; TTR: time in therapeutic range; VKA: vitamin K antagonist. g p r o t w r i a c p O fi t s i o u t d d i v i b t m t w o i s a c I f e a c g f t b s f p S S A W e B M h o ( F T C A R t F S v i a c D S t o r C ( B t B e s r i ood option, as, without increased hemorrhagic risk, it would revent intra LAA thrombus formation in patients who are al- eady periodically taking an anticoagulant drug anyway, albeit ff label for AF. However, it should be emphasized that the pa- ient cohorts in which the CHA 2 DS 2 VASc and HASBLED scores ere created and validated did not include ESKD patients. Our esults raise the issue of the need to develop scores, also usable n dialysis patients with AF who have special and different char- cteristics from those of other AF populations. The choice of the type of post-procedure therapy in this frail ohort of patients is very hard. There is evidence that in dialysis atients, antiplatelet is an important risk factor for bleeding [ 33 ]. ur data show a high number of bleeding cases, especially in the rst three months after the procedure, when patients frequently ook double antiplatelet therapy, but also in patients taking a ingle antiplatelet. Because we observed no device thrombosis n our population, perhaps we could consider prescribing only ne antiplatelet and for a short period of time in dialysis patients ndergoing LAA occlusion. Although our results suggest that LAA occlusion is better han OAT for thromboembolic protection in HD patients, we o not think this evidence is enough to state that the proce- ure is indicated in all patients with ESKD and AF. In our opin- on, the decision should be made taking into account the indi- idual patient’s clinical situation. Although RCTs demonstrat- ng the efficacy of DOACs for the prevention of thromboem- olic events in HD population are still lacking, it is important hat further efforts be made in this direction. LAA occlusion re- ains an invasive procedure, and this is a factor that needs o be taken into account in a population as frail as the one e are talking about. A proposed algorithm for the treatment f HD patients with AF is shown in Fig. 3 . An important lim- tation of our study is that this is not a RCT, so the compari- on made between the LAA occlusion cohort and the Warfarin nd No-OAT cohorts, even if performed with a rigorous statisti- al criterion ( Cox model adjusted for possible confounders and PTW analysis ) may be biased, especially due to unobserved con- ounders. However, given that the only two RCTs designed to valuate the effect of the procedure in HD patients, Watch-AFIB nd STOP-HARM, were prematurely ended due to lack of re- ruitment ( 14 ) , we think that our results may be useful in sug- esting that ESKD patients with AF should not be precluded rom accessing a non-therapeutic alternative for the preven- ion of thromboembolic events, when OAT has been shown to e ineffective and unsafe in this population. Further evidence is till needed to confirm that LAA occlusion could be an answer or the unsolved problem of antithrombotic treatment in ESKD atients. UPPLEMENTARY DATA upplementary data are available at ckj online. CKNOWLEDGEMENTS e are grateful to Dr Jacopo Oreglia, Dr Mario Gaggiotti, Dr Fed- rica Ettori, Dr Roberto Palumbo, Prof. Francesca Viazzi, Dr Marco reschi, Dr Paolo Orselli, Dr GianMaria Iadarola, Dr Consuela azzucchelli, Dr Marco Contarini and Dr Stefano Bianchi for elping in the data collection. We thank the Ethics Committee f the Province of Monza and Brianza for approving the study LAAO-DIA, 17032016 ) . UNDING his work was supported by Italian Ministry of Health—Ricerca orrente. UTHORS’ CONTRIBUTIONS esearch idea and study design: S.G. and L.P.; data acquisi- ion: G.S., G.C., S.B., F.A., M.B., M.G., F.P., G.R., A.M., E.P., G.M., .A., M.A., A.G., G.DA., P.M., G.V.; Data analysis/interpretation: .G., L.P., P.R. and P.M.; Statistical analysis: L.P. and P.R.; Super- ision or mentorship: S.G. and P.M. Each author contributed mportant intellectual content during manuscript drafting and grees to be personally accountable for the individual’s own ontributions. ATA AVAILABILITY STATEMENT .G., L.P. and P.R. had full access to all of the data in the study and ake responsability for the integrity of the data and the accuracy f the data analysis. Please contact the corresponding author egarding data requests. ONFLICT OF INTEREST STATEMENT Honoraria for speaking at symposia or consultation ) . S.G.: oston Scientific; G.C.: Abbott Structural Heart, Boston Scien- ific, Lifetech; G.R.: Boston Scientific, Abbott Structural Heart, iosense, Medtronic, Biotronik, Hylomorph ; G.M.: Boston Sci- ntific; M.A.: Abbott Structural Heart, Medtronic, Edwards Life- ciences; P.M.: Abbott Vascular, Boston Scientific. 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Clin J Am Soc Nephrol 2009; 4 :1347–55. https:// doi.org/10.2215/CJN.00810209 This is an Open Access article distributed under the terms of the Creative icenses/by-nc/4.0/ ) , which permits non-commercial re-use, distribution, or commercial re-use, please contact journals.permissions@oup.com https://doi.org/10.1016/j.recesp.2021.07.016 https://doi.org/10.1016/j.ijcard.2016.01.003 https://doi.org/10.1007/s00392-020-01638-5 https://doi.org/10.1016/j.hroo.2021.08.002 https://doi.org/10.2215/CJN.00810209 https://creativecommons.org/licenses/by-nc/4.0/ mailto:journals.permissions@oup.com INTRODUCTION MATERIALS AND METHODS Left atrial appendage occlusion Data collection Statistical methods see supplementary material for extended statistical methods Sensitivity analysis RESULTS Thromboembolic and hemorrhagic events Mortality and cardiovascular events Post‑procedural antithrombotic therapy and bleeding Thromboembolic and hemorrhagic events expected and observed DISCUSSION SUPPLEMENTARY DATA ACKNOWLEDGEMENTS FUNDING AUTHORS’ CONTRIBUTIONS DATA AVAILABILITY STATEMENT CONFLICT OF INTEREST STATEMENT REFERENCES