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Randomized Trial of Surgical Left Atrial Appendage Closure: Protection Against Cerebrovascular Events

Open AccessPublished:June 28, 2022DOI:https://doi.org/10.1053/j.semtcvs.2022.06.012
      Following open-heart surgery, atrial fibrillation and stroke occur frequently. Left atrial appendage closure added to elective open-heart surgery could reduce the risk of ischemic stroke. We aim to examine if routine closure of the left atrial appendage in patients undergoing open-heart surgery provides long-term protection against cerebrovascular events independently of atrial fibrillation history, stroke risk, and oral anticoagulation use. Long-term follow-up of patients enrolled in the prospective, randomized, open-label, blinded evaluation trial entitled left atrial appendage closure by surgery (NCT02378116). Patients were stratified by oral anticoagulation status and randomized (1:1) to left atrial appendage closure in addition to elective open-heart surgery vs standard care. The primary composite endpoint was ischemic stroke events, transient ischemic attacks, and imaging findings of silent cerebral ischemic lesions. Two neurologists blinded for treatment assignment adjudicated cerebrovascular events. In total, 186 patients (82% males) were reviewed. At baseline, mean (standard deviation (SD)) age was 68 (9) years and 13.4% (n = 25/186) had been diagnosed with atrial fibrillation. Median [interquartile range (IQR)] CHA2DS2-VASc was 3 [2,4] and 25.9% (n = 48/186) were receiving oral anticoagulants. Mean follow-up was 6.2 (2.5) years. The left atrial appendage closure group experienced fewer cerebrovascular events; intention-to-treat 11 vs 19 (P = 0.033, n = 186) and per-protocol 9 vs 17 (P = 0.186, n = 141). Left atrial appendage closure as an add-on open-heart surgery, regardless of pre-surgery atrial fibrillation and oral anticoagulation status, seems safe and may reduce cerebrovascular events in long-term follow-up. More extensive randomized clinical trials investigating left atrial appendage closure in patients without atrial fibrillation and high stroke risk are warranted.

      Graphical Abstract

      Keywords

      Abbreviations:

      AF (atrial fibrillation), CABG (coronary artery bypass grafting), CeV (cerebrovascular events), CT (computed tomography), LAA (left atrial appendage), LAACS (left atrial appendage closure by surgery), MRI (magnetic resonance imaging), OAC (oral anticoagulation), SCI (silent cerebral ischemic), TIA (transient ischemic attack)
      Unlabelled image
      Cumulative incidence plot of cerebral events according to left atrial appendage closure.
      Central Message
      Randomized add-on surgical left atrial appendage closure seems safe and may prevent cerebrovascular events independently of atrial fibrillation and stroke risk in long-term follow-up.
      Perspective Statement
      Our findings add to the evolving evidence that surgical closure of the left atrial appendage seems safe and may prevent cerebrovascular events, even in patients without a history of atrial fibrillation or high stroke risk. Results from ongoing, larger RCTs are needed before guidelines – and clinical practice – can be changed.

      INTRODUCTION

      Background

      Patients frequently experience atrial fibrillation (AF) after open-heart surgery, ranging from 35% after coronary artery bypass grafting (CABG) to 50% after mitral valve surgery, and have an increased risk of ischemic stroke in the range of 1-5% per year.
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      New onset postoperative atrial fibrillation is associated with a long-term risk for stroke and death following cardiac surgery.
      Secondly, patients with AF after surgery have a several-fold higher risk for a later recurrence of AF, alongside a substantial risk for long-term adverse outcomes, including stroke.
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      Consequently, recent guidelines recommend that long-term OACs should be considered in the presence of paroxysmal new-onset postoperative AF.
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      There are many possible reasons for SCI lesions in the first months after cardiac surgery, but in the subsequent years, AF and embolisms are likely to cause new SCI lesions.
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      Since patients undergoing open-heart surgery are generally at high risk of AF, SCI lesions, and strokes, an appealing approach would be to close the LAA during surgery.
      • Dawson AG
      • Asopa S
      • Dunning J
      Should patients undergoing cardiac surgery with atrial fibrillation have left atrial appendage exclusion?.
      ,
      • Blackshear JL
      • Odell JA
      Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation.
      Current American and European guidelines recommend that LAA exclusion may be considered in patients with AF undergoing heart surgery, though recognizing that evidence is still weak.
      • January CT
      • Wann LS
      • Calkins H
      • et al.
      2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation ACC/AHA TASK FORCE MEMBERS.
      ,
      • Hindricks G
      • Potpara T
      • Dagres N
      • et al.
      2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European association for cardio-thoracic surgery (EACTS).
      Recently, data from the largest randomized clinical trial to date, LAAOS-III, reported a reduced risk of thromboembolism in patients with AF and CHA2DS2-VASc ≥2 receiving concomitant LAA closure.
      • Whitlock RP
      • Belley-Cote EP
      • Paparella D
      • et al.
      Left atrial appendage occlusion during cardiac surgery to prevent stroke.
      In 2018, we published the first randomized study indicating that surgical closure of the LAA prevents CeV events independently of pre-surgery AF status and CHA2DS2-VASc score.
      • Park-Hansen J
      • Holme SJV
      • Irmukhamedov A
      • et al.
      Adding left atrial appendage closure to open heart surgery provides protection from ischemic brain injury six years after surgery independently of atrial fibrillation history: The LAACS randomized study.
      Although encouraging, the sample size of the study was too small to support a change in guidelines. Here we report the long-term follow-up of that trial to determine if the protective effect of systematic LAA closure persists up to 10 years after surgery.

      METHODS

      Trial Design and Setting

      The left atrial appendage closure by surgery (LAACS) study methods have previously been described (NCT023781167; https://doi.org/10.1186/s13019-018-0740-7).
      • Park-Hansen J
      • Holme SJV
      • Irmukhamedov A
      • et al.
      Adding left atrial appendage closure to open heart surgery provides protection from ischemic brain injury six years after surgery independently of atrial fibrillation history: The LAACS randomized study.
      Briefly, the LAACS study was the first prospective, randomized, open-label, blinded evaluation trial to investigate the effect of routine LAA closure concomitant to elective first-time open-heart surgery in both patients with – and without – a history of AF (Supplemental Table 1). Important exclusion criteria were off-pump surgery, planned LAA closure, and planned ablation (Supplemental Table 1). Patients were stratified by OAC status and randomized to LAA closure vs standard care (open LAA) (1:1) just prior to surgery (Video Abstract). The protocol recommended LAA closure by double closure, ie, with purse string and running suture; however other closure methods were applied at the surgeons’ discretion. Beyond closure of the LAA or control, patients were managed according to general practice without restrictions on the preferred use of medications for anticoagulation, rhythm control, or conversion procedures. The study was conducted from August 2010 to September 2015 at the Departments of Cardiac Surgery, Copenhagen University Hospital, Gentofte and Rigshospitalet, Copenhagen, Denmark.
      In the current patient chart review (performed October 2020), we registered new-onset stroke (including TIA) and new abnormal cerebral magnetic resonance imaging (MRI)/computed tomography (CT) scans with new SCI lesions. In addition, we registered recurring or new-onset AF or atrial flutter, current medications (rhythm and frequency modulators and OACs defined as vitamin-K antagonists or direct oral anticoagulants), and death. The study has been approved by the Danish Data Protection Agency (BFH-2017-112) and the Danish Patient Safety Authority (31-1521-87). All procedures followed are in accordance with the ethical standards of the Helsinki Declaration and with patients’ informed consent.

      Outcomes

      Primary (composite) endpoint:
      • (i)
        Clinical stroke events (including TIA, ie, symptoms of stroke lasting <24 hours), with or without relevant lesions on CT/MRI scan, and SCI (ie, asymptomatic fresh lesion on cerebral CT/MRI scans or new-onset non-fresh lesion in patients with multiple scans). Both ischemic and hemorrhagic events are included.
      Secondary endpoints:
      • (i)
        Clinical stroke events (including TIA) and thrombolytic therapy with complete remission. Both ischemic and hemorrhagic events are included.
      • (ii)
        All-cause mortality.
      • (iii)
        Occurrence or recurrence of AF.
      Two senior neurologists blinded for treatment assignment adjudicated the neurological events. The adjudicators evaluated anonymized reports based on patient charts, including cerebral CT or MRI scans performed in the clinical setting. In case of discrepancy, the events were assigned by consensus. SCI lesions are included in the primary outcome due to the assumption that these asymptomatic lesions are signs of thromboembolisms associated with AF and have an assumed origin in the LAA.
      • Das RR
      • Seshadri S
      • Beiser AS
      • et al.
      Prevalence and correlates of silent cerebral infarcts in the Framingham offspring study.
      ,
      • Smith EE
      • Saposnik G
      • Biessels GJ
      • et al.
      Prevention of stroke in patients with silent cerebrovascular disease: A scientific statement for healthcare professionals from the American heart association/American stroke association.
      Thus, we expected that the frequency of new SCI lesions could be reduced by LAA closure. Consulting cardiologists evaluated the cardiological events in the clinical setting.

      Statistical Analyses

      All primary analyses were performed on both intention-to-treat (ITT) and per-protocol (PP) basis. Study participation will be considered complete at the occurrence of the primary endpoint or follow-up until October 31, 2020. The exposure time will be calculated as the time between randomization and event (stroke including TIA), the date of death, the date of the last study visit, the date of withdrawal or loss to follow-up, whichever comes first. Cumulative incidence curves in Aalen-Johansen plots with death as a competing risk will be used for primary analyses. Gray's test will be used to test group differences. Cause-specific Cox regression is used to estimate hazard ratios (HR) and 95% confidence intervals when comparing primary and secondary neurological outcomes between randomization groups. Kaplan-Meier plots and Cox proportional-hazards models will be used to calculate HRs and 95% confidence intervals to compare mortality rates in the 2 study groups. The proportional hazard assumption was tested graphically by stratified Cox models and cumulative residuals. Risk ratios will be calculated for AF recurrence, and a comparison of postoperative AF vs non-postoperative AF groups will be performed by the Pearson Chi-Squared test. Shapiro-Wilk test will be applied to test for normality. Continuous variables will be presented as either mean (±standard deviation) or median (interquartile range). Continuous variables will be compared by t tests or Wilcoxon signed-rank tests as applicable. Categorical variables will be presented as frequency (percentages) and compared by Chi-Squared tests. RStudio (Version 1.1.463, Boston, MA) is used for statistical analyses Figure 1.
      Figure 1
      Figure 1Presents a concise visual summary of the study.

      RESULTS

      Demographics and Clinical Data

      The patient flowchart is displayed in Figure 2. We reviewed electronic patient charts from 186 patients (82% males). At study entry, mean age was 68 (9) years, 13.4% (n = 25/186) had been diagnosed with AF, median [IQR] CHA2DS2-VASc score was 3 [2,4], and 25.9% (n = 48/186) were receiving OACs. Mean follow-up was 6.2 (2.5) years yielding a total of 1159 person-years. There were 634 years of observation in the LAA closure group and 525 years in the control group. Randomization groups were comparable on all parameters (Table 1). At study-end, an overall 29.5% (n = 55/186) received OACs, and 4.3 (n = 6/186) were in dual therapy with direct oral anticoagulation and acetylsalicylic acid or clopidogrel (Supplemental Table 2). The recommended primary closure method was double closure with running suture and purse-string. LAA closure was primarily performed by suture (>95%). In a sample of ten patients, transesophageal echocardiography was performed at a mean of 524 days postoperatively, finding all LAA closures complete.
      Figure 2
      Figure 2Patient flowchart displays the flow of patients throughout the study. LAA (Left atrial appendage).
      Table 1Demographics and Clinical Data According to Randomization
      VariableLevelRandomized to Open LAA
      LAA (Left atrial appendage).
      (n = 86)
      Randomized to Closed LAA
      LAA (Left atrial appendage).
      (n = 100)
      P-value
      Age (y)mean (sd)69.5 (8.7)67.2 (9.5)0.092
      Sexfemale11 (12.8)18 (18.0)
      male75 (87.2)82 (82.0)0.439
      AF at baselineno72 (88.9)82 (83.7)
      yes9 (11.1)16 (16.3)0.432
      CHA2DS2-VAScmedian (IQR)3 [2,4]3 [2,4]0.934
      Surgery typeCABG
      CABG (coronary artery bypass graft).
      40 (46.5)50 (50.0)
      mitral valve6 (7.0)11 (11.0)
      other
      Other surgery (other valve surgery with or without CABG).
      40 (46.5)39 (39.0)0.461
      Anticoagulation at dischargeno65 (75.6)72 (72.7)
      yes21 (24.4)27 (27.3)0.784
      Postoperative AF
      AF (atrial fibrillation).
      no44 (51.2)62 (62.0)
      yes42 (48.8)38 (38.0)0.180
      Recurring AF*no38 (47.5)46 (49.5)
      yes42 (52.5)47 (50.5)0.916
      Follow-up time (y)mean (sd)6.1 (2.5)6.3 (2.5)0.525
      Continuous variables are presented as mean (±standard deviation) or median (interquartile range) as application. Mean values are compared by t tests and median values by Wilcoxon signed-rank test. Categorical variables are presented as frequency (percentages) and compared by Chi-Squared tests.
      low asterisk AF (atrial fibrillation).
      CABG (coronary artery bypass graft).
      LAA (Left atrial appendage).
      § Other surgery (other valve surgery with or without CABG).

      Primary Outcome

      Stroke, Transient Ischemic Attack, and Silent Cerebral Ischemic Lesions

      In the ITT analysis (n = 186), 22.1% (n = 19/86) of patients experienced a primary event in the control group vs 11.0% (n = 11/100) in the LAA closure group. Event rates were 1.7 per 100 person-years in the LAA closure group and 3.6 per 100 person-years in the control group. The cumulative incidence curve was significantly lower for the LAA closure group compared with the control group (P = 0.033) (Fig. 3). Randomization to LAA closure reduced the risk ratio of a primary event occurrence by 53% (HR 0.46 [0.22-0.98], P = 0.043). In the PP analysis (n = 141), 22.1% (n = 17/77) experienced an event in the control group vs 14.1% (n = 9/64) in the LAA closure group (Supplemental Figure 1) (P = 0.186). A breakdown of events is seen in Table 2. There were no differences in the absolute numbers of ischemic and hemorrhagic strokes between treatment groups.
      Figure 3
      Figure 3Primary outcome according to randomization (intention-to-treat) displays the cumulative incidence of the primary outcome according to randomization in an intention-to-treat analysis. The figure shows an Aalen-Johansen plot with death as a competing risk. Gray's test is used for group comparison. Shading specifies 95% confidence intervals. Fewer primary events are seen in patients with closed LAA (P = 0.033) (solid red curve) vs open LAA (dotted grey curve). LAA closure provides protection again cerebrovascular events up to 10 years after surgery. LAA (Left atrial appendage). (Color version of figure is available online.)
      Table 2Absolute Number of Events According to Randomization
      EventRandomized to Open LAA
      LAA (left atrial appendage).


      (n = 86)
      Randomized to Closed LAA
      LAA (left atrial appendage).
      (n = 100)
      P-value
      Stroke4 (4.7)7 (7.0)0.715
      TIA
      TIA (transient ischemic attack).
      8 (9.3)3 (3.0)0.132
      SCI
      SCI (silent cerebral ischemic lesions).
      7 (8.1)1 (1.0)0.042
      Categorical variables are presented as frequency (percentages) and compared by Chi-Squared tests.
      low asterisk TIA (transient ischemic attack).
      SCI (silent cerebral ischemic lesions).
      LAA (left atrial appendage).

      Secondary Outcomes

      Stroke and Transient Ischemic Attack

      In the ITT analysis, 15.1% (n = 13/86) of patients experienced an event in the control group vs 10.0% (n = 10/100) in the LAA closure group. Event rates were 1.6 per 100 person-years in the LAA closure group and 2.6 per 100 person-years in the control group. The cumulative incidence curves did not differ (P = 0.252) (Fig. 4). Randomization to LAA closure did not reduce the risk ratio for the occurrence of symptomatic stroke and TIA (HR 0.62 [0.27-1.43] (P = 0.267)). In the PP analysis, 15.6% (n = 12/77) of patients experienced an event in the control group vs 12.5% (n = 8/64) in the LAA closure group (Supplemental Figure 2) (P = 0.538). There were no differences in the absolute numbers of ischemic and hemorrhagic strokes between treatment groups.
      Figure 4
      Figure 4Secondary outcome according to randomization (intention-to-treat) displays the cumulative incidence of the secondary neurological outcome, that is, symptomatic stroke including TIA events and patients who undergo thrombolytic therapy with complete remission, according to randomization in an intention-to-treat analysis. The figure shows an Aalen-Johansen plot with death as a competing risk. Gray's test is used for group comparison. Shading specifies 95% confidence intervals. The cumulative incidence rates do not differ significantly (P = 0.252) between closed LAA (ie, left atrial appendage) (solid red curve) vs open LAA (dotted grey curve). LAA closure might prevent symptomatic stroke/TIA events, but the sample size is too small to give definite answers. LAA (Left atrial appendage), TIA (Transient ischemic attack). (Color version of figure is available online.)

      Safety Analyses

      In the ITT analysis, we observed 24 (27.9%) vs 23 (23.0%) deaths for control and LAA closure groups, respectively. For the PP analysis, deaths were 20 (26.0%) vs 15 (23.4%), respectively. Neither the Kaplan-Meier nor (Supplemental Figures 3 and 4) the Cox regression indicated an effect of LAA closure, that is, HR 0.78 [0.44;1.39] (P = 0.401) in the ITT analysis and HR 0.84 [0.43;1.64] (P = 0.608) in the PP analysis. The effect of LAA closure did vary in a time-dependent manner. We observed no cases of cardiac ischemia due to the involvement of coronary arteries after LAA closure. Cumulative incidence curves of the primary outcome stratified by randomization and high vs low or moderate CHA2DS2-VASc score were produced. The CHA2DS2-VASc score had a nonsignificant association with the outcome in both ITT and PP analyses (P = 0.059 and P = 0.211, respectively) (Supplemental Figures 5 and 6).

      New-Onset and Recurrent Atrial Fibrillation

      At baseline, 13.4% (n = 25/186) had been diagnosed with AF. Among both patients with and without known AF at baseline, 45.1 % (n = 78/173) developed postoperative AF, and 75.6% (n = 59/78) of those experienced AF recurrence during a mean follow-up of ∼6 years (Supplemental Table 3a). The estimated risk ratio for recurring AF in the presence of postoperative AF was 2.8 (P< 0.001), independent of AF status before surgery.
      Concerning the sub-group of patients without baseline AF, 37.2 % (n = 54/145) developed postoperative AF, and 70.4% (n = 38/54) of those experienced a later AF recurrence (Supplemental Table 3b). The estimated risk ratio for recurring AF in the presence of postoperative AF in patients without known AF was 2.3 (P < 0.001).

      Subgroup Analyses of Patients Without AF at Baseline

      In the subgroup of 154 patients without AF at baseline, 22.2% (n = 16/72) in the control group and 13.4 (n = 11/82) in the LAA closure group experienced a primary outcome (ITT), and 16.7% (n = 12/72) and 12.2 (n = 10/82) a secondary outcome (ITT). Supplemental Figures 7 and 8 show cumulative incidence curves according to ITT and PP analyses of patients without AF at baseline (Gray's test: P = 0.124 and P = 0.476, respectively). Supplemental Figures 9 and 10 show the Kaplan-Meier plots by ITT and PP analyses. Cox regression did not indicate an effect of LAA closure, that is, HR 0.72 [0.35;1.47] (P = 0.366) in the ITT analysis and HR 0.84 [0.38;1.86] (P = 0.663) in the PP analysis.

      DISCUSSION

      Main Findings

      In total, 186 patients (82% males) from the LAACS trial were followed for up to 10 years after randomization to LAA closure vs control. At baseline, mean age was 68 (9) years, 13.4% (n = 25/186) had been diagnosed with AF, CHA2DS2-VASc score was 3 [2,4] and 25.9% (n = 48/186) were receiving OACs. Patients in the LAA closure group had significantly fewer new CeV events (11.0% vs 22.1%) and a trend toward fewer new clinical stroke and TIA events (10.0% vs 15.1) compared with the control group.

      Systemic Thromboembolisms After LAA Closure

      Recently, the randomized clinical trial, LAAOS-III, showed a 33% risk reduction of stroke, including systemic embolisms in patients with AF, CHA2DS2-VASc score ≥2 (mean 4.2), and ∼75% concomitantly treated with OACs after an average follow-up time of 3.8 years (HR, 0.67 [0.53;0.85], P = 0.001).
      • Whitlock RP
      • Belley-Cote EP
      • Paparella D
      • et al.
      Left atrial appendage occlusion during cardiac surgery to prevent stroke.
      An observational, retrospective study of 4210 patients with AF undergoing CABG surgery found a 26% lower thromboembolic risk for patients with concomitant LAA closure over 1-year mean follow-up, but not on isolated ischemic stroke risk.
      • Soltesz EG
      • Dewan KC
      • Anderson LH
      • et al.
      Improved outcomes in CABG patients with atrial fibrillation associated with surgical left atrial appendage exclusion.
      A large, retrospective cohort study of patients with AF older than 65 years reported a 33% lower thromboembolic risk (sHR. 0.67 [0.79;0.97], P = 0.001) among mixed cardiac surgeries with concomitant LAA.
      • Friedman DJ
      • Piccini JP
      • Wang T
      • et al.
      Association between left atrial appendage occlusion and readmission for thromboembolism among patients with atrial fibrillation undergoing concomitant cardiac surgery.
      Caliskan et al. presented results from a prospective cohort study of patients with concurrent LAA closure, where a lower rate of thromboembolic events was observed compared with a cohort of patients with similar stroke risk and follow-up time.
      • Caliskan E
      • Sahin A
      • Yilmaz M
      • et al.
      Epicardial left atrial appendage AtriClip occlusion reduces the incidence of stroke in patients with atrial fibrillation undergoing cardiac surgery.
      The abovementioned studies align with findings from the current study indicating a protective effect of concomitant LAA closure for patients undergoing open-heart surgery. Limited studies have found contrasting evidence, but in a propensity-matched cohort of 461 pairs, LAA closure did not affect the rate of stroke.
      • Melduni RM
      • Schaff HV
      • Lee H-CC
      • et al.
      Impact of left atrial appendage closure during cardiac surgery on the occurrence of early postoperative atrial fibrillation, stroke, and mortality: A propensity score-matched analysis of 10 633 patients.
      As evident, most studies have focused on patients either with a history of AF or a high stroke risk (high CHA2DS2-VASc score). The use of CHA2DS2-VASc to risk stratifies patients undergoing cardiac surgery for stroke seems suitable. The population is generally above 65 years of age, has at least 1 cardiovascular comorbidity, and has a high risk of AF in the years following surgery. All factors result in a high risk of stroke. Thus, one could argue that patients above 65 years undergoing cardiac surgery should have a stroke risk assessment performed and undergo considerations of anticoagulation therapy prior to surgery even though they are not known with AF. Nonetheless, the question of what to do in patients planned for open-heart surgery without AF or a low á priori stroke risk remains unanswered. Our data support that postoperative AF is frequent and followed by a high recurrence rate in this population.
      • Ahlsson A
      • Fengsrud E
      • Bodin L
      • et al.
      Postoperative atrial fibrillation in patients undergoing aortocoronary bypass surgery carries an eightfold risk of future atrial fibrillation and a doubled cardiovascular mortality.
      ,
      • Pillarisetti J
      • Patel A
      • Bommana S
      • et al.
      Atrial fibrillation following open heart surgery: Long-term incidence and prognosis.
      ,
      • Lee SH
      • Kang DR
      • Uhm JS
      • et al.
      New-onset atrial fibrillation predicts long-term newly developed atrial fibrillation after coronary artery bypass graft.
      Several studies have shown an elevated stroke risk related to new-onset postoperative AF,
      • Horwich P
      • Buth KJ
      • Légaré JF
      New onset postoperative atrial fibrillation is associated with a long-term risk for stroke and death following cardiac surgery.
      ,
      • Gialdini G
      • Nearing K
      • Bhave PD
      • et al.
      Perioperative atrial fibrillation and long-term risk of ischaemic stroke.
      ,
      • Lin MH
      • Kamel H
      • Singer DE
      • et al.
      Perioperative/postoperative atrial fibrillation and risk of subsequent stroke and/or mortality: A meta-analysis.
      and thus, there is an unmet need to investigate the efficacy and safety of LAA closure in this patient cohort. In the present study, the difference in outcome was mainly driven by fewer TIA events (3% vs 9%) and SCI lesions (1% vs 8%) in the LAA closure group compared with the control group. Both TIA and SCI lesions are well-known risk factors for future stroke.
      • Giles MF
      • Rothwell PM
      Transient ischaemic attack: Clinical relevance, risk prediction and urgency of secondary prevention.
      • Kang D-W
      • Han M-K
      • Kim H-J
      • et al.
      Silent new ischemic lesions after index stroke and the risk of future clinical recurrent stroke.
      • Due Andersen S
      • Skjøth F
      • Yavarian Y
      • et al.
      Multiple silent lacunes are associated with recurrent ischemic stroke.
      It is possible that with longer follow-up, the difference would increase. Our subgroup analyses of patients without prior AF did not differ between treatment groups. However, whether this is due to LAA closure not protecting against CeV in patients without prior AF or lack of power is yet to be determined. We believe our study adds to the concept that patients undergoing open-heart surgery have a beneficial effect of LAA closure regardless of prior AF status and CHA2DS2-VASc score. To provide definite answers, 2 randomized clinical trials, LAACS-2 (NCT03724318) and the LAA closure study (NCT02321137), are currently enrolling patients without pre-surgery AF. Moreover, in the case of the LAACS-2 study, also without restrictions on the CHA2DS2-VASc score.

      Complications, Readmissions, and Mortality After LAA Closure

      In line with the present study results, Whitlock et al. did not observe an increased risk of perioperative complications, myocardial infarction, heart failure, or major bleeding.
      • Whitlock RP
      • Belley-Cote EP
      • Paparella D
      • et al.
      Left atrial appendage occlusion during cardiac surgery to prevent stroke.
      Soltesz et al. report a lower hospital readmission rate and all-cause mortality for patients with concomitant LAA closure with the AtriClip device; however, this difference is likely explained by the lower rate of comorbidity in the intervention group.
      • Soltesz EG
      • Dewan KC
      • Anderson LH
      • et al.
      Improved outcomes in CABG patients with atrial fibrillation associated with surgical left atrial appendage exclusion.
      A retrospective cohort study of 10,000 patients with AF older than 65 years, investigating LAA closure concomitant to various types of cardiac surgery, observed a lower risk of readmission due to thromboembolisms during long-term follow-up (3 years).
      • Friedman DJ
      • Piccini JP
      • Wang T
      • et al.
      Association between left atrial appendage occlusion and readmission for thromboembolism among patients with atrial fibrillation undergoing concomitant cardiac surgery.
      These studies are in contrast with a large retrospective register study of 253,287 patients with AF undergoing isolated CABG, in which 7.0% had concomitant LAA closure and where they detected an increased risk of 30-day readmission (odds ratio, 1.64 [1.60;1.68], P < 0.001).
      • Mahmood E
      • Matyal R
      • Mahmood F
      • et al.
      Impact of left atrial appendage exclusion on short-term outcomes in isolated coronary artery bypass graft surgery.
      Unfortunately, the study lacks essential information on methods of LAA closure, success rate, and use of OACs. One could speculate that as current guidelines are vague and the use of LAA closure is up to surgeons’ discretion, the patients receiving concomitant LAA closure are those with a high risk of bleeding and used as an alternative to OACs.
      All-cause mortality was not affected by LAA closure in the LAAOS-III study (LAA closure group 538 (22.6%) vs control 537 (22.5%) (HR, 1.00 [0.89;1.13]), nor in the study by Melduni et al.
      • Melduni RM
      • Schaff HV
      • Lee H-CC
      • et al.
      Impact of left atrial appendage closure during cardiac surgery on the occurrence of early postoperative atrial fibrillation, stroke, and mortality: A propensity score-matched analysis of 10 633 patients.
      Soltesz et al. observed lower mortality in patients with concomitant LAA closure, possibly explained by a lower comorbidity burden.
      • Soltesz EG
      • Dewan KC
      • Anderson LH
      • et al.
      Improved outcomes in CABG patients with atrial fibrillation associated with surgical left atrial appendage exclusion.
      Mortality rates did not vary between treatment groups in our dataset.
      Finally, there was no sign of an increased stroke risk associated with surgical LAA closure, as Katz et al.
      • Katz ES
      • Tsiamtsiouris T
      • Applebaum RM
      • et al.
      Surgical left atrial appendage ligation is frequently incomplete: a transesophageal echocardiograhic study.
      suggested, where the primary concern was insufficient closure. In the LAACS trial, ten patients accepted transesophageal echocardiography following surgery with no sign of recanalization. In addition, no debilitating strokes with severe sequelae were observed in those with intended ligation. These results suggest that surgical LAA closure is a safe procedure if performed appropriately.

      Postoperative and Recurrent Atrial Fibrillation

      The frequencies of postoperative and recurrent AF were similar to previous reports,
      • Ahlsson A
      • Fengsrud E
      • Bodin L
      • et al.
      Postoperative atrial fibrillation in patients undergoing aortocoronary bypass surgery carries an eightfold risk of future atrial fibrillation and a doubled cardiovascular mortality.
      ,
      • Pillarisetti J
      • Patel A
      • Bommana S
      • et al.
      Atrial fibrillation following open heart surgery: Long-term incidence and prognosis.
      ,
      • Lee SH
      • Kang DR
      • Uhm JS
      • et al.
      New-onset atrial fibrillation predicts long-term newly developed atrial fibrillation after coronary artery bypass graft.
      further adding to evolving evidence that AF constitutes a major burden after cardiac surgery and postoperative AF is not necessarily an ephemeral event. Unfortunately, data on AF types, burden, and conversion treatment are unavailable in the present study. Recent studies have utilized continuous cardiac rhythm monitoring and describe late recurrent AF as primarily paroxysmal, self-limiting events.
      • Bidar E
      • Zeemering S
      • Gilbers M
      • et al.
      Clinical and electrophysiological predictors of device-detected new-onset atrial fibrillation during 3 years after cardiac surgery.
      ,
      • Charitos EI
      • Herrmann FEM
      • Ziegler PD
      • et al.
      Atrial fibrillation recurrence and spontaneous conversion to sinus rhythm after cardiac surgery: Insights from 426 patients with continuous rhythm monitoring.

      Limitations

      The main limitation is the moderate sample size with many cross-over cases at a single center. The study included patients undergoing various types of surgery, with and without prior AF, and various degrees of comorbidity at baseline, leading to potential biases. Nevertheless, the stratification for preoperative use of anticoagulation and subsequent randomization provided an even distribution of patients in each treatment group, reducing the risk of bias. Unrecognized confounders may be applicable even in a well-balanced randomized clinical trial. Furthermore, surgeons predominantly performed LAA closure by suture, but the closure method was not always documented in detail in the patient files and cannot be reported. Closures were controlled and deemed sufficient in a sample of ten patients, but undiagnosed incomplete LAA closures might have occurred and attenuated the LAA closure effect. Nonetheless, despite the small sample size, we observed an effect of LAA closure in this long-term follow-up data. Logistical challenges resulted in many protocol deviations, potentially diminishing the effect of randomization. Nevertheless, ITT and PP analyses were comparable and consistent throughout the follow-up period. Additional study-specific long-term follow-up cerebral CT/MRI scans were not performed, potentially leading to a lower event rate in both groups. In addition, the primary outcome included both ischemic and hemorrhagic stroke. While the hemorrhagic transformation of ischemic stroke is relatively common, we cannot discern these cases from hemorrhagic strokes without an ischemic component, which may confound the outcome. The present data do not support LAA closure as a method of hemorrhagic stroke prevention. Lastly, while no patients have received surgical left atrial ablation or LAA exclusion during follow-up, percutaneous radiofrequency ablation procedures have not been registered. Despite the randomized study design, a possible bias cannot be discarded. Thus, results should be applied with caution to other populations.

      CONCLUSIONS

      Long-term follow-up data from the LAACS trial suggests that routine LAA closure in addition to open-heart surgery, regardless of AF history and OAC status, may reduce the long-term risk of postoperative CeV events. Importantly, we found no increase in stroke risk related to surgical LAA closure. The results warrant more extensive randomized trials to determine the effect of LAA closure on ischemic stroke, especially in patients without a history of AF and with an á priori low stroke risk.

      Supplementary Material

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      Linked Article

      • Commentary: Concomitant LAA Closure; A No-Brainer to Protect the Brain?
        Seminars in Thoracic and Cardiovascular Surgery
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          Settled science and unanswered questions. There has been a renewed interest in concomitant closure of the left atrial appendage (LAA) during open heart surgery. The paper by Madsen et al adds to that body of literature and addresses important questions.1 If a surgeon is performing a cardiac operation what is the risk, and long-term benefit, of closing the LAA? It has been reported that 90% of strokes in patients with atrial fibrillation (AF) originate in the LAA,2 and for many years surgeons have sought to obliterate the “most lethal attachment.”3 There have been 2 large retrospective registry reports, and a meta-analysis, that investigated this question and concluded that there is little risk (with the caveat that surgeons must be aware of, and careful to avoid, the potential for bleeding and circumflex coronary artery injury), with statistically and clinically important benefits.
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