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Abstract
Objective There is limited evidence regarding the effectiveness of left atrial appendage (LAA) closure during surgical ablation of atrial fibrillation (AF) in yielding superior clinical outcomes. This study aimed to evaluate the association of LAA closure versus preservation with the risk of adverse clinical outcomes among patients undergoing surgical ablation during cardiac surgery.
Methods We evaluated 1640 patients (aged 58.8±11.5 years, 898 women) undergoing surgical ablation during cardiac surgery (including mitral valve (MV), n=1378; non-MV, n=262) between 2001 and 2018. Of these, 804 had LAA preserved, and the remaining 836 underwent LAA closure. Comparative risks of stroke and mortality between the two groups were evaluated after adjustments with inverse-probability-of-treatment weighting (IPTW). Longitudinal echocardiographic data (n=9674, 5.9/patient) on transmitral A-wave and E/A-wave ratio were analysed by random coefficient models.
Results Adjustment with IPTW yielded patient cohorts well-balanced for baseline profiles. During a median follow-up of 43.5 months (IQR 19.0–87.3 months), stroke and death occurred in 87 and 249 patients, respectively. The adjusted risk of stroke (HR 0.85; 95% CI 0.52–1.39) and mortality (HR 0.80; 95% CI 0.61 to 1.05) did not differ significantly between the two groups. Echocardiographic data demonstrated higher transmitral A-wave velocity (group-year interaction, p=0.066) and lower E/A-wave ratio (group-year interaction, p=0.045) in the preservation group than in the closure group.
Conclusions LAA preservation during surgical AF ablation was not associated with an increased risk of stroke or mortality. Postoperative LA transport functions were more favourable with LAA preservation than with LAA closure.
- atrial fibrillation
- stroke
- cardiac surgical procedures
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
The closure of left atrial appendage (LAA) has been advocated for an effective strategy for stroke reduction in the surgical treatment of atrial fibrillation (AF); however, there is limited evidence regarding the effectiveness of LAA closure in the dedicated setting of surgical AF ablation.
WHAT THIS STUDY ADDS
In this study, the long-term risks of stroke and mortality according to LAA preservation versus closure were evaluated in patients with AF undergoing surgical ablation concomitant to cardiac surgery.
The risk of stroke (HR 0.85; 95% CI 0.52 to 1.39) and mortality (HR 0.80; 95% CI 0.61 to 1.05) did not significantly differ between patients with LAA preservation and closure.
Left atrial transport function was more favourable with LAA preservation.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
These study findings argue against the indiscriminate routine exclusion of LAA in the dedicated setting of surgical ablation.
Randomised controlled trials are necessary to offer definitive evidence on this issue.
Introduction
Left atrial appendage (LAA) is the main site of thrombus formation in the presence of atrial fibrillation (AF), which predisposes patients to ischaemic embolic stroke. Exclusion of the LAA has been advocated as an effective prevention strategy for stroke in the surgical treatment of AF, and recommended in the current guidelines,1–3 and also frequently performed even in the absence of AF.4–8
Several recent studies, however, have raised counterarguments that LAA closure may lead to a loss of inherent functions of the LAA such as reservoir and contractile capacities, with resultant adverse impacts on postoperative outcomes.9 10 As surgical ablation (SA) of AF reportedly offers excellent efficacy in eliminating AF and restoring effective atrial contraction, concerns surrounding the LAA as a thromboembolic source may be negated in the majority of these patients.11 12 In this regard, indiscriminate LAA closure may not be an optimal strategy in the setting of SA.
Due to a paucity of data from randomised controlled trials (RCTs),13 the decision on how to manage the LAA during SA depended on expert opinions and several large-scale observational studies. However, such studies may have limitations, including heterogeneous cohorts with a varying prevalence of AF and SA.4 5 Accordingly, potential mixed associations of LAA closure with several key factors may have obscured the true clinical effect of LAA closure. Therefore, we analysed the association of LAA preservation versus closure with the risk of stroke and mortality in a more homogenous setting of concomitant SA during cardiac surgery, taking relevant clinical factors into account in a reasonably sized cohort. We also analysed postoperative atrial functions through serial echocardiographic data depending on LAA preservation versus closure.
Methods
Study cohort
We examined the institutional cardiac surgery database to identify consecutive adult patients (≥18 years) with AF who underwent SA concomitantly to cardiac surgery from January 2001 to December 2018. We excluded patients including those with evidence of LAA thrombus to form a homogenous cohort with reasonable comparability (figure 1).
Study flow chart. AF, atrial fibrillation; LAA, left atrial appendage; TEE, trans-oesophageal echocardiography.
During the study period, the decision to perform LAA preservation versus closure was influenced by several factors including the estimated risk of stroke and postoperative ablation failure, surgical access and operating surgeons’ preference.
Surgical procedure and postoperative management
The LAA was closed by (1) excising the LAA, either by a cut-and-sew method or by stapling (resection), (2) ligating the endocardial surface of the LAA orifice (endocardial closure) or (3) using an LA occlusion clip in cases with minimally invasive approach since 2016. AF was ablated in either the left atrial or biatrial lesions.14 The decision to perform left atrial or biatrial ablation was based on the AF burden, right heart disease and the surgeon’s preference.15 16
The postablation arrhythmia was monitored daily with 12-lead ECG and single-lead ECG tracing >30 s during hospitalisation. A 24-hour Holter monitoring was usually performed before hospital discharge. After discharge, arrhythmia was mainly monitored with ECG every 3–6 months at the outpatient clinic visit, and 24-hour Holter monitoring was performed annually to validate the AF-free status. Any episodes of AF, atrial flutter or tachyarrhythmia lasting ≥30 s after a 3-month blanking period were regarded as AF recurrence.17
As the guidelines3 18 did not indicate the general consensus regarding the anticoagulation strategy after SA, it has been determined primarily based on the use of mechanical valve, the estimated risk of thromboembolism and restoration of sinus rhythm.19 20 Warfarin was maintained permanently after mechanical valve replacement, and for 3–6 months after bioprosthetic valve replacement or valve repair with annuloplasty ring. Patients who underwent coronary bypass surgery or valve repair without prosthesis received anticoagulation with either warfarin or preferentially direct oral anticoagulant (OAC) for 3–6 months. The decision to discontinue anticoagulation thereafter was guided by an individual patient’s risk of thromboembolism and postoperative rhythm status.
Outcomes of interest and clinical follow-up
The primary outcome of interest was stroke. Stroke was defined as a newly developed neurological deficit postoperatively, which was demonstrated by imaging studies and confirmed by attending neurologists.21 For further measures, early postoperative complications (those occurring within 30 days of surgery), overall mortality and serial echocardiographic parameters that represent LAA contractile and left ventricular (LV) functions were evaluated.
Clinical follow-up data were obtained until April 2020. Patients without any episodes of stroke were censored at the end of the follow-up. Vital status was validated by the data from the National Population Registry of the Korea National Statistical Office.22
Patient and public involvement
Patients or the public were not involved in the design, conduct, reporting or dissemination plans of this study.
Statistical analysis
Descriptive statistics are presented as mean±SD or median with IQR for continuous variables and as counts (%) for categorical variables. Categorical variables were compared with χ2 test or Fisher’s exact test, and continuous variables were compared using Student’s t-test or Mann-Whitney U test based on the normality test.
The potential for selection bias between patients with LAA preservation and closure was addressed using inverse-probability-of-treatment weighting (IPTW) based on propensity score (PS) modelling. The PS was defined as the probability of a patient preserving the LAA conditional on baseline and operative profiles, and was estimated from the logistic regression analysis incorporating all covariates listed in table 1. The balance of the covariates was assessed by the standardised mean difference (SMD), in which a difference of <10% was considered to indicate a reasonable balance.
Baseline characteristics between left atrial appendage preservation versus mechanical closure groups
In the IPTW model, stroke events were analysed by using a competing risk model, with all-cause death accounting for a competing risk, and a subdistributional hazard function was generated by the Fine-Gray method. To address the effect of OAC on the stroke risk postoperatively, we performed a sensitivity analysis to assess the effect of LAA closure combined with OAC use during follow-up. For the assessment of mortality, Cox proportional hazard model was used to yield a hazard function; the proportional hazard assumption was tested with Schoenfeld residuals. The early postoperative outcomes were evaluated by using the logistic regression model. Subgroup analyses involving Fine-Gray and Cox models were performed according to the prespecified baseline profiles. As the efficacy of LAA closure can differ among various closure techniques, we generated two separate IPTW models for comparisons of preservation against ‘resection’ and ‘endocardial closure’ to account for the effect of each closure technique.
To evaluate the repeated measurements of echocardiographic parameters representing LAA contractile and LV function, we used random coefficient models over time according to the management of LAA with the fixed effect of time, group, interaction between time and group and the random effects of patients and interaction between patients and time. The relationships between time and these echocardiographic parameters were represented as a non-linear function using restricted cubic spline transformation of time.
All reported p values were two-sided, and p values <0.05 were considered statistically significant. R software, V.3.4.0 (R Foundation for Statistical Computing, Vienna, Austria) and SAS software V.9.4 (SAS Institute) were used for statistical analyses.
Results
Patient characteristics and operative profiles
During the study period, 2255 patients were identified to undergo SA combined with cardiac surgery at our institution. After excluding those who had an LAA thrombus (n=128) and the other exclusion criteria (n=487), 1640 patients were included in the final study population. The LAA was preserved in 804 patients, and 836 received LAA closure (figure 1). Among the patients with LAA closure, resection, endocardial closure and device closure were performed in 570, 189 and 77 patients, respectively (online supplemental table 1).
Supplemental material
Table 1 (left column) summarises the baseline characteristics between the two groups. The patients with LAA preservation, on average, were younger, and less commonly had persistent AF, chronic kidney disease and coronary artery disease than those with LAA closure. Further details on the operative profiles are presented in online supplemental table 2. Single procedure, valve replacement with mechanical prosthesis and minimally invasive cardiac surgery was more common in the patients with LAA preservation than in those with LAA closure.
Comparative clinical outcomes
IPTW adjustment yielded well-balanced cohorts for the baseline characteristics, with SMDs of <10% for all covariates in table 1 (right column). The incidence of adverse events and the outcomes of risk analyses are demonstrated in table 2, and the proportion of patients with OACs did not significantly differ between the two groups (online supplemental table 3). During a median follow-up of 43.5 months (IQR 19.0–87.3 months), stroke and death occurred in 87 (5.3%) and 249 (15.2%) patients, respectively. There was no significant difference in the risk of stroke between the two groups in either the crude or IPTW models (subdistributional HR (sHR) 0.85; 95% CI 0.52 to 1.39; p=0.512) (figure 2). When further adjusted with the use of OAC, the risk of stroke was still comparable between the two groups in the IPTW model (sHR 1.19; 95% CI 0.73 to 1.96; p=0.483). The risk of mortality also did not significantly differ in the IPTW model (table 2).
Early and overall clinical outcomes of the left atrial appendage preservation versus closure groups
Adjusted time-to-event curves for stroke (panel A) and all-cause death (panel B). sHR, subdistributional HR.
Subgroup analyses: ‘preservation versus resection’ and ‘preservation versus endocardial closure’
The ITPW models that compared the preservation group with the resection and endocardial closure subgroups are demonstrated in online supplemental table 4 and 5, respectively. In the comparison between the preservation and the resection subgroups (table 3), the risk of stroke was comparable in the crude and IPTW models. Of note, LAA preservation was associated with a decreased risk of mediastinal bleeding requiring exploration (OR 0.63; 95% CI 0.40 to 0.996; p=0.048) compared with LAA resection; however, the risk of bleeding originating from a site other than the LAA was comparable between the two groups (OR 0.71; 95% CI 0.45 to 1.13; p=0.149). In comparing the preservation and the endocardial closure subgroups, the risk of early and overall adverse events (including stroke) was also comparable between the two subgroups (table 4).
Early and overall clinical outcomes of the left atrial appendage preservation versus resection (sub)groups
Early and overall clinical outcomes of the left atrial appendage preservation versus endocardial closure (sub)groups
Subgroup analyses according to risk profiles
There was no significant interaction in the various subgroups with regard to the risk of stroke depending on the treatment of LAA, and subgroup analyses showed no significant differences in the risk of stroke in any of the subgroups (figure 3A). There was a significant interaction for the risk of mortality according to the history of stroke and the procedural complexity, significantly favouring LAA preservation in patients without a history of stroke and in those undergoing multiple complex procedures (figure 3B).
Subgroup analysis for the risk of stroke (panel A) and all-cause death (panel B) in the IPTW model. eGFR, estimated glomerular filtration rate; IPTW, inverse-probability-of-treatment weighting; LA, left atrium; LVEF, left ventricular ejection fraction; MV, mitral valve. *(n) indicates %/patient-year.
Rhythm and echocardiographic outcomes
The risk of early AF recurrence (<3 months) was comparable in the IPTW model (table 2). Similar patterns were observed in the two subgroup analyses that compared LAA preservation against LAA resection and endocardial closure (tables 3 and 4). The risk of AF recurrence after a 3-month blanking period was also comparable between the patients with LAA preservation and closure as well as between the subgroup comparisons (online supplemental figure 1 and 2).
During follow-up, 9674 echocardiographic measurements were performed (4699 in patients with LAA preservation, and 4975 in those with LAA closure). In the adjusted random coefficient model, the slopes of the A-wave showed an increasing trend until 1 year after surgery and shifted in the opposite direction in both groups (figure 4A). The A-wave was shown to be persistently higher in the patients with LAA preservation in the early period (at 1 year; p=0.015), but the discrepancy began to be mitigated at 5 years after surgery. The slopes for the E/A ratio showed a reverse pattern compared with those for the A-wave, with a more prominent between-group difference (figure 4B). In contrast to LAA contractile function, there was no significant difference in the parameters representing LV function over time (figure 4C) as well as LV dimension (online supplemental figure 3A-B) between the two groups.
Plots presenting a random coefficient model with restricted cubic spline functions for the adjusted non-linear relationship between time since surgical ablation and A-wave velocity (panel A), E-wave/A-wave ratio (panel B) and left ventricular ejection fraction (LVEF) (panel C). A-wave indicates the peak left atrial contraction wave, and E-wave indicates the peak early filling wave in the left atrium. LAA, left atrial appendage.
Discussion
This study demonstrated that the long-term risk of stroke or mortality was not significantly associated with preservation versus closure of the LAA in the setting of SA. The subgroup patients undergoing LAA resection had a higher incidence of postoperative bleeding than those with LAA preservation. In addition, with no significant difference in the late AF-free rate, we recognised an overall higher A-wave velocity and a lower E/A ratio with LAA preservation than with LAA closure, which implies superior LA transport function augmented by the preserved LAA.
LAA is known to account for 90% of the locations where thrombi are formed.1 Given that LAA itself is a cause of thromboembolic events, the current guideline recommends that LAA closure be performed during SA (class II indication).3 Regarding this issue, two large-scale observational studies have assessed the association of LAA closure versus preservation with the risks of stroke and mortality.4 5 In the study by Yao et al, the authors performed PS matching to produce a cohort with or without LAA closure (4295 per each group).5 While 74.9% (n=6438) had a history of AF in the matched cohort, SA was performed in 2.9% of the original cohort (n=2196). The risk of mortality and stroke was reduced with LAA closure in only a subgroup of patients with AF. Notably, the risk of death and stroke was comparable between LAA closure and preservation in a subgroup of patients without AF at baseline, which casts argument against the potential benefits of LAA closure in circumstances where AF is presumed to be absent.
In the study by Friedman et al,4 LAA closure was found to be associated with significantly lower rates of thromboembolism and mortality. Of note, 94% of patients with LAA closure underwent SA, whereas only 12% received SA among those with LAA preservation. More importantly, SA was not incorporated into the PS model to balance in the comparisons, and SA might have functioned as an effect modifier in comparing LAA closure and preservation.11
Recently, the landmark RCT (Left Atrial Appendage Occlusion Study, LAAOS III) that compared patients with LAA closure and preservation showed that the risk of stroke or systemic embolism was significantly lower in the patients with LAA closure. SA was performed in 809 (34.0%) and 753 (31.5%) patients in the closure and the preservation group, respectively. LAAOS III trial primarily included the patients with CHA2DS2-VASc Score ≥2 and excluded those undergoing mechanical valve replacement, and differences in the results between the LAAOS III trial and our study may arise from differences in the study design and discrepancies in baseline characteristics such as age or CHA2DS2-VASc Score (lower in our study). In the subgroup analysis, in addition, it was unclear whether the effect of LAA closure differ according to the performance of SA because the interaction testing was not demonstrated, and LAA closure was not associated with a decrease in stroke in the subgroup without baseline AF. Therefore, the effect of LAA closure on the stroke risk may be modified by the dedicated effort to correct AF particularly in patients with low-risk profiles for stroke, and RCTs evaluating the effect of LAA closure in the setting of SA are required.
In contrast, several recent studies have suggested that LAA closure may be associated with increased risks of 30-day readmission, respiratory failure or kidney injury postoperatively.9 10 The recent practice guideline that endorsed these findings recommended against preemptive LAA closure in patients without AF.2 Consistent with these results, we assume that the risk of stroke may not be increased by LAA preservation in patients who undergo SA because AF is expected to be converted to sinus rhythm in the majority of these patients. Also, previous studies have demonstrated that LAA closure does not increase the operative risk.7 8 12 23 However, serious complications after LAA closure, such as intractable bleeding around the stump of resected LA or adjacent left coronary circumflex artery injuries, exist, although the low incidences may not produce statistically significant differences.11 24 As LAA closure may pose increased procedural risks in select patients, it needs to be considered with balanced estimation between potential benefits and risks. In this regard, this study is unique in demonstrating that LAA resection carries a significantly increased risk of bleeding compared with LAA preservation.
Of note, the subgroup analysis showed a survival benefit associated with LAA closure seemed to be more evident in the subgroup of patients with a history of stroke or those undergoing a single procedure (figure 3B). The subgroup analysis for the risk of stroke, however, showed the lack of significant interaction with the treatment of LAA in all subgroups, presumably due to the limited number of stroke events. These analyses imply that LAA closure is an effective treatment option in select patients at high risk for ablation failure or stroke and those undergoing cardiac surgeries where the addition of LAA closure does not significantly increase procedural burdens.
The analyses of echocardiographic data showed that LA transport function was favourable with LAA preservation, but this finding did not translate into improved LV function or clinical outcomes. These results imply that LAA may contribute to an increase in LA stroke volumes by restoring the booster capacity after SA.25 Several studies showed improved LV functions by SA, which can be explained by the elimination of tachycardia-induced cardiomyopathy and incorporation of the LA booster function into LV diastolic function.26 27 Under the latter assumption, we speculated that LV function would be superior with LAA preservation. However, the absolute differences in A-wave velocity and E/A ratio were not clinically relevant despite the statistical significance, and more favourable LA transport function gained by LAA preservation may have only marginal clinical benefit for those undergoing SA.
Limitations
This study must be interpreted with caution in light of selection bias given that the decision on the treatment of the LAA was not randomised. Also, this study included the patients over 18 years with different closure techniques performed by multiple surgeons, and the incidence of incomplete exclusion of LAA may have varied with each technique postoperatively. We have not routinely evaluated the postclosure status of LAA, which may have confounded the effect of LAA preservation versus closure on the outcomes.
It should also be noted that the postoperative incidence of stroke and mortality may have been affected by the postoperative AF recurrence, the anticoagulation strategy and the use of antiarrhythmic drugs. We did not systematically collect the detailed information on the long-term use of these medications after SA, and the heterogeneity in the choice of medications and their therapeutic effects may have varied substantially between the two groups or even within each patient over time. Although we demonstrated that postoperative AF burdens were comparable between the two groups, the unmeasured effect of postoperative medication use may have still confounded the study results.
Conclusions
Among patients who underwent surgical AF ablation concomitantly to cardiac surgery, the preservation of LAA was not associated with an increased risk of stroke and mortality during long-term follow-up, compared with the closure of LAA. These findings argue against the routine exclusion of LAA in this setting. RCTs dedicated to the setting of surgical AF ablation are necessary to offer definitive evidence on this issue.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Ethics statements
Patient consent for publication
Ethics approval
This study was approved by the Institutional Review Board of Asan Medical Center. The requirement for informed consent was waived due to the retrospective nature of the study design.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors Study concept and design: HJK, JBK; data acquisition and outcome measure: HJK, DHC, KK, JKK; data analysis and interpretation: HJK, JBK, SOK; manuscript drafting: HJK, JBK; critical review and revision: HJK, JBK, SHJ, JWL; approval of final version: HJK, JBK, SOK, SHJ, DHC, KK, JKK and JWL. JBK is responsible for the overall content of the study as aguarantor
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.