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Abstract
Background This present study aimed to investigate the impact of left atrial appendage (LAA) isolation on adverse clinical outcomes, with a further stratified analysis by biatrial (BA) and left atrial lesion sets, in patients with atrial fibrillation (AF) undergoing surgical ablation (SA) concurrent with mitral valve (MV) surgery.
Methods We evaluated 875 patients (aged 65.1±12.0 years) who underwent SA of AF concomitant to MV surgery, excluding those with mechanical prostheses requiring lifelong anticoagulation, between 2005 and 2017 in five tertiary cardiac centres in South Korea. Of these, 458 had isolated the LAA, whereas the remainder (n=417) had the LAA preserved. Comparative risk of stroke, mortality and AF recurrence was assessed between the groups, considering death as a competing event. Inverse-probability treatment weighting was used for baseline adjustment.
Results During the median follow-up of 57.4 months (IQR, 32.5–92.4 months), the adjusted risk of long-term stroke was significantly lower in the patients who underwent LAA isolation compared with those who preserved the LAA (subdistribution HR (SHR), 0.28; 95% CI 0.15 to 0.51; p<0.001). However, there were no significant differences in the adjusted risk of mortality (HR, 0.85; 95% CI 0.57 to 1.27; p=0.429) or AF recurrence (SHR, 0.92; 95% CI 0.78 to 1.08; p=0.291) between LAA isolation and preservation. In the subgroup of patients who underwent BA ablation, LAA isolation was associated with a lower long-term risk of stroke and AF recurrence (SHR, 0.77; 95% CI 0.61 to 0.94; p=0.029) compared with LAA preservation.
Conclusions Concomitant LAA isolation during SA of AF in patients undergoing MV surgery was associated with a significantly lower risk of long-term stroke, but no survival benefit was observed.
- Atrial Fibrillation
- STROKE
- Heart Valve Prosthesis Implantation
Data availability statement
Data are available upon reasonable request. Data are available upon reasonable request and appropriate permissions.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Although the left atrial appendage (LAA) isolation has been known to have a stroke-preventive effect in the surgical ablation (SA) of atrial fibrillation (AF), its long-term effect, especially in two different lesion sets remains elusive yet.
WHAT THIS STUDY ADDS
The present study investigated the long-term stroke, as well as mortality and AF recurrence, in patients with AF undergoing SA concomitant to mitral valve surgery stratified according to the lesion set.
The risk of stroke was significantly lower in the patients who had isolated the LAA, yet the risk of mortality did not differ between the groups, irrespective of the lesion set.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
This study result underscores the stroke-prevent benefits of LAA isolation in patients undergoing SA concomitant to mitral surgery, irrespective of the particular lesion set used during the SA.
Introduction
Atrial fibrillation (AF) is the most common sustained arrhythmia, which shares a strong epidemiological association with valvular heart disease.1 In the presence of AF, the left atrial appendage (LAA) is highly prone to stasis and thrombus formation due to contractile dysfunction and atrial cardiopathy, and consequently, patients with AF are at substantially increased risk of thromboembolic stroke.2 3 Adjunctive isolation of LAA in patients undergoing cardiac surgeries has been advocated as a strategy to prevent ischaemic stroke.4 5 However, only a few randomised controlled trials and large-scale observational studies are available on this topic, and even these studies are often limited by their heterogeneous study populations, characterised by a diverse prevalence of AF and rates of surgical ablation (SA).6–9 Moreover, various studies have suggested that LAA isolation provides an insignificant stroke prevention effect and impairs its various inherent functions as a decompression chamber, which potentially gives rise to adverse haemodynamic responses.10–13 Although isolating the LAA as a potential source of thrombi appears to be a logical strategy for reducing stroke risk, there is a lack of robust data conclusively proving this proposition, especially in patients with AF undergoing SA. In this context, we investigate the actual efficacy of LAA isolation in patients undergoing SA concomitant to mitral valve (MV) surgery, excluding those receiving MV replacement with a mechanical valve, which requires mandatory lifelong anticoagulation, to accentuate its efficacy. Given the ongoing controversy between biatrial (BA) and left atrial (LA) ablation in the surgical treatment of AF, this study specially assessed outcomes stratified by these two distinct lesion sets of ablation.
Methods
Study population
We identified 1841 adult patients (≥18 years) who underwent SA of AF concomitant to MV surgery in five tertiary cardiac centres in South Korea (Severance Hospital, Asan Medical Center, Samsung Medical Center, Pusan National University Yangsan Hospital and Korea University Anam Hospital) between January 2005 and December 2017 in the current study. Participants who had replaced their MV with mechanical prostheses were excluded to obviate the effect of warfarin on clinical outcomes. Participants who had replaced their mitral or tricuspid valve (TV) with mechanical prostheses were excluded to eliminate the effect of warfarin on clinical outcomes. Additionally, those with right atrial (RA) ablation only or SA using a microwave energy source were also excluded. Finally, a total of 875 patients were identified. Of these, 471 had LAA isolated (Isolation group), whereas the remainder (n=458) preserved the LAA (Preservation group) during AF surgery (figure 1).
Consolidated Standards of Reporting Trials diagram detailing patient selection. LAA, left atrial appendage; MV, mitral valve; MVR, mitral valve replacement; TVR, tricuspid valve replacement.
Surgical techniques
For LAA isolation, the following methods were employed based on surgical access and surgeon’s preferences: external resection (n=320, 69.6%), endocardial obliteration (n=111, 24.1%), application of linear auto-suture stapler (n=13, 2.8%) and utilisation of epicardial clip device (n=16, 3.5%).
The general lesion sets used in SA were derived from the modified Cox-Maze III and were implemented as follows. The LA lesion set consisted of (1) a box lesion encircling the bilateral pulmonary veins, (2) a line connecting the box lesion to the LAA, (3) a mitral isthmus lesion connecting the box lesion to the mitral annulus and (4) an epicardial coronary sinus lesion. The RA ablation lesion set included (1) a cavo-cavo line along the superior and inferior vena cava, (2) the RA free wall down to the tricuspid annulus and (3) the cavotricuspid isthmus. Minor variations of lesion sets may exist among institutions or surgeons.
Postoperative management and rhythm follow-up
Anticoagulant therapy with warfarin was maintained for 3–6 months after surgery, aiming for a target international normalised ratio (INR) between 2.0 and 2.5. Adjunctive heparin or low-molecular-weight heparin was administered until the INR exceeded 1.5. The decision to continue warfarin medication afterward was determined by individual participants’ thromboembolic risk, rhythm status and presence of effective atrial contraction confirmed by the echocardiographic examination. The rhythm statuses of participants were generally evaluated by performing follow-up 12-lead ECG at 3, 6, 12, 18 and 24 months postoperatively and once every year thereafter. Those considered to have restored sinus rhythm on follow-up stat ECG were examined using 24-hour Holter monitoring to verify AF-free status. Amiodarone or beta-blocker was administered to patients experiencing a recurrence of AF during the initial 3 months of blanking period to restore sinus rhythm.
Outcome measures and definition
The primary outcome of interest was ischaemic stroke, rigorously defined as the abrupt onset of neurological deficits persistent longer than 24 hours without apparent non-vascular causes and corroborated by brain imaging modalities such as CT scan or MRI. The secondary outcome of interest was all-cause mortality and the recurrence of AF after the blanking period. Early mortality was defined as death occurring within 30 days after the surgery. Recurrence of AF was defined as atrial tachycardia lasting longer than 30 s following the 3-month blanking period.
Data collection
Data were collected from institutional electronic medical records across five participating institutions as needed. Preoperative data, including baseline characteristics and echocardiographic information, as well as operative data encompassing concomitant cardiac surgeries, lesion sets of SA, and cardiopulmonary bypass and aorta-cross clamping time, were amassed. Postoperative data concerning the adverse events were collected for comprehensive analysis. Clinical follow-up information on participants was obtained through July 2021. For analysis, a median follow-up of 57.4 months (IQR 1–3, 32.5–92.4 months) encompassing 4619.1 patient-year (PY) was accessible.
Statistical analyses
In the original data, categorical variables are presented by numbers with alongside respective frequencies, and are compared using either χ2 test or Fisher’s exact test, depending on appropriateness. The continuous variables are presented as median with IQR and compared using the Mann-Whitney U test. Variables with the same median and IQR were further assessed using rank sum analysis to verify any statistical difference. In the weighted data, categorical variables were reported as counts with corresponding frequencies and compared using PROC SURVEYREQ. The continuous variables were presented as mean±SD and compared using PROC SURVEYREG.
To minimise the impact of selection bias and potential confounding factors while preserving the size of the study population, a propensity-score (PS)-based inverse-probability of treatment weighting (IPTW) method was used. The values of PS were estimated as 1/PS for patients who isolated LAA and 1/(1−PS) for those who preserved LAA. The PS was defined as the probability of isolating the LAA conditional on baseline profiles and was estimated through logistic regression analysis incorporating all the variables summarised in table 1 (online supplemental figure 1). In a subgroup analysis based on the lesion set of SA, the same adjustment method was applied with the balance of all variables summarised in table 1, except for the lesion set (online supplemental figures 2 and 3). The adequacy of covariate balance was evaluated using standardised mean differences (SMDs), with SMDs of nearly all covariates within 10%, indicating satisfactory balance.
Supplemental material
Supplemental material
Supplemental material
Patient characteristics
A logistic regression model was adopted to compare the risk of postoperative complications. A Cox proportional hazard model was used to compare all-cause death, while comparing risk model was employed to compared other valve-related adverse events and AF recurrence throughout the follow-up period. The subdistribution HR (SHR) was measured by the Fine and Gray method, accounting for death as a competing risk. Kaplan-Meier plots were generated to delineate mortality, with intergroup differences in Kaplan-Meier estimates compared using a long-rank test. The cumulative incidence curves for adverse events were constructed using Gray’s test, with death considered as a competing event. Linearised event rates are calculated by dividing the number of events by the total number of PY of follow-up. All reported p values were two-sided, and p values <0.05 were considered statistically significant. R V.3.4.0 software (R Foundation, Vienna, Austria; http://www.R-project.org/) and SAS software V.9.4 (SAS Institute) were used.
Patient and public involvement
Patients or the public were not involved in the design, conduct, reporting or dissemination plans of this current study.
Results
Baseline and operative profiles
Baseline profiles of the study cohort are summarised in table 1. Patients in the Isolation group were more female-dominant (55.2% vs 43.8%; p=0.001) and presented a higher CHA2DS2-VASc score (2.0 (1.0–3.0) vs 2.0 (1.0–3.0); p=0.032) compared with those in the Preservation group. The Isolation group more commonly had a long-standing AF (45.4% (n=209) vs 33.9% (n=140); p<0.001) with a significantly longer duration of AF (8.0 (1.0–66.0) months vs 4.0 (0.0–36.0) months; p<0.001) and a greater LA diameter (58.0 (52.0–64.0) mm vs 54.0 (48.0–60.0) mm; p<0.001) than the Preservation group. Compared with the Preservation group, concomitant TV surgery was more frequent in the Isolation group (74.2% (n=342) vs 45.5% (n=187); p<0.001), and patients in the Isolation group more commonly had BA lesion set (85.2% (n=392) vs 49.4% (n=204); p<0.001) (table 1).
Primary outcome: stroke
After adjustment, no significant difference in the risk of early stroke was evident between the Isolation and Preservation groups (OR, 0.71; 95% CI 0.38 to 1.34; p=0.289) (table 2). During the follow-up period, 8 (0.3% PY) and 18 (0.8% PY) patients had a stroke in the Isolation and Preservation groups, respectively. The patients who underwent LAA isolation exhibited an approximately 70% reduction in the risk of late stroke (SHR, 0.28; 95% CI 0.15 to 0.51; p<0.001) compared with those who preserved the LAA. The cumulative incidence of stroke at 5- and 10-years was 1.3% and 2.1%, respectively, in the Isolation group and 5.2% and 9.8%, respectively, in the Preservation group (figure 2).
Comparative outcomes of the left atrial appendage Isolation and Preservation groups
Adjusted cumulative incidence curves of stroke comparing the Isolation and Preservation groups. LAA, left atrial appendage; SHR, subdistributional HR.
The adjusted risk of early mortality was comparable between the groups (OR, 1.16; 95% CI 0.52 to 2.45; p=0.720) (table 2). The incidence of late mortality was 2.6% PY (n=67) in the Isolation group and 2.8% PY (n=67) in the Preservation group, with no significant difference in its risk (HR, 0.85; 95% CI 0.57 to 1.27; p=0.429) (figure 3A). The adjusted risk of AF recurrence also did not differ significantly (SHR, 0.92; 95% CI 0.78 to 1.08; p=0.291) (figure 3B).
Adjusted cumulative incidence curves of stroke comparing the Isolation and Preservation groups. LAA, left atrial appendage; SHR, subdistributional HR.
Outcome comparison according to the lesion set
Patients with BA and LA ablation were 596 (68.3%) and 277 (31.7%), respectively. In the cohort of patients who had BA ablation, the LAA isolation was associated with a significantly lower risk of both early (OR, 0.09; 95% CI 0.02 to 0.16; p=0.004) and late (SHR, 0.28; 95% CI 0.12 to 0.65; p=0.003) stroke. Of the participants who underwent LA ablation, the Preservation group reported 10 cases of late stroke, corresponding to an incidence of 0.5% PY, whereas no late stroke was documented in any patient who isolated the LAA.
There was no significant difference in the risk of mortality between the groups either in the BA or LA ablation setting (table 3). The patients who had isolated the LAA presented a superior rhythm outcome to those who preserved the LAA in BA lesion set (SHR, 0.77; 95% CI 0.61 to 0.94; p=0.029).
Comparative outcomes of the LAA Isolation and Preservation groups according to the lesion set
Discussion
In the present study, the concomitant isolation of LAA was associated with a significantly reduced long-term risk of stroke (SHR, 0.28; 95% CI 0.15 to 0.51; p<0.001) in patients undergoing SA of AF concomitant to MV surgery irrespective of lesion sets of SA. The long-term risk of mortality or AF recurrence did not differ significantly between the groups. However, in the subset of participants who had BA ablation, the patients who isolated the LAA had a higher chance of restoring and maintaining sinus rhythm in a long-term perspective than those who preserved the LAA.
As approximately 90% of AF-related thrombi originate from the LAA, adjunctive isolation of LAA appears to be a reasonable strategy to prevent stroke in patients with AF undergoing cardiac surgery.14 Prior reports on the surgical isolation of LAA have generally supported the notion that LAA isolation is associated with a reduction in the risk of stroke.4 5 8 9 However, these study results have often been weakened by the heterogeneity in the presence of preoperative AF or SA among the study population. The present study circumscribed the study cohort to patients with AF undergoing SA concurrent with MV repair or replacement using a bioprosthetic valve, which is avoidable of lifelong anticoagulation with successful AF surgery. The analysis demonstrated that LAA isolation was associated with reducing the long-term risk of stroke in this subset of patients (SHR, 0.28; 95% CI 0.15 to 0.51; p<0.001). Moreover, the result remained consistent in the subgroup analysis stratified by the lesion set of SA. Even in the setting of BA ablation, which is generally known to provide a higher chance of restoring and maintaining sinus rhythm, the risk of stroke was significantly lower in the Isolation group than in the Preservation group (SHR, 0.09; 95% CI 0.12 to 0.65; p=0.003), further validating its role as an effective stroke prevention strategy.
In contrast, several studies have suggested that the risk of stroke was not associated with the treatment of the LAA.13 15 16 In the study of Kim et al, the authors performed a comparative analysis between LAA isolation and preservation among 1640 patients with AF undergoing SA adjunctive to cardiac surgeries.13 They demonstrated that patients who preserved the LAA presented a comparable risk of stroke and mortality to those who isolated the LAA. Of note, the study cohort consisted of participants undergoing diverse cardiac procedures, each with different requirements for short- and long-term anticoagulation. Furthermore, although 811 (49.5%) patients had their heart valves replaced using a mechanical prosthesis, the details regarding the locations of these replacements were not provided. Consequently, the diverse requirement for lifelong anticoagulation with different target INR may have introduced effect modification when comparing LAA isolation and preservation.
In a PS-matched study (461 patients for each group) conducted by Melduni et al, the LAA closure was found to be not only uninfluential on the risk of stroke but also associated with an increased risk of postoperative AF in patients undergoing non-AF related cardiac surgery, and suggested an uncertain role of prophylactic LAA treatment.15 In this study cohort, 46.0% (n=422) of patients had AF at the time of surgery. However, the details of AF, including types or duration, which are essential inherent stroke profiles in participants, especially in those without AF surgery, were not provided or incorporated into the analysis. Moreover, the conclusions were drawn without data on anticoagulation or details regarding the types of valve prostheses implanted, which is a major determinant for long-term anticoagulation. Therefore, the impact of LAA isolation in this study should be interpreted with caution.
The subgroup analysis showed that patients who isolated LAA were at a significantly lower risk of AF recurrence than those who preserved LAA in the BA ablation setting. There is limited literature assessing the efficacy of LAA isolation for rhythm control, with prior studies yielding inconsistent findings concerning post-procedural rhythm outcomes. Cited reports described that the loss of atrial distensibility, leading to LA and PV stretch, and local atrial inflammation in response to mechanical LAA isolation could trigger postoperative AF.12 15 16 In contrast, several studies have added value to LAA isolation in achieving sinus rhythm. A canine model study by Syed et al demonstrated that LAA isolation promotes sinus rhythm by eliminating the appendage triggers.17 Moreover, Kawamura et al found that LAA ligation may contribute to maintaining sinus rhythm by developing reverse electrical atrial remodelling in patients with AF.18 In line with the aforementioned studies, an observational study investigating patients with cardiac implantable electronic devices reported that LAA exclusion reduces AF burden and plays a complementary role in maintaining sinus rhythm.19 However, most studies above primarily concentrated on early outcomes, without thoroughly assessing mid to long-term impact of LAA on sustaining an AF-free state in a small sample size. In the current study, improved rhythm outcomes in the Isolation group were observed only in a specific subgroup of patients who attempted to achieve complete lesion sets by ablating both atria. We speculate that remnant AF drivers in the RA among patients who underwent LA ablation may have contributed to an increased risk of AF recurrence and obscured the rhythm benefits of LAA isolation in this particular subset of patients. To evaluate the impact of LAA isolation on AF treatment, further studies may require detailed information on antiarrhythmic strategies for each participant during follow-up, as well as comprehensive electrophysiological data indicating the locations of residual signals causing AF recurrence.
Limitation
The present study contains several limitations to be acknowledged. First, this is a retrospectively designed study with its inherent limitations. Second, the current study includes patients subjected to various isolation techniques performed by multiple surgeons over 12 years without routine evaluation of the post-closure status, which may have confounded the impact of LAA isolation versus preservation on the outcomes. Moreover, data on the completeness of LAA isolation, as assessed by imaging studies is lacking in the present study. Third, we did not methodically collect the data regarding the long-term use of anticoagulants, which may have affected the incidence of stroke or mortality. However, this study focused on a homogenous population by excluding those who require lifelong anticoagulation, and this study design may have minimised the confounding effect of anticoagulation.
Conclusion
Among patients undergoing SA of AF concomitant to MV surgery, the addition of LAA isolation was associated with a reduced long-term risk of stroke without survival benefit. These findings provide supporting evidence of routine exclusion of LAA in this subset of patients.
Data availability statement
Data are available upon reasonable request. Data are available upon reasonable request and appropriate permissions.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and the study protocol was approved by the Institutional Review Board of each participating centre (4-2023-1553). The requirement for informed consent from individual participants was waived owing to the retrospective design of this study.
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.
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 SHL, WKP, JBK, YHC, HJK and H-GJ contributed to the conception and design of the work; SHL, JBK, YHC, HJK and H-GJ contributed to the acquisition of data; WKP and SHL contributed to analysis and interpretation of the data; WKP drafted and edited the manuscript; SHL edited the manuscript. All authors read and approved the final version of the manuscript. SHL is responsible for the overall content and serves as a guarantor.
Funding This study was supported by a grant from the Korea Health Technology R &D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI19C0481 & HC190C0273)
Competing interests The authors have nothing to disclose with regard to commercial support for the completion of this study.
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.