Five-year-outcome of new-onset perioperative atrial fibrillation after left atrial appendage amputation concomitant with cardiac surgery

Background Recent data demonstrated the benefit of left atrial appendage (LAA)-amputation in patients with atrial fibrillation (AF). However, the long-term impact of LAA-amputation for patients with new-onset perioperative atrial fibrillation (POAF) is still unknown. Methods Patients with no history of AF undergoing coronary artery bypass grafting by off-pump technique (OPCAB) between 2014 and 2016 were retrospectively examined. Cohorts were divided by the concomitant execution of LAA-amputation. Propensity score (PS) matching was applied by all available baseline characteristics. The composite of all-cause mortality, stroke and rehospitalization in patients with POAF and patients maintaining sinus rhythm posed as the primary endpoint. Results A total of 1522 patients were enrolled, of whom 1208 and 243 were included in the control and the LAA-amputation group, respectively and were matched to 243 patients in each group. In total, patients with POAF without LAA-amputation showed a significantly higher rate of the composite endpoint (17.3% vs 32.1%, p = 0.007). However, patients with LAA-amputation showed no significant difference in the composite endpoint (23.2% vs 26.7%, p = 0.57). The significantly higher occurrence of the composite endpoint was driven by all-cause mortality (p = 0.005) and rehospitalization (p = 0.029). Subgroup analysis revealed a CHA2DS2-VASc-score of ≥ 3 to be associated with the high rate of the primary endpoint (p = 0.004). Conclusion POAF is associated with a higher rate of the combined endpoint of all-cause mortality, stroke and rehospitalization. The composite endpoint in patients with LAA-amputation concomitant with OPCAB surgery developing new-onset POAF in a 5-year follow-up was not increased compared to a control cohort maintaining sinus rhythm. Graphical abstract Five-year outcome of patients with POAF and LAA-amputation; 95% CI, 95% confidence interval, CPR, cardiopulmonary resuscitation, ECLS, extracorporeal life support, HR, hazard ratio, IABP, intra-aortic balloon pump, LAA, left atrial appendage, OPCAB, off-pump coronary artery bypass grafting, PAPs, systolic pulmonary artery pressure, SR, sinus rhythm, VT, ventricular tachycardia. Supplementary Information The online version contains supplementary material available at 10.1007/s00392-023-02255-8.


Introduction
Perioperative atrial fibrillation (POAF) is a common complication in cardiac surgery, associated with a high rate of longterm atrial fibrillation (AF), decreased cognitive and renal function, as well as an elevated use of medical resources such as extended hospitalizations and the need of intensive care and also an increased mortality rate [1][2][3].The occurrence rate of POAF is varying between 20 and 50% [4,5].Therefore, the current guidelines recommend restoring sinus rhythm by antiarrhythmic medication, as well as electrical cardioversion, and reducing the risk of thromboembolic stroke by anticoagulation [6].
Once POAF occurs, the range of complications is similar to none-surgery related atrial fibrillation.For that reason, surgery-related AF, along with several other factors predisposing to develop AF such as age, genetic predisposition, diabetes mellitus, arterial hypertension, or obesity [7][8][9], should be considered as a relevant comorbidity (Fig. 1).
The baseline strategy and gold standard for stroke prevention in persistent AF is medical anticoagulation [6].Since the left atrial appendage (LAA) is known to be the major origin of stroke caused by thrombi [10], the exclusion of the left atrial appendage by intervention or surgery (concomitant with cardiac surgery) has become a field of rising interest [10].
In fact, the LAA is easy to access during cardiac surgery by median sternotomy or anterolateral thoracotomy, leading to develop and establish techniques to exclude the LAA through ligation or amputation concomitant with e.g.coronary or valvular cardiac surgery [11,12].The previous hesitant recommendations to perform LAA-amputation have been strengthened by increasing evidence of stroke prevention through LAA-amputation in patients with AF, with the most famous to mention LAAOS III trial [13].
However, stroke prevention through LAA-amputation has also been observed in patients with sinus rhythm and a high CHA 2 DS 2 -VASc-score [14].Thus, the prophylactic impact of LAA-amputation on stroke, all-cause mortality, and rehospitalization might be most effective in POAF patients.However, a dedicated analysis with long-term follow-up in POAF patients undergoing LAA-amputation has yet to be performed.(www.strobe-state ment.org).Furthermore, the study was conducted in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Patient recruitment and follow up
All patients undergoing isolated coronary artery bypass grafting in off-pump technique (OPCAB) between January 2014 and December 2016 in our department (Herz-und Diabeteszentrum NRW, Bad Oeynhausen, Germany) were retrospectively selected in a single-center assessment.Preoperative exclusion criteria were a history of AF, valvulopathy, and pulmonary arterial hypertension.Perioperative exclusion criteria were the need of a permanent pacemaker, extracorporeal life support, intraaortic balloon pump, ventricular tachycardia, resuscitation, or defibrillation.A detailed description of the patient recruitment strategy was given before [15].

Surgical technique
The surgical procedure was performed utilizing the off-pump technique through median sternotomy, and well-established grafts such as the left and/or right internal mammary artery, radial artery, and saphenous vein were employed.After pericardial exposure the accessibility of the LAA was judged by the surgeon.If the LAA was deemed accessible and suitable for amputation, the procedure was completed by ligation, LAA resection, and double continuous suture.Transesophageal echocardiography was conducted both before and after LAA amputation to detect any pre-existing thrombus formation or residual appendage post-amputation.

Anticoagulation
All patients were initially treated with dual antiplatelet therapy consisting of acetylsalicylic acid 100 mg and Clopidogrel 75 mg (a P2Y12 inhibitor).The dual antiplatelet regimen was recommended for a duration of 6 months, after which a transition to mono antiplatelet therapy with acetylsalicylic acid 100 mg was advised.If POAF occurred, a switch of the dual antiplatelet therapy to a combination of single antiplatelet (acetylsalicylic acid 100 mg) and oral anticoagulation strategy (Phenprocoumon) for at least 3 months was recommended.Further follow-up of the anticoagulation therapy was not part of the presented data.

POAF
To retrospectively detect the occurrence of POAF, a detailed browsing flowchart was developed, as described before [15].In brief, prehospital reports, in-hospital transfer and discharge reports, any custodial and visit documentation in the data management systems of the intensive (COPRA, COPRA System GmbH; Germany) and standard care (ORBIS, Dedalus HealthCare, Germany) units were analyzed for any signs of arrhythmia.Furthermore, patient data was inspected for the use of antiarrhythmic medication, whereas a rhythm control was achieved by per standard used postoperative telemetry until discharge.ECG was performed at least four times for each patient (on admission, immediately after surgical intervention, first postoperative day, and before discharge).A flowchart summarizing the POAF detection protocol is provided in Fig. 2.

Outcome
The primary outcome was defined as a composite endpoint of all-cause mortality, stroke and rehospitalization.Secondary endpoints were defined as the isolated parameters of the composite endpoint.The endpoint stroke was defined as either the confirmation of stroke through cerebral imaging (computed tomography or MRI) or the presence of unequivocal neurological impairment, such as hemiplegia.Additionally, instances of stroke confirmed by a neurologist reported to our department during the follow-up period were also included in the definition.The endpoints were assessed by using four sources of information: a review of our medical records; an annual, standardized form (post-discharge) completed by the patients themselves, as well as by their out-patient care physician, and annual consultation with the respective registration office in case of missing post-discharge forms.Follow-up data was then assessed between the date of surgery (2014-2016) and December 2021.Patients were censored at their last follow-up.
To assess subgroup differences, subgroup analyses of older patients (age > 70) and patients with an increased stroke risk (CHA 2 DS 2 -VASc-score ≥ 3) were performed.All analyses were done in the total cohort, the LAA-amputation cohort, and the control cohort.

Statistical analysis
Statistical analysis was performed using the SPSS-Software (Version 28, IBM, New York, NY, USA) and R (Version 4.2.2,R Core Team, Vienna, Austria).Categorical variables are given as absolute and relative frequencies, continuous variables as means with standard deviations.Since the surgical technique was chosen in a nonrandomized fashion, we used 1:1 PS matching by 20 baseline characteristics using nearest neighbor matching with a caliper of 0.2 (Table 1), which was described in detail before [15], resulting in groups of 243 patients with and without LAA-amputation.To assess the patient outcome, patients were divided into an SR group and a POAF group.To conclude, the balance of baseline covariates was assessed by computing the z-difference (balance achieved, if ≤ |± 1.96|) and for categorical variables by additionally computing the standardized mean difference (balance achieved if < 0.1) [16,17].
A time-to-event analysis was performed regarding the primary composite endpoint and the secondary endpoints with the use of Kaplan-Meier survival curves, stratified log-rank testing, and a stratified Cox proportional-hazards model.Categorical baseline variables were compared with the use of the Chi-square test or Fisher's exact test.
Parameter estimates are given with their hazard ratio, 95% confidence interval (95% CI) and the corresponding p value.p values < 0.05 were considered statistically significant.

Cohort
After the exclusion of 59 patients (4.7%) in the control group and 12 patients (4.7%) in the LAA-amputation group due to perioperative exclusion criteria, a total of 1208 and 243 patients were included, respectively.These were paired via PS matching to 243 patients in each group, achieving a standardized mean difference of < 0.1 and a z-difference of ≤ |± 1.96|.Twenty (8.2%) of the patients in the LAA group were included despite showing a CHA 2 DS 2 VASc-score of 1, due to smoke/thrombus formation in perioperative transesophageal echocardiography.The mean age of the patients was 69.6 (8.1) and 69.1 (7.6) years in the control and LAA-amputation group, respectively, while 19.0% and 21.4% were female.POAF after OPCAB was observed in 31.2% of LAA patients compared to 33.3% in the control group (HR 0.94; 95% CI [0.62; 1.41], p = 0.75) [15].The baseline characteristics of the matched cohorts are illustrated in Table 1.Baseline characteristics divided by the development of POAF are provided in supplementary table 1.

POAF in the LAA-amputation and control group
Among the control group, patients with POAF showed a worse outcome with a considerably higher frequency of the composite endpoint [17.3% vs

Subgroup analysis in the LAA-amputation and control group
Regarding the subgroup analysis in the LAA-amputation and control group, no subgroup showed a noteworthy difference between patients with SR and POAF in the LAAamputation cohort (Composite endpoint: age < 70 years p = 0.25; > 70 years p = 0.89; CHA 2 DS 2 -VASc-score < 3 p = 0.53; > 3 p = 0.62).

Discussion
This is the first study to assess the long-term impact of LAA-amputation on the outcome in patients with newonset POAF.Our analysis underlines the considerably worse outcome of patients developing POAF after OPCAB with regard to the composite endpoint of all-cause mortality, stroke, and rehospitalization.Furthermore, the outcome of patients with POAF who underwent LAA-amputation is not inferior compared to patients with maintained SR.
The rising evidence of stroke prevention by LAAamputation in patients with atrial fibrillation (LAAOS III trial [13]) has led to an essential guideline recommendation for concomitant LAA-amputation [18].Additionally, stroke prevention in patients with sinus rhythm undergoing cardiac surgery has also been demonstrated [14].The results of this study go one step further and show that the prognosis of patients with POAF might be restored to that with maintained sinus rhythm.Furthermore, the safety of LAA-amputation with no extension of the cardiopulmonary bypass time and no increase of postoperative complications including bleeding, accompanied by a fast learning curve [19], strengthens the idea of expanding the indication for LAA-amputation in patients with risk factors assessed by the CHA 2 DS 2 -VASC-score.Even concerns about morphological effects on the left atrial geometry such as an increased intraatrial pressure causing dilation of the left atrium resulting in a higher rate of POAF [20], have been resolved [15].
Nevertheless, the conclusive result of this manuscript is the impaired outcome regarding all-cause mortality of patients who developed new-onset POAF after OPCAB surgery.This underlines the severity of an allegedly easyto-handle postoperative complication and its influence on long-term patient prognosis.The impaired outcome of patients with POAF is in concordance with several studies demonstrating similarly severe mortality [21,22].Therefore, it is of utmost interest to identify risk factors for POAF and thus to develop strategies to avoid them.
In the current analysis, patients with POAF and no LAAamputation showed an impaired outcome in relation to the composite endpoint, driven by all-cause mortality and rehospitalization.In contrast, POAF patients with LAAamputation had no adverse effects compared to patients with maintained SR.On the other hand, there are hints that patients with maintained SR who received concomitant LAA-amputation have a slightly higher rate of all-cause  2).A prolongation of hospitalization and an onset of heart failure symptoms have been described in literature [23].In this regard, analysis of the often-discussed humoral impact of the LAA being the main source of atrial natriuretic peptide regulating renal clearance of electrolytes and water [24], is of utmost interest, and further research on this topic is warranted.Additionally, in contrast to our results, Melduni et al. demonstrated no benefit regarding all-cause mortality and rehospitalization in patients undergoing concomitant LAAamputation [20].Hence, each case should be individually discussed, and the decision determined after careful risk factor evaluation for POAF.
Our analysis could proof the beneficial effect with regard to all-cause mortality and rehospitalization, particularly in patients with older age and an elevated stroke/comorbidity risk assessed by the CHA 2 DS 2 VASc-score, which itself includes older age.Thus, taking the current results into account, the CHA 2 DS 2 VASc-score, which is already being the main decision-making variable [6,18], should be used for patients without preoperative AF, as well.
Patient selection has to always be a core point in prophylactic treatment approaches such as LAA-amputation, since the weight of responsibility is even greater, when recommending an additional procedure for treatment of a potential postoperative complication that could increase the risk of adverse outcomes, even though it might not manifest itself in the first place.When discussing a broad prophylactic Fig. 4 Survival analysis of the secondary endpoints; HR, hazard ratio, POAF, perioperative atrial fibrillation, SR, sinus rhythm recommendation, it is of utmost interest to establish the best possible technique for LAA amputation, which is still depending mostly on established habits, institutional experience, and economic considerations with the most commonly employed techniques of suturing, stapling and clipping [25].This necessitates a levelheaded evidence-based discussion on general technical differences, patient-based differences and surgery-based differences (e.g.minimally invasive cardiac surgery, OPCAB, conventional cardiac surgery) to attain the required knowledge to form the surgeon's preference, which is and will remain the decisive factor in making the choice.
Interestingly, in terms of the single endpoint stroke, no notable difference could be revealed.This raises the question of whether some stroke events are concealed within all-cause mortality without further investigation of the mortality cause.However, since several studies' reporting's range from "association" [3,26,27] to "no association", the impact of POAF on long-term stroke risk needs to be further elucidated.Hsu et al. were able to demonstrate similar outcomes after POAF in a cohort of over 8000 patients with a higher mortality and rehospitalization rate but no increase in the stroke rate [28].In contrast, subresults of the EXCEL trial showed comparable results for patients with POAF with poor outcomes, indicating that POAF could be identified as an independent risk factor for stroke [29].

Limitations
Several limitations apply to our study.The main limitation of the analysis is the retrospective and single center study design.Furthermore, the anticoagulation strategy and patients' compliance were not part of the follow-up, so a potential bias due to medical treatment differences cannot be ruled out.Nonetheless, similar to the LAAOS III cohorts [13] and following the guideline recommendations [6], all patients were treated with oral anticoagulation at least during hospitalization.Detailed information regarding LAAamputation strategy was not given, however, the cohort assessed is an amputation-only cohort.

Conclusion
POAF is associated with a higher rate of the composite endpoint of all-cause mortality, stroke and rehospitalization.The combined endpoint in patients with LAA-amputation concomitant with OPCAB surgery developing new-onset POAF in a 5-year follow-up was not increased compared to a control cohort maintaining sinus rhythm.
Approval including patient consent waiver was obtained by the local ethics committee of the Ruhr University Bochum (No: 2020-688_1; Date: 12.08.2022).Every patient received a thoroughly dedicated patient information concerning the LAA-amputation.The investigation was performed in accordance with the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement

Fig. 1
Fig. 1 Hypothesis of stroke prevention by LAA-amputation; CAD coronary artery disease, LAA left atrial appendage

Table 1
Baseline characteristics of the PS matched cohorts ASA American Society of Anesthesiologists, BMI body mass index, CAD coronary artery disease, DVT deep vein thrombosis, IQR interquartile range, NYHA New York Heart Association, PSM propensity score matching, TSH thyroid stimulating hormone

Table 2
Primary composite and single endpoints of patients with perioperative maintenance of sinus rhythm and perioperative atrial fibrillation in the total cohort (with and without LAAamputation) HR hazard ratio, POAF perioperative atrial fibrillation, SR sinus rhythm Bold value indicates p-values < 0.05 were considered statistically significant Fig. 3 Survival analysis of the primary composite endpoint; HR hazard ratio, POAF perioperative atrial fibrillation, SR sinus rhythm Detailed results are provided in Table 5 and Fig. 4.

Table 5
Subgroup analysis of older age (> 70 years) and high stroke risk (CHA 2 DS 2 -VASc-socre ≥ 3) in the LAA-amputation group and the control group HR hazard ratio, POAF perioperative atrial fibrillation, SR sinus rhythm