Mid-Term Feasibility of Percutaneous Left Atrial Appendage Occlusion in Elderly Patients with Non-Valvular Atrial Fibrillation

Background: Percutaneous left atrial appendage occlusion (LAAO) therapy using the WATCHMAN system has been introduced to prevent thrombosis and minimize the use of anticoagulants in patients with non-valvular atrial fibrillation. Given the high risk of bleeding and stroke in elderly patients, these patients would be good candidates for this therapy. However, the efficacy and feasibility of LAAO therapy in elderly patients remains uncertain. Methods: Consecutive patients who underwent LAAO therapy using the WATCHMAN system in a large academic center between June 2020 and March 2023 were included. The safety and efficacy of LAAO therapy during the 1-year observation period in patients aged ≥85 years old were compared with those in the younger cohort. Results: A total of 188 patients (78.4 ± 6.9 years old, 133 male patients) were included. 34 patients were ≥85 years old, 96 were between 75 and 84 years old, and 58 were <75 years old. The elderly group had a higher CHA2DS2-VASc score and were at greater risk of falling-related bleeding compared with the younger cohort. The device implantations were successful in all patients except for one. During the 1-year observation period, one patient had a peri-device leak >5 mm and there were 6 device-related cases of thrombosis, whose incidence was not significantly different between the groups (p = 0.98). The cumulative incidences of bleeding and thrombotic events in the elderly group were as low as in the younger cohort (p > 0.05 for both). Most anticoagulants were terminated regardless of age. Conclusion: The mid-term feasibility and efficacy of percutaneous LAAO therapy using the WATCHMAN system in elderly patients aged ≥85 years were as acceptable as in the younger cohort.


Background
The number of patients with non-valvular atrial fibrillation (NVAF) has been increasing as the population ages [1].Elderly patients with NVAF have an incremental risk of stroke, while they also have an incremental risk of falling-related major bleeding [2,3].Thus, anticoagulation therapy in elderly patients with NVAF poses a therapeutic dilemma [4][5][6][7][8].The recently introduced direct oral anticoagulant (DOAC) is superior to conventional warfarin but has not yet completely resolved the therapeutic dilemma.In addition, the addition of a DOAC in elderly patients presents several problems related to polypharmacy and adherence [9].
Most of the cases of intra-cardiac thrombus originate from the left atrial appendage (LAA) [10].Several percutaneous LAA occlusion (LAAO) devices have been innovated to suppress the formation of thrombus in LAA [11][12][13].In the PROTECT AF and PREVAIL trials, the WATCHMAN system was non-inferior to warfarin in preventing stroke in patients with NVAF and a high-risk of bleeding [11,12].The device was non-inferior to the DOAC in the PRAGUE-17 trial [13].
The rates of procedural success and procedural complication improved in the EVO-LUTION registry [14].The feasibility of the WATCHMAN system was further enhanced by the system innovation from WATCHMAN 2.5 to WATCHMAN FLX [15,16].In light J. Clin.Med.2023, 12, 6024 2 of 13 of the SALUTE trial, which demonstrated the feasibility of the WATCHMAN system in 42 Japanese patients, the device was approved by the Japanese government in 2019 [17].
Clinical outcomes of LAAO therapy in real-world clinical practice have been reported, while those of the elderly cohort at high risk of stroke/bleeding remain uncertain.In this retrospective study, we evaluated the feasibility of LAAO therapy in the real-world elderly cohort.

Patient Selection
We prospectively included consecutive patients with NVAF who underwent percutaneous LAAO therapy using the WATCHMAN system from June 2020 in a large academic center in our registry database.We conducted this study retrospectively using this dataset.We used the WATCHMAN 2.5 until June 2021 and converted the system to WATCHMAN FLX in June 2021.We included patients who underwent LAAO therapy until March 2023.All patients gave statements of informed consent to be included in our registry.The ethics committee of our center approved the study protocol (R2020077).

Indication of LAAO
The indication of LAAO was determined according to the guidelines of The Japanese Society of Cardiology [18].Patients with NVAF who were at high risk of stroke according to CHADS 2 scores and CHA 2 DS 2 -VASc scores were eligible for LAAO therapy [19].Patients who had a high-risk of bleeding with a HAS-BLED score of ≥3 points, those who had a history of repeated falling, those with diffuse cerebral amyloid angiopathy, those who required multiple antiplatelets for over 1 year, and those with a history of major bleeding assigned to BARC type 3, were eligible.Patients who were contraindicated to anticoagulation were also considered to be eligible.The final indication was determined by the multidisciplinary heart and valve team.

Procedure
Percutaneous LAAO therapy was performed under general anesthesia using angiography and transesophageal echocardiography supports, according to the standard procedure.All procedures were performed by the two proctor-certified operators.Intra-procedure echocardiography was performed by the board-certified echocardiologist who had received a specific training program for the procedure.

Post-Procedure Management
Post-procedural antithrombotic therapy was administered according to the recommended regimen.Following the procedure, anticoagulation therapy, using warfarin or a DOAC, and antiplatelet therapy, using one of three agents (aspirin, clopidogrel, and prasugrel), were performed for 45 days, after which transesophageal echocardiography was performed.Then, anticoagulation therapy was terminated, and dual antiplatelet therapy was initiated, unless a major para-device leak or device-related thrombus was observed.Dual antiplatelet therapy was downgraded to single antiplatelet therapy six months later.The detailed medical therapy regimen was adjusted at the discretion of the attending physicians, considering the risks of bleeding and thrombosis.

Study Outcome
All patients were stratified into three groups according to their age: <75 years, 75-84 years, and ≥85 years.Clinical outcomes as detailed below were compared between the three groups.
Procedure-related events were counted during the procedure and for 1-week postprocedure, or until the index discharge.Procedure-related events were defined as death, cerebrovascular events, systemic embolism, air embolism, bleeding, pericardial effusion, device embolization, and acute kidney injury.Of these, major procedure-related events were death, cerebrovascular events, systemic embolism, bleeding assigned to BARC 3-5, relevant pericardial effusion, device embolization, and acute kidney injury.
Mid-term clinical events were counted at 45 days, 1 year, and over 1 year, including death, cardiovascular death, cardiovascular event, systemic embolism, bleeding, myocardial infarction, ischemic stroke, hemorrhagic stroke, transient ischemic attack, and bleeding.
A performance target of acute event rates was defined as <10% according to the SALUT trial.Another performance target of LAA closure with a peri-device leak < 5 mm was defined as >94%, also according to the SALUTE trial [17].

Statistical Analysis
Continuous variables were expressed as a mean and standard deviation and compared between the three groups using an analysis of variance.Categorical variables were expressed as numbers and percentages and compared between the three groups using Fisher's exact test.Cumulative incidences of the clinical events were compared between the three groups using log-rank tests.A value of p < 0.05 was considered statistically significant.Statistical analyses were performed using SPSS Statistics 24 (SPSS Inc., Armonk, NY, USA).

Baseline Characteristics
A total of 188 patients were included (Table 1).Age was 78.5 ± 6.8 years old and 54 (29%) were female patients.All patients had NVAF.The CHADS 2 score was 3.5 ± 1.3 and HAS-BLED score was 2.9 ± 1.0.34 (18%) patients had a high risk of bleeding due to falling and 96 (51%) had a history of relevant bleeding.Most of the patients had received single anticoagulation therapy or single anticoagulation and single antiplatelet therapy.58 patients were <75 years old, 96 patients were between 75 and 84 years old, and 34 patients were ≥85 years old.A higher age was associated with an incremental CHADS 2 score (p < 0.01).The HAS-BLED scores were lower in patients with older age, whereas the prevalence of high risk for falling-related bleeding was higher in the elderly patients (p < 0.01 for both).

Procedure Data
All procedures were successful under general anesthesia with a transesophageal echocardiography guide, except for one patient, in whom the LAA size was too large to place the device (Figure 1A).The WATCHMAN 2.5 was implanted in 48 patients and the WATCHMAN FLX was implanted in 139 patients (Table 2).The most prevalent size of the WATCHMAN 2.5 was 33 mm and that of the WATCHMAN FLX was 31 mm.No patients had a peri-device leak >5 mm.Most patients (72%) received an anticoagulant and single antiplatelet at index discharge.
WATCHMAN FLX was implanted in 139 patients (Table 2).The most prevalent size of the WATCHMAN 2.5 was 33 mm and that of the WATCHMAN FLX was 31 mm.No patients had a peri-device leak >5 mm.Most patients (72%) received an anticoagulant and single antiplatelet at index discharge.Procedure-related parameters were not significantly different between the groups, including the procedure time and contrast amount (p > 0.05).The prevalence of medication type was not significantly different between the groups (p > 0.05 for all).

Clinical Events
Table 5 summarizes the clinical outcomes after the procedure.There were two procedure-related events: progression of anemia that required trans-infusion and minor pericardial effusion.In the patient who required blood transfusion, there was no intra-procedural pericardial effusion, no bleeding at the puncture site, and no progression of anemia.The patient had heart failure, and 4 days after the procedure, a blood transfusion was performed to further improve anemia.No patients had device migration or device embolization.There were two procedure-unrelated events: sudden death due to myocardial infarction and gastrointestinal bleeding that required trans-infusion.A patient died suddenly at home 5 days after the procedure.The autopsy demonstrated that he died due to atherosclerosis-related acute myocardial infarction.The event rates were not significantly different between the groups (p = 0.10; Figure 1B).Acute event rates were within 10%, which was a performance target defined according to the SALUT trial, regardless of age (Figure 5A).The rates of effective LAA closure with a peri-device leak < 5 mm, were over 94%, which was also a performance target defined according to the SALUT trial, regardless of age (Figure 5B).

Discussion
In this retrospective study conducted in a single academic center using prospectively collected registry data, we compared clinical outcomes between elderly patients aged ≥85 years and others.Percutaneous LAAO therapy using the WATCHMAN system was effective and feasible even in the elderly patients who had high a CHADS-VASc score and HAS-BLED score.Anticoagulation therapy could also be terminated in this elderly cohort without increasing thromboembolic events.

Clinical Implication of LAAO in the Elderly Patients with NVAF
Anticoagulation therapy is a gold standard therapy for patients with NVAF to prevent stroke [19].Elderly patients have an incremental incidence of NVAF and greater risk of stroke due to multiple risk factors [20].Nevertheless, they have a higher risk of falling due to increasing frailty [21].The issue of polypharmacy is particularly evident in this cohort [22].Furthermore, they have a higher risk of bleeding [3].Although the DOAC has been introduced as a superior alternative to conventional warfarin, the DOAC cannot completely overcome the above dilemma in the elderly patients with NVAF, who have higher risk of both bleeding and stroke [23].
Thus, the less invasive and effective LAAO therapy has been receiving great attention as a good alternative to the DOAC in elderly patients with NVAF.

Device Innovation
The 1-year clinical efficacy of the WATCHMAN 2.5 was demonstrated by the EVOLU-TION trial and NCDR registry [24,25].The mid-term clinical outcome of the next generation WATCHMAN FLX was shown in the PINACLE FLX trial and FLXibility trial.Our team also demonstrated the comparable feasibility of the WATCHMAN FLX to the WATCH-MAN 2.5 [26].Thus, we combined clinical data of both devices in this study.In this study, the procedure success rate was 100% in patients receiving the WATCHMAN FLX, and procedure-related complications in the WATCHMAN FLX therapy was 0%.WATCHMAN FLX would be a more suitable device for elderly patients.

Safety of LAAO in the Elderly Patients
Percutaneous interventions are generally less invasive than the surgical approach and would be suitable for elderly patients, since such patients require particularly safe approaches in comparison to younger patients.Several procedure-related complications have been reported, including thromboembolism, stroke, cardiac tamponade, and vascular injury.The incidence of these complications has decreased considerably due to procedural improvement and device innovation [15,16,24,25].
In this study, the feasibility of LAAO therapy was shown to be comparable to that of recent large-scale studies [15,16].It is noteworthy that the procedure was feasible regardless of high age.High age may not be a contraindication of LAAO therapy, although further studies are warranted for optimal patient selection.

Efficacy of LAAO in the Elderly Patients
Elderly patients have higher risks of both bleeding and stroke [9,23].Theoretically, they are rather good candidates for LAAO therapy, since this therapy decreases the risk of bleeding and stroke by terminating the use of anticoagulants.In our study, the stroke rate in the elderly patients was as low as that of the younger cohort, whereas the use of anticoagulants could be terminated in most elderly patients safely at a comparable level to the younger cohort.

Medication after LAAO
Anticoagulation and antiplatelet therapy were performed according to the guidelines, in principle, whereas a few studies reported the feasibility of a non-anticoagulation regimen [27].Several risk factors of device-related thrombosis, which is one of the critical complications, have been reported, including spontaneous echo contrast in the left atrium, and peri-device leak [28].However, the detailed mechanism of device-related thrombosis remains uncertain, and repeated follow-ups using echocardiography and/or computed tomography would be essential to adjust medication.In this study, anticoagulation, which is associated with the risk of bleeding, could be terminated in elderly patients.

Limitations
The patients' number was moderate.It is noteworthy that the sample size of elderly patients aged ≥85 years old was small.We demonstrated non-inferiority in the clinical outcomes of the elderly patients compared to the younger patients, but statistical nonsignificance does not necessarily indicate similarity between the groups, particularly in a small sample sized study with a low event rate.The observation period was mid-term, given the recent availability of LAAO therapy.Further long-term multi-center studies are warranted to validate the efficacy and feasibility of LAAO therapy in elderly patients.We believe that the present study could be a proof-of-concept for larger studies including the target population from a variety of geographic areas.

Conclusions
The feasibility and efficacy of percutaneous LAAO therapy using the WATCHMAN system in elderly patients with NVAF were as high as those of the younger cohort.Longterm multi-center studies are warranted to validate our findings.

Figure 1 .
Figure 1.Procedure success rate and major adverse event rate.(A) WATCHMAN implant success rates stratified by age.(B) Major adverse events within 7 days of procedure stratified by age.Event rates were compared between the groups using Fisher's exact test.

Figure 2 .
Figure 2. Medication and complication at 1-year follow-up.(A) The rate of anticoagulation therapy.(B) The rate of device leak >5 mm.(C) The rate of DRT, DRT, device related thrombus.Event rates were compared between the groups using Fisher's exact test.

Figure 2 .
Figure 2. Medication and complication at 1-year follow-up.(A) The rate of anticoagulation therapy.(B) The rate of device leak > 5 mm.(C) The rate of DRT, DRT, device related thrombus.Event rates were compared between the groups using Fisher's exact test.

Figure 2 .
Figure 2. Medication and complication at 1-year follow-up.(A) The rate of anticoagulation therapy.(B) The rate of device leak >5 mm.(C) The rate of DRT, DRT, device related thrombus.Event rates were compared between the groups using Fisher's exact test.

Table 5 .
Clinical events for follow-up period.procedure related events within 7 days

Figure 4 .Figure 5 .
Figure 4. Cumulative incidence of any bleeding events (A) and thrombosis-related events (B) stratified by age.Kaplan-Meier curves were compared between the groups using log-rank test.

Figure 5 .
Figure 5.The rate of acute events (A) and effective LAAO defined as peri-device flow ≤ 5 mm (B) in each age-stratified group.Performance target was recommended according to the findings of SALUTE trial.

Table 2 .
Procedural characteristics and post-procedural medications.
Figure 1.Procedure success rate and major adverse event rate.(A) WATCHMAN implant success rates stratified by age.(B) Major adverse events within 7 days of procedure stratified by age.Event rates were compared between the groups using Fisher's exact test.

Table 2 .
Procedural characteristics and post-procedural medications.

Table 3 .
Transesophageal echocardiography findings and medications at 45-day follow-up.
SAPT, Single Antiplatelet Therapy; DAPT, Dual Antiplatelet Therapy; DOAC, Direct Oral Anti Coagulants.Continuous variables were compared by unpaired t-test.Categorical variables were compared by Fisher's exact test.

Table 4 .
Transesophageal echocardiography findings and medications at 1-year follow-up.