Left Atrial Appendage Occlusion as Adjunctive Therapy to Anticoagulation for Stroke Recurrence

Left atrial appendage occlusion (LAAO) is currently accepted in patients with non-valvular atrial fibrillation (NVAF) and a formal contraindication to oral anticoagulation (OAC) but it might also be considered for those at high risk of bleeding or drug cessation (IIB indication).^1-3 Other medical conditions might, however, derive a potential benefit from this novel therapy. Among others, stroke recurrence despite optimal OAC might represent a valid indication for LAAO as an adjunctive therapy to OAC. In fact, the risk of repeated cardioembolic events in patients who have already had a first cardioembolic stroke seems to be present in up to 9% of the population, but it is even higher if the events occurred under optimal OAC treatment.^4,5 Importantly, the heterogeneity of these patients is generally high, since the presence of valvular atrial fibrillation (VAF), cardiac mechanical valves, or even coagulation disorders is common.^4,5 Large left atria (LA) or the presence of echo-contrast, sludge, or even thrombus inside the LAA despite optimal OAC are also conditions that might explain the higher recurrence of stroke in these patients and the rationale to justify the beneficial role for LAAO. In addition, the lack of validity of the CHADS₂ and CHA₂DS₂-VASc scales in patients without NVAF represent a major limitation to predict the risk of strokes in this setting. The aim of the present study was to explore the role of LAAO as an adjunctive therapy to OAC in patients with recurrent stroke despite optimal OAC and no contraindication for it.

Methods

This was an observational study that included consecutive patients who underwent percutaneous LAAO with different occlusion devices between June 2009 and June 2017 at nine reference centers. After excluding non-cardioembolic sources, patients who presented with stroke despite optimal OAC and who underwent LAAO as adjunctive therapy to OAC were included in the analysis. Patients with an absolute or relative contraindication to OAC were not included in the study. All patients included in this study were totally compliant with anticoagulation therapy, including novel oral anticoagulant (NOAC) and, for those under vitamin K antagonist, all had therapeutic international normalized ratios (INRs). If the patient was not compliant to OAC, or if INR was unknown/out of therapeutic range at the time of stroke, patients were not included in the analysis. All patients signed informed consent before the procedure. The study was approved by the institutional ethics committee of every participating institution. Details regarding LAAO procedure have been published elsewhere.⁶

Endpoints. Since LAAO was added to OAC as adjunctive therapy, the primary study endpoint was the reduction in the number of strokes/transient ischemic attacks (TIAs) or systemic embolism before and after LAAO. Secondary end-points included procedural events, major bleedings, cardiovascular mortality, non-cardiovascular mortality, and all-cause mortality.

Definitions. Procedural success was defined as successful implantation of the device in the LAA. Report of periprocedural adverse events (occurring during day 0-7 post procedure or before hospital discharge, whichever is last) was based on the VARC criteria¹⁵ and included death, myocardial infarction, stroke, TIA, systemic embolization, air embolization, device embolization, significant pericardial effusion or cardiac tamponade, and major bleeding (requiring surgery or transfusion). Major adverse events (MAEs) were defined as follows: acute occurrence (0-7 days post procedure) of death, stroke (ischemic or hemorrhagic), systemic embolism, and procedure-related or device-related complications requiring major cardiovascular or endovascular intervention.

The presence of echo contrast inside the LAA was assessed by transesophageal echocardiography (TEE) before LAAO and classified as absent, low-grade, or high-grade spontaneous echo contrast, as previously described.⁷

Clinical follow-up. Clinical follow-up included implanted patients and was carried out by patient visits or phone contact, per center or operator protocol. Report of adverse events during follow-up was based on the VARC criteria⁸ and included death (cardiovascular or non-cardiovascular), stroke, TIA, systemic embolism, and major bleeding.

Imaging follow-up. Patients underwent TEE or computed tomography (CT) at follow-up to detect device thrombosis or peridevice leaks. Successful LAAO was defined as the absence of significant leak (>3 mm) at last TEE or CT.^9,10 The presence of any image compatible with thrombus over the device was reported as device thrombosis.

Statistical analysis. Continuous variables were explored for normal distribution using the Kolmogorov-Smirnov test. Variables following normal distribution were expressed as mean ± standard deviation and non-normally distributed variables were expressed as median with interquartile range (IQR). Categorical variables were expressed as count with percentage. Baseline characteristics between groups were compared using the t-test for continuous variables and Chi-square test for categorical variables. Comparisons between the number of strokes before and after LAA closure were performed using Wilcoxon matched-pairs signed-rank tests. Statistical analysis was performed using STATA version 13 (STATA Corporation).

Results

Among 837 patients who underwent LAAO between the study period, a total of 22 patients (2.6%) were subjects who presented with cardioembolic events despite optimal OAC without any absolute or relative contraindication to OAC, and were therefore included in the study. Baseline population characteristics are shown in Table 1. Of note, in this specific cohort of patients, there was a high percentage of  VAF patients (38%), all of whom had previous valve surgery (22% with mechanical valves). In addition, up to 59% of patients presented with >1 cardioembolic event within the 2 years before the intervention.

All patients underwent successful implantation of the device. No procedural MAEs were reported in any case. Table 2 shows procedural characteristics. Most patients presented with some degree of spontaneous echo contrast (79%) and most patients (86%) received the Amplatzer cardiac plug (ACP)/Amulet device (Abbott Medical). Despite not having any contraindication to OAC, it was ceased in 3 patients after LAAO and DAPT for 3 months and subsequent indefinite aspirin was started.

With a median clinical follow-up of 1.8 years (IQR, 0.7-2.8 years), only 1 stroke and 1 TIA were reported (Figure 1). This fact translated into a significant reduction of cardioembolic events within the 2 years before LAAO (mean, 2.0 ± 1.0 events) and 1.9 years after LAAO (mean, 0.1 ± 0.3 events) (P<.01). Importantly, these 2 cerebrovascular events occurred in patients taking only single-antiplatelet therapy at the time of the event (13 months after LAAO for the stroke and 9 months after LAAO for the TIA). In both patients, OAC was restarted after the event with no additional problems. Hemorrhagic events occurred in only 1 patient who was taking NOAC + aspirin at follow-up and presented with recurrent hematuria. In this patient, aspirin was stopped with no more recurrent bleedings. Finally, another patient died 3 years after LAAO as a result of a prosthetic valve endocarditis.

Imaging follow-up was available in 17 patients (77%) and was performed 3.5 months (IQR, 2-8 months) after LAAO. Imaging follow-up was done with TEE in 13 patients and CT in 4 patients. No significant peridevice leaks were detected. Only 1 patient who was taking low-molecular-weight heparin (LMWH) presented with device thrombosis over the disc of an Amulet device 6 months after LAAO. No clinical events were reported and the type of LMWH was changed from enoxaparin to tinzaparin, with thrombus resolution at follow-up. Of note, no optimal antithrombotic compliance after LAAO could be ensured in this patient.

When comparing NVAF and VAF patients (Table 3), no significant differences in the number of strokes before LAAO were observed, although patients with NVAF were older and presented higher CHADS₂, CHA₂DS₂-VASc, and HASBLED scores. In addition, all patients with VAF compared to 57% of those with NVAF presented some degree of echo contrast in the LAA, highlighting the presence of a high thrombotic environment in this setting.

Discussion

The main findings of the present study were the following: (1) LAAO seems to be feasible and safe in patients with previous cardioembolic events despite optimal OAC; (2) LAAO as an adjunctive therapy to OAC was associated with low rate of cardioembolic events after LAAO; (3) LAAO was beneficial in spite of a high prevalence of VAF in this group of patients, LAAO added to OAC resulted in similar rates of clinical events and device thrombosis as compared with previous series of patients with NVAF undergoing LAAO.

One of the first objectives of the present study was to test the feasibility and safety of LAAO in a group of patients with this particular indication in whom the prevalence of VAF (38%), cardiac mechanical valves (22%), or relevant LAA echo-contrast (79%) was relatively high. In this sense, the incidence of procedural MAEs in our series (0%) was lower compared to previous large registries with ACP/Amulet or Watchman devices (Boston Scientific), in which the rate of procedural events ranged between 2.5% and 4.97%,^9-11 highlighting the fact that LAAO seems to be feasible and safe in the short term for this group of patients.

Another relevant question was to evaluate the efficacy of adding a second line of treatment to OAC in order to reduce the risk of stroke after ruling out non-cardioembolic sources. For this reason, the study only included patients without contraindication to OAC in whom OAC could be continued after LAAO. The inclusion of this uniform population in terms of antithrombotic treatment before and after LAAO allowed a more valid assessment of the individual role of LAAO, as 86% of patients continued OAC after the therapy, with LAAO the only therapeutic change during the study period. The high number of recurrent cerebrovascular events of these patients despite optimal OAC before LAAO (2.0 ± 1.0) and the relevant reduction of the risk after LAAO (0.1 ± 0.3) (Figure 1) are noteworthy, and suggest that LAA thrombus might be the most plausible source of most previous cardioembolic events. One potential explanation for this finding is the high thrombotic environment in the LA/LAA, as depicted by the high prevalence of spontaneous echo contrast (79%) regardless of optimal OAC treatment. Another potential explanation, although not reported by the patients or blood test, might be the INR liability in patients under vitamin K antagonists. Importantly, most of the cardioembolic events before LAAO occurred with therapeutic INRs or in patients with NOACs who adhered to proper treatment compliance. Finally, the presence of some hematologic disorders, such as sticky platelet syndrome and other conditions, have also been linked to recurrent strokes despite OAC,¹² although in our series, no specific hematologic disorders could be detected. Finally, a total of 3 patients (14%) received additional interventions (2 patent foramen ovale and 1 atrial septal defect closure), which might have also reduced the potential risk of paradoxical embolism. Importantly, the only patient with stroke recurrence after LAAO also underwent successful patent foramen ovale closure. In fact, the only 2 patients with recurrent cerebrovascular events (1 stroke and 1 TIA) after LAAO were the ones in whom OAC was ceased and DAPT started despite no contraindication to OAC.

The high incidence of cardioembolic events despite OAC in specific patients has already been reported.^4,5,13 This clinical condition is a disturbing situation for physicians and patients, who generally tend to change the type of anticoagulant or add additional antithrombotic treatments such as antiplatelet agents without formal scientific evidence.¹⁴ In our series, only 3 patients (14%) were taking aspirin and OAC before LAAO. One of the potential alternatives for these patients would have been to add a second antithrombotic agent instead of undergoing LAAO, but this option was not considered in most of the patients to avoid the increased hemorrhagic risk.

VAF is a completely different condition that needs to be clearly differentiated from NVAF. It is important to point out that the CHADS₂ and CHA₂DS₂-VASc scores are not valid scales to predict cardioembolic events. In fact, NVAF patients were older and presented higher CHADS₂ and CHA₂DS₂-VASc scores than VAF patients, even though the number of cardioembolic events before LAAO was similar among groups. In VAF, although the LAA is the most frequent source of thrombus, the prevalence of thrombus outside of the LAA is significantly higher than in NVAF.^15,16 To date, LAAO has not been tested in VAF in large registries. Nonetheless, specific patients in large registries or even series of patients treated with MitraClip and LAAO could be potential examples of this setting.¹⁷ In any case, since the source of thrombus might be more distributed, our recommendation would be to maintain OAC when possible.

Since thrombotic LA and LAA environment was considered high, as depicted by the high prevalence of spontaneous echo contrast, the incidence of device thrombosis was one of the main focuses of our study. With a median imaging follow-up of 3.5 months (IQR, 2-8 months), only 1 patient (4.5%) presented device thrombosis on the surface of the disc of an Amulet device. The thrombus was detected by CT scan 6 months after LAAO, and the patient presented with no clinical events. The rate of device thrombosis of our study was comparable to previous series and large registries of patients with NVAF, in which the rate ranged between 1.5% and 5%,^1,9 or even 14% in some specific series with higher TEE surveillance.¹⁸ Despite the high thrombotic environment, the fact that OAC was not ceased after LAAO may probably explain this comparable rate of device thrombosis.

In our series, most of the patients (86%) were treated with ACP/Amulet device. The main difference with previous series in terms of sizing was that >20% of patients had devices ≥30 mm compared to <10% in previous large registries;^1,9 this reflects the larger LAA size of these patients and the subsequent need for bigger devices. In this sense, no specific device recommendation could be inferred other than to try to choose the one that provides more complete LAA closure.

Study limitations. The present paper has several limitations. This is a non-randomized, retrospective, observational study that included many large-volume centers. There was no control group, but we used each patient as its own control before and after LAAO. As this was a retrospective study, all results and conclusions were based on observed associations that will need to be proven in further randomized studies. Although all included patients under NOAC acknowledged full drug compliance, no specific drug compliance test was performed. The clinical and TEE results were self reported and there was no independent adjudication. However, all the important events were discussed within the study group members to keep as much homogeneity as possible.

Conclusion

LAAO seems to be feasible and safe in patients with previous cardioembolic events despite optimal OAC. In addition, LAAO as an adjunctive therapy to OAC was associated in our series with a low rate of cardioembolic events after LAAO. Despite the high prevalence of VAF in this setting, LAAO added to OAC resulted in similar rates of clinical events and device thrombosis as compared with previous series of patients with NVAF undergoing LAAO.

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From the ¹Hospital Clinic de Barcelona, Institut Clínic Cardiovascular, Barcelona, Spain; ²Hospital Universitario de Salamanca, Salamanca, Spain; ³Hospital Clínico San Carlos, Madrid, Spain; ⁴Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain; ⁵Hospital Universitario de León, León, Spain; ⁶Hospital Universitario Virgen Macarena, Sevilla, Spain; ⁷Hospital Universitario Son Espases, Mallorca, Spain; ⁸Hospital Clínico Universitario de Valladolid, Valladolid, Spain; ⁹Hospital Universitari de la Santa Creu i Sant Pau, Barcelona, Spain; and ¹⁰Hospital Universitario Infanta Cristina de Badajoz, Badajoz, Spain.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Freixa, Estévez-Loureiro, Bethencourt, and Arzamendi report proctor income from Abbott Medical. Dr Ruiz-Salmerón and Dr Cruz-González report proctor income from Abbott Medical and Boston Scientific. Dr Pérez de Prado reports proctor income from Boston Scientific. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted February 24, 2019, provisional acceptance given March 26, 2019, final version accepted April 26, 2019.

Address for correspondence: Xavier Freixa, MD, PhD, Hospital Clinic de Barcelona, c/ Villarroel 170, Escala 3 Planta 6, 08015 Barcelona, Spain. Email: xavierfreixa@hotmail.com

Key words: anticoagulation, atrial fibrillation, left atrial appendage, stroke