Author + information
- Received March 21, 2016
- Revision received April 19, 2016
- Accepted May 20, 2016
- Published online July 27, 2016.
- Alexander Sedaghat, MD,
- Jan-Wilko Schrickel, MD,
- René Andrié, MD,
- Robert Schueler, MD,
- Georg Nickenig, MD and
- Christoph Hammerstingl, MD∗ ()
- Med. Klinik und Poliklinik II, Herzzentrum, Universitätsklinikum Bonn, Rheinische-Friedrich-Wilhelms Universität Bonn, Bonn, Germany
- ↵∗Reprint requests and correspondence:
Dr. Christoph Hammerstingl, Med. Klinik und Poliklinik II–Herzzentrum, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
Objectives This study sought to define the ideal post-procedural anticoagulant regime and to systematically study the incidence of device-related thrombus.
Background Left atrial appendage occlusion (LAAo) is an alternative to life-long oral anticoagulation in selected patients with atrial fibrillation.
Methods This study included 24 atrial fibrillation patients (ages 79 ± 8 years; 75% male, CHA2DS2VASc [Congestive Heart Failure, Hypertension, Age ≥75 Years, Diabetes Mellitus, Previous Stroke or Transient Ischemic Attack or Thromboembolism, Vascular Disease, Age 65 to 74 Years. Sex] score: 4.3 ± 1.5, HASBLED [Hypertension, Abnormal Renal and Liver Function, Stroke, Bleeding, Labile International Normalized Ratio, Elderly, Drugs or Alcohol] score: 3.6 ± 0.8) after LAAo with the use of the Amplatzer Amulet system. Dual antiplatelet therapy for 3 months was prescribed in 95.6% of the cases.
Results Transesophageal echocardiography identified a high rate of device adherent thrombi (16.7%, n = 4 of 23) after a mean of 11.0 ± 8.2 weeks. Thrombus formation occurred under dual antiplatelet therapy (3 of 4) or clopidogrel monotherapy (1 of 4). When compared with patients without thrombi, echocardiography showed higher degrees of spontaneous echo contrast grades within the LAA (3.0 ± 1.0 vs. 1.3 ± 1.1), lower LAA peak emptying velocities (17.5 ± 5.0 cm/s vs. 48.3 ± 21.1 cm/s), and decreased left ventricular function (39 ± 10% vs. 50 ± 13%) in patients with device-related thrombus. All thrombi were observed within the untrabeculated region of the LAA ostium between the left upper pulmonary vein ridge and the occluder disc, indicating suboptimal LAA occlusion.
Conclusions Device-related thrombus is a frequent finding after LAAo with the Amplatzer Amulet device. Our results emphasize the need for an optimized post-LAAo anticoagulation regimen, a revised implantation strategy, and possibly modified patient selection criteria.
Left atrial appendage occlusion (LAAo) has been introduced in clinical practice as an alternative to life-long oral anticoagulation (OAC) focused on patients that are unamenable for OAC (1). The concept of LAAo is intriguing as it promises the combination of reduced thromboembolic events and a potential benefit concerning bleeding events when OAC is stopped after implantation. However, the optimal regimen of post-procedural anticoagulation or platelet inhibition after LAAo is an unresolved issue and manufacturers’ recommendations vary from initiation of vitamin K antagonist therapy for 45 days followed by dual antiplatelet therapy (DAPT) after implantation of the Watchman device (Boston Scientific, Natick, Massachusetts), to DAPT alone up to 6 months after LAAo with the Amplatzer Amulet system (St. Jude Medical, St. Paul, Minnesota) (2,3). Also, LAAo has yet to prove its efficacy concerning the reduction of major bleeding events in high-risk atrial fibrillation patients (4) and is in competition with the improved safety of direct OAC (5).
Thrombus formation on the Amplatzer Cardiac Plug device (St. Jude Medical) has been described in up to 17% of cases (6) and the new Amplatzer Amulet device has been recently introduced with novel design features also aiming to reduce thrombogenicity (7).
The incidence of device-related thrombus (DRT) formation with the new Amulet occluder has not been examined in clinical routine with serial transesophageal echocardiographic examinations. Therefore, we investigated safety and efficacy of LAAo with the Amulet system in a prospective cohort study with regard to thrombus formation.
Methods and Results
We performed clinical and echocardiographic follow-up in patients who underwent LAAo with the use of the Amulet device at our center between November 2014 and November 2015. All patients had to provide informed consent for participation to our LAAo registry, which was approved by the local ethics committee.
We present a series of 24 patients, which does not allow for detailed, inferential statistical analysis. Values are presented as means ± SD if normally distributed; categorical variables are given as frequencies and percentages.
Patients undergoing LAAo
Twenty-four patients underwent LAAo with the Amplatzer Amulet device. These patients were 78 ± 9 years of age, predominantly male (75%), and at a high thromboembolic as well as bleeding risk (CHA2DS2VASc [Congestive Heart Failure, Hypertension, Age ≥75 Years, Diabetes Mellitus, Previous Stroke or Transient Ischemic Attack or Thromboembolism, Vascular Disease, Age 65 to 74 Years. Sex] score: 4.3 ± 1.5, HASBLED [Hypertension, Abnormal Renal and Liver Function, Stroke, Bleeding, Labile International Normalized Ratio, Elderly, Drugs or Alcohol] score: 3.6 ± 0.8). The indication for LAAo was driven by a history of bleeding events in 75% of patients, or an anticipated high risk of bleeding in 25% of patients. Levels of serum creatinine were 1.5 ± 0.6 mg/dl.
LAAo was performed under conscious sedation in all patients with a mean procedure time of 37 ± 12 min; the mean device size was 24 ± 3 mm. During LAAo, 37 ± 36 ml of contrast dye were used.
LAAo was successful in all patients. Peri-interventional complications occurred in 2 of 24 of patients (8.3%), consisting of minor pericardial effusion in 1 patient and 1 pericardial tamponade with the need for pericardiocentesis. Post-procedurally, DAPT was prescribed for a minimum of 3 months in the majority of patients (23 of 24, 95.8%). One patient was maintained on OAC based on patient’s preferences.
Comparison of patients with and without device-related thrombi
Transesophageal echocardiography identified 4 patients (16.7%) with large DRT after a mean of 11.0 ± 8.2 weeks (4, 4, 16, and 20 weeks). DRT were detected prior to electrocardioversion in 1 case (Patient #1) and during routine follow-up in the other 3 patients (Patients #2 to #4). Of note, Patient #4 had suffered from a transient ischemic attack (TIA) 2 weeks before follow-up. Three of the 4 patients were still under dual platelet therapy when DRT was diagnosed; 1 patient was on monotherapy with clopidogrel after planned cessation of DAPT (Table 1).
Predictors for thrombus formation
When comparing groups according to the occurrence of DRT, baseline echocardiography showed that patients with thrombi had lower left ventricular ejection fractions (39 ± 10% vs. 50 ± 13%), higher degrees of spontaneous echo contrast within the LAA (3.0 ± 0.8 vs. 1.3 ± 1.1), and lower LAA peak emptying velocities (17.5 ± 5.0 cm/s vs. 48.3 ± 21.1 cm/s). Additionally, patients with thrombi on the Amulet device more often had a history of LAA thrombi (75.0% vs. 19.2%) (Table 2).
Of interest, all thrombi were located within the angle between the left upper pulmonary vein–ridge and the occluder disc in the untrabeculated transition between LAA ostium and neck, resulting in incomplete sealing of the LAA ostium in these patients (Figure 1). In contrast, the rate of incomplete LAA sealing in patients without thrombi was 41.2% (Table 2).
Treatment regimen of DRT
Due to the safety profile and their potential to resolve LAA thrombi (8), we initiated OAC by use of direct acting OAC in all patients. Patient #1 was treated with apixaban (5 mg twice daily), whereas Patient #2 was prescribed 30 mg of edoxaban, due to chronic renal disease. In 2 patients (Patients #3 and #4), reduced-dose dabigatran therapy with 110 mg twice daily was initiated. Follow-up echocardiography was performed after a mean of 6 ± 2 weeks and documented resolution of thrombi in all patients. During this period, no stroke/TIA or bleeding events were observed.
In our study on patients undergoing LAAo with the novel Amplatzer Amulet occluder, we found a high rate of DRT of 16.7% despite continued antiplatelet therapy. One patient developed DRT under clopidogrel monotherapy after planned cessation of DAPT 3 months after LAAo. Our findings suggest a similar thrombogenicity of the novel Amulet device as compared to its precursor, despite device modifications. Following our results, occurrence of DRT appears to be related to patient characteristics as well as implantation technique.
Risk factors for thrombus formation
Overall, the clinical data concerning thrombus formation on devices used for occlusion of the LAA are scarce. Among several case reports, only Plicht et al. (6) performed a systematic follow-up of patients treated with the Amplatzer Plug device and reported an incidence of 17.6% of patients. In their analysis, several risk factors for thrombi were identified, including higher CHA2DS2-VASc and HASBLED scores as well as reduced left ventricular function. In our study, we found lower left ventricular ejection fraction in patients with thrombi, whereas thromboembolic and bleeding risk scores were not different. In contrast to the data by Plicht et al. (6), we found echocardiographic markers of left atrial hemostasis to be risk factors for thrombus formation on the occluder device, including higher degrees of spontaneous echo contrast within the LAA and lower LAA peak emptying velocities.
Interestingly, with the Watchman device, DRT are reported in a significantly lower percentage of patients, approximately 5.7% (9,10). In addition to differences in device design, the reduced incidence may be due to the mandatory initial phase of OAC after LAAo with the Watchman device, potentially allowing for complete endothelialization of the occluder (11). The debate on post-procedural therapy is further stimulated by a recent analysis on clopidogrel nonresponse after LAAo (10). In this study of 4 patients with DRT, Ketterer et al. (10) identified three-quarters of patients as clopidogrel nonresponders, deeming the current concepts of DAPT inappropriate and insufficient therapy after LAAo.
Device-related thrombi after LAAo—an avoidable issue?
The presented data underline the unmet need to define an optimized post-procedural anticoagulant regimen after LAAo. Given the common use of LAAo in patients at prohibitive bleeding risk under OAC, DRT leaves both patients and physicians with a dilemma: it provides an iatrogenic indication for therapeutic anticoagulant therapy. Although there is hardly any scientific evidence on the relevance of DRT (9), effective resolution of these thrombi is usually aimed for in daily clinical routine (12). Due to the potential thromboembolic risk associated with DRT, we felt obliged to initiate OAC in all patients with thrombi. The need for medical treatment was further emphasized by the fact that 1 patient suffered a TIA. Although causality between the DRT and the TIA in this patient cannot be proven retrospectively, the early presentation of the patient as well as the scientific evidence on the increased thromboembolic risk associated with LAA thrombi (13) indicate a direct relationship.
Our study indicates that more individualized anticoagulation regimens might be warranted after LAAo with the Amulet device. Thrombi occurred in most patients with echocardiographic evidence/indicators of left atrial hemostasis and/or a history of LAA thrombus. In fact, three-quarters of patients with DRT in our study had a history of LAA thrombi, suggesting a predisposition for (local) thrombus formation and underlining the role of left atrial hemodynamics. As a clinical consequence of our findings, we introduced a course of direct OAC treatment of 6 weeks after LAAo in our practice, followed by aspirin monotherapy after transesophageal echocardiogram control examination. Additionally, our study emphasizes, that complete sealing of the LAA ostium should be aimed for by means of optimized device sizing and implantation technique, because all thrombi were found between the device disc and the large left upper pulmonary vein ridge. The observed predilection site strongly suggests that incomplete sealing of the LAA ostium (14) and the creation of a cul-de-sac or “neo-appendage” may act as a nidus for thrombi and increase thrombogenicity (Figure 1H). In this context, intraprocedural 3-dimensional echocardiography as well as future technological improvements such as steerable transseptal sheaths may lead to optimal procedural results.
Overall, our analysis indicates a multifactorial cause of DRT with the Amulet occluder device. Given the limited number of patients included in this analysis, large-scale randomized studies are needed to further address this topic and general recommendations cannot be given at this point. However, when DRT are encountered on the Amulet device, a temporary regimen of direct OAC appears to be safe and effective, at least in selected patients. Until these issues are addressed, close echocardiographic and clinical follow-up should be performed.
The sample size in our study is clearly an important limitation. However, the presented finding could have an impact on daily clinical practice and treating physicians should be aware of this fact.
DRT formation after LAAo with the Amulet system seems a frequent finding, which appears to be associated with patient-derived risk factors, implantation technique, and post-procedural anticoagulant regimen. Our observations and the cited data underscore the need for future prospective studies on optimized implantation goals followed by individualized anticoagulant treatment strategies after LAAo.
COMPETENCY IN MEDICAL KNOWLEDGE: DRT on the Amulet device appear to be a frequent finding. In clinical practice, the occurrence of these thrombi should prompt echocardiographic follow-up of patients after LAAo, especially in patients with a high risk for DRT, including those with echo contrast within the atrium, reduced LAA emptying velocities, and a history of LAA thrombi. When DRT are encountered, temporary treatment with direct OAC is a safe and effective treatment option.
TRANSLATIONAL OUTLOOK: The results of this analysis emphasize the need for future studies on the post-procedural anticoagulation after LAAo. It is for randomized studies to determine the optimal duration and type of anticoagulation after LAAo, including the use of direct OAC, with regard to safety and efficacy.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Sedaghat and Schrickel contributed equally to this work.
- Abbreviations and Acronyms
- dual antiplatelet therapy
- device-related thrombus
- left atrial appendage
- left atrial appendage occlusion
- oral anticoagulation
- transient ischemic attack
- Received March 21, 2016.
- Revision received April 19, 2016.
- Accepted May 20, 2016.
- American College of Cardiology Foundation
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