Introduction

Percutaneous left atrial appendage (LAA) closure has evolved as an alternative to oral anticoagulation for stroke prevention in patients with atrial fibrillation (AF) who are unable to take long-term oral anticoagulation.^1-4 Although the procedural safety has substantially improved with operator experience, the choice and duration of post-procedural antithrombotic regimen has remained an unresolved issue.^3,4 Typically, endocardial LAA closure devices require short-term postprocedural oral anticoagulation for a few weeks to months during device endothelization.⁵ In some patients, however, complete endothelization may not occur and increases the risk of peri-device leak and device-related thrombus (DRT). There is wide variation in the reported incidence of DRT due to differences in the type of LAA closure device, choice and duration of post-procedural antithrombotic regimen, and timing of surveillance imaging (Table 1).^6-19 The clinical implications of DRT are uncertain, and its association with ischemic stroke and systemic thromboembolism is debatable.^8,9,12,15 Currently, there is no consensus regarding the optimal management strategy for DRT. In this expert analysis, we discuss the incidence, predictors, clinical implications, and management of DRT in patients receiving percutaneous LAA closure.

Table 1: Studies Reporting DRT Post-WATCHMAN (Boston Scientific; Marlborough, MA), AMPLATZER Cardiac Plug (ACP) or Amulet (Abbott; Abbott Park, IL) LAA Closure

Authors (Year)Ref	Study Population	Type of Study	Type of LAA Closure	Incidence of DRT (%)	Post-Procedural Antithrombotic Strategy	Transesophageal Echocardiography (TEE) or Cardiac Computed Tomography (CT) Surveillance
Dukkipati et al. (2018)8	1,739	Two randomized clinical trials (PROTECT-AF & PREVAIL) and two prospective observational registries (CAP & CAP2)	WATCHMAN	3.74%	Aspirin 81 mg daily + warfarin for 45 days, dual antiplatelet therapy (DAPT) for 4.5 months and then lifelong aspirin 81 mg daily	45 days, 6 months and 1 year
Bergman et al. (2018)6	605	Prospective, observational registry	WATCHMAN	4%	DAPT	Variable, 87% received at least one TEE during follow-up
Fauchier et al. (2018)9	469	Retrospective	WATCHMAN & AMPLATZER	7.2%	Oral anticoagulation 29%; oral anticoagulation + single antiplatelet 4.6%; DAPT 23%; single antiplatelet 36%; and none 7.7%	1-3 months and 12 months
Pracon et al. (2018)20	102	Prospective	WATCHMAN & AMPLATZER	7.1%	DAPT	1.5, 3, 16, and 12 months
Sawaya et al. (2017)18	64	Prospective, observational	Amulet	3.4%	DAPT	3 months
Sedaghat et al. (2017)17	24	Prospective, observational	Amulet	16.7%	DAPT for 3 months	Variable, 4-20 weeks
Boersma et al. (2017)7	1,025	Prospective, observational registry	WATCHMAN	3.7%	Vitamin K antagonists 16%; non-vitamin K oral anticoagulant 11%; single antiplatelet 7%; DAPT 60%; and none 6%.	Variable, 87% had at least one TEE during follow-up
Saw et al. (2017)15	339	Retrospective analysis	AMPLATZER	3.2%	DAPT 1-3 months followed by aspirin for at least 3 months	Variable, mean follow-up of TEE 198.2 ± 181.3 days
Kubo et al. (2017)10	119	Retrospective	WATCHMAN	3.4%	Aspirin 81 mg daily + warfarin for 45 days, DAPT for 4.5 months and then lifelong aspirin 81 mg daily	45 days, 6 months and 1 year
Tzikas et al. (2016)3	632	Prospective	ACP	4.4%	DAPT	3-11 months
Enomoto et al. (2016)22	214	Retrospective	WATCHMAN	0.5% (non-vitamin K oral anticoagulant) and 0.9% (Warfarin)	Warfarin/ non-vitamin K oral anticoagulant	6 weeks to 4 months and 12 months
Urena et al. (2013)16	52	Prospective, non-randomized study	ACP	0%	DAPT/single antiplatelet	6 months
Reddy et al. (2013)14	150	Prospective, non-randomized study	WATCHMAN	4%	DAPT for 6 months then lifelong aspirin	3, 12 months
Plicht et al. (2013)13	34	Retrospective	ACP	17.6%	DAPT	3, 6, 12 months
Lam et al. (2012)11	20	Prospective, non-randomized study	ACP	0%	DAPT for 4 weeks followed by single antiplatelet	2 months

Incidence of DRT

The reported incidence of DRT with the WATCHMAN LAA closure device is highly variable and ranges from 0 to 9%.^{6,8-10,12,19,20} Table 1 summarizes the available clinical trials reporting DRT with percutaneous endocardial LAA closure. In the largest prospective evaluation by Dukkipati et al. including 1,739 patients who received WATCHMAN LAA closure in four US Food and Drug Administration clinical trials—PROTECT-AF (WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation), PREVAIL (Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy), CAP (Continued Access to PROTECT-AF) Registry, and CAP 2 (Continued Access to PREVAIL) Registry—the incidence of DRT was 3.74%.⁸ The post-procedural antithrombotic strategy included aspirin 81 mg daily with warfarin (international normalized ratio goal 2-3) for 45 days followed by DAPT with aspirin 81 mg daily and clopidogrel 75 mg daily for 4.5 months and then lifelong aspirin 81 mg daily. TEE surveillance was performed at 45 days, 6 months (for PROTECT-AF and PREVAIL only) and 1 year, respectively. From published experience from the multicenter, prospective non-randomized EWOLUTION registry of WATCHMAN implantation including 1,025 patients, the incidence of DRT was 2.6% and 3.7% at 3 and 12 months, respectively.^7,21 However, there was substantial variation regarding the choice of post-procedural antithrombotic regimen (vitamin K antagonist in 16%, non-vitamin K oral anticoagulant [NOAC] in 11%, single antiplatelet therapy with either aspirin or clopidogrel in 7%, DAPT in 60%, and no antithrombotics in 6%) and frequency of TEE surveillance among patients in the registry.⁷ In a subsequent analysis of patients who received post-procedural DAPT, the incidence of DRT was 4% at 1-year follow-up.⁶ Similar incidence of DRT (4%) was previously reported in the ASAP (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology) study that was performed in patients who were ineligible for warfarin and received 6 months of DAPT with aspirin and clopidogrel.¹⁴ However, it currently remains unclear if post-procedural DAPT is warranted in patients post-WATCHMAN implantation; this subject needs further investigation. The results of the ongoing ASAP-TOO (Assessment of the WATCHMAN™ Device in Patients Unsuitable for Oral Anticoagulation) (NCT02928497) are awaited. There are also limited data regarding the use of post-procedural warfarin or NOAC among patients receiving a WATCHMAN device. One retrospective study showed that there was no significant difference in DRT between short-term warfarin and NOAC (0.5% vs. 0.9%, p = 1.0).²²

Unlike WATCHMAN, there are no available randomized controlled trials or prospective registries evaluating the incidence of DRT with ACP or Amulet. Most of the published experience is from retrospective studies with substantial variability regarding choice of post-procedural antithrombotic regimen and TEE surveillance. The incidence of DRT reported with ACP/AMPLATZER ranges from 0 to 17.6%.^{9,11-13,15-18} Fauchier et al., in an observational multicenter, "real-life practice" study from France including 469 patients who received WATCHMAN (n = 272) and AMPLATZER (n = 197), reported a higher DRT incidence of 7.2% (WATCHMAN 5.5%, ACP/Amulet 8.2%) after a mean follow-up of 13 ± 13 months.⁹ The post-procedural antithrombotic regimen included single antiplatelet (36%), DAPT (23%), oral anticoagulation (29%), oral anticoagulation + single antiplatelet (4.6%), and nothing (7.7%). Contrary to the above findings, a lower incidence of DRT (3.2%) with the ACP was reported from the Canadian multicenter experience from an analysis of 339 TEEs.¹⁵ Tzikas et al., in a large multicenter prospective study including 1,047 patients receiving ACP, reported an incidence of DRT of 4.4% in the 63% of patients who received TEE at 7-months follow-up.³

Compared with the prior generation ACP, the newer generation Amulet has a larger disc diameter and longer waist and lobe length with a recessed central screw set with a novel design aimed to reduce thrombogenicity. However, the rate of DRT was reported to occur in 16.7% in a small series of 24 patients during treatment with DAPT in 3 patients and clopidogrel monotherapy in 1 patient. Notably, 3 of the 4patients had a history of LAA thrombus, and all 3 had incomplete closure of the limbus with the Amulet device.¹⁷ In an accompanying letter to the editor, Sawaya et al. reported a DRT rate of 3.1% at 3 months in 64 patients receiving Amulet LAA closure device. The 2 reported cases of DRT were due to incomplete closure of the LAA limbus with the Amulet device.¹⁸ A systematic review of 30 published studies on DRT reported a cumulative incidence of 3.9% (WATCHMAN 3.4%, ACP 4.8%, and Amulet 2.0%) from 2,118 LAA closure devices.¹² In the majority of cases when the ACP/Amulet is adequately implanted, post-procedural DAPT therapy appears to be sufficient.

DRT and Risk of Stroke and Systemic Thromboembolism

Several prior studies have demonstrated low incidence of ischemic stroke/systemic embolism in patients with DRT and emphasized that DRT was a benign finding.^4,6,7,10 However, these analyses were limited by the small number of patients and short duration of follow-up.^3,4,12 Our recent pooled analysis from PROTECT-AF, PREVAIL, CAP, and CAP 2 demonstrated that over 5 years, 25% of patients with DRT developed ischemic stroke/systemic thromboembolism compared with 6.8% without DRT (adjusted rate ratio 3.55, 95% confidence interval 2.18-5.79; p < 0.001). There was also a temporal association between diagnosis of DRT and occurrence of stroke/systemic thromboembolism (47.4% and 63.2% occurred within 1 and 6 months, respectively).⁸ In addition, the rates of hemorrhagic stroke were also increased in the DRT patients (risk ratio 7.98, p = 0.002); however, the overall number of events (n = 3) were small, and escalated anticoagulation following DRT diagnosis may have been partially contributory.

The association of stroke and systemic thromboembolism with DRT was also demonstrated in a recent study from France. Ischemic stroke occurred in 15.3% vs. 3.2% (adjusted hazard ratio 4.39) with and without DRT, respectively.⁹ These higher rates are likely due to differences in patient selection and variation in post-procedural antithrombotics in clinical practice compared with clinical trials. Overall, however, it appears that the majority of patients with DRT do not suffer stroke or systemic thromboembolism, and even in patients who had a stroke, it is impossible to rule out a non-cardioembolic source. Furthermore, there is no suggestion that DRT increases risk of all-cause or cardiac mortality compared with those who did not have a DRT or even those AF patients not treated with oral anticoagulation or LAA closure due to risk of major bleeding.

Predictors of DRT

There are several patient and procedural predictors of DRT that have been reported. However, it is important to note that none of them have a cut-off threshold to guide LAA closure implantation or management. Patient-related predictors for DRT post-WATCHMAN include persistent AF, prior history of stroke/systemic thromboembolism, larger LAA diameter, lower LAA flow velocity, lower left ventricular ejection fraction (LVEF), higher CHA₂DS₂-VASc score, and early discontinuation of oral anticoagulants.^{8-10,12,20,23} Additional procedure-related factors include type of post-procedural antithrombotic therapy, larger device, incomplete LAA occlusion, and implantation deep into the LAA.^10,20,23 Similar predictors were also reported with DRT post-ACP/Amulet device.^12,17,18

In general, the pathophysiology of DRT appears to be related to an increased prothrombotic state typically seen in elderly patients with prior stroke/systemic thromboembolism, vascular disease, and high CHA₂DS₂-VASc score. In addition, local factors such as lower LVEF and larger LAA diameter can lead to pooling of blood, promoting thrombus formation. Deep or incomplete implantation may increase the risk of a DRT by exposing areas of trabeculations outside the device, and larger devices increase DRT risk due to their greater fabric areas. Although there is no cut-off for what is considered deep implantation, a gap of <10 mm distance from the pulmonary ridge to the device shoulder has been considered adequate.

Clopidogrel resistance was reported to be associated with adverse consequences in some patients receiving clopidogrel post-LAA closure.²⁴ This phenomenon is rare, and routine blood testing is currently not recommended. In the authors' experience, DRT typically occurs related to the connector pin/metal hub in both available endocardial LAA devices. Newer generation investigational devices such as WATCHMAN FLX (NCT02702271) are designed to minimize exposure of the metal hub (flat and recessed) into the left atrium; whether this will decrease DRT has yet to be determined.

Management of DRT

Currently, there is no consensus on specific recommendations regarding the management of DRT post-LAA closure. There is no question that DRT is at risk of embolization and that acute treatment with therapeutic anticoagulation and aggressive follow-up with imaging to monitor resolution must be considered. However, the long-term management strategy in these patient remains uncertain because some of them may require extended duration of anticoagulation with surveillance imaging with either TEE or cardiac CT. The choice and duration of antithrombotic regimen must be tailored, taking into account patient characteristics (CHA₂DS₂-VASc score, HAS-BLED score, creatinine clearance), echocardiographic findings (low LVEF, smoke in left atrium, decreased LAA velocity), and procedural factors (large device, deep implantation, incomplete closure). Both warfarin and NOACs are effective treatment options.^10,25 As such, in the authors' institution, the post-procedural antithrombotic strategy includes aspirin 81 mg daily with warfarin/NOAC for 6 weeks, followed by another 6 weeks of aspirin 81 mg daily and clopidogrel 75 mg daily, followed by lifelong aspirin 81 mg daily. Surveillance imaging with a TEE/cardiac CT is performed at 4 months and 1 year post-WATCHMAN implantation. We delay the initial TEE to 4 months until the patient is on only aspirin 81 mg daily, when the risk of DRT should be the highest. If DRT is detected, then anticoagulation with either warfarin or NOAC is resumed with repeat imaging in 6 weeks to monitor resolution (Figure 1).

Figure 1: Flowchart Suggesting the Management of DRT Post-WATCHMAN

Conclusion

Overall, the incidence of DRT post-LAA closure is rare but can be associated with an increased risk of stroke and systemic embolism. When detected, DRT warrants treatment with anticoagulation and aggressive follow-up with appropriate surveillance imaging.

References

1. Reddy VY, Doshi SK, Kar S, et al. 5-Year Outcomes After Left Atrial Appendage Closure: From the PREVAIL and PROTECT AF Trials. J Am Coll Cardiol 2017;70:2964-75.
2. Holmes DR Jr, Doshi SK, Kar S, et al. Left Atrial Appendage Closure as an Alternative to Warfarin for Stroke Prevention in Atrial Fibrillation: A Patient-Level Meta-Analysis. J Am Coll Cardiol 2015;65:2614-23.
3. Tzikas A, Shakir S, Gafoor S, et al. Left atrial appendage occlusion for stroke prevention in atrial fibrillation: multicentre experience with the AMPLATZER Cardiac Plug. EuroIntervention 2016;11:1170-9.
4. Reddy VY, Holmes D, Doshi SK, Neuzil P, Kar S. Safety of percutaneous left atrial appendage closure: results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued Access Registry. Circulation 2011;123:417-24.
5. Kar S, Hou D, Jones R, et al. Impact of Watchman and Amplatzer devices on left atrial appendage adjacent structures and healing response in a canine model. JACC Cardiovasc Interv 2014;7:801-9.
6. Bergmann MW, Ince H, Kische S, et al. Real-world safety and efficacy of WATCHMAN LAA closure at one year in patients on dual antiplatelet therapy: results of the DAPT subgroup from the EWOLUTION all-comers study. EuroIntervention 2018;13:2003-11.
7. Boersma LV, Ince H, Kische S, et al. Efficacy and safety of left atrial appendage closure with WATCHMAN in patients with or without contraindication to oral anticoagulation: 1-Year follow-up outcome data of the EWOLUTION trial. Heart Rhythm 2017;14:1302-8.
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11. Lam YY, Yip GW, Yu CM, et al. Left atrial appendage closure with AMPLATZER cardiac plug for stroke prevention in atrial fibrillation: initial Asia-Pacific experience. Catheter Cardiovasc Interv 2012;79:794-800.
12. Lempereur M, Aminian A, Freixa X, et al. Device-associated thrombus formation after left atrial appendage occlusion: A systematic review of events reported with the Watchman, the Amplatzer Cardiac Plug and the Amulet. Catheter Cardiovasc Interv 2017;90:E111-E121.
13. Plicht B, Konorza TF, Kahlert P, et al. Risk factors for thrombus formation on the Amplatzer Cardiac Plug after left atrial appendage occlusion. JACC Cardiovasc Interv 2013;6:606-13.
14. Reddy VY, Möbius-Winkler S, Miller MA, et al. Left atrial appendage closure with the Watchman device in patients with a contraindication for oral anticoagulation: the ASAP study (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology). J Am Coll Cardiol 2013;61:2551-6.
15. Saw J, Tzikas A, Shakir S, et al. Incidence and Clinical Impact of Device-Associated Thrombus and Peri-Device Leak Following Left Atrial Appendage Closure With the Amplatzer Cardiac Plug. JACC Cardiovasc Interv 2017;10:391-9.
16. Urena M, Rodés-Cabau J, Freixa X, et al. Percutaneous left atrial appendage closure with the AMPLATZER cardiac plug device in patients with nonvalvular atrial fibrillation and contraindications to anticoagulation therapy. J Am Coll Cardiol 2013;62:96-102.
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18. Sawaya FJ, Chow DHF, Millan-Iturbe O, De Backer O. Device-Related Thrombus Formation With the Amplatzer Amulet LAA Device: Optimal Implantation = Optimal Results. JACC Clin Electrophysiol 2017;3:189-90.
19. Main ML, Fan D, Reddy VY, et al. Assessment of Device-Related Thrombus and Associated Clinical Outcomes With the WATCHMAN Left Atrial Appendage Closure Device for Embolic Protection in Patients With Atrial Fibrillation (from the PROTECT-AF Trial). Am J Cardiol 2016;117:1127-34.
20. Pracon R, Bangalore S, Dzielinska Z, et al. Device Thrombosis After Percutaneous Left Atrial Appendage Occlusion Is Related to Patient and Procedural Characteristics but Not to Duration of Postimplantation Dual Antiplatelet Therapy. Circ Cardiovasc Interv 2018;11:e005997.
21. Bergmann MW, Betts TR, Sievert H, et al. Safety and efficacy of early anticoagulation drug regimens after WATCHMAN left atrial appendage closure: three-month data from the EWOLUTION prospective, multicentre, monitored international WATCHMAN LAA closure registry. EuroIntervention 2017;13:877-84.
22. Enomoto Y, Gadiyaram VK, Gianni C, et al. Use of non-warfarin oral anticoagulants instead of warfarin during left atrial appendage closure with the Watchman device. Heart Rhythm 2017;14:19-24.
23. Kaneko H, Neuss M, Weissenborn J, Butter C. Predictors of thrombus formation after percutaneous left atrial appendage closure using the WATCHMAN device. Heart Vessels 2017;32:1137-43.
24. Gianni C, Horton R, O'Grady C, et al. CLOPIDOGREL RESISTANCE IN PATIENTS UNDERGOING LEFT ATRIAL APPENDAGE CLOSURE WITH THE WATCHMAN DEVICE. J Am Coll Cardiol 2018;71(11 Supplement):A408.
25. Freixa X, Scalone G, Martín-Yuste V, Vidal B. Large protruding thrombus over left atrial appendage occlusion device successfully treated with apixaban. Eur Heart J 2015;36:1427.

Keywords: Anticoagulants, Aspirin, Atrial Fibrillation, Atrial Appendage, Brain Ischemia, Confidence Intervals, Creatinine, Echocardiography, Embolism, Factor VIII, Feasibility Studies, Fibrinolytic Agents, Follow-Up Studies, Goals, Heart Atria, Incidence, International Normalized Ratio, Odds Ratio, Patient Selection, Prospective Studies, Registries, Retrospective Studies, Smoking, Stroke, Stroke Volume, Thromboembolism, Thrombosis, Ticlopidine, Tomography, X-Ray Computed, United States Food and Drug Administration, Vitamin K, Warfarin

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