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Left atrial appendage closure device implantation in patients at very high risk for stroke
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Left atrial appendage closure device implantation in patients at very high risk for stroke Q8
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Erika Hutt, MD,* Oussama M. Wazni, MD,† Simrat Kaur, MD,* Walid I. Saliba, MD,† Khaldoun G. Tarakji, MD,† Samir Kapadia, MD,‡ Jose Aguilera, MD,* Amr F. Barakat, MD,x Mouin Abdallah, MD,{ Wael Jaber, MD,k Peter Rasmussen, MD,** Shazam Hussain, MD,** Ken Uchino, MD,** Dolora Wisco, MD,** Bruce D. Lindsay, MD,† Mohamed Kanj, MD,† Ayman A. Hussein, MD† From the *Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, †Section of Cardiac Pacing and Electrophysiology, Cleveland Clinic Foundation, Cleveland, Ohio, ‡Section Head of Invasive and Interventional Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio, xDepartment of Cardiovascular Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, { Section of Clinical Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio, kSection of Cardiovascular Imaging, Cleveland Clinic Foundation, Cleveland, Ohio, and **Department of Cerebrovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio.
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BACKGROUND Little is known about the role of left atrial appendage closure using the Watchman device (Boston Scientific) in patients who are at very high risk for stroke. OBJECTIVE The purpose of this study was to assess the role of Watchman in patients with CHA2DS2-VASc 5. METHODS All patients undergoing procedures for Watchman implant at our institution were enrolled in a prospective registry. All 104 consecutive recipients with CHA2DS2-VASc 5 were included. RESULTS Median patient age was 78.5 6 6.4 years, 56% were male, mean CHA2DS2-VASc was 5.7 6 0.9, and mean HASBLED was 4.0 6 1.0. Indications for implantation were significant prior bleeding (73%), unacceptable bleeding risk (21%), and unacceptable stroke and bleeding risk (6%). Watchman implantation was successful in all patients. All but 2 patients completed 45 days of postprocedural anticoagulation; 56% used warfarin and 44% used a novel oral anticoagulant. Transesophageal echocardiogram at 45
Introduction The Watchman device (Boston Scientific, St. Paul, MN) is increasingly being used in clinical practice for left atrial appendage closure (LAAC) and stroke prevention in patients
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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Drs Wazni, Saliba, and Kanj are advisory board consultants for Boston Scientific Corporation. All other authors have reported that they have no conflicts relevant to the contents of this paper to disclose. Address reprint requests and correspondence: Dr Ayman A. Hussein, Heart and Vascular Institute, Cleveland Clinic, Section of Cardiac Pacing and Electrophysiology, 9500 Euclid Avenue, J22, Cleveland, OH 44195. E-mail address: [email protected].
days revealed no significant peridevice leak. One patient was found to have a small mobile, filamentous echodensity attached on the medial aspect of the Watchman device. This resolved with longer anticoagulation with dabigatran and did not result in adverse outcome. At 1-year follow up, ischemic stroke had occurred in 3 patients (2.8%) at 96, 119, and 276 days after the procedure. CONCLUSION In a population of patients with mean CHA2DS2-VASc of 5.7, Watchman implantation seemed to be safe and efficacious, with a residual annual ischemic stroke risk of 2.8%. In an atrial fibrillation population with a similar CHA2DS2-VASc score, the estimated annual risk of stroke is z12% off anticoagulation and .4% on warfarin. KEYWORDS Anticoagulation; Atrial fibrillation; Left atrial appendage closure; Stroke; Watchman device (Heart Rhythm 2019;-:1–6) © 2019 Published by Elsevier Inc. on behalf of Heart Rhythm Society.
with atrial fibrillation (AF) who cannot tolerate long-term oral anticoagulation.1,2 Approval of the device was based Q4 on 2 clinical trials, PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) and PREVAIL (Prospective Randomized Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy),3–5 which showed that Watchman is a safe alternative to anticoagulation for stroke prevention.6 The PROTECT AF trial included 707 patients, whereas PREVAIL included 407 patients, with 463 and 269 patients in each intervention arm (Watchman device implantation), respectively. However, patients included in
1547-5271/$-see front matter © 2019 Published by Elsevier Inc. on behalf of Heart Rhythm Society.
https://doi.org/10.1016/j.hrthm.2019.07.011
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these trials were primarily patients at low to intermediate risk for stroke, with mean CHADS2 scores of 2.2 6 1.2 and 2.6 6 1.0 in PROTECT-AF and PREVAIL, respectively. Data are limited on the safety and efficacy of Watchman implantation in patients who are at higher stroke risk, such as those with CHA2DS2-VASc 5, which corresponds to an annual risk of stroke of at least z12% off anticoagulation and .4% on warfarin. A multicenter French registry evaluated percutaneous LAAC in patients at high risk of stroke (mean CHADS2-VASc 4.5) who could not tolerate longterm oral anticoagulation and found that LAAC decreased the risk of stroke compared to the predicted risk.7 However, this was associated with complications and elevated postprocedural morbidity. Such complication rates and increased morbidity could reflect the early experience with LAAC, spanning the period between 2013 and 2015. We sought to assess the safety and efficacy of Watchman device implantation in patients with CHA2DS2-VASc 5 at a large tertiary care center in the United States.
Methods All patients undergoing procedures for Watchman implantation at our institution were enrolled in a prospectively maintained data registry and screened for inclusion in the current study. Between May 2015 and November 2017, all 104 consecutive patients with CHA2DS2-VASc 5 were included. The study was reviewed and approved by the Institutional Review Board. All patients were evaluated and followed at a multidisciplinary AF stroke prevention clinic. A robust shared medical decision process was in place and involved discussions among patients, cardiac electrophysiologists, cardiologists, and neurologists/neurosurgeons.
Periprocedural anticoagulation and Watchman implant procedures All procedures were performed with therapeutic oral anticoagulation with either warfarin or a direct oral anticoagulant (DOAC). The choice of anticoagulation strategy was up to the multidisciplinary team, accounting for the patients’ comorbid conditions. For patients on warfarin, therapeutic levels of international normalized ratio (2–3) were required preprocedurally, on the day of the procedure, and during follow-up. For patients on DOACs, anticoagulants were started ideally 2–3 weeks before the procedure and at least 24–48 hours before the procedure. All patients on DOACs received an appropriate dose of anticoagulation, accounting for kidney function when necessary. Only a single dose was held immediately before the procedure, except for rivaroxaban, which was uninterrupted (typically taken in the afternoon the day before the procedure). DOACs were then restarted immediately after device implantation. Our Watchman device implantation protocol was previously reported in detail.8 All devices were implanted with patients under general anesthesia and with transesophageal echocardiography (TEE) guidance. Transseptal access was
performed with intracardiac echocardiography and fluoroscopy guidance. Intravenous heparin was initiated before transseptal access and maintained during the procedure to target an activated clotting time of 300 seconds. An angiogram was performed to delineate the size and shape of the left atrial appendage (LAA), with a pigtail catheter selectively placed in the appendage. The Watchman delivery system was advanced, and an appropriately sized device was deployed to cover the ostium. Complete occlusion of the LAA was confirmed by TEE. Appropriate compression of the device was confirmed by TEE measurements, and a tug test was performed under fluoroscopy. The device was released, and sheaths were pulled back to the inferior vena cava. Heparin was reversed with protamine, and femoral vascular hemostasis was achieved with manual pressure. Patients were admitted for overnight observation and discharged the following day with planned 45 days of anticoagulation. All patients were assessed for procedural complications immediately after the procedure and before hospital discharge. Upon discharge, patients were encouraged to immediately report any bleeding or other symptoms. A follow-up visit was scheduled 45 days postprocedure, during which a repeat TEE was performed to ensure effective occlusion of the LAA and to assess for thrombi. All TEEs were performed at our institution. If complete occlusion or a nonsignificant device leak (5 mm) was confirmed by TEE in the absence of device-related thrombi, patients were taken off oral anticoagulation and switched to a combination of acetylsalicylic acid (ASA) and clopidogrel, typically Q5 planned until 6 months postimplantation, then ASA alone thereafter. Alternatively, continuation of apixaban and ASA for a total of 4–6 months, then ASA alone thereafter was an anticoagulation option, at the discretion of the managing electrophysiologist. Additional follow-up visits were scheduled at 6 and 12 months after the procedures and yearly thereafter. More frequent visits were scheduled as clinically needed. The outcomes of interest were the safety and efficacy of Watchman implantation, primarily periprocedural complications including stroke and stroke at 12-month follow-up. In addition, we aimed to assess for bleeding events, successful LAAC at 45-day TEE, device-related thrombosis, and mortality at 12-month follow-up.
Statistical analysis Continuous variables are expressed as mean 6 SD or median (interquartile range [IQR]) as appropriate. Categorical variables are presented as absolute number and percentage (%).
Results Patient population A total of 104 consecutive patients with AF and CHA2DS2VASc 5 who had undergone procedures for Watchman implantation between April 2015 and November 2017 at our program were included. Median age was 78.5 6 6.4 years, and 56% were male. Baseline patient characteristics are listed
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Table 1
Watchman in High Stroke Risk Baseline characteristics of the study population
Age (y) Male gender Hypertension Diabetes mellitus Smoking history CAD CHF LVEF (%) History of TIA/CVA
CHA2DS2-VASc CHADS2 HASBLED Rhythm at baseline History of atrial fibrillation ablation Warfarin for OAC DOAC for OAC
Indications for device implantation
78.5 6 6.4 (74–83) 56 (54) 90 (86) 38 (37) 44 (42) 59 (57) 24 (23) 53 6 10 (50–60) 56 (54) CVA 32: 67% ischemic/cardioembolic, 28% hemorrhagic, 5% ischemic/ thrombotic TIA 17 Recurrent CVA or TIA 13 TIA and CVA 7 CVA while on OAC 15 (26%) 5.7 6 0.9 (5–6) 3.5 6 1 (3–4) 4.0 6 1.0 (3–5) Persistent 54 (52) Paroxysmal 39 (37) Paced 11 (11) 12 (12) 58 (56) 46 (44) Apixaban 41 Dabigatran 3 Rivaroxaban 2 Prior major bleeding events 76 (73) Gastrointestinal 36 Intracranial hemorrhage/subdural hematoma 20 Genitourinary 4 Retroperitoneal 4 Soft tissue hematoma/hemarthrosis 3 Epistaxis 2 Other 7: retinal hemorrhage, obscure bleeding, multiple sites Unacceptable bleeding condition 22 (21) Recurrent falls 15 Hematologic disorders 5 Cerebrovascular malformation 2 Recurrent stroke on OAC 3 (3) Patient preference 2 (2) Recurrent LAA thrombus 1 (1)
Values are given as mean 6 SD (Q1–Q3) or n (%) unless otherwise indicated. CAD 5 coronary artery disease; CHF 5 congestive heart failure; CVA 5 cerebrovascular accident; DOAC 5 direct oral anticoagulant; LAA 5 left atrial appendage; LVEF 5 left ventricular ejection fraction; OAC 5 oral anticoagulant; TIA 5 transient ischemic attack.
in Table 1. Mean CHA2DS2-VASc score was 5.7 6 0.9, with a median value of 5.0 (IQR 5–6). Mean HASBLED score was 4.0 6 1.0, with a median value of 4.0 (IQR 3–5). The indications for implantation were significant prior bleeding in 76 (73%), unacceptable bleeding risk in 22 (21%), and unacceptable stroke risk along with concerns regarding bleeding on anticoagulation in the remaining 6 (6%). Of the total 104 patients, 56 (54%) had a history of prior cerebrovascular accident (CVA) and/or transient ischemic attack (TIA).
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Watchman implant procedure At the time of the procedure, 54 patients (52%) were in AF, 39 (38%) were in sinus rhythm, and 11 (10%) had paced ventricular rhythms (5 underlying AF and 6 sinus rhythm with high-degree atrioventricular block). Watchman was successfully implanted in all patients. Oral anticoagulants used periprocedurally are listed in Table 1. Only 1 procedure-related complication occurred (a groin hematoma that required transfusion). No pericardial effusions or procedure-related strokes occurred.
Postprocedural anticoagulation and follow-up Postprocedurally, all patients were prescribed 45 days of oral anticoagulant (OAC) and lifetime aspirin. All but 2 patients completed 45 days of anticoagulation: 1 had a spontaneous retroperitoneal hematoma 30 days postimplantation on warfarin and 1 had intracranial hemorrhage (ICH) resulting in death (original implant indication was recurrent falls) 10 days postimplant on apixaban. Of the patients who completed 45 days of anticoagulation, 58 (57%) used warfarin and 44 (43%) a DOAC (39 apixaban, 2 dabigatran, 2 rivaroxaban). Transesophageal echocardiograms performed 45 days postimplant revealed no peridevice leak .5 mm. One patient was found by TEE to have a small mobile, filamentous echodensity attached on the medial aspect of the Watchman device. This patient was switched from warfarin to dabigatran on day 45 and completed a total of 12 weeks of anticoagulation. Follow-up TEE performed 130 days postimplantation showed resolution of the echodensity, and the patient was switched to low-dose aspirin. No stroke occurred during follow-up of this patient. Dual antiplatelet therapy (DAPT) was completed to 6 months postimplant in 48 of 101 living patients at 6 months. Of the remaining 53 patients, 21 used a shorter course of DAPT and 32 used no DAPT. Reasons for shorter course or no DAPT are summarized in Figure 1. Shorter duration of DAPT ranged between 1 and 4 months (mean 3.0 6 0.9 months). Among patients who did not use DAPT, the duration of longer OAC was variable, based on indication and physician/patient preference, but ranged between 3 months to maximum duration of follow up (45 months at time of analysis). All patients except 2 remained on aspirin: 1 because of recurrent stroke who is now taking clopidogrel only with avoidance of DAPT given the patient’s history of bleeding, and the other because of a new indication for OAC (pulmonary embolism that occurred 6 months after LAAC). In the latter patient, the combination of aspirin and OAC with apixaban was avoided given the patient’s history of ICH. Median duration of OAC with aspirin, DAPT, and OAC alone was 45 days (IQR 45–45), 4 months (IQR 0–6), and 45 days (IQR 45–45), respectively.
Twelve-month outcomes Ischemic stroke had occurred in 3 patients (2.8%) at 1-year follow-up. The timing of ischemic strokes were 96, 119,
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Figure 1
Duration of dual antiplatelet therapy (DAPT) and reasons for shorter course of therapy. AF 5 atrial fibrillation; OAC 5 oral anticoagulant.
and 276 days after the procedure. Figure 2 describes all events in detail. All patients underwent TEE at the time of the event. No patient was found to have significant peridevice leak or device-related thrombus at the time of the event (0.4cm leak was documented in the patient who experienced stroke on day 96). Suspected etiologies for these events were paradoxical embolism in 2 patients and carotid atheroembolism in 1 patient. Upon follow-up, a total of 42 patients(40%) remained in persistent/permanent AF, 38 (37%) continued to have paroxysmal AF, and 24 (23%) had paced rhythms, 5 of whom had underlying AF with ventricular pacing. A total of 31 (30%) had undergone ablation procedures (pulmonary vein isolation 26, AV nodal ablation 5). Of the ablation procedures, 20 were performed before Watchman (median time 1141 days before, minimum 20 days before), 7 at the time of the
Day 96
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procedure, and 4 after Watchman procedures (median time 312 days after, minimum 180 days after). Bleeding events during the 12-month follow-up period occurred in 14 patients (13%). The majority consisted of gastrointestinal and genitourinary bleeds (n 5 8), followed by ICH (n 5 2), retroperitoneal bleed (n 5 1), and traumarelated lower extremity hematoma (n 5 3). All except 4 occurred within 45 days while on OAC and aspirin. Bleeding events after 45 days occurred on days 60, 69, 300, and 307 while on DAPT (n 5 2), aspirin (n 5 2), and longer OAC (n 5 1, for concomitant AF ablation). Only 1 bleeding event was fatal (ICH at day 10). The remaining were treated conservatively with blood transfusions and/or hospitalization with clinical recovery. Four deaths had occurred during 12-month follow-up. One was related to a bleeding complication (ICH); the
• On DAPT at time of stroke, restarted on apixaban • AF documented at time of event • History of recurrent stroke prior to device implantation • Suspected etiology: paradoxycal embolism, presence of PFO
Day 119
• On DAPT at time of stroke, restarted on warfarin • AF documented at time of event • History of recurrent stroke prior to device implantation • Suspected etiology: paradoxycal embolism, presence of PFO and pulmonary hypertension
Day 276
• On aspirin only at the time of ischemic stroke and switched to clopidogrel only • Did not receive 6 months of DAPT because of thrombocytopenia • NSR at time of event • Suspected etiology: carotid atheroembolism
Figure 2 Characteristics of observed strokes (n 5 3) at 1-year follow up. AF 5 atrial fibrillation; DAPT 5 dual antiplatelet therapy; NSR 5 normal sinus rhythm; PFO 5 patent foramen ovale. FLA 5.6.0 DTD HRTHM8079_proof 30 July 2019 6:50 pm ce
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Watchman in High Stroke Risk
remaining 3 were related to heart failure (n 5 2) or severe pulmonary hypertension (n 5 1).
Discussion In this study, AF patients at very high stroke risk with CHA2DS2-VASc 5 and unacceptable bleeding risk were found to benefit from Watchman implantation with high efficacy and low complication rates. Such patients would have an estimated annual stroke risk of 10%–12% without anticoagulant therapy and .4% with warfarin,9 but the observed stroke rate over 1-year follow-up was 2.8%, suggesting reduction in stroke risk with Watchman implantation. This corresponds to an approximately 30% relative risk reduction of stroke with Watchman vs warfarin. Compared to apixaban, which has an estimated annual stroke risk of 3.3% in a similar population, the relative risk reduction is 15%. The elevated CHA2DS2-VASc score of this patient population was largely the result of the high prevalence of prior CVA and/or TIA. This subgroup of patients did not seem to be at increased risk for recurrence of cerebrovascular events from implantation of a Watchman device. The efficacy of the Watchman device for stroke prevention in patients with nonvalvular AF was assessed in the PROTECT and PREVAIL trials, which compared the device to warfarin. These studies used the CHADS2 score to stratify patients’ stroke risk. Mean CHA2DS2 in PROTECT and PREVAIL were 2.2 and 2.6, respectively, which translates to an annual risk of stroke between 2% and 3%. The population of patients in the studies leading to approval of the device was, as such, a population at relatively low stroke risk, and little is known about the benefit of such devices in patients with much higher stroke risks. In clinical practice, comorbid conditions that predispose patients to stroke can also predispose them to bleeding. In our practice, most patients being referred for Watchman implantation were at increased risk for both stroke off anticoagulation and bleeding on anticoagulation. The current study suggests that Watchman implantation might have a net clinical benefit in patients at very high stroke risk and should be considered, especially in cases with concerns regarding the safety of long-term anticoagulation. The French Nationwide Observational LAAC (FLAAC) registry reported similar thromboembolic outcomes in a high-stroke risk population such as the one included in this study.7 However, they also reported a high rate of serious complications, including device-related complications, similar to those reported in PROTECT and PREVAIL. Of note, even though only 23.5% of these patients received short-term OAC per Watchman protocol, a higher incidence of serious pericardial effusions requiring intervention was reported. They concluded that LAAC can decrease the predicted risk of thromboembolism in a population intolerant to anticoagulation, but that given the high incidence of serious complications, the decision to pursue LAAC should be made with caution. Our experience is in contrast to this multicenter French registry with regard to the complication
5 rate, which was much lower in our registry. We believe this is due to early procedural hazard in the FLAAC registry, which reported LAAC outcomes of procedures performed between 2013 and 2015, in contrast to our data, which includes “post-FDA approval” procedures performed between 2015 and 2017. In addition, our center is a highvolume center with approximately 100 Watchman procedures performed per year. This translates into high operator experience, which PREVAIL proved to be associated with lower procedure-related severe adverse events. In addition, the systematic use of intracardiac echocardiography to guide transseptal access, ensuring air-free irrigation lines, maintaining heparinized saline through transseptal sheaths, and adhering to standard implantation techniques have helped our center maintain excellent safety profiles of the procedures, even during the early stages. Despite the high bleeding risk profile of our study population (mean HASBLED 4.0), postprocedural short-term anticoagulation seems to be tolerated even by patients who had experienced prior ICH.10 We previously reported bleeding outcomes in a population at high risk for bleeding,8,10 and we favor the completion of short-term OAC after Watchman implantation as it has been associated with fewer events of device-related thrombosis. The majority of patients included in this study were considered to have “contraindication” to anticoagulation, but under close surveillance and for a short period of time, most of these patients tolerated short-term anticoagulation for the purpose of Watchman device implantation. It is important to emphasize certain technical aspects in our practice that added to the safety of the procedure, including ensuring that all lines and sheaths were free of air bubbles and initiation of intraprocedural heparin before transseptal access. Furthermore, patient education with emphasis on the importance of compliance to medications, especially postprocedurally, is essential to achieve excellent outcomes.
Study limitations This study has the limitation of observational studies, but data were derived from a prospectively maintained registry of procedural profiles and outcomes. Referral bias cannot be fully excluded due to the observational nature of the data, but the data presented reflect the outcomes of a multidisciplinary assessment involving neurologists, neurosurgeons, and gastroenterologists on a case-by-case basis, and as such the findings emphasize the importance of such collaboration, especially in challenging clinical scenarios. Finally, the study reflects the experience of a tertiary care large-volume center and may not be generalizable to all centers performing such implants.
Conclusion In a population of patients with mean CHA2DS2-VASc of 5.7, Watchman implantation seemed to be safe and efficacious, with a residual annual ischemic stroke risk of 2.8%. In such a high-risk population, the estimated annual risk of stroke is otherwise z12% off anticoagulation and .4% on
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warfarin. These findings suggest that Watchman implantation is beneficial in patients at very high stroke risk and should be considered, especially in clinical scenarios with concerns regarding the safety of long-term anticoagulation.
Acknowledgments We thank the Art Institute at Cleveland Clinic for their contribution to the design and illustration of the graphical abstract. Special thanks to Ross Papalardo, CMI.
References 1. Dawson AG, Asopa S, Dunning J. Should patients undergoing cardiac surgery with atrial fibrillation have left atrial appendage exclusion? Interact Cardiovasc Thorac Surg 2010;10:306–311. 2. Squiers JJ, Edgerton JR. Surgical closure of the left atrial appendage: the past, the present, the future. J Atr Fibrillation 2018;10:1642. 3. Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomized non-inferiority trial. Lancet 2009;374:534–542.
4. Holmes DR Jr, Kar S, Price MJ, et al. Prospective randomized evaluation of the WatchmanÔ left atrial appendage closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial. J Am Coll Cardiol 2014; 64:1–12. 5. Reddy VY, Doshi SK, Sievert H, et al. Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation: 2.3-year follow-up of the PROTECT AF (WatchmanÔ Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) Trial. Circulation 2013;127:720–729. 6. 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;17:41187–41189. 7. Teiger E, Thambo JB, Defaye P, et al. Percutaneous left atrial appendage closure is a reasonable option for patients with atrial fibrillation at high risk for cerebrovascular events. Circ Cardiovasc Interv 2018;11:e005841. 8. Barakat AF, Hussein AA, Saliba WI, et al. Initial experience with high-risk patients excluded from clinical trials: safety of short-term anticoagulation after left atrial appendage closure device. Circ Arrhythm Electrophysiol 2016; 9:e004004. 9. Loewen P. SPARC—Stroke Prevention in Atrial Fibrillation Risk Tool. September 2017. Retrieved April 8, 2018. Available at http://www.sparctool. com. 10. Hutt E, Wazni OM, Saliba WI, et al. Left atrial appendage closure device implantation in patients with prior intracranial hemorrhage. Heart Rhythm 2019; 16:663–668.
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Left atrial appendage closure device implantation in patients at very high risk for stroke Q8
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Erika Hutt, MD,* Oussama M. Wazni, MD,† Simrat Kaur, MD,* Walid I. Saliba, MD,† Khaldoun G. Tarakji, MD,† Samir Kapadia, MD,‡ Jose Aguilera, MD,* Amr F. Barakat, MD,x Mouin Abdallah, MD,{ Wael Jaber, MD,k Peter Rasmussen, MD,** Shazam Hussain, MD,** Ken Uchino, MD,** Dolora Wisco, MD,** Bruce D. Lindsay, MD,† Mohamed Kanj, MD,† Ayman A. Hussein, MD† From the *Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, †Section of Cardiac Pacing and Electrophysiology, Cleveland Clinic Foundation, Cleveland, Ohio, ‡Section Head of Invasive and Interventional Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio, xDepartment of Cardiovascular Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, { Section of Clinical Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio, kSection of Cardiovascular Imaging, Cleveland Clinic Foundation, Cleveland, Ohio, and **Department of Cerebrovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio.
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BACKGROUND Little is known about the role of left atrial appendage closure using the Watchman device (Boston Scientific) in patients who are at very high risk for stroke. OBJECTIVE The purpose of this study was to assess the role of Watchman in patients with CHA2DS2-VASc 5. METHODS All patients undergoing procedures for Watchman implant at our institution were enrolled in a prospective registry. All 104 consecutive recipients with CHA2DS2-VASc 5 were included. RESULTS Median patient age was 78.5 6 6.4 years, 56% were male, mean CHA2DS2-VASc was 5.7 6 0.9, and mean HASBLED was 4.0 6 1.0. Indications for implantation were significant prior bleeding (73%), unacceptable bleeding risk (21%), and unacceptable stroke and bleeding risk (6%). Watchman implantation was successful in all patients. All but 2 patients completed 45 days of postprocedural anticoagulation; 56% used warfarin and 44% used a novel oral anticoagulant. Transesophageal echocardiogram at 45
Introduction The Watchman device (Boston Scientific, St. Paul, MN) is increasingly being used in clinical practice for left atrial appendage closure (LAAC) and stroke prevention in patients
Q1
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Drs Wazni, Saliba, and Kanj are advisory board consultants for Boston Scientific Corporation. All other authors have reported that they have no conflicts relevant to the contents of this paper to disclose. Address reprint requests and correspondence: Dr Ayman A. Hussein, Heart and Vascular Institute, Cleveland Clinic, Section of Cardiac Pacing and Electrophysiology, 9500 Euclid Avenue, J22, Cleveland, OH 44195. E-mail address: [email protected].
days revealed no significant peridevice leak. One patient was found to have a small mobile, filamentous echodensity attached on the medial aspect of the Watchman device. This resolved with longer anticoagulation with dabigatran and did not result in adverse outcome. At 1-year follow up, ischemic stroke had occurred in 3 patients (2.8%) at 96, 119, and 276 days after the procedure. CONCLUSION In a population of patients with mean CHA2DS2-VASc of 5.7, Watchman implantation seemed to be safe and efficacious, with a residual annual ischemic stroke risk of 2.8%. In an atrial fibrillation population with a similar CHA2DS2-VASc score, the estimated annual risk of stroke is z12% off anticoagulation and .4% on warfarin. KEYWORDS Anticoagulation; Atrial fibrillation; Left atrial appendage closure; Stroke; Watchman device (Heart Rhythm 2019;-:1–6) © 2019 Published by Elsevier Inc. on behalf of Heart Rhythm Society.
with atrial fibrillation (AF) who cannot tolerate long-term oral anticoagulation.1,2 Approval of the device was based Q4 on 2 clinical trials, PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) and PREVAIL (Prospective Randomized Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy),3–5 which showed that Watchman is a safe alternative to anticoagulation for stroke prevention.6 The PROTECT AF trial included 707 patients, whereas PREVAIL included 407 patients, with 463 and 269 patients in each intervention arm (Watchman device implantation), respectively. However, patients included in
1547-5271/$-see front matter © 2019 Published by Elsevier Inc. on behalf of Heart Rhythm Society.
https://doi.org/10.1016/j.hrthm.2019.07.011
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these trials were primarily patients at low to intermediate risk for stroke, with mean CHADS2 scores of 2.2 6 1.2 and 2.6 6 1.0 in PROTECT-AF and PREVAIL, respectively. Data are limited on the safety and efficacy of Watchman implantation in patients who are at higher stroke risk, such as those with CHA2DS2-VASc 5, which corresponds to an annual risk of stroke of at least z12% off anticoagulation and .4% on warfarin. A multicenter French registry evaluated percutaneous LAAC in patients at high risk of stroke (mean CHADS2-VASc 4.5) who could not tolerate longterm oral anticoagulation and found that LAAC decreased the risk of stroke compared to the predicted risk.7 However, this was associated with complications and elevated postprocedural morbidity. Such complication rates and increased morbidity could reflect the early experience with LAAC, spanning the period between 2013 and 2015. We sought to assess the safety and efficacy of Watchman device implantation in patients with CHA2DS2-VASc 5 at a large tertiary care center in the United States.
Methods All patients undergoing procedures for Watchman implantation at our institution were enrolled in a prospectively maintained data registry and screened for inclusion in the current study. Between May 2015 and November 2017, all 104 consecutive patients with CHA2DS2-VASc 5 were included. The study was reviewed and approved by the Institutional Review Board. All patients were evaluated and followed at a multidisciplinary AF stroke prevention clinic. A robust shared medical decision process was in place and involved discussions among patients, cardiac electrophysiologists, cardiologists, and neurologists/neurosurgeons.
Periprocedural anticoagulation and Watchman implant procedures All procedures were performed with therapeutic oral anticoagulation with either warfarin or a direct oral anticoagulant (DOAC). The choice of anticoagulation strategy was up to the multidisciplinary team, accounting for the patients’ comorbid conditions. For patients on warfarin, therapeutic levels of international normalized ratio (2–3) were required preprocedurally, on the day of the procedure, and during follow-up. For patients on DOACs, anticoagulants were started ideally 2–3 weeks before the procedure and at least 24–48 hours before the procedure. All patients on DOACs received an appropriate dose of anticoagulation, accounting for kidney function when necessary. Only a single dose was held immediately before the procedure, except for rivaroxaban, which was uninterrupted (typically taken in the afternoon the day before the procedure). DOACs were then restarted immediately after device implantation. Our Watchman device implantation protocol was previously reported in detail.8 All devices were implanted with patients under general anesthesia and with transesophageal echocardiography (TEE) guidance. Transseptal access was
performed with intracardiac echocardiography and fluoroscopy guidance. Intravenous heparin was initiated before transseptal access and maintained during the procedure to target an activated clotting time of 300 seconds. An angiogram was performed to delineate the size and shape of the left atrial appendage (LAA), with a pigtail catheter selectively placed in the appendage. The Watchman delivery system was advanced, and an appropriately sized device was deployed to cover the ostium. Complete occlusion of the LAA was confirmed by TEE. Appropriate compression of the device was confirmed by TEE measurements, and a tug test was performed under fluoroscopy. The device was released, and sheaths were pulled back to the inferior vena cava. Heparin was reversed with protamine, and femoral vascular hemostasis was achieved with manual pressure. Patients were admitted for overnight observation and discharged the following day with planned 45 days of anticoagulation. All patients were assessed for procedural complications immediately after the procedure and before hospital discharge. Upon discharge, patients were encouraged to immediately report any bleeding or other symptoms. A follow-up visit was scheduled 45 days postprocedure, during which a repeat TEE was performed to ensure effective occlusion of the LAA and to assess for thrombi. All TEEs were performed at our institution. If complete occlusion or a nonsignificant device leak (5 mm) was confirmed by TEE in the absence of device-related thrombi, patients were taken off oral anticoagulation and switched to a combination of acetylsalicylic acid (ASA) and clopidogrel, typically Q5 planned until 6 months postimplantation, then ASA alone thereafter. Alternatively, continuation of apixaban and ASA for a total of 4–6 months, then ASA alone thereafter was an anticoagulation option, at the discretion of the managing electrophysiologist. Additional follow-up visits were scheduled at 6 and 12 months after the procedures and yearly thereafter. More frequent visits were scheduled as clinically needed. The outcomes of interest were the safety and efficacy of Watchman implantation, primarily periprocedural complications including stroke and stroke at 12-month follow-up. In addition, we aimed to assess for bleeding events, successful LAAC at 45-day TEE, device-related thrombosis, and mortality at 12-month follow-up.
Statistical analysis Continuous variables are expressed as mean 6 SD or median (interquartile range [IQR]) as appropriate. Categorical variables are presented as absolute number and percentage (%).
Results Patient population A total of 104 consecutive patients with AF and CHA2DS2VASc 5 who had undergone procedures for Watchman implantation between April 2015 and November 2017 at our program were included. Median age was 78.5 6 6.4 years, and 56% were male. Baseline patient characteristics are listed
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Table 1
Watchman in High Stroke Risk Baseline characteristics of the study population
Age (y) Male gender Hypertension Diabetes mellitus Smoking history CAD CHF LVEF (%) History of TIA/CVA
CHA2DS2-VASc CHADS2 HASBLED Rhythm at baseline History of atrial fibrillation ablation Warfarin for OAC DOAC for OAC
Indications for device implantation
78.5 6 6.4 (74–83) 56 (54) 90 (86) 38 (37) 44 (42) 59 (57) 24 (23) 53 6 10 (50–60) 56 (54) CVA 32: 67% ischemic/cardioembolic, 28% hemorrhagic, 5% ischemic/ thrombotic TIA 17 Recurrent CVA or TIA 13 TIA and CVA 7 CVA while on OAC 15 (26%) 5.7 6 0.9 (5–6) 3.5 6 1 (3–4) 4.0 6 1.0 (3–5) Persistent 54 (52) Paroxysmal 39 (37) Paced 11 (11) 12 (12) 58 (56) 46 (44) Apixaban 41 Dabigatran 3 Rivaroxaban 2 Prior major bleeding events 76 (73) Gastrointestinal 36 Intracranial hemorrhage/subdural hematoma 20 Genitourinary 4 Retroperitoneal 4 Soft tissue hematoma/hemarthrosis 3 Epistaxis 2 Other 7: retinal hemorrhage, obscure bleeding, multiple sites Unacceptable bleeding condition 22 (21) Recurrent falls 15 Hematologic disorders 5 Cerebrovascular malformation 2 Recurrent stroke on OAC 3 (3) Patient preference 2 (2) Recurrent LAA thrombus 1 (1)
Values are given as mean 6 SD (Q1–Q3) or n (%) unless otherwise indicated. CAD 5 coronary artery disease; CHF 5 congestive heart failure; CVA 5 cerebrovascular accident; DOAC 5 direct oral anticoagulant; LAA 5 left atrial appendage; LVEF 5 left ventricular ejection fraction; OAC 5 oral anticoagulant; TIA 5 transient ischemic attack.
in Table 1. Mean CHA2DS2-VASc score was 5.7 6 0.9, with a median value of 5.0 (IQR 5–6). Mean HASBLED score was 4.0 6 1.0, with a median value of 4.0 (IQR 3–5). The indications for implantation were significant prior bleeding in 76 (73%), unacceptable bleeding risk in 22 (21%), and unacceptable stroke risk along with concerns regarding bleeding on anticoagulation in the remaining 6 (6%). Of the total 104 patients, 56 (54%) had a history of prior cerebrovascular accident (CVA) and/or transient ischemic attack (TIA).
3
Watchman implant procedure At the time of the procedure, 54 patients (52%) were in AF, 39 (38%) were in sinus rhythm, and 11 (10%) had paced ventricular rhythms (5 underlying AF and 6 sinus rhythm with high-degree atrioventricular block). Watchman was successfully implanted in all patients. Oral anticoagulants used periprocedurally are listed in Table 1. Only 1 procedure-related complication occurred (a groin hematoma that required transfusion). No pericardial effusions or procedure-related strokes occurred.
Postprocedural anticoagulation and follow-up Postprocedurally, all patients were prescribed 45 days of oral anticoagulant (OAC) and lifetime aspirin. All but 2 patients completed 45 days of anticoagulation: 1 had a spontaneous retroperitoneal hematoma 30 days postimplantation on warfarin and 1 had intracranial hemorrhage (ICH) resulting in death (original implant indication was recurrent falls) 10 days postimplant on apixaban. Of the patients who completed 45 days of anticoagulation, 58 (57%) used warfarin and 44 (43%) a DOAC (39 apixaban, 2 dabigatran, 2 rivaroxaban). Transesophageal echocardiograms performed 45 days postimplant revealed no peridevice leak .5 mm. One patient was found by TEE to have a small mobile, filamentous echodensity attached on the medial aspect of the Watchman device. This patient was switched from warfarin to dabigatran on day 45 and completed a total of 12 weeks of anticoagulation. Follow-up TEE performed 130 days postimplantation showed resolution of the echodensity, and the patient was switched to low-dose aspirin. No stroke occurred during follow-up of this patient. Dual antiplatelet therapy (DAPT) was completed to 6 months postimplant in 48 of 101 living patients at 6 months. Of the remaining 53 patients, 21 used a shorter course of DAPT and 32 used no DAPT. Reasons for shorter course or no DAPT are summarized in Figure 1. Shorter duration of DAPT ranged between 1 and 4 months (mean 3.0 6 0.9 months). Among patients who did not use DAPT, the duration of longer OAC was variable, based on indication and physician/patient preference, but ranged between 3 months to maximum duration of follow up (45 months at time of analysis). All patients except 2 remained on aspirin: 1 because of recurrent stroke who is now taking clopidogrel only with avoidance of DAPT given the patient’s history of bleeding, and the other because of a new indication for OAC (pulmonary embolism that occurred 6 months after LAAC). In the latter patient, the combination of aspirin and OAC with apixaban was avoided given the patient’s history of ICH. Median duration of OAC with aspirin, DAPT, and OAC alone was 45 days (IQR 45–45), 4 months (IQR 0–6), and 45 days (IQR 45–45), respectively.
Twelve-month outcomes Ischemic stroke had occurred in 3 patients (2.8%) at 1-year follow-up. The timing of ischemic strokes were 96, 119,
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Figure 1
Duration of dual antiplatelet therapy (DAPT) and reasons for shorter course of therapy. AF 5 atrial fibrillation; OAC 5 oral anticoagulant.
and 276 days after the procedure. Figure 2 describes all events in detail. All patients underwent TEE at the time of the event. No patient was found to have significant peridevice leak or device-related thrombus at the time of the event (0.4cm leak was documented in the patient who experienced stroke on day 96). Suspected etiologies for these events were paradoxical embolism in 2 patients and carotid atheroembolism in 1 patient. Upon follow-up, a total of 42 patients(40%) remained in persistent/permanent AF, 38 (37%) continued to have paroxysmal AF, and 24 (23%) had paced rhythms, 5 of whom had underlying AF with ventricular pacing. A total of 31 (30%) had undergone ablation procedures (pulmonary vein isolation 26, AV nodal ablation 5). Of the ablation procedures, 20 were performed before Watchman (median time 1141 days before, minimum 20 days before), 7 at the time of the
Day 96
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procedure, and 4 after Watchman procedures (median time 312 days after, minimum 180 days after). Bleeding events during the 12-month follow-up period occurred in 14 patients (13%). The majority consisted of gastrointestinal and genitourinary bleeds (n 5 8), followed by ICH (n 5 2), retroperitoneal bleed (n 5 1), and traumarelated lower extremity hematoma (n 5 3). All except 4 occurred within 45 days while on OAC and aspirin. Bleeding events after 45 days occurred on days 60, 69, 300, and 307 while on DAPT (n 5 2), aspirin (n 5 2), and longer OAC (n 5 1, for concomitant AF ablation). Only 1 bleeding event was fatal (ICH at day 10). The remaining were treated conservatively with blood transfusions and/or hospitalization with clinical recovery. Four deaths had occurred during 12-month follow-up. One was related to a bleeding complication (ICH); the
• On DAPT at time of stroke, restarted on apixaban • AF documented at time of event • History of recurrent stroke prior to device implantation • Suspected etiology: paradoxycal embolism, presence of PFO
Day 119
• On DAPT at time of stroke, restarted on warfarin • AF documented at time of event • History of recurrent stroke prior to device implantation • Suspected etiology: paradoxycal embolism, presence of PFO and pulmonary hypertension
Day 276
• On aspirin only at the time of ischemic stroke and switched to clopidogrel only • Did not receive 6 months of DAPT because of thrombocytopenia • NSR at time of event • Suspected etiology: carotid atheroembolism
Figure 2 Characteristics of observed strokes (n 5 3) at 1-year follow up. AF 5 atrial fibrillation; DAPT 5 dual antiplatelet therapy; NSR 5 normal sinus rhythm; PFO 5 patent foramen ovale. FLA 5.6.0 DTD HRTHM8079_proof 30 July 2019 6:50 pm ce
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Watchman in High Stroke Risk
remaining 3 were related to heart failure (n 5 2) or severe pulmonary hypertension (n 5 1).
Discussion In this study, AF patients at very high stroke risk with CHA2DS2-VASc 5 and unacceptable bleeding risk were found to benefit from Watchman implantation with high efficacy and low complication rates. Such patients would have an estimated annual stroke risk of 10%–12% without anticoagulant therapy and .4% with warfarin,9 but the observed stroke rate over 1-year follow-up was 2.8%, suggesting reduction in stroke risk with Watchman implantation. This corresponds to an approximately 30% relative risk reduction of stroke with Watchman vs warfarin. Compared to apixaban, which has an estimated annual stroke risk of 3.3% in a similar population, the relative risk reduction is 15%. The elevated CHA2DS2-VASc score of this patient population was largely the result of the high prevalence of prior CVA and/or TIA. This subgroup of patients did not seem to be at increased risk for recurrence of cerebrovascular events from implantation of a Watchman device. The efficacy of the Watchman device for stroke prevention in patients with nonvalvular AF was assessed in the PROTECT and PREVAIL trials, which compared the device to warfarin. These studies used the CHADS2 score to stratify patients’ stroke risk. Mean CHA2DS2 in PROTECT and PREVAIL were 2.2 and 2.6, respectively, which translates to an annual risk of stroke between 2% and 3%. The population of patients in the studies leading to approval of the device was, as such, a population at relatively low stroke risk, and little is known about the benefit of such devices in patients with much higher stroke risks. In clinical practice, comorbid conditions that predispose patients to stroke can also predispose them to bleeding. In our practice, most patients being referred for Watchman implantation were at increased risk for both stroke off anticoagulation and bleeding on anticoagulation. The current study suggests that Watchman implantation might have a net clinical benefit in patients at very high stroke risk and should be considered, especially in cases with concerns regarding the safety of long-term anticoagulation. The French Nationwide Observational LAAC (FLAAC) registry reported similar thromboembolic outcomes in a high-stroke risk population such as the one included in this study.7 However, they also reported a high rate of serious complications, including device-related complications, similar to those reported in PROTECT and PREVAIL. Of note, even though only 23.5% of these patients received short-term OAC per Watchman protocol, a higher incidence of serious pericardial effusions requiring intervention was reported. They concluded that LAAC can decrease the predicted risk of thromboembolism in a population intolerant to anticoagulation, but that given the high incidence of serious complications, the decision to pursue LAAC should be made with caution. Our experience is in contrast to this multicenter French registry with regard to the complication
5 rate, which was much lower in our registry. We believe this is due to early procedural hazard in the FLAAC registry, which reported LAAC outcomes of procedures performed between 2013 and 2015, in contrast to our data, which includes “post-FDA approval” procedures performed between 2015 and 2017. In addition, our center is a highvolume center with approximately 100 Watchman procedures performed per year. This translates into high operator experience, which PREVAIL proved to be associated with lower procedure-related severe adverse events. In addition, the systematic use of intracardiac echocardiography to guide transseptal access, ensuring air-free irrigation lines, maintaining heparinized saline through transseptal sheaths, and adhering to standard implantation techniques have helped our center maintain excellent safety profiles of the procedures, even during the early stages. Despite the high bleeding risk profile of our study population (mean HASBLED 4.0), postprocedural short-term anticoagulation seems to be tolerated even by patients who had experienced prior ICH.10 We previously reported bleeding outcomes in a population at high risk for bleeding,8,10 and we favor the completion of short-term OAC after Watchman implantation as it has been associated with fewer events of device-related thrombosis. The majority of patients included in this study were considered to have “contraindication” to anticoagulation, but under close surveillance and for a short period of time, most of these patients tolerated short-term anticoagulation for the purpose of Watchman device implantation. It is important to emphasize certain technical aspects in our practice that added to the safety of the procedure, including ensuring that all lines and sheaths were free of air bubbles and initiation of intraprocedural heparin before transseptal access. Furthermore, patient education with emphasis on the importance of compliance to medications, especially postprocedurally, is essential to achieve excellent outcomes.
Study limitations This study has the limitation of observational studies, but data were derived from a prospectively maintained registry of procedural profiles and outcomes. Referral bias cannot be fully excluded due to the observational nature of the data, but the data presented reflect the outcomes of a multidisciplinary assessment involving neurologists, neurosurgeons, and gastroenterologists on a case-by-case basis, and as such the findings emphasize the importance of such collaboration, especially in challenging clinical scenarios. Finally, the study reflects the experience of a tertiary care large-volume center and may not be generalizable to all centers performing such implants.
Conclusion In a population of patients with mean CHA2DS2-VASc of 5.7, Watchman implantation seemed to be safe and efficacious, with a residual annual ischemic stroke risk of 2.8%. In such a high-risk population, the estimated annual risk of stroke is otherwise z12% off anticoagulation and .4% on
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warfarin. These findings suggest that Watchman implantation is beneficial in patients at very high stroke risk and should be considered, especially in clinical scenarios with concerns regarding the safety of long-term anticoagulation.
Acknowledgments We thank the Art Institute at Cleveland Clinic for their contribution to the design and illustration of the graphical abstract. Special thanks to Ross Papalardo, CMI.
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4. Holmes DR Jr, Kar S, Price MJ, et al. Prospective randomized evaluation of the WatchmanÔ left atrial appendage closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial. J Am Coll Cardiol 2014; 64:1–12. 5. Reddy VY, Doshi SK, Sievert H, et al. Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation: 2.3-year follow-up of the PROTECT AF (WatchmanÔ Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) Trial. Circulation 2013;127:720–729. 6. 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;17:41187–41189. 7. Teiger E, Thambo JB, Defaye P, et al. Percutaneous left atrial appendage closure is a reasonable option for patients with atrial fibrillation at high risk for cerebrovascular events. Circ Cardiovasc Interv 2018;11:e005841. 8. Barakat AF, Hussein AA, Saliba WI, et al. Initial experience with high-risk patients excluded from clinical trials: safety of short-term anticoagulation after left atrial appendage closure device. Circ Arrhythm Electrophysiol 2016; 9:e004004. 9. Loewen P. SPARC—Stroke Prevention in Atrial Fibrillation Risk Tool. September 2017. Retrieved April 8, 2018. Available at http://www.sparctool. com. 10. Hutt E, Wazni OM, Saliba WI, et al. Left atrial appendage closure device implantation in patients with prior intracranial hemorrhage. Heart Rhythm 2019; 16:663–668.
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