revue neurologique 171 (2015) 426–432
Available online at
Percutaneous left atrial appendage occlusion for stroke prevention in patients with atrial fibrillation and contraindication for anticoagulation L’occlusion percutane´e de l’auricule gauche dans la pre´vention de l’infarctus ce´re´bral chez les patients avec fibrillation atriale et contre-indication aux anticoagulants D. Grosset-Janin a,*, E. Barth b, B. Bertrand b, O. Detante a,c a
Stroke unit, neurology, university hospital, boulevard de la Chantourne, 38043 Grenoble cedex 9, France Cardiology, university hospital, boulevard de la Chantourne, 38043 Grenoble cedex 9, France c Inserm U 836 UJF-CEA, team 5, Grenoble institut neurosciences, universite´ Joseph-Fourier, site sante´, baˆtiment Edmond-J.-Safra, chemin Fortune´-Ferrini, 38706 La Tronche cedex, France b
Background. – Stroke, as the third cause of death in developed countries, is a public health
Received 22 September 2013
issue. Atrial fibrillation is an important cause of ischemic stroke and its prevention is
Received in revised form
efficient with oral anticoagulation. However, oral anticoagulation can be contraindicated
27 September 2014
because of hemorrhagic risk related to these treatments. Percutaneous left atrial appendage
Accepted 11 November 2014
occlusion is a new alternative of oral anticoagulation for patients with atrial fibrillation and
Available online 23 April 2015
high risk of cardio-embolic stroke but contraindicated for oral anticoagulation. Methods. – We describe in this paper the procedure of left atrial appendage occlusion with
the Amplatzer cardiac plug device, used in our center in Grenoble university hospital, for the
first three patients who have been treated with this device. These three patients (one man
Left atrial appendage
and two women) have all atrial fibrillation with neurological complication of this arrhyth-
mia, as ischemic stroke. Oral anticoagulation is indicated to prevent another ischemic stroke. However, they all have a high risk of cerebral bleeding for different reasons
Mots cle´s :
(cavernomatosis, history of intracerebral hemorrhage and aneurysm of the polygon of
Willis). Consequently, they have a high risk of cardio-embolic complication but contraindi-
Occlusion de l’auricule gauche
cation for oral anticoagulation. They have been treated by left atrial appendage occlusion
with Amplatzer cardiac plug device by percutaneous and trans-septal access. Then, they have been followed by neurologist and cardiologist, with clinical and paraclinical evaluation by echocardiography. Results. – Our three first patients have been successfully implanted, without periprocedural complication. No latest adverse event was observed, and particularly no cardiac or neurologic adverse event.
* Corresponding author. E-mail address: [email protected]
(D. Grosset-Janin). http://dx.doi.org/10.1016/j.neurol.2014.11.009 0035-3787/# 2015 Published by Elsevier Masson SAS.
revue neurologique 171 (2015) 426–432
Conclusion. – The technique of left atrial appendage occlusion is a very interesting and promising technique for ischemic stroke prevention in patient with high risk of cardioembolic complication because of atrial fibrillation, but high risk of bleeding and contraindication for oral anticoagulation. Because of frequency of both atrial fibrillation and contraindication for oral anticoagulation, occlusion of the left atrial appendage should become an interesting alternative for many patients. However, it remains an invasive procedure and efficacy and indications need to be evaluated in further clinical trials. Risk/benefit ratio must be carefully assessed and compared to that of the new anticoagulant drugs. # 2015 Published by Elsevier Masson SAS.
r e´ s u m e´ Introduction. – L’accident vasculaire ce´re´bral est un proble`me de sante´ publique. L’anticoagulation orale est efficace dans la pre´vention de l’infarctus ce´re´bral d’origine cardioembolique. Cependant, elle peut eˆtre contre-indique´e en raison du risque he´morragique induit par ces traitements. L’occlusion percutane´e de l’auricule gauche est une nouvelle alternative a` l’anticoagulation orale pour les patients atteints de fibrillation atriale mais contre-indique´s aux anticoagulants. Me´thodes. – Nous de´crivons la proce´dure d’occlusion percutane´e de l’auricule gauche avec le dispositif Amplatzer cardiac plug, pour trois premiers patients traite´s au centre hospitalier universitaire de Grenoble. Ces trois patients avaient tous une fibrillation atriale complique´e d’un infarctus ce´re´bral et donc une indication the´orique d’anticoagulation curative. Cependant, ils avaient un haut risque he´morragique contre-indiquant cette anticoagulation. Ils ont e´te´ traite´s par occlusion, par voie percutane´e et trans-septale, de l’auricule gauche avec le dispositif Amplatzer cardiac plug. Re´sultats. – Ces trois premiers patients ont e´te´ implante´s avec succe`s, sans complication perproce´dure ou a` distance. Conclusion. – L’occlusion de l’auricule gauche est une technique prometteuse dans la pre´vention de l’infarctus ce´re´bral chez les patients pre´sentant une fibrillation atriale et une contre-indication aux anticoagulants. Cependant, cela reste une proce´dure invasive, devant eˆtre e´value´e par d’autres essais. Le rapport be´ne´fice/risque doit eˆtre soigneusement e´value´ et devra eˆtre compare´ a` celui des « nouveaux » anticoagulants. # 2015 Publie´ par Elsevier Masson SAS.
1. LAA AF OAC TEE MRI ACP MCA
Abbreviations Left atrial appendage Atrial fibrillation Oral anticoagulation Transesophageal echocardiography Magnetic resonance imaging Amplatzer cardiac plug Middle cerebral artery
Stroke is the third leading cause of death and the first cause of disability in developed countries. Atrial fibrillation (AF) is responsible for 15% of strokes [1,2]. After a stroke, AF leads to an increase of mortality (32.5% vs. 16.2% without AF)  and an increase of severe disability at one year (Barthel index < 40 for 30.0% vs. 10.9% without AF) . AF is therefore associated with an independent risk of serious cardiac adverse events after an
ischemic stroke . In non-valvular AF, more than 90% of atrial thrombi form in the left atrial appendage (LAA) [6,7]. The current European society of cardiology guidelines for management of AF recommend oral anticoagulation (OAC) for patient with a CHADS2-Vasc2 score of 1 or higher . But OAC carries the risk for hemorrhagic complications. Warfarin, the most commonly applied drug for OAC, reduces the risk for ischemic stroke in AF population study by 65% , but in real life, patients often appear to have an INR outside the therapeutic window . Also, because of the bleeding risk, OAC is often not prescribed although indicated. New OAC drugs such as anti-Xa factors provide similar or better stroke prevention than Warfarin but are still associated with bleeding complications . Oral anticoagulation is clearly superior to antiplatelet agents (Clopidogrel and/or Aspirin) in prevention of vascular events notably stroke. When OAC is unsuitable, the use of double antiplatelet agents leads to a risk of hemorrhage . Many patients have both contraindications for OAC, because of high risk of bleeding, and a high risk of cardioembolic complications such as ischemic stroke. Several techniques are developed in alternative to anticoagulation
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in AF . Exclusion LAA from the blood flow is currently the more promising. In patients with AF having contraindication for OAC, percutaneous LAA occlusion could be an alternative for ischemic stroke prevention. Many clinical studies assessed feasibility and safety of different techniques of occlusion of the LAA . Different implant systems have been developed. In European countries, Plaato device (eV3 Inc, Plymouth, MN, USA) was implanted from 2001 to 2007. Its efficacy was observed with a reduction of thromboembolic events in a prospective multicenter trial (PLAATO Study) . Watchmann device (Atritech Inc/Boston Scientific, Plymouth, MN, USA) has been implanted since 2002. It was compared to the current standard of therapy (OAC) in a large prospective population: embolic protection in patients with atrial fibrillation: Protect AF . Results found a rate of all cause stroke (ischemic and hemorrhagic) lower in device group, and non-inferiority to Warfarin . Performance and safety of the new Amplatzer cardiac plug (ACP) has already been assessed by a multicenter retrospective European registry enrolling 143 patients. The implant success rate was 96%. However, long-term efficacy is not yet published. Short-term results in 2003 from 15 patients who underwent LAA occlusion with this approach were favorable . The initial Asia-pacific experience with ACP, published in 2012, shows successful LAA occlusion in 95% of the patients and good results, no death and no stroke, after one-year follow-up . In August of 2012, the European society of cardiology (ESC) indicated that percutaneous LAA closure seems to be an interesting concept, but need to be evaluated for efficacy and safety in bigger controlled clinical trials. Today this technique remains reserved for patients with a high stroke risk and contraindications for long-term OAC. The ACP device was applied in our center for 3 first patients at high risk for relapse of stroke. They were referred by neurologists for LAA occlusion because of contraindication for OAC due to cerebral bleeding risk.
Device and procedure
Amplatzer device (AGA, St. Jude Medical, Plymouth, MN, USA) is a cardiac plug designed for occlusion of the LAA, delivered through a trans-septal sheath curved to point at the LAA. It is a self-expandable nitinol cage covered with an occlusive expanded polytetrafluoroethylene membrane. It consists of a lobe and a disk. While the lobe is retained within the neck of the LAA and stabilized by retention wires the disk seals the LAA orifice (Fig. 1). For these first cases, the operator (BB), who had experience in interventional cardiology by trans-septal access, had training with Amplatzer proctor. Under general anesthesia, transesophageal echocardiography (TEE) was performed to assess the size and shape of the LAA, to eliminate atrial thrombi and to localize left coronary artery ostium. After percutaneous femoral venous puncture and transseptal access, the ACP device was expanded in LAA under fluoroscopy and TEE control. Left coronary artery was injected at the end of procedure to check that coronary blood flow was not compromised by the device. All patients were treated by aspirin (75 or 160 mg per day) and clopidogrel (75 mg per day) during 3 weeks to 6 months after procedure. After that, only aspirin (75 or 160 mg per day) was maintained for an unlimited period.
Patient 1 was a 73-year-old woman hospitalized in October 2010 for an ischemic stroke of the right middle cerebral artery (MCA) deep territory secondary to permanent AF (CHA2DS2VASc = 5). MRI showed multiples hypointense signals in T2* sequence corresponding to microbleeds (Fig. 2A and B). A familial cavernomatosis was genetically diagnosed (her
Fig. 1 – The Amplatzer cardiac plug positioned in the LAA by the dedicated delivery system.
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Fig. 2 – A. MRI diffusion > acute ischemic stroke. B. T2* microbleeds due to cavernomatosis.
daughter has been treated for a post-partum hemorrhagic stroke due to a cavernomatosis). Because of high risk of hemorrhage, she presented a contraindication for OAC, and LAA occlusion seemed to be an interesting alternative therapy. She had percutaneous LAA occlusion with ACP in November 2010. First, TEE provided measures of the LAA anatomy (Fig. 3A). Then, she underwent an occlusion of the LAA without any complication (Fig. 3B and 3C). After the procedure, she was treated by both aspirin 75 mg per day and clopidogrel 75 mg per day during 3 weeks, and then aspirin 75 mg per day for an unlimited period. One month
later, TEE showed a complete exclusion of the LAA and the device was stable (Fig. 3D). One year later, she experienced no recurrence of stroke and TEE showed a persistent complete occlusion.
Patient 2 was a 74-year-old man. He had paroxystic AF, diabetes, and hypertension. OAC was changed for double antiplatelet therapy (aspirin and clopidogrel) because of occurrence of a myocardial infarction. In August 2009, he
Fig. 3 – A. Pre-procedure TEE (LAA measurement). B. Pre-procedure fluoroscopy of the LAA. C. Occlusion of the LAA with Amplatzer device, under TEE control. D. TEE control of the LAA occluding device, one month after procedure.
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Fig. 4 – A. MRI T2* gradient-echo sequence, right temporal hemorrhage under antiplatelet. B. CT-scan. Ischemic stroke of right middle cerebral artery territory due to untreated AF.
presented an intracerebral temporal hemorrhage (Fig. 4A). Nine months after stopping antithrombotic drugs, he had a right MCA ischemic stroke (Fig. 4B), whose origin is a cardioembolism mechanism from AF. Clopidogrel was introduced carefully, but a symptomatic hemorrhagic transformation of this ischemic stroke happened soon after. First hemorrhage occurred under double antiplatelet therapy and the second was an acute complication of stroke after beginning clopidogrel, indicating a high risk of bleeding complication in this patient. Considering both risks, of cardiac thrombo-embolism on one side (CHA2DS2-VASc = 6), and of cerebral bleeding under OAC and antiplatelet on the other side, a percutaneous LAA occlusion with ACP was proposed. After the procedure, he was treated by double antiplatelet therapy (aspirin 160 mg and clopidogrel 75 mg per day) during 6 months and then aspirin 160 mg a day alone for an unlimited period. The follow-up at 2 years did not report any cardio-neuro-vascular event.
Patient 3 was a 65-year-old woman who was first hospitalized for a diplopia because of a paralysis of the third cranial nerve. The CT-scan revealed a right intracranial carotid aneurysm, and a left MCA aneurysm. Embolization of the carotid one was done, but the MCA one needed a neurosurgical treatment which has not been done at the same time. Thirteen months later, she presented an ischemic stroke of left MCA territory due to paroxystic AF (CHA2DS2-VASc score = 6). Although there has been no bleeding complication of these aneurysms, after a multidisciplinary discussion (between cardiologists, neurologists, radiologists and neurosurgeons), LAA occlusion procedure was done with ACP in February of 2011, and no neurological or cardiac complication occurred at 12-months follow-up. She was treated by aspirin and clopidogrel during 3 months. Then, neurosurgery was allowed after antiplatelet window in September 2011. Then, Aspirin was maintained for an unlimited period.
We reported here the first 3 cases of ACP LAA occlusion in France. No adverse event was observed during the procedure and the follow-up. In management of AF, estimation of thrombo-embolism risk is relatively easy thanks to Chads2-vasc2 score established use. The evaluation of bleeding risk under OAC is more difficult but the HAS BLED score can be helpful. Percutaneous occlusion of the LAA could be an alternative strategy to OAC for stroke prevention. Feasibility and safety of different procedures was assessed. In the prospective multicenter trial PLAATO , a group of 111 patients having contraindication for OAC and risk factor for ischemic stroke were randomized. Implantation was successful in 108 patients. At 9.8 months follow-up, the relative annual stroke rate reduction was 65% compared to aspirin, likely the same as warfarin . The Protect AF randomized trial  showed the noninferiority of percutaneous closure of the LAA versus warfarin therapy for prevention of stroke in patients with AF. The expected benefit seems even better than the cerebrovascular risk is high (higher CHA2DS2-VASc score) . However, these results should be considered with caution because of several limits: no blinded study, several patients kept treatment by warfarin even after the procedure, and were not really contraindicated to OAC. Thus, it is difficult to adjust these results to the target population of this new procedure. The new Amplatzer cardiac plug has already been assessed in the European prospective observational study (unpublished data) enrolling 204 patients with non-valvular AF in 15 centers from Germany, Spain, United Kingdom, Ireland and Czech Republic. The implant success rate is 96.6% with a closure rate of 99.5% at implant. Several adverse events have been described. Major periprocedural complications are: stroke, device embolization, cardiac perforation or significant pericardial effusion requiring pericardiocentesis. In the initial European registry, the rate
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of major periprocedural complications was 7.3% and it is similar with Watchman device (6% in Protect AF) . More recently, there is only 2.9% of major periprocedural complications in the recent European prospective observational study with no stroke or transient ischemic accident periprocedural. These data show a learning curve effect and the operator experience is an important factor for success and safety of the procedure . In several studies, the rate of major complications is less than 2%, so less than the embolic risk of AF in patients with CHADS2-VASC score of 2. It is important to underline that OAC remains the first treatment recommended in secondary prevention of stroke in patients with AF. Warfarin and new OAC such as dabigatran or rivaroxaban have shown their efficiency [11,23]. Currently, no study was reported comparing LAA occlusion and new OAC. Procedure to close LAA remains an invasive technique and should not be proposed in first for prevention of cardioembolic stroke. It could be an alternative to OAC in patients with contraindication to these drugs. Note that the device is not reimbursed in France. In our center, all patients were successfully implanted. No periprocedural or latest complication occurred (initial training with Amplatzer proctor). These 3 patients received a double antiplatelet therapy by aspirin and clopidogrel after procedure for 3 weeks at least and 3 months when it was possible. Time for complete endothelialization of the device (Watchman device) seems to be 90 days . So, the optimal duration for double antiplatelet therapy should be about 3 months, but several situations cannot afford this therapy because of an especially high bleeding risk. This problem may be a limit for proposing LAA occlusion. Thus, studies are needed to answer this question of anti-aggregant therapy after such a procedure. Aspirin duration must be evaluated depending on the bleeding risk as well. Clinical experience of percutaneous LAA occlusion is still limited and evidence base is still poor. Longer follow-up of patients with LAA closure is necessary to evaluate safety and efficiency, but the first data seem to be favorable . Registers are set up in different centers using this technique. Efficacy and indications need to be evaluated in further clinical trials. But considering the major thrombo-embolism further risk after a primary cardio-embolic stroke, such a procedure is a reasonable option for secondary prevention of stroke in patients with contraindications for OAC.
Atrial fibrillation is an important cause of stroke and prevention of cardio-embolic stroke by OAC is efficient. However, a lot of patients have contraindications for OAC, because of high risk of bleeding. Percutaneous occlusion of the LAA is an innovative alternative of OAC in patient with AF and high vascular risk. However, it remains an invasive technique reserved for patients who have contraindicated for OAC. Our patients who first benefited of occlusion of the LAA with ACP in Grenoble were all indicated in secondary prevention of stroke. In the future, LAA closure could probably be proposed in primary prevention in patients with AF, high vascular risk
and OAC contraindication. Risk/benefit ratio must be carefully assessed and compared to that of the new anticoagulant drugs.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements The authors would like to thank the Amplatzer Society whose cardiac device was used to treat the patients.
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