Credits:Sven Mobius-Winkler, M.D1, Ingo Dähnert3 , Gerhard C. Schuler M.D1 and Peter B. Sick M.D2
1Universität Leipzig, Herzzentrum GmbH, Department of Internal Medicine/Cardiology, Leipzig, Germany
2Krankenhaus Barmherzige Brüder Regensburg, Department of Internal Medicine III/Cardiology, Regensburg, Germany
3Universität Leipzig, Herzzentrum GmbH, Department of Pediatric Cardiology, Leipzig, Germany
Address for correspondence: Sven Moebius-Winkler M.D., Klinik für Innere Medizin/Kardiologie, Universität Leipzig – Herzzentrum GmbH, Strümpellstr.39, 04289 Leipzig, Germany.
The diagnosis of atrial
fibrillation (AF) significantly increases the risk of having cardio embolic
events. Cerebrovascular events are still a leading cause of death and
disability worldwide. Current guidelines
recommend an antithrombotic regimen to
prevent thromboembolism in medium and high risk patients with AF. However,
a substantial number of patients are not eligible for this therapy. Therefore,
an exclusion of the left atrial appendage (LAA) from circulation seems to be an
alternative strategy for stroke prevention in AF. This review focuses on the different strategies for LAA exclusion with a special
focus on the WATCHMAN®-device.
Two devices are currently in use for percutaneous
transcatheter occlusion of the LAA: the WATCHMAN®-device and the AMPLATZER®–Cardiac plug. Only for the WATCHMAN®-device safety, feasibility and
non inferiority data compared to standard therapy data are currently available.
about 200 patients at high risk for thromboembolic stroke and contraindications
for oral anticoagulation therapy received the PLAATO® –device which is
currently off the market.
was implanted in 800 patients that were eligible for long-term anticoagulation
therapy with a moderate risk for thromboembolic stroke due to non-valvular AF.
evidence indicates an equivalent risk of
stroke compared to oral anticoagulation with a reduced rate of bleeding
complications at least for the WATCHMAN®-device. Hence, another
therapeutic option now is available to prevent thrombembolic events in patients
with atrial fibrillation not suitable for medical anticoagulation therapy.
Key Words : atrial fibrillation, stroke, left atrial appendage, WATCHMAN® - device, Amplatzer® septal occluder, Amplatzer® cardiac plug
Stroke is a major cause of death
and low quality of life worldwide. About 15-20% of ischemic strokes have a cardio
embolic origin . Atrial fibrillation (AF) affects
3-5% of the population older than 65 years and is the most common arrhythmia of
clinical relevance. The incidence of atrial fibrillation increases with age
from about 2% in patients aged 60-69 years to approximately 8% in patients
older than 79 years . With an aging population, the prevalence of AF is
likely to increase 2.5 fold over the next 50 years .
Additionally, several factors have
been identified as indicators for an increased risk for thromboembolic events.
The CHADS2 stroke risk index was developed to estimate the stroke
rate in AF patients and has become a standard tool for estimating the risk of
cardioembolic events [Table 1+ 2]
Table 1: CHADS2 * Risk Score
* CHADS2 is an acronym derived from the initial letter from the risk factors and the scoring 2 for prior strok or TIA.
The Score is calculated by the scores of the present risk factors.
Table 2: Classification of risk groups through the CHADS2 Score
international guidelines for therapy of AF recommend an antithrombotic regimen with warfarin as a class 1A
indication to prevent thromboembolism in all patients with AF and a CHADS2
score of >1, except for those with contraindications .
Without anticoagulant therapy the risk of stroke is
about 5 % per year in patients < 65 years and increases to over 8% per year
in patients over 75 .
According to the CHADS2 Score the rates of stroke in
patients without anticoagulation therapy were 1.9 per 100 patient-years for
those with CHADS2 Score 0; 2.8 per 100 patient-years for those with CHADS2
Score 1; 4.0 per 100 patient-years for CHADS2 Score 2; 5.9 per 100
patient-years for CHADS2 Score 3; 8.5 per 100 patient-years for CHADS2
Score 4; 12.5 per 100 patient-years for CHADS2 Score 5 and
18.2 per 100 patient-years for those patients with CHADS2 Score 6 .
Data from Metaanalysis indicate that therapy with Aspirin alone reduces
stroke rates by about 20% in AF patients .The effectiveness
of an anticoagulation therapy to prevent ischemic strokes related to atrial
fibrillation was demonstrated in numerous studies. One of the largest, the SPAF
– I trial-demonstrated a risk reduction of about 67% with warfarin as compared to
Several studies addressed the effects of warfarin as
compared to aspirin, clopidogrel or a combination of both. Currently, none of
them were able to show a superiority of one of these alternative therapies over
Unfortunately less than half of all
patients with an indication for anticoagulation therapy receive warfarin
therapy for various reasons [11, 12].
Additionally, the therapy with oral anticoagulation has a close therapeutic window with the need
for a close monitoring and a potential risk of severe bleeding complications
when exceeding the therapeutic range. Several pharmacological interactions as
well as the influence by diet, herbal
supplements or concomitant diseases have been described. The discontinuation
rate for those under therapy is estimated to be 38 % per year approximately .
Therefore several investigations that are focused on the development of novel therapeutic
tools to prevent AF related strokes were conducted. Besides new medical therapy,
one development that might be promising is the percutaneous exclusion of the
left atrial appendage (LAA) from circulation.
In patients with atrial
fibrillation lasting longer than 48h the incidence of thrombus formation is
8-15% . These thrombi were
predominantly revealed in the LAA (91% to 98 %) .
Virchow postulated stasis, hypercoagulation and vascular trauma as the
mechanisms leading to thrombus formation, the pathophysiology of
thromboembolism in atrial fibrillation remains uncertain .
mechanical contraction of the left atrium and especially the LAA in patients
with AF leads to a reduced blood flow velocity and is supposed to result in spontaneous echo contrast, thrombus formation, and consecutive
embolic events [15-20].
In addition, the morphology of the LAA might have an impact
on the risk of thrombus formation. The LAA is usually a long, tubular, hooked
structure with a large variability in morphology. Its size ranges from 20 to 45
mm in length and 15 to 35 mm in orifice diameter 
Post mortem analysis indicate a higher
volume, larger orifices, and fewer branches of LAA in patients with AF as
compared to those of patients with sinus rhythm .
Mechanical analyses suggest that the myocardium of the
LAA is more distensible then the myocardium of remaining the left atrium which
underlines the LAA´s a role as a “decompression“-chamber. Molecular analysis
indicates the LAA as a source of production of atrial natriuretic peptide.
For more than 50 years physicians try to exclude the
LAA from circulation in patients with AF for thromboembolie prophylaxis. Even in
the pre-warfarin era (1946) the surgical amputation of the LAA was described in
two patients for prevention of thromboembolic events .
This procedure of LAA obliteration/ amputation has initially
been performed in patients undergoing mitral valve surgery or maze procedure.
In this setting, the results of LAA exclusion were inconclusive. In 2003 Garcia
– Fernandez and coworkers reported a series of 58 patients, in whom ligation of
the LAA was performed during mitral valve surgery. In about 10% of patients an
incomplete sealing of the LAA was seen in follow up-transesophageal echo studies.
In these patients the risk of late embolism was significantly increased with an
odds ratio of 6.7 .
On the other hand, a recently published prospective
study by Almahameed et al. could show that also in patients after LAA exclusion
during mitral valve surgery the rate of thromboembolism was 15 % in those
without and 10% in patients with postoperative warfarin therapy after 3.6 years
of follow up. In 61 % of these patients persistent AF or a history of AF was
reported at baseline. The authors concluded that LAA exclusion does not provide
optimal protection against thrombembolic events in this small patient cohort .
In patients undergoing other cardiac surgery than
mitral valve surgery, the amount of available data is limited. The first
published data are out of the Left Atrial Appendage Occlusion Study-[LAAOS] pilot
trial in 77 patients undergoing coronary artery bypass surgery. In this setting
occlusion of the LAA seemed not prolong overall length of procedure. Since data
are limited so far, major conclusions cannot be drawn out of the results of this trial and
the benefit of surgical LAA occlusion/ amputation, with respect to mortality
and morbidity, remains unknown at least until this ongoing study has enrolled
the scheduled 2500 patients .
Considering the fact, that several studies reported an
incomplete occlusion of the LAA after surgical ligation in a high percentage of patients, the need for an ongoing development of
the surgical technique is given [27,
Salzberg and colleagues reported on a new LAA Clip [AtriCure Inc. West Chester,
Ohio] that was successfully tested in animals. So far, the clip provided a
total exclusion of the LAA from circulation .
However, also nonsurgical, interventional devices that exclude the LAA from
circulation have been developed.
Three different interventional devices have been
described for transcatheter LAA occlusion so far:
currently no longer commercially available
Amplatzer septal occluder –
commercially available but not approved for this indication
WATCHMAN® Device –FDA-approved
Further Devices- under
A) PLAATO® System
The PLAATO® System (originally produced by ev3
Inc., Plymouth, Minnesota, USA) consists of a self-expandable nitinol cage
covered with a non-thrombogenic ePTFE membrane to exclude blood flow from the
LAA. Different sizes (15-32mm) of the device were available and a 14 French
introducer sheath was required for implantation. (Figure 4)
Nakai et al. were the first to report on the Percutaneous
LAA Transcatheter Occlusion (PLAATO®) – System.
Feasibility and safety of this transseptal system was evaluated in 25 dogs .
The LAA could be occluded successfully in all 25 dogs safely and quickly. The
sealing of the LAA seemed to be complete in all cases.
Sievert et al. published the first in man experience
with the PLAATO® System. Fifteen patients with chronic atrial
fibrillation and contraindication for warfarin therapy were enrolled into the
study. In all patients the LAA could be occluded successfully. At 1 month
follow up there were no complications or embolic events .
At present, more than 200 patients were treated with
the PLAATO® device. 98% of patients could be successfully treated with
minor complications. There was one device embolisation but 3% of patients
developed pericardial effusions during/after the implantation procedure. One of
these patients died due to cerebral hemorrhage after surgical pericardiocentesis
. After the implantation
procedure all patients received 300 mg Aspirin/day and 75mg Clopidogrel up to 6
months after the implantation.
The study group analyzed a follow up of 250 patient
years and documented an annual stroke rate of 3.2 % in patients having the
PLAATO® device. The expected annual stroke risk according to the
CHADS2 Score was 6.5% under aspirin therapy in these individuals.
One percent of the PLAATO® patients developed a flat thrombus
attached to the surface of the device, which resolved under therapy with
aspirin, clopidogrel and low molecular weight heparin. No mobile clots, mitral
valve damage or pulmonary vein obstructions were
observed. Therefore, the investigators concluded that LAA occlusion with the
PLAATO® device reduces the relative risk of stroke by 51% [31, 32].
Currently the device is no longer available, solely
due to commercial and not to medical reasons.
B) Amplatzer® septal occluder
The first and only study of left atrial appendage
occlusion with the Amplatzer® septal occluder (AGA Medical Corp. Golden Valley, MN; USA) devices was published in 2003. The ease use of percutaneous
devices to occlude patent foramen ovale or atrial septal defects lead to first
experimental occlusion of LAA with derived devices by Meier et al .
This first report included 16 patients that were
treated in four centers with successful implantation in 15 patients. One acute
device embolisation occurred which required surgical removement. After 4 months
of follow up, there were no further complications, the devices were stable in
position and the LAA was completely occluded in all cases. Furthermore, no
thromboembolic complications were reported within this follow up period.
Nevertheless, there are no further data available in
LAA occlusion with this particular device and large scale studies are lacking. After
this first evaluation of the Amplatzer® septal occluder, the company made
further development on the device and offers now the Amplatzer® cardiac plug, a
system that is CE marked (Figure 5). Currently no data are available for this
The Watchman ®- Left Atrial Appendage
Occlusion Device (Atritech Inc., Plymouth, Minnesota, USA) is comprised of a
self-expanding nitinol frame structure with fixation barbs and a permeable
polyester fabric [Figure 1
and 2] that covers
the left atrial facing surface of the device. Currently, the device is
available in a size ranging from 21 to 33 mm. For WATCHMAN® device
implantation, a transseptal access sheath (14 Fr) and a delivery catheter is
Figure 1: Watchman – Device © by Atritech
Figure 2: Schematic view of an implanted WATCHMAN Device
In a pilot trial 75 patients were included to asses
safety and feasibility of the device. Patients had an average CHADS²
Score of 1.8 points corresponding to a moderate risk for stroke .
Patients with impaired left ventricular function (< 35%), congenital heart
disease, symptomatic carotid disease, prosthetic heart valves and significant
neurological defects after prior stroke were excluded. The implantation
procedure was performed under general anesthesia and TEE guidance.
In 66 of the 75 patients (88 %) the device could be implanted
successfully [Figure 3].
Implantation failure occurred in 9 patients due to unsuitable LAA anatomy (7
patients), core wire malfunction (1 patient) and impossible transseptal
crossing (1 patient).
Figure 3: : Implanted WATCHMAN Device
a) CT Scan: the device is in situ in the LAA
b) Fluoroscopy: The device was released in the LAA (arrow), the sheath is positioned in LA for fluoroscopic control (asterisk)
Complications occurred in 5 of the first 16 patients
treated with the first generation of the device. There were two embolisations
of the device, one delivery system failure, one surgical device explantation
after incorrect positioning. One patient suffered transient air embolism.
Therefore, the device and the delivery system were
modified after these first 16 patients. Fifty-three additional patients were
implanted with the second-generation device and no further device embolization
occurred. There was one significant pericardial effusion due to an overly
vigorous tug test but no other relevant complications .
After a mean follow up of 24 months there were no
major strokes at all. Two deaths occurred during follow up period, which were
not device related. In one patient, who died 9 months after device implantation
due to a Type A aortic dissection, a complete endothelialization of the device
and the LAA was observed at autopsy.
These data provided considerable evidence that
implantation of the re-designed device was safe and feasible.
Another randomized, prospective, multicenter study
(The WATCHMAN® Left Atrial Appendage System for Embolic PROTECTion
in Patients With Atrial Fibrillation (PROTECT AF- study), which is the first
controlled trial in this field, compares Watchman device implantation with
standard anticoagulation therapy. The recruitment period for this study was
finished in summer 2008
. The study included 800 patients at 59 centers in Europe and the
United States. Patients were randomized in a 2:1 fashion for device
implantation vs. medical therapy only. All patients randomized in this study were
eligible for standard warfarin therapy. To demonstrate of non-inferiority of the
device compared to warfarin therapy to reduce the incidence of stroke, 900
patient years of follow up were analyzed .
The implantation was successful in 88 % of patients. The
mean follow up was 16 months. Most patients of the Watchman group were on
CHADS2 Score 1, 2 or 3 (34.1%/ 33.9%/ 19%). After 45 days of follow up 87 % of
implanted patients discontinued warfarin and switched over to Clopidogrel 75
mg+ Aspirin 100-300 mg/day until 6 month of follow up, continued by Aspirin
100-300 mg alone.
results of this trial were reported by Holmes et al. 
After a total of 1065 patient years the non inferiority of the WATCHMAN® device
compared to medical therapy with warfarin could be demonstrated in this
population. Although there was a higher rate of adverse safety
events in the intervention group than in the control group, events in the
intervention group were mainly a result of peri-procedural complications. The primary efficacy event rate, that was defined as a composite of
the occurrence of stroke (including ischemic or haemorrhagic stroke),
cardiovascular or unexplained death, or systemic embolism, was 3·0 per 100
patient-years in the intervention group and 4·9 per 100 patient-years in the
The safety analysis of the PROTECT-AF data showed that
patients in the interventional arm had a higher risk for safety end points like
device embolisation, major bleedings or pericardial effusions. Further analysis
revealed that most events occurred on the day of device implantation. The most
frequent safety event was pericardial effusion which occurred in 4.8% of
patients. The rates of occurrence of periprocedural events declined with increasing
The data of these trial lead to approval of the device
– under investigation
An ecg guided, epicardial approach
(engineered by Acess-PointTechnologies, Rogers, MN, USA) was described by
Freidman and colleagues in an animal model. The authors used a percutaneous
transpericardial access. After implantation of a sheath an appendage grasper
was introduced under electrocardiographic control, contrast medium was injected
into the pericardial space and the LAA was captured. In a second step a hollow
suture was advanced over the LAA, pushed over the base of the LAA and chinched
under echocardiographic control. The suture then was cutted by a specific
suture cutter and all materials were withdrawn. First data of 4 animals showed
a complete closure of LAA in all cases without significant trauma .
under investigation is the Anchorage
Closure Device™ (Epitek; Bloomington, MN, USA) that was developed to occlude, ligate or appose soft tissue. It is designed to enable
physicians to ligate soft tissue in a minimally invasive manner, thus avoiding
open surgical procedures. Until now no further data for closure of the LAA are
with atrial fibrillation, especially in the older population, have an increased
risk of stroke/TIA or PRIND, presumably due to stagnant blood flow within the
left atrial appendage- a highly complex structure of the left atrium-, leading
to subsequent thrombus formation. Till date, three therapeutic options exist to
reduce thrombembolic events in those patients: The first and most popular is
chronic anticoagulation therapy with warfarin, which is highly effective in preventing
cardioembolic events and superior to other pharmacological approaches so far . However, oral anticoagulation is associated
with several problems and significant risks: In about one third of patients there
is a contraindication for anticoagulation ,
the rate of discontinuation of therapy is up to 38%/year  and there is a narrow
therapeutic window with a potential risk for severe bleeding events of about 2
% per year  Furthermore, less than half of
all patients who are receiving anticoagulant treatment are within the
therapeutic range with regard to INR . Therefore,
new oral medication for anticoagulation without the risks and problems of
vitamin K antagonists are under way and are tested at present in phase III-
The second way to prevent thromboembolism
from the LAA is it´s exclusion from circulation by surgical techniques. Regardless
of the technique, first established in 1946, there are rare data available with
concerning the rate of successful LAA occlusion and complications. In addition,
it has never been addressed that such an approach really reduces the incidence
of stroke. Further large scale studies with clinical endpoints are required to
underline the effectiveness of these surgical interventions. Studies,
investigating new surgical occlusion devices are currently running. However,
one has to keep in mind that all these approaches are only suitable for
patients undergoing heart surgery for other reasons.
During the last ten years,
percutaneous occlusion systems were developed in order to seal the LAA in a
less traumatic way as a third way to prevent thrombembolic events in AF
patients. The reported periinterventional success rates are high for all the
devices. However, the number of patients treated with such devices so far is
small in relation to the population receiving warfarin and long term follow up
data are still lacking.
The first system developed for
interventional LAA occlusion was the PLAATO®-
System. The safety and feasibility of the system in humans was shown in
patients with contraindication for chronic oral anticoagulation therapy. A risk
reduction of about 50% for the incidence of ischemic strokes in this patient
population was demonstrated after implantation of the device and chronic
aspirin administration as compared with their statistically calculated risk.
However, procedural complications like pericardial effusions/tamponade, device
embolisation and device failure have been described in about 5% of patients.
The second system developed to
occlude the LAA, is the WATCHMAN®-
device. Implantation of the device was shown to be safe and feasible in a pilot
trial in humans with atrial fibrillation. The patient population in this study
had a lower risk for ischemic stroke with a CHADS² Score of 1.8
points as compared to 2.5 points in patients treated with the PLAATO®- device. To avoid thrombus formation on
the surface of the device an oral anticoagulation for 45 days after
implantation procedure and a double therapy with aspirin and clopidogrel thereafter
for up to 6 months is required.
The first generation of the device
had a higher complication rate (device embolisation, device failure) which was reduced
after re-designing the device. Data from the Protect AF Trial-(a FDA approval
trial) clearly show the non inferiority of the device implantation compared to
standard warfarin therapy. After more than 1000 patient-years of follow up a
strong trend in reduction of the combined primary endpoint was shown in the
device group. Given the fact that most complications in this group occurred
during the implantation procedure it is expected that the event free survival
curves will further diverse with advantage to the device group. Complications
of the warfarin group, however occured continuously during follow up. Furthermore
this results show that there is a remarkable learning curve for intervenionalists
indicating a reduction of complications during device implantation with more
The third interventional method,
implantation of an Amplatzer® septal occluder into the orifice of the LAA was
shown only in a single center series with few patients. With only short term
results. Furthermore the device is not approved for this indication and
randomized data are lacking. Therefore the manufacturer now offers a special
designed device, the Amplatzer® cardiac plug. Since this device is new, no data
are available with regards to safety and feasibility (table 3).
Table 3: Comparison of the three interventional devices for LAA occlusion
* data are only available for the Amplatzer® septal occluder, not approved for LAA occlusion
** Amplatzer® cardiac plaque occluder available
Taken together, only mid term data
but no long term data for percutaneous LAA occlusion devices are available so
far and the question which therapeutic options do we provide patients with
contraindication for warfarin therapy is still not fully addressed. Another
point of discussion is the medical treatment after device implantation.
Patients with contraindication to warfarin therapy often have contraindication
to a combination therapy with aspirin and clopidogrel as well. The issue if it’s
really necessary to enact them a combination therapy up to 6 months is not
supported by data so far. The development of new oral anti-Xa –inhibitors that
are under investigation and probably will be approved within a few months
raises even more questions. Will an interventional device still be non inferior
as compared to this class of drugs?
Today and with the current
knowledge the authors would recommend the implantation of the Watchman® device only
in experienced centers with strong surgical back up in patients with middle to
high risk of stroke according CHADS2 Score > 1 who have an
increased risk for bleeding complications under warfarin therapy. In patients
with AF who refuse warfarin therapy for personal reasons, the implantation of the
Watchman® device might be eligible.
occlusion with the available devices is safe and feasible. At present only the Amplatzer®
cardiac plug and the WATCHMAN® occluder are commercially available, both
devices are CE marked but only the Watchman Device is approved by the FDA for
the occlusion of the LAA in patients with AF.
prevalence of AF especially in the elderly, where anticoagulation therapy carries
a high risk or is contraindicated substantiates these devices as an attractive
solution to prevent atrial fibrillation-related thromboembolic events.
Nevertheless, the measurable risk
in implanting such new devices with an investigators learning curve at the
beginning and newly developed drugs like oral Factor Xa Inhibitors like
rivaroxaban (Bayer Health Care; Leverkusen Germany); DU-176 b (Daichi-Sankyo
Ltd. Tokyo Japan) or Dabigatran (Boehringer Ingelheim, Ingelheim, Germany)
which are currently investigated, have to be considered.
From the authors point of view it
is crucial that potential patients derive their decision for either warfarin
therapy of LAA occlusion from a balanced and fully informed basis.
When the decision is made, the interventional
occlusion of LAA in patients with AF has to be done with strict caution and only
in centers with high experience in this technique.
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