J INVASIVE CARDIOL 2008;20:E109-E113
Stroke is the third leading cause of mortality in the developed world.1 The incidence of first-ever strokes was > 731,000 in 1996 in the United States alone.2 In addition, stroke is the leading cause of serious disability and morbidity and has devastating consequences, not only on the functional status of affected patients, but also on their family and caregivers.1
Atrial fibrillation (AF) is one of the most common cardiac arrhythmias and its association with stroke is well known. Certain therapies are available to reduce the risk of stroke associated with AF. This paper discusses the therapies available to reduce AF-associated stroke risk and focuses on the novel approach of percutaneous left atrial appendage (LAA) exclusion.
Stroke and atrial fibrillation. The frequency of AF in the general population has been estimated to be 0.9%.3 Its prevalence is age-dependent, rising from 1% among those 55–59 years of age to > 13% for those 3 80 years of age.4 The rate of ischemic stroke among patients with non-rheumatic (NR) AF averages 5% per year,5,6 a 5- to 6-fold excess risk of stroke independent of other factors.7 NRAF is responsible for 18–29% of all ischemic strokes,8,9 and conversely, as many as 20% of all ischemic strokes occur in patients with AF, with the elderly being particularly susceptible.7,10 The frequency of AF in patients admitted for a first-ever stroke increased from 3.8% in those < 50 years of age to 34.3% in those ≥ 90 years of age.9
Cardioembolic strokes account for approximately 20% of all ischemic strokes, with AF — responsible for about 50% of all cardiac emboli — being the most common cause of cause of cardiogenic embolism.11 More importantly, patients with stroke and AF tend to be more severely disabled on admission and have a 50% increased mortality and greater disability at 3 months, independent of other baseline risk factors.8,9
The risk of stroke in patients with AF, however, is dependent on several factors. There are various scoring systems available to classify stroke risk due to AF, and one commonlyused system to predict stroke risk in AF is the CHADS2 score. This score is an acronym that utilizes variables such as recent congestive heart failure (CHF), hypertension, and age > 75 years, diabetes mellitus and history of stroke or transient ischemic attack (TIA) to predict the risk of stroke (Table 1).12 A CHADS2 score of 0–1 puts the patient at low risk of stroke; 2–3 represents moderate risk, and ≥ 4 represents high risk.
Reduction of stroke risk in atrial fibrillation. Oral anticoagulation has been shown to reduce stroke risk in patients with AF by 62–68%,6 and is currently the most effective preventive therapy for this group of patients. This treatment modality benefits patients with AF at moderate-to-high risk of stroke (CHADS2 ≥ 2). The risks of warfarin therapy, however, may not outweigh the benefits in the low-risk AF group, and aspirin, which reduces stroke risk in AF by approximately 22%, is the alternative treatment option.13 A dual-antiplatelet regimen of aspirin and clopidogrel was shown to be inferior to anticoagulation with warfarin,14 and similarly, low-intensity warfarin plus aspirin was also inferior to optimal warfarin therapy (International Normalized Ratio [INR] 2.0–3.0) for stroke prevention in AF.15
Although warfarin is effective in stroke prevention in AF, there are many factors that prohibit more widespread use. It has a narrow therapeutic potential, requires frequent blood sample monitoring, has significant drug-todrug interactions, and increases the risk of bleeding, especially in the elderly, and some patients may simply be unable to maintain a stable INR. One previous study found contraindications present in 17% of patients with AF, and of those who were eligible, only 78% actually received warfarin therapy.16
Previous studies indicate that the risk of stroke rose steeply at INRs < 2.0, while the risk of hemorrhage increased rapidly at INRs > 4.0.17,18 Major bleeding was reported to occur in 6.5% of patients per year, with age ≥ 65 years, history of gastrointestinal bleeding or stroke being independent risk factors.19 In a recent study, elderly patients (≥ 80 years old) who are at the highest risk of stroke had a major hemorrhage rate of 13.1% compared to 4.7% in those < 80 years of age.20 Within the first year, 26% of these elderly patients stopped taking warfarin, with safety issues the perceived reason in 81% of them.20 In addition, rates of major hemorrhage and warfarin termination were highest among patients with CHADS2 scores ≥ 3, ironically the group that would derive the greatest benefit from oral anticoagulation.
Patients with paroxysmal AF should be treated no differently from sustained AF patients, as both groups have similar stroke rates.14,21 In addition, high-risk patients with paroxysmal AF could be identified using the same clinical criteria applied to sustained AF.21
Current guidelines recommend (ACC/ AHA Class 1a) oral anticoagulation adjusted to maintain an INR between 2–3 in patients at high risk of stroke unless contraindicated.5 In reality, warfarin is underprescribed, administered in only 23–40% of eligible patients.22–24 Even in treated patients, it has been documented that the INR was subtherapeutic in 44% and supratherapeutic in 19%.25 Warfarin therapy is used least frequently in the elderly, despite the fact that they derive the greatest relative benefit.9,22–24,26 Therefore, alternative treatments to prevent stroke in patients with AF are needed.
Importance of the left atrial appendage in atrial fibrillation. The LAA is a multi-lobed structure of variable anatomy that is attached to the LA. One autopsy study of 500 hearts documented that 54% of LAAs had 2 lobes and 34% had ≥ 3 lobes, with these lobes often lying in different planes.27 The principal axis was noted to be markedly bent or spiral in 70%,28 and therefore the assessment of LAA dimensions and LAA thrombus by transesophageal echocardiography (TEE) is dependent on the imaging plane.29 The LAA orifice is asymmetrical and oval in shape, with its anterobasal portion in direct contact with the left circumflex artery in up to 48% of patients with AF.30 Larger LAA size and greater LAA dysfunction has been found in patients with AF,30,31 which are markers for increased embolic risk.32,33
In rheumatic AF, 57% of LA thrombi have been shown to be located in the LAA, whereas in NRAF, 91% of LA thrombi were found in the LAA.34 Previous observations have demonstrated that most embolic phenomena were associated with LAA thrombus in patients with AF.35,36 Therefore, it appears that treatments that obliterate the LAA may reduce stroke risk in AF.
In a retrospective study, the risk of stroke was found to be significantly reduced in patients who underwent LAA exclusion during mitral valve (MV) replacement compared to those who did not.35 However, there are no randomized data and an observational study actually showed a higher subsequent stroke rate in patients who had LAA exclusion during MV surgery if warfarin was stopped than if it was continued, suggesting that LAA exclusion itself may provide inadequate stroke prevention.37
Exclusion of the LAA during cardiac surgery can be safely performed either with sutures or staples.38 Incomplete exclusion of the LAA, however, has been reported in 36–55% of patients.38,39 The presence of LAA thrombus has been documented in these partially-excluded LAAs, and may account for observed thromboembolic phenomena.39 Surgical exclusion is an invasive procedure, and is most often performed during valve surgery or during Maze procedures, although isolated LAA exclusion via a thorascopic approach has been shown to be feasible and safe.40,41
Percutaneous left atrial appendage exclusion. Based on the surgical experience, less invasive options of excluding the LAA were developed. The first of these was the percutaneous left atrial appendage transcatheter occlusion (PLAATO) system (ev3, Inc., Plymouth, Minnesota) (Figure 1). This system consists of a self-expanding nitinol implant covered with an occlusive ePTFE (expanded polytetrafluoroethylene) membrane, and a 14 Fr and subsequently 12 Fr transseptal delivery catheter.42 The membrane was designed to occlude the orifice of the LAA and allow tissue incorporation into the device. Small anchors along the struts and passing through the occlusive membrane help anchor the device and encourage healing. Device diameters ranged from 15–32 mm, and were selected to be 20–40% larger than the diameter of the LAA ostium.42
In a nonrandomized multicenter registry, 111 patients with NRAF of at least 3 months’ duration who had contraindications to warfarin were studied.43 Implantation was successful in 97.3%, with 3 unsuccessful procedures due to the presence of LAA thrombus, vessel perforation during vascular access, and cardiac tamponade after transseptal puncture. Five patients (4.5%) experienced pericardial effusions which were uneventful in 4; the last remaining patient underwent pericardiocentesis and a hospital stay that was complicated by deep vein thrombosis and ultimately death from probable cerebral hemorrhage due to the institution of anticoagulation. At 6 months, TEE showed successful LAA occlusion in all 108 devices implanted, with no device migration or mobile thrombus.43 The LAAs distal to the device were thrombosed; the structural and functional integrity of the left upper pulmonary vein and MV were unaffected.44 The annual stroke rate was 2.2%, which was a 65% relative risk reduction compared to a CHADS2 score predicted stroke rate of 6.3%.43 Despite these initially encouraging results, this device is no longer in development due to financial reasons.
The second device specifically designed for percutaneous transcatheter LAA exclusion is the Watchman Left Atrial Appendage System (Atritech Inc., Plymouth, Minnesota) (Figure 2). This is a three-part system consisting of a transseptal sheath, a delivery catheter, and an implantable device. The implant is a self-expanding nitinol frame structure with fixation barbs and a permeable polyester fabric that covers the atrial side, and is available in diameters from 21–33 mm.45 The device is chosen to be 10–20% larger than the LAA body to have sufficient compression for stable positioning.
The main difference of this device is that patients have to be eligible for warfarin therapy, as warfarin and aspirin are required for 6 weeks postimplantation.45 The early nonrandomized results have been reported.45 Patients with chronic or paroxysmal NRAF with a CHADS2 score of ≥ 1, and a life expectancy of at least 2 years were eligible. Of 75 patients, the implantation success rate was 88%. The reasons for procedural failure were the inability to place the transseptal sheath into the LAA, core wire malfunction (1 case), and the remainder was due to unsuitable LAA anatomy for device placement. At 45 days, 93% of devices showed successful sealing of the LAA. The first-generation device experienced 3 failures — 2 embolizations and 1 delivery-system failure due to a fractured delivery wire. Percutaneous retrieval was successful for both embolized devices, whereas surgical removal was required for the broken delivery wire. In addition, there was an incidence of air embolism leading to malignant arrhythmia requiring cardiopulmonary resuscitation. The device was redesigned after use in the initial 16 patients, and no further embolizations or fractured delivery wires occurred. There were 2 cases of pericardial effusions related to transseptal puncture in one and an overly-vigorous “tug test” in the other. Two patients died of unrelated causes, with no major strokes during a mean follow-up period of 24 months (CHADS2 predicted stroke rate was 1.9/ year). There is currently an ongoing randomized trial comparing the Watchman device to a control group taking long-term warfarin alone (PROTECT-AF) with planned follow up to 5 years.46
The third device — the Amplatzer Septal Occluder (ASO) — is the only device used in LAA exclusion not specifically designed for that purpose. Access is obtained through a transseptal puncture or through a patent foramen ovale or atrial septal defect, and devices were chosen to be a few millimeters smaller than the neck of the LAA. In a series of 44 patients treated at 4 centers, of which the results of the initial 16 patients have been published,47 there were 6 device embolizations and 2 deaths, both unrelated to the procedure or device. Several of these were combined procedures (Figure 3). No embolic events occurred during cumulative follow up of 100 patient-years. There were 3 incomplete LAA exclusions, 1 requiring a second device (Table 2). The advantages of this technique are the technical simplicity and widespread availability of equipment, although a steep learning curve is to be expected, and patient selection according to LAA anatomy is of the utmost importance.
Despite the encouraging results of percutaneous LAA exclusion, more widespread use of these technologies must await randomized data. It remains to be proven if percutaneous transcatheter LAA exclusion or surgical LAA exclusion is superior to oral anticoagulation therapy, and for patients with contraindications to long-term warfarin therapy, more data are needed to determine if mechanical or surgical closure is superior to aspirin therapy alone.
AF is a well-known predisposing factor for stroke, raising the risk significantly. Oral anticoagulation with warfarin is the most effective therapy for stroke risk reduction; however, this therapy increases the risk of bleeding and is often underutilized, contraindicated, or when administered, often subtherapeutic. It has been documented that the LAA is the main source of LA thrombus, especially in NRAF. Therefore, LAA exclusion may reduce the risk of stroke in AF, and retrospective surgical data have demonstrated a reduced risk of embolic events if surgical LAA exclusion was also performed during mitral valve replacement. Recently, several percutaneous transcatheter techniques of LAA exclusion have become available, with initially encouraging results. There is currently an ongoing randomized trial comparing percutaneous LAA exclusion to long-term oral anticoagulation therapy. Until such data are available, however, oral anticoagulation should remain the standard of care for stroke prevention in patients with AF.
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