What to Do With the Left Atrial Appendage?

Atrial fibrillation (AF) affects 2.2 million Americans currently, and it is projected that 16 million will have the disorder by 2050.¹ The incidence of embolic stroke increases with the diagnosis of AF, and the embolic source is many times the left atrial appendage (LAA). The primary problem with the LAA has to do with its anatomy, which magnifies the problem of decreased flow turbulence with AF.

The purpose of this paper is to discuss the special features of the LAA and to review the various approaches that have been tried to prevent strokes from occurring in the patient with AF. First we’ll examine what is unique about the LAA, and then we’ll review the pharmacologic, surgical, and catheter-based approaches to LAA management.

Anatomy

Appendages are present in both the right and left atria, but normally the LAA is smaller. The endocardium of the LAA contains pectinate muscles,² muscular strips that line the inner surface. The ridges within the pectinate muscles are places where, when decreased turbulence of flow occurs during AF, clot formation can occur more easily. The ‘out-of-the-way’ orientation of the LAA also places it away from where much of the traffic of blood flow occurs.

As the AF disease process progresses, structural remodeling of the atria occurs, further changing the landscape.³ In addition, there appears to be highly individual variability of the aperture at the base of the LAA, plus great variability in size and dimension of the structure itself.⁴

A 2011 MRI study⁵ of 144 patients with AF found that those with a stoke history had higher LAA volume, depth, and long and short axes of the LAA neck. This work suggests that the dimensions of the LAA might be used to predict strokes or TIAs in AF patients, and that MRI may possibly help to risk stratify this population. A study by Walker et al in 2011⁶ looked at 59 patients having AF ablation who had pre-procedural multi-slice CT scans. The LAA orifice dimensions and LA and LAA volumes were measured. The mean LAA orifice dimension was 27.2±4 mm for the persistent AF patients, while with paroxysmal AF, the mean dimension was 22.9±3 mm. The increasing LAA volume, maximal LAA orifice dimension, and left atrial volume were also strongly correlated. The authors of this study felt that this information could impact occlusion device sizing for the LAA.

Interventions to tie off or obstruct or remove the LAA cause structural tissue changes. The closure of the LAA by device or ligation causes it to become atretic, fibrotic, and involuted. The left atrial endocardium in the aperture region evolves into a smooth surface.⁷

Pharmacological Approaches

The pharmacological options available for ischemic stroke prevention have been limited mostly to warfarin, a vitamin K antagonist, and aspirin. Warfarin use requires ongoing anticoagulant monitoring in addition to dosage adjustments. The effectiveness of warfarin therapy has been called into question. Researchers have found that during randomized clinical trials, patients on warfarin were only within therapeutic range two-thirds of the time.⁸ The problem is most likely associated with the multiple diet and drug interactions seen with warfarin use,⁹ although compliance may play a role too. Warfarin users have a risk of bleeding of 2 percent per year. However, warfarin does seem to reduce ischemic stroke risk.¹⁰

The drug dabigatran has been approved for prevention in the AF population, as has been rivaroxaban. Apixaban is also undergoing FDA review currently. These new drugs exert their effects through different portions of the coagulation cascade than warfarin. Anticoagulation monitoring is not required with these drugs. These new agents will no doubt begin to play a larger role in stroke prevention in the AF population.

Surgical Approaches

Surgical exclusion of the LAA has been performed since 1946. Most recently, the ACC/AHA 2006 Guidelines for the Management of Patients with Valvular Heart Disease recommended that LAA amputation be performed routinely with mitral valve surgery.¹¹

The success rate for completely removing/excluding the LAA surgically has not been an overwhelming success, as reported by Healey, with success rates seen between 50–90%.¹² The LAAOS (Left Atrial Appendage Occlusion Study) trial enrolled 77 AF patients with CHADS2 scores >2, who were undergoing CABG procedures. They were randomized into three groups: LAA occlusion by staples, LAA occlusion by sutures, and a control group. There were 9 LAA injuries that had to be repaired intraoperatively. Assessment prior to discharge found 45% effectiveness with suture occlusion and 72% effectiveness with the stapler occlusion. Two patients experienced thromboembolic events while in the hospital. Of concern is the apparent fragility of the LAA plus the fact that ligation may be incomplete and patients may still be at risk after removal.^12-15

Cox-Maze Procedure

The Cox-Maze procedure for atrial fibrillation has been performed since 1987. This involves isolation of the pulmonary veins, and surgical excision of both atrial appendages.¹⁶ This is an open-heart procedure on bypass pump. A center recently reported that with a mean follow-up of >5 years, just one patient in >200 had experienced a stroke. However, a disadvantage of the Cox-Maze procedure is that only a small group of the AF population qualifies due to their age and co-morbidities.

AtriClip^®

Researchers from Switzerland and the U.S. have reported on an epicardial clip being used on the LAA during elective cardiac surgery.^17,18 The AtriClip^® (AtriCure, Inc., West Chester, OH) is a self-closing, sterile, implantable clip with a reusable deployment tool (Figure 1). The clip is made of 2 parallel rigid titanium tubes with elastic nitinol springs, and covered with a knit-braided polyester sheath. It comes in four clip sizes: 35 mm, 40 mm, 45 mm, and 50 mm (Figure 2). No device-related complications have been reported with this procedure. Stable clip location and appendage occlusion were seen at 3-month follow-up. The U.S. trial, EXCLUDE, utilized the device in 67 patients. In CT and ultrasounds on 61 patients at 3-month follow-up, all but one patient showed complete LAA occlusion.¹⁹ In June 2010, the FDA approved the clip for stroke prevention in AF, and it may be used in the open-heart or minimally invasive approaches, using the designated deployment tool.

The Minimaze Procedure

The Minimaze procedure^20-22 is a minimally invasive, video-assisted, off-pump surgical procedure incorporating a bipolar RF clamp that clamps around the PVs to achieve isolation, incorporates ablation of ganglionic plexi, creates linear lesions, and excludes the LAA. Candidates are those who have failed antiarrhythmic drugs or are intolerant of warfarin. Greater than 80% of patients in initial studies have been found free from AF at 3-month follow-up. Anticoagulants are maintained for 2–3 months after surgery. In earlier studies, the excision of the LAA was achieved with surgical staples. The recent report from a web-based registry summarized the multicenter experience from 2006–2011 with 118 patients.²² The LAA was excluded in 112 patients (95%) with no deaths related to the procedure. Fifty-four patients underwent exclusion with a linear stapler using a 4-mm clip load without a knife; 45 patients had excision after stapling using a 4-mm clip load with a knife, and in 12 patients the AtriClip was used. No peripheral embolic events, strokes or MIs occurred. However, 3 patients required conversion to a bypass procedure for repair of left atrial injury. All recovered from this procedure.

Endocardial Catheter-Based Approaches

Three devices will be covered in this discussion: the PLAATO device, the WATCHMAN^®, and the Amplatzer. Each involves a transseptal puncture and the placement of a device in the left atrium.

PLAATO Device

The PLAATO device (Appriva Medical Inc., Sunnyvale, CA) is a device introduced percutaneously and transseptally into the opening of the LAA, with the goal of blocking the opening and eventually achieving a sealed-off chamber. It has a self-expanding nitinol cage, covered with a polytetrafluoroethylene membrane. It was used in patients in whom warfarin was contraindicated. Initial results were good. Complications seen with the devices included pericardial effusion/tamponade, device embolization, and device failure in 5 percent.²³ The manufacturer has discontinued device development.

WATCHMAN^®

The WATCHMAN^® LAA closure device (Boston Scientific/Atritech, Inc., Plymouth, MN) is a mushroom-shaped device with a self-expanding nitinol frame, which contains fixation barbs and permeable polyester fabric that covers the left atria-facing surface of the device (Figure 3). Deployment is achieved percutaneously with transseptal access to the left atrium. The device blocks the entrance to the LAA as seen in Figure 4. WATCHMAN^® is still in the investigational stage. Patients receiving the device are prescribed warfarin for 45 days post implant (until endothelialization occurs), and clopidogrel for 6 months. The clinical trial Embolic Protection in Patients with Atrial Fibrillation (PROTECT AF) enrolled paroxysmal, persistent, and permanent AF patients for a comparison of WATCHMAN^® to warfarin. Complications of the study included pericardial effusion, periprocedural stroke, embolization, and post-implant sepsis. The trial did demonstrate noninferiority of the device compared with warfarin for stroke prevention.^24-26 At 18-month follow-up there was no significant difference between the two groups. Subsequent analysis of the study data showed that a significant improvement in safety of the WATCHMAN^® device occurred when there was an increase in operator experience.²⁷

Amplatzer Cardiac Plug^®

The Amplatzer Cardiac Plug^® (AGA Medical, Golden Valley, MN) is being used for percutaneous closure of atrial septal defects. An initial trial enrolling AF patients for LAA occlusion had 16 patients, with occurrence of one device embolization. In follow-up, all patients maintained LAA occlusion after 5 years.²⁸ A European trial has been conducted with 10 centers reporting 132 of 137 successfully implanted devices. Ten patients experienced serious complications (3 strokes, 2 embolizations of the device, and 5 clinically significant pericardial effusions which required pericardiocentesis).²⁹

The Amplatzer Cardiac Plug^® (ACP) is a three-part system, including a transseptal access sheath, a delivery catheter, and an implantable self-expanding device. The device is made of nitinol mesh and a polyester patch. There is a lobe section and a disc section. The lobe contains stabilizing wires to hook into the tissue, while the disc seals the outer LAA orifice. It comes in 8 sizes, from 16–30 mm. The device’s deployment is guided by TEE and fluoroscopy.

Each of these endocardial approaches involved placement of a device to occlude the LAA. Correct sizing of the devices is important to prevent possible leakage around the edges of the device. Walker et al⁶ measured LAA dimensions in AF patients. They found the maximal LAA orifice dimension was >31 mm in 21% of their patients with persistent AF. This would exclude them from receiving either the WATCHMAN^® or Amplatzer Cardiac Plug^®. This is important data that needs to be considered by the people in research and development.

Epicardial Catheter-Based Approaches

Epicardial-based approaches include the LARIAT^® Suture Delivery Device, Aegis Medical System Device, and the Cardioblate Closure System^®.

LARIAT^® Suture Delivery Device

The LARIAT^® Suture Delivery Device (SentreHeart, Palo Alto, CA) includes an endocardial guidewire and an epicardial guidewire, each containing magnet tips of opposite polarity. The endocardial guidewire and balloon catheter are advanced into the LAA after a transseptal puncture. Intracardiac echo and contrast fluoroscopy help to secure correct positioning within the LAA. The balloon catheter is inflated to help confirm proper position. Meanwhile, a subxiphoid epicardial puncture is performed and the epicardial guidewire and LARIAT^® snare are advanced into the pericardial space. The LARIAT^® snare is placed over the balloon (with magnetic assist) and then tightened, and the LAA is excluded with a suture delivery and the balloon is removed. Figure 5 shows the balloon, which is placed in the LAA and the magnet at its tip plus the LARIAT® device itself. Figure 6 shows the LARIAT^® delivery system, which is placed within the pericardial space to meet and ensnare the balloon, thus occluding and tying off the LAA. In 2010, Lee reported use of the system in a canine study.^33,34 At 1- and 3-month follow-up, complete endothelialization of the LAA orifice was seen. Use of the system in man was reported in 2011,³⁵ using intraoperative and percutaneous approaches with excellent results. The equipment for the LARIAT^® procedure has been approved by the FDA, and the procedure is being performed in multiple centers.

Aegis Medical System

Aegis Medical Systems in Vancouver, Canada has developed a subxiphoid epicardial approach to LAA exclusion utilizing electrical navigation. Canine studies have been reported thus far.^7,30 The system includes an appendage grabber that captures the LAA while being guided by EGMs. The EGM is recorded between the 2 jaws and helps with distinguishing epicardial fat and ventricular tissue from LAA tissue. The other part of the system is a ligator, a looped hollow suture preloaded with a central wire for control and visualization. The jaws can be opened and closed until satisfactory closure is obtained. Correct position is confirmed via the use of a contrast injection to outline the LAA and through TEE or intracardiac echocardiography. Once the position is confirmed, the loop is tightened remotely and the suture is cut. The wire is removed and the suture is left behind. A suture clip is applied to secure this. In one canine study, flow to the LAA was abolished in 5 of 6 dogs. EGMs disappeared after ligation. There was no need for peri-procedural anticoagulation for this procedure as there was no transseptal puncture involved, just a single sheath puncture in the epicardium.

Cardioblate^® Closure System

The Cardioblate^® Closure System (Medtronic, Inc, Minneapolis, MN) has been tested in a canine study and a swine study, and a multicenter phase II trial is under development. The device is introduced into the pericardial space. The system includes a deployment device and a band applied to the LAA that exerts constant pressure, thus occluding LAA blood flow. The band is made of silicone and covered with polyester fabric. In the canine study, left and right atrial appendages were treated. There was a 100 percent occlusion rate with no bleeding, rupture, or embolism. The appendages eventually became necrotic and were replaced by scar tissue.^31,32

Summary

Pharmacologic, surgical, epicardial, and endocardial approaches are all being explored in an effort to decrease the incidence of stroke caused by the LAA. The next few years will no doubt continue to bring a flurry of activity aimed at finding the safest and most efficacious approaches.

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