Approaches to Left Atrial Appendage Management: The Next Tools for Reducing the Risk of Embolization in Atrial Fibrillation

Atrial fibrillation (AF) is one of the most complex diseases of the modern world. As the life expectancy increases, the incidence of AF also increases.¹ AF is the most common and clinically significant sustained arrhythmia, ranging from 0.4-1.0% in the U.S., and as high as 5.9% in those older than 65 years.^2-4 It is currently estimated that AF affects three million people in the United States, and is projected to affect 10 to 12 million people by 2050. There is an ongoing debate in the field of cardiology whether to treat AF patients with a rhythm control strategy via drugs or ablation versus a rate control strategy with drugs. There is an increased mortality and morbidity associated with AF when all other variables are kept constant; this increase in mortality associated with AF is due to the occurrence of embolic events including stroke.²

AF is characterized by uncoordinated atrial activity that leads to the deterioration of atrial mechanical function. As the atrial contraction fails, there is reduced cardiac output, which in turn leads to hemodynamic stasis and clot formation.^5-7 These clots are vulnerable to emboli in the brain and systemic circulation. Brain emboli can cause minor transient ischemic attacks (TIAs) or major stroke, which can be catastrophic, resulting in an increase in morbidity and mortality in this patient population.¹ AF is independently associated with a near fivefold increase in the risk for stroke, and two-thirds of all strokes are cardioembolic. Strokes due to AF embolization are also associated with an increased 30-day mortality of 25% and one-year mortality of 50%, respectively.^8,9 It has been shown in multiple pathological and echocardiographic studies that approximately 90% of such strokes come from the left atrial appendage (LAA), which acts as a pouch for clot formation.¹⁰ 

There have been multiple clinical models developed to predict stroke risk in this patient population. The most commonly used are the CHADS₂ (congestive heart failure, hypertension, age >75, diabetes mellitus, and stroke or TIA) and newer CHA₂DS₂-VASc (in addition to CHADS₂, this includes vascular disease, age 65-74 years, and female gender) scores. As the score goes higher, the risk of stroke is higher. Even at lower scores, there is still a chance of having a cardioembolic event.^11,12 These scoring models do not completely risk stratify our patient population for risk of embolic events.

Strategies to prevent cardioembolic events with anticoagulation are not completely benign. The most commonly used anticoagulation is warfarin. Multiple studies have shown that 50% of the patients at risk for stroke are not prescribed anticoagulation because of the concern of bleeding and its complications. Out of those prescribed, only 40% remain on treatment by four years. Another frequent and significant issue is the variable INRs with Coumadin — only 60% are in the therapeutic range serially as shown in multiple randomized trials.¹³ There are also considerations for long-term INR monitoring, adapted eating habits and multiple drug-to-drug interactions. Bleeding risk models (e.g., ATRIA, HEMORR2HAGES and HAS-BLED) have also demonstrated poor performance rates.¹⁴ The most common clinical practice is to calculate both the stroke risk and bleeding risk scores, compare them, and then weigh the risks and benefits of anticoagulation.

Alternative newer oral anticoagulants (NOACs) have been well received due to the challenges associated with the use of Coumadin. These include dabigatran (Pradaxa [Boehringer Ingelheim] – a direct thrombin inhibitor available as 150 mg twice daily and 75 mg twice daily regimens), rivoraxaban (Xarelto [Janssen Pharmaceuticals] – a factor Xa inhibitor available as 20 mg once daily and 15 mg once daily regimens), and apixaban (Eliquis [Bristol-Myers Squibb] – a factor Xa inhibitor available as 5 mg twice daily and 2.5 mg twice daily regimens). There are several other medications in ongoing trials. The studies involving these NOACs have shown they are either noninferior or superior to warfarin for stroke reduction. However, the bleeding rates are somewhat concerning. In these trials, major bleeding rates were in the range of 2% to 3%, and minor bleeding rates were in the range of 10% per year. Though the rates of intracranial bleeding were less compared to warfarin, there were still deaths related to major bleeding.¹⁵ Also, if life-threatening bleeding occurs or emergency surgery is required, there is no antidote available at this time to reverse the action of these NOACs. Because monitoring is not required, patient compliance is also a concern that can increase the risk of stroke.

Due to these issues with anticoagulation, and considering that 90% of those clots are located in the LAA, the idea of isolating the appendage was well received. For most of our patients who undergo coronary artery bypass surgery or valve replacement of repair surgery by open thoracotomy, our surgeons have always ligated the LAA either by suture or excision. However, these techniques can have issues — up to 30-40% of these appendages are incompletely isolated and there is a residual flow in the LAA.¹⁶ Hence, there was a need for newer devices that could be used to safely perform percutaneous catheter-based LAA occlusion without any significantly higher complications.

AMPLATZER^™ Cardiac Plug

Last year we performed the first patient implant of the AMPLATZER Cardiac Plug (ACP, St. Jude Medical) in the United States. The study is approved by the FDA and initiated under a feasibility phase to be followed by an expanded pivotal phase. This device is approved for CE Mark and is widely used in Europe. We have successfully deployed seven ACP devices so far. All of our patients have complete occlusion of the LAA without any complications. Our first patient was a 70-year-old male with paroxysmal atrial fibrillation, hypertension, and diabetes (CHADS₂ score of 2 and CHA₂DS₂-VASc score of 3). The initial screening included transesophageal echocardiogram (TEE) (Figure 1), which showed an adequate LAA orifice and landing zone. The patient underwent successful placement of the ACP via a transseptal approach without any complications. Figure 2 shows the fluoroscopic image of the ACP after deployment, with lobe and disc of the ACP plug in the LAA. A TEE at 45 days post-ACP placement demonstrates the device to be well seated, as shown in Figure 3, with no evidence of color Doppler into the LAA (no residual leak). The patient’s Coumadin was stopped at 45 days post-ACP deployment. At one-year follow-up, TEE confirmed excellent placement without any residual leak. The patient is doing very well without any cardioembolic events.¹⁷ The AMPLATZER Cardiac Plug European Multicenter Observational Study showed a 65% reduction in stroke risk from estimated stroke rate (with 101 patient years the actual stroke rate was 1.98% compared to an expected annual stroke risk of 5.6%).

WATCHMAN Device

On December 11, 2013, the FDA’s Circulatory System Devices Panel voted 13-1 to recommend marketing approval for the WATCHMAN Left Atrial Appendage Closure Device (Boston Scientific) to prevent stroke or systemic embolism in patients with nonvalvular AF both for efficacy and safety. In the PROTECT AF, Continued Access Registry and PREVAIL trials, this device was non-inferior to warfarin for the primary endpoint of stroke, cardiovascular death and systemic embolism. At a mean follow-up of 45 months, superiority criteria to warfarin has also been achieved. There were 2.3 events per 100 patient years in the WATCHMAN group versus 3.8 events in the warfarin group. There were also fewer fatal and disabling strokes in the device group.¹⁸ There was up to 5% incidence of pericardial effusions in the early years, but the rate decreased to 2.9% in the CAP (Continued Access Protocol) Registry as the operator’s techniques and experience improved. 

Short- and Long-Term Complications and Outcomes

These devices are not without flaws. The WATCHMAN device was designed to deploy in the body of the LAA, which theoretically would leave a potential space at the ostium of LAA and can be a nidus for clot formation. However, this was not seen in the trials. The ACP device was designed to deploy at the LAA ostium. Theoretically, there should not be any space at the ostium of the LAA, but there have been few cases of thrombus formation in the cul-de-sac of the ACP device at the tip of the disk when the device was placed inside the LAA instead of ostium. The differences are demonstrated in Figures 4 and 5. Though the rates of pericardial effusion were higher early on, rates have decreased significantly with operator experience. There were also cases of peri-device leaks, which are attributed to mismatch between the device and LAA as well as variations in LAA anatomy, but the rates of leak less than 3 mm were clinically insignificant in the studies; the size of leak that should be bothersome is still not known. There have also been reports of device migration, but again, the chances are very minimal.

Long-term outcomes of leaving intracardiac devices in the LAA and the risk of erosions are not well known. From our personal experience implanting atrial septal defect occluder devices and implantable cardiac devices, we know that the risks of having any catastrophic complications are low. The cumulative risk of infective endocarditis is also low in view of epithelization of these devices.

LARIAT^® Device

We have also had the opportunity to use the LARIAT Suture Delivery Device (SentreHEART, Inc.) in two of our patients, without any complications. This device, which is approved to occlude soft tissue, received 501(k) approval for opposing tissue planes. It involves an external transpericardial approach in which the suture is placed externally to occlude the LAA. However, there is a need for a transseptal approach to place the magnetically-tipped guide wire in the dominant lobe of the LAA, so that a suture designed as a LARIAT can slide and tighten the LAA at the ostium. In a recent study, 85 patients underwent successful LAA ligation with the LARIAT device, and 95% of these patients had complete LAA closure by TEE.¹⁹ Adverse events included pericarditis, and long-term sequelae are unknown. The number of cases prior to approval for this device was too small to make any definite conclusions on its safety.

Conclusion

In our opinion, percutaneous transcatheter LAA closure devices will evolve over time and supplement the newer oral anticoagulants in reducing the risk of stroke in patients with atrial fibrillation. We hope that the use of devices will be restricted to a few expert centers so that complication rates are kept to a minimum, and that a registry will be maintained for surveillance.²⁰

Disclosures: The authors have no conflicts of interest to report. 

References

1. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation. 2006;114:119-125.
2. Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol. 2011;57:e101-198.
3. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22:983-988.
4. Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med. 1995;155:469-473.
5. Narayan SM, Cain ME, Smith JM. Atrial fibrillation. Lancet. 1997;350:943-950.
6. Guyton AC, Hall JE. Hemostasis and blood coagulation. In: Guyton AC, Hall JE, eds. Textbook of Medical Physiology. 10th ed. Philadelphia, PA: WB Saunders Co; 2000:419-429.
7. Hemostasis. In: Porter RS, Kaplan JL, Homeier BP, Beers MH, eds. The Merck Manual Online. 18th ed. Whitehouse Station, NJ: Merck and Co, Inc; 2006.
8. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke. 1996;27:1760-1764.
9. Marini C, De Santis F, Sacco S, et al. Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a population-based study. Stroke. 2005;36:1115-1119.
10. Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg. 1996;61:755-759.
11. Olesen JB, Lip GY, Hansen ML, et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ. 2011;342:d124.
12. Van Staa TP, Setakis E, Di Tanna GL, et al. A comparison of risk stratification schemes for stroke in 79,884 atrial fibrillation patients in general practice. J Thromb Haemost. 2010;9:39-48.
13. Go AS, Hylek EM, Borowsky LH, Phillips KA, Selby JV, Singer DE. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the Anticoagulation and risk Factors in Atrial Fibrillation (ATRIA) study. Ann Intern Med. 1999;131:927-934.
14. Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. Performance of the HEMMOR(2)HAGES, ATRIA, and HAS-BLED bleeding risk prediction scores in patients with atrial fibrillation undergoing anticoagulation: the AMADEUS (Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients with Atrial Fibrillation) study. J Am Coll Cardiol. 2012;60:861-867.
15. Baker WL, Phung OJ. Systematic review and adjusted indirect comparison meta-analysis of oral anticoagulants in atrial fibrillation. Circ Cardiovasc Qual Outcomes. 2012;5:711-719.
16. Katz ES, Tsiamtsiouris T, Applebaum RM, Schwartzbard A, Tunick PA, Kronzon I. Surgical left atrial appendage ligation is frequently incomplete: a transesophageal echocardiographic study. J Am Coll Cardiol. 2000;36:468-471.
17. Amruthlal Jain S, Darda S, Machado C. Amplatzer Cardiac Plug: Percutaneous Left Atrial Appendage Occlusion Device in Non-valvular Atrial Fibrillation for the Prevention of Thromboembolism. The Journal of Innovations in Cardiac Rhythm Management. 2014;5:1486-1492.
18. Reddy VY, Holmes DR, Doshi SK, Neuzil P, Kar S. Safety of percutaneous left atrial appendage closure: results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued Access Registry. Circulation. 2011;123:417-424.
19. Bartus K, Han FT, Bednarek J, et al. Percutaneous left atrial appendage suture ligation using the LARIAT device in patients with atrial fibrillation: initial clinical experience. J Am Coll Cardiol. 2013;62:108-118.
20. Holmes DR Jr, Lakkireddy D, Whitlock RP, Waksman R, Mack MJ. Left atrial appendage occlusion: opportunities and challenges. J Am Coll Cardiol. 2014;63:291-298.