In deciding whether to start anticoagulation, weigh the risks of both stroke and bleeding.
David C. Peritz, MD
Department of Medicine/Pediatrics, University of North Carolina School of Medicine, Chapel Hill
Eugene H. Chung, MD, FACC, FHRS, FAHA
Associate Professor of Medicine, Division of Cardiology, Cardiac Electrophysiology, University of North Carolina School of Medicine, Chapel Hill
Address: David C. Peritz, MD, Department of Medicine/Pediatrics, University of North Carolina at Chapel Hill, 160 Dental Circle, CB 7075, Chapel Hill, NC 27599; e-mail: firstname.lastname@example.org
Dr. Chung has disclosed consulting for Biosense Webster.
ABSTRACTAtrial fibrillation is associated with a risk of stroke, primarily from embolization of clots that form in the left atrial appendage. This structure has been targeted to reduce stroke risk in patients who have contraindications to oral anticoagulation. This article appraises the current literature describing surgical and percutaneous isolation of the left atrial appendage.
Can patients with atrial fibrillation undergo a percutaneous procedure to reduce their risk of stroke, thereby eliminating the need for lifelong treatment with an oral anticoagulant drug? The data are preliminary, but this is an emerging option that physicians should be aware of.
We review here the current evidence and techniques aimed at isolating the left atrial appendage to prevent stroke, and we emphasize the need for continued systematic comparisons between oral anticoagulation and percutaneous treatment options.
NOVEL TREATMENTS ARE NEEDED
Atrial fibrillation is the most common cardiac arrhythmia,1 affecting an estimated 1% to 2% of people worldwide. In 2001, an estimated 2.3 million persons in the United States had atrial fibrillation, and that number is expected to more than double by 2050.2
Atrial fibrillation independently increases the risk of stroke by a factor of 4 to 5.3 The American Heart Association ranks stroke as the fourth most common cause of death and the leading cause of disability in the United States.4 Atrial fibrillation accounts for 15% of strokes in people of all ages and 30% in those over age 80.5 Untreated, 2% to 5% of patients with atrial fibrillation suffer a stroke in any given year.6 Most of these strokes are cardioembolic, with thrombi originating in the left atrial appendage.7 Furthermore, it has been estimated8,9 that patients with atrial fibrillation who have already had a stroke and cannot tolerate oral anticoagulants have an annual risk of stroke close to 12% and a relative risk of approximately 3.0 compared with those with atrial fibrillation and prior stroke who can tolerate anticoagulation.
Oral anticoagulation effectively prevents thromboembolic events associated with atrial fibrillation,10 but several factors limit its efficacy and applicability. The risk of bleeding complications, the need for frequent monitoring, and challenges with compliance create a large population of patients who would benefit from alternative approaches. Consequently, physicians have looked for other ways to prevent stroke—especially surgical and transcatheter procedures—that are not associated with an ongoing risk of hemorrhage and a lifelong need to take an anticoagulant.
THE LEFT ATRIAL APPENDAGE: A SITE OF CLOT FORMATION
The left atrial appendage is the most common site of thrombus formation, particularly in patients with nonvalvular atrial fibrillation. Nearly 90% of thrombi discovered in the left atrium form in the appendage.7 A study of 233 patients not on long-term anticoagulation revealed that after 48 hours of atrial fibrillation, 15% had a left atrial thrombus, and all but one of the thrombi were in the appendage.11
Atrial fibrillation increases the risk of stroke by a factor of 4 to 5
Believed to function as a decompression chamber during left ventricular systole, the left atrial appendage is embryologically derived from the left wall of the primary atrium. It is in close proximity to the free wall of the left ventricle, and therefore its flow can vary with left ventricular function. Relative stasis due to its location and extensive trabeculations, especially in times of poor forward flow, make it a high-risk site for clot formation.12
ANTICOAGULATION: EFFECTIVE BUT IMPERFECT
In deciding whether a patient with atrial fibrillation should be prescribed anticoagulation therapy, the physician must balance the risk of stroke against the risk of bleeding. Several tools for assessing these two risks have been developed. Of note, some of the risk factors for stroke are the same as some of the risk factors for bleeding.
CHADS2 and CHA2DS2-VASc are the two most commonly used tools for assessing the risk of stroke, but only the newer CHA2DS2-VASc has received a class I recommendation (the highest) from the European Society of Cardiology (ESC).13
CHADS2 risk factors are Congestive heart failure (1 point), Hypertension (1 point), Age 75 or older (1 point), Diabetes (1 point), and Stroke or transient ischemic attack (2 points). Risk of stroke is considered low with a score of 0, intermediate with a score of 1, and high with a score of 2 or more.
CHA2DS2-VASc risk factors are Congestive heart failure or left ventricular ejection fraction ≤ 40% (1 point), Hypertension (1 point), Age ≥ 75 (2 points), Age 65–74 (1 point), Diabetes mellitus (1 point), Stroke, transient ischemic attack, or thromboembolism (2 points), Vascular disease (1 point), and female Sex (1 point). Low risk is defined as a score of 0 for a man or, for a woman with no other risk factors, a score of 1. A score of 1 for a man indicates moderate risk, and a score of 2 or more is high risk.
Tools for assessing bleeding risk include ATRIA2 and HAS-BLED,14 the latter carrying a class I recommendation from the ESC.13
HAS-BLED risk factors are Hypertension (1 point), Abnormal renal or liver function (1 point each), Stroke (1 point), Bleeding (1 point), Labile international normalized ratio (INR) (1 point), Elderly (age > 65) (1 point), and Drug or alcohol use (1 point each). The risk of bleeding is considered high with a score of 3 or higher.
Oral anticoagulation is the standard treatment for preventing stroke in patients with atrial fibrillation, and the vitamin K antagonist warfarin remains the foundation.
Though highly effective, warfarin requires close monitoring and frequent dose adjustments because of its numerous food and drug interactions. Bleeding risk and the challenge of frequent monitoring rule out treatment with warfarin in 14% to 44% of patients with atrial fibrillation.15 Even in “ideal” candidates, warfarin is underused, with one study reporting that only 38% of those with clinical indications for it had been prescribed warfarin, and of those for whom it had not been prescribed, 63% were also not taking aspirin.16 Moreover, a meta-analysis suggested that the average patient treated with warfarin has his or her INR in the therapeutic range only about 55% of the time.17
Newer, target-specific oral anticoagulants such as dabigatran (a direct thrombin inhibitor) and rivaroxaban and apixaban (both factor Xa inhibitors) do not require monitoring and have fewer drug interactions. But like warfarin, they also confer a risk of serious bleeding.18–20 Most of the studies of these newer drugs have compared them with warfarin, with the preponderance of evidence showing them to be either noninferior or superior to warfarin for stroke reduction. But bleeding complication rates remain significant, apixaban having lower rates of major bleeding than dabigatran and rivaroxaban.
Untreated, 2%–5% of patients with atrial fibrillation will suffer a stroke in any given year
In a meta-analysis, Ruff et al21 concluded that the target-specific oral anticoagulants provide a favorable balance of risk and benefit. Compared with warfarin, these new drugs reduced the rate of stroke or systemic embolic events by 19%. There was also a significant reduction in rates of intracranial hemorrhage and all-cause mortality. The risk of major bleeding was similar to that with warfarin, though there was a higher risk of gastrointestinal bleeding with target-specific agents. These effects were consistent across a wide range of patients.
Given the difficulties, risks, and serious side effects of anticoagulant therapy, many patients stop taking these drugs soon after starting them, either on their own or on their physician’s recommendation. In the RE-LY trial (Dabigatran vs Warfarin in Patients With Atrial Fibrillation), 10% of patients receiving dabigatran and 17% of those receiving warfarin stopped the treatment within 1 to 2 years.22 In a similar trial of rivaroxaban vs warfarin in nonvalvular atrial fibrillation (the ROCKET-AF trial), 24% of those treated with rivaroxaban and 22% of those treated with warfarin stopped treatment during the study.19 In the ARISTOTLE trial (Apixaban vs Warfarin in Patients With Atrial Fibrillation), 25% of patients discontinued apixaban and 28% discontinued warfarin.20
The results of these trials show a clear need for treatments without high attrition rates, since patients with atrial fibrillation need protection from stroke for the rest of their life.
In deciding whether to start anticoagulation, weigh the risks of both stroke and bleeding.