Stroke Prevention in Nonvalvular Atrial Fibrillation

Stroke is the 3rd leading cause of death in patients with atrial fibrillation (AF). The risk of stroke is 5 times higher in patients with AF than in those without AF.^1,2 Furthermore, the Framingham study³ showed that the mortality rate of strokes related to AF is twice as high as that of strokes unrelated to AF, and functional deficits are more severe in AF-related strokes.

In AF patients, 87% of strokes are thromboembolic. Irregular heartbeats disrupt blood flow, which results in stagnation of the blood and formation of a blood clot that can dislodge and embolize to the brain. More than 90% of thrombi in AF patients originate in the left atrial appendage (LAA).^1,4,5 Therefore, exclusion of the LAA cavity from the circulation is a reasonable approach to preventing thromboembolism in AF patients.^4,6,7

In 2005, Healey and colleagues⁸ reported results from the 1st randomized trial of the surgical occlusion of the LAA. They showed that this approach was safe and effective in patients undergoing coronary artery bypass grafting.⁸ On the basis of this surgical experience, less invasive percutaneous devices for LAA closure, such as the WATCHMAN, AMPLATZER, and LARIAT, have been developed.

Warfarin

Warfarin is the cornerstone of medical therapy in stroke prevention and has been shown to be an effective anticoagulant.⁹ Cooper and colleagues¹⁰ showed that the standard dose of warfarin prevented 28 of 51 ischemic stroke events per 1,000 person-years but resulted in 11 major or fatal bleeding episodes. In 6 trials of warfarin versus placebo, a 62% reduction in stroke was seen with the use of adjusted-dose warfarin. Furthermore, 5 randomized controlled trials showed that adjusted-dose warfarin resulted in a relative risk reduction of 36% when compared with aspirin.¹¹ As a result of these studies, both the Seventh American College of Chest Physicians and the American College of Cardiology/American Heart Association/European Society of Cardiology developed guidelines recommending the use of either a vitamin K antagonist or aspirin to reduce the risk of stroke in AF patients.¹² Finally, a meta-analysis of 13 trials showed that adjusted-dose warfarin significantly reduced the risk of stroke or embolism when compared with aspirin or placebo.¹³

Warfarin is a double-edged sword in that it prevents stroke but can predispose patients to fatal bleeding if the dosage is too high. Consequently, the international normalized ratio (INR) must be closely and frequently monitored to reduce the risk of bleeding, and caution is urged.¹⁴ Because food and other drugs can alter the effectiveness of warfarin, multiple adjustments might be warranted. The therapeutic INR range for warfarin is relatively narrow—between 2.0 and 3.0. Not all eligible patients are treated with warfarin, because of intolerance or noncompliance. Moreover, among treated patients, a significant number do not stay within the therapeutic INR range. The SPORTIF (Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation) trials showed that warfarin-treated patients stayed within the therapeutic INR range only 68% of the time.¹⁵ This number was even lower (59%) in the report by Amouyel and colleagues.¹⁶

Dabigatran

Dabigatran is a potent direct competitive inhibitor of thrombin. The oral prodrug dabigatran etexilate is converted by a serum esterase to dabigatran, which has a bioavailability of 6.5% and a serum half-life of 12 to 17 hours. About 80% of the given dose is excreted by the kidneys. Dabigatran was approved by the U.S. Food and Drug Administration (FDA) in 2010 for the prevention of stroke and systemic embolism in patients with nonvalvular AF. The recommended dose is 150 mg twice a day for patients with a creatinine clearance (CrCL) of 30 mL/min or greater and 75 mg twice daily for patients with severe renal insufficiency (CrCL of 15–30 mL/min). There are no dosing recommendations for patients with a CrCL <15 mL/min or for patients on dialysis.

The RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study showed that dabigatran etexilate (150 mg twice daily) was more successful in reducing strokes and systemic embolism than warfarin but had a similar rate of major hemorrhage.¹⁷ The lower dosage of dabigatran etexilate (110 mg twice daily) had the same result as warfarin in reducing the rate of stroke and systemic embolism, with a lower rate of major hemorrhage than warfarin, whereas dabigatran at a dose of 150 mg was significantly more effective than warfarin or lower-dose dabigatran (110 mg).¹⁷ The 110-mg twice-daily dose used in the RE-LY trial did not receive FDA approval in the United States.

There is no specific antidote for dabigatran. Surgical intervention or supportive therapy with an infusion of fresh-frozen plasma may be needed in cases of severe bleeding.¹⁷

WATCHMAN LAA Closure Technology

The WATCHMAN LAA closure procedure was developed to prevent the embolization of thrombi, which can form in the LAA in patients who have such disposing conditions as AF.^18,19 This approach has the potential of replacing warfarin therapy in patients with nonvalvular AF.²⁰ The WATCHMAN® LAA Closure Device (Atritech, Inc.; Plymouth, Minn) comprises a 3-part system of a transseptal access sheath, a delivery catheter, and an implantable device. The device is placed in the LAA (covering the neck of the LAA) to exclude the LAA and prevent clot formation; over time, endothelialization of the device should occur. For at least 45 days after device placement, patients need to take warfarin.

The PROTECT AF (WATCHMAN Left Atrial Appendage System for Embolic PROTECTion in Patients with Atrial Fibrillation) investigators compared stroke prevention in AF patients after implantation of the WATCHMAN device with stroke prevention in AF patients undergoing warfarin therapy.¹⁹ The study showed that 87% of patients who underwent implantation of the WATCHMAN device were able to discontinue warfarin at 45 days, and at 2-year follow-up, 94% had stopped taking warfarin. These findings suggest that the WATCHMAN device is a viable alternative to warfarin therapy for preventing strokes in patients with nonvalvular AF.

Although the WATCHMAN device is a permanent solution, it carries a risk of embolization and breakage. Patients still require warfarin for a period of time long enough to promote endothelialization.

AMPLATZER Cardiac Plug

The AMPLATZER® Cardiac Plug (AGA Medical Corporation, a part of St. Jude Medical, Inc.; St. Paul, Minn) is a 3-part system that comprises a transseptal access sheath, a delivery catheter, and an implantable, self-expanding patch. It has been used for LAA exclusion since 2002.²¹

In a retrospective study of 143 patients, Park and colleagues²² demonstrated the feasibility of using the AMPLATZER Cardiac Plug technique for LAA closure by showing that only 17 of the 143 patients (12%) had sequelae. Warfarin anticoagulation was not necessary after the procedure, but patients were advised to take clopidogrel and aspirin for 1 to 3 months, followed by aspirin alone for ≥5 months for platelet inhibition.²²

Use of the AMPLATZER Cardiac Plug device is still being studied; more data are necessary to clearly identify the advantages and disadvantages of this approach.

LARIAT Procedure

The LARIAT procedure is an alternative approach for closing the LAA that uses both endocardial and epicardial access. During the LARIAT procedure, a magnet-tipped guidewire is threaded through a pericardial access, while a second, similar guidewire is threaded through the transseptal access to establish a track to the LAA. Both wires are positioned under fluoroscopic guidance. Following the established track, the LARIAT™ Suture Delivery Device (SentreHEART, Inc.; Palo Alto, Calif) is guided over the LAA in an over-the-wire approach to slip a pre-tied suture loop over the LAA, which is then closed under transesophageal echocardiographic guidance. Because of the need for pericardial access, patients with a history of coronary artery bypass surgery or pericarditis who may have adhesions in this space are not suitable candidates for the LARIAT procedure.

Unlike the WATCHMAN approach, the LARIAT procedure does not require the use of immediate postprocedural anticoagulation therapy with warfarin. Because of the unavoidable irritation of the pericardium associated with the pericardial access used in the LARIAT procedure, the risk of pericarditis should be considered.

In Europe, Bartus and colleagues²³ showed promising results of the LARIAT procedure in 13 patients, but more data are needed on this approach. In a study of 37 dogs, this method was shown to be 100% successful.²⁴ Furthermore, the preliminary results from clinical cases have shown that pericardial access was successful in 78 of 82 cases (95%), with a 97% success rate of acute closure at 30-day follow-up (personal communication from SentreHEART, February 2011). The results of this ongoing registry will provide more details on the clinical efficacy of the LARIAT procedure.