Because of the long-term disability and mortality associated with stroke, it remains perhaps the most feared medical event for adult patients. In the United States alone, approximately 800,000 strokes occur per year, the majority of which are first occurrences. These strokes are the third leading cause of death and the leading cause of disability in the United States and account for up to $75 billion of health care.
The age-associated incidence of stroke has been well documented, with higher rates in older patients and increased prevalence as the population ages. The majority of strokes (approximately 80%) are either ischemic or thromboembolic. Cardioembolic strokes are associated with the worst long-term outcomes, probably related to the amount of thrombotic material involved.
Atrial fibrillation (AF) is a major risk factor for stroke; patients with this arrhythmia have an approximately 5-fold higher risk of stroke. The relationship between increasing age, the increasing incidence of AF, and the increasing rate of stroke has been well documented.
Antithrombotic therapy with warfarin (and more recently dabigatran) has been the cornerstone of stroke prevention in patients with AF, but issues such as bleeding, individual variability in response to drug dosing, and need for laboratory testing have led to its underutilization.
Left atrial appendage occlusion devices are being tested as an alternative to antithrombotic therapy for patients with nonvalvular AF. "The finding that the left atrial appendage is the source of approximately 90% of the thrombus in patients with stroke has been responsible for the great interest in a device strategy," says David R. Holmes, MD, an interventional cardiologist at Mayo Clinic in Rochester, Minnesota.
To date, a single randomized trial has been completed. Only 1 device was tested in that trial (Watchman; Atritech, Inc, Plymouth, Minnesota). In such a trial, the patient population included, the trial performance, and the primary endpoints are of crucial importance.
The Embolic PROTECTion in Patients With Atrial Fibrillation (PROTECT AF) trial randomized patients with nonvalvular AF at risk of stroke (CHADS2 [congestive heart failure, hypertension, age >75 years, diabetes mellitus, and prior stroke or transient ischemic attack] score e1) either to device implantation or to conventional therapy with warfarin.
To qualify for enrollment in the study, patients had to be able to receive warfarin; those unable to receive warfarin or in whom warfarin was contraindicated were not eligible.
In the device group, patients were treated with warfarin for 45 days on the basis of the assumption that by the end of 45 days, the device would have become fully endothelialized, after which warfarin was discontinued. Aspirin and clopidogrel were administered for 6 months and then aspirin alone. Both primary efficacy and primary safety endpoints were used with a noninferiority design. The efficacy endpoint was a composite of all-cause death, stroke or thromboembolism, and major bleeding. The safety endpoints are compared in the Table.
The device was noninferior to warfarin therapy for the primary efficacy endpoint. There was, however, an early safety hazard in the device limb, with increased perioperative events, mainly pericardial effusion. In addition, a small number of perioperative strokes occurred, usually the result of air embolism during the procedure. Subsequent to completion of the study, a continued access protocol was initiated, which documented continued efficacy of the device and a reduction in procedural complications, the latter of which was achieved by improved operator experience and implantation techniques and equipment design modifications.
"The PROTECT AF trial substantiated the hypothesis that the left atrial appendage was responsible for the majority of strokes in patients with nonvalvular AF," says Dr Holmes. It also documented that device placement is noninferior to chronic warfarin therapy for stroke prevention, systemic embolization, and mortality.
As could be expected, the trial also identified the fact that invasive procedures carry with them procedural risks which, while infrequent, account for a potential early safety hazard. The risk-benefit ratio of this early safety hazard with the device needs to be compared with the long-term potential for adverse effects with antithrombotic therapy in the consideration of specific therapeutic strategies for each individual patient.
Another trial, PREVAIL, with a similar design using this specific device has been initiated. This multicenter, randomized trial will involve 50 investigational sites and will enroll up to 475 patients. Patients must have nonvalvular AF, be eligible for warfarin therapy, and have a CHADS2 score of 2 or more.
Randomization will be 2:1 to receive the device vs warfarin-only therapy. The primary endpoint is a composite of hemorrhagic stroke, ischemic stroke, systemic embolism, and cardiovascular or unexplained death. This follow-on trial will have several aims:
The documentation of efficacy of left atrial appendage occlusion for stroke prevention in patients with nonvalvular AF has sparked great interest in the field, and several companies are involved in the development and testing of devices. Currently, 2 percutaneous devices have European CE mark approval and are being used clinically, and more are expected. These devices have the potential to dramatically improve patient care, especially in patients not eligible for long-term antithrombotic therapy.
For additional information about enrolling patients in PREVAIL, contact Dr Holmes or study coordinator Linda Tesmer, RN, at 507-255-8354.