Left Atrial Appendage Occlusion vs Warfarin for Nonvalvular AF
Abstract & Commentary
By Andrew J. Boyle, MBBS, PhD, Assistant Professor of Medicine, Interventional Cardiology, University of California, San Francisco. Dr. Boyle reports no financial relationships relevant to this field of study.
This article originally appeared in the April 2013 issue of Clinical Cardiology Alert. It was edited by Michael H. Crawford, MD, Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco, and peer reviewed by Ethan Weiss, MD, Assistant Professor of Medicine, Division of Cardiology and CVRI, University of California, San Francisco. Dr. Crawford reports no financial relationships relevant to this field of study, and Dr. Weiss is a scientific advisory board member for Bionovo.
Sources: Reddy VY, et al. Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation 2.3-year follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation) trial. Circulation 2013;127:720-729. Alli O, et al. Quality of life assessment in the randomized PROTECT AF trial of patients at risk for stroke with non-valvular atrial fibrillation. J Am Coll Cardiol 2013; Feb. 28. [Epub ahead of print.]
Atrial fibrillation (AF) is a major source of morbidity in patients and cost to the health care community. In the presence of risk factors for thromboembolism, AF is associated with an increased risk of stroke, and this risk is reduced with warfarin. However, warfarin has limitations, including the risk of bleeding and the need for regular blood tests. The left atrial appendage (LAA) is thought to be a nidus for thrombus that can result in stroke or systemic embolism. The Watchman Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation (PROTECT AF) trial was a randomized controlled trial of percutaneous device closure of the LAA with the Watchman device vs continued warfarin therapy. In these studies, Reddy and colleagues present the final long-term outcomes of this trial, and Alli et al present the quality-of-life (QOL) outcomes.
The main inclusion criteria for the PROTECT AF study were age > 18 years; a history of paroxysmal, persistent, or permanent nonvalvular AF plus at least one additional stroke risk factor (age ≥ 75 years, hypertension, diabetes mellitus, heart failure, prior stroke, transient cerebral ischemic attack, or systemic thromboembolism); and eligibility for warfarin therapy, i.e., a CHADS2 score ≥ 1. Exclusion criteria were the presence of atrial septal defect, mechanical prosthetic heart valve, patent foramen ovale accompanied by atrial septal aneurysm (because of the potential for paradoxical embolization), left ventricular ejection fraction < 30%, intracardiac thrombus, morphologically complex (mobile or ulcerated) aortic atheroma, or symptomatic carotid artery disease. Patients (n = 707) were randomized in a 2:1 fashion to receive the device or continue warfarin. The initial results have been presented, but in these studies we are given the longer-term efficacy and safety outcomes, and the QOL outcomes.
For patients randomized to Watchman device implantation (n = 463), warfarin was continued for ≈ 45 days, followed by clopidogrel for 4.5 months and then lifelong aspirin. In the warfarin group (n = 244), the time in therapeutic range was 66%. In the study by Reddy et al, after 2.3 ± 1.1 years of follow-up (1588 patient years), the event rates of the composite primary efficacy endpoint of stroke, systemic embolism, and cardiovascular death were 3.0% and 4.3% (percent per 100 patient years) in the Watchman and warfarin groups, respectively (relative risk [RR], 0.71; 95% confidence interval [CI], 0.44-1.30% per year), which met the criteria for non-inferiority. There were more primary safety events in the Watchman group (5.5% per year; 95% CI, 4.2-7.1% per year) than in the control group (3.6% per year, 95% CI, 2.2-5.3% per year; RR, 1.53; 95% CI, 0.95-2.70% per year). When the effect of LAA closure was isolated from complications of implantation and concomitant transient anticoagulation in a secondary analysis, the Watchman device was superior to warfarin (probability of superiority = 0.953). Among patients with stroke before they entered the study, the two strategies were equally effective, with rates of 5.3% per year and 8.2% per year, respectively, (RR, 0.64; 95% CI, 0.24-1.74% per year). Similar trends were seen in patients with CHADS2 scores ≥ 2. The authors conclude that the “local” strategy of LAA closure is noninferior to “systemic” anticoagulation with warfarin, and that PROTECT AF has, for the first time, implicated the LAA in the pathogenesis of stroke in AF.
In the study by Alli et al, QOL using the SF-12-V2 measurement tool was obtained at baseline and 12 months in a subset of 547 patients (361 device and 186 warfarin patients). The analysis cohort consisted of those for whom either paired QOL data were available after 12 months of follow-up or in patients who died. In the device and warfarin arms respectively, the total physical score improved in 34.9% and 24.7%, and was unchanged in 29.9% and 31.7% (P = 0.01). There was a significant improvement in QOL in patients randomized to device for total physical score, physical function, and in physical role limitation compared to controls. Interestingly, there were significant differences in the change in total physical score among warfarin-naïve and not-warfarin-naïve subgroups in the device group compared to controls, but larger gains were seen with the warfarin-naïve subgroup with a 12-month change of 1.3 ± 8.8 vs -3.6 ± 6.7 (P = 0.0004) device compared to warfarin. The authors conclude that patients with nonvalvular AF at risk for stroke treated with LAA closure have favorable QOL changes at 12 months vs patients treated with warfarin.
The results of these studies are very provocative, suggesting that for patients with any type of nonvalvular AF (paroxysmal, persistent, or permanent), closure of the LAA can result in similar outcomes to warfarin with improved QOL. Based on these results, the device has been approved in Europe and now carries a class IIB recommendation in the European guidelines. However, it should be emphasized that this device is not FDA approved for use in the United States.
The PROTECT AF trial is a well-designed study with large numbers of patients for a device trial (although small numbers for a drug trial). The consistency of the results across subgroups and across intention-to-treat and per-protocol analyses, as well as in the landmark analysis (after the brief period of warfarin in the device group), strengthen the conclusions drawn by the authors. However, several issues should be noted. First, patients with significant aortic and carotid atheroma were excluded, as were patients who cannot tolerate warfarin. The role of LAA occlusion in these patient groups remains to be studied. Second, the follow-up period was really only medium-term (2.3 years) and long-term data will be necessary to definitely make conclusions between groups. Third, the cost effectiveness of this strategy has yet to be presented in the U.S. system. Some patients may prefer a single procedure to avoid long-term warfarin, and the QOL data suggest this is a reasonable strategy. But what costs this will impose and who will pay remain to be determined. Overall, however, these data are encouraging that we may one day be able to offer our patients a “local” strategy to reduce the risk of stroke as an alternative to systemic anti-coagulation, and they may feel better for it.