Randomised control trial Using the Watchman device to close the left atrial appendage reduces risk of stroke in atrial fibrillation, compared to using warfarin 10.1136/ebmed-2014-110154 Martin J Swaans, Arash Alipour, Lucas V Boersma Department of Cardiology, St Antonius Hospital, Nieuwegein, The Netherlands Correspondence to: Dr Martin Swaans, Department of Cardiology, St Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands; m.swaans@antoniusziekenhuis.nl Commentary to: Reddy VY, Sievert H, Halperin J, et al.; PROTECT AF Steering Committee and Investigators. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial. JAMA 2014;312:1988–98. Context Atrial fibrillation (AF) is a common arrhythmia in clinical practice. The major complication of AF is thromboembolic stroke. Patients with AF have a fivefold higher risk of stroke and a twofold increase in mortality. 1 As complete cure for AF is never certain, the aims of AF therapy are symptom relief and prevention of thromboembolic events. The latter can be managed by vitamin-K-antagonists (VKA), but is accompanied by several disadvantages including increased risk of bleeding and the need for monitoring with regular lab work. New oral anticoagulants (NOAC) regimens are simpler but are still associated with bleeding risk. These problems, added by the fact that the majority of thrombi origin- ate from the left atrial appendage (LAA), have led to the strategy of mechanically sealing the LAA with the Watchman device to prevent thromboembolic events by excluding it from the systemic circulation. 2 It has been shown that LAA-closure is feasible and non-inferior to warfarin. 3 Methods This multicentre study evaluated 707 patients with non-valvular AF and at least one additional stroke risk factor. Patients were randomly assigned in a 1:2 ratio to either warfarin or LAA-closure. The objective was to establish non-inferiority of LAA-closure versus warfarin for a composite primary efficacy end point of stroke, systemic embolism or cardiovascular death. Study protocol and hypothesis were clear. A critical note is that proof of non-inferiority and not superiority, were the objectives in the original study. Findings At mean 3.8 year follow-up, the primary efficacy event rate was lower in the LAA-closure group (2.3%, (95% CI 1.7 to 3.1%)) compared to the controls (3.8%, (95% CI 2.7 to 5.3)), which is a 39% (95% CI 0.38 to 0.97) relative risk reduction (RRR) with a 96% probability of superiority. Efficacy was not diminished among patients with a history of TIA. Although rates of all stroke and ischaemic stroke did not differ, there were fewer fatal or disabling strokes in the LAA-closure group. Secondary analysis also showed superiority in all-cause mortality (3.2%, (95% CI 2.5 to 4.2%) vs 4.8%, (95% CI 3.6 to 6.4%), which is a 34% RRR and 60% RRR in cardiovascular mortality (1%, (95% CI 0.6 to 1.5%) vs 2.4%, (95% CI 1.4 to 3.4%)). Causes of death were balanced between the groups, but those treated with warfarin were more likely to die from haemorrhagic stroke. Commentary The most intriguing finding of this study is that the direct positive effect of LAA-closure was driven by fewer haemorrhagic and cardiovascular deaths, while rates of ischaemic stroke in LAA-closure (1.4%, (95% CI 0.9 to 2.1%)) and warfarin patients (1.1%, (95% CI 0.5 to 1.7%)) did not differ; a surprising finding since the procedure was performed to prevent thromboembolic strokes. Apparently, other causes such as carotid/aortic atherosclerotic disease may still be substantial contributors. We postulate that LAA-closure-related thrombus formation and incomplete sealing, especially in the first months after implant may also cause thrombo- embolic strokes. From safety point of view the long-term follow-up data show that although warfarin had a clear advantage with regard to the primary safety end point early after LAA-closure, at mean 3.8 years the difference in the number of events had equalised between the groups. With progress in operator’s learning curve, one might expect that safety profile (catheter/device-related complications) may improve as shown in the Continued Access Protocol (CAP) Registry. 4 Implications for practice Long-term efficacy from this study and safety results of CAP and PREVAIL provide evidence that LAA-closure is a viable alternative to warfarin for stroke reduction in non-valvular AF. 45 Our expectation is that the data on preventing ischaemic strokes would improve after better patient selection, especially excluding those with severe atherosclerosis in the carotid arteries/aorta. Improving safety by increased operator experi- ence may improve the results for the LAA-closure. A future trial should be designed to compare LAA-closure versus NOAC. Competing interests The Cardiology Department of St Antonius Hospital receives proctoring fees for training/educational services from Atritech/Boston Scientific. Provenance and peer review Commissioned; internally peer reviewed. References 1. Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation. Eur Heart J 2010;31:2369–429. 2. Odell JA, Blackshear JL, Davies E, et al. Thoracoscopic obliteration of the left atrial appendage: potential for stroke reduction? Ann Thorac Surg 1996;61:565–9. 3. Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 2009;374:534–42. 4. Reddy VY, Holmes D, Doshi SK, et al. Safety of percutaneous left atrial appendage closure. Circulation 2011;123:417–24. 5. Holmes DR Jr, Kar S, Price MJ, et al. Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial. J Am Coll Cardiol 2014;64:1–12. Evid Based Med June 2015 | volume 20 | number 3 | 101 Therapeutics/Prevention