Net Clinical Benefit of Left Atrial Appendage Closure Versus Warfarin in Patients With Atrial Fibrillation: A Pooled Analysis of the Randomized PROTECT-AF and PREVAIL Studies

Abstract

Background The PROTECT-AF (Watchman Left Atrial Appendage Closure Technology for Embolic Protection in Patients With Atrial Fibrillation) and PREVAIL (Evaluation of the Watchman LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy) trials demonstrated noninferiority of left atrial appendage closure (LAAC) to warfarin for the composite end point of stroke, systemic embolism, or cardiovascular death. This study aims to quantify the net clinical benefit (NCB) of LAAC versus warfarin, accounting for differences in clinical impact of different event types. Methods and Results We performed a post hoc analysis of the PROTECT-AF and PREVAIL trials, which randomized atrial fibrillation patients to LAAC or warfarin in a 2:1 fashion. The trials enrolled patients in the United States and Europe between 2005 and 2012 with paroxysmal, persistent, or permanent atrial fibrillation and CHADS2 risk scores ≥1. Relative to an index weight for death (1.0), events were assigned weights based on their disabling effect: (1) stroke event weights were based on modified Rankin scores in the base case analyses, and (2) major bleed (0.05) and pericardial effusion (0.05). NCB was calculated as the sum of weight-adjusted events per 100 patient-years. Among 1114 randomized subjects, the NCB of LAAC was 1.42% per year (95% CI 0.01-2.82, P=0.04) and a relative risk of 0.74 (95% CI 0.56-1.00). NCB point estimates favored warfarin early in follow-up, but trended in favor of LAAC after 1 to 2 years. The benefit of LAAC was preserved across subgroups, with particular benefit observed in the subgroup of prior stroke and without diabetes mellitus. Conclusions This analysis demonstrates long-term NCB of LAAC with Watchman over warfarin therapy, as the upfront risk of periprocedural events is counterbalanced over time by reduced bleeding events and mortality. Clinical Trial Registration UR: http://www.clinicaltrials.gov. Unique identifiers: NCT01182441 and NCT00129545.

Keywords: anticoagulation; atrial fibrillation; left atrial appendage.

Figures

Figure 1

Net clinical benefit by different weight scenarios. Base case 1: mRS score for ischemic and hemorrhagic stroke are used and fixed weights for major bleed and PE of 0.05. Sensitivity 1: mRS score for ischemic and hemorrhagic stroke are used and fixed weights for major bleed and pericardial effusion of 0.10. Sensitivity 2: mRS score for ischemic and hemorrhagic stroke are used and fixed weights for major bleed and pericardial effusion of 0.15. Standardized weights 1: fixed weights for ischemic of 0.1, for hemorrhagic stroke of 0.3 and for major bleed and PE of 0.05. Standardized weights 2: fixed weights for ischemic of 0.2, for hemorrhagic stroke of 0.6, and for major bleed and pericardial effusion of 0.05. Lowered PE incidence: scenario where the PE incidence is artificially lowered to 1%. mRS score for ischemic and hemorrhagic stroke are used and fixed weights for major bleed and PE of 0.05. mRS indicates modified Rankin Scale; PE, pericardial effusion.

Figure 2

Net clinical benefit of LAAC compared with warfarin therapy over time. The figure presents the absolute risk difference at different time points during follow‐up. Below zero reflects a benefit of warfarin, whereas above zero reflects a benefit of LAAC. The dotted lines reflect the 95% CI. LAAC indicates left atrial appendage closure.

Figure 3

Forrest plot of subgroups. ARR, absolute risk reduction, events presented per 100 patient‐years follow‐up; TIA, transient ischemic attack.