Extracranial systemic embolic events in patients with atrial fibrillation: an individual patient-level meta-analysis of 71 683 patients randomized to NOAC vs warfarin from the COMBINE-AF study

Abstract Background Atrial Fibrillation (AF) poses a significant risk for both ischemic stroke and systemic embolic events (SEE). While the effectiveness of NOAC in preventing ischemic stroke is well-established, there is a lack of detailed analyses specifically characterizing SEE, which constitutes 5- 10% of all embolic events. Purpose To study the clinical characteristics, procedural management, and outcomes by randomized treatment (NOAC vs warfarin) of patients with SEE. Methods Using the COMBINE AF dataset, we conducted an individual patient level meta-analysis of 4 global RCTs (RE-LY, ROCKET AF, ARISTOTLE, ENGAGE AF-TIMI 48) of warfarin vs. NOAC in AF to assess risks of SEE. Outcomes were analyzed as time-to-first-event using a Cox proportional hazards model. Two authors independently reviewed deaths within 30 days after SEE to identify fatal SEE. Moreover, we independently assessed post SEE procedures to determined relatedness to SEE. Results There were 188 total SEEs, 9 patients (5%) had SEE then developed ischemic stroke; 16 patients (9%) had ischemic stroke then developed SEE; 1 patient had SEE and ischemic stroke simultaneously. Among the 171 patients with SEEs as first event, the median (IQR) age was 75 (68-80) years, 49.7% were female, median (IQR) of BMI was 27.5 (23.5-30.7) kg/m2, mean (SD) of CHADS2-VASC score was 4.7 (1.5). As compared with ischemic stroke (n=1789), SEE patients were more likely to have, PAD (16.5% vs. 5.4%, p <0.001), prior MI (24% vs. 17%, p = 0.02), be Vitamin K Antagonist experienced (57% vs 46%; p=0.007), have worse renal function (median CrCl mL/min; 58 vs 62, p = 0.02) and less likely to have paroxysmal AF (14% vs. 20%, p = 0.05). Of the total of 188 SEEs, 33 (18%) were fatal, 62 (31%) patients underwent surgical or percutaneous intervention (Fig). Standard dose (SD) NOAC significantly reduced the risk of SEE by 29% (95% CI 1-49%, p=0.04) compared with warfarin, However, no significant difference in the risk of SEE was observed between low dose (LD) NOAC and warfarin (Fig). Conclusion Standard dose NOAC was superior to warfarin in preventing SEE in AF patients. This benefit trends to be more pronounced for fatal cases. While SEE were about 1/10th as frequent as ischemic stroke in patients with AF, they were associated with significant morbidity and mortality and often required surgical or percutaneous intervention to restore blood flow.