Journal Pre-proof Residual Stroke Risk Despite Oral Anticoagulation in Patients with Atrial Fibrillation

2 Background: Oral anticoagulation (OAC) reduces the risk of thromboembolic events in patients with 3 atrial fibrillation (AF); however, thromboembolism (TE) can still occur despite OAC. Factors associated 4 with residual risk for stroke, systemic embolism or transient ischemic attack events despite OAC have not 5 been well described. 6 Objective: Evaluate the residual risk of thromboembolic events in patients with AF despite OAC. 7 Methods: 18,955 patients were analyzed in the Outcomes Registry for Better Informed Treatment of Atrial 8 Fibrillation (ORBIT-AF I and II) using multivariable Cox proportional hazard modeling. The mean age was 72 9 (SD 10.7) and 42% were women. There were 451 outcome events. 10 Results: The risk of TE despite OAC increased with CHA 2 DS 2 -VASc score: 0.76 (95% CI 0.63, 0.92) events 11 per 100 patient years when CHA 2 DS 2 -VASc < 4 vs. 2.01 (95% CI 1.81, 2.24) events per 100 patient years 12 when CHA 2 DS 2 -VASc > 4. Factors associated with increased risk were prior stroke or transient ischemic 13 attack (HR 2.87, 2.30-3.59, p < 0.001), female sex (HR 1.52, 1.24-1.86, p < 0.001), hypertension (HR 1.50, 14 1.09-2.06, p = 0.01), and permanent AF (HR 1.47, 1.12-1.94, p = 0.001). When transient ischemic attack was 15 excluded, the results were similar but permanent AF was no longer significantly associated with TE events. 16 Conclusion: Patients with AF have a residual risk of TE with increasing CHA 2 DS 2 -VASc score despite 17 OAC. Key risk markers include prior stroke/transient ischemic attack, female sex, hypertension and 18 permanent AF.