NOACs vs Aspirin: Apixaban is the only NOAC that has been compared with aspirin in AF patients. The Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial compared apixaban 5 mg bid with aspirin in AF patients who were not candidates for VKA The trial was stopped early for bene t as apixaban signi cantly reduced the risk of stroke or systemic embolism compared with aspirin (HR, 0.45; 95% CI, 0.32-0.62; P < .001) (e-Table 16). There was no signi cant difference in major bleeding (HR, 1.13; 95% CI, 0.74-1.75; P .57) between apixaban and aspirin. Real-World Observational Data: With the availability of large health-care system administrative data and the advent of quality improvement and postmarketing anticoagulation registries, the number of observational outcome studies on OAC in AF far outnumber randomized trials. Although these data have helped to successfully identify treatment variation and gaps in care, the use of these data for comparative effectiveness and safety studies of OACs must be interpreted with prudence. Despite the use of sophisticated, high quality methods to minimize confounding and bias and improve causal inference, even very small amounts of residual confounding by treatment selection or measurement error can attenuate or amplify the small absolute risk differences observed in the randomized trials. Similarly, de nitive conclusions cannot be drawn from indirect comparisons such as network meta-analyses of NOACs to each other due to small absolute risk differences. Real-world or observational data are generally insuf cient to guide selection of individual anticoagulant drugs. 