There is growing interest in the role for non–vitamin K antagonist oral anticoagulants (NOACs) in patients without atrial fibrillation (AF). We aimed to provide a comprehensive assessment of the risks of ischemic stroke, myocardial infarction (MI), AF, and major bleeding in patients without previously diagnosed AF.

Using a large US administrative database, we identified 6,495,875 patients ≥50 years between January 1, 2011, and September 30, 2016, who were not diagnosed with AF and were not treated with oral anticoagulants or nonaspirin antiplatelet agents. We assessed the risks by age, sex, the number of risk factors, and the combination of risk factors. We also calculated the number needed to treat or harm based on the untreated risks in our data set and relative risks of NOAC treatment derived from a recent clinical trial.

The event rates were 0.67%/y for ischemic stroke or MI, 0.96%/y for AF, and 0.52%/y for major bleeding. Among patients who had a stroke during follow-up, 84% were not diagnosed with AF at any time, and only 5% were diagnosed with AF before the stroke. Patients who had low number needed to treat for cardiovascular risk reduction (ie, potentially benefiting the most from the addition of NOACs) also had low number needed to harm for major bleeding (ie, facing serious harm).

Patients without diagnosed AF but with certain risk factors were at a particularly high cardiovascular risk and may require new prevention approaches. In addition to the ongoing trials, future trials in other high-risk populations, for example, diabetes and chronic kidney disease, may be warranted.