Yan Hou, MD, PhD

Paciaroni M, Agnelli G, Caso V, Silvestrelli G, Seiffge DJ, Engelter S, et al. Causes and Risk Factors of Cerebral Ischemic Events in Patients With Atrial Fibrillation Treated With Non–Vitamin K Antagonist Oral Anticoagulants for Stroke Prevention: The RENo Study. Stroke. 2019;50:2168–2174

Non–vitamin K antagonist oral anticoagulants (NOACs) are currently recommended as the stroke prevention for patients with nonvalvular atrial fibrillation (AF). Despite compliance with NOAC, patients with nonvalvular AF may still experience ischemic cerebrovascular events. The RENO study is a multicenter case-control study to identify the etiology and risk factors for ischemic events occurring during NOACs (dabigatran, apixaban, rivaroxaban, or edoxaban) therapy in patients with nonvalvular AF.

The study included 713 cases (641 ischemic strokes and 72 TIA) and 700 controls (patients did not experience cerebrovascular events). Cases who did not guarantee compliance or who had suspended NOAC at least 24 hours before the cerebrovascular event were excluded. Most strokes (64%) occurring during NOACs therapy were caused by cardioembolism, but about 30% of strokes were found due to non-cardioembolic etiology. Among the risk factors (age, sex, hypertension, diabetes mellitus, current cigarette smoking, hyperlipidemia, ischemic heart disease, peripheral artery disease, alcohol abuse, obesity, previous stroke/transient ischemic attack, creatinine clearance, duration of NOAC treatment, doses of NOACs, AF classification, CHA2DS2-VASc score, left atrial enlargement on echo), off-label low doses of NOACs (OR, 3.18), atrial enlargement (OR, 6.64), hyperlipidemia (OR, 2.40), and high CHA2DS2-VASc score (OR, 1.72 for each point increase) were associated with ischemic events. The reasons for prescribing low doses of NOAC included fear of bleeding, history of bleeding, concomitant antiplatelet therapy, recurrent falls, amyloid angiopathy, anemia, history of cancer, age, gastrointestinal discomfort, and hypertension or other causes. Low clearance of creatinine (OR, 0.98 for 1 mL/min increase) and high CHA2DS2-VASc score (OR, 1.35 for each point increase) were also found associated with prescription of low-dose NOACs.   

The RENO study has two major limitations. First, given NOACs such as rivaroxaban and Eliquis are partly metabolized by the liver, drug interactions may interfere with the anticoagulant effect. Second, although low dose (off label) NOAC prescription have a higher risk of stroke, it may decrease bleeding risk, which may affect risk and benefit consideration.

Despite the limitations, the strength of the study includes adequate sample size and real-world experiences. Reduction in off-label low dose prescription of NOAC potentially decreases incidence of stroke in patients with nonvalvular AF. Patients with moderate to severe atrial enlargement and high CHA2DS2-VASc score (≥4) may need stronger anticoagulant therapy.