Off-Label Use of NOACs and Adverse Outcomes

Study Questions:

What is the frequency of off-label nonvitamin K antagonist oral anticoagulant (NOAC) dosing among atrial fibrillation (AF) patients, and the association with clinical outcomes in community practice?


The authors evaluated 5,738 patients with nonvalvular AF treated with NOACs at 242 sites participating in the ORBIT-AF II (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation phase II) registry with available follow-up data (median follow-up, 0.99 years). NOAC doses were classified as underdosed, appropriately dosed, or overdosed based on the Food and Drug Administration (FDA) labeling assessed at the time of registry enrollment. Longitudinal outcomes included stroke or systemic embolism, myocardial infarction, major bleeding (defined by International Society on Thrombosis and Hemostasis), cause-specific hospitalizations, and all-cause mortality.


Overall, 541 (9.4%) patients were underdosed, 197 (3.4%) were overdosed, and 5,000 (87%) were appropriately dosed, per FDA labeling. As compared to those with appropriate doses, the off-label dosing patients were older, less likely to be treated by an electrophysiologist, and had higher CHA2DS2-VASc scores, and higher ORBIT bleeding scores. After dose adjustment, NOAC overdosing was associated with an increased all-cause mortality as compared with appropriate dosing (8.1 vs. 3.0 per 100 patient-years, adjusted hazard ratio [aHR], 1.91; 95% confidence interval [CI], 1.02-3.60; p = 0.04). Underdosing was associated with an increased cardiovascular hospitalization risk (aHR, 1.26; 95% CI, 1.07-1.50; p = 0.007).


The authors concluded that a significant number of patients received off-label NOAC doses (nearly one in eight), and that these patients were at higher risk for adverse events.


This large national practice-based registry confirms prior studies demonstrating significant problems with off-label dosing of NOAC medications. Importantly, this study linked the off-label use of NOACs to serious adverse outcomes, such as all-cause mortality and hospitalizations. However, the authors did not investigate how frequently doses were changed or renal function changed to impact the dosing appropriateness (either off-label to appropriate, or appropriate to off-label) during the follow-up period. Identifying systems to help prevent overdosing and underdosing, such as referral to anticoagulation clinics, remain to be tested and to undergo economic evaluation for NOAC-treated patients.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Prevention, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias

Keywords: Anticoagulants, Arrhythmias, Cardiac, Atrial Fibrillation, Cost-Benefit Analysis, Embolism, Hemorrhage, Hemostasis, Myocardial Infarction, Off-Label Use, Primary Prevention, Stroke, Thrombosis, Vitamin K

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