Nearly 1 in 8 patients with atrial fibrillation (AF) receive “off-label” doses of non-vitamin K antagonists (NOACs), according to trial results published in the Journal of the American College of Cardiology.

The ORBIT-AF II analysis (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation phase 2; ClinicalTrials.gov identifier: NCT01701817) is the first of its kind to assess NOAC dosing and its potential affect on clinical outcomes in patients with AF. The investigators noted that while NOACs have shown to be at least as effective and safe as warfarin, adherence to US Food and Drug Administration label recommendations remains a major concern.

Study outcomes included all-cause death, stroke or systemic embolism, myocardial infarction, cause-specific hospitalization (cardiovascular, bleeding, or noncardiovascular, nonbleeding), and major bleeding classified by the International Society on Thrombosis Haemostasis criteria.


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Of the 5738 patients who were treated with NOACs, 541 were considered underdosed, 197 were overdosed, and 5000 were dosed according to US labeling. Compared with patients who received the recommended dose, those who received inappropriate dosing were more likely older (median age: 79 and 80 years of age vs 70 years of age, respectively; P <.0001), less likely to be treated by an electrophysiologist (18% and 19% vs 27%, respectively; P <.0001), and had higher CHA2DS2-VASc scores (96% and 97% ≥ 2 vs 86%, respectively; P <.0001). Patients who were under or overdosed also had higher ORBIT bleeding scores (25% and 31% >4 vs 11%; P <.0001).

Overdosing of NOACs was associated with increased all-cause mortality compared with the recommended dosing (adjusted hazard ratio [aHR]: 1.91; 95% CI, 1.02-3.60; P =.04), while underdosing was associated with increased cardiovascular hospitalization (aHR: 1.26; 95% CI, 1.07-1.50; P =.007).

In addition, patients with impaired renal function had particularly worse bleeding outcomes when NOACs were overdosed.

“It is difficult to ascertain physician intent from these registry data; however, the underlying risks of the cohort suggest potential intentional deviation from approved doses,” the researchers wrote. They noted that physicians may be adjusting doses based on an individual patient’s risk—eg, having higher CHA2DS2-VASc scores or ORBIT bleeding scores—despite evidence of “favorable risk-benefit profiles across risk strata.”

While most of the ORBIT-AF II registry patients received the recommended NOAC doses, the investigators urged careful attention and future studies to address the minority who were inappropriately treated.

Study Limitations

  • Dose groups were not randomized and therefore residual and/or unmeasured confounding may exist and introduce bias. 
  • Clinical events may not be causally related to dosing.
  • Off-label dosing trends over time were not analyzed.
  • The multivariate analysis presumed all off-label doses—regardless of the agent and dose itself—would carry a consistent effect.

Disclosures: The ORBIT-AF registry was sponsored by Janssen Scientific Affairs. Dr Steinberg has received research support from Janssen Scientific and is a consultant for BMS-Pfizer. Other ORBIT-AF investigators report financial relationships with the following pharmaceutical companies: Bristol-Myers Squibb, Pfizer, Janssen, Daiichi-Sankyo, Boehringer Ingelheim, Alere, Medtronic, Boston Scientific, St. Jude Medical, Johnson & Johnson, Portola, Merck, Sanofi Aventis, Amgen, Tenax, AstraZeneca, Bayer, Eli Lilly, Forest Laboratories, and Genetech, among others.

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Reference

Steinberg BA, Shrader P, Thomas L, et al; for the ORBIT-AF investigators and patients. Off-label dosing of non-vitamin K antagonist oral anticoagulants and adverse outcomes. The ORBIT-AF II registry. J Am Coll Cardiol. 2016;68(24):2597-2604. doi:10.1016/j.jacc.2016.09.966.