Original Investigation
Off-Label Dosing of Non-Vitamin K Antagonist Oral Anticoagulants and Adverse Outcomes: The ORBIT-AF II Registry

https://doi.org/10.1016/j.jacc.2016.09.966Get rights and content
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Abstract

Background

Although non-vitamin K antagonist oral anticoagulants (NOACs) do not require frequent laboratory monitoring, each compound requires dose adjustments on the basis of certain clinical criteria.

Objectives

This study assessed the frequency of off-label NOAC doses among AF patients and the associations between off-label dose therapy and clinical outcomes in community practice.

Methods

We evaluated 5,738 patients treated with a NOAC at 242 ORBIT-AF II (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation phase II) sites. NOAC doses were classified as either underdosed or overdosed, consistent with Food and Drug Administration labeling. Longitudinal outcomes (median follow-up: 0.99 years) included stroke or systemic embolism, myocardial infarction, major bleeding (International Society of Thrombosis and Haemostasis criteria), cause-specific hospitalization, and all-cause mortality.

Results

Overall, 541 NOAC-treated patients (9.4%) were underdosed, 197 were overdosed (3.4%), and 5,000 were dosed according to U.S. labeling (87%). Compared with patients receiving the recommended dose, those who were receiving off-label doses were older (median: 79 and 80 years of age vs. 70 years of age, respectively; p < 0.0001), more likely female (48% and 67% vs. 40%, respectively; p < 0.0001), less likely to be treated by an electrophysiologist (18% and 19% vs. 27%, respectively; p < 0.0001), and had higher CHA2DS2-VASc scores (96% and 97% ≥2 vs. 86%, respectively; p < 0.0001) and higher ORBIT bleeding scores (25% and 31% >4 vs. 11%, respectively; p < 0.0001). After dose adjustment, NOAC overdosing was associated with increased all-cause mortality compared with recommended doses (adjusted hazard ratio: 1.91; 95% confidence interval [CI]: 1.02 to 3.60; p = 0.04). Underdosing was associated with increased cardiovascular hospitalization (adjusted hazard ratio: 1.26; 95% CI: 1.07 to 1.50; p = 0.007).

Conclusions

A significant minority (almost 1 in 8) of U.S. patients in the community received NOAC doses inconsistent with labeling. NOAC over- and underdosing are associated with increased risk for adverse events. (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II [ORBIT-AF II]; NCT01701817)

Key Words

apixaban
atrial fibrillation
dabigatran
off-label use
outcomes
rivaroxaban

Abbreviations and Acronyms

AF
atrial fibrillation
CrCl
creatinine clearance
NOAC
nonvitamin K antagonist oral anticoagulant

Cited by (0)

The ORBIT-AF registry was sponsored by Janssen Scientific Affairs, LLC. Dr. Steinberg has received research support from Janssen Scientific; and is a consultant for BMS-Pfizer. Dr. Ansell is a consultant for and advisory board member for Bristol-Myers Squibb, Pfizer, Janssen, Daiichi, Boehringer Ingelheim, and Alere. Dr. Fonarow is a consultant for and receives research support from Janssen. Dr. Gersh has received research support from and is an advisory board member of Medtronic, Baxter Healthcare Corporation, InspireMD, Cardiovascular Research Foundation, PPD Development, LP, Boston Scientific, and St. Jude. Dr. Kowey is a consultant for and advisory board member with Boehringer Ingelheim, Bristol-Myers Squibb, Johnson & Johnson, Portola, Merck, Sanofi, and Daiichi-Sankyo. Dr. Mahaffey has received research grants from Amgen, Daiichi, Johnson & Johnson, Medtronic, Merck, St. Jude Medical, Tenax; has received consulting fees from the American College of Cardiology, AstraZeneca, BAROnova, Bayer, Bio2Medical, Boehringer Ingelheim, Bristol-Myers Squibb, Cubist, Eli Lilly, Elsevier, Epson, Forest, Johnson & Johnson, and Medtronic; and has equity in BioPrintFitness. Dr. Peterson has received research support from Eli Lilly & Co., Janssen Pharmaceuticals, and American Heart Association; and is a consultant and advisory board member for Boehringer Ingelheim, Bristol-Myers Squibb, Janssen Pharmaceuticals, Pfizer, and Genentech Inc. Dr. Piccini has received research support from Johnson & Johnson, Janssen Pharmaceuticals, Bayer HealthCare Pharmaceuticals, Boston Scientific, Johnson & Johnson; and is a consultant and advisory board member for Forest Laboratories, Inc., Medtronic, Johnson & Johnson, and Janssen Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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