Off-label dosing of non-vitamin K anticoagulants associated with worse outcomes
Overdosing with non-vitamin K anticoagulants was associated with increased all-cause mortality compared with recommended doses, while underdosing was associated with increased risk of cardiovascular hospitalization.
Almost 1 in 8 patients with atrial fibrillation received doses of non-vitamin K antagonist oral anticoagulants (NOACs) that were inconsistent with drug labeling, placing the patients at increased risk for adverse events, a study found.
To assess the frequency of off-label anticoagulant doses among atrial fibrillation patients in community practice and the associations with clinical outcomes, researchers evaluated 5,738 patients treated with an NOAC at 242 sites of ORBIT-AF II (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation phase II). Patients were classified as underdosed or overdosed based on FDA labeling. Study outcomes included stroke or systemic embolism, myocardial infarction, major bleeding, cause-specific hospitalization, and all-cause mortality. Results were published in the Dec. 20 Journal of the American College of Cardiology, which appeared online Dec. 12.
Overall, 541 NOAC-treated patients (9.4%) were underdosed, 197 were overdosed (3.4%), and 5,000 were dosed properly (87%). Compared with patients receiving the recommended dose, those who received off-label doses were older (median age, 79 and 80 years vs. 70 years, respectively; P<0.0001), more likely to be 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 more likely to have a CHA2DS2-VASc score of 2 or greater (96% and 97% vs. 86%, respectively; P<0.0001) or an ORBIT bleeding score above 4 (25% and 31% vs. 11%, respectively; P<0.0001).
After adjustment, NOAC overdosing was associated with increased all-cause mortality compared with recommended doses (adjusted hazard ratio [HR], 1.91; 95% CI, 1.02 to 3.60; P=0.04). Underdosing was associated with increased risk of cardiovascular hospitalization (adjusted HR, 1.26; 95% CI, 1.07 to 1.50; P=0.007).
“Doses consistent with the [prescribing information] in most of our patients represents success for the prevention of stroke and systemic embolism and compares favorably with time in therapeutic range for dose-adjusted warfarin,” the authors wrote. “The fact that nearly 9 of 10 subjects received doses consistent with the label suggests that use of NOACs is largely consistent with clinical trials and prescribing recommendations from the FDA.”
An editorial noted, “Unfortunately, these results likely underestimate the true magnitude of non-approved NOAC doses in real-world clinical practice and represent an important warning to clinicians prescribing NOACs. Oral anticoagulants are high-risk medications, and it is clear that precise dosing decisions and a structured management approach to clinical use of these medications is needed regardless of whether warfarin or NOACs are prescribed.”