Improper dosing of NOACs may increase risk of mortality, cardiac hospitalization

Nearly 13 percent of patients with atrial fibrillation did not receive the correct dose of non-vitamin K antagonist oral anticoagulants (NOACs), according to a registry analysis.

After adjusting for doses, overdosing of the medications was associated with increased all-cause mortality and underdosing was associated with increased cardiovascular hospitalization compared with recommended dosing.

Lead researcher Benjamin A. Steinberg, MD, MHS, of the University of Utah Health Sciences Center, and colleagues published their results online in the Journal of the American College of Cardiology on Dec. 13.

The FDA has approved four NOACs: apixaban (Eliquis), dabigatran (Pradaxa), rivaroxaban (Xarelto) and edoxaban (Savaysa). The medications are intended to prevent stroke or systemic embolism in patients with nonvalvular atrial fibrillation.

The researchers mentioned that studies have shown NOACs are at least as safe and effective as dose-adjusted warfarin and do not require routine or frequent laboratory monitoring. They added that the FDA approved each of the NOACs at a specific dose with adjustments based on certain patient factors such as renal function and age.

For this analysis, they examined 5,738 patients with atrial fibrillation who were treated with a NOAC for stroke prevention. All of the patients enrolled in phase II of the ORBIT-AF trial at 242 sites in the U.S. from February 2013 to January 2016. ORBIT-AF is a prospective registry of patients with atrial fibrillation who were at least 21 years old.

Patients were excluded if they received treatment with an anticoagulant that fewer than 100 patients had used. They were also excluded if they had no dosing information or if they had significant mitral stenosis or mechanical valve replacement.

Of the patients, 7.4 percent were treated with dabigatran, 53.6 percent were treated with rivaroxaban and 39 percent were treated with apixaban.

The researchers found that 9.4 percent of patients received lower doses than the FDA recommended, 3.4 percent received higher doses and the remaining 87.2 percent received doses consistent with the labeling.

Patients who received off-label doses were more likely to be older, female and have higher bleeding scores and less likely to be treated by an electrophysiologist compared with those who received the recommended doses. They also had higher CHA2DS2-VASc scores.

Of the patients taking dabigatran, those with an estimated creatinine clearance of 30 to 50 ml/min had the highest rates of off-label dosage. Of the patients taking rivaroxaban, those with an estimated creatinine clearance of 15 to 50 ml/min had the highest rates of off-label dosage. Of the patients taking apixaban, those undergoing dialysis and hemodialysis had the highest rates of off-label dosage.

The study had a few limitations, according to the researchers, including that it could be subject to residual and/or unmeasured confounding. They also mentioned that they did not assess trends in off-label dosing over time. Further, the results might not be generalizable to practices that did not participate in the ORBIT-AF trial.

“Future studies of variability in clinical outcomes would be informed by correlations among doses, serum drug concentrations, and clinical outcomes,” the researchers wrote.