In the Journals

Off-label nonvitamin K antagonist oral anticoagulant dosing linked to adverse events

Approximately one in eight patients in the United States receive dosing of nonvitamin K antagonist oral anticoagulants that is inconsistent with the FDA-approved recommendation on the label, according to data published in the Journal of the American College of Cardiology.

Researchers determined the associations between off-label dose therapy and clinical outcomes in community practice among patients with atrial fibrillation from the ORBIT-AF II registry.

“On the basis of pivotal, phase 3 randomized controlled trials in patients with nonvalvular AF, the U.S. FDA approved each [nonvitamin K antagonist oral anticoagulant] at a specific dose, with recommended adjustments based on selected patient factors (eg, renal function, age) or concomitant medications,” Benjamin A. Steinberg, MD, MHS, of the division of cardiovascular medicine at the University of Utah Health Science Center in Salt Lake City, and colleagues wrote. “However, whether these dose recommendations are adhered to in the community practice remains a major concern.”

The researchers evaluated 5,738 patients treated with nonvitamin K antagonist oral anticoagulants at 242 sites from the ORBIT-AF II registry.

Physicians tested the association between off-label dose and outcomes using unadjusted Cox models. Models were stratified by anticoagulant type and drug-specific regulator criteria for dose.

Dosing issues

In the cohort, 541 (9.4%) patients were underdosed, 197 (3.4%) were overdosed and 5,000 (87%) were receiving the FDA-recommended label dosage, according to the results.

Patients who were receiving off-label dosing tended to be older (underdosed group, 79 years; overdosed group, 80 years) compared with those taking the proper dosage (aged 70 years; P = .0001). Patients with off-label doses were also more likely to be women (underdosed, 48%; overdosed, 67%; properly dosed, 40%; P < .0001), were less likely to be treated by an electrophysiologist (underdosed, 18%; overdosed, 19%; properly dosed, 27%; P < .0001), were more likely to have CHA2DS2-VASc score 2 (underdosed, 96%; overdosed, 97%; properly dosed, 86%; P < .0001) and were more likely to have ORBIT bleeding score > 4 (underdosed, 25%; overdosed, 31%; properly dosed, 11%; P < .0001).

Patients who received higher-than-recommended anticoagulant doses had an increased risk for all-cause mortality compared with those who received the recommended dosage (adjusted HR = 1.91; 95% CI, 1.02-3.6), and underdosing was linked to increased risk for CV hospitalization (adjusted HR = 1.26; 95% CI, 1.07-1.5), according to the researchers.

Improving therapy quality

“The study by Steinberg et al highlights an important opportunity to improve [nonvitamin K antagonist oral anticoagulant] therapy quality and outcomes,” Daniel M. Witt, PharmD, from the department of pharmacotherapy, and Alisyn L. Hansen, PharmD, from the Associated Regional and University Pathologists Family Health Clinic, both at the University of Utah College of Pharmacy, wrote in a related editorial. “Whatever the reason for failing to follow approved dose recommendations, the results of the study by Steinberg et al provide important evidence indicating that clinicians prescribing [nonvitamin K antagonist oral anticoagulants] should ensure that doses are consistent with approved product labeling.” – by Dave Quaile

Disclosure: The ORBIT-AF registry is sponsored by Janssen Scientific Affairs. Steinberg reports consulting for Bristol-Myers Squibb/Pfizer and receiving research support from Janssen Scientific. Please see the full study for a list of the other researchers’ relevant financial disclosures. Hansen and Witt report no relevant financial disclosures.

Approximately one in eight patients in the United States receive dosing of nonvitamin K antagonist oral anticoagulants that is inconsistent with the FDA-approved recommendation on the label, according to data published in the Journal of the American College of Cardiology.

Researchers determined the associations between off-label dose therapy and clinical outcomes in community practice among patients with atrial fibrillation from the ORBIT-AF II registry.

“On the basis of pivotal, phase 3 randomized controlled trials in patients with nonvalvular AF, the U.S. FDA approved each [nonvitamin K antagonist oral anticoagulant] at a specific dose, with recommended adjustments based on selected patient factors (eg, renal function, age) or concomitant medications,” Benjamin A. Steinberg, MD, MHS, of the division of cardiovascular medicine at the University of Utah Health Science Center in Salt Lake City, and colleagues wrote. “However, whether these dose recommendations are adhered to in the community practice remains a major concern.”

The researchers evaluated 5,738 patients treated with nonvitamin K antagonist oral anticoagulants at 242 sites from the ORBIT-AF II registry.

Physicians tested the association between off-label dose and outcomes using unadjusted Cox models. Models were stratified by anticoagulant type and drug-specific regulator criteria for dose.

Dosing issues

In the cohort, 541 (9.4%) patients were underdosed, 197 (3.4%) were overdosed and 5,000 (87%) were receiving the FDA-recommended label dosage, according to the results.

Patients who were receiving off-label dosing tended to be older (underdosed group, 79 years; overdosed group, 80 years) compared with those taking the proper dosage (aged 70 years; P = .0001). Patients with off-label doses were also more likely to be women (underdosed, 48%; overdosed, 67%; properly dosed, 40%; P < .0001), were less likely to be treated by an electrophysiologist (underdosed, 18%; overdosed, 19%; properly dosed, 27%; P < .0001), were more likely to have CHA2DS2-VASc score 2 (underdosed, 96%; overdosed, 97%; properly dosed, 86%; P < .0001) and were more likely to have ORBIT bleeding score > 4 (underdosed, 25%; overdosed, 31%; properly dosed, 11%; P < .0001).

Patients who received higher-than-recommended anticoagulant doses had an increased risk for all-cause mortality compared with those who received the recommended dosage (adjusted HR = 1.91; 95% CI, 1.02-3.6), and underdosing was linked to increased risk for CV hospitalization (adjusted HR = 1.26; 95% CI, 1.07-1.5), according to the researchers.

Improving therapy quality

“The study by Steinberg et al highlights an important opportunity to improve [nonvitamin K antagonist oral anticoagulant] therapy quality and outcomes,” Daniel M. Witt, PharmD, from the department of pharmacotherapy, and Alisyn L. Hansen, PharmD, from the Associated Regional and University Pathologists Family Health Clinic, both at the University of Utah College of Pharmacy, wrote in a related editorial. “Whatever the reason for failing to follow approved dose recommendations, the results of the study by Steinberg et al provide important evidence indicating that clinicians prescribing [nonvitamin K antagonist oral anticoagulants] should ensure that doses are consistent with approved product labeling.” – by Dave Quaile

Disclosure: The ORBIT-AF registry is sponsored by Janssen Scientific Affairs. Steinberg reports consulting for Bristol-Myers Squibb/Pfizer and receiving research support from Janssen Scientific. Please see the full study for a list of the other researchers’ relevant financial disclosures. Hansen and Witt report no relevant financial disclosures.