Not Following NOAC Dosing Instructions Tied to Worse Clinical Outcomes

Prescribing physicians should and can do better in terms of dosing the NOACs, one expert says.

Not Following NOAC Dosing Instructions Tied to Worse Clinical Outcomes

The vast majority of patients with A-fib treated with non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention receive the dose recommended on the package insert, but either over- or underdosing is not uncommon, a registry study shows. Use of an off-label dose, however, is associated with poorer clinical outcomes.

The study is the second in recent months to suggest that physicians are using subjective criteria to use higher or lower doses while using the newer agents, potentially putting patients at risk.

In the current analysis, patients who received a higher dose were more likely to die over roughly 1 year of follow-up, whereas those treated with a lower dose were more likely to be hospitalized for cardiovascular reasons, lead author Benjamin Steinberg, MD (University of Utah Health Sciences Center, Salt Lake City), and colleagues report in a study published in the December 20, 2016, issue of the Journal of the American College of Cardiology.

But off-label dosing was not associated with bleeding or stroke outcomes, which would be expected to mediate the relationships with mortality and hospitalization, suggesting that residual confounding may explain those findings, Jonathan Hsu, MD (University of California, San Diego), pointed out.

Commenting on the study for TCTMD, Hsu said he did not want to downplay the potential impact on clinical outcomes but added that messages regarding how the drugs are being used are more important to take away.

The study “highlights a potential gap in appropriate use in treatment with these NOAC medications that prescribing physicians and patients need to know about,” he said. “We should and can do better in regards to dosing of these medications.”

Most Dosing Consistent With FDA Labeling

NOACs have been considered easier to use than warfarin because they avoid the need for regular laboratory monitoring and frequent dose adjustments. Dosing does, however, need to be tailored based on certain criteria described on the package inserts approved by the US Food and Drug Administration (FDA), including age, weight, renal function, and concomitant medications.

To explore how NOACs are being dosed and what impact that might have on outcomes, the investigators looked at data on 5,738 patients with A-fib treated with a NOAC for stroke prevention at 242 sites participating in phase II of the ORBIT-AF registry. Overall, 87% of patients received doses consistent with FDA labeling, 9.4% received lower doses, and 3.4% received higher doses.

“The fact that nearly nine 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,” Steinberg et al write. But, they add, the findings may be a bit optimistic because all centers were participating in a registry.

“We were pleasantly surprised by the large majority dosed appropriately, but there certainly remains room for improvement,” Steinberg said in an email to TCTMD.

Overdosing was associated with a higher risk of all-cause mortality during follow-up (8.1% vs 3.0%; adjusted HR 1.91; 95% CI 1.02-3.60) and underdosing was associated with an elevated risk of cardiovascular hospitalization (26.1% vs 24.2%; adjusted HR 1.26; 95% CI 1.07-1.50).

Why Use Off-label Doses?

The registry data cannot be used to determine why physicians would use an off-label dose but it’s possible that some doses were modified intentionally, the authors point out. Supporting that idea are the association between overdosing and higher CHA2DS2-VASc scores and the relationship between underdosing and higher bleeding scores.

Another explanation for the use of off-label doses, however, could be uncertainty about dosing in patients with intermediate renal dysfunction. The investigators note that “many electronic medical records estimate renal function via the Modification of Diet in Renal Disease (MDRD) formula, whereas drug dose approval and dose adjustments are consistently determined using the Cockcroft-Gault formula.” That discrepancy may not make much of a difference for patients with very high or very low creatinine clearance but could lead to clinically relevant differences in the intermediate range and potentially cause dosing errors, they say.

Yet another possible reason for using off-label doses is simply lack of familiarity with dose guidelines, especially among physicians who are less likely to prescribe NOACs, the authors say. That possibility is consistent with the observed relationship between off-label dosing and a lower likelihood of being treated by an electrophysiologist.

Role of Anticoagulation Clinics

In an accompanying editorial, Daniel Witt, PharmD, and Alisyn Hansen, PharmD (University of Utah College of Pharmacy, Salt Lake City), say the study’s findings “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.”

They hint at the possibility that patients taking NOACs would benefit from oversight by the same anticoagulation clinics that were set up to manage warfarin-treated patients. “Six years after NOACs hit the market, health systems are still struggling with how best to manage NOAC therapy and whether specialized anticoagulation services should monitor patients receiving NOACs in addition to those receiving warfarin therapy,” they write.

Steinberg indicated that those clinics do, in fact, continue to have a role for managing NOAC treatment. “I think it’s important not to downplay the role of anticoagulation clinics in the NOAC era,” he said. “Their involvement goes well beyond drug dosing, and includes patient education, medication interaction management, perioperative management, ongoing assessment of the risk/benefit profile of anticoagulation, and much more. All of these tasks are just as important for the patient on a NOAC, and I frequently refer my NOAC patients to our thrombosis clinic. They remain an invaluable resource.”

Hsu said providing NOAC-treated patients with the same oversight as those on warfarin should be considered, but he noted that part of the appeal—and possibly the cost-effectiveness—of using NOACs is the reduction in the use of healthcare resources.

Todd Neale is the Associate News Editor for TCTMD and a Senior Medical Journalist. He got his start in journalism at …

Read Full Bio
  • Steinberg BA, Shrader P, Thomas L, et al. Off-label dosing of non-vitamin K antagonist oral anticoagulants and adverse outcomes: the ORBIT-AF II registry. J Am Coll Cardiol. 2016;68:2597-2604.

  • Witt DM, Hansen AL. Non-vitamin K anticoagulant dose selection: it’s best to read and follow the directions. J Am Coll Cardiol. 2016;68:2605-2607.

  • The ORBIT-AF registry was sponsored by Janssen Scientific Affairs.
  • Steinberg reports having received research support from Janssen Scientific and serving as a consultant for Bristol-Myers Squibb-Pfizer.
  • Hsu reports serving on advisory boards for Bristol-Myers Squibb and Janssen Pharmaceuticals and receiving honoraria from St. Jude Medical, Medtronic, and Biotronik.