Inappropriate NOAC Dosing Common, May Be Compromising Safety

Liam Davenport

June 08, 2017

ROCHESTER, MN — Inappropriate dosing of non–vitamin K antagonist oral anticoagulants (NOACs) for atrial fibrillation (AF) was common in a large US cohort study, including inappropriate dosage reductions when there weren't renal indications for them and failures to drop the dosages when renal dysfunction called for it[1].

Such practices can lead to NOAC overdosing and underdosing that can compromise the drugs' safety without improving their effectiveness, note the authors of the report, led by Dr Xiaoxi Yao (Mayo Clinic, Rochester, MN) published June 5, 2017 in the Journal of the American College of Cardiology.

The study of data from almost 15,000 patients with AF showed that over two-fifths who had a renal indication for a dosage reduction continued receiving the standard dose, while over 10% without an indication for a dosage reduction were underdosed.

The lack of an indicated dosage reduction (ie, inadvertent overdosing) in patients with AF was associated with a doubling of the risk of major bleeds, with inappropriate underdosing increasing the risk of stroke almost fivefold.

Overdosing "is really an issue of not being aware of the renal function at the time of the scrip or that there's a change in renal function over time that goes unnoticed by the clinician, and as a result the dose needs to be adjusted," senior author Dr Peter A Noseworthy (Mayo Clinic) told heartwire from Medscape.

"That's sort of an error, whereas the underdosing, I think, as a clinician, is more of a deliberate choice among clinicians who make a decision to reduce the dose because they perceive the patient to be at higher risk of bleeding, and they're trying to hedge their bets."

While that may expose patients to an increased risk of stroke, "it doesn't protect from bleeding," Noseworthy explained. These drugs "are quite safe," he said, when given in line with the labeling.

The researchers analyzed data on Medicare Advantage enrollees from the OptumLabs Data Warehouse, identifying 14,865 with nonvalvular AF who had started apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), dabigatran (Pradaxa, Boehringer Ingelheim), or rivaroxaban (Xarelto, Bayer/Johnson & Johnson) between 2010 and 2015 and had baseline serum creatinine (SCr) results available.

A renal indication for a NOAC dose reduction was defined as a dabigatran prescription with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, rivaroxaban with an eGFR <50 mL/min/1.73 m2, or apixaban with an SCr ≥1.5 mg/dL.

Of the cohort, 1473 patients had a renal indication for a NOAC dose reduction. Of these, 43.0% received standard NOAC doses and thus were potentially overdosed.

Their stroke event rate was 2.32 per 100 person-years, compared with 1.85 per 100 person-years in those who received the indicated dosage reduction (P=0.48).

However, their rates of major bleeding were 11.29 and 5.06 per 100 person-years, respectively, for a hazard ratio of 2.19 (95% CI 1.07–4.46, P=0.03) for major bleeding among those with a renal indication for dosage reduction but who received standard dosing.

Among the 13,392 patients without a renal indication for a NOAC dosage reduction, 13.3% received a reduced NOAC dosage and therefore were underdosed.

The stroke event rate was 1.43 per 100 person-years in patients without an indication for a dose reduction and who received the standard NOAC dose, compared with 1.70 per 100 person-years in those given a reduced dose. The corresponding event rates of major bleeding were 5.03 and 5.43 per 100 person-years, respectively.

Of note, according to the group, reduced-dose apixaban was associated with a significantly increased risk of stroke vs the standard dose, at a hazard ratio of 4.87 (95% CI 1.30–18.26, P=0.02). However, there was no increased risk of major bleeding with reduced apixaban (P=0.61), and there was no increased risk of either adverse event with either dabigatran or rivaroxaban.

"This finding raises the question: is the underdosing effect unique to apixaban or was the present study simply better powered to detect a difference in these patients?" the group writes. "We cannot be certain, but it is likely that both explanations are true to some extent."

The study is "important and well done," according to an accompanying editorial from Dr Sean D Pokorney and colleagues[2]. Despite several limitations to the investigation, they write, they say the analysis highlights potential reasons for inappropriate NOAC dosing, including older age, which has not previously been identified.

As such, they highlight that guidelines and prescribing recommendations "often have to be tailored to the needs of an individual patient."

The editorial continues, "Although the desire to avoid bleeding is a natural inclination, this study demonstrated that reduced dosing without a formal indication does not lead to improved outcomes and may be hazardous.

"Although less may be more in various aspects of life, less NOAC does not provide more to patients who should receive a standard dose, and underdosing may predispose patients to higher and fully avoidable risks."

Noseworthy would like to see the study "repeated in other countries and in other databases" to determine whether the underdosing effect is specific to apixaban "or whether it's just a product of our data and American practice patterns," he said.

"We also had the limitation of not measuring body weight, so it would be nice if somebody could repeat the study in a database that has weight and we could get a more accurate assessment of the dose attenuation or lack thereof."

Yao reports no relevant relationships; disclosures for the coauthors are listed in the article. Pokorney discloses modest consulting support from Bristol-Myers Squibb, Boston Scientific, and Medtronic; modest research support from Gilead, Boston Scientific, Bristol-Myers Squibb, and Janssen Pharmaceuticals; and significant research support from the Food and Drug Administration; disclosures for the other editorialists are in listed the publication.

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