GARFIELD-AF: Wrong DOAC Dose Can Be Lethal in A-fib

More than one-quarter of patients receive a nonrecommended dose, and that is associated with a greater risk of dying.

GARFIELD-AF: Wrong DOAC Dose Can Be Lethal in A-fib

Use of a different dose of a direct oral anticoagulant (DOAC) than the one recommended on the package insert—usually a lower one—is common around the world and is associated with poorer outcomes, data from the GARFIELD-AF registry affirm.

Even after accounting for baseline differences, patients prescribed a nonrecommended dose (27.1% of the cohort) had a higher risk of all-cause mortality through 2 years of follow-up than those who received a dose aligned with recommendations on the label (4.3% vs 2.5%; HR 1.24; 95% CI 1.04-1.48), according to researchers led by A. John Camm, MD (St George’s, University of London, England).

The findings were similar both for patients who were underdosed and those who were overdosed, the researchers report in a study published in the September 22, 2020, issue of the Journal of the American College of Cardiology.

“More pervasive strategies are needed to promote approved dosing of DOACs,” the investigators conclude.

They note that there are some differences in regulatory guidance for DOACs from country to country, as well differences in how dosing is determined from agent to agent, taking into account age, kidney function, body weight, bleeding risk, and drug-drug interactions.

“In this context, the rules for the correct prescription dose may be to some extent poorly understood, and may be the cause of inappropriate dosing (either underdosing or overdosing),” Camm et al write.


To assess whether these dosing issues could be having an effect on outcomes, the investigators turned to the GARFIELD-AF registry, which enrolled patients with A-fib and at least one risk factor for stroke from 35 countries. The current analysis focused on 10,426 people who were enrolled between 2013 and 2016 and were treated with a DOAC.

Most patients (72.9%) received the recommended dose, with 23.2% receiving a reduced dose and 3.8% a higher dose. Those who received nonrecommended doses tended to be older and female and to have a higher CHA2DS2-VASc score and elevated GARFIELD-AF scores for risks of death, stroke/systemic embolism, and bleeding.

Part of the reason is that you get blamed for a bleed, but you don’t get blamed for not preventing a stroke. Gerald Naccarelli

Of note, about two-thirds of patients who received a higher-than-recommended dose had moderate-to-severe chronic kidney disease. “The investigators may have unintentionally disregarded the rules of prescription related to renal function or may have relied on different rules issued by national or regional organizations,” the authors write.

Rates of all-cause death and stroke/systemic embolism were numerically higher among patients who received nonrecommended doses, whereas rates of major bleeding were lower in underdosed patients and higher in overdosed patients.

After accounting for potential confounders, however, only the risk of all-cause death was significantly higher in patients taking DOACs at doses that strayed from the drug label. The excess deaths were primarily related to cardiovascular conditions, including heart failure and MI, in underdosed patients. 

Careful With the Art of Medicine

Frequent underdosing with DOACs also has been seen in prior studies, including ORBIT-AF. In that registry, which was smaller than GARFIELD-AF and limited to the United States, 13% of patients received doses inconsistent with labeling from the US Food and Drug Administration, with underdosing being much more common than overdosing. Use of an off-label dose was associated with poorer outcomes.

Gerald Naccarelli, MD (Penn State Health Heart and Vascular Institute, Hershey, PA), who was a co-author on the ORBIT-AF paper, told TCTMD that neither that analysis nor the GARFIELD-AF data can pinpoint the reasons why patients received a nonrecommended dose. Both studies indicated that older age, female sex, and higher stroke and bleeding risk scores were associated off-label dosing.

Underdosing is more likely than overdosing to be a purposeful decision on the part of prescribing physicians as they try to limit bleeding risk, Naccarelli indicated. “Part of the reason is that you get blamed for a bleed, but you don’t get blamed for not preventing a stroke.”

On the other hand, he writes in an accompanying editorial, “overdosing of a DOAC is harder to justify and may be secondary to ignorance of the proper dosing schedules or proper dose adjustments not being made as patients’ renal functions change over time.”

Although there are times when going off-label is justified, Naccarelli said, the decision should be made judiciously. “As a general rule, you really need to use the doses that have been very well studied and recommended,” he advised. “That doesn’t mean you should never use another dose, but you should really think hard and carefully in an individual patient.”

In his editorial, he says that “proper dosing can be reemphasized by education, dosing protocols in electronic medical prescribing software, prescription reconciliation during clinic encounters, and proper monitoring of renal function.”

Clinicians “should be careful with the art of practice” when making decisions about DOAC dosing, he advised. “We’ll continue to learn if there are some nuances to this. Follow the rules and keep in mind that if you don’t follow the rules, it’s a very slippery slope and by accident you may do what you’re trying not to do—that is hurt the patient.”

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

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  • The study was supported by an unrestricted research grant from Bayer AG (Berlin, Germany) to the Thrombosis Research Institute, which sponsors the GARFIELD-AF registry.
  • Camm reports having received institutional grants and personal fees from Bayer, Boehringer Ingelheim, Pfizer/Bristol-Myers Squibb, and Daiichi-Sankyo outside of the submitted work.
  • Naccarelli reports having consulted and participated in research funding for Janssen; and having served as a consultant for Milestone, Sanofi, Omeicos, and Acesion.