DOACs Maintain Advantage Over Warfarin in A-fib Patients With Low Body Weight

These results are reassuring because how DOACs work in patients with lower body weights has been a concern, one expert says.

DOACs Maintain Advantage Over Warfarin in A-fib Patients With Low Body Weight

Direct oral anticoagulants (DOACs) are safe and effective even in patients with atrial fibrillation who weigh less than 60 kg (132 pounds), a study out of Korea—where people are more likely to have a low body weight than in Western countries—shows.

Overall, patients who received a DOAC versus warfarin had lower risks of ischemic stroke and major bleeding, driven by a reduction in intracranial hemorrhage (ICH), according to researchers led by So-Ryoung Lee, MD (Soon Chun Hyang University Hospital Seoul, South Korea).

Net clinical benefit—a composite of ischemic stroke, ICH, hospitalization for GI bleeding, and all-cause death—also favored DOACs, they report in a study published online ahead of the March 5, 2019, issue of the Journal of the American College of Cardiology.

To the best of our knowledge, this was the first comparison of the effectiveness and safety of warfarin and DOACs in a large nationwide atrial fibrillation cohort with data on low body weight,” they write.

Commenting for TCTMD, Renato Lopes, MD, PhD (Duke University School of Medicine, Durham, NC), noted that there has been concern about what to do with DOACs in patients who have extreme body weights—both high and low—and said that this study “gives reassurance that using the regimens that were tested in the trials worked in the low body weights.”

The study, he added, also touches on another critical question surrounding DOACs—appropriate dosing. Underdosing due to fear of bleeding is prevalent around the world, and in fact, most of the DOAC-treated patients in the Korean cohort (about 60%) received a reduced dose.

Lopes pointed out that there was a numerically higher rate of ischemic stroke among patients who received a reduced versus standard dose in this study. That “reinforces that using the appropriate criteria to adjust the dose is very important,” he said.

“In other words, we have to make sure we adjust the dose of DOACs and not just lower the dose because when you lower the dose—which means inappropriately lowering the dose—you’re going to likely increase your risk of ischemic events,” Lopes explained. “If you adjust the dose—in other words, if you reduce the dose based on the criteria that were set in the trials—then you keep the efficacy and the effectiveness of these drugs.”

Best Outcomes With On-Label Dosing

Using 2014-2016 data from the Korean National Health Insurance Service, the study included patients (mean age 73) newly treated with oral anticoagulants for nonvalvular A-fib who had a body weight of 60 kg or less; 14,013 received a DOAC and 7,576 received warfarin. Overall, 28% had an extremely low body weight of less than 50 kg (110 pounds).

After inverse probability weighting to balance characteristics between groups, DOAC therapy was associated with a lower risk of all six outcomes examined in the study compared with warfarin through a median follow-up of 1.2 years. The findings were consistent in the subset of patients with extremely low body weight.

           Clinical Outcomes: DOACs vs Warfarin



95% CI

Ischemic Stroke



Major Bleeding



Intracranial Hemorrhage



Admission for GI Bleeding



All-Cause Death



Composite Outcomea



           aIschemic stroke, intracranial hemorrhage, hospitalization for GI bleeding, all-cause death.

Both standard and reduced doses of DOACs performed similarly against warfarin. Within the DOAC-treated cohort, reduced doses were tied to numerically higher rates of ischemic stroke and lower rates of ICH, although hazard ratios for all six outcomes indicated no significant differences.

The researchers further divided the cohort by adherence to on-label dosing, with about two-thirds of patients receiving on-label doses, 30.7% receiving off-label reduced doses, and 4% receiving off-label increased doses. Outcomes were best with on-label dosing and worst with off-label overdosing.

Lopes said the results are consistent with an analysis from his team published recently in Circulation, which showed that in the ARISTOTLE trial, apixaban (Eliquis; Bristol-Myers Squibb) was safe and effective at both high and low extremes of body weight.

People forget that the goal in patients with atrial fibrillation is not to prevent bleeding. The goal in atrial fibrillation is to prevent stroke at a minimal cost of bleeding. Renato Lopes

Lopes said that the reason why DOAC underdosing is so prevalent in current practice is because of a fear of anticoagulation-related bleeding instilled during the warfarin era. Data from the large, pivotal trials of the DOACs, he pointed out, have shown that appropriately adjusting the dose based on established criteria—as opposed to simply lowering the dose based on concerns about bleeding—provides the best outcomes for patients.

“Because people are so paranoid about bleeding, they just lower the dose thinking that they’re doing good for patients, but they’re actually not because patients are going to have increased risk of stroke,” Lopes said.

He added: “People forget that the goal in patients with atrial fibrillation is not to prevent bleeding. The goal in atrial fibrillation is to prevent stroke at a minimal cost of bleeding.”

In an accompanying editorial, Freek Verheugt, MD, PhD (OLVG Heart Center, Amsterdam, the Netherlands), notes that kidney function, age, and body weight are important factors to consider for proper dosing of DOACs, with specific criteria listed on each drug’s label.

The fact that off-label dosing did not result in significantly worse outcomes in this study contrasts with prior analyses, including one from the ORBIT-AF registry showing that use of an off-label dose was associated with an increased risk of mortality (for a higher dose) or cardiovascular hospitalization (for a lower dose), Verheugt points out.

Though the Korean study counters fears that DOACs might increase bleeding and mortality in patients with A-fib and very low body weight, he says, there are some limitations, including the shortcomings of registry data, the lack of information on the intensity of anticoagulation and time in therapeutic range, the unequal distribution of the types of DOACs used, and the high proportion of patients on a reduced dose.

“Although the current study is reassuring that DOACs can be used in atrial fibrillation patients with low to very low body weight, we must take into account that the study results originate from a region where low body weight is common,” Verheugt says. “Because of this characteristic, the results do not necessarily apply for such patients in the Western world.”

  • The study was supported by the Korean National Research Foundation of Korea, which is funded by the Ministry of Education, Science, and Technology; the Technology Innovation Program, which is funded by the Ministry of Trade, Industry & Energy (MOTIE, Korea); and the Soon Chun Hyang University Research Fund.
  • Lee reports no relevant conflicts of interest.
  • Verheugt reports having received educational and research grants from Bayer Healthcare and Boehringer Ingelheim and honoraria for consultancies and/or presentations from Daiichi Sankyo, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, and Bayer Healthcare.
  • Lopes reports receiving research grants from Amgen, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Medtronic, and Sanofi-Aventis and consulting/advisory boards fees from Bristol-Myers Squibb/Pfizer, Bayer, and Boehringer Ingelheim.

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