Nonrecommended doses of DOACs up death risk in AF patients

Patients with atrial fibrillation (AF) enrolled in the prospective Global Anticoagulant Registry in the FIELD-AF (GARFIELD-AF) have been prescribed the recommended direct oral anticoagulant (DOAC) doses according to country-specific guidelines. However, use of nonrecommended doses persists and is associated with a higher risk of death, mostly of cardiovascular nature, reveals a study.

“Treatment above the recommended doses was relatively rare compared with nonrecommended low dosing,” the researchers said. “The highest-risk patients were more prone to receive nonrecommended doses of DOACs.”

A total of 34,926 patients were enrolled (2013–2016) in the prospective GARFIELD-AF, of whom 10,426 received a DOAC. Majority of these patients (72.9 percent) received a recommended dosing, 23.2 were underdosed, and 3.8 percent were overdosed.

Compared with recommended dosing, nonrecommended dosing (underdosage and overdosage combined) correlated with an increased risk of all-cause mortality (hazard ratio [HR], 1.24, 95 percent confidence interval [CI], 1.04–1.48; HR for underdosing, 1.25, 95 percent CI, 1.04–1.50; HR for overdosing, 1.19, 95 percent CI, 0.83–1.71). [J Am Coll Cardiol 2020;76:1425-1436]

Such deaths were mainly cardiovascular, including heart failure and myocardial infarction. On the other hand, the risks of stroke or systemic embolism (SE) and major bleeding were not significantly different regardless of dosing level, but underdosed patients had a significantly lower bleeding risk.

In addition, there was a nonsignificant trend towards higher risks of stroke/SE (HR, 1.51, 95 percent CI, 0.79–2.91) and major bleeding (HR, 1.29, 95 percent CI, 0.59–2.78) in overdosed patients. Of those treated over the recommended doses, 67.5 percent had moderate-to-severe chronic kidney disease relative to 8.6 percent of patients with recommended dosing and 7.1 percent of those with underdosing.

“Kidney function, age, and body weight are important characteristics to take into account when deciding the dose of DOACs,” the researchers said.

Such consideration is seen in the Summaries of Product Characteristics (SPCs) or drug labels that vary for each DOAC and according to regulatory agencies. The European Medicines Agency, Food and Drug Administration, and Pharmaceuticals and Medical Devices Agency each issued different SPCs for four different DOACs. [Br J Haematol 1995;89:157-162; Hum Mutat 1995;5:48-57; Biochim Biophys Acta 1994;1224:480-488]

“The uptake of DOACs for the prevention of stroke in patients with AF at risk is rapidly growing worldwide but with large variations depending mostly, but not only, on the socioeconomic status of the countries under consideration,” the researchers said. [Expert Rev Cardiovasc Ther 2018;16:857-873; PLoS One 2016;11:e0149142]

“This has resulted in an increase in the rates of at-risk patients receiving guideline-recommended anticoagulant therapy,” they added. [Heart 2017;103:307-314; J Am Coll Cardiol 2017;69:777-785]

Notably, access to high-quality healthcare highly differed between countries, including those involved in GARFIELD-AF. Such condition might have had affected compliance to prescription rules and recommended dosage of anticoagulants, according to the researchers. [Lancet 2018;391:2236-2271]