Off-label dose-reduced DOACs tied to poor efficacy in atrial fibrillation
Treatment with off-label dose-reduced direct oral anticoagulants (DOACs) leads to reduced effectiveness with no safety benefit among patients with nonvalvular atrial fibrillation (AF), according to a study, suggesting that compliance with per-label dosage may significantly improve outcomes.
“Almost four of 10 patients in this study were treated with off-label dose-reduced DOAC at the time of an event or end of the follow-up period,” the researchers said. “Off-label dose-reduced DOAC was associated with reduced effectiveness without a safety benefit.”
Overall, 8,425 patients were included in the study. Of these, 5,149 (61 percent) were treated with DOACs at per-label dosing and 3,285 (39 percent) received off-label dose-reduced DOAC.
Off-label dose-reduced treatment was shown to be associated with a higher rate of the composite outcome of all-cause mortality, stroke or myocardial infarction (adjusted hazard ratio [aHR], 1.57, 95 percent CI, 1.34–1.83; p=0.008) and a higher rate of bleeding (aHR, 1.63, 1.14–2.34; p=0.008). [Am J Med 2019;132:847-855.e3]
“In this study of newly diagnosed patients with nonvalvular AF initiating DOAC treatment, we found that off-label dose-reduced DOAC administration that occurred in 39 percent of patients at the time of an event was associated with a significant increase of a composite of death, myocardial infarction or stroke events,” the researchers said.
“Similarly, the HR for severe bleeding events was increased among patients receiving off-label reduced DOAC dosing,” they added.
DOACs are the preferred treatment for most nonvalvular AF patients who need anticoagulation. [Europace 2012;14:1385-1413; Circulation 2014;130:2071-2104]
Although several studies have confirmed the effectiveness and safety of these drugs relative to vitamin K antagonists in both randomized controlled trials (RCTs) and in clinical practice, the use of lower DOAC doses has become more prevalent in routine clinical practice than in RCTs. [Am J Med 2016;129:1198-1204; J Am Coll Cardiol 2016;68:2597-2604; BMJ 2017;356:510; Thromb Res 2018;169:140-142]
A study by Fay and colleagues showed the widespread practice of prescribing lower-dose DOACs for nonvalvular AF from 4,600 physicians in France, Germany and the UK during 2015. Forty-four percent of apixaban-treated patients and 32.4 percent of those treated with rivaroxaban received a reduced dose. [ESC Congress 2016, abstract 2597]
“These proportions are similar to that described in the current study,” the researchers said. “[H]owever, it should be noted that in their study, Fay [and colleagues] did not distinguish between off-label and per-label lower dose use.”
The current study enrolled newly diagnosed patients with nonvalvular AF who had initiated DOAC therapy between 2011 and 2017 at Clalit Health Services in Tel Aviv, Israel. Effectiveness was defined as the composite outcome of all-cause mortality, stroke or myocardial infarction. The safety outcome was defined as bleeding events requiring hospitalization.
The researchers followed patients until 30 March 2018 or until occurrence of an outcome event. They used multivariate regression to adjust HRs for 21 variables, including comorbidities, concomitant medications and socioeconomic factors.
“Further studies are required to understand the reasons for off-label dose-reduced DOAC administration,” the researchers said.