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Off-label dose-reduced DOACs tied to poor efficacy in atrial fibrillation

Stephen Padilla
19 Aug 2019

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.

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Most Read Articles
Audrey Abella, 20 Dec 2019
The combination of the immunomodulatory agent lenalidomide and the monoclonal antibody rituximab (R2) proved effective and safe in individuals ≥70 years with relapsed/refractory indolent non-Hodgkin lymphoma (R/R iNHL) compared with rituximab alone, according to a post hoc analysis of the phase III AUGMENT* trial presented at ASH 2019. 
27 Nov 2017
The amino sulphonic acid taurine may safely and effectively reduce portal pressure in cirrhotic patients, a study has shown.
26 Nov 2019
Podcast: Professor R. Scott Wright speaks about the potential role of inclisiran in providing durable reductions in LDL-cholesterol levels in patients with atherosclerotic cardiovascular disease.
Jairia Dela Cruz, 12 Dec 2019
Use of isatuximab (Isa) in combination with pomalidomide and dexamethasone (PomDex) appears to lead to more favourable outcomes in elderly patients with relapsed/refractory multiple myeloma (RRMM) as compared with PomDex alone, according to the results of a subgroup analysis of the ICARIA-MM trial presented at the 61st Annual Meeting of the American Society of Hematology (ASH 2019).