ARE LOW DOSES OF DIRECT-ACTING ORAL ANTICOAGULANTS JUSTIFIED AND APPROPRIATE IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION?



Antoni Martinez-Rubio, M.D., Ph.D., Univ. Hosp. of Sabadell, Univ. Autonoma of Barcelona, Sabadell, Spain

The novel direct-acting oral anticoagulants (NOAC) (dabigatran, rivaroxaban, apixaban and edoxaban) overcome most drawbacks of vitamin K antagonists and have proven efficacious and safe in well-designed multicenter randomized clinical trials. Therefore, various cardiology societies recommend NOAC as the first-choice oral anticoagulants in patients with nonvalvular AF.

However, the four pivotal NOAC trials in patients with AF have very important differences in design, doses, population, and results. Importantly, in the trials different subgroups of patients received reduced doses of NOAC with different criteria. In the RELY trial, all patients randomized to either dose of dabigatran received the full dose, whereas in the ROCKET-AF (with rivaroxaban), ARISTOTLE (with apixaban) and ENGAGE-AF (with edoxaban) trials, the dose of NOAC was reduced at baseline (after randomization to NOAC) in 20.7%, 4.7%, and 25.4% of the patients, respectively.Subgroup analyses of low-dose regimens in the pivotal studies of NOAC in nonvalvular AF revealed no alert signs versus the higher dose (non-significant interaction p-value). Nevertheless, physicians should be aware that only limited numbers of patients received the reduced doses of rivaroxaban, apixaban, and edoxaban in the pivotal studies. In summary, low-dose NOACs are justified in patients who present a high risk of bleeding for any reason. However, the reduction of hemorrhagic risk comes at the cost of lower antithrombotic protection. Therefore, patients must be carefully evaluated before being prescribed low-dose NOACs and reevaluated during the follow-up. Inappropriate application of low-dose NOAC regimens will probably lead to worse thromboembolic results than those observed in the large randomized clinical trials and will probably compromise patient safety. As is true for all drug classes, clinicians need to be educated in all aspects of NOAC treatment, from choosing the most appropriate drug and dose to managing possible complications.