![]() In the current analysis, published in the March 9, 2021, issue of the Journal of the American College of Cardiology, the researchers evaluated three net clinical outcomes: The lower-dose edoxaban regimen carried a higher risk of ischemic stroke compared with warfarin but a lower risk of all-cause death, “raising the possibility that this dosing regimen might be beneficial for certain patient profiles,” Steffel et al say. The main results showed that both doses were noninferior to warfarin in terms of stroke or systemic embolism, with less major bleeding and cardiovascular death with the DOAC. I think 90% or more of the patients should get the standard dose, but there are some individuals where it may make good medical sense to use a reduced dose. Both the 60- and 30-mg doses of the DOAC were cut in half in patients who had moderate renal insufficiency, had a body weight of 60 kg or less, or were using a strong P-glycoprotein inhibitor. The trial randomized 21,105 patients with AF and a moderate-to-high risk of stroke to warfarin or one of two edoxaban doses. More Stroke, Less Bleeding With Lower DoseĪcknowledging that use of lower-than-recommended doses of the DOACs is common out in practice, the investigators decided to compare the two edoxaban dosing regimens from ENGAGE AF-TIMI 48. “It’s just a question of what your tolerance is for a bleed versus a stroke and what the patient’s risk is,” he explained, but reiterated, “I think the vast majority of patients should receive the standard approved dose.” In those cases, and after a discussion about the potential risks (increased stroke) and benefits (less bleeding) with the patient, it might be decided that the lower dose is the way to go, Giugliano said. “But we all inevitably run into patients in clinical practice who are either very risk averse to bleeding or very high risk for bleeding.” “For the majority of patients, they ought to continue to receive the approved dosing regimen, the higher-dose regimen, according to the label,” Giugliano said about edoxaban. But physicians are largely in an “evidence-free zone” when they do so, he pointed out, because only two of the pivotal DOAC trials- RE-LY and ENGAGE AF-TIMI 48 -evaluated more than one dose of the study drug (not counting dose reductions according to prespecified criteria). And it’s been associated with worse outcomes. Though the researchers, led by Jan Steffel, MD (University Heart Center Zurich, Switzerland), conclude that the approved higher-dose regimen “remains the standard therapy” for stroke prevention in patients with AF, they indicate that these findings might be helpful for physicians considering whether to use the lower dose in select cases.ĭeliberate use of lower-than-recommended doses of DOACs, usually related to concerns about bleeding, is widespread in practice, senior author Robert Giugliano, MD (Brigham and Women’s Hospital, Boston, MA), told TCTMD. However, there was a trade-off with the lower dose-it was associated with a greater risk of stroke/systemic embolism compared with the higher dose but with reduced risks of major, intracranial, GI, and life-threatening bleeding. ![]() The rate of a net clinical outcome incorporating stroke/systemic embolism, major bleeding, or death was significantly lower in patients who received the lower- versus higher-dose regimen (7.26% vs 8.01% HR 0.90 95% CI 0.84-0.98). The trial evaluated two doses of the direct oral anticoagulant (DOAC) versus warfarin-60 and 30 mg once daily both could be cut in half in patients meeting certain criteria. The lower dose of edoxaban (Savaysa Daiichi-Sankyo) evaluated in ENGAGE AF-TIMI 48 provides a net clinical benefit, according to a new analysis of the trial, suggesting it may be useful for some patients with atrial fibrillation (AF).
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