A new analysis from the ENGAGE AF-TIMI 48 trial provides a modicum of support for low-dose edoxaban (Sayaysa) in select patients with atrial fibrillation (AF).
The parent trial reported that once-daily edoxaban 30 mg and 60 mg was noninferior to warfarin for preventing stroke and systemic embolism in more than 20,000 AF patients at moderate to high risk for thromboembolism.
Both edoxaban doses, which could be halved in patients meeting certain criteria, significantly reduced the risk of major bleeding and death. But for ischemic stroke, the risk went up 41% with low-dose edoxaban, compared with warfarin, and the US Food and Drug Administration (FDA) subsequently approved only the full dose of the factor Xa inhibitor for stroke prevention in nonvalvular AF.
In this prespecified analysis that compared the two edoxaban regimens, the low dose was associated with a significantly more favorable net clinical outcome — a composite of stroke/systemic embolism, major bleeding, and death — than the standard full dose (7.26% vs 8.01%; hazard ratio [HR], 0.90; 95% CI, 0.84 - 0.98).
The benefit came, however, with a familiar tradeoff. The low dose was associated with a greater risk for stroke/systemic embolism (2.04% vs 1.56%; HR, 1.31; 95% CI, 1.12 - 1.52) but less major, intracranial, gastrointestinal, and life-threatening bleeding.
"The vast majority of patients ought to get the standard-dose anticoagulant, as it was studied in the trial," senior author Robert Giugliano, MD, Brigham and Women's Hospital, Boston, told theheart.org | Medscape Cardiology. "But I'm a practicing cardiologist and we all see patients who are at very high risk of bleeding or they didn't tolerate a standard dose of anticoagulant."
For these patients, there are very few data to be had, he noted. Only ENGAGE AF-TIMI 48 and the RE-LY trial pitted more than one dose of a direct oral anticoagulant against warfarin but, even then, RE-LY evaluated dabigatran 150 mg and 110 mg but not 75 mg.
"In practice, we were seeing enormously high utilization of off-label or nonrecommended low doses, particularly with apixaban," Giugliano said. "Apixaban has very little data with 2.5 milligrams in the patients who deserve to be dose-reduced, and they have no randomized data with 2.5 milligrams in patients who should be getting the full dose."
A number of studies, however, have shown that underdosing is associated with an increased risk for ischemic strokes and thrombotic events without an appreciable benefit in bleeding, he said.
Conversely, the recent ELDERCARE-AF study found that edoxaban 15 mg once daily reduced the risk for stroke or systemic embolism by two-thirds, with no fatal bleeds and virtually no intracranial hemorrhages, compared with placebo in Japanese octogenarians.
In ENGAGE AF-TIMI 48, both the 60 mg and 30 mg doses were reduced by 50% in patients who had moderate renal insufficiency, weighed 60 kg or less, or required use of a strong P-glycoprotein inhibitor.
"Our study provides an important piece of the puzzle," Giugliano said. "At least now we can be informed, we can talk to our patients and say, 'I understand you didn't tolerate the standard dose…but another option is to give you a half dose of edoxaban. The good of it is your risk of bleeding is much lower; the bad side is that it doesn't protect you as well from stroke.'"
As reported in the March 9 issue of the Journal of the American College of Cardiology, there was no difference between the 60 mg and 30 mg groups for the secondary (disabling stroke, life-threatening bleeding, or all-cause mortality) or tertiary (stroke/systemic embolism, life-threatening bleeding, or all-cause mortality) net clinical outcomes.
In line with the main results, the risk for the primary endpoint of stroke or systemic embolism was higher with the low dose (2.04% vs 1.56%; HR, 1.31; P < .001), driven primarily by a 43% increase in ischemic strokes (1.77% vs 1.24%; HR, 1.43; P < .001). Disabling strokes and fatal strokes were similar in the two groups.
In contrast, bleeding events occurred less frequently with the lower dose:
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Major bleeding: 1.82 vs 2.87% (HR, 0.64; P < .001)
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Intracranial hemorrhage: 0.25% vs 0.38% (HR, 0.65; P = .035)
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Major gastrointestinal 0.87% vs 1.53% (HR, 0.57; P < .0001)
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Fatal/life-threatening: 0.38% vs 0.62% (HR, 0.61; P = .002).
In a podcast accompanying the study, JACC editor in chief Valentin Fuster, MD, said high-dose edoxaban remains the "standard therapy" for stroke prevention, but that the differences in the endpoints were "rather trivial" and could be significant because of the large number of participants.
"In our view, a good point of the study presented today in JACC is that at least [it's] maybe a call to the FDA for the approval of low-dose edoxaban," he said.
Certainly, the study is "trying to tell us that, overall, low-dose edoxaban may not be unjustified in a significant number of patients, with overall favorable results in terms of integrating both sides of the balance — stroke and thromboembolism on one side and bleeding on the other," Fuster added.
In a linked editorial, Jonathan Halperin, MD, and Eman Rashed, MD, PhD, both from Mount Sinai Medical Center, New York City, say that the analysis adds to the evidence regarding direct oral anticoagulants but stress the need to tread carefully in clinical practice.
"Although low-dose edoxaban was associated with significantly less bleeding in ENGAGE-AF than the standard high-dose edoxaban regimen, this was accompanied by a reduction in all-cause mortality and frequency of ischemic events, and those, after all, represent the outcomes that anticoagulant therapy are designed to prevent," they write.
Giugliano observed that although it caused a 41% increase in ischemic stroke compared with warfarin, "the odd thing" about the lower dose is that it had a little stronger signal on all-cause mortality than the higher dose, but it was not statistically significant (3.78% vs 3.98%; P = .30).
"It would be reasonable for the FDA to reassess their initial decision not to consider a lower-dose regimen," but whether the company is willing to invest the time and money is unclear, he said.
The ENGAGE AF-TIMI 48 trial was supported by Daiichi-Sankyo Pharma Development. Giugliano has received consulting fees from Bristol Myers Squibb, Janssen, Daiichi-Sankyo, Merck, Pfizer, Portola, SAJA Pharmaceuticals, and Servier; and has received grant support, through his institution, from Anthos Therapeutics, AstraZeneca, Daiichi-Sankyo, Merck, Johnson & Johnson, Pfizer, and Sanofi. Halperin has received consulting fees involving the development of anticoagulant drugs from Bayer Healthcare, Boehringer Ingelheim, and Ortho-McNeil-Janssen; and has served on the steering committees for the ENGAGE-AF TIMI 48 and CATALYST trials. Rashed reported having no relevant relationships.
J Am Coll Cardiol. 2021;77:1197–1207, 1208-1210. Full text, Editorial
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