Disclosures: Giugliano reports he received research support from Amgen, Anthos Therapeutics, Daiichi Sankyo; honoraria for CME lectures from Amgen, Daiichi Sankyo, Merck; and consultant fees from Amarin, American College of Cardiology, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers-Squibb, CryoLife, CVS Caremark, Daiichi Sankyo, Eli Lilly, Esperion, Gilead, GlaxoSmithKline, Janssen, Lexicon, Merck, Pfizer, SAJA Pharmaceuticals, Samsung and Servier. Please see the study for all other authors’ relevant financial disclosures.
February 23, 2021
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High-dose edoxaban safety favorability vs. warfarin greater in women than men

Disclosures: Giugliano reports he received research support from Amgen, Anthos Therapeutics, Daiichi Sankyo; honoraria for CME lectures from Amgen, Daiichi Sankyo, Merck; and consultant fees from Amarin, American College of Cardiology, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers-Squibb, CryoLife, CVS Caremark, Daiichi Sankyo, Eli Lilly, Esperion, Gilead, GlaxoSmithKline, Janssen, Lexicon, Merck, Pfizer, SAJA Pharmaceuticals, Samsung and Servier. Please see the study for all other authors’ relevant financial disclosures.
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Among women with atrial fibrillation at elevated CV risk, treatment with high-dose edoxaban vs. warfarin conferred greater reduction in hemorrhagic stroke and major bleeding compared with men, with similar efficacy, researchers reported.

Robert P. Giugliano

“The principal findings of this secondary analysis ... were that the magnitude of reduction in multiple serious bleeding endpoints with a higher-dose edoxaban regimen vs. warfarin, including intracranial hemorrhage, fatal or life-threatening bleeding, and the composite of clinically relevant major or nonmajor bleeding, were greater in women than in men,” Robert P. Giugliano, MD, ScM, a cardiovascular medicine specialist at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, and colleagues wrote. “Stroke or systemic embolic events, cardiovascular death and the net outcome were reduced to a similar degree in both women and men.

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Source: Adobe Stock

“Similar to previous studies, higher rates of stroke but lower event rates of cardiovascular death occurred in women as compared with men, yet these differences did not meet statistical significance after multivariable adjustment,” the researchers wrote. “However, women had a significantly higher risk of clinically relevant nonmajor and any overt bleeding than men after multivariable adjustment.”

The ENGAGE AF-TIMI 48 trial included 21,105 patients with AF and CHADS2 score of at least 2 (38% women) who were randomly assigned a high- or low-dose edoxaban (Savaysa, Daiichi Sankyo) regimen or warfarin. The high-dose edoxaban regimen was 60 mg daily; the low-dose regimen was 30 mg daily.

As Healio previously reported, edoxaban was noninferior to warfarin for the prevention of stroke or systemic embolism and conferred lower risk for bleeding and CV death.

Sex-based analysis

For this analysis of the ENGAGE AF-TIMI 48 trial, researchers evaluated the efficacy and safety profile of edoxaban among women compared with men.

Researchers found that high-dose edoxaban conferred greater reduction in hemorrhagic stroke compared with warfarin among women vs. men (HR for women = 0.3; 95% CI, 0.15-0.59; HR for men = 0.7; 95% CI, 0.46-1.06; P for interaction = .037).

No significant interactions in other efficacy outcomes were observed for high-dose edoxaban compared with warfarin.

According to the researchers, women who received high-dose edoxaban, compared with men, experienced greater reductions in:

  • life-threatening or fatal bleeding (HR for women = 0.23; 95% CI, 0.13-0.39; HR for men = 0.71; 95% CI, 0.53-0.96; P for interaction < .001);
  • intracranial bleeding (HR for women = 0.2; 95% CI, 0.1-0.39; HR for men = 0.63; 95% CI, 0.44-0.89; P for interaction = .003);
  • major or clinically relevant nonmajor bleeding (HR for women = 0.76; 95% CI, 0.68-0.85; HR for men = 0.92; 95% CI, 0.84-1; P for interaction = .011); and
  • any bleeding (HR for women = 0.78; 95% CI, 0.7-0.87; HR for men = 0.92; 95% CI, 0.85-1; P for interaction = .01).

Increased major gastrointestinal bleeding with high-dose edoxaban compared with warfarin was similar for both women and men (HR for women = 1.34; 95% CI, 0.96-1.87; HR for men = 1.19; 95% CI, 0.94-1.5; P for interaction = .59).

For low-dose edoxaban, risk for ischemic stroke was significantly increased compared with warfarin; however, all bleeding endpoints, mortality and the net outcome were decreased to a similar degree among both women and men (P for interaction for all > .05).

The ‘sweet spot’

“The safety profile of high-dose edoxaban in comparison with warfarin was even more favorable in women than in men, even after accounting for baseline differences between the sexes in a sensitivity analysis,” the researchers wrote. “This could be at least partially related to the higher proportion of women who qualified for dose reductions: 36% vs. 19% at the time of randomization, and 8.7% vs. 6.7% during follow-up.

“It is noteworthy that an analysis of the causes of death and their relationships to bleeding in the ENGAGE AF-TIMI 48 trial found that more than half of the reduction in deaths in the edoxaban-treated patients could be attributed to a reduction in major bleeding,” the researchers wrote. “It is therefore possible that the dose-reduction criteria selected in this trial were particularly favorable for women, and a ‘sweet spot’ balancing anti-ischemic efficacy and the risk of bleeding was found. However, further in-depth analyses restricting patients who did and did not meet criteria for dose reduction indicate a consistently more favorable safety profile in women as compared with men.”