Effect of edoxaban versus warfarin on epistaxis frequency and severity in AF

In a post-hoc analysis of the ENGAGE AF-TIMI 48 trial, 1 in 20 anticoagulant-treated AF patients experienced epistaxis. Compared with warfarin, edoxaban 30 mg daily, but not 60 mg, reduced this risk.

This summary is based on the publication of Semco RS, Bergmark RW, Murphy SA, et al. - Epistaxis Versus Nonepistaxis Bleeding in Anticoagulated Patients With Atrial Fibrillation: Results From the ENGAGE AF‐TIMI 48 Trial. J Am Heart Assoc. 2025 Jan 21;14(2):e031434. doi: 10.1161/JAHA.123.031434

Introduction and methods

Background

Epistaxis is common in patients receiving antithrombotic therapy [1-4]. Although the ENGAGE AF‐TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48) trial has shown that edoxaban reduced the risk of nongastrointestinal bleeding events compared with warfarin [5], the effect of this oral direct factor Xa inhibitor on epistaxis has not been investigated.

Aim of the study

In a post-hoc analysis of the ENGAGE AF-TIMI 48 trial, the authors examined the frequency, severity, and clinical outcomes of epistaxis and the treatment effects of edoxaban versus warfarin in AF patients.

Methods

The ENGAGE AF-TIMI 48 trial was an international, double-blind, placebo-controlled, phase 3 RCT in which 21,105 patients with AF and CHADS₂ score ≥2 were randomized to higher-dose edoxaban (60 mg daily; dose reduction to 30 mg if needed), lower-dose edoxaban (30 mg daily; dose reduction to 15 mg if needed), or warfarin [6]. Median follow-up duration was 2.8 years. In the current analysis, patients with intracranial hemorrhage during follow-up were excluded, leaving 20,792 patients in the on-treatment safety cohort.

Outcomes

The study’s primary efficacy endpoint was the time to the first adjudicated stroke (ischemic or hemorrhagic) or systemic embolic event. The principal safety endpoint comprised adjudicated major bleeding events during treatment as defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria.

Main results

Frequency and severity of epistaxis

• In the on-treatment safety cohort, 5247 patients (25.2%) experienced ≥1 bleeding events: 1008 (4.8%) had epistaxis and 4239 (20.4%) had nonepistaxis bleeding events only.

• Epistaxis events were less severe than nonepistaxis bleeding events (ISTH major bleeding: 3.2% vs. 20.7%; clinically relevant nonmajor bleeding: 64.7% vs. 60.1%; minor bleeding: 32.1% vs. 19.2%; P<0.001).

• The frequency of permanent study drug discontinuation was similar between patients with epistaxis and those with nonepistaxis bleeding events (33.6% vs. 35.7%; P=0.21). There was also no significant difference in the rate of permanent study drug discontinuation between patients with epistaxis and those with no bleeding events (33.5%; P=0.94).

• When patients were divided by bleeding severity, the proportion of permanent study drug discontinuation was similar following epistaxis versus nonepistaxis bleeding among patients with ISTH major bleeding events (59.4% vs. 53.6%; P=0.52) or clinically relevant nonmajor bleeding events (32.5% vs. 33.3%; P=0.70) but higher in patients with minor bleeding events (33.3% vs. 23.9%; P=0.001).

Treatment effect

• Cox proportional hazards analysis showed patients on the higher-dose edoxaban regimen (n=6951) had a similar risk of epistaxis as those treated with warfarin (n=6880) (2.59%/year vs. 2.37%/year; HR: 1.09; 95%CI: 0.95–1.26; P=0.224).

• However, patients in the lower-dose edoxaban group (n=6961) (1.72%/year) had a reduced epistaxis risk compared with those in the warfarin group (HR: 0.73; 95%CI: 0.62–0.86; P<0.001).

Conclusion

In this post-hoc analysis of the ENGAGE AF-TIMI 48 trial, epistaxis was frequent (5% over ~3-year follow-up) in anticoagulant-treated AF patients but was less severe than nonepistaxis bleeding events. One-third of patients discontinued their anticoagulant treatment, regardless of whether they experienced epistaxis, nonepistaxis bleeding events, or no bleeding events at all. Lower-dose edoxaban (30 mg daily) reduced the risk of epistaxis by 27% compared with warfarin, whereas higher-dose edoxaban (60 mg daily) had no effect.

Find this article online at J Am Heart Assoc.

References

1. Seikaly H. Epistaxis. N Engl J Med. 2021;384:944–951. doi: 10.1056/NEJMcp2019344
2. Seidel DU, Jacob L, Kostev K, Sesterhenn AM. Risk factors for epistaxis in patients followed in general practices in Germany. Rhinology. 2017;55:312–318. doi: 10.4193/Rhin17.105
3. Stadler RR, Kindler R, Holzmann D, Soyka MB. The long-term fate of epistaxis patients with exposure to antithrombotic medication. Eur Arch Otorrinolaringol. 2016;273:2561–2567. doi: 10.1007/s00405-016-3913-9
4. Abrich V, Brozek A, Boyle TR, Chyou PH, Yale SH. Risk factors for recurrent spontaneous epistaxis. Mayo Clin Proc. 2014;89:1636–1643. doi: 10.1016/j.mayocp.2014.09.009
5. Bergmark BA, Kamphuisen PW, Wiviott SD, Ruff CT, Antman EM, Nordio F, Kuder JF, Mercuri MF, Lanz HJ, Braunwald E, et al. Comparison of events across bleeding scales in the ENGAGE AF-TIMI 48 trial. Circulation. 2019;140:1792–1801. doi: 10.1161/CIRCULATIONAHA.119.041346
6. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093–2104. doi: 10.1056/NEJMoa1310907