Gastrointestinal Bleeding With Edoxaban Versus Warfarin: Results From the ENGAGE AF-TIMI 48 Trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction)

Circ Cardiovasc Qual Outcomes. 2018 May;11(5):e003998. doi: 10.1161/CIRCOUTCOMES.117.003998.

Abstract

Background: The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction) compared higher-dose edoxaban regimen (HD-ER) and lower-dose edoxaban regimen with well-managed warfarin in 21 105 patients with atrial fibrillation. The risk factors and clinical impact of gastrointestinal bleeding (GIB) in this trial have not been described in detail.

Methods and results: This analysis was undertaken to identify risk factors for major GIB (MGIB) and compare the severity and outcomes of GIB with edoxaban and warfarin. During 2.8 years mean follow-up, there were 579 MGIB (1.22% per year), of which 63 were life-threatening or fatal (0.13% per year). Male sex, increased age, prior GIB, concomitant aspirin, lower baseline hemoglobin, renal dysfunction, and higher HAS-BLED and CHADS2 scores were independently associated with the risk of MGIB. Whereas the annual rate of MGIB was higher with HD-ER than with warfarin (1.53% and 1.25%, respectively; hazard ratio, 1.23; 95% confidence interval, 1.02-1.48; P=0.033), the annual rates of life-threatening or fatal GIB were similar (0.15% and 0.18%, respectively). Several indicators of more severe GIB, including hemodynamic instability, hospitalization, ≥ 4 U transfusion, and hemoglobin loss ≥5 g/dL, were similar with HD-ER and warfarin, whereas surgery required to manage bleeding was less frequent with HD-ER. Lower-dose edoxaban regimen, which achieved 50% lower trough edoxaban levels, was associated with significantly less MGIB than warfarin.

Conclusions: MGIB occurred more frequently with HD-ER than warfarin. The rates of life-threatening or fatal GIB were low and similar with both HD-ER and warfarin. Clinical outcomes were generally favorable. The correlation between dose, trough edoxaban level, and the risk of GIB risk suggests GIB is exposure-related.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00781391.

Keywords: atrial fibrillation; edoxaban; hospitalization; risk factors; warfarin.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Anticoagulants / administration & dosage
  • Anticoagulants / adverse effects*
  • Atrial Fibrillation / blood
  • Atrial Fibrillation / diagnosis
  • Atrial Fibrillation / drug therapy*
  • Atrial Fibrillation / mortality
  • Blood Coagulation / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Monitoring / methods
  • Factor Xa Inhibitors / administration & dosage
  • Factor Xa Inhibitors / adverse effects*
  • Female
  • Gastrointestinal Hemorrhage / chemically induced*
  • Gastrointestinal Hemorrhage / diagnosis
  • Gastrointestinal Hemorrhage / mortality
  • Humans
  • International Normalized Ratio
  • Male
  • Middle Aged
  • Pyridines / administration & dosage
  • Pyridines / adverse effects*
  • Randomized Controlled Trials as Topic
  • Retrospective Studies
  • Risk Assessment
  • Risk Factors
  • Thiazoles / administration & dosage
  • Thiazoles / adverse effects*
  • Time Factors
  • Treatment Outcome
  • Warfarin / administration & dosage
  • Warfarin / adverse effects*

Substances

  • Anticoagulants
  • Factor Xa Inhibitors
  • Pyridines
  • Thiazoles
  • Warfarin
  • edoxaban

Associated data

  • ClinicalTrials.gov/NCT00781391