Author + information
- Received March 2, 2019
- Revision received April 24, 2019
- Accepted April 29, 2019
- Published online July 8, 2019.
- Arman Qamar, MD, MPHa@AqamarMD,
- Elliott M. Antman, MDa@eantman,
- Christian T. Ruff, MD, MPHa,
- Francesco Nordio, PhDa,
- Sabina A. Murphy, MPHa,
- Laura T. Grip, ABa,
- Norton J. Greenberger, MDb,
- Ophelia Q.P. Yin, PhDc,
- Youngsook Choi, MDc,
- Hans J. Lanz, MDc,
- Michele F. Mercuri, MD, PhDd,
- Eugene Braunwald, MDa and
- Robert P. Giugliano, MD, SMa,∗ (, )@timistudygroup@rgiugliano
- aTIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
- bGastroenterology, Hepatology, and Endoscopy Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
- cDaiichi-Sankyo Pharma Development, Basking Ridge, New Jersey
- dDaiichi-Sankyo, Munich, Germany
- ↵∗Address for correspondence:
Dr. Robert P. Giugliano, TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Hale Building for Transformative Medicine, 60 Fenwood Road, 7th Floor, Boston, Massachusetts 02115.
Background Patients with liver disease have increased risk of thrombosis and bleeding but are typically excluded from trials of direct oral anticoagulant agents.
Objectives This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), clinical efficacy and safety of edoxaban versus warfarin in patients with atrial fibrillation (AF) and history of liver disease.
Methods ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction Study 48) was a randomized, double-blind trial comparing edoxaban with warfarin in patients with AF followed for 2.8 years. History of liver disease was defined as investigator-reported liver disease or >2-fold transaminase elevation at randomization. The primary efficacy and safety endpoints of stroke or systemic embolic event (SSEE) and major bleeding were assessed stratified by history of liver disease. PK/PD assessments of edoxaban included endogenous and extrinsic factor Xa activity and edoxaban concentration.
Results Among 21,105 patients, 1,083 (5.1%) had a history of liver disease; they had a higher prevalence of many comorbidities. The adjusted risks of SSEE were similar (adjusted hazard ratio [HRadj]: 0.90; 95% confidence interval [CI]: 0.67 to 1.22; p = 0.50), but major bleeding was more common in patients with liver disease (HRadj: 1.38; 95% CI: 1.10 to 1.74; p = 0.005). There were no significant differences in PK/PD assessment of edoxaban in patients with versus without liver disease. The HRs for higher-dose edoxaban versus warfarin for SSEE were 0.86 (95% CI: 0.73 to 1.01) in patients without and 1.11 (95% CI: 0.54 to 2.30) with liver disease (p for interaction [pint] = 0.47), major bleeding 0.80 (95% CI: 0.70 to 0.91) in patients without and 0.91 (95% CI: 0.56 to 1.47) with liver disease (pint = 0.63). There were no significant differences in hepatic adverse events between the 2 treatment groups.
Conclusions Among patients with AF receiving oral anticoagulation, bleeding, but not thromboembolic events, was increased in patients with liver disease. A history of liver disease did not alter the relative efficacy and safety of edoxaban compared with warfarin. Hepatic adverse events were similar between edoxaban and warfarin.
ENGAGE AF-TIMI 48 was supported by Daiichi-Sankyo Pharma Development. The current analysis did not receive any additional funding. Dr. Qamar is supported by the National Heart, Lung, and Blood Institute T32 postdoctoral training grant T32HL007604 and the American Heart Association Strategically Focused Research Network in Vascular Disease grants 18SFRN3390085 and 18SFRN33960262. Dr. Qamar has received grant support through Brigham and Women’s Hospital from Daiichi-Sankyo; and has received fees for educational activities from the American College of Cardiology, Society for Cardiovascular Angiography and Interventions, Pfizer, Medscape, and Clinical Exercise Physiology Association. Dr. Antman has received grant support through his institution from Daiichi-Sankyo. Dr. Ruff has received consulting fees/honoraria from Boehringer Ingelheim, Bayer, Daiichi-Sankyo, Janssen, and Portola; and has received research grants from Boehringer Ingelheim and Daiichi-Sankyo. Ms. Murphy has received grants from Abbott Laboratories, Amarin, Amgen, AstraZeneca, Critical Diagnostics, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia Therapeutics, Merck and Co., Roche Diagnostics, Takeda, Gilead, Poxel, Novartis, MedImmune, Janssen Research Development, and Genzyme. Drs. Yin, Choi, and Lanz are employees of Daiichi-Sankyo. Dr. Mercuri is a former employee of Daiichi-Sankyo. Dr. Braunwald has received research grants to his institution from Daiichi-Sankyo, AstraZeneca, GlaxoSmithKline, Merck, Novartis, and Duke University; has performed uncompensated consultancies and lectures for Merck, The Medicines Company, and Novartis; has received consulting fees/honoraria from The Medicines Company Cardurion, MyoKardia, Sanofi, Verve, and Theravance; and has received speaker fees from Medscape. Dr. Giugliano has received consulting fees/honoraria from Portola, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Daiichi-Sankyo, Janssen, Lexicon, and Merck; and has received research grants from Daiichi-Sankyo and Merck. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Received March 2, 2019.
- Revision received April 24, 2019.
- Accepted April 29, 2019.
- 2019 American College of Cardiology Foundation