ENGAGE AF-TIMI 48

The purpose of this study was to demonstrate the safety and efficacy profile, in two different dose regimens of DU-176b, (an investigational new drug being tested for the prevention of stroke/systemic embolic events (SEE)), in individuals with atrial fibrillation. Patients were randomized to one of three treatment groups: High Dose Regimen, Low Dose Regimen, & Warfarin.

MAIN RESULTS:
Edoxaban versus warfarin in patients with atrial fibrillation

N Engl J Med. 2013 Nov 28;369(22):2093-104.

PRESENTATIONS

TIMI 48 Slides
Relationship Between Edoxaban Dose, Concentration, Anti-Factor Xa Activity, and Outcomes in the ENGAGE AF-TIMI 48 Trial (Ruff, ESC 2014)
Biomarkers for the Assessment of Stroke-Systemic Embolism and Bleeding Risk in Patients with AF in ENGAGE (Berg AHA 2018)
HF Hospitalization and Mortality in Non-Valvular AF (Inciardi ESC 2019)
Edoxaban versus Warfarin in Atrial Fibrillation Patients with Low, Mid and High Body Weight in ENGAGE (Boriani ESC 2019)
ENGAGE Genetics (Marston AHA 2019)

OTHER PUBLICATIONS

Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J. 2010 Oct;160(4):635-41.

Novel oral anticoagulants in atrial fibrillation: a meta-analysis of large, randomized, controlled trials vs warfarin. Clin Cardiol. 2013 Feb;36(2):61-7. 

Current and new oral antithrombotics in non-valvular atrial fibrillation: a network meta-analysis of 79 808 patients. Heart. 2014 Mar;100(5):396-405.

Left atrial structure and function in atrial fibrillation: ENGAGE AF-TIMI 48. Eur Heart J. 2014 Jun 7;35(22):1457-65.

Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014 Mar 15;383(9921):955-62.

Cerebrovascular events in 21 105 patients with atrial fibrillation randomized to edoxaban versus warfarin: Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48. Stroke. 2014 Aug;45(8):2372-8.

Transition of patients from blinded study drug to open-label anticoagulation: the ENGAGE AF-TIMI 48 trial. J Am Coll Cardiol. 2014 Aug 12;64(6):576-84.

Edoxaban vs. warfarin in vitamin K antagonist experienced and naive patients with atrial fibrillation. Eur Heart J. 2015 Jun 14;36(23):1470-7.

Genetics and the clinical response to warfarin and edoxaban: findings from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet. 2015 Jun 6;385(9984):2280-7.

Association between edoxaban dose, concentration, anti-Factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet. 2015 Jun 6;385(9984):2288-95.

Edoxaban vs. warfarin in patients with atrial fibrillation on amiodarone: a subgroup analysis of the ENGAGE AF-TIMI 48 trial. Eur Heart J. 2015 Sep 1;36(33):2239-45.

Systemic, Non-cerebral, Arterial Embolism in 21,105 Patients with Atrial Fibrillation Randomized to Edoxaban or Warfarin: Results from the ENGAGE AF-TIMI 48 Trial. Am Heart J. 2015 Oct;170(4):669-74.

Cost-effectiveness of edoxaban vs warfarin in patients with atrial fibrillation based on results of the ENGAGE AF–TIMI 48 trial. Am Heart J. 2015 Dec;170(6):1140-50.

Effects of Regional Differences in Asia on Efficacy and Safety of Edoxaban Compared With Warfarin- Insights From the ENGAGE AF-TIMI 48 Trial. Circ J. 2015;79(12):2560-7.

Edoxaban versus Warfarin in Patients With Atrial Fibrillation in the US FDA Approval Population: An Analysis From the ENGAGE AF-TIMI 48 Trial. Am Heart J. 2016 Feb;172:144-51.

Edoxaban vs warfarin in patients with nonvalvular atrial fibrillation in the US Food and Drug Administration approval population: An analysis from the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial. Am Heart J. 2016 Feb;172:144-51.

Edoxaban vs. Warfarin in East Asian Patients With Atrial Fibrillation- An ENGAGE AF-TIMI 48 Subanalysis. Circ J. 2016;80(4):860-9.

Concomitant Use of Single Antiplatelet Therapy With Edoxaban or Warfarin in Patients With Atrial Fibrillation: Analysis From the ENGAGE AF-TIMI 48 Trial. J Am Heart Assoc. 2016 Feb 23;5(2):e002587.

Mortality in Patients With Atrial Fibrillation Randomized to Edoxaban or Warfarin: Insights from the ENGAGE AF-TIMI 48 Trial. Am J Med. 2016 Aug;129(8):850-857.e2.

Cardioversion of Atrial Fibrillation in ENGAGE AF-TIMI 48. Clin Cardiol. 2016 Jun;39(6):345-6.

The Prognostic Significance of Cardiac Structure and Function in Atrial Fibrillation: The ENGAGE AF-TIMI 48 Echocardiographic Substudy. J Am Soc Echocardiogr. 2016 Jun; 29(6): 537–544.

Efficacy and Safety of Edoxaban in Elderly Patients With Atrial Fibrillation in the ENGAGE AF-TIMI 48 Trial. J Am Heart Assoc. 2016 May 20;5(5):e003432.

Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants After Cardioversion for Nonvalvular Atrial Fibrillation. Am J Med. 2016 Oct;129(10):1117-1123.e2.

Efficacy and safety of edoxaban compared with warfarin in patients with atrial fibrillation and heart failure: insights from ENGAGE AF-TIMI 48. Eur J Heart Fail. 2016 Sep;18(9):1153-61.

The Impact of Renal Function on Outcomes With Edoxaban in the ENGAGE AF-TIMI 48 Trial. Circulation. 2016 Jul 5;134(1):24-36.

Outcomes With Edoxaban Versus Warfarin in Patients With Previous Cerebrovascular Events: Findings From ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48). Stroke. 2016 Aug;47(8):2075-82.

Sudden Cardiac Death in Patients With Atrial Fibrillation: Insights From the ENGAGE AF-TIMI 48 Trial. J Am Heart Assoc. 2016 Jul 8;5(7):e003735.

Management of Bleeding With Non-Vitamin K Antagonist Oral Anticoagulants in the Era of Specific Reversal Agents. Circulation. 2016 Jul 19;134(3):248-61.

Population Pharmacokinetics of Edoxaban in Patients with Non-Valvular Atrial Fibrillation in the ENGAGE AF-TIMI 48 Study, a Phase III Clinical Trial. Clin Pharmacokinet. 2016 Sep;55(9):1079-90.

Standard dose versus low dose non-vitamin K antagonist oral anticoagulants in Asian patients with atrial fibrillation: A meta-analysis of contemporary randomized controlled trials. Heart Rhythm. 2016 Dec;13(12):2340-2347.

Edoxaban Versus Warfarin in Atrial Fibrillation Patients at Risk of Falling: ENGAGE AF-TIMI 48 Analysis. J Am Coll Cardiol. 2016 Sep 13;68(11):1169-1178.

Non-Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation. Hematol Oncol Clin North Am. 2016 Oct;30(5):1019-34.

Efficacy and Safety of Novel Oral Anticoagulants in Patients With Atrial Fibrillation and Heart Failure: A Meta-Analysis. JACC Heart Fail. 2016 Nov;4(11):870-880.

Cardiovascular Biomarker Score and Clinical Outcomes in Patients With Atrial Fibrillation: A Subanalysis of the ENGAGE AF-TIMI 48 Randomized Clinical Trial. JAMA Cardiol. 2016 Dec 1;1(9):999-1006.

Stroke and Mortality Risk in Patients With Various Patterns of Atrial Fibrillation: Results From the ENGAGE AF-TIMI 48 Trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48). Circ Arrhythm Electrophysiol. 2017 Jan;10(1):e004267.

Edoxaban for the Prevention of Thromboembolism in Patients With Atrial Fibrillation and Bioprosthetic Valves. Circulation. March 28, 2017Vol 135, Issue 13.

Valvular Heart Disease Patients on Edoxaban or Warfarin in the ENGAGE AF-TIMI 48 Trial. J Am Coll Cardiol. 2017 Mar 21;69(11):1372-1382.

A novel risk prediction score in atrial fibrillation for a net clinical outcome from the ENGAGE AF-TIMI 48 randomized clinical trial. Eur Heart J. 2017 Mar 21;38(12):888-896.

Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Valvular Heart Disease. J Am Coll Cardiol. 2017 Mar 21;69(11):1363-1371.

Extracranial arterial and venous thromboembolism in patients with atrial fibrillation: A meta-analysis of randomized controlled trials. Heart Rhythm. 2017 Apr;14(4):599-605.

Cost-Effectiveness of Edoxaban vs. Warfarin in Patients with Atrial Fibrillation Based on Results of the ENGAGE AF – TIMI 48 Trial: Taiwanese Perspective. Value Health Reg Issues. 2017 May;12:74-83.

Digoxin Use and Subsequent Clinical Outcomes in Patients With Atrial Fibrillation With or Without Heart Failure in the ENGAGE AF-TIMI 48 Trial. J Am Heart Assoc. 2017 Jun 30;6(7):e006035.

Impact of Spontaneous Extracranial Bleeding Events on Health State Utility in Patients with Atrial Fibrillation: Results from the ENGAGE AF-TIMI 48 Trial. J Am Heart Assoc. 2017 Aug 11;6(8):e006703.

Once- or twice-daily non-vitamin K antagonist oral anticoagulants in Asian patients with atrial fibrillation: A meta-analysis of randomized controlled trials. J Formos Med Assoc. 2017 Aug;116(8):591-598. 

First experience with edoxaban and atrial fibrillation ablation – Insights from the ENGAGE AF-TIMI 48 trial. Int J Cardiol. 2017 Oct 1;244:192-195.

Drug Class, Renal Elimination, and Outcomes of Direct Oral Anticoagulants in Asian Patients: A Meta-Analysis. J Stroke Cerebrovasc Dis. 2018 Apr;27(4):857-864.

Clinical events after interruption of anticoagulation in patients with atrial fibrillation: a subgroup analysis from ENGAGE AF-TIMI 48 trial. Int J Cardiol. 2018 Apr 15;257:102-107.

Gastrointestinal Bleeding With Edoxaban versus Warfarin: Results From the ENGAGE AF-TIMI 48 Trial. Circ Cardiovasc Qual Outcomes. 2018 May;11(5):e003998.

Peri-operative Adverse Outcomes in Patients with Atrial Fibrillation Taking Warfarin or Edoxaban: Analysis of the ENGAGE AF-TIMI 48 Trial. Thromb Haemost. 2018 Jun;118(6):1001-1008.

Linking Endogenous Factor Xa Activity, a Biologically Relevant Pharmacodynamic Marker, to Edoxaban Plasma Concentrations and Clinical Outcomes in the ENGAGE AF-TIMI 48 Trial. Circulation. 2018 Oct 30;138(18):1963-1973.

Edoxaban in atrial fibrillation patients with established coronary artery disease: Insights from ENGAGE AF-TIMI 48. Eur Heart J Acute Cardiovasc Care. 2019 Mar;8(2):176-185.

Efficacy And Safety Of Edoxaban In Patients With Atrial Fibrillation And Active Malignancy: An Analysis Of ENGAGE AF – TIMI 48 Randomized Clinical Trial. J Am Heart Assoc. 2018 Aug 21;7(16):e008987.

Edoxaban Versus Warfarin in Latin American Patients With Atrial Fibrillation: The ENGAGE AF-TIMI 48 Trial. J Am Coll Cardiol. 2018 Sep 25;72(13):1466-1475.

The efficacy and safety of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation and coronary artery disease: A meta-analysis of randomized trials. Eur Heart J Acute Cardiovasc Care. 2019 Sep;8(6):554-561.

Linking endogenous factor X activity, a biologically relevant pharmacodynamic marker, to edoxaban plasma concentration and clinical outcomes in the ENGAGE AF-TIMI 48 trial. Circulation. 2018 Oct 30;138(18):1963-1973.

Edoxaban and implantable cardiac device interventions: insights from the ENGAGE AF-TIMI 48 triaEuropace. 2019 Feb 1;21(2):306-312.l. 

Performance of the ABC Scores for Assessing the Risk of Stroke or Systemic Embolism and Bleeding in Patients With Atrial Fibrillation in ENGAGE AF-TIMI 48. Circulation. 2019 Feb 5;139(6):760-771.

Efficacy and safety of reduced-dose non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: a meta-analysis of randomized controlled trials. Eur Heart J. 2019 May 14;40(19):1492-1500.

Relationship between body mass index and outcomes in patients with atrial fibrillation treated with edoxaban or warfarin in the ENGAGE AF-TIMI 48 trial. Eur Heart J. 2019 May 14;40(19):1541-1550.

Clinical outcomes, edoxaban concentration, and anti-factor Xa activity of Asian patients with atrial fibrillation compared with non-Asians in the ENGAGE AF-TIMI 48 trial. Eur Heart J. 2019 May 14;40(19):1518-1527.

Edoxaban Versus Warfarin in Patients With Atrial Fibrillation and History of Liver Disease. J Am Coll Cardiol. 2019 Jul 16;74(2):179-189.

Edoxaban Versus Warfarin Stratified by Average Blood Pressure in 19 679 Patients With Atrial Fibrillation and a History of Hypertension in the ENGAGE AF-TIMI 48 Trial. Hypertension. 2019 Sep;74(3):597-605.

Comparison of Events Across Definitions of Major Bleeding in the Engage AF-TIMI 48 Trial. Circulation. 2019 Nov 26;140(22):1792-1801.

Left atrial structure and function and the risk of death or heart failure in atrial fibrillation. Eur J Heart Fail. 2019 Dec;21(12):1571-1579.

Pharmacogenetic-guided and clinical warfarin dosing algorithm assessments with bleeding outcomes risk-stratified by genetic and covariate subgroups. Int J Cardiol. 2020 Oct 15;317:159-166.

Efficacy and safety of edoxaban in patients with diabetes mellitus in the ENGAGE AF-TIMI 48 trial. Int J Cardiol. 2020 Apr 1;304:185-191.

Efficacy and safety of edoxaban compared with warfarin according to the burden of diseases in patients with atrial fibrillation: insights from the ENGAGE AF-TIMI 48 trial. Eur Heart J Cardiovasc Pharmacother. 2020 Jul 1;6(3):167-175.

Edoxaban versus Warfarin in Patients with Atrial Fibrillation at the Extremes of Body Weight: An Analysis from the ENGAGE AF-TIMI 48 Trial. Thromb Haemost. 2020 Sep 13. doi: 10.1055/s-0040-1716540.

Cardiovascular- and Bleeding-Related Hospitalization Rates With Edoxaban Versus Warfarin in Patients With Atrial Fibrillation Based on Results of the ENGAGE AF-TIMI 48 Trial. Circ Cardiovasc Qual Outcomes. 2020 Nov;13(11):e006511.

Individual Patient Data from the Pivotal Randomized Controlled Trials of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation (COMBINE AF): Design and Rationale: From the COMBINE AF (A COllaboration between Multiple institutions to Better Investigate Non-vitamin K antagonist oral anticoagulant usE in Atrial Fibrillation) Investigators. Am Heart J. 2020 Dec 6;233:48-58.

Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation with warfarin or edoxaban: An in-depth analysis from the ENGAGE AF-TIMI 48 randomized trial. J Clin Neurosci. 2021 Jan 11;S0967-5868(20)31595-2.

Edoxaban versus Warfarin in Patients with Atrial Fibrillation in Relation to the Risk of Stroke: A Secondary Analysis of the ENGAGE AF-TIMI 48 Study. Am Heart J. 2021 Jan 22:S0002-8703(21)00017-X. doi: 10.1016/j.ahj.2021.01.013.

Comparison of the Efficacy and Safety Outcomes of Edoxaban in 8040 Women Versus 13 065 Men With Atrial Fibrillation in the ENGAGE AF-TIMI 48 Trial. Circulation. 2021 Feb 16;143(7):673-684. doi: 10.1161/CIRCULATIONAHA.120.052216.