Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 - ENGAGE AF-TIMI 48

Contribution To Literature:

Highlighted text has been updated as of July 12, 2024.

The ENGAGE AF-TIMI 48 trial shows that edoxaban 60 mg daily and 30 mg daily are both noninferior for stroke prophylaxis in patients with AF when compared with warfarin. This adds to the armamentarium of oral factor Xa inhibitors for stroke prophylaxis in AF.


Oral factor Xa agents such as rivaroxaban and apixaban have recently been Food and Drug Administration (FDA) approved for the stroke prophylaxis in patients with atrial fibrillation (AF), for use in lieu of warfarin. The current trial sought to study the safety and efficacy of edoxaban, another oral direct factor Xa inhibitor, as compared with warfarin in the treatment of AF.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Age ≥21 years
  • AF on electrocardiogram within 12 months
  • CHAD2 ≥2
  • Number of enrollees: 21,105
  • Duration of follow-up: 2.8 years (median)
  • Mean patient age: 72 years
  • Percentage female: 38%


  • AF or atrial flutter due to reversible causes (e.g., thyrotoxicosis, pericarditis)
  • Clinically significant (moderate or severe) mitral stenosis
  • Increased bleeding risk believed to be a contraindication to oral anticoagulation (e.g., previous intracranial hemorrhage)
  • Conditions other than AF that require chronic anticoagulation (e.g., prosthetic mechanical heart valve)
  • Simultaneous treatment with both aspirin and a thienopyridine
  • Acute coronary syndrome, stroke, or revascularization within 30 days

Primary Endpoints:

  • Primary efficacy outcome: stroke or systemic embolism
  • Primary safety outcome: ISTH major bleeding

Secondary Endpoints:

  • Stroke, systemic embolism, or cardiovascular death
  • MI, stroke, systemic embolism or cardiovascular death
  • Stroke, systemic embolism, or all-cause mortality

Drug/Procedures Used:

Patients were randomized in a 1:1:1 fashion to receive either edoxaban 60 mg daily (high-dose), 30 mg daily (low-dose), or warfarin to achieve an international normalized ratio (INR) of 2.0-3.0. The edoxaban dose was halved for patients with glomerular filtration rate (GFR) between 30 and 50 ml/min, weight <60 kg, or concomitant use of verapamil, dronedarone, or quinidine.

Concomitant Medications:

Aspirin (29%), amiodarone (12%), and digoxin (30%)

Principal Findings:

A total of 21,105 patients were randomized, 7,035 to high-dose edoxaban, 7,034 to low-dose edoxaban, and 7,036 to warfarin. Baseline characteristics were fairly similar between the three arms. The mean CHADS2 score was 2.8, with the majority having a score of ≤3 (77%). Nearly 28% had a history of prior cardiovascular disease. AF was paroxysmal in 25% of patients, and permanent in 51%. Target therapeutic range was 68.4% in the warfarin arm.

Noninferiority was demonstrated for the primary endpoint of stroke or systemic embolic event in the modified intent-to-treat population between warfarin and high-dose edoxaban arms (annualized rate 1.5% vs. 1.18%, hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.63-0.99, p for noninferiority < 0.001), and warfarin and low-dose edoxaban (1.5% vs. 1.61%, HR 1.07, 95% CI 0.87-1.31, p for noninferiority = 0.005). In the intent-to-treat population, superiority testing was performed with borderline results (p = 0.08, p = 0.10, respectively). On subgroup analysis, patients who had never received warfarin had a significant reduction with high-dose edoxaban compared with warfarin (p < 0.05 for interaction). All strokes were similar (annualized rate 1.69% vs. 1.49% vs. 1.91%, p < 0.05), but hemorrhagic strokes were lower (annualized rate 0.47% vs. 0.26% vs. 0.16%, p < 0.001). Major adverse cardiac event rates were lower with high-dose edoxaban (annualized rate 4.98% vs. 4.41% vs. 4.90%; p = 0.01, p = 0.69, respectively).

The primary safety outcome of International Society on Thrombosis and Haemostasis (ISTH) major bleeding was higher in the warfarin arm (annualized rate 3.43% vs. 2.75% vs. 1.61%, p < 0.001 for both comparisons). Fatal bleeding (annualized rate 0.38% vs. 0.21% vs. 0.13%, p = 0.006, p < 0.001, respectively) and intracranial hemorrhage (0.85% vs. 0.47% vs. 0.26%, p < 0.001 for both) were also lower. Gastrointestinal (GI) bleeding was higher in the high-dose edoxaban arm, but lower in the low-dose edoxaban arm (1.23% vs. 1.51% vs. 0.82%, p < 0.05). Other adverse events including elevation of liver enzymes were similar.

On subgroup analysis, patients with paroxysmal AF overall had lower rates of stroke/systemic embolization compared with patients with persistent or permanent AF (HR 0.77, 95% CI 0.66-0.91). Mortality was also lower. However, bleeding risk was similar between the three subtypes. In all three subtypes, results for efficacy and safety of edoxaban (both doses) vs. warfarin were comparable to those noted in the overall population. In the subgroup of patients on amiodarone, edoxaban levels tended to be higher (due to P-glycoprotein inhibition). The primary efficacy endpoint was significantly lower in patients on low-dose edoxaban compared with warfarin in amiodarone-treated patients (HR 0.60, p for interaction = 0.009). No such interaction was observed in the high-dose edoxaban group. Major bleeding rates were also similar.

Genetic analysis: 14,348 patients were included in the genetic analysis, of which 4,833 were on warfarin. Patients were genotyped for polymorphisms in CYP2C9 (*2 and *3 alleles) and VKORC1 (–1639G→A), and classified as normal responders (61.7%), sensitive responders (35.4%), and highly sensitive responders (2.9%) to warfarin. Major or clinically relevant bleeding was lowest in normal responders and highest in highly sensitive responders (4.6% vs. 5.8% vs. 14.1%; HRs = 1.26 and 3.21, p < 0.05, respectively). In the edoxaban arm, there was no effect of genotype on risk of bleeding. Compared with warfarin, the risk of major or clinically relevant bleeding within 90 days was lowest in the low-dose edoxaban arm, but also reduced in the high-dose arm.

In patients in whom the dose of edoxaban was reduced for clinical reasons (creatinine clearance 30-50 ml/min, bodyweight 60 kg or less, or concomitant medication with potent P-glycoprotein interaction), antifactor Xa levels were reduced in a commensurate fashion, with no change in efficacy, but a greater reduction in bleeding compared with warfarin (major bleeding: higher dose p interaction = 0.02, lower dose p interaction = 0.002).

Efficacy of edoxaban based on renal function: There appeared to be lower efficacy of edoxaban 60 mg in patients with higher levels of creatinine clearance (CrCl) >95 ml/min (HR for edoxaban vs. placebo for primary endpoint: 1.36, 95% CI 0.88-2.10, p for interaction = 0.08). Bleeding was lower with edoxaban for all levels of CrCl.

Efficacy in patients at high risk for falls (n = 900, 4.3%): These patients were older, and had a higher prevalence of comorbidities including prior stroke/transient ischemic attack, diabetes, and coronary artery disease. These patients had a higher risk of bone fractures, major and life-threatening bleeding, and all-cause death; ischemic events including stroke/systemic embolic events were similar. The primary endpoint of stroke/systemic embolic event was similar between the high-dose edoxaban and warfarin arms (2.81% vs. 2.85%, p for interaction = 0.74). Major bleeding was also similar (5.43% vs. 5.55%, p for interaction = 0.45).

Interaction with body mass index (BMI): In an adjusted analysis, higher BMI (continuous, per 5 kg/m2 increase) was significantly and independently associated with lower risks of stroke/systemic embolic event (hazard ratio [HR] 0.88, p = 0.0001), ischemic stroke/systemic embolic event (HR 0.87, p < 0.0001), and death (HR 0.91, p < 0.0001), but with increased risks of major bleeding (HR 1.06, p = 0.025) and major or clinically relevant nonmajor bleeding (HR 1.05, p = 0.0007). Trough edoxaban concentration and anti-Factor Xa activity were similar across BMI groups >18.5 kg/m2 regardless of whether a dose adjustment in edoxaban was performed, while time in therapeutic range for warfarin improved significantly as BMI increased (p < 0.0001). The efficacy and safety profiles of edoxaban relative to warfarin were similar across BMI groups.

Subanalysis among Asian patients (n = 2,909): Asians on average weighed about 20 kg (44 lbs) less than non-Asians, and had a higher prevalence of chronic kidney disease requiring dose adjustments. The trough edoxaban concentration and anti-Factor Xa activity were 20–25% lower for Asians compared with non-Asians, particularly when the lower dose was used. Even after adjusting for lower dose, levels were lower (possibly due to younger age and lower use of concomitant amiodarone). Despite a lower time in therapeutic range and a greater percentage of time with a subtherapeutic INR, Asian patients treated with warfarin had a higher adjusted risk of intracranial hemorrhage (ICH) (adjusted HR 1.71 [1.05–2.77], p = 0.03), and clinically relevant nonmajor bleeding (adjusted HR 1.56 [1.34–1.82], p < 0.001) compared with non-Asians. Compared to warfarin, higher-dose edoxaban significantly reduced ICH, while preserving the efficacy of stroke prevention in both Asians and non-Asians.

Low-dose vs. high-dose edoxaban: Composite of stroke/systemic embolism, major bleeding, and death was less frequent with low-dose edoxaban compared with high-dose edoxaban (7.3% vs. 8.0%, HR 0.90, 95% CI 0.84-0.98, p = 0.014). However, stroke/systemic embolism was higher (2.0% vs. 1.6%, HR 1.31, 95% CI 1.12-1.52, p < 0.001), including a higher risk of stroke (1.9% vs. 1.5%, p = 0.001); MI (0.9% vs. 0.7%, p = 0.03). Major bleeding was lower (1.8% vs. 2.9%, p < 0.0001), including intracranial hemorrhage (0.3% vs. 0.4%, p = 0.035) and GI major bleeding (0.9% vs. 1.5%, p < 0.0001).

Dose reduction among patients ≥80 years of age (n = 2,966): Dose reduction was warranted among patients with creatinine clearance of ≤50 mL/min, body weight ≤60 kg, or taking strong P-glycoprotein (permeability glycoprotein) inhibitors at the time of randomization or during the treatment phase. 1,700 patients met dose reduction criteria: edoxaban 30 mg (n = 578), edoxaban 60 mg (n = 560), or warfarin (n = 562). Patients ≥80 years who received edoxaban 30 mg, regardless of dose-reduction criteria, had a median trough concentration that approximated that of patients <80 years who received edoxaban 60 mg. In patients ≥80 years receiving edoxaban 60 mg, the median (IQR) trough edoxaban concentration was 35% higher than in patients <80 years receiving edoxaban 60 mg. Among patients ≥80 years, irrespective of dose-reduction criteria, the net clinical outcome was 22% lower (HR 0.78, 95% CI 0.68-0.91, p = 0.001) with edoxaban 30 mg compared with warfarin. Rates of stroke or systemic embolic event were similar between groups (HR 0.93, 95% CI 0.69-1.27, p = 0.66), but major bleeding events overall were lower with edoxaban 30 mg (HR 0.59, 95% CI 0.45-0.77, p < 0.001). All-cause death was 17% lower (HR 0.83, 95% CI 0.70-1.00, p = 0.046) with edoxaban 30 mg vs. warfarin in patients ≥80 years. Although rates of ischemic stroke were not different between treatments, intracranial hemorrhage was 51% lower (HR 0.49, 95% CI 0.28-0.87, p = 0.02) in patients randomized to edoxaban 30 mg.


The results of the ENGAGE AF-TIMI 48 study indicate that both edoxaban 60 mg daily and 30 mg daily are noninferior for stroke prophylaxis in patients with AF when compared with warfarin. In a subgroup analysis, low-dose edoxaban significantly reduced stroke or systemic embolism compared with warfarin in patients taking concomitant amiodarone. Edoxaban resulted in a significant dose-related reduction in bleeding when compared with warfarin, although high-dose edoxaban resulted in an excess of GI bleeding. Also, in patients with high CrCl (>95 ml/min), the efficacy of edoxaban appeared attenuated. This is likely because of excessive renal clearance of the drug in these patients (correlated with drug trough levels in this analysis). Accordingly, there is a US FDA “black box warning” against the use of edoxaban for stroke prophylaxis in nonvalvular AF among patients with CrCl >95. This does not apply for use in venous thromboembolism treatment.

Among patients ≥80 years of age, patients randomized to and receiving edoxaban 30 mg irrespective of dose-reduction status, experienced lower rates of net outcomes, major bleeding, and all-cause death vs. warfarin with similar rates of stroke or systemic embolism. The pharmacokinetic and pharmacodynamic analyses demonstrated that patients ≥80 years achieved higher edoxaban concentrations and inhibition of endogenous factor Xa, indicating that the same dose of edoxaban had a more pronounced anticoagulant effect in older patients than in younger patients. These data suggest that lower-dose anticoagulants such as edoxaban 30 mg once daily may be considered in all patients ≥80 years with AF irrespective of dose-reduction criteria.

These results are similar to those observed in ARISTOTLE for apixaban, ROCKET-AF for rivaroxaban (both factor Xa inhibitors), and RE-LY for dabigatran (oral direct thrombin inhibitor). Although there are subtle differences between the four agents and these trials, the current overall evidence supports safety and efficacy of all four agents when compared with warfarin for stroke prophylaxis in patients with AF. Direct head-to-head comparisons and cost-effectiveness analyses are eagerly awaited.

The genetic subanalysis suggests that patients at higher risk of bleeding with warfarin (~39%) appeared to benefit the most from edoxaban, especially the lower dose. It remains unknown whether incorporating routine genetic testing into clinical practice would be a cost-efficient method for edoxaban/other novel oral anticoagulant use. Among Asian patients, there is a higher likelihood of achieving lower edoxaban trough levels and anti-Factor Xa levels, suggesting that the higher dose may be more appropriate.


Zimerman A, Braunwald E, Steffel J, et al. Dose Reduction of Edoxaban in Patients 80 Years and Older With Atrial Fibrillation: Post Hoc Analysis of the ENGAGE AF-TIMI 48 Randomized Clinical Trial. JAMA Cardiol 2024;Jul 10:[Epublished].

Steffel J, Ruff CT, Yin Y, et al. Randomized, Double-Blind Comparison of Half-Dose Versus Full-Dose Edoxaban in 14,014 Patients With Atrial Fibrillation. J Am Coll Cardiol 2021;77:1197-1207.

Editorial Comment: Halperin JL, Rashed ER. Low-Dose Anticoagulation for Atrial Fibrillation: When Is a Floor a Trap Door? J Am Coll Cardiol 2021;77:1208-1210.

Chao TF, Chen SA, Ruff CT, et al. 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;40:1518-27.

Boriani G, Ruff CT, Kuder JF, et al. 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;Jan 8:[Epub ahead of print].

De Caterina R, Renda G, Carnicelli AP, et al. Valvular Heart Disease Patients on Edoxaban or Warfarin in the ENGAGE AF-TIMI 48 Trial. J Am Coll Cardiol 2017;69:1372-82.

Carnicelli AP, De Caterina R, Halperin JL, et al., on behalf of the ENGAGE AF-TIMI 48 Investigators. Edoxaban for the Prevention of Thromboembolism in Patients With Atrial Fibrillation and Bioprosthetic Valves. Circulation 2017;135:1273-5.

Steffel J, Giugliano RP, Braunwald E, et al. Edoxaban Versus Warfarin in Atrial Fibrillation Patients at Risk of Falling: ENGAGE AF–TIMI 48 Analysis. J Am Coll Cardiol 2017;68:1169-78.

Bohula EA, Giugliano RP, Ruff CT, et al. Impact of Renal Function on Outcomes With Edoxaban in the ENGAGE AF-TIMI 48 Trial. Circulation 2016;134:24-36.

Ruff CT, Giugliano RP, Braunwald E, et al. 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;385:2288-2295.

Steffel J, Giugliano RP, Braunwald E, et al. Edoxaban vs. warfarin in patients with atrial fibrillation on amiodarone: a subgroup analysis of the ENGAGE AF-TIMI 48 trial. Eur Heart J 2015;May 13:[Epub ahead of print].

Mega JL, Walker JR, Ruff CT, et al. Genetics and the Clinical Response to Warfarin and Edoxaban: Findings From the Randomised, Double-Blind ENGAGE AF-TIMI 48 Trial. Lancet 2015;385:2280-2287.

Giugliano RP, Ruff CT, Braunwald E, et al., on behalf of the ENGAGE AF-TIMI 48 Investigators. Edoxaban Versus Warfarin in Patients With Atrial Fibrillation. N Engl J Med 2013;369:2093-2104.

Presented by Dr. Robert Giugliano at the Heart Rhythm Society Scientific Sessions, San Francisco, CA, May 9, 2014.

Presented by Dr. Robert P. Giugliano at the American Heart Association Scientific Sessions, Dallas, TX, November 19, 2013.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Dyslipidemia, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Novel Agents

Keywords: Atrial Fibrillation, Factor Xa, Stroke

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